Multiple Sclerosis

"A Disorder of the Brain and Spinal Cord"


MRI images of demyelinating lesions.


What is Multiple Sclerosis?

Multiple sclerosis is an inflammatory demyelinating disease of the central nervous system. Usually it follows an exacerbating and remitting pattern and usually affects young adults, mostly women. Most regard MS as an autoimmune disorder occurring in genetically predisposed individuals. The factors triggering the pathological change in MS remain poorly understood.

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Diagnostic criteria

The diagnostic criteria for MS depends upon demonstration of lesions disseminated in time and space. New diagnostic criteria for multiple sclerosis was proposed and published in the Annals Of Neurology 1983 by Poser et al, and are as follows:

Clinically definite multiple sclerosis.

  1. Attacks and clinical evidence of two separate lesions.
  2. Two attacks, clinical evidence of one and paraclinical evidence of another separate lesion.

Laboratory supported definite multiple sclerosis:

  1. Two attacks, either clinical or paraclinical evidence of one lesion, and CSF immunologic abnormalities.
  2. One attack, clinical evidence of two separate lesions and CSF abnormalities.
  3. One attack, clinical evidence of one and paraclinical evidence of another separate lesion, and CSF abnormalities.

Clinically probable multiple sclerosis:

  1. Two attacks and clinical evidence of one lesion.
  2. One attack and clinical evidence of two separate lesions.
  3. One attack, clinical evidence of one lesion, and paraclinical evidence of another separate lesion.

Laboratory supported probable multiple sclerosis:

  1. Two attacks and CSF abnormalities.

In each of these above situations and attack is defined by neurologic symptoms and signs lasting more than 24 hours. Second attack must be separated by the first by at least one month.

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Clinical History

Clinical history of MS usually is complaint of numbness, weakness or visual disturbance of some sort. When the presentation is sensory, the symptoms can be paresthesias, burning, tightness, diminished sensation, etc.. Many times the distribution of complaints is not conforming to anatomic territories which make it seem puzzling. When the presenting symptoms are weakness, it can be in one or both legs or can be hemiparesis. Optic neuritis is a common presentation of MS, complaining of monocular visual acuity loss or central scotoma or loss of color vision. Less frequently, symptoms can include vertigo, gait ataxia, diplopia, tremor, or even sexual dysfunction.

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When the patient presents with a single episode and the signs point to a solitary anatomic location, one must look and ask about previous episodes of attacks. Neurologic examination may reveal Babinski's on one side or the other or both, loss of vibration sense, or possibly weakness.

By far, the most sensitive test available is magnetic resonance imaging. It can reveal lesions that are not symptomatic, can also reveal second lesions in patients that have only mono-symptomatic presentations.

MS plaques are typically found in the periventricular region, corpus callosum, centrum semiovale, and deep white matter structures and basal ganglia. They can also be seen in the posterior fossa, brain stem, cervical and thoracic spinal cord. The typical shape of these plaques are oval shaped, with long axis of the plaque directly perpendicular to the anterior posterior dimension and ependyma of the lateral ventricle.

The MRI is far more sensitive at detecting these lesions than CT scan. Furthermore, these plaques are easily seen in the posterior fossa on MRI and are virtually invisible on CT scan because of the limitations of the technology of CT.

Delineating differences from acute and chronic lesions: the acute lesions tend to be larger with somewhat ill defined margins and eventually become smaller with sharper well defined margins as resolution occurs. This presumably reflects resolution of edema and inflammation present at the time of acute plaque formation, leaving only residual areas of demyelination, gliosis, and enlarged extracellular space with remission.

These plaques typically are hyperintense on the proton density, T2, and FLAIR sequences of MRI and appear hypointense on T1 weighted images without gadolinium.

Gadolinium-DTPA, a paramagnetic contrast agent that crosses disrupted blood brain barrier, is used to assess plaque activity. Gadolinium increases signal intensity on T1 weighted images. The accumulation of gadolinium in plaques is associated with new or newly active plaques which are thought to have breakdown of blood brain barrier. The gadolinium thus detects active lesions of MS. Gadolinium enhancement of acute plaques usually persists for less than one month but may persist up to 8 weeks. Gadolinium enhancement diminishes or disappears after treatment with cortico-steroids which is thought to restore integrity of the blood brain barrier. When plaques are chronic and old, they typically do not enhance with gadolinium.

CT scans are helpful to exclude other possible cause of symptoms such as stroke or hemorrhage. However, the sensitivity of CT scans for plaques it not high. Even with double dose contrast 50 to 60% of these scans will reveal abnormality on acute relapse of MS compared to a 90% sensitivity with MRI.

CSF evaluation cannot make or exclude the diagnosis of MS but can be helpful adjuncts to clinical criteria. In many patients the CSF may be normal. Total white count in the CSF can be normal in two-thirds of patients with MS and only exceeding 15 cells per microliter in less than 5% of patients with MS and only rarely exceeding 50 cells per microliter. More than 50 cells may raise suspension of other etiologies such as infection or tumor, etc.. The predominant cell type is T-lymphocytes. The CSF protein can be normal in the majority of MS patients.

