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Multiple Sclerosis – Pathophysiology, Classification


  • Demyelination results in disordered transmission of nerve impulses.
  • Inflammatory changes lead to scarring of the affected nerve fibers.

Blood-brain barrier breakdown

The blood brain barrier is a capillary system that should prevent entrance of T cells into the nervous system. The blood–brain barrier is normally not permeable to these types of cells, unless triggered by infection or a virus, which decreases the integrity of the tight junctions forming the barrier. When the blood–brain barrier regains its integrity, usually after infection or virus has cleared, the T cells are trapped inside the brain.


MS is currently believed to be an immune-mediated disorder mediated by a complex interaction of the individual’s genetics and as yet unidentified environmental insults. The immune system attacks the nervous system, possibly as a result of exposure to a molecule with a similar structure to one of its own.


MS lesions most commonly involve white matter areas close to the ventricles of the cerebellum, brain stem, basal ganglia, spinal cord and optic nerve. The function of white matter cells is to carry signals between grey matter areas, where the processing is done, and the rest of the body. The peripheral nervous system is rarely involved.

More specifically, MS destroys oligodendrocytes, the cells responsible for creating and maintaining a fatty layer—known as the myelin sheath—which helps the neurons carry electric signals. MS results in a thinning or complete loss of myelin and, as the disease advances, the cutting (transection) of the neuron’s extensions or axons.   When the myelin is lost, a neuron can no longer effectively conduct electric signals. A repair process, called  remyelination takes place in early phases of the disease, but the oligodendrocytes cannot completely rebuild the cell’s myelin sheath. Repeated attacks lead to successively fewer effective remyelinations, until a scar-like plaque is built up around the damaged axons. Different lesion patterns have been described.


Apart from demyelination, the other pathologic hallmark of the disease is inflammation. According to a strictly immunological explanation of MS, the inflammatory process is caused by T cells, a kind of lymphocyte. In MS, T cells gain entry into the brain via the previously described blood brain barrier. Evidence from animal models also point to a role of B cells in addition to T cells in development of the disease. The T cells recognize myelin as foreign and attack it as if it were an invading virus. This triggers inflammatory processes, stimulating other immune cells and soluble factors like cytokines and antibodies. Leaks form in the blood–brain barrier, which in turn cause a number of other damaging effects such as swelling, activation of macrophages, and more activation of cytokines and other destructive proteins.


Several subtypes, or patterns of progression, have been described. Subtypes use the past course of the disease in an attempt to predict the future course. They are important not only for prognosis but also for therapeutic decisions. In 1996 the United States National Multiple sclerosis Society standardized four sub-type definitions:

  1. Relapsing remitting,
  2. Secondary progressive,
  3. Primary progressive, and
  4. Progressive relapsing.

The relapsing-remitting subtype

  • Characterized by unpredictable relapses followed by periods of months to years of relative quiet with no new signs of disease activity (remission).
  • Deficits suffered during attacks may either resolve or leave sequelae, the latter being more common as a function of time.
  • This describes the initial course of 80% of individuals with ms.
  • When deficits always resolve between attacks, this is sometimes referred to as benign ms, although patients will still accrue some degree of disability in the long term.
  • It usually begins with a clinically isolated syndrome (CIS). In CIS, a patient has an attack suggestive of demyelination, but does not fulfill the criteria for multiple sclerosis. However only 30 to 70% of persons experiencing CIS later develop MS.
  • Relapsing remitting (RR) clearly defined acute attacks evolve over days to weeks. Partial recovery of function occurs over weeks to months. Average frequency of attacks is once every 2 years and neurologic stability remains between attacks without disease progression. (At the time of onset, 90% of cases of MS are diagnosed as RR.)

Secondary progressive MS

  • Sometimes called “galloping MS”
  • Describes around 65% of those with an initial relapsing-remitting MS, who then begin to have progressive neurologic decline between acute attacks without any definite periods of remission.
  • Occasional relapses and minor remissions may appear.
  • The median time between disease onset and conversion from relapsing-remitting to secondary progressive MS is 19 years.
  • Secondary progressive (SP) always begins as RR but clinical course changes with declining attack rate, with a steady deterioration in neurologic function unrelated to the original attack. (Fifty percent of those with RR will progress to SP within 10 years; 90% will progress within 25 years.)

The primary progressive subtype

  • Describes approximately 10–15% of individuals who never have remission after their initial MS symptoms.
  • It is characterized by progression of disability from onset, with no, or only occasional and minor, remissions and improvements.
  • The age of onset for the primary progressive subtype is later than for the relapsing-remitting, but similar to mean age of progression between the relapsing-remitting and the secondary progressive.
  • In both cases it is around 40 years of age.
  • Primary progressive (PP) characterized by steady progression of disability from onset without exacerbations and remissions. More prevalent among males and older individuals. Worst prognosis for neurologic disability. (Ten percent of cases of MS are diagnosed as PP.)

Progressive relapsing MS

  • Describes those individuals who, from onset, have a steady neurologic decline but also suffer clear superimposed attacks.
  • This is the least common of all subtypes.
  • Progressive relapsing (PR) the same as PP except that patients experience acute exacerbations along with a steadily progressive course. (Rarest form)

Multiple sclerosis also behaves differently in children, taking more time to reach the progressive stage. Nevertheless they still reach it at a lower mean age than adults.