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Multiple Sclerosis and Other Demylinating Disorders

Author: Dr Rhodes, Posted on Sunday, October 05 @ 00:00:00 IST by RxPG  

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Multiple sclerosis (MS)

Pathology: Inflammation destroys oligodendrocytes and myelin in acute CNS lesions, probably evolving over 1 week until symptoms are the most severe. Healed lesions follow the sudden onset with a slow resolution to a non myelinated "scar" termed a "plaque." Axons are largely spared at first, but lack of myelin and the glial scar around axons prevents normal electrical conduction. Eventually, axonal degeneration ensues, and this is now thought to be the cause of late CNS dysfunction.

Etiology: Undetermined (idiopathic), although certain human lymphocyte antigens (HLA) may be involved in an unproved manner. A person who migrates from a high risk area to a low risk area carries a high risk of MS. However, if emigration occurs prior to age 15 years, the risk is that of the country to which the person migrated. Theory: Antigen antibody reaction directed at a myelin epitope destroys myelin and its parent oligodendrocyte, and this reaction develops following childhood exposure to an unknown agent.

Current ideas on MS: MS is an autoimmune disease mediated by autoreactive CD4+ T helper cells with specificity for myelin antigens. There is probably IgG reactivity to myelin basic protein. An additional factor may be "bystander" damage from extracellular enzymes from inflammatory cells, oxygen metabolites, nitric oxide and cytokines. Normally, T cells are deleted by apoptosis, but MS patients have a specific block in apoptosis of T cells that are reactive to myelin basic protein. Also, there may be a block in killing of autoreactive T cells by cytotoxic T cells. MS is thought to result from a series of related autoimmune reactions to a variety of different disease initiators. Molecular identity of oligodendrocyte proteins and viral capsid proteins is implicated (Epstein-Barr virus, herpes simplex virus type-1, human herpesvirus type-6 and endogenous retrovirus type 9). Some T-cell clones have "degenerate" antigen recognition and do not require close sequence identity; this may allow easier autoimmune reactivity. The autoimmune reactions themselves are probably dependent upon genetic and non-genetic factors that modify the responses. The balance of genetic and environmental components may differ between patients. For instance, HLA haplotypes will differ. Environmental input is uncertain; however, molecular mimicry may follow an infection, and even twins can differ in their T-cell receptor shifts.

Clinical findings: Often described as varying in time and space. Lesion episodes occur at various times, often years apart, while anatomically widely spaced demyelinated lesions anywhere in the entire CNS give different symptoms or signs depending on the neural tissue they affect. Most patients have a series of exacerbations, each followed by remission or stabilization, leaving in its wake some evidence of permanent neurologic deficit upon which succeeding acute manifestations are superimposed. After many years, there is now thought to be an accumulation of axonal loss as well as of demyelinated plaques, and the "late onset" of chronic progressive disease is probably the result of gradual but unrelenting axonal loss over many years. Young patients may have this pathology at its early stage with symptoms not observed until they are mature. It is thought this is based on age-related maturation of immune responsiveness, with subclinical MS present until maturity. Interferon therapy is being shown to have benefit, but treatment includes a variety of measures to improve function in everyday living.

Leukoencephalopathy ("white-brain-disease," or "something wrong with the white matter"). This is an imprecise term under which many diseases can be referred to (here a few are mentioned).

Genetic dysmyelinating diseases, such as sulfatide lipidosis (metachromatic leukodystrophy), gangliosidoses (Tay Sachs disease is now variant B of GM2 gangliosidosis) & Niemann Pick disease.
Allergic demyelinating disease, often of uncertain etiology, with antibody attack of myelin or possibly immune (antigen antibody) complexes entering brain via leaky venules, attaching nonspecifically to myelin, and activating complement that lyses myelin.
Vascular disease, usually in newborns, where small infarcts or hemorrhages affect periventricular white matter ("periventricular leukomalacia").


CSF summary: Opening pressure 50 180 mm of CSF.
Appearance clear & colorless; can have 500 cells/mm3 and still be clear.
Xanthochromia (usually yellow) Traumatic tap, bilirubin, old hemorrhage.
Cells 0 10/mm3.
Polys with bacteria, lymphs with fungi & viruses.
Protein < 450 mg/L; 36 types, mostly from serum.
Glucose = two thirds concurrent blood glucose level.

Meningitis: Bacterial (including tuberculosis); fungal; viral; protozoal.

Bacterial Pus (polys) in subarachnoid space, where bacteria can gain access. In CNS parenchyma, the blood brain barrier effectively excludes bacteria.

in neonate: Gram positive cocci/Gram negative rods of skin/birth canal.
Group B hemolytic streptococci (S. agalactiae) and E. coli.
in young children: Haemophilus influenzae type b.
Neisseria meningitides (meningococcus).
Streptococcus pneumoniae (pneumococcus).
in adults: Neisseria meningitides.
Streptococcus pneumoniae.

