Eyeing Neurodegeneration

NEW ORLEANS—Damage to the retina in multiple sclerosis might be the canary in the coalmine, reflecting neurodegeneration and disease processes throughout the central nervous system, according to research reported on Tuesday, April 24, at the annual meeting of the American Academy of Neurology in New Orleans.  

Imaging such damage could provide an accurate tool for assessing disease state through a method that is cheaper and easier than current techniques, the study’s lead investigator says. Currently, researchers rely on MRI imaging, which is well-established—but conventional uses of that modality do not reflect a patient’s clinical state in a clear-cut way, nor do they provide information about what exactly is happening: demyelination, inflammation, other pathological processes, or even remyelination (see “More Than Meets The Eye”). A direct measure of neurodegeneration would therefore be a valuable addition to the available imaging techniques.

MS patients often experience thinning of cells in the innermost part of the retina called the retinal nerve fiber layer (RNFL). This phenomenon, which has been documented with a highly sensitive quantitative imaging technique called optical coherence tomography (OCT), correlates with disability, brain atrophy, and other clinical measures. Few studies have examined changes in retinal cells over time, however, so how their development relates to disease progression is unknown. But Shiv Saidha, a neurology fellow at Johns Hopkins University in Baltimore, Maryland, has now conducted such an investigation in 164 multiple sclerosis patients and 59 healthy individuals.

In previous work (Saidha et al., 2011), Saidha and his colleagues established that changes in cells that lie just below the RNFL—in the ganglion cell layer and the underlying inner plexiform layer (GCIP)—showed an even stronger structure-function relationship with MS-related disability than did changes in the RNFL. Furthermore, unlike the RNFL, the GCIP doesn’t swell during an attack of optic neuritis, providing the opportunity for unobscured imaging.

In the new study, the team used OCT to view the GCIP every 6 months for an average of 21 months and found that the annual rate of GCIP thinning was 46% greater in patients than in the healthy controls. One-third of the patients relapsed, developed new lesions, or saw a rise in disability during the study; and in the individuals who experienced such disease activity, GCIP thinning also occurred 36% to 54% faster than it did in those whose conditions remained stable. (The exact percent increase differed depending on the type of disease activity: new T2 lesions, new gadolinium-enhanced lesions, nonocular relapses, and disability progression.)

The results suggest that subclinical inflammation in the retina mirrors—in a quantifiable way—disease activity elsewhere in the brain, Saidha says. “OCT measures may reflect global central nervous system processes”—processes that are also occurring in the optic nerve but below the threshold of producing detectable changes on MRI or in symptoms, he says.

The researchers also noticed that the GCIP thinned at a rate 43% faster in patients who had been sick for less than 5 years than in those who had had MS longer. That observation could indicate that the early stage of the disease is marked by especially strong inflammatory activity, or it could mean that there are more axons to lose at that point, Saidha says.

The results must be replicated in other MS cohorts and on a variety of OCT instruments, Saidha stresses, but he adds that GCIP thickness, especially in early MS patients with active disease, could provide a useful outcome measure alongside MRI in clinical trials.

Although the eye is part of the brain, it is physically separate and morphologically distinct, with its own blood supply, a characteristic cellular and molecular organization, and a lack of myelin. Therefore, it’s surprising that OCT measurements of retinal deterioration—in this study and others—are turning out to reflect the damage MS causes in the brain, says Daniel Reich, a neuroradiologist at the U.S. National Institutes of Health Clinical Center in Bethesda, Maryland. “It’s sort of happily surprising because [the eye] is so accessible—you can image it with such high resolution just by looking through the pupil.”

Saidha’s results suggest that the retina is a microcosm of the brain, Reich says—and they highlight some valuable insights about MS. For one thing, the fact that such extensive inflammation and neuronal damage appears in the absence of myelin “raises questions about the extent to which demyelination is secondary or primary in the disease,” he says.

If GCIP thinning proves to be a valid way to track neurodegeneration, it could take a place alongside MRI as an outcome measure in clinical trials. It might prove especially useful for assessing neuronal repair and protection from neurodegeneration, Reich adds. “The more independent measurements you make, the more accurately you can measure,” he says. “That translates into shorter trials and fewer patients.”

Image credit

Thumbnail image on landing page. "New Orleans, Louisiana, USA." Nighttime view of multi-story building with decorative iron galleries, Royal Street at St. Peter, French Quarter. Copyright, 2004, Falkue. Released under the GNU Free Documentation License.