More Evidence Retinal Thinning May Track MS Progression

Pauline Anderson

December 24, 2012

Patients with multiple sclerosis (MS) who exhibit new lesions early on in their disease experience relatively fast thinning of the ganglion cell and inner plexiform (GCIP) layers of the retina, a new study has found.

The findings are important because it may be useful to include patients with accelerated GCIP thinning in future clinical trials that test MS therapies, said study author Peter A. Calabresi, MD, professor, neurology, and director, MS Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.

"We previously showed that OCT [optical coherence tomography] can detect this thinning and now we're trying to cull out those who are going to be what we call in clinical trials 'informative patients' — those who are going to give us the most information."

The study was published online January 1 issue of Neurology.

Optical Coherence Tomography

The researchers included 116 patients with relapsing-remitting MS, 24 with secondary progressive MS, 16 with primary progressive MS, and 8 with clinically isolated syndromes (CIS) who have experienced a central nervous system inflammatory attack compatible with MS but don't fulfill MS diagnostic criteria. The study also included 59 healthy controls.

Dr. Peter A. Calabresi

Using OCT, a noninvasive and relatively inexpensive imaging technique, researchers measured the thickness of the GCIP and of the retinal nerve fiber layer (RNFL) every 6 months. According to the authors, the RNFL is composed of axons of the ganglion cells. Demyelination or transection of optic nerve axons derived from the RFNL cause retrograde degenerations, resulting in atrophy of the RNFL and ganglion cell body death, they note.

Participants also underwent brain MRI annually. The mean follow-up period was 21.1 months.

During the study, the rate of GCIP thinning was 46% faster in patients with MS/CIS than in healthy controls (P = .008), whereas the rate of RNFL thinning did not significantly differ between patients with MS/CIS and controls.

The study found that several factors influenced the rate of GCIP thinning. These included having the following:

  • Nonocular relapses (42% faster: –0.55 vs –0.32 μm/year for those without these relapses; P = .007);

  • New gadolinium enhancing lesions (54% faster: –0.63 vs –0.29 μm/year for persons without these lesions; P < .001);

  • New T2 lesions (36% faster: –0.50 vs –0.32 μm/year for those without these lesions; P = .02);

  • Disease duration less than 5 years (43% faster: –0.54 vs 0.31 μm/year for those with disease duration more than 5 years P = .003); and

  • Disability progression of a 1-point or greater increase on the Expanded Disability Status Scale (EDSS) score (37% faster: –0.52 vs –0.33 μm/year for persons without this progression; P = .01).

Patients with new T2 lesions and disease duration of less than 5 years had the fastest rate of GCIP thinning (–0.86 vs –0.26 μm/year for those without these characteristics, or 70% faster; P < .001).

The study showed that GCIP measurements were "more robust" than those for RNFL in terms of being able to detect these changes, said Dr. Calabresi.

The eyes are "extensively involved" in MS, noted Dr. Calabresi, adding that postmortem data show that up to 99% of patients with MS demonstrate optic nerve lesions. This causes "a huge amount of visual disability," he said. Many of his patients in their 40s say they can't drive at night and have problems with contrast. "These are subtle changes in nerves that creep up on patients."

Enrolling patients in clinical trials with significant disease progression has many advantages. Currently, only about 30% of the patients with MS in trials demonstrate a real change on EDSS scores, which is the standard outcome measure, said Dr. Calabresi. "But if you know which patients are going to change, then you're more likely to be able to see a change, and then if you have a neuroprotective drug, you can try to stop that change."

The research is also important from a pathophysiologic standpoint because it helps inform the debate about how axons and neurons die in MS. "I would say that this paper suggests that it's related more to inflammation because we're capturing the biggest changes in patients who have other markers of inflammation," noted Dr. Calabresi.

OCT probably won't replace MRI for monitoring patients with MS, but the test could be "a relatively cheap add-on," said Dr. Calabresi. The machines, with a price tag of about $60,000 to $70,000 each, are widely used in ophthalmology. The cost of a scan is about one tenth that of an MRI scan, and results are available immediately, he said.

OCT is also safe; because it uses infrared light, there's no radiation, he added.

Enriching Trials

In an accompanying editorial, Robert A. Bermel, MD, Mellen Center for MS Treatment and Research, Cleveland, Ohio, and Matilde Inglese, MD, PhD, Department of Neurology, Radiology and Neurosciences, Mount Sinai School of Medicine, New York, New York, noted that the study is one of the largest of its kind to date.

The findings require replication, "but at face value provide some interesting data that may help to optimize the future design of clinical trials using OCT as an outcome measure," the commentators write.

Although such trials may better detect neuroprotective effects using OCT, testing neuroprotection in the setting of ongoing active inflammation has some hazards, they note. Visible new lesions and relapses are less common in progressive MS, where the need for neuroprotective therapies is greater. As well, in the setting of active inflammation, separating primary neuroprotection from immune modulation or secondary neuroprotection becomes difficult.

"One practical way to enrich clinical trials utilizing OCT in progressive MS based on these data would be to require evidence of active progression and shorter disease duration as inclusion criteria for study entry," Drs. Bermel and Inglese write. "Alternately, trials in long-standing, slowly progressive MS in the absence of inflammatory disease activity may be more difficult to power sufficiently for OCT outcomes."

The editorial authors also noted that the study results provide indirect evidence that active inflammation — even if subclinical or occurring in a different functional system — is connected with greater rates of retinal neurodegeneration.

And they agreed that as new therapeutics are developed, ganglion cell analysis by OCT may play a key role in measuring their efficacy.

Asked for her views on the study, Lily Jung Henson, MD, a neurologist at the Swedish Medical Center, Seattle, Washington, and a member of the American Academy of Neurology, said that GCIP "appears to be a good marker for neurodegeneration."

She added that there also appears to be a correlation between neurodegeneration and inflammation. "More study is needed, but having good biomarkers helps us in better evaluating our progressive patients," she said.

The study was supported by the National Multiple Sclerosis Society, the National Eye Institute, and Braxton Debbie Angela Dillon and Skip Donor Advisor Fund. Dr. Calabresi has provided consultation services to Novartis, Teva, Biogen Idec, Vertex, Vaccinex, and Genentech and has received grant support from EMD-Serono, Teva, Biogen Idec, Genentech, Bayer, Abbott, and Vertex. For disclosures of other study authors, see original paper. Dr. Bermel has served as a consultant or advisory board member for Biogen Idec, Teva, Novartis, and Astellas. Dr. Inglese and Dr. Henson has disclosed no relevant financial relationships.

Neurology. 2013;80:47-54, 19-20. Abstract Editorial