Multiple Sclerosis

Multiple Sclerosis

Multiple Sclerosis.

Multiple sclerosis is a devastating illness, it affects the majority of women in their prime soon after the birth of a child, robbing their happiness, finance, and family lives, and produce lifelong disabilities, often patients are bedridden or wheelchair bound. It is an autoimmune disease but what triggers the misdirected immune response is still unknown. Recent advances, in new blood and cerebrospinal fluid tests and refinements in neuroimaging, made early detection of the disease possible and newer drug therapies have increased the odds of reversing or preventing the progression of the disease.

For centuries physicians were treating patients with symptoms which we know today as Multiple Sclerosis (MS) but they had no idea about the nature of the illness was, until in 1868 a French physician Dr. Jean Martin Charcot demonstrated scar tissue, which he called plaques, in the brain and spinal cord at the postmortem examination of one of his patients and correlated sites of lesions with patient's symptoms. In 1828 Dr. Louis Ranvier discovered that Oligodendrocytes produced Myelin, the insulating layer around the axon (nerve fiber), which was destroyed in MS and caused patients' symptoms. Dr. Thomas River identified immune cells that actually destroyed the myelin and subsequently, the immune cells were known as B cells and T cells. This led the way to huge excitement in MS research and the discovery of new drugs was possible. It was subsequently proved that T cells not only damaged the myelin but also the axon and the nerve cells as well, explaining the development of permanent disabilities in MS patients.

Most recent research indicates that MS autoimmune disease is related, if not the actual cause, to the two different metabolic paths the tissue resident T-cells can take. In normal people, the tissue resident T-cells use fatty acid- Oleic acid as the energy source in the suppression of excessive inflammatory activities. In MS patients the Oleic acid content of fatty tissue is deficient. Published reports show EB virus infection triggers immune reactions which are misdirected to myelin and destroy it.

One of the three ways patients may present with Multiple Sclerosis (MS).

Relapsing and Remitting: This is the usual presentation. Sudden onset of some or all of the following symptoms - difficulty in focusing, double vision, difficulty in maintaining balance, weakness of legs or clumsiness of movements of hands, various sensory disturbances of the limbs and trunk. Then a period of steady improvement for months or years, then a return of the same symptoms and more new symptoms appear. And the pattern then repeats at intervals. Difficulty in voiding and retention of urine usually accompany.

Secondary Progressive: in some of the above groups of patients years later a change in the behavior of the illness results in a steady deterioration of the condition without any remission in between attacks. 

Primary Progressive: This type of presentation is less frequent. From the onset, symptoms are progressive and relentless. Severe disability followed by early death is common.

Another type of MS is known as Devic's disease, patients present with sudden blindness or no vision in the center of the visual field and are associated with loss of movement of both lower extremities with sensory loss of both lower limbs (transverse myelitis).

Laboratory Tests:

The cerebrospinal fluid (CSF) shows an increase in immunoglobulin concentration, an increase in cell count of mixed cell types (pleocytosis) and a narrow spike of gamma globulin on electrophoresis (oligoclonal band). CSF cytokines CXCL13, TNF and IFNy are elevated in relapsing recurrent MS patients. Recently, various degradation products of myelin have been found in blood tests. These are, however, also seen in a few other diseases of CNS.

Neuroimaging:

MRI is the most sensitive modality to detect damaged myelin sheath of the brain and the spinal cord in MS. Multiple areas of lesions of varying sizes and ages should be present. Lesions are located in the white matter above the caudate nucleus, around the ventricles, cerebellum and the long tracts, both motor and sensory tracts of the spinal cord and optic nerves. MRI images are several types -T1, T2 weighted images, gadolinium enhanced images are many others. These special images are taken to increase the sensitivity and specificity of the test.

Evoke Potential Tests:

Delays in response to visual, auditory, somatic sensory stimulation are observed in this test by attaching recording electrodes to appropriate points on the skull. In MS visual evoked potential test is usually positive even when patients may not have eye symptoms.

Diagnosis:

Relapse and remitting features of the disease, spastic paralysis, urinary retention, gait and balance disturbances, pleocytosis and oligoclonal band in the CSF with MRI of the brain and spinal cord showing evidence of multiple lesions of varies stages of development should make the diagnosis of MS with confidence. Certain infections of CNS like Lyme disease, HIV, syphilis, should be excluded. Lupus, Sjogren syndrome, lymphoma and subacute combined degeneration of the spinal cord from vitamin B12 deficiency should not be confused when making MS diagnosis.

