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Presented by William I. Rosenblum, MD


This chapter contains four interrelated sections. LINKS TO THE OTHER 3 SECTIONS ARE FOUND AT THE END OF THIS PARAGRAPH. These sections are related because some  diseases of myelin are storage diseases and some storage diseases involve not  myelin primarily but the neuron instead. In many cases the storage diseases are related  in the sense that they depend upon  a lack of an enzyme normally found in lysosomes, or sometimes in peroxisiomes. Each enzyme  deficiency disease is characterized by its own enzyme deficiency, but the fact that  lysosomal enzymes are involved has led many writers to lump these diseases together as  lysosomal disorders. The problem with this method of classification is that it loses the distinction  between diseases primarily affecting  grey matter [neuronal cell bodies] and diseases primarily affecting white matter [myelin]. Since this anatomic difference helps make  a diagnosis when the brain is examined by imaging or at autopsy and also  has some effect on early symptoms, we prefer to emphasize the older classification of white matter diseases [ADE, MS and leukodystrophies] on the one hand and the  other storage diseases which have been called neuronal lipidoses on the other. Indeed a traditional term for the neuronal storage diseases has been the term "lipidoses". Because of the pathogenetic similarity between some of the leukodystrophies [white matter lipid storage or lysosomal disorders of white matter] and the neruonal lipidoses [lysosomal disorders] we have included a section [section 4] concerning the latter in this chapter.The other three sections are:

      Section 1 - Acute Disseminated Encephalomyelitis
      Section  3 - Leukodystrophies
      Section  4 - Neuronal Lipidoses

Section 2: Multiple Sclerosis

PRETEST: Answers can be found in the text of this section or click on link at end of questions

  1. The gross lesion of MS is called a ______________________ .
  2. The classical view of MS says that myelin is more affected than axons [true or false?].
  3. What role does axon degeneration play in the disease?
  4. What cell is depleted in the affected white matter?
  5. Two different but possibly cooperating  pathways of pathogenesis  have been implicated--what are they?
  6. What is Devic's disease?



1. Demyelinating, but axonal injury is also important

2. CNS only - not peripheral nervous system - reason unknown but probably reflects different antigenic makeup of the peripheral vs central myelin.

3. Preservation of axons is relative, and axon loss is important in progressive disease. The lesion of myelin loss with relative axon preservation is well circumscribed and is called a plaque.

4. On gross inspection, plaques are circumscribed, grey or translucent, often juxta ventricular.

Myelin stains display these areas, called plaques, as circumscribed unstained zones of pallor (image below). Oligodendroglia are markedly diminished within the mature plaque [arrows demarcate loss of myelin below].


The plaque is also recognizable in the gross brain as a well circumscribed zone of altered color and density (arrow, image below).


In "young" plaques with active demyelination, the myelin debris is present in macrophages, which then stain for fats. The fat-laden macrophages carry away the fat by passing into the perivascular spaces (Virchow-Robin), which are extensions of the subarachnoid space. As plaques grow, their centers may be free of macrophages which then appear only at the actively expanding perimeter of the lesion. Quiescent plaques contain no lipid-laden macrophages. During or following myelin breakdown, astrocytes proliferate within the plaque and astrocytic processes increase in length and number. The ultimate degree of astrocytosis is quite variable. Marked astrocytosis imparts a firmness to the plaque in the unfixed brain. This firmness  or hardness is responsible for the term "sclerosis" in the name of the disease.

Although plaques are easier to recognize in white matter because of the contrast between the plaque and the densely myelinated normal background, plaques also occur in grey matter since all CNS axons are myelinated along their entire course. In addition to containing conventional demyelinating plaques the grey matter may have plaques of a different pathogenesis. Rather than the events described below under PATHOGENESIS some areas of grey matter may begin to degenerate under the influence of gathering microglia that release agents causing release of glutamate from the adjacent neurons. As a result of the excessive local glutamate there is progressive degeneration of oligodendroglia and myelin.

Perivascular infiltrate of lymphocytes and monocytes is found in fresh or actively growing plaques.

Axon degeneration also occurs in plaques and may begin early. Progression of disease is related to increasing amounts of axonal damage.


Some workers believe the lymphocytes and monocytes participate in the destruction of the myelin, which is mediated by an antibody bound to the mononuclear cell and directed against a myelin antigen. Indeed the presence of a venule with a monocytic\lymphocytic perivascular infiltrate near the center of fresh plaques bears a resemblance to the lesion of acute disseminated encephalomyelitis, a known immunomodulated demyelinating disease of CNS. This similarity has been used to support the hypothesis that MS is an immuno disease. However in ADE the CD4 T cell is present in the lesions whiole in MS it is the CD8 lymphocyte. This implies an immunologic driving force in both diseases but also an immunologic difference between them. Other evidence supporting an immunologic drive in MS includes the fact that plasma phoresis is beneficial in some patients--implying a causative antiobody circulating in plasma.

Moreover certain immuno-modulating drugs have been affective in slowing or arresting disease progression. One of these prevents lymphocytes from attaching to endothelium and passing from blood into brain.

