Demyelinating Diseases

Demyelinating Diseases• Are acquired conditions characterized by

preferential damage to myelin, with relative preservation of axons.

• Clinical deficits are due to the effect of myelin loss on the transmission of electrical impulses along axons.

• The natural history of demyelinating diseases is determined, in part, by the limited capacity of the CNS to regenerate normal myelin and by the degree of secondary damage to axons that occurs as the disease runs its course.

• Other disease processes can involve myelin. In Progressive Multifocal Leukoencephalopathy, the JC virus infection of oligodendrocytes results in loss of myelin.

• In addition, there are inherited disorders that affect myelin synthesis and turnover. These disorders are termed leukodystrophies.

Multiple Sclerosis• MS is an autoimmune demyelinating disorder

characterized by distinct episodes of neurologic deficits, separated in time, attributable to white matter lesions that are separated in space.

• It is the most common of the demyelinating diseases, with a prevalence of 1 per 1000 persons in most of the USA and Europe.

• The disease becomes clinically apparent at any age, although onset in childhood or after 50 years is relatively rare. Women are affected twice as often as are men.

• In most patients with MS, the clinical course of the illness evolves as relapsing and remitting episodes of neurologic deficit during variable intervals of time (weeks to months to years), followed by gradual, partial recovery of neurologic function.

• The frequency of relapses tends to decrease during the course of time, but there is a steady neurologic deterioration in most patients.

Multiple SclerosisPathogenesis:• The lesions of MS are caused by a cellular

immune response that is inappropriately directed against the components of the myelin sheath.

• The likelihood of developing this autoimmune process is influenced by genetic and environmental factors.

• The risk of developing MS is 15-fold higher when the disease is present in a first-degree relative and even an order of magnitude greater for monozygotic twins.

• Genetic linkage of MS susceptibility to the DR2 extended haplotype of the major histocompatibility complex is also well established.

** The molecular basis for the influence of this particular haplotype on the risk of developing MS is unknown; other genetic loci are involved as well.

• Given the prominence of chronic inflammatory cells within and around MS plaques, immune mechanisms that underlie the destruction of myelin have been the focus of much investigation.

• The available evidence indicates that the disease is initiated by CD4+ TH1 T cells that react against self myelin antigens and secrete cytokines, such as IFN-γ, that activate macrophages.

• The demyelination is caused by these activated macrophages and their injurious products.

• The infiltrate in plaques and surrounding regions of the brain consists of T cells (mainly CD4+, some CD8+) and macrophages.

• Antibodies are also frequently present; their role in demyelination is less clear.

• How the autoimmune reaction is initiated is also not understood; as in other autoimmune disorders, microbial triggers and a number of susceptibility genes are thought to play a role.

Clinical Features:• Although MS lesions can occur anywhere in the

CNS and, as a consequence, may induce a wide range of clinical manifestations, certain patterns of neurologic symptoms and signs are commonly observed.

• Unilateral visual impairment during the course of a few days, due to optic nerve involvement, is a frequent initial manifestation of MS. However, only some patients with optic neuritis go on to develop MS.

• Involvement of the brainstem produces cranial nerve signs, ataxia, nystagmus, and internuclear ophthalmoplegia from interruption of the fibers of the medial longitudinal fasciculus.

• Spinal cord lesions give rise to motor and sensory impairment of trunk and limbs, spasticity, and difficulties with the voluntary control of bladder function.

• CSF examination in MS patients shows a mildly elevated protein level, and in ⅓ of cases, there is moderate pleocytosis.

• The proportion of gamma globulin is increased, and most MS patients show oligoclonal (few) bands. This increase in CSF immunoglobulin is the result of proliferation of B-cells within the nervous system; the target epitopes (simplest form of an antigenic determinant) of these antibodies are widely variable.

Multiple Sclerosis Variants• Some individuals, especially Asians, develop

a demyelinating disease similar to MS with presenting symptoms of bilateral optic neuritis and prominent spinal cord involvement. This is neuromyelitis optica or Devic disease.

• Lesions in Devic disease are considerably more destructive, and gray matter involvement of the spinal cord can be striking.

• Another variant, acute MS (Marburg form), tends to occur in young individuals and is characterized clinically by a fulminant course during a period of several months.

• On pathologic examination, the plaques are large and numerous, and there is widespread destruction of myelin with some axonal loss.

ADEM• Acute Disseminated Encephalomyelitis, ADEM,

or perivenous encephalomyelitis – is a monophasic demyelinating disease that follows either a viral infection or, rarely a viral immunization.

• Symptoms typically develop a week or two after the antecedent infection and include evidence of diffuse brain involvement with headache, lethargy, and coma rather than focal findings, as seen in MS.

• Symptoms progress rapidly, with a fatal outcome in as many as 20% of cases; in the remaining patients, there is complete recovery.

ANHE• Acute Necrotizing Hemorrhagic Encephalomyelitis,

ANHE, or acute hemorrhagic leukoencephalitis of Weston Hurst – is a fulminant syndrome of CNS demyelination, typically affecting young adults and children.

• The illness is almost invariably preceded by a recent episode of URTI; sometimes, it is due to Mycoplasma pneumoniae, but often it is of indeterminate cause.

• The disease is fatal in many patients, but some have survived with minimal residual symptoms.

Other Diseases With Demyelination• Central pontine myelinolysis is characterized

by loss of myelin (with relative preservation of axons and neuronal cell bodies) in a roughly symmetric pattern involving the basis pontis and portions of the pontine tegmentum.

• Extra pontine lesions occur in the supratentorial compartment, with similar appearance and apparent etiology.

• The condition is believed to be caused by rapid correction of hyponatremia; however, alternative pathogenetic hypotheses attribute the disorder to extreme serum hyperosmolarity or other metabolic imbalance.

• The clinical presentation of central pontine myelinolysis is that of a rapidly evolving quadriplegia; radiologic imaging studies localize the lesion to the basis pontis.

• It occurs in a variety of clinical settings, including alcoholism, severe electrolyte or osmolar imbalance, and normal liver transplantation.

• Marchiafava-Bignami disease is a rare disorder of myelin characterized by relatively symmetric damage to the myelin of central fibers of the corpus callosum and anterior commissure.

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