Demyelination can be defined as a loss of myelin with relative preservation of axons. Demyelinating diseases of central nervous system(CNS) can be classified according to their pathogenesis. The categories are demyelination due to inflammatory processes, viral demyelination, demyelination caused by acquired metabolic derangements, hypoxic-ischaemic forms of demyelination and demyelination caused by focal compression. This journal review provides an overview of all these categories of demyelinating diseases in the central nervous system. Diagnosis of demyelination have important therapeutic and prognostic implications. Immunohistochemical stains, biosy specimens, clinical findings and radiological findings are the common steps used to diagnose this demyelinating diseases of CNS
Myelin sheaths are multilayered membranes which wrapped around axons. Oligodendrocytes and Schwann cells are the two main myelin supporting cells in the central and peripheral nervous system respectively. Plasma membranes in their cytoplasmic extensions undergo compaction and fusion to form the myelin lamella. However, chemical composition of myelin lamellae is similar but
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not identical to that of the plasma membranes of the myelin-supporting
cells. More importantly, myelin contains an encephalitogenic basic protein which is
capable of inducing autoimmune demyelination when injected into susceptible
Mvelin covers axons in segmental pattern. Node of Ranvier is the unmyelinated area between two myelin segments. Oligodendrocytes are responsible for the myelination of axons the central nervous system while Schwann cells myelinate axons in the peripheral nervous system. The most significant difference between these two types of myelination is that myelin segments done by Schwann cells are readily undergo repair after destruction whereas in the oligodendrocytes, a more widespread and lasting injury will occur.
Demyelination is a kind of pathologic process which happens when then the myelin sheaths are destroyed without affecting the axons. Damage to the myelin lamellae or myelin supporting cells are known to cause primary demyelination.
Demyelinating diseases of the CNS can be classified according to their pathogenesis as follows:
a) Demyelination due to inflammatory processes
b) Viral demyelination
c) Demyelination caused by acquired metabolic derangements,
d) Hypoxic'ischaemic forms of demyelination
e) Demyelination caused by focal compression
Some of these distinctions are rather simplistic such that there is overlap of pathogenesis between the each different categories. However, this classification provides a conceptual framework that are useful to diagnose accurately.
3.1 INFLAMMATORY DEMYELINATION
Multiple sclerosis, acute-disseminated encephalomyelitis (ADEM) and acute haemorrhagic leucoencephalitis (AHL) are classified into this category. Multiple sclerosis which is the commonest among the three diseases, is pathologically and pathogenetically heterogeneous. It has been divided according to clinical and pathological features into four main subtypes: classical, acute, neuromyelitis optica and concentric sclerosis.
3.1.1 Multiple sclerosis
It is thought to be caused by the combination of multiple genetic and environmental factors. The risk of developing multiple sclerosis is estimated to increase 100-fold to 190-fold if an identical twin has the disease, 20-fold to 40-fold in a full sibling, 7-fold to 13-fold in a half-sibling and 5.5-fold in an affected parent. The concordance rate is 25'30% in monozygotic twins compared with 2'5% between dizygotic twins with multiple sclerosis.i'The strongest evidence for the involvement of environmental factors in multiple sclerosis comes from prevalence and migration studies. The prevalence of multiple sclerosis varies markedly in different geographical area, from below 5/100 000 in many areas of Africa, South America and Asia, to over 100/100 000 in Scotland and parts of Scandinavia and Canada.ii'Migration before 15 years of age from a high-prevalence to a lower-prevalence area reduces the risk of developing multiple sclerosis. Migration to a higher-prevalence area between 11 and 45 years of age increases the risk of multiple sclerosis.'Genetic studies have shown linkage of multiple sclerosis to region of the major histocompatibility complex on chromosome 6p21; among northern European populations, this seems to be largely attributable to human leucocyte antigen-DR2 allele.iii
Pathological similarities between multiple sclerosis and experimental allergic encephalomyelitis, and the detection of T cells reactive against components of myelin, have been deducted as evidence that multiple sclerosis is an autoimmune disease.'As evidence to the contrary, researchers point to a failure to induce demyelination by transfer of patient serum or T cells and a lack of specific immune markers for most forms of the disease.iv Several epidemiological, serological and virological studies have suggested a role for viruses in multiple sclerosis, those most consistently implicated being Epstein'Barr virus and human herpesvirus 6.'Possible mechanisms include direct viral injury to the CNS that causes immunogenic exposure of myelin antigens and subsequent autoimmune damage to myelin, and molecular mimicry between viral antigens and myelin, whereby the immune response that is directed at the virus also results in damage to structurally homologous constituents of the myelin sheath.
