Multiple sclerosis is an inflammatory demyelinating disease of the CNS in which activated immune cells invade the central nervous system and cause inflammation, neurodegeneration, and tissue damage. The underlying cause is currently unknown. Current research in neuropathology, neuroimmunology, neurobiology, and neuroimaging, together with clinical neurology, provide support for the notion that MS is not a single disease but rather a spectrum. There are three clinical phenotypes: relapsing-remitting MS (RRMS), characterized by periods of neurological worsening following by remissions; secondary-progressive MS (SPMS), in which there is gradual progression of neurological dysfunction with fewer or no relapses; and primary-progressive MS (MS), in which neurological deterioration is observed from onset. Pathophysiology is a convergence of pathology with physiology. Pathology is the medical discipline that describes conditions typically observed during a disease state; whereas physiology is the biological discipline that describes processes or mechanisms operating within an organism. Referring to MS, the physiology refers to the different processes that lead to the development of the lesions and the pathology refers to the condition associated with the lesions.
Pathology
Multiple sclerosis can be pathologically defined as the presence of distributed glial scars (or sclerosis) in the central nervous system disseminated in time (DIT) and space (DIS). The gold standard for MS diagnosis is pathological correlation, though given its limited availability, other diagnosis methods are normally used. The scleroses that define the disease are the remainders of previous demyelinating lesions in the CNS white matter of a patient (encephalomyelitis) showing special characteristics, such as confluent instead of perivenous demyelination. There are three phases for how an unknown underlying condition may cause damage in MS:
An unknown soluble factor (produced by CD8+ T-cells or CD20+ B-cells), creates a toxic environment that activates microglia. MRI-abnormal areas with hidden damage appear in the brain and spine (NAWM, NAGM, DAWM). Some clusters of activated microglia, axonal transection and myelin degeneration are present. Leaks in the blood–brain barrier appear and immune cells infiltrate, causing demyelination. and axon destruction. Multiple sclerosis differs from other idiopathic inflammatory demyelinating diseases in its confluent subpial cortical lesions. These types of lesions are the most specific finding for MS, being exclusively present in MS patients, though currently they can only be detected at autopsy. Most MS findings take place inside the white matter, and lesions appear mainly in a periventricular distribution (clustered around the ventricles of the brain). Apart from white matter demyelination, the cortex and deep gray matter (GM) nuclei can be affected, together with diffuse injury of the NAWM. GM atrophy is independent of classical MS lesions and is associated with physical disability, fatigue, and cognitive impairment in MS At least five characteristics are present in CNS tissues of MS patients: Inflammation beyond classical white matter lesions, intrathecal Ig production with oligoclonal bands, an environment fostering immune cell persistence, and a disruption of the blood–brain barrier outside of active lesions. The scars that give the name to the condition are produced by astrocytes healing old lesions. MS is active even during remission periods.
Meningeal tertiary lymphoid-like structures Follicle-like aggregates in the meninges are formed only in secondary progressive MS. and correlate with the degree of subpial cortical demyelination and brain atrophy, suggesting that they might contribute to cortical pathology in SPMS These ectopic lymphoid follicles are composed mainly of EBV infected B-cells.
Demyelination patterns Four different damage patterns have been identified in patient's brain tissues. The original report suggests that there may be several types of MS with different immune causes, and that MS may be a family of several diseases. Though originally a biopsy was required to classify the lesions of a patient, since 2012 it is possible to classify them by a blood test looking for antibodies against 7 lipids, three of which are cholesterol derivatives Cholesterol crystals are believed to both impair myelin repair and aggravate inflammation. It is believed that they may correlate with differences in disease type and prognosis, and perhaps with different responses to treatment. In any case, understanding lesion patterns can provide information about differences in disease between individuals and enable doctors to make more effective treatment decisions. According to one of the researchers involved in the original research, "Two patterns (I and II) showed close similarities to T-cell-mediated or T-cell plus antibody-mediated autoimmune encephalomyelitis, respectively. The other patterns (III and IV) were highly suggestive of a primary oligodendrocyte dystrophy, reminiscent of virus- or toxin-induced demyelination rather than autoimmunity." The four identified patterns are:
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