Specific tests of CSF exist. For example, the CSF IgG level, is compared to the serum level of IgG and through a formula an IgG index is determined. An abnormality of this IgG index is found in more than 90% of clinically definite MS patients. Linked to the elevation of IgG is the finding of oligoclonal bands in the gel electrophoresis analysis of CSF. A discrete band on the gel electrophoresis represents excess antibody produced by one or more clones of plasma cells. The sensitivity for oligoclonal banding of IgG is approximately 85 to 95% of definite MS patients. Another specific CSF test that can be helpful is the presence of myelin basic protein. This is less specific for MS but is seen in other processes that show CSF myelin destruction and demyelinating activity.

The differential diagnosis in multiple sclerosis is quite extensive. Other inflammatory diseases might include granulomatous angiitis, SLE, Sjogren's, Behcet's, polyarteritis nodosa, paraneoplastic syndromes, ADEM and post infectious encephalomyelitis. Infectious diseases in the differential might include Lyme, HTLV1, HIV, PML, and neurosyphilis. Granulomatous processes include sarcoid, Wegener's granulomatosis, lymphomatoid granulomatosis. Myelin diseases might include metachromatic leuko dystrophy and adrenomyeloleukodystrophy . Nutritional deficiencies that might mimic MS would include B12 deficiency and structural causes include Arnold-Chiari malformation.

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Symptom pharmacotherapy include treatment for spasticity can be treated with Baclofen or Diazepam. Depression is significant problem and should be treated aggressively because it has significant negative impact on the quality of life and continued function.

Pain syndromes can be common in MS patients and can be treated with Tegretol, Elavil, Dilantin or Baclofen. Neurontin has recently been tried with some reported successes.

Pharmacotherapy- for multiple sclerosis disease include the following:
IV Methylprednisolone in 1 gram per day for 3 to 5 days followed by a 60 mg. Prednisone taper over 12 days. This usually shortens the duration of the relapse and accelerates recovery.

In the optic neuritis treatment trial it was found that IV Methylprednisolone for 3 days followed by Prednisone taper was superior to oral Prednisone alone at preventing the chance of developing MS with patients that had a first onset of optic neuritis. These results led to widespread use of IV Methylprednisolone for patients with optic neuritis and abnormal findings on MRI of the brain. These results also renewed a debate over whether intravenous Methylprednisolone has long term benefits for patients with multiple sclerosis. A clinical trial is underway presently to determine whether pulsed dose steroids given every other month slowed disease progression in patients with moderate disability and secondary progressive multiple sclerosis.

Interferon beta which two forms are available in the United States, 1A and 1B.

Interferon beta 1B was the first of the two available. It is called Betaseron. It is given subcutaneous injection every other day. The dose typically is 8 million units. It was found that it reduced the relapse rate by approximately 31% and increased the proportion of patients who are relapse free and reduced the number of patients how had moderate and severe relapses compared to placebo.

Interferon beta 1A was available later and it is called Avonex and consist of one injection per week intramuscularly of 6 million units. It was also found to be beneficial.

Both types of Interferon beta are well tolerated usually but the most common side effect is a flu-like symptom that last 24 to 48 hours. These symptoms usually subside after 2 to 3 months of treatment. The injection site also can become red, tender and can be infected.

Another new drug on the market is Glatiramer acetate, trade name is Copaxone, is a synthetic mixture of polypeptides which was found to inhibit autoimmune encephalomyelitis and it has been found clinically to be helpful in relapsing remitting multiple sclerosis. Treatment consist of daily subcutaneous injections of 20 mg.. Copaxone was approved by the FDA in 1996.

Another medication Azathioprine depresses both cell mediated and humeral immunity. Studies suggest that oral doses of 2 to 3 mg. per kilogram per day reduces the rate of relapse in multiple sclerosis but has no effect on the progression of disability. There is also concern that prolonged Azathioprine therapy increases the risk of non-Hodgkin's lymphoma and skin cancer.

Intravenous immunoglobulin has been studied in patients with relapsing and remitting multiple sclerosis comparing IVIG and placebo. The difference between the two groups was small in outcome.

Methotrexate has been studied for chronic progressive multiple sclerosis suggesting there is less disease progression. The clinical benefits were considered moderate. Low dose oral Methotrexate may be helpful for chronic progressive MS. Recent review article published in New England Journal of Medicine, vol. 337, #22, page 1604-11 written by Rudick et al, examines present management of multiple sclerosis.

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In summary, multiple sclerosis is a central nervous system demyelinating disorder that is diagnosed primarily by detailed clinical evaluation and the use of superior technologies such as MRI imaging and CSF evaluation.

Hopeful treatments for MS have until recently been unavailable but new medications such as Interferon beta and Glatiramer acetate give new hope in slowing the progression and the severity of attacks in patients with multiple sclerosis.

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