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Multiple sclerosis affects twice as many women as men and most patients are between about 15 and 55 years of age at the time of initial presentation. Acute inflammatory demyelination in a patient less than 10 years of age is more likely to be due to ADEM.
The clinical manifestations of multiple sclerosis are wide ranging, with common presenting features such as weakness, paraesthesia or focal sensory loss, optic neuritis, diplopia, ataxia and vertigo. Autonomic motor abnormalities of bladder, bowel and sexual function are also common. Other manifestations includes painful muscle spasms, trigeminal neuralgia, fatigue and depression, subtle cognitive difficulties, psychiatric disturbances and seizures. Lesions can be seen on magnetic resonance imaging (MRI), and oligoclonal bands of immunoglobulins on electrophoresis of the cerebrospinal fluid (CSF). Neurophysiological investigation often display delayed visual or other sensory-evoked responses.
Multiple sclerosis variants and their pathological features
Classical multiple sclerosis
Plaques of demyelination of varied size and shape involve cerebral cortex and subcortical white and grey matter, cerebellar white matter, brain stem and spinal cord. Periventricular white matter, optic pathways and spinal cord are extensively affected. Several schemes have been proposed for subdividing plaques according to disease activity, stage and presumed pathogenesis but some of these schemes are quite complex and are primarily of use in research.v A simple practical approach depends on a combination of a myelin stain such as luxol fast blue/cresyl violet or solochrome cyanin, a macrophage marker such as antibody to CD68 and a stain for axons such as Palmgen silver impregnation or immunohistochemistry for neurofilament proteins to subdivide plaques into the following:
-The macrophages contain myelin debris, which can be observed with suitable stains.
* -Silver impregnation or immunohistochemistry for neurofilament proteins usually shows reduce in the density of axons.
-However, it includes a peripheral zone that is densely infiltrated by lipid-laden macrophages, within some of which myelin debris can usually be visualised.
Astrocytic gliosis in plaques is usually shown in sections stained with haematoxylin and eosin, but can be observed more clearly by immunolabelling the astrocytes'for example, with antibody to glial fibrillary acidic protein.
A combination of different plaque types is diagnostic for multiple sclerosis. Other features strongly suggestive of multiple sclerosis include:
-plaques of variable size and shape
-markedly asymmetrical cerebral
-cerebellar or brain stem involvement
-plaques in the cerebral cortex (especially in the subpial region), deep cerebral grey matter or spinal cord
When demyelination is not due to multiple sclerosis, clinical history is usually the strongest indication. Although a precise diagnosis can also be made on the basis of the neuropathological findings at autopsy, this is not the case for small biopsy specimens.
Acute (Marburg-type) multiple sclerosis
This term refers to a rare, fulminant variant of multiple sclerosis. It is believed, based on anecdotal evidence, to affect primarily in children and young adults. Some patients diagnosed with this disease may also had aggressive forms of ADEM before. vi'This designation may also overlap acute inflammatory demyelination presenting as a space-occupying lesion.vii
Neuromyelitis optica (Devic's disease)
This variant is characterised by the formation of optic neuritis and acute transverse myelitis within days, weeks or occasionally months. Most patients with this type of multiple sclerosis present with visual loss and subsequently develop paraplegia and sensory loss. Neuromyelitis optica is pathogenetically distinct from most other types of multiple sclerosis because the demyelination is antibody dependent and complement mediated.'During the acute disease, the CSF contains a lot of polymorphonuclear leucocytes. Oligoclonal bands of immunoglobulins are much less often seen in neuromyelitis optica when compared to other types of multiple sclerosis,'and the serum of many petients contains autoantibodies with high specificity for the disorder.viii
The disease usually results in extensive demyelination of optic nerve and of the affected segments of the spinal cord. During the acute phase, the cord is swollen and includes an infiltrate of foamy macrophages, perivascular neutrophils and eosinophils, but relatively few T cells. Immunoglobulins, especially IgM, and C9neo antigen are often immunohistochemically demonstrable in the vicinity of small blood vessels.ix'The vessel walls become thickened and fibrotic. In patients who survive the acute stage, the spinal cord often shows considerable axonal degeneration, which may be due of additional ischaemic damage due to the combination of oedema and microvascular changes. Affected segments of cord are often severely gliotic and atrophic and multiple sclerosis plaques are usually present elsewhere in the CNS, but may be small and sparsely distributed.
