Daniel M. Keller, PhD

May 08, 2014

PHILADELPHIA, Pennsylvania — Researchers saw a decrease in macular volume during the first year of fingolimod (Gilenya, Novartis) treatment among patients with multiple sclerosis (MS), according to a new report.

Macular volume decreased regardless of patient age, sex, duration of disease, or a history of optic neuritis, they note. Using optical coherence tomography (OCT), the investigators measured changes in different layers and parts of the retina.

"Up to 180 days, we didn't detect any change in macular volume in our cohort. At 1 year, we noticed a decrease in macular volume...that appears to be sustained at year 2," lead author Pavle Repovic, MD, PhD, a neurologist at the Swedish Neuroscience Institute of the Swedish Medical Center in Seattle, Washington, concluded.

Dr. Repovic reported their findings here at the American Academy of Neurology (AAN) 66th Annual Meeting.

Correlation of Eye and Brain

Previous studies have shown a correlation of OCT measurements with MS disease measures. The peripapillary retinal nerve fiber layer (RNFL) has been seen to thin after optic neuritis but also in eyes with or without optic neuritis in patients with MS and across MS subtypes. In other studies, total macular volume correlated with visual acuity and brain parenchymal fraction.

A dose-dependent adverse effect of fingolimod is macular edema, occurring in 0.5% of cases in some trials. Onset has occurred as soon as just over a week after initiation of therapy with fingolimod and as long as about 2.6 years. Risk factors are diabetes and uveitis.

The objectives of the single-center, retrospective, longitudinal study reported here were to follow macular volume changes in patients with MS receiving fingolimod for more than 6 months, to look at the effect on ganglion cell/inner plexiform (GCIP) and peripapillary RNFL thickness, and to evaluate various factors potentially predisposing to any changes that may be observed.

Patients (n = 126 evaluated; 252 eyes) started fingolimod after it was approved by the US Food and Drug Administration in September 2010. They had at least 2 OCT examinations while receiving the drug in addition to an OCT examination within 6 months before starting the drug. Exclusion criteria included any condition that could affect OCT measurements and a history of optic neuritis within 6 months.

Patients averaged about 46 years of age, had an Expanded Disability Status Scale score of 3.32±2.07, had a timed 25-foot walk speed of 7.77±6.39 seconds, first experienced symptoms 12.1±7.9 years earlier, and were diagnosed 9.6±7.1 years earlier.

Eighty-one percent had a diagnosis of relapsing-remitting MS, and 40% had a history of optic neuritis. At baseline, the men in the study had greater total macular volumes than the women in both the right (P = .011) and left (P = .025) eyes. RNFL and GCIP thicknesses at baseline did not significantly differ.

Macular Volume Decreased

Macular volume did not change between baseline and 6 months in either eye, but "within subjects, the effect was very significant, and specifically between 12 months and baseline and [between] 12 months and 6 months," Dr. Repovic said.

Table. Change in Macular Volume

Endpoint Baseline 6 Months 12 Months Within-Subject Effect: P Value 6 Months vs Baseline: P Value 12 Months vs Baseline: P Value 12 Months vs 6 Months: P Value
Total macular volume: right eye (mm3) 9.80±0.60 9.82±0.62 9.71±0.61 <.001 1.00 .009 <.001
Total macular volume: left eye (mm3) 9.83±0.54 9.82±0.56 9.75±0.60 .001 1.00 .003 .008


The researchers saw a decrease in the thickness of the left eye GCIP only within patients (P = .033) but not for the group at 6 or 12 months. GCIP did not significantly thin within the right eye of patients or at either time point for the group.

A history of optic neuritis, sex, age, and disease duration had no association with macular volume.

Dr. Repovic concluded that during the first 12 months of treatment with fingolimod, macular volume decreased by an average of 0.087 mm3 from pretreatment baseline. A trend but no significant effect was seen in RNFL and GCIP thinning.

Underlying Atrophy

"[T]here may be some underlying, ongoing atrophy of the macula over time, and this needs to be potentially correlated with brain volume loss. Dr. Robert Naismith

Commenting to Medscape Medical News, Robert Naismith, MD, assistant professor of neurology at Washington University in St. Louis, Missouri, said that the clinical utility of the findings remains to be determined.

The observation that macular volumes decreased during 12 months following initiation of treatment with fingolimod "suggests that there may be some underlying, ongoing atrophy of the macula over time, and this needs to be potentially correlated with brain volume loss," he said.

If one sees an effect in the same groups of patients on macular volume as well as brain volume loss, "it suggests an overall neurodegenerative component to multiple sclerosis which may not be fully understood," he said.

The loss of macular volume occurred in the first year and then seemed to stabilize in the second year. Dr. Naismith wonders whether this effect might be evidence of a neuroprotective effect of fingolimod.

"We really would need to see a comparator group to really understand that for sure," using a different actively treated or placebo control group, he said.

Dr. Repovic has received personal compensation for activities with Acorda Therapeutics, Biogen Idec, EMD Serono, Genzyme Corp, Novartis, Pfizer Inc, Questcor, and Teva Neuroscience as a consultant, advisory board member, or speaker. He has received research support from Novartis. Dr. Naismith has consulted for Acorda, Biogen Idec, Bayer, EMD Serono, Genzyme, Genentech, and Questcor.

American Academy of Neurology (AAN) 66th Annual Meeting. Abstract S4.004. Presented April 29, 2014.


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