MULTIPLE SCLEROSIS

MULTIPLE SCLEROSIS

A 32-year-old woman comes to the emergency department complaining of numbness and tingling in her right hand. Her symptoms began several days ago and have worsened over the last several hours. She states that 3 years ago she had an episode of “seeing double” that lasted 2 days and resolved on its own. Physical examination is significant for hyperreactive reflexes bilaterally in her lower extremities. Increased spasticity is also noted in her lower extremities.

Definition. An autoimmune inflammatory disease of the CNS white matter characterized by a relapsing or progressive course.

Etiology. The cause of multiple sclerosis (MS) is thought to be multifactorial. There is evidence that genetic susceptibility plays an important role. The disease occurs primarily in female pop- ulations of Northern European descent and of child-bearing age, respectively. This implies a role for some sort of environmental trigger (infectious, dietary, climatic). Pathologically, focal areas of demyelination are characteristic of the disease.

Clinical Presentation. Commonly, patients will present complaining of weakness, numbness, tingling, or unsteadiness of a limb. Urinary urgency or retention, blurry vision, and double vision are all common initial manifestations of the disease. Symptoms may persist for several weeks or may resolve spontaneously over a few days.

There are several forms of  the disease that may change the course of  management and    are therefore important to recognize. Most patients will have a months-long to years-long disease-free period after their first exacerbation.

• Relapsing remitting disease: progression is characterized by relapses of active dis- ease with incomplete recovery during the periods of remission

• Secondary progressive disease: progression becomes more aggressive so that a con- sistent worsening of function occurs

• Primary progressive disease: symptoms are progressive from the onset of disease with the early onset of disability (least common form)

It is important to understand when the diagnosis of multiple sclerosis should be suspected. Classically, the diagnosis is made clinically when a young patient (usually age <55) presents with a history of multiple neurologic complaints that cannot be explained by the presence of one CNS lesion. In other words, suspect the diagnosis when a patient presents with multiple neurologic deficits separated by time and space (anatomy).

A number of triggers are known to exacerbate the disease. Infections  or  trauma  may acutely worsen the disease. Pregnancy, especially the 2 to 3 months following birth, may also exacerbate symptoms. However, there are generally fewer attacks during the pregnancy. Uncomplicated MS typically has no adverse effects on the outcome of the pregnancy.

Diagnosis. To diagnose MS you have to rely on clinical criteria supplemented with radiologic and laboratory confirmations. The advent of MRI scanning of the brain has dramatically changed the methods by which multiple sclerosis is diagnosed.

MRI of the brain is the most accurate test to diagnose MS, reaching a sensitivity of 85 to 95% in symptomatic persons. Increased T2 and decreased T1 intensity represent the increased

water content of demyelinated plaques in the cerebrum and spine. Enhancement of lesions with gadolinium indicates active MS lesions that may enhance for up to 2 to 6 weeks after an exacerbation. MS is an unusual disease in that the best initial test for the diagnosis is also the most sensitive one, namely MRI of the brain and spine.

Evoked response potentials detect slow or abnormal conduction in response to visual, audi- tory, or somatosensory stimuli. The limitation of this test for the diagnosis of MS is that many other neurologic diseases can give an abnormal result. The test is not specific for the diagnosis of MS. As a result, evoked potentials are rarely used to make the diagnosis.

Cerebrospinal fluid (CSF) analysis usually reveals a mild pleocytosis (usually <50 cells/L) and a total protein that is mildly elevated. A protein level exceeding 100 mg/dL is unusual and should be considered as evidence against the diagnosis of MS. An elevated IgG index (oligo- clonal bands) is found in 70 to 90% of patients with MS. The finding is nonspecific, and as a result, CSF for oligoclonal banding is recommended only when the MRI is nonconfirmatory but clinical suspicion for MS remains high.

Treatment. The treatment of multiple sclerosis can be divided into disease-modifying therapy, treatment of complications, and treatment for symptomatic relief during an acute exacerba- tion. The specific agents used depend on progression of the disease at the time of diagnosis.

In relapsing-remitting disease, there are 3 disease-modifying agents that have been shown to reduce the number of clinical exacerbations and the number of MRI lesions:

• Interferon-1a

• Interferon-1b

• Glatiramer acetate

More importantly, these medications seem to delay the onset of significant disability. Glatiramer is also known as copolymer I.

In secondary progressive disease, interferon-1b and mitoxantrone have been shown to reduce the number of exacerbations, decrease MRI activity, and delay onset of disability. In patients who receive mitoxantrone, dose-related cardiotoxicity is a concern; mitoxantrone should be given only to patients with a normal ejection fraction. Mitoxantrone is not a first-line agent to prevent disease progression because of its cardiotoxicity. In patients with relapsing-remitting disease or secondary progressive disease who cannot tolerate treatment with IFN-1b, IFN-1a, or glatiramer acetate, you can consider treatment with methotrex- ate, mitoxantrone, cyclophosphamide, intravenous immunoglobulin, or azathioprine. ACTH is no longer used.

No approved disease-modifying therapy exists at this time for primary progressive disease. Mitoxantrone, cyclophosphamide, and natalizumab are not used for a first episode of disease.

Natalizumab is associated with progressive multifocal leukoencephalopathy (PML).

The length and intensity of an acute exacerbation is shortened by the administration of gluco- corticoids. Typically, an acute exacerbation is treated with 3 days of intense intravenous steroids followed by a course of oral medication tapered over 4 weeks. In patients with severe disease who are unresponsive to steroid therapy, plasma exchange can be used as an alternative treatment.

For patients with spasticity, baclofen is the most effective medication. Tizanidine and diaz- epam are useful for nocturnal spasticity but are limited in their use for daytime symptoms because they cause intense somnolence. Pain secondary to trigeminal neuralgia and dys- esthesias  responds  well  to  carbamazepine, gabapentin, phenytoin, pregabalin, or  tricyclic

antidepressants. Bladder hyperactivity is treated with oxybutynin, whereas urinary retention is treated with bethanechol. Fatigue may be treated with amantadine or fluoxetine. Erectile dysfunction can be treated with sildenafil acetate.

All disease-modifying therapies are relatively contraindicated in pregnancy. Interferon and glatiramer should both be stopped for a pregnancy.

Fingolimod is an oral disease-modifying medication that decreases rates of MRI progression. It prevents lymphocytes from proliferating outside of lymph nodes. Cardiac toxicity can be severe.

Dalfampridine is an oral disease-modifying medication that increases walking speed. It       is a unique potassium channel blocker for which the precise mechanism of action (for improved walking speed) is not clearly  known.