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Acute neuromyelitis optica (Devic's disease)
(A) The arrows show perivascular accumulation of foamy macrophages in affected cord. Note the hyaline thickening of blood vessel walls.
(B) The arrows show oedematous demyelinated tissue which contains scattered eosinophils.
(C) The immunohistochemical demonstration of perivascular immunoglobulin M in demyelinated spinal white matter.?
Concentric sclerosis (Bal's sclerosis)
This rare and unmistakable variant of multiple sclerosis is characterised by lesions composed of alternate bands of demyelinated and myelinated white matter, forming concentric rings or irregular stripes. Concentric sclerosis is often rapidly progressive but the distinctive lesions may be admixed with other, typical plaques and can occur in chronic multiple sclerosis. Macrophages and microglia in the bands of demyelination release mediators of oxidative stress, such as nitrous oxide and superoxide, causes protective preconditioning of oligodendrocytes, which is therefore preserved from demyelination as the inflammatory process spreads outwards until it reaches the next region with oligodendrocytes that are still susceptible.
Concentric sclerosis (Bal's sclerosis).
A horizontal section through the pons and adjacent part of the cerebellum includes several Bal'-type plaques, composed of zones of demyelination intersected by irregular stripes of myelinated tissue that has been stained dark grey or black. Dn means dentate nucleus; v means vermis.?
3.1.2 Acute-disseminated encephalomyelitis
This inflammatory demyelinating disease mainly affects children and typically occurs within 3 weeks of infection, vaccination or giving drugs, and is thought to be due to a T cell hypersensitivity reaction.'Viral infections such as measles, mumps, varicella, rubella or infectious mononucleosis are often responsible for this infection, but'Mycoplasma pneumoniae,Campylobacter jejuni, group A streptococci or other bacteria are sometimes the causative agents. Vaccination is a less common antecedent, and drug-induced ADEM is also rare. The incidence of recorded ADEM is about 0.4/100 000/year, but this is probably underestimated as in children with encephalopathy the diagnosis is readily missed unless MRI is carried out.x
The most prominent clinical features of ADEM are usually ataxia, headache and weakness.'Other manifestations include vomiting, slurring or impairment of speech, extraocular or other cranial nerve nerve palsies, agitation, seizures, lethargy, delirium and stupor. About 80% of patients make a full recovery. Although ADEM is classically a monophasic disease, relapses have been reported in 5'10% of cases; if relapse occurs on more than one occasion, a diagnosis of multiple sclerosis rather than multiphasic disseminated encephalomyelitis is more accurate.xi
The lesions are usually present bilaterally, although not exactly symmetrically, within the cerebral white matter and brain stem, and sometimes the cerebellum and spinal cord. Lymphocytes, macrophages and occasional plasma cells surround the small veins and venules in the affected white matter. A sleeve of adjacent white matter is oedematous and demyelinated and occasional foci of demyelination may be more extensive. Arteries and arterioles are relatively free of inflammation but there may be small perivascular haemorrhages and some axonal fragmentation.
3.1.3 Acute haemorrhagic leucoencephalitis
This rare, usually fatal, disease is thought to be a hyperacute variant of ADEM and may be preceded by viral or'M pneumoniae'infection. Other rare associations are ulcerative colitis, Crohn's disease, septicaemia and some drugs. There is no obvious precipitant in many patients.
A typical presentation of acute haemorrhagic leucoencephalitis are pyrexia, headache, vomiting, multifocal neurological deficits and seizures, progressing within 2 or 3 days through drowsiness and coma to death. The outcome is usually death or severe disability, but there is good recovery after aggressive medical and surgical reduction of raised intracranial pressure and after giving intravenous immunoglobulin.xii
The abnormalities are more asymmetrical than those in ADEM and may be confined to a single lobe or hemisphere. Affected parts of the brain are oedematous and contain parenchymal blood vessels. These vessels have undergone fibrinoid necrosis and are surrounded by zones of demyelinated, acutely haemorrhagic or necrotic tissue, containing neutrophils, mononuclear inflammatory cells and nuclear debris. Ring-shaped and ball-shaped haemorrhages often predominate, and should be distinguished from the scattered petechial haemorrhages that may result from microemboli, especially fat emboli and coagulopathies.
Acute haemorrhagic leucoencephalitis. The biopsy from a patient with a suspected glioblastoma shows perivascular demyelination, centred on a small blood vessel with a narrow surrounding zone of necrosis. The lower edge of the figure is a collection of mononuclear inflammatory cells and nuclear debris. There is a small ball-shaped haemorrhage.?
