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Multiple Sclerosis : What We Now Know

Multiple sclerosis (MS) is a prototypical chronic autoimmune demyelinating disease of the central nervous system (CNS), characterized by plaques of inflammation, demyelination, and gliosis disseminated in time (DIT) and space (DIS).  The signs and symptoms depend on the location of the lesions within the brain and spinal cord. The prevalence of MS is estimated to be 100 or more persons per 100,000 in northern Europe and North America. It is twice as common in temperate regions than in the tropics.  And although the etiology is unknown, three factors enhance the occurrence of MS. The first is genetic vulnerability, the second factor is an environmental/infectious exposure, and the third is the status of the host immune system that ultimately wages the attack on the CNS.  

Genetic predisposition is an important risk factor in MS with siblings of affected patients having a 2% to 5% increased lifetime risk, and parents and children of MS patients having a 1% lifetime risk. Genetic linkage studies implicate the major histocompatibility complex and other immunoregulatory genes as important determinants of this hereditary risk. 

The critical environmental exposure occurs before age 15.  Those who reside further from the equator and are exposed to less sunlight have lower vitamin D levels placing them at increased risk of MS.  Women are affected twice as often as men, and whites have a much higher incidence rate than other races. The incidence of MS peaks in the fourth decade of life, but the disease commonly presents between ages 15 and 60. Childhood onset occurs but is uncommon. Overall, MS is the third commonest cause of disability in the United States (US) in 15- to 50-year-old individuals. 

A change in an individual’s cellular Immune status, invoking activation of T-cells and B-cells is the final determinant in the development of MS. Circulating T-cells bind to specific receptors along blood vessels of the blood brain barrier (BBB) and pass into brain tissue where they are stimulated by microglial cells to proliferate, recruiting more cells from the circulation, destroying myelin, activating B-cells, and stimulating secretion of inflammatory cytokines.  Increased levels of Th1–like cytokines in the cerebrospinal fluid (CSF) of patients with MS have been associated with progression of disease, as have cytokines released from activated T-cells that amplify the immune response within the CNS, promoting the expression of adhesion molecules on adjacent blood vessels, and up-regulating T-cells through interaction with main histocompatibility (MHC) class II molecules. A variety of inflammatory mediators, including tumor necrosis factor (TNF), oxygen radicals, nitric oxide, and other cytokines modulate axonal conduction and synaptic transmission and contribute to structural myelin damage.  Pathogenic B-cell activation is suggested by elevated CSF oligoclonal bands (OCB), increased levels of CSF immunoglobulin-G (IgG) and anti-myelin associated glycoprotein (MAG) antibody in affected patients. There is an association of MS with latent Epstein-Barr virus (EBV) infection and other viral infections based on the presence of immune activation of latent virus in active MS lesions of some patients.  
The diagnosis of MS is based upon two discrete episodes of neurological dysfunction at least 30 days apart in different locations of the CNS, alternatively, in those with one relapse who show evidence of dissemination in time and space (DIT and DIS) on MRI.  Patients with a single attack that does not meet formal criteria for MS are considered to have a clinically isolated syndrome (CIS), while those with imaging consistent with MS but discovered incidentally are considered to have a radiographically-isolated syndrome (RIS).  The diagnosis of MS is therefore based upon the demonstration of multiple lesions DIT and DIS, while excluding alternative diagnoses through clinical, radiographic, and laboratory methods.  

Treatment favorably impacts MS by employing immune modulation, enhancing myelination, improving conduction through demyelinated pathways and by providing symptomatic improvement without directly affecting the underlying pathology.  Immune modulatory therapy diminishes the activation and proliferation of immune cells and their migration into the CNS by enhancing intrinsic suppressor activity or limiting the destruction caused by inflammatory processes. Such disease-modifying medications include injectable (interferon-beta and glatiramer acetate) and oral medications (fingolimod, teriflunimode, and dimethyl fumarate), monoclonal antibodies (natalizumab and alemtuzumab) and one chemotherapeutic agent (mitoxantrone). They are all indicated for patients with relapsing and remitting MS (RRMS) still in relapses, but other than mitoxantrone, they do not have a role in the progressive phase of the illness.  In patients with newly diagnosed MS and low disease activity, most authorities suggest starting treatment as soon as possible to influence the frequency of relapses, stabilize disease activity, and lessen long-term disability.  The nonspecific immunosuppressants azathioprine and cyclophosphamide have been used frequently without clearly established efficacy.  Cladribine, mitoxantrone, antilymphocyte globulins, cyclosporine, and tacrolimus are chemotherapeutic agents with use as semi-specific suppressors of MS disease activity.  In extremely severe cases, total lymphoid irradiation may modulate the immune system, potentially benefiting MS, though controlled trials are lacking.  Several peptides are being explored that interfere with binding within the trimolecular complex (T-cell receptor, antigen, and MHC class II molecule), potentially leading to more specific agents decreasing the activity of the disease with minimal systemic immunosuppression.

Acute exacerbations are often initially treated with corticosteroids which enhance the resolution of symptoms and signs, though do not significantly affect the long-term outcome of an exacerbation.  There are no certain dosing guidelines although intravenous corticosteroids at a dose of 1g for 5 days is an appropriate course of treatment.  Pulse therapy with corticosteroids is associated with many temporary side effects such as insomnia, irritability, fluid retention, increased appetite, weight gain, hyperglycemia, hypertension, dyspepsia, depression, psychosis, bone fractures, and osteoporosis.  In patients with poor venous access or otherwise intolerable reactions to corticosteroids, adrenocorticotropic hormone can be used instead.  Plasma exchange is sometimes used in severe relapses, refractory to corticosteroids.  Therapies focused on improving conduction include 4-aminopyridine (4-AP) and 3, 4-diaminopyridine (3, 4-DAP), both potassium channel blockers, that amplify and prolong action potentials.  

Symptomatic therapy for MS is an important aspect of management. Paresthesia may respond to antidepressants and anticonvulsants.  Anticholinergic and beta blocker medications can improve bladder function. Fatigue may improve with amantadine and CNS stimulants.  There are no medications currently available to treat muscle weakness, although physical therapy can optimize muscle function.  Spasticity, muscle cramps, and spasms respond to stretching and anti-spasticity medications including baclofen, tizanidine, and benzodiazepines.   If necessary, botulinum toxin can be introduced into specific muscles, or, if generalized spasticity is refractory to other treatments intrathecal baclofen administered by an implantable subcutaneous pump or dorsal root rhizotomy may be considered. Adaptive equipment includes ankle-foot orthoses (AFO) for foot-drop dysfunction, as well as canes, walkers, and wheelchairs for mobility. Tremor may respond to a variety of medications including propranolol or primidone, although isoniazid, buspirone, trazadone, baclofen, carbamazepine, gabapentin, benzodiazepines, and unilateral thalamotomy may all be effective for refractory tremor.