Immune mechanisms that underlie the destruction of myelin are the focus of much investigation. The available evidence indicates that the disease is initiated by TH1 and TH17 T cells that react against myelin antigens and secrete cytokines. Experimental autoimmune encephalomyelitis, an animal model of MS in which demyelination and inflammation occur after immunization of animals with myelin proteins, can be passively transferred to unimmunized animals with TH1 and TH17 cells that recognize myelin antigens. TH1 cells secrete IFN-γ, which activates macrophages, and TH17 cells promote the recruitment of leukocytes. The demyelination is caused by 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. B lymphocytes and antibodies also play an important, but poorly defined, role in the disease, as indicated by the surprising success of B cell depleting therapies.
MORPHOLOGYMSisprimarilyamultifocalwhitematterdisease.Grossly,thecharacteristiclesions,termedplaques,arediscrete,slightlydepressed,glassy-appearing,andgray-tanincolor(
Fig.23.23A ).Plaquesarecommonneartheventriclesandalsofrequentlyoccurintheopticnervesandchiasm,brainstem,ascendinganddescendingfibertracts,cerebellum,andspinalcord.Thelesionshavesharplydefinedbordersatthemicroscopiclevel(see
Fig.
23.23B ).Active plaques containabundantmacrophagesstuffedwithmyelindebris,evidenceofongoingmyelinbreakdown.Lymphocytesalsoarepresent,mostlyasperivascularcuffs.Smallactivelesionsoftenarecenteredonsmallveins.Axonsarerelativelypreservedbutmaybereducedinnumber.Whenplaquesbecomequiescent(inactive plaques), theinflammationmostlydisappears,leavingbehindlittletonomyelin,astrocyticproliferation,andgliosis.
The course of MS is variable, but commonly there are multiple relapses followed by episodes of remission; typically, recovery during remissions is not complete. As a consequence, over time there is usually a gradual, often stepwise, accumulation of neurologic deficits. Imaging studies have demonstrated that there are often more lesions in the brains of patients with MS than might be expected from the clinical examination, and that lesions can come and go much more often than was previously suspected. Changes in cognitive function can be present, but are often much milder than the other deficits. In any individual patient, it is difficult to predict when the next relapse will occur; most current treatments, which are intended to control the immune response, aim at decreasing the rate and severity of relapses rather than recovering lost function.
The CSF in patients with MS shows a mildly elevated protein level with an increased proportion of immunoglobulin; in one-third of cases, there is moderate pleocytosis. When the immunoglobulin is examined further, oligoclonal bands usually are identified. These antibodies are directed against a variety of antigenic targets and can be used as markers of disease activity. The contribution of these antibodies to the disease process is unclear.
Immune-mediated demyelination can occur after a number of systemic infectious illnesses, including http://ebooksmedicine.net
Fig. 23.23 Multiplesclerosis(MS).(A)Sectionoffreshbrainshowingaplaquearoundoccipitalhornofthelateralventricle.(B)Unstainedregionsofdemyelination(MSplaques)aroundthefourthventricle.Luxolfastblue–periodicacid–Schiffstainformyelin.