Marek Bodzioch
Department of Pediatric Neurology
Polish-American Children's Hospital CM UJ
Cracow, Poland

Demyelinating disorders or disorders of the myelin sheath constitute a large, polyetiological group of diseases varying in clinical presentation and prognosis. The clinical entities that fall into this category are usually described in several different chapters of neurology textbooks. It is mainly for the practical reasons. For example, Guillain-Barre syndrome should be included in the differential of flaccid paresis rather than progressive encephalopathy, which in its turn requires investigation to confirm or rule out leukodystrophy. In spite of numerous differences, all these diseases have at least one thing in common - the same target of the underlying etiopathological processes - the myelin sheath.

The myelin sheath, which surrounds the axon, is made up mainly of lipid and protein particles. In the brain and spinal cord the myelin is produced by oligodendrocytes, a specialized population of glial cells. The oligodendrocyte winds around the axon many times and the myelin sheath is formed by multiple layers of the oligodendrocyte's cell membrane. Alongside the single axon there are plenty of seperate oligodendrocytes, each responsible for the construction of a short segment of the myelin sheath. Schwann cells are the counterparts of oligodendrocytes in the peripheral nerves.

The myelin sheaths in central and peripheral nervous systems share many similarities but also have important differences. The evidence for the similar chemical content and metabolic pathways is the involvement of both the central and peripheral myelin in some diseases (e.g. Krabbe disease, one of leukodystrophies). On the other hand, different antigenic composition might explain the presence of predominantly central lesions in multiple sclerosis and solely peripheral in Guillain-Barre syndrome.

Demyelination can be primary or secondary. The primary demyelination is defined as the damage to the myelin with the sparing of the axon and the whole neuron. However, protracted or repetitive injuries of the myelin sheath might in consequence lead to the irreversible neuronal atrophy. The course of multiple sclerosis often takes the form of periodic bouts of neurological deterioration, which are separated by intervals marked by recovery of many of the recently lost functions. This can be explained by the functional disturbance of neuronal activity at the time of myelin loss and return to normal with remyelination.

The secondary demyelination accompanies all processes leading to the death of neurons. For example, in gangliosidoses the primary pathological process, accumulation of unnecessary substances, affects neurons. Cells filled with storage material die, their axons degenerate and the myelin sheath is no longer needed, so the process of its breakdown soon begins.

Some pathological factors damage both neurons and myelin producing cells at the same time. Hypoxic-ischemic injury is the example.

Myelination of the central nervous system starts about 4 months gestational age. At birth the best myelinated structures are diencephalon, brain stem and spinal cord. The first year of life is marked by intensive myelination of cerebral hemispheres and cerebellum, which is consistent with a progress in psychomotor development of an infant. The processes of myelin maturation are continued into the adolescence. We can explain uncommon occurrence of multiple sclerosis in childhood assuming that the autoantigens, which are the targets of the immunological response, appear only in the fully matured myelin.

The use of terms describing the pathological processes involving myelin is often unprecise. Demyelination should be considered as the damage to the myelin sheath occurring only after its maturation has been finished. Disturbances of myelination affecting the still developing myelin sheath should be properly called dysmyelination. However, the term demyelination is commonly used in a more general meaning, referring to all processes damaging myelin. When the demyelination is used in this broader context, it indicates functional rather than structural abnormality. The myelin lesions, irrespective of their nature, produce similar functional effects resulting from impaired neuronal activity.

The etiological factors of the demyelinating diseases can be divided into two large groups. One of them comprises presumably autoimmunological syndromes and the other includes inborn errors of metabolism. A simplified classification of the primary demyelinating diseases is presented in table I.

Degenerative diseases of the white matter of the brain are a diverse group of genetically transmitted metabolic defects, whose most pronounced consequence is the impairment of myelination of the central nervous system. Although the white matter lesions are most conspicuous, the enzymatic block may also affect other parts of the central and peripheral nervous systems as well as extraneural organs (e.g. adrenal insufficiency in adrenoleukodystrophy). The clinical onset of leukodystrophies is variable, depending on the type of a genetic defect. Symptoms may appear soon after birth, in early or late childhood, or even in adults. Leukodystrophies usually have a progressive course, however, sometimes deterioration may develop very slowly. Clinical manifestations include variuos neurological deficits like paresis, visual and hearing impairments, ataxia etc. Psychomotor retardation is usually present. Other neurodegenerative diseases must be ruled out. Leukodystrophies are sometimes mistakenly diagnosed as multiple sclerosis (especially in late-onset cases). If the disease afflicts several members of a family and there are also symptomatic children, the diagnosis of multiple sclerosis is unlikely and an extensive search for a genetic defect is warranted. Generally, there are no effective treatments available for white matter degenerative disorders. Sometimes, a special diet may be of some benefit. It is worth remembering that untreated phenyloketonuria leads to mental retardation mainly through the impairment of normal myelination. Permanent brain damage can be prevented with the early introduction of the diet low in phelyloalanine. Effective screening programs made the dysmyelination in phenyloketonuria so uncommon that no one would ever consider it a demyelinating disease. Table II contains basic characteristics of some of the leukodystrophies.

