Controversies in Neurology

D ISEASE-MODIFYING agents approved for treatment of patients with multiple sclerosis (MS) are glatiramer acetate, interferon beta-1b and -1a, and mitoxantrone hydrochloride. Natalizumab was Food and Drug Administration approved in November 2004, but the manufacturers suspended marketing and clinical trials in 2005 because of safety concerns. Interferon beta-1a is approved for individuals with clinically isolated syndromes (CISs) who are at relatively high risk to “convert to MS.” Opinions vary about whom and when to treat. On one hand, the Medical Advisory Board of the National Multiple Sclerosis Society consensus statement (updated in February 2005) recommends initiation of a disease-modifying agent “as soon as possible following definite diagnosis of MS with a relapsing course, and in selected patients with first attack who are at high risk for MS (CIS).” Alternatively, the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the MS Council for Clinical Practice Guidelines suggest “it is appropriate to consider” treatment with approved therapies in these patients. We do not believe that all patients with MS or CIS should begin indefinite treatment at the time of diagnosis. Until it is clear that the patient has continuing disease activity clinically and/or radiologically, in which case the need for treatment is clear to the physician and to the patient, it is advisable to observe a period of no treatment while monitoring for inflammatory disease activity. The final decision about whether and when to initiate treatment should be shared by the patient and physician after an unbiased review of the relevant information with the patient. Our current approach is predicated on the following: (1) MS often has a favorable natural history; (2) disease-modifying drugs are only partially effective in the short-term and prevention of disability in the long-term is unproven; (3) with prolonged treatment, it is hard to distinguish whether a favorable outcome reflects a favorable natural history or successful treatment in an individual patient, especially if treatment is started without a period of observation; (4) expense, adverse effects, and neutralizing antibodies are a concern and patients may be reluctant to commit to long-term parenteral medications, especially within the first few months following diagnosis; and (5) prospective clinical and magnetic resonance imaging (MRI) monitoring may allow identification of patients who need treatment. Because disease-modifying agents do not benefit patients with primary progressive MS (approximately 10% of all patients with MS) and their benefit in secondary progressive MS (approximately 30% of all patients with MS) remains questionable, this discussion is limited to patients with a diagnosis of relapsing-remitting MS and CIS. Patients with MS often do well without any treatment. A recent Olmsted County, Minnesota, study found that patients with minimal or nodisability(ExpandedDisabilityStatus Scale [EDSS] score 2) at more than 10 years from onset have a 90% chanceofremainingfullyambulatory (EDSSscore 3.0)10yearslater. This group accounted for 17% of all patients with MS or 33.3% (28/94) of patientswith relapsing-remittingMS in that population-based cohort. Kurtzke et al reported similar findings. Extrapolating these data to all patientswith“destined tobebenign” MS in the United States would result in approximately 35 870 individuals (17% of 211 000 patients with MS in the United States) unnecessarily receiving a potentially lifelong medication. Currently available approved treatments offer a mild to moderate short-term benefit in individuals with active recent disease who are most likely to respond. However, long-term efficacy is unproven. One needs to treat 5.6 patients with interferon beta-1b, 6.3 with interferon beta-1a, and 14.3 with glatiramer acetate to generate 1 person free of relapse for 2 years. Reduction in relapse rate is most evident in the first year and then declines. Number needed to treat (NNT) estimates for natalizumab are more favorable; early results suggest that the NNT to render 1 patient relapse free after 2 years of therapy is 2 to 2.4. However, serious safety concerns have led to voluntary cessation of natalizumab production. Author Affiliations: Department of Neurology, Mayo Clinic, Rochester, Minn (Drs Pittock, Weinshenker, Noseworthy, Lucchinetti, Keegan, and Rodriguez), Scottsdale, Ariz (Drs Wingerchuk and Carter), and Jacksonville, Fla (Dr Shuster).