Demyelinating and Autoimmune Diseases

Diseases of Myelin

• 1.

  What is myelin?

  Myelin is the proteolipid membrane that ensheathes and surrounds nerve axons to improve their ability to conduct electrical action potentials. Oligodendrocytes make central nervous system myelin and wrap the myelin around axons, leaving gaps called nodes of Ranvier , where membrane ionic channels are heavily concentrated and powerful action potentials can thus be generated.

• 2.

  How does demyelination cause symptoms?

  When myelin is stripped away from the axon, the underlying membrane does not contain a high enough concentration of sodium, potassium, and other ionic channels to permit a sufficient flow of ions to cause depolarization. The membrane thus becomes inert. The loss of myelin makes it impossible to depolarize the membrane to conduct an action potential, so the nerve is rendered useless.

• 3.

  What is multiple sclerosis (MS)?

  MS is the most common condition that destroys myelin in the central nervous system. It affects approximately 250,000 Americans, mostly between the ages of 20 and 40, making it the leading disabling neurologic disease of young people.

• 4.

  How does MS cause demyelination?

  The demyelination is largely an inflammatory process. Lymphocytes, macrophages, and other immunocompetent cells accumulate around venules focally in the central nervous system and exit into the brain, attacking and destroying the local myelin, in what appears to be an autoimmune process. In many patients with MS, a more degenerative (and poorly understood) pathology appears, with less inflammation and more generalized atrophy.

• 5.

  Are there other demyelinating diseases?

  Yes, but they are rare. MS is the only common demyelinating disease in adults. Other rare conditions include:

  • Central pontine myelinolysis , a syndrome of myelin destruction in the pons, associated with rapid correction of hyponatremia.

  • Progressive multifocal leukoencephalopathy , an opportunistic infection of oligodendrocytes by the John Cunningham (JC) virus, seen most often in patients with acquired immunodeficiency syndrome or other immunosuppression.

  • Acute disseminated encephalomyelitis , a monophasic, acute, autoimmune demyelination producing encephalopathy, especially in childhood.

  • Inborn errors of myelin metabolism , usually presenting in childhood:

    • Metachromatic leukodystrophy, a deficiency of the enzyme aryl sulfatase

    • Adrenoleukodystrophy, a defect in metabolism of very long chain fatty acids

    • Krabbe’s globoid leukodystrophy, a deficiency of the enzyme galactosylceramidase

  • Neuromyelitis optica or Devic’s disease , an autoimmune disease predominantly affecting the optic nerves and spinal cord. Patients have relapses, usually every few years, causing primarily visual and spinal cord deficits. Severe disability often results. Patients have antibodies to aquaporin-4, regulating a water channel on astrocytes, leading to inflammation and secondary demyelination.

Sobel RA, Moore GRW: Demyelinating diseases. In Love S, Louis DN, Ellison DW (eds): Greenfield’s neuropathology , ed 8. London: Oxford University Press, pp. 1513-1608, 2008.

Papadopoulos MC, Verkamn AS: Aquaporin 4 and neuromyelitis optica. Lancet Neurol 11(6):525-544, 2012.

Clinical Features of Multiple Sclerosis

• 6.

  What are the most common symptoms of MS?

  • Pyramidal weakness—45%

  • Visual loss—40%

  • Sensory loss—35%

  • Brain stem dysfunction—30%

  • Cerebellar ataxia and tremor—25%

  • Sphincter disturbances—20%

• 7.

  Are there any symptoms that MS does not cause?

  Not many. Virtually every neurologic problem has been described in MS, at least as a case report. However, because MS is predominantly a disease of myelin (white matter), it only rarely causes neuronal (gray matter) symptoms, such as aphasia, seizures, and movement disorders.

• 8.

  What is the clinical course of MS?

  MS usually follows one of a few distinctive patterns, classified largely on the timing of the symptoms:

  • Clinically isolated syndrome

  • Relapsing–remitting

  • Primary progressive

  • Secondary progressive

• 9.

  What is a clinically isolated syndrome (CIS)?

  A CIS is the first presentation of signs and symptoms that show characteristics of inflammatory demyelination that could be MS but is only a single monophasic event (not disseminated in time). An example of a CIS would be an episode of either optic neuritis or transverse myelitis or other single isolated event. If such patients have abnormal magnetic resonance imaging (MRI) showing other (asymptomatic) lesions characteristic of MS, it is highly likely that a CIS is actually the initial attack of MS.

• 10.

  What is relapsing–remitting MS?

  Relapsing–remitting MS is the most common pattern, accounting for about 80% of all MS. Patients have the sudden onset (over hours or days) of neurologic symptoms that usually last several weeks and then resolve, often leaving few or no deficits. On average these attacks/relapses/exacerbations occur every 3 years.

• 11.

  What is progressive MS?

  Some patients develop symptoms slowly and gradually, progressive over 6 to 12 months or more. If this gradual worsening develops after an initial relapsing–remitting disease course, it is referred to as secondary progressive MS . Approximately 10% to 15% of all MS patients never experience a CIS or a relapse but rather have chronic progressive symptoms from the onset. This is referred to as primary progressive MS . The only distinction between these progressive forms is the presence (secondary progression) or absence (primary progression) of relapses prior to the appearance of the progressive symptoms. There are otherwise no known pathophysiological differences between the two forms.

• 12.

  What is the prognosis of MS?

  MS varies greatly, not only in its symptoms and clinical course but also in its prognosis. Although not a fatal disease, MS is associated with a slight statistical shortening of lifespan as a result of secondary complications that may afflict severe cases, such as aspiration pneumonia, decubitus ulcers, urinary tract infections, and falls. As a general rule, approximately one-third of patients with MS do well throughout their life, without accumulating significant disability. Another one-third accumulate neurologic deficits sufficient to impair activities but not serious enough to prevent them from leading a normal life—holding a job, raising a family. The final third of people with MS become disabled, requiring a walker, wheelchair, or even total care.

• 13.

  What factors help to predict the course of MS?

  The variability of MS makes accurate prediction fallible, but a few factors may portend a good prognosis:

  • Early age of onset (first symptoms before age 40)

  • Sensory symptoms at onset (as opposed to weakness, ataxia, or other motor abnormalities)

    Lublin FD, Reingold SG, Cohen JA, Cutter GR, Sørensen PS, Thompson AJ, et al.: Defining the clinical course of multiple sclerosis. The 2013 revisions. Neurology 83(3):1-9, 2014.

  • A relapsing–remitting course (vs a primary progressive symptom at onset)

  • Female gender: women do better than men.

• 14.

  What is the Expanded Disability Status Score (EDSS)?

  The EDSS is a number that rates a patient’s degree of disability from MS on a scale of 0 to 10. Deficits are determined in various functional systems (motor, sensory, cerebellar, etc.). A patient with a score of 6 requires a cane to walk and with a score of 8 is confined to a wheelchair. The EDSS is widely used as a standard method of evaluating MS patients.