Inborn metabolic defects influencing myelin development cannot be sharply divided into those with the central or peripheral nervous system involvement. Both Krabbe disease and Refsum disease produce pathologic changes of the myelin sheath in the brain and spinal cord but also in peripheral nerves. However, the clinical picture of Krabbe disease is dominated by CNS abnormalities, while peripheral neuropathy is the primary manifestation in Refsum disease. The underlying etiology in Refsum disease is a metabolic block resulting in increased levels of phytanic acid. Reduction of this acid in a diet is associated with some clinical improvement.

Segmental demyelination of peripheral nervous fibers with the development of characteristic "onion bulbs" is seen in some genetically transmitted motor sensory neuropathies (e.g. Charcot-Marie-Tooth disease, Dejerine-Sotas disease). The differential diagnosis of these syndromes should include other, congenital or aquired, causes of neuropathies.

In some disorders autoimmunological processes are suspected to play a key role in the destruction of the myelin sheath. It is believed that some myelin antigens are mistakenly recognized as alien by the patient's own immunological system and become targets of the autoimmunological response. It is possible that at the base of this abnormal reaction lies the structural similarity between the myelin antigens and the antigens of some microorganisms.

There is a strong association between Campylobacter jejuni infection and subsequent development of Guillain-Barre syndrome. This bacterium contains particles with antigenic properties similar to ganglioside GM₁, which is a component of the myelin of the peripheral nerves.

Parainfectious encephalitis or encephalomyelitis is a complication of an exanthematous infectious disease like chickenpox, measles or rubella. The development of CNS changes is thought to be mediated autoimmunologically since no virus can be detected either in CSF or cerebral tissue.

Viral infection may trigger autoimmunological response in multiple sclerosis. However, genetic factors have also important contribution. Incidence of multiple sclerosis is considerably higher in some ethnic groups and in individuals with certain HLA genes.

Multiple sclerosis is rarely seen in children and usually not before puberty.A limited area of demyelination, called a plaque, is the typical lesion of multiple sclerosis. There might be plenty of plaques involving any region of the central nervous system. Periventricular location of plaques is the most characteristic of multiple sclerosis. The diagnosis of multiple sclerosis is based on clinical (multifocal CNS lesions), radiological (plaques identified in MRI) and laboratory data (e.g. elevated CNS immunoglobulin level and the presence of oligoclonal IgG). It is difficult to establish the true diagnosis in the early phase of the disease, before the development of multiple neurological deficits. It should be remembered that retrobulbar optic neuritis, appearing as a decreased visual acuity, is often the initial symptom of multiple sclerosis in childhood. No effective treatment modalities are as yet available for multiple sclerosis. Numerous attempts have been undertaken to modulate the immunological activity through different agents and methods (e.g. interferon-beta or plasma exchange). The evaluation of those various methods is a difficult task since the disease itself has often a variable and unpredictable course with periods of relapse and spontaneous improvement.

Transverse myelitis is also considered to have autoimmunological origins. Devic disease is diagnosed if transverse myelitis is accompanied by retrobulbar optic neuritis.

Parainfectious encephalitides cannot be distinguished on the clinical grounds from encephalitides caused directly by the infectious agents, so the maganegement is, at least initialy, the same.

Differential diagnosis of Guillain-Barre syndrome will include other causes of acute neuropathy. Both plasma exchange and intravenous immunoglobulins proved effective in the treatment of Guillain-Barre syndrome. Effectiveness of plasma exchange is probably due to the removal of hypothetical autoantibodies from circulation. These autoantibodies may also be blocked by the exogenous immunoglobulins, which is the rationale for the use of IVIG.

Disorders of the myelin sheath are a large polyetiological group of diseases, but as they all share the same target of pathological processes, is it conceivable that in the future some methods of myelin regeneration will be developed, which will prove useful in the treatment of these conditions.