Acid fast bacilli are increasingly multi drug resistant. M. Tbc is acquired by droplet inhalation; manageable if not resistant to known drugs. Involvement of meninges generally causes severe complications with basal fibrous scars that cause hydrocephalus.

Brain abscess A space increasing mass, clinically like a tumor, but often with an identifiable source of infection. Bacteria that cause cerebritis are attacked by neutrophils, necrosis ensues, and perivascular fibroblasts wall off bacteria, pus and necrotic brain with granulation tissue. Finally, there develops a thick fibrotic wall surrounded by reactive astrogliosis.

Seen in multiple settings:

Contiguous focus of infection: Otitis/mastoiditis.
Paranasal sinusitis.
Dental infection.
Facial and scalp infections.

Cranial trauma: Neurosurgical or accidental; abscess can occur years after traumatic event (via healed tract?).

Hematogenous: Chest or other distant focus of infection.
Congenital heart disease with right to left shunt, especially in tetralogy of Fallot.

Fungal Cryptococcus neoformans is most common mycotic cause of human basal meningitis.

Protozoal Toxoplasmic meningitis, trypanosomiasis (Chagas' disease in South America; African sleeping sickness).

Encephalitis: Generally defined as non suppurative inflammation of the brain. However, Candida and Toxoplasma have an early acute inflammatory response.

Viral Herpes simplex virus type 1, arboviruses, HIV 1, and many others.

Viral infections of the CNS: Include agents causing meningitis, encephalomyelitis, or both (meningoencephalomyelitis). The virus must gain access to the CNS past the blood brain barrier or blood CSF barrier or via retrograde axonal transport. The virus must then replicate within the CNS and produce damage to the CNS.

Herpes simplex virus type 1 (HSV 1) The most common non epidemic cause of acute encephalitis, infecting most prominently the medial temporal lobes and other limbic system regions. HSV 1 penetrates mucosae (i.e., the lip), is transported in a retrograde manner in sensory axons to their ganglia, and then to the CNS. Destroys neurons & glial cells, causing hemorrhage and necrosis. Since neocortex is involved, seizures can result.

Arboviruses Spread by insects (arthropod borne), as shown by Walter Reed in 1901. Usual hosts may be small rodents, and human infection is outside the usual cycle and is not adapted to the subclinical infection of the usual natural host. Eastern equine encephalitis virus, western equine encephalitis virus, Japanese encephalitis virus and many others, going under various classifications, cause regional outbreaks of encephalitis or meningitis.

Human immunodeficiency virus type 1 (HIV 1) Secondary replication in macrophages and hematogenous spread brings one strain into CNS perivascular spaces from which HIV infected macrophages enter CNS parenchyma. Another HIV strain preferentially infects CNS endothelial cells, probably aiding in blood brain barrier breakdown. Infection of choroid plexus epithelial cells also occurs. HIV infection of brain is early, and HIV abortively infects neurons and glial cells, causing uncertain damage. Much HIV encephalitis appears to be toxic from HIV proteins, or immune mediated responses against HIV proteins, normal brain epitopes that resemble proteins of HIV or possibly against opportunistic infections. The remainder of CNS pathology in AIDS patients is mostly from opportunistic infections and vascular pathology, the latter being a function of chronic illness of any type (pathogenesis not known). Some primary CNS lymphomas occur.

Fungal Cryptococcus neoformans, Candida, Aspergillus, Zygomyces (mucormycosis).

Protozoal Unusual except with severe immunosuppression, as in AIDS (Toxoplasma gondii).

Allergic Post measles allergic reaction (perivenous encephalitis), post vaccination or immunization. Antibodies or inflammatory reaction products (superoxides, released digestive enzymes) attack myelin and/or oligodendrocytes; seldom seen.

Prion disease:

Creutzfeldt Jakob disease (CJD) The most common form of prion (proteinaceous infectious particle) disease. No DNA or RNA has been found. The CNS disease is called spongiform encephalopathy. Not a contagious disease (no person to person spread), although ritual rubbing of dead relative's brain on the skin presumably allows prions to gain hematogenous access through small wounds (Fore people of New Guinea). Can be spread by implantation in CNS experimentally, and by hematogenous route iatrogenically with growth hormone injections. Prion is abnormal isoform of a ubiquitous cellular protein (function unknown) that must be endocytosed into a cell and bind with the normal protein isoform. It is then thought that the abnormal isoform causes conformational alteration of the normal protein into the cytotoxic isoform. This, in effect, "replicates" the abnormal isoform, and increases its number. After about 20 years, enough damage is done that symptoms appear. The abnormal isoform is non degradable by the cell and appears to split the lipid bilayer of cellular membranes, killing the cell. The immune system does not appear to recognize an abnormal amino acid sequence in prions, so there is no inflammatory response. Neurons disappear, with spongiform changes prominently seen in cerebral cortex, basal ganglia and cerebellum. Amyloid plaques may be found.

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