3.2 VIRAL DEMYELINATION
3.2.1 Progressive multifocal leucoencephalopathy
Progressive multifocal leucoencephalopathy (PML) is the principal viral demyelinating disease in humans. It is caused by the papovavirus or JC virus. Approximately 50% of adolescents and 75% of adults have serological evidence of JC virus infection, but it is usually asymptomatic. B cells, kidney and CNS are the common site for virus to establishes latent infection. Condition of impaired cell-mediated immunity such as after organ transplantation and AIDS is more likely to allow virus reactivation.xiii
Clinical features found in patients are insidious onset of neurological deficits that often affect motor function, speech, vision, personality and cognition. Conventional examination of the CSF is unable to show abnormality, but polymerase chain reaction (PCR)xiv can detect the JC viral nucleic acids. In'MRI, multiple small lesions in the white matter can be seen, but their size may increase rapidly, and occasionally end up with mass effect.'PML was usually a rapidly progressive fatal disease until recent years. Even so, successful reversal of impairment of cell-mediated immunity such administration of antiretroviral drugs to patients with AIDS, can lead to remission of PML.
Pathological findings are shown in affected white matter which contains multiple foci of demyelination. Small round foci of demyelination with good preservation of axons are often found along the junction between cerebral cortex and white matter. There are abundant of foamy macrophages, but lymphocytes are sparse in number. In more advanced disease, the white matter contains large, confluent foci, some with central cavitations. Located at the periphery of foci of active demyelination are oligodendrocytes with enlarged nuclei that contain homogeneous amphophilic inclusions. The demyelinating lesions also contain large astrocytes with bizarre, pleomorphic, hyperchromatic nuclei. The oligodendroglial inclusions and bizarre astrocytes are both immunopositive for papovavirus. In chronic disease, especially after successful treatment of the underlying immunosuppression such as in AIDS patient, the lesions may lack viral inclusions or antigen. Administration of highly active antiretroviral treatment to patients with AIDS and PML may cause a lymphocytic inflammatory response to the virus and exacerbation of the disease.xv
3.2.2 Other viral demyelinating diseases
HIV infection can cause a range of white matter abnormalities which include microglial nodule or multinucleated giant cell encephalitis, diffuse leucoencephalopathy and vacuolar myelopathy. In addition, patients with AIDS receiving highly active antiretroviral treatment may occasionally develop severe inflammatory demyelination that is not cause by PML.xvi'There is an intense perivascular inflammatory infiltrate of lymphocytes and macrophages and viral RNA is usually abundant.
Subacute sclerosing panencephalitis, due to measles virus can cause perivascular inflammation and gliosis of white matter, as well as grey matter. This can be associated with patchy or extensive loss of myelinated fibres. Axonal loss is usually commensurate with that of myelin but, axons are sometimes relatively preserved particularly towards the edges of severely affected white matter. Measles virus intranuclear inclusion bodies may be seen, but tend to be less. In most of the cases the clinical and serological findings are diagnostic, and viral RNA can be detected by PCR.
Rarely, in patients with AIDS, varicella-zoster virus causes multifocal lesions in cerebral white matter. Viral inclusions and antigen can be seen in oligodendrocytes of the patient.
3.3 ACQUIRED METABOLIC DEMYELINATION
The most common diseases in this category are central pontine myelinolysis (CPM) and extrapontine myelinolysis (EPM) respectively. Very rarely, demyelination occurs due to chronic alcoholism and malnourishment such as Marchiafava'Bignami disease.
CPM is a monophasic demyelinating disease that occurs in the pons and lower midbrain. It mostly occurs in association with alcoholic liver disease or correction of hyponatraemia, especially if the hyponatraemia is marked and the correction rapid.xvii'Another clinical context in which CPM is increasingly common is in patients with liver transplant, in whom high ciclosporin levels may play a role.'CPM rarely happens in patients who are normonatraemic or hypernatraemic. Approximately 25'50% of patients with CPM also have EPM; the cerebellum is usually affected but may also involves parts of the cerebrum. The demyelination is exclusively extrapontine in up to 25% of patients.
The clinical presentation is usually rapid onset of confusion, mutism and limb weakness which often progress to spastic tetraparesis. Other frequent manifestations include dysphagia, ataxia and hypotension. Movement disorders such as dystonia, choreoathetosis and parkinsonism occur in some patients and are probably related to EPM. With good supporting medical care, most patients with CPM and EPM now survive the acute disease, but many have residual neurological deficits.
