HIVcandirectlycausemeningoencephalitis,orindirectlyaffectthebrainbyincreasingtheriskforopportunisticinfections(toxoplasmosis,CMV)orCNSlymphoma.
Priondiseasesaretransmittedbyanalteredformofanormalcellularprotein.Theycanbesporadic,transmitted,orinherited.
Within the CNS, axons are tightly ensheathed by myelin, an electrical insulator that allows rapid propagation of neural impulses. Myelin consists of multiple layers of highly specialized, closely apposed plasma membranes that are assembled by oligodendrocytes. Although myelinated axons are present in all areas of the brain, they are the dominant component in the white matter; therefore, most diseases of myelin are primarily white matter disorders. The myelin in peripheral nerves is similar to the myelin in the CNS, but with several important differences: (1) peripheral myelin is made by Schwann cells, not oligodendrocytes; (2) each Schwann cell in a peripheral nerve provides myelin for only one internode, while in the CNS, many internodes are created by processes coming from a single oligodendrocyte; and (3) the specialized proteins and lipids are also different. Most diseases of CNS myelin do not involve the peripheral nerves to any significant extent, and vice versa.
Fig. 23.22 Priondisease.(A)HistologicfeaturesofCreutzfeldt-Jakobdisease(CJD)includespongiformchangeinthecerebralcortex.Inset, Highmagnificationofaneuronwithvacuoles.(B)VariantCJD(vCJD)ischaracterizedbyamyloidplaques(inset) thatsitintheregionsofgreatestspongiformchange.
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In general, CNS diseases involving myelin are separated into two broad groups.
Demyelinating diseases of the CNS are acquired conditions characterized by preferential damage to previously normal myelin. The most common diseases in this group result from immune-mediated injury, such as multiple sclerosis (MS) and related disorders. Other processes that can cause this type of disease include viral infection of oligodendrocytes, as in progressive multifocal leukoencephalopathy (see earlier), and injury caused by drugs and other toxic agents.
By contrast, in other diseases, myelin is not formed properly or has abnormal turnover kinetics. As would be expected, most of these are caused by mutations that disrupt the function of proteins required for the formation of normal myelin sheaths. These diseases are grouped under leukodystrophy or dysmyelinating diseases.
MS is an autoimmune demyelinating disorder characterized by episodes of disease activity, separated in time, that produce white matter lesions that are separated in space. It is the most common demyelinating disorder, having a prevalence of approximately 1 per 1000 individuals in the United States and Europe, and its incidence appears to be increasing. The disease may present at any age, but onset in childhood or after 50 years of age is rare. Women are affected twice as often as men.
The lesions of MS are caused by an autoimmune response directed against components of the myelin sheath. As in other autoimmune diseases (Chapter 5), the development of MS is related to genetic susceptibility and largely undefined environmental triggers. 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. Only a portion of the genetic basis of the disease has been explained, and many of the identified loci are associated with other autoimmune diseases. There is a strong effect of the major histocompatibility complex; each copy of the HLA-DRB1*1501 allele an individual inherits brings with it a roughly 3-fold increase in the risk for MS. Other genetic loci that are associated with MS include the IL-2 and IL-7 receptor genes and other genes encoding proteins involved in immune responses.