How Early Should DMT Be Started?
The National MS Society consensus statement endorses consideration of therapy in selected first-attack/high-risk patients. This is based on 2 phase 3 trials, the Controlled High-risk Subjects Avonex Multiple Sclerosis Prevention Study (CHAMPS) and Early Treatment Of MS (ETOMS). In both studies, patients randomized to DMT were significantly less likely to experience a second attack or to develop new brain MRI lesions during the study period than if they received placebo treatment.

CHAMPS enrolled patients between the ages of 18 and 50 years who had a clinically isolated syndrome (unilateral optic neuritis, incomplete transverse myelitis, isolated brainstem/cerebellar syndrome), abnormal brain MRI, and no better diagnosis for their neurologic attack.[34] Brain MRI had to show at least 2 unrelated T2 lesions >/= 3mm in size, at least 1 of which had to be ovoid in shape or periventricular in location (both these lesion features are suggestive of MS). Patients were randomized to receive IFN beta-1a 30 mcg IM weekly or placebo for 18 months. In a recent analysis of the placebo arm of the CHAMPS trial, 2 or more Gd+ lesions at presentation predicted that 52% of patients would experience a second clinical attack within 18 months, 92% would have an attack or demonstrate 2 or more new or enlarging T2 brain lesions, and 96% would have a clinical attack or at least 1 new or enlarging MRI lesion.[35] The presence of >/= 2 Gd+ lesions was the best predictive marker for development of clinically definite MS.

The ETOMS study entered 308 first-attack patients, ages 18 to 40 years, with unifocal or multifocal (39%) CNS presentations and abnormal brain MRI.[36] The MRI was required to show 4 T2 white matter lesions, or 3 T2 white matter lesions if 1 was enhancing or infratentorial. Patients were assigned to receive IFN beta-1a 22 mcg SC weekly or placebo, and were followed for 2 years. In both the CHAMPS and ETOMS studies, conversion to clinically definite MS (a second relapse) within the next 18 to 24 months occurred significantly less frequently in the IFN beta-treated groups.

The number of new/enlarging MRI lesions and lesion burden were also significantly less with treatment. In the ETOMS study, which used a very low dose of IFN beta-1a, 84% of treated patients had either a clinical relapse or new MRI lesions, as did 94% of those who received placebo. Patients with a multifocal presentation experienced an approximately 2-fold higher conversion to clinically definite MS. ETOMS suggests that MS is easier to treat early, since the dose of SC IFN beta-1a used in that trial failed to treat established relapsing MS in the Once Weekly Interferon for MS (OWIMS) trial.[37] In view of these data, which support therapy as soon as possible in the disease process, it would seem prudent to treat first-attack patients who fall into a high-risk group for MS. CHAMPS had the least stringent MRI entry requirements, yet was quite successful in identifying first-attack MS patients. Suggested criteria for offering DMT to first-attack patients are outlined in Table 10.

Table 10. Proposed Criteria for Treatment of First-attack/High-risk Patients
Appropriate age


- 10 to 50 years

Suggestive clinical syndrome


- Unilateral optic neuritis with pain and without macular abnormality

- Incomplete transverse myelitis

- Isolated brainstem/cerebellar syndrome (eg, internuclear ophthalmoplegia, trigeminal neuralgia)

- Paroxysmal attacks

- Lhermitte sign

- Multifocal white matter syndrome (not suggestive of acute disseminated encephalomyelitis)

Abnormal brain MRI*


- Lesions unrelated to clinical attack

- Lesions >/= 3 mm

- >/= 2 contrast lesions, or >/= 2 T2 lesions (1 periventricular or ovoid)

Other diagnoses ruled out





*Minimal MRI criteria are adapted from the CHAMPS study.

T2 MRI has a very high sensitivity for detecting tissue changes, and many disorders can produce brain MRI lesions. However, there are recognized lesion features that have high predictive value for MS (Table 11; Figure). These can be used to increase confidence of the MS diagnosis.


Figure 1. MRI changes in multiple sclerosis. This composite shows some of the changes captured by serial MRI that are characteristic of the dynamic nature of the underlying pathologic disease activity in multiple sclerosis. The patient was evaluated serially by high-resolution MRI, and the images were quantified automatically. The patient had no clinically defined change in his neurologic symptoms or findings during this 7-month interval despite the significant activity demonstrated by MRI. Source: Lindsey JW, Wolinsky, JS. Section IX: Demyelinating Diseases. Chapter 11: Neurology. In: Dale DC, Federman DD, eds.WebMD Scientific American® Medicine Online. New York, NY: WebMD Corp; 2001. Reproduced with permission of publisher.



Table 11. Brain MRI Features That Increase Likelihood of Further Disease Activity
High number of T2 lesions


High volume of T2 lesions


Gd+ lesions


Juxtacortical, infratentorial, corpus callosum lesions


Large T2 lesions



In summary, immunomodulator DMT should be initiated as soon as there is a confident diagnosis of a relapsing form of MS. It can also be offered to first-attack/high-risk patients who meet criteria that indicate high likelihood of MS (Table 10).