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This is usually proceeded by a viral infection or vaccination and is thought to be due to a hypersensitivity reaction mediated by T-lymphocytes. A detailed classification of lymphocytes and their function is beyond the scope of this script but they are responsible for immune responses and are divided into two main classes: B lymphocytes produce antibodies, and T lymphocytes kill cells, particularly infected cells (i.e. they are cytotoxic) and regulate the activities of other white blood cells such as helping B cells to form antibodies. Lymphocytes are responsible for immune specificity.
It usually occurs 1-2 weeks after a viral infection in children or young adults; these infections include measles, mumps, chicken pox, german measles, influenza and infectious mononucleosis. Cases following vaccination, usually against smallpox or rabies, are referred to as postvaccinial encephalitis. Although rare, up to 20% mortality has been reported, particularly following measles infection.
The brain may be swollen and histological examination demonstrates that many small veins are surrounded by lymphocytes, macrophages and plasma cells. This is associated with demyelination and there may be perivascular haemorrhages. In the late stages the lesions are associated with marked reactive changes within astrocytes.
Figure 5
| Figure 5 is a section of brain from a patient who had developed disseminated encephalomyelitis following vaccination. Note the pale areas of demyelination surrounding veins. The section has been stained for myelin, which is dark in colour. |
Patients usually present with rapid onset of headache, vomiting and pyrexia. Symptoms relating to spinal cord involvement may predominate but there may be widespread abnormalities including motor and sensory loss, ataxia, visual impairment, variable degrees of loss of consciousness, and incontinence. It usually resolves over several weeks but some patients are left with permanent neurological defects such as weakness or sensory loss or, particularly in children, variable degrees of mental retardation.
This is a disorder of uncertain aetiology that predominantly affects middle aged or elderly patients suffering from a variety of disorders causing malnutrition and debilitation. These include alcoholism, carcinoma, chronic renal, hepatic or pulmonary disease. It is associated with marked fluid/electrolyte imbalance and often occurs when hyponatraemia low serum sodium level) is rapidly corrected. The brain shows well demarcated demyelination within the centre of the pons.
Figure 6
 | Figure 6 is a cross section of pons from a case of central pontine myelinolysis, stained for myelin. The pale area in the middle is an area of demyelination. |
Chronic alcoholics, particularly heavy drinkers of red wine, may show demyelination within the corpus callosum and white matter of the centrum ovale. Other parts of the brain and nervous system sometimes also show damage.
This disease most commonly affects patients who are immunosuppressed, particularly those with lymphoma and/or AIDS. It is due to infection of oligodendrocytes by a papovavirus virus known as the JC virus. The virus is common in the community. It results in foci of demyelination, particularly at the junction of the cortical grey matter and underlying white matter of the cerebral cortex, the white matter of the cerebellum, and brainstem. Relevant antigens may be detected in both frozen and paraffin-embedded sections. Virus particles can sometimes also be detected in the nuclei of oligodendrocytes using electron microscopy. The lesions contain the breakdown products of myelin within macrophages and astrocytes show reactive changes including the formation of bizarre pleomorphic nuclei, which can easily misinterpreted as neoplasm (tumour).
Patients present with a wide variety of neurological signs and symptoms relating to the cerebral hemispheres, cerebellum and brainstem. Lesions can usually be demonstrated on a CT scan. Most patients die within a few months although some survive several years.
This is a rare and usually fatal disorder usually proceeded by a systemic viral or respiratory infection. The aetiology is unknown. The brain shows multiple petechial haemorrhages, particularly within the white matter, seepage of fibrin through the blood vessel wall, multiple areas of perivascular haemorrhage and necrosis and variable degrees of demyelination are seen if the patient survives long enough.
Alcohol
The problem of excessive chronic alcohol intake has been referred to above. A variety of chronic lesions have been described, resulting in loss of neurons, myelinated nerve fibres and reactive gliosis. The aetiology is complex but involves vitamin deficiencies, including thiamine and nicotinic acid.
Vitamin B12
This vitamin is required for the formation of myelin and other proteins. Problems are usually associated with involvement of the spinal cord or peripheral nerves but less common disturbances include visual impairment, depression, irritability, and variable degrees of loss of intellectual function including dementia. The most common lesion is demyelination of the dorsal sensory columns and/or the cortico-spinal tracts of the spinal cord and it is usually associated with a megaloblastic anaemia.
Deficiency of the vitamin is usually a nutritional disorder, the most common of which is failure of absorption of the vitamin due to autoimmune atrophic gastritis. This results in inadequate formation of intrinsic factor by the parietal cells in the stomach, which is required for absorption of the vitamin. Other malabsorption syndromes may also be the cause.
