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NEUROPATHOLOGY MINI-COURSE Presented by William I. Rosenblum, MD CHAPTER 4 DEMYELINATING DISEASES; LEUKODYSTROPHIES; STORAGE DISEASES INVOLVING MYELIN OR NEURONS This chapter contains four interrelated sections. They 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 concerning the latter in this chapter.The other three sections are: Section 1 - Acute Disseminated Encephalomyelitis Section 2: Multiple Sclerosis PRETEST: Answers can be found in the text of this section
PATHOLOGY 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, but 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. 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. PATHOGENESIS 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 ADE lesions contain CD4 T cells while lesions of MS often contain CD8 T cells. While this suggest an important difference between the two diseases, the presence of the CD8 cells in MS lesions certainly supports an immunological basis for the disease or for its progression. Further support comes form the presence of CD8 T cells in the lesion. Moreover certain immuno-modulating drugs have been affective in slowing or arresting disease progression. These include drugs which block the egress of lymphocytes through blood vessels and into the brain. In additon some patients benefit greatly from plasma phoresis which is thought to work by removiog an antiobody from the plasma. Interestingly, different patients respond consistantly but differently to different therapies. This may imply that there are really different pathogenetic pathways to the same phenotypic expression of disease. If this should turn out to be true then it might be best to divide MS into different disease categories depending upon pathogenesis. In additon to evidence favoring an immunologic basis for MS, much circumstantial evidence suggests a link 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 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 immunological attack on the latter as the body fights the infection. However the relevant ganglioside appears to be in the axon membrane and not in the myelin and the clinical picture of this type of Guillain Barre differs from that found in patients without the preceding GI infection or the antibodies to the ganglioside. If this example of molecular mimicry has nothing to do with myelin what can it have to do with MS? The answer is two fold. First remeber that when axons die the myelin aroung themn will also die. Second, as stated above, axon damage is an important aspect of MS. It was note by Charcot and then ignored and subsequently rediscovered by "modern" workers. Its basis is not understood but again we have two possible causes -the immunoligc and the infectious agent as well as the possible interactions between the two. 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. GREY MATTER LESIONS As indicated above the grey matter also displays plaques because the axons in grey matter are myelinated. The plaques may be less distinct because the myelinated axons are not arranged in compact bundles as they are in the white matter. However very recently evidence has appeared indicating that grey matter degeneration in MS may have a pathogenesis more complex than that in the white matter. Microglia appear early at the site of the grey matter lesion and stimulate increased release of glutamate--the principle excitatory neurohumoral agent--from the neurons. This increased glutamate is then associated with a decrease in the myelin and in the number of oligoglia at the lesion site. Whatever the cause, grey matter lesions play a significant role in the progression of symptoms including cognitive decline in MS. The changes in grey matter are reflected in imaging of the brain which shows atrophy as the disease progresses. REMISSIONS 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. However, inflammation in early plaques 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. MRI studies and autopsies often find so-called "silent" plaques. These are -were- producing no symptoms. Sometimes this is because they are in "silent" areas of the brain but this is not always the case. Recently it has been suggested that in such plaques the axons have developed the increase in sodium channels necessary to resume transmission even though the axons have not undergone remyelination. Sometimes MS is progressive at onset rather than remittent. Sometimes remittent MS becomes progressive. Recently it has been found that progressive MS of either type is characterized by axon damage and loss as well as myelin loss. The axon damage explains the failure to remit. Axonal loss occurs early in all forms of the disease and appears to be the basis for atrophy of the brain in MS. Two other diseases are thought to be related to MS or to be variants of that disease. DEVIC'S 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 are destroyed as well as myelin, 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 Japanese workers have found that many but not all patients with neuromyelitis optica have serum antibodies to aquaporin 4 which is contained in the feet of astrocytes-especially in the grey matter. Moreover these studies show that there is loss of aquaporin 4 in the typical ,massively destructive lesion of neuromyelitis optica but not in the typcial plaques of MS. The antibody to aquaporin 4 is detected in the destructive grey matter lesions on neuomyelitis optica. However destructive lesions also appear in the white matter and some patients have both typical demyelinated MS plaques and the more totally destroyed lesions of Devic's; the latter lesions being in the optic nerves and spinal cord. Because of the new aquaporin related findings, some workers believe that Devics [Neuromyelitis optica] can be considered a disease seperate from MS. However because some cases contain both types of lesions, Dr Rosenblum [and others] believes that the aquaporin deprived cases are still a variant of MS--probably another reflection of deranged local immunologic attack . To believe otherwise would mean that we have to give some patients two simultaneous diseases, one leading to typical MS plaques and the other to the destructive lesions of Devics in the cord and optic nerves. 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.
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