On the other hand, much circumstantial evidence suggests a ling to some infectious agent, possibly a virus. This evidence includes a geographic distribution favoring a vector--such as an insect--which likes temperate as opposed to tropical climates. In addition, MS patients and their close relatives have been found to have excessive antibody titers to several different viruses including measles. Similar populations have also been reported to have characteristic patterns of histocompatibility markers which might explain persistent antibody in such people. These facts--sometimes disputed as facts-have led to several hypotheses such as:

[1] increased susceptibility to a virus which attacks the CNS myelin or 
[2] molecular mimicry with a marker on oligo or oligo produced myelin which shares epitopes with the virus and so is attacked by the persistent antibody to the virus; 
[3] or the attack is on some other cell which releases [or the attacking cell releases] cytokines that attack meylin--an innocent "bystander" theory. 

Some support for molecular mimicry concept comes from a peripheral nervous system disease. That disease is one form of Guillain Barre disease in which the patients have had a preceding infection with campylobacter jejuni. The organism has a ganglioside that mimics one in the peripheral nerve leading to an immuno attack on the latter as the body fights the infection. However the ganglioside in in the axon membrane and not in the myelin. Indeed patients with this form of Guillain Barre have a different clinical picture from those who lack the preceding history of GI infection or who lack the antibody. Since this example involves axon injury rather than myelin attack it may seem removed from MS. Nevertheless this example of molecular mimicry provides "proof of principle" and in addition may indeed be relevant to MS for two reasons: first, remember that axon damage leads to myelin loss and second, remember that axon injury and loss is, in fact, an important aspect of MS. The cause of the axon loss is unknown but might indeed by immunologic. The axon loss occurs early and accounts both for atrophy of the brain in MS and for the ultimately progressive deterioration of patients presenting initially with or later deveolping a progressive form of the disease.

Some support for the  innocent bystander concept comes from a demyelinating disease or peripheral nervous system that devastates flocks of chickens. This is Marick's disease where cells attacking one site in the nerve release cytokines that attack innocent adjacent Schwann cells. 

Finally, the two immuno theories of MS and the viral theory may combine to account first for the initial injury at a given site [related to a viral attack or attack by an anti viral antibody?] and then for the continuation or progression of the lesion via some immuno mechanism.


MS is usually characterized by remissions and exacerbations. The reason for remissions is not well understood but again may have something to do with the interweaving of the pathogenic pathways discussed above. The ability to remit may depend upon preservation of axons and possibly on minimal remyelination sufficient to restore the capacity to conduct. Remyelinated plaques are often still pale in comparison with normal areas of white matter and have been called shadow plaques. Another reason fro remissions may concern the inflammation in early plaques. This is accompanied by local leaks from vessels and edema. The waxing and waning of edema in and around the plaque had been thought by some workers to account for the ups and downs of the clinical picture but MRI studies have failed to find the correlation between edema or leaking vessels and clinical status.

It is also possible that inflammatory cells release substances that impair transmission and wax and wane. In addition, an increased number of sodium channels develops after axons lose their myelin. These axons then resemble unmyelinated axons and can conduct electrical impulses. However, if an adaptive increase in sodium channels accounts for remissions in MS, we have no explanation for recurrence of identical symptoms unless (A) they are really due to new plaques, or (B) there is an intermittent factor which inhibits transmission.


Two other diseases are thought to be related to MS or to be variants of that disease.


The first of these, Devic's disease or syndrome, is also known as neuromyelitis optica, a name which emphasizes the preferential distribution of the lesions in the spinal cord and optic nerve. Pathologically, in many cases, the lesions are indistinguishable from those of MS. However, in a subgroup of cases, the lesions differ from the usual MS lesions in the following respects: axons and myelin are destroyed to the same extent, and a marked acute inflammatory cell infiltrate (polymorphonuclear cells) is present. Some workers believe that these lesions are simply a hyperacute form of MS, rapidly progressing, and indeed, typical MS plaques can be seen in the same case. Recently it has been discovered that cases of Devic's disease display antibodies to aquaporin 4. These antibodies localize in the destructive lesions of Devics disease and there is a local reduction in the amount of this aquaporin, normally present in astrocytic processes. The relationship of theses findings to the local tissue destruction is unknown however the conventional plaques of MS do not display these findings. Consequently some workers now believe that they have shown that Devics and MS are seperate diseases.  However since both types of lesion can be found in the same case, with the destructive lesions confined to optic nerves and spinal cord, it would be necessary to say that there were two diseases in the same individual. While this is possible it seems more likely that the lesions of Devic are a hyperacute manifestation of the problems underlying MS; for example --hypothesis--there might be an immunologic attack not only upon oligoglia to produce typcial MS plaques, but also upon aquaporin 4 in astrocytes so that cases of MS develop the destructive lesionsof Devic as well; while in other patients, for undetermined reasons, only the attack on aquaporin is manifest and a case of "pure" Devics develops.

The second variant of MS has been called Schilder's disease after the doctor who supposedly described it. The same disease name has also been applied to a form of leukodystrophy [adrenoleukodystrophy] which leads to confusion. In the context of MS, the term Schilder's disease should be dropped and one should simply speak of hyperacute MS. 

The hyperacute disease is characterized by massive degeneration of white matter--both myelin and axons, with profound astrocytosis. We can only relate this to MS by observing, in the same patients, relatively spared areas of CNS that have more typical MS plaques.

Last Updated 07-Sep-2007