Many metabolic diseases that have their onset early in life are due to an inherited biochemical disorder. Most of them are rare and seen mainly in paediatric practice. The classification is largely biochemical, depending upon the abnormality, which is usually an enzyme deficiency. The gene responsible for production of the enzyme is either absent or has mutated so that it no longer functions properly. This can result in disturbance of function of a variety of organs and in many cases the brain is involved. In some cases the metabolic and genetical abnormalities have not yet been established. There may even be multiple enzyme defects and there is considerable overlap in the clinical and pathological characteristics.
In the case of inherited diseases diagnosis may be particularly important to the family. In recent years diagnosis has greatly improved with the development of a wide range of enzyme assays which in many cases can be carried out on sample of blood. In some cases diagnosis can be made in utero. Diagnosis is a very complicated procedure and requires access to a specialised laboratory.
The disorders can broadly be divided into two main groups depending upon involvement of grey and/or white matter. Abnormal metabolites may be stored within neurons and other cells, in which case they are known as storage disorders", or the disease may result in damage to the white matter, in which case they are known as leucodystrophies. A more recent classification depends upon subcellular localisation of the abnormality to intracellular components such as mitochondria, lysosomes, or peroxisomes. The latter are tiny organelles found in all nucleated cells and they are particularly important in the production of cell membranes and myelin.
Inheritance is usually autosomal-recessive but a few cases show X-linked recessive inheritance. There is some variation in the incidence of different types in different ethnic groups.
Since a wide variety of cells types may contain abnormal storage products biopsies of organs other than the nervous system, such as skin, rectum and liver have proved useful. Skeletal muscle is particularly useful in the diagnosis of mitochondrial disorders. The latter, in particular, may show sporadic mutations and a few show autosomal dominant inheritance and some of the syndromes are associated with visual abnormalities.
Disorders that affect predominantly white matter usually show widespread abnormalities of myelin but there is often sparring of nerve fibres lying immediately beneath the cortical grey matter. The white matter of the cerebral hemispheres is usually affected more severely than that elsewhere but some show marked abnormalities of myelin in the peripheral nervous system. The process is predominantly a failure to produce normal myelin and should therefore be regarded as dysmyelination rather than demyelination.
Diagnosis can be extremely difficult and during life is based upon a combination of factors including age of onset, sex, ethnic group, clinical presentation (including appearance, distribution of symptoms and signs, range of organ involvement and rate of progress), family history, radiological appearances, biopsy (rectum, skin, skeletal muscle, peripheral nerve and rarely brain). Antenatal diagnosis will involve examination of chorionic villi, cultured fibroblasts from amniotic fluid, examination of foetal and/or placental tissue. Samples of fresh or frozen tissue should be sent for biochemical assay and a wide variety of histological stains are available for histological assessment. Electron microscopy will provide important information on subcellular abnormalities.
Clinical symptoms and signs vary widely within the various disorders and there is considerable overlap. Atypical cases are common and in some cases diagnosis is only obtained postmortem. Radiological appearances are important. Visual abnormalities are, however, common in some of the disorders and include blindness. A few show a cherry-red spot at the macula.
Detailed classification is too complicated to include in this script and is continually changing as new disorders are defined. For further information the leader is referred to the reading list at the end of the script.
The mitochondrial genome is a circular strand of DNA. A wide range of diseases involving mitochondria have been described, resulting from deletions and mutations of DNA and these tend to involve the brain and skeletal muscle, both of which use large amounts of energy. Abnormalities may be primary genetic defects or due to secondary mutations. No all involve the central nervous system. Some disorders of mitochondrial metabolism involve proteins that are encoded by nuclear DNA.
A variety of names, largely reflecting the clinical profile, have been used to classify them such as "mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS)", in which there may be pigmentary retinal degeneration; "mitochondrial epilepsy with ragged-red fibres (MERRF)"; "Kearns-Sayre syndrome (KSS)", and its relationship to other chronic progressive external ophtalmoplegia (CPEO) syndromes, which may show progressive external ophtalmoplegia and pigmentary degeneration of the retina; Leber's hereditary optic neuropathy (LHON), which shows abnormalities of the white matter with demyelination; neuropathy, ataxia, and retinitis pigmentosa (NARP). For a more detailed classification of these disorders the reader is referred to the reading list at the end of the script.
Identification of the precise defect is complicated and frequently requires biochemical analysis of freshly isolated mitochondria. Muscle biopsy is often performed as an aid to diagnosis and some mitochondrial abnormalities can be identified by a mixture of light microscopy, histochemistry and electron microscopy. A variety of structural abnormalities have been described but not all mitochondria are involved and not all cases show abnormalities demonstrable by these techniques.