Advances in diagnosis
The diagnosis of MS remains clinical. There must be symptoms and signs indicating the presence of a progressive, multifocal, central nervous system process not explained by other illnesses. However, laboratory-based criteria for defining such changes have evolved. The newest criteria, published in the Annals of Neurology (McDonald, et al.), include changes on MRI. The appearance of new lesions, even in the absence of clinical changes, in a pattern suggestive of an inflammatory process (Barkhof, et al.), is sufficient to demonstrate disease progression. Since only one out of ten new lesions on MRI are associated with any clinical change in MS, the McDonald criteria allow more rapid diagnosis of MS and earlier initiation of disease-modifying therapy.

Classifications of MS
Defining the clinical course of MS is critical to choosing patients for treatment with new disease-modifying drugs. Four patterns of disease are described by Lublin et al.

The most common, present in about 85 percent of individuals, is relapsing remitting MS. It is characterized by rapid onset of neurological symptoms over hours to days, with complete, or more likely incomplete, resolution of symptoms over weeks to months. This pattern of MS is most amenable to treatment by the disease-modifying drugs. MRIs in persons with relapsing remitting MS often show increasing numbers of lesions, some with active inflammation, characterized by contrast enhancement of the lesions following administration of gadolinium.

About 50 percent of patients with relapsing remitting MS experience a change in their pattern of disease to secondary progressive MS. These patients note decreasing relapses with gradual and continuous progression of neurologic disability. Disease-modifying drugs are much less effective in treating this pattern of MS. MRIs may show lesion progression but with few if any contrast-enhancing lesions, yet increasing degrees of brain atrophy.

Ten percent of individuals have primary progressive MS. Their course, often starting in their thirties to fifties, is one of gradual, insidious progression of neurologic difficulties with no relapses. MRIs in primary progressive MS show lesions mainly in the spinal cord, with little active inflammation. There are no proven treatments for this form of MS.

The least common pattern is progressing relapsing MS, a pattern similar to that of primary progressive MS but with superimposed relapses. It is not known whether disease-modifying drugs are effective for this form of MS.

The new drugs
All of the new disease-modifying drugs act on the immune system, reducing inflammation in the central nervous system and, it is hoped, reducing tissue destruction. In that context, multiple studies have shown these agents work best when started early in the course of disease, when tissue destruction caused by inflammation is most prominent. Delaying treatment even for two years can result in irreversible changes in neurologic status. Some clinicians delay treatment, waiting to see if a person�s MS is "benign." While this can happen, it is relatively uncommon and can be diagnosed only in retrospect.

Disease-modifying drugs fall into two groups. The first group comprises drugs that modify the course of relapsing remitting MS. They decrease numbers of relapses by 18 percent to 33 percent, decrease the appearance of acute and chronic lesions on MRI, and have a modest effect in delaying progression of disability. Drugs in this group are divided into two classes, the beta interferons and glatiramer acetate.

The second group of drugs can modify the course of relapsing remitting MS refractory to the first group and also can modify rapidly evolving secondary progressive MS. Decreased relapses, delays in disease progression, and decreased MRI lesion accumulation are seen with drugs in the second group.

Beta interferons. The beta interferons are made from the human gene using recombinant DNA technology. Two forms of beta interferons are approved for use in this country: beta interferon 1a, sold as either Avonex or Rebif; and beta interferon 1b, sold as Betaseron. Dosage, frequency, and route of administration (either intramuscularly or subcutaneously) differ for the two forms, but their side effect and toxicity profiles are similar.

Controlled trials with high-dose and lower dose preparations of beta interferon suggest that higher doses are more effective, both clinically and using MRI criteria. Beta interferons can cause flu-like symptoms, which often resolve over time, and can cause changes in blood counts, liver functions, and thyroid functions. Monitoring these parameters is important, especially when initiating therapy. About 10 percent of individuals on beta interferons develop persistent, high titers of neutralizing antibodies to beta interferon. While this is still an area of controversy, accumulating data indicate the presence of persistent neutralizing antibodies to beta interferon is associated with a loss of drug efficacy.

The issue for the clinician caring for a person with MS is when to test for neutralizing antibodies to beta interferon. In my practice, I do not do this routinely. However, if a person has been doing well on a beta interferon, then has a change in clinical course, with more frequent relapses or the appearance of greater numbers of lesions on MRI (especially contrast-enhancing lesions), I will test for the presence of neutralizing antibodies. If present in high titer (>30 to 40) and the person has been on a beta interferon for more than 18 months, I will recommend changing to glatiramer acetate. If no neutralizing antibodies to beta interferon are present and the individual is on low-dose interferon, switching to a higher-dosed preparation can be considered.

