http://www.medpagetoday.com/Neurology/MultipleSclerosis/tb/1727
By Neil Osterweil, Senior Associate Editor, MedPage Today
Reviewed by Zalman S. Agus, MD; Emeritus Professor at the University of Pennsylvania School of Medicine.
September 13, 2005
MedPage Today Action Points

* Advise patients that in this very small study, Betaseron appeared to be effective at protecting the brain against some but not all new MS lesions.

* Explain that in this study, Betaseron did not reduce the length of duration of existing lesions, suggesting that it may not help heal existing damage.

Review
BETHESDA, Md., Sept. 13-Although treatment with Betaseron (interferon β-1b) appears to reduce the frequency of so-called black hole lesions, as seen by MRI scans of patients with multiple sclerosis, the drug does not contain the damage if one forms.

That's the conclusion of researchers at the National Institute of Neurological Diseases and Stroke here, who studied whether treatment with Betaseron could truncate the duration of black holes over a three-year period in six patients with MS.

"We demonstrate that new black holes may significantly accumulate over time even when interferon β-1b is administered," wrote Francesca Bagnato, M.D., and colleagues in an early online edition of the November Archives of Neurology. "However, repeated administration of the drug did significantly decrease the rate of black hole formation, thus protecting the brain tissue from accumulating degenerative lesions."

As the name implies, black holes appear as areas of darkness on MRI scans of patients with multiple sclerosis. Although Betaseron has been shown to reduce formation of both black holes and contrast-enhanced MS lesions on MRI, it had been unclear whether the drug had any effect on the duration of lesions once they've formed, wrote Dr. Bagnato and colleagues.

"This is clinically relevant because black holes of shorter duration are believed to be associated with the presence of transient edema, and chronic, persisting black holes reflect areas of irreversible axonal loss and permanent damage," the investigators wrote. "Hence, by shortening the duration of black holes, the formation of permanent detriment lesions may be prevented, ultimately exerting a neuroprotective effect."

To test this hypothesis, they clinically assessed and then imaged six MS patients monthly for a total of 72 months. The study covered a 36-month natural history phase and 36-month treatment phase. All scans were performed on a 1.5 Tesla MRI with standard precontrast and postcontrast imaging. Gadopentate dimeglumine 0.1 mmoL/kg was used for contrast.

The investigators counted the lesions present at baseline, but included in the statistical analysis only black holes newly arising from contrast-enhanced lesions during the course of the study. They counted lesions separately during the natural-history phase and treatment phase, and did not include lesions present at the end of the natural-history phase in the count for the next phase.

During the treatment phase, patients received Betaseron 8 MIU every other day.

One of the six patients did not have any contrast-enhanced lesions or new black holes during the treatment phase; this patient was excluded from the statistical analysis.

In each of the remaining five patients, there were increases in the number of new black holes during both the natural history phase and treatment phase, although the rate of accumulation was significantly lower while the patients were receiving Betaseron.

In all, 156 new black holes arose during the natural history period, compared with 31 during the treatment period. Half (49.7%) of the new black holes seen in the natural history phase and 38.9% of those seen in the treatment phase persisted until the end of the respective study phases, and were therefore censored from the analysis.

On Kaplan-Meier analysis, the investigators found that the duration of new black holes that cropped up during treatment were no shorter than those that first arose during the natural history phase.

In all but one of the five patients in the analysis, there were "dramatic" decreases in the number of contrast-enhanced lesions, suggesting an effect of treatment with Betaseron. The patient who did not have a decrease in lesion formation had neutralizing antibody titters that appeared during the third month of therapy, peaked at 1:695 at 16 months, and then declined -- but did not disappear -- to below 1:100 at the beginning of the third treatment year.

"One can postulate that although IFNβ may reduce the frequency of black holes, after the lesion occurs, the drug is not changing the pathological process," the investigators wrote. "However, the significance levels at which differences were detected are not straightforward. Heterogeneity in the number of new black holes for each patient as well as large proportions of censored observations during the study phases may potentially bias these results. Consequently, we cannot distinguish between the possible ability of IFNβ-1b to promote either the formation of less aggressive new black holes or faster recovery from them."