What’s the primary pathology of ms?

The pathologic hallmark of MS is the presence of multifocal regions of inflammation and myelin destruction in the CNS (brain, spinal cord, and optic nerve). Because of demyelination, axonal conduction is slowed or blocked, giving rise to a host of neurologic signs and symptoms. As inflammation subsides, damaged tissue is replaced by astrocyte-derived filaments, forming scars known as scleroses, hence the disease name. It is important to note that, in addition to stripping off myelin, inflammation may injure the underlying axon, and may also damage oligodendrocytes, the cells that produce CNS myelin. Axon injury can also occur in the absence of inflammation, and can be seen early in the course of the disease.

How does inflammation occur?

The mechanism appears to be autoimmune: Cells of the immune system mistakenly identify components of myelin as being foreign, and hence mount an attack against them. For the attack to occur, circulating lymphocytes (T cells) and monocytes (macrophages) must adhere to the endothelium of CNS blood vessels, migrate across the vessel wall, and then initiate the inflammatory process. The end result is an inflammatory cascade that destroys myelin and may also injure the axonal membrane and nearby oligodendrocytes.

What initiates the autoimmune process?

No one knows. The most likely candidates are genetics, environmental factors, and microbial pathogens. We suspect a genetic link for two reasons. First, the risk of MS for first-degree relatives of someone with the disease is 10 to 20 times higher than the risk for people in the general population. Second, the risk of MS differs for members of different races. For example, the incidence is highest among Caucasians (especially those of northern European descent), much lower among Asians, and nearly zero among Inuits (the indigenous people of the Arctic). We suspect environmental factors because the risk is not the same in all places: In the United States, MS is more common in northern states than in southern states; around the globe, MS is most common in countries that have a moderately cool climate, whether in the northern or southern hemisphere; and, as we move from the equator toward the poles, the incidence of MS increases. Microbial pathogens suspected of initiating autoimmunity include Epstein-Barr virus, human herpesvirus 6, and Chlamydia pneumoniae. The bottom line? Multiple sclerosis appears to be a disease that develops in genetically vulnerable people following exposure to an environmental or microbial factor that initiates autoimmune activity.

What happens when an acute attack is over?

When inflammation subsides, some degree of recovery occurs, at least in the early stages of the disease. Three mechanisms are involved: (1) partial remyelination, (2) functional axonal compensation (axons redistribute their sodium channels from the nodes of Ranvier to the entire region of demyelination), and (3) development of alternative neuronal circuits that bypass the damaged region. Unfortunately, with recurrent episodes of demyelination, recovery becomes less and less complete. Possible reasons include mounting astrocytic scarring, irreversible axonal injury, and the death of neurons and oligodendrocytes.

Does MS injure the myelin sheath of peripheral neurons?

No. Myelin in the periphery is made by Schwann cells, whereas myelin in the CNS is made by oligodendrocytes. Although myelin produced by these two cell types is very similar, it is not identical. Because peripheral myelin differs somewhat from CNS myelin, the immune system does not identify peripheral myelin as foreign, and hence this myelin is spared.

Disease-modifying therapy

Disease-modifying drugs can decrease the frequency and severity of relapses, reduce development of brain lesions, decrease future disability, and help maintain quality of life. In addition, they may prevent permanent damage to axons. However, it is important to note that, although these drugs can slow disease progression, they do not cure MS. Also, they do not work for all patients. Those with relapsing-remitting MS benefit most.

There are two main groups of disease-modifying drugs: immunomodulators and immunosuppressants (Table 23–2). The immunomodulators—interferon beta, glatiramer acetate, natalizumab, and fingolimod—are safer than mitoxantrone (the major immunosuppressant in use), and hence are generally preferred.

Treating an acute episode (relapse)

A short course of a high-dose IV glucocorticoid (eg, 500 mg to 1 gm of methylprednisolone daily for 3 to 5 days) is the preferred treatment of an acute relapse. Glucocorticoids suppress inflammation and can thereby reduce the severity and duration of a clinical attack. As discussed in Chapter 72, these drugs are very safe when used short term, elevation of blood glucose being the principal concern. By contrast, long-term exposure can cause osteoporosis and other serious adverse effects. Accordingly, frequent use (more than 3 times a year) or prolonged use (longer than 3 weeks at a time) should be avoided.

Acute relapse may also be treated with IV gamma globulin. This option can be especially helpful in patients intolerant of or unresponsive to glucocorticoids. Results have been good.

Drug therapy of symptoms

All four subtypes of MS share the same symptoms (eg, fatigue, spasticity, pain, bladder dysfunction, bowel dysfunction, sexual dysfunction). Accordingly, the drugs used for treatment are the same for all patients, regardless of MS subtype. Specific treatments are discussed below under Drugs Used to Manage MS Symptoms.

Description and mechanism

Interferon beta is a naturally occurring glycoprotein with antiviral, antiproliferative, and immunomodulatory actions. Natural interferon beta is produced in response to viral invasion and other biologic inducers. In patients with MS, it is believed to help in two ways. First, it inhibits the migration of proinflammatory leukocytes across the blood-brain barrier, thereby preventing these cells from reaching neurons of the CNS. Second, it suppresses T helper cell activity.

Two forms of interferon beta are used clinically: interferon beta-1a [Avonex, Rebif] and interferon beta-1b [Betaseron, Extavia]. Both forms are manufactured using recombinant DNA technology. Interferon beta-1a contains 166 amino acids plus glycoproteins, and is identical to natural human interferon beta with respect to amino acid content. Interferon beta-1b contains only 165 amino acids and has no glycoproteins, and hence differs somewhat from the natural compound. The two preparations of interferon beta-1a—Avonex and Rebif—differ slightly in their glycoprotein content, and are administered by different routes (see below). The two preparations of interferon beta-1b—Betaseron and Extavia—are identical. In fact, they are both manufactured in the same plant.

Therapeutic use

All four interferon beta products are approved for relapsing forms of MS. These drugs can decrease the frequency and severity of attacks, reduce the number and size of MRI-detectable lesions, and delay the progression of disability. Benefits with Rebif, Betaseron, and Extavia may be somewhat greater than with Avonex, perhaps because Avonex is given less frequently and in lower dosage (see below).

In addition to its use in relapsing MS, interferon beta-1b [Betaseron] is approved for patients with secondary progressive MS.

Adverse effects and drug interactions

Interferon beta is generally well tolerated, although side effects are common.