Glatiramer acetate. The second drug for relapsing remitting MS is glatiramer acetate, sold as Copaxone. This drug, composed of polymers of four amino acids found in high frequency in myelin basic protein, exerts its protective effects via mechanisms different from those of the beta interferons. Side effects and toxicities also are different; there are no flu-like symptoms or changes in blood, liver, or thyroid functions. Additionally, while persons on glatiramer acetate produce antibodies to the drug, there are no consistent data to indicate that these antibodies affect drug efficacy.

Long-term follow-up of patients responding to glatiramer acetate showed continued benefit in terms of relapse rate reduction over a period of ten years compared to historical controls from other studies. However, lack of a study control group makes it difficult to determine whether the reduction in relapse rate is the natural history of the disease or a direct effect of the drug. Rarely, individuals receiving injections of glatiramer acetate experience brief feelings of shortness of breath and heart palpitations, which subside without sequelae. This reaction may represent an inadvertent IV injection of the drug.

Mitoxantrone. The only FDA-approved drug approved for persons with refractory relapsing remitting MS or rapidly evolving secondary progressive MS is mitoxantrone, marketed as Novantrone. It is administered intravenously every three months for two years, after which it must be discontinued because of the risks of cardiac toxicity. Because of this potential toxicity, and the fact that secondary progressive MS most often is seen in older individuals, careful determination and monitoring of cardiac function with MUGA scans before and during mitoxantrone treatment are necessary. The beta interferons have been tested in persons with secondary progressive MS, and results have been either negative or marginally effective. A large clinical trial of glatiramer acetate in persons with primary progressive MS did not show any statistically significant changes. Thus, the only approved use of the beta interferons and glatiramer acetate is in persons with relapsing remitting MS.

The mechanisms of action of the beta interferons or glatiramer acetate are not known. What is known is that some patients do very well on one or the other of the above drugs and other patients do not. These observations may reflect the possibility that MS is a syndrome rather than a single disease. Data from the Mayo Clinic and University of Vienna suggest that pathogenic mechanisms of demyelination vary among individuals. Thus, it is possible that the actions of the beta interferons will benefit one individual with one pattern of demyelination, but not another person with a different pattern, and vice-versa for glatiramer acetate.

Since none of the drugs have an immediate effect on the disease, nor can they stop or cure it, careful follow-up is needed to determine whether an individual�s response to a disease-modifying drug is below reasonable expectations or should be changed or supplemented. Though criteria for determining "insufficient response" are published, in the final analysis decisions are subjective, based on knowledge of the patient�s previous course; changes on MRI; tolerability of the medication; and, in the case of the beta interferons, the absence or presence of persistent, high titers of neutralizing antibodies.

Use of MRIs in management of MS
The use of MRIs in the management of MS is controversial, because changes on MRI do not correlate directly with the clinical state of an individual. The reasons for this are not clear but probably have to do with the location of the lesions, the intensity of the inflammation, and the plasticity of the brain to compensate for the injury. However, several studies have shown that the presence of multiple lesions in the central nervous system at the time of initial presentation of MS is a strong predictor not only of the probability of relapse, but also of the probability of significant disease progression.

In addition, recent MRI data indicate that not all MS lesions on MRI are equivalent in their prognostic implications. Lesions can be divided into three general groups: those seen on T1 imaging; those present on T2 or fast-spin echo imaging; and those showing contrast enhancement. Destructive processes are most pronounced in persistent T1 lesions; these correlate highly with brain atrophy, a phenomenon occurring early in the course of disease and correlating strongly with cognitive impairment. Since inflammatory activity in the central nervous system of persons with MS occurs subclinically, and since destructive processes, even if not immediately apparent, can lead to impairment over the long term, many MS specialists, including myself, monitor their patients with periodic MRIs. If there are substantive increases in lesion load, especially in T1 lesions, or continuing numbers of contrast-enhancing lesions, even in the absence of clinical concomitants, a change in disease-modifying therapy may be considered.

New MRI techniques such as magnetization transfer and MR spectroscopy will lead to further insights into the changes that occur in the central nervous system of persons with MS�and to new understandings of this enigmatic illness.

Gary Birnbaum, M.D., practices at the Minneapolis Clinic of Neurology�s Golden Valley office.

This article originally appeared in the April 2004 edition of Minnesota Physician and is reprinted with the permission of Minnesota Physician Publishing Inc.