MULTIPLE SCLEROSIS

Multiple sclerosis (MS) is an autoimmune demyelinating disorder characterized by distinct episodes of neurologic deficits, separated in time, attributable to white matter lesions that are separated in space. It is the most common of the demyelinating disorders, having a prevalence of approximately 1 per 1000 persons in most of the United States and Europe. The disease may become clinically apparent at any age, although onset in childhood or after age 50 years is relatively rare. Women are affected twice as often as are men. In most individuals with MS, the clinical course takes the form of relapsing and remitting episodes of variable duration (weeks to months to years) marked by neurologic defects, followed by gradual, partial recovery of neurologic function. The frequency of relapses tends to decrease during the course of time, but there is a steady neurologic deterioration in most affected individuals.
Pathogenesis.

The lesions of MS are caused by an immune response that is directed against the components of the myelin sheath.[27,][28] As in other autoimmune disorders, the pathogenesis of this disease involves both genetic and environmental factors ( Chapter 6 ). The incidence of MS is 15-fold higher when the disease is present in a first-degree relative and roughly 150-fold higher with an affected monozygotic twin. Genetic linkage of MS susceptibility to the DR2 extended haplotype of the major histocompatibility complex is also well established. A recent genome-wide screen supported this association and identified additional associations with single-nucleotide polymorphisms in IL-2 and IL-7 receptor genes.[29] The current thinking is that these cytokine receptor polymorphisms may influence the balance between pathogenic effector T cells and protective regulatory T cells. These genetic associations point to the importance of the immune system in the susceptibility to MS. Given the prominence of chronic inflammatory cells within and around MS plaques as well as this genetic validation, immune mechanisms that underlie the destruction of myelin are the focus of much investigation. The available evidence indicates that the disease is initiated by CD4+ TH1 and TH17 T cells that react against self myelin antigens and secrete cytokines. TH1 cells secrete IFN , which activates macrophages, and TH17 cells promote the recruitment of leukocytes ( Chapter 6 ). The demyelination is caused by these activated leukocytes and their injurious products. The infiltrate in plaques and surrounding regions of the brain consists of T cells (mainly CD4+, some CD8+) and macrophages. How the autoimmune reaction is initiated is not understood; a role of viral infection (e.g., EBV) in activating self-reactive T cells has been proposed but remains controversial. Experimental autoimmune encephalomyelitis is an animal model of MS in which demyelination and inflammation occur after immunization of animals with myelin proteins.[30] Many of our concepts of MS pathogenesis have been derived from studies in this model. The experimental disorder can be passively transferred to other animals with TH1 and TH17 cells that recognize myelin antigens.

Based on the growing understanding of the pathogenesis of MS, therapies are being developed that modulate or inhibit T cell responses and block the recruitment of T cells into the brain. A potential contribution of humoral immunity has also been suspected for a long time, based on the early observation of oligoclonal bands of immunoglobulin in CSF.[31] The demonstration that Bcell depletion can decrease the incidence of demyelinating lesions lends support to this idea.[32] Morphology. MS is a white matter disease that is best appreciated in sections of the brain and spinal cord. Lesions appear as multiple, well-circumscribed, somewhat depressed, glassy, graytan, irregularly shaped plaques ( Fig. 28-33 ). In the fresh state these are firmer than the surrounding white matter (sclerosis). Plaques can be found throughout the white matter and also extend into gray matter, since these have myelinated fibers running through them. The size of lesions varies considerably, from small foci that are only recognizable microscopically to confluent plaques that involve large portions of the centrum semiovale. The lesions often have sharply defined borders ( Fig. 28-34 ). Plaques commonly occur adjacent to the lateral ventricles. They are also frequent in the optic nerves and chiasm, brainstem, ascending and descending fiber tracts, cerebellum, and spinal cord. Microscopically, in an active plaque there is evidence of ongoing myelin breakdown with abundantmacrophages containing lipid-rich, PAS-positive debris. Inflammatory cells, including both lymphocytes and monocytes, are present, mostly as perivascular cuffs, especially at the outer edge of the lesion ( Fig. 28-35A ). Active lesions are often centered on small veins. Within a plaque there is relative preservation of axons ( Fig. 28-35B ) and depletion of oligodendrocytes. In time, astrocytes undergo reactive changes. As lesions become quiescent, the inflammatory cells slowly disappear. Within inactive plaques, little to no myelin is found, and there is a reduction in the number of oligodendrocyte nuclei; instead, astrocytic proliferation and gliosis are prominent. Axons in old gliotic plaques show severe depletion of myelin and are also greatly diminished in number. Active plaques can also be grouped into four basic patterns: those that are sharply demarcated and centered on blood vessels, either with (pattern I) or without (pattern II) deposition of immunoglobulin and complement, and those that are less well demarcated and are not centered on vessels (patterns III and IV). These latter two are distinguished by the distribution of oligodendrocyte apoptosis (III, widespread; IV, central only). It has been observed that only one pair of patterns (I/II or III/IV) may be present in a given individual, suggesting that these may reflect distinct mechanisms rather than different stages of lesion. In some MS plaques (shadow plaques) the border between normal and affected white matter is not sharply circumscribed. In this type of lesion some abnormally thinned-out myelin sheaths can be demonstrated, especially at the outer edges. This phenomenon is most commonly interpreted as evidence of partial and incomplete remyelination by surviving oligodendrocytes. Abnormally myelinated fibers have also been observed at the edges of typical plaques. Although these histologic findings suggest a limited potential for remyelination in the CNS, the remaining axons within most MS plaques remain unmyelinated; studies aimed at promoting remyelination are an important focus of research
Clinical Features.

Although MS lesions can occur anywhere in the CNS and consequently may induce a wide range of clinical manifestations, certain patterns of neurologic symptoms and signs are commonly observed. Unilateral visual impairment, due to involvement of the optic nerve (optic neuritis, retrobulbar neuritis), is a frequent initial manifestation of MS. However, only some affected individuals (10% to 50%, depending on the population studied) with optic neuritis go on to develop MS. Involvement of the brainstem produces cranial nerve signs, ataxia, nystagmus, and internuclear ophthalmoplegia from interruption of the fibers of the medial longitudinal fasciculus. Spinal cord lesions give rise to motor and sensory impairment of trunk and limbs, spasticity, and difficulties with the voluntary control of bladder function. Examination of the CSF in individuals with MS shows a mildly elevated protein level, and in one third of cases, there is moderate pleocytosis. IgG levels in the CSF are increased and oligoclonal IgG bands are usually observed on immunoelectrophoresis; these are indicative of the presence of a small number of activated B cell clones, postulated to be self-reactive, in the CNS. Radiologic studies using magnetic resonance imaging, typically based on identifying gadolinium-enhancing lesions, have taken on a prominent role in assessing disease progression; these studies, when correlated with autopsy studies as well as clinical findings, have indicated that some plaques may be clinically silent even in otherwise symptomatic patients.