Topic: Optic Neuritis: Early Diagnosis and Treatment
Review of three double-blind, placebo-controlled studies investigating the use of interferon (IFN) beta for the early treatment of clinically isolated syndromes (CIS) such as optic neuritis indicates that early treatment is more effective than treatment of established disease. Importantly, results out of the CHAMPS, ETOMS and the BENEFIT trials clearly show that early treatment of CIS, when one or more lesions are seen on MRI, significantly delays or prevents conversion to MS.
“Given the high probability of conversion to MS in those patients who have a positive MRI and the convincing data supporting the use of IFN-beta in CIS, treatment of demyelinating syndromes should be started as early as possible,” said Robert Herndon MD, Professor of Neurology, University of Mississippi Medical Center, Jackson, MI, and Recipient of the Consortium of Multiple Sclerosis Centers’ Lifetime Achievement Award.
Clinically isolated syndromes (CIS) are inflammatory demyelinating syndromes of the central nervous system (CNS). The most common forms of CIS affect the optic nerve (optic neuritis), the spinal cord (incomplete transverse myelitis), and the brainstem. Some patients, noted Dr. Herndon, experience recurrent optic neuritis without any other CNS involvement.
In almost 90% of patients with MS, the initial presentation is demyelinating lesions consistent with CIS, said Dr. Herndon. “MRI is widely used to help diagnose and monitor the evolution of CIS into MS. Follow-up MRI studies in CIS have revealed that, in many patients, new demyelinating lesions appear over time, yet are clinically silent.”
Long-term follow-up studies show that up to 80% of patients with CIS and a positive MRI, go on to develop MS. In recent years, IFN beta has been established as the gold standard for the treatment of MS, slowing disability progression, reducing clinical relapses and reducing development of brain lesions.
In all three phase III trials of interferons in MS, patients in whom treatment was delayed never caught up with their peers who were treated early, noted Dr. Herndon. “In terms of disability, the placebo group has failed to catch up to the treated group in all three trials, whether at two years or five years.” Further, the death rate at 16 years was notably higher in the placebo group than in the treated group in the phase III interferon (IFN) beta-1b pivotal trial group, said Dr. Herndon.
Since many patients with optic neuritis will not yet meet formal diagnostic criteria, it’s key that you “keep an open mind regarding the diagnosis in the early stages,” said Dr. Herndon, who is also Director of the MS center at the Jackson Veterans Administration Medical Center. Predictors of early progression to clinically definite multiple sclerosis include: the number and volume of T2 lesions, the presence of GAD+ lesions; and a new lesion on three-month MRI “would meet the criteria for MS at this point,” noted Dr. Herndon.
The basis for the CHAMPS study, in which treated patients received once-weekly 30 mcg IFN beta-1a IM, was the rationale that immunomodulation might be more effective if begun early, before epitope spreading has occurred.
The CHAMPS study showed that there was a 44% decrease in the probability of CDMS over three years in the treated group versus placebo. In addition, there was a 1% increase in T2 lesion volume in the treated group versus a 16% increase in the placebo group. Finally, there were 42% fewer Gad+ lesions in the treatment group at six months and the effect on MRI “increased significantly over time,” noted Dr. Herndon. At 18 months, for instance, the treatment group had 67% fewer Gad+ lesions on MRI.
Ultimately, a post hoc analysis of CHAMPs showing that those with the most MRI lesions had the largest effect, suggests that this trial was an “example of what you anticipate not being what you get,” Dr. Herndon told delegates. The message being, “don’t let your bias influence outcome.”
In the CHAMPIONS study, “we really do see a bigger effect of IFN beta-1a when it is given earlier,” reported Dr. Herndon. The incidence of CDMS in the group given immediate treatment was 36% versus 49% in the delayed treatment group. The annualized relapse rate was 0.17 in the treated group versus 0.32 in the delayed treatment group and the median number of new or enlarging T2 lesions was 3.5 in the group that was treated and 6.0 in the group in which treatment was delayed.
In the ETOMS study, which looked at a smaller dose of IFN beta-1a 20 mcg subq once-weekversus placebo, the difference between the groups was not quite as large, noted Dr. Herndon. “The treated group took almost twice as long to develop CDMS,” he reported. Furthermore, the change in EDSS and SNRS scores were not significantly different in the two groups.
The 24-month BENEFIT study, which is the most recent, looks at the use of IFN beta-1b in a 5:3 treatment versus placebo ratio in newly-emerging MS. Inclusion criteria was a single neurologic event with at least two clinically silent lesions on MRI. Although there was no difference in result when sorted by age group, the BENEFIT study showed that not only does early treatment appear to be more effective but that the treatment effects are greater in patients with monofocal presentations of disease. “We’re not sure what to make of this, ” said Dr. Herndon.
The caveat to the early treatment rule would be the presence of benign MS. “These patients would not appear to require early treatment,” noted Dr. Herndon. Although there are some early indicators for benign MS, reliability is poor, he added, pointing out that benign cases were not included in any of the IFN beta-1b pivotal trials since patient selection was based on disease activity.