Treatment:

There are increasing numbers of new drugs available for targeted therapy – to induce remission of an acute attack, prevent the progression of the disease and reduce the frequency of attacks.

For remission of acute attacks:

Intravenous Methylprednisolone is given for 1 to 3 days followed by oral prednisone in high doses until symptoms abate then the dose is slowly reduced.

Plasma Exchange:

The blood of the patient is withdrawn and the plasma is separated from the cells, the plasma is discarded, the cells are transfused back into an albumin solution. It is done in cases where IV steroid therapy is ineffective.

Disease Modifying Therapy (DMD): These are very briefly discussed under the heading - by injection and by oral route.

Drugs are given by subcutaneous injections or IV.
Glatiramer Acetate. It is a synthetic protein containing 4 basic antigenic amino acids of myelin. When injected in patients it attracts immunocytes CD4, CD8 and T cells and thus spares the myelin sheath from inflammatory effects; it also increases Thymic 2 T cells in the CNS which act as a suppressor of inflammation. Side effects are local reactions at the injection sites, flashing, chest pain and GI disturbances.

Interferon Beta: it is a polypeptide. It is normally produced by fibroblasts; for medical use, it is manufactured by engineered E. coli. When injected, it binds with the receptors on the surface of cells then directs the production of cytokines which results in a reduction of Thymic 17, a subset of T lymphocytes. It decreases the entry of immune cells into the brain and facilitates healing. Side effects are fever and chills like flu, and local reactions at the injection site, anxiety, and irritability.

Humanized monoclonal antibody:

Four drugs of this group are approved for use in recurrent relapsing MS and primary progressive MS.

1. Natalizumab. It is an alpha 4 integrins blocker on the lymphocyte surface, preventing it from binding with the endothelium of CNS blood vessels, preventing them from crossing the blood-brain barrier. Patients receiving it must be negative for the JCV antibody test, otherwise, progressive multifocal leukoencephalopathy (PML) may follow. An increased incidence of melanoma transformation of cutaneous nevus is seen.

2. Rituximab. It is an anti CD20 antibody. It causes apoptosis of beta cells of the circulation; decreases complement and cellar cytotoxicity. Side effects are patients become susceptible to infections and thrombotic events.

3. Ocrelizumab. It is also an anti CD20 antibody.

4. Alemtuzumab. It binds with CD52, expressed on the surface of T and B lymphocytes, macrophages and eosinophils. Its use is associated with the reactivation of CMV, listeria meningitis, ITP (Idiopathic Thrombocytopenic Purpura), nephropathy and low TSH.

Oral agents:

Fingolimod. It is a sphingosine 1 phosphate analog (S1P). It binds with receptors expressed on the surface of B and T lymphocytes. The fingolimod then degrades the receptors and prevents the release of lymphocytes from the lymph nodes. As a result, T and B  lymphocyte cell numbers decrease in blood and CNS. It also decreases Thymic 17 cells. Fingolimod crosses blood brain barrier and protects neurons and helps repair damaged tissues.

Side effects: Headache, rise in liver enzymes, macular edema, increased chance of infections.

Teriflunomide. It interrupts the pyrimidine synthesis of T and B lymphocytes. It blocks inflammatory response. Side effects are headaches, raised liver enzymes, alopecia, and nausea. It is teratogenic and should not be used in pregnancy.

Dimethyl fumarate. It decreases memory T cells and lowers Thymic 1 and Thymic 17 memory cells thereby proinflammatory activities are decreased and also activates Th2 anti-inflammatory cell population. Side effects are flushing, abdominal pain, skin rashes and itching, lymphopenia and an increased chance of PML.

Cladribine. An orally administered purine nucleotide analog. It is cytotoxic to lymphocytes. Side effects are Hairy cell leukemia, reactivation of tuberculosis, and teratogenic to developing fetus.

Many other S1P agents are in various stages of development and approval from FDA.

Besides the specific treatment of the primary cause of MS, several associated disabilities and complications have to be managed properly and adequately. These are not discussed here.
Recent animal experiments have shown that damaged axion of nerves can be repaired by Metalloprotease 4, an analog of human Metalloprotease 17, by stabilizing Fusogen EFF-1 at the damaged site and then beginning repairs. 

High-efficacy therapies included rituximab, ocrelizumab, alemtuzumab, mitoxantrone, and natalizumab.

The window of therapeutic opportunity refers to the first 5 years of the disease when inflammation is highest.
The benefits of early high-efficacy treatment seemed to continue past the time when all patients were on high-efficacy treatment.

 

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