The estimated number of patients with MS in the United States is between 350,000 and 450,000. MS is a disorder of young adults, with the onset of disease most frequently between the ages of 20 and 35 years among women, and 35 and 45 years among men. The prevalence of MS is approximately four times higher among women than among men, and the disease is much more common among white persons than among other races. Although there are no definite Mendelian patterns of inheritance with MS, first-degree relatives of the person with the index case have a 10- to 20-fold increased risk of the disorder. This genetic risk has been borne out in twin studies, in which the monozygotic concordance rate is approximately 30%, compared with 5% for dizygotic twins. HLA studies have shown a subtle but significant correlation between MS and different HLA antigens within various ethnic groups. Two different alleles have been liked to MS, but their actual influence is small. These are HLA-DRB1 and HLA-DQB1. The HLA-DRB1 has the larger effect of these genes, increasing the risk of developing MS 3-fold when present. Recent findings suggest a vitamin D response element to the promoter region of HLA-DRB1. It is suspected that vitamin D specifically interacts with HLA-DRB1 to alter its expression and thereby probably decrease ones susceptibility to develop MS. There are also non-MHC genes that induce a smaller effect. In summary, facts suggest that there is a genetic predisposition toward development of the disorder, but noninherited factors play a more dominant role.

The exact pathogenesis of MS remains elusive, but substantial clinical, laboratory data, and response to immune-modulating therapy suggest an autoimmune process. In immunologic terms, there is blood-brain barrier (BBB) breakdown allowing CD4 TH1 type lymphocytes into the CNS where they secrete inflammatory cytokines resulting in damage of myelin and amplification of the immune response. This damaged myelin is then stripped by a cell such as a macrophage and conduction anomalies develop. Less frequently the offending cell in a CD8 cytotoxic cell, directly damaging the oligodendroglia. Finally, there can be antibodymediated destruction of the myelin, either directly or through activation of complement. B cell contribution will be discussed later in this section. Finally, oligodendrocytes death may occur, with or without apoptosis and support of development or repair of myelin ceases.

Myelin is important for saltatory conduction along the axon. Demyelination frequently occurs in localized areas. The result is a pathologic lesion called a plaque. These plaques are usually located deep in the cerebral white matter, near the ventricles, but they can occur anywhere, including gray matter, cerebellum, brainstem, spinal cord, and proximal nerve roots. This almost limitless variation of distribution is responsible for the variety of clinical presentations. The pathologic appearance of the plaque changes with repeated episodes of demyelination and chronicity. In an early active plaque, there is breakdown of the BBB with demyelination but typically relative sparing of the axons. Perivascular infiltrates of lymphocytes, macrophages, and occasionally plasma cells are present in small veins
and venules. Demyelination may spread outward from the plaque, especially along these vessels. Perivascular and interstitial edema may be prominent. At the edge of the plaque, there is hyperplasia of oligodendrocytes and activated astrocytes. These hyperplastic oligodendrocytes are probably involved in remyelination, but thin myelin sheaths found at electron microscopic examination suggest that this remyelination often is suboptimal and incomplete. In older plaques, oligodendroglia disappear, astrocytes show hypertrophy and hyperplasia (sclerosis), and axonal loss occurs. Evidence is present, by such techniques as MRI spectroscopy and histology studies, that there is substantial axonal dropout, in some patients, even in early disease.

The contribution of B cells, plasma cells, and antibody wax and wanes in popularity. The recent increase in the importance of B cells partially stems from the highly beneficial effects of rituximab on the disease course.

In MS patients, B cells sometimes appear in clusters or “germinal centers” in the CNS, and these areas appear to correlate with disease progression. At least a portion of these B cell may have been “immortalized” by Epstein-Barr viruses. B cells release inflammatory cytokines that up-regulate T cells and antigen-presenting cells and B cells sometimes become antigenpresenting cells. Antibodies can cause demyelination directly or through complement fixation.

The more recent advances in understanding the pathogenesis of MS involves T regulatory (T REG) cells and dendritic cells (DC). T REG cells are essential for the maintenance of immuno-tolerance, and their dysfunction is associated with the development of organ autoimmunity, as shown in both animals and humans. Data suggest that the dysfunction (temporary or permanent) of suppressor function of certain T REG cells is associated with MS. “Tolerogenic” DCs can modulate the expansion and function of T REG cells during CNS inflammation, or “immunogenic” DCs can induce effector T cell that result in demyelination. This interplay results in homeostasis or disease activity. MS seems to be associated with the dysfunction or impaired maturation of certain T REG-cell and DC populations. In the future, transient or even continuous augmentation of T REG-cell function could develop as an integral component of the therapeutic management of CNS autoimmunity and the course of MS.

Areas of CNS demyelination or plaques can produce conduction abnormalities with delayed or blocked conduction, impaired response to repetitive stimulation, or ephaptic conduction. The first three conduction defects can result in negative signs or symptoms. Depending on the extent of the conduction defect and location of the lesion in the CNS, the patient may have visual loss, numbness, weakness, ataxia, or nearly any loss of function attributable to a CNS lesion. Often the lesion comes and goes in a clinically silent area of the brain, the patient is not aware of any symptoms. Ephaptic conduction may result in positive signs and symptoms, including pain and paroxysmal syndromes. The variations of positive and negative signs and symptoms that may develop, further contribute to the complexity of the clinical disorder.

An accurate diagnosis of MS is extremely important because the disorder mimics many diseases of the CNS. Unfortunately, the diagnosis cannot be achieved reliably through any single paraclinical study. Rather, the entire clinical syndrome must be evaluated with a careful clinical history and examination. Those findings direct further laboratory studies to eliminate other disorders or to support the diagnosis of MS with paraclinical studies such as MRI, evoked potentials (see Chapter 33), and examination of the CSF (see Chapter 33).

The complex, highly variable signs and symptoms of MS result in a clinical disorder that often is a challenge to manage. Therapy for MS is both symptomatic and immune modulating. Symptomatic therapy involves management of fatigue, spasticity, neurobehavioral disorders, paroxysmal disorders, pain, bladder dysfunction, and cerebellar dysfunction. Immune-modulating therapies are directed at altering the clinical course. This may involve management of acute exacerbations or the overall progression of the disease.