CPM affects the base of the pons which is usually central or symmetrical, but also can be neither. On the other hand, EPM usually affects the cerebellar folia but can affect the lateral geniculate body, capsula externa or extrema, superficial subcortical cerebral white matter, basal ganglia, thalamus, or internal capsule; with the lesions to be approximately symmetrical. The lesions are sharply demarcated. During active disease, the lesion contain sheets of lipid-laden macrophages and large numbers of reactive astrocytes. However, infiltration by lymphocytes is sparse or absent and axons and neurones are mostly well preserved. In patients with multiple foci of pontine or extrapontine demyelination, all lesions are of the same age and demyelinating activity , which is unlike those in multiple sclerosis. The presence of symmetrically spared 'islands' of myelinated white matter is common in CPM. On the other hand, this is not a feature of multiple sclerosis. Occasionally, suboptimal fixation can impair staining of myelin in the central part of the pons, and therefore appears to be demyelination. However, the lack of foamy macrophages and poorly defined outline of the 'demyelination' will be able prevent confusion with CPM.
Central pontine myelinolysis or CPM. (A) Typical central demyelination at the base of the pons. (B) The demyelination (arrows) is neither central nor exactly symmetrical. Luxol fast blue and cresyl violet are used as staining material.
3.4 HYPOXIC'ISCHAEMIC DEMYELINATION
As a result of hypoxia or ischemia, brain tissue generally undergoes necrosis rather than demyelination. However, in some circumstances the myelinating oligodendrocyte bears the damage of the hypoxia or ischaemic.
The Subcortical white matter often shows ischaemic damage in patients with severe small vessel cerebrovascular disease and hypertension. In most of the time, these patients develop dementia with superimposed focal neurological deficits which are related to lacunar infarcts. Pathological investigation shows marked arteriosclerosis and arteriolosclerosis, particularly within the deep cerebral white matter. These tend to be hypocellular, but may contain little to moderate numbers of foamy macrophages. Lymphocytic inflammation is not a feature in this condition.
Global brain hypoxia due to cardiac arrest, asphyxia or depression of cardiorespiratory function by drug overdose rarely causes a leucoencephalopathy with relative sparing of grey-matter structure.xviii'The damage is predominantly necrotic, but there may be some demyelination.
Exposure to carbon monoxide, which leads to hypoxaemia by binding to haemoglobin with greater affinity than oxygen, can cause damage to white matter as well as grey matter structures. White matter damage becomes significant only in patients who survive the acute intoxication. The level and duration of exposure will determine the likelihood of sustaining this damage. The subcortical U fibres in arcuate zone tend to be spared. The deep cortical white matter is diffusely rarefied and gliotic. This is due to a mixture of axonal degeneration and demyelination. In small vessel cerebrovascular disease, the demyelinated white matter may contain foamy macrophages but shows decrease in the number of oligodendrocytes.
Mitochondrial toxins, such as hydrogen sulphide and cyanide,' rarely cause 'histotoxic' hypoxia. Demyelination resembling that in multiple sclerosis can also happen in those subtypes of the mitochondrial disease Leber's hereditary optic neuropathy that are caused by the G11778A'or T14484C mutation'in mitochondrial DNA.xix
White matter damage as a result of carbon monoxide poisoning. The deep white matter appears rarefied. However, the subcortical U fibres are relatively spared.?
3.5 COMPRESSION-INDUCED DEMYELINATION
This is rarely encountered in routine diagnostic neuropathology.
Routine diagnostic neuropathology rarely encounter this type of demyelination. It is best documented in those compression-induced demyelination that causes trigeminal neuralgia. The trigeminal nerve root fibres are compressed by an overlying artery or vein, approximately the zone of entry of the nerve root into the pons.
This results in a focal region of non-inflammatory demyelination in the proximal part of the nerve root where the compression has occurred.'It is found that there are often groups of demyelinated fibres in close juxtaposition. They allow non-synaptic, direct transmission of nerve impulses from one to another.xx
In conclusion, accurate interpretation of the pathological findings in demyelination depends on the knowledge on the results of clinical, radiological and other laboratory investigations. This is very important when it comes to interpreting and making best diagnostic use of the biopsy material. Other details such as the age of the patient, signs and symptoms, the course of disease, presence or absence of a preceding illness, number and distribution of lesions within the CNS, electrolyte concentrations, and results of CSF examination may all be relevant in making the diagnosis.