Neuro-ophthalmology research moves toward more effective treatments

Researchers are gaining insights into the molecular processes behind neuro-ophthalmic diseases with sophisticated science and better imaging.

The best way to understand where neuro-ophthalmology is and where it is going, according to one subspecialist, is to compare it to the state of parasitology 50 to 60 years ago, and the effort at that time to understand and cure malaria.

Alfredo A. Sadun

“Nobody could cure malaria or schistosomiasis until they understood the nature of these diseases,” said Alfredo A. Sadun, MD, PhD. “Then some good parasitologists took advantage of new scientific techniques that were available to them to understand at the cellular level what was going on. Instead of just labeling the species of mosquito or snail that was the carrier, instead of taxonomy, they used their new tools to look more carefully at the parasite. They asked what was happening at the cellular level and discovered, for example, how certain parasites used certain molecular tricks to hide from the immunological system of the host.”

Parasitologists ultimately learned how to block the molecular messages of the parasite, such as the protozoan Plasmodium, and created new treatments for the disease.

By looking at neuro-ophthalmologic diseases on a cellular level, Dr. Sadun said, he is confident that neuro-ophthalmologists will be able to make similar advances in treatment in a field where currently there are few therapeutic options.

“I think that within the next 5 years, we are going to discover ways of interrupting the cascade of molecular events that cause forms of blindness,” he told Ocular Surgery News in a telephone interview. “Neuro-ophthalmologists are actually intervening and fixing problems that they used to only and characterize. We are now going beyond the traditions of simple phenomenology.”

Leber’s research key

As a professor of ophthalmology and neurologic surgery at Doheny Eye Institute, Dr. Sadun has been among the neuro-ophthalmologists at the forefront of research in the field who have recently taken an interest in Leber’s hereditary optic neuropathy (LHON). He said that study of this inherited disease may be key to understanding and ultimately treating other systemic neurologic diseases such as Alzheimer’s and Parkinson’s diseases.

According to Dr. Sadun, LHON is an ideal model for neuro-ophthalmologic research because it presents as sudden blindness in one eye followed a few weeks later by blindness in the fellow eye. Hence, the first eye flags events about to develop in the second eye, and this offers a unique opportunity to conduct studies into the mechanisms of the disease and the efficacy of potential treatments.

In addition, he said, it is believed that the apoptotic mechanisms that cause retinal ganglion cell death in LHON may be the same mechanisms that cause neuronal cell death elsewhere in the brain in diseases such as Parkinson’s and Alzheimer’s.

“It’s very exciting to realize that now we can work with neurologists and neuroscientists with insights gleaned from the eye and then hand off to principles that may have applications for the rest of the body,” Dr. Sadun said.

Molecular biology of Leber’s

The joint efforts between neurologists, neuroscientists and neuro-ophthalmologists in this research have broken down barriers between the fields, Dr. Sadun said.

He has collaborated on a number of studies with Italian neurologist Valerio Carelli, MD, PhD. Dr. Sadun said Dr. Carelli’s understanding of the complex molecular biology of LHON makes him an invaluable partner in reaching an overall understanding of the disease.

“I consider [Dr. Carelli] a molecular biologist. He probably understands the genetic control of mitochondria for these diseases better than anybody else, and that makes him an extremely precious collaborator,” Dr. Sadun said.

Drs. Carelli, Sadun and colleagues recently published several papers describing examinations in asymptomatic carriers of LHON in which they found color vision defects in patients with seemingly healthy vision. Until this finding, LHON was always thought to be characterized by sudden vision loss. These and other studies by this group showed that even seemingly asymptomatic carriers could manifest subtle but chronic changes.

In another paper, recently published in the American Journal of Human Genetics, the two physicians and their colleagues looked at the mitochondrial DNA of Leber’s cases for clues into the genetic mutations present.

In an editorial published this month in the British Journal of Ophthalmology, Drs. Sadun and Carelli described mitochondria as intracellular organelles that carry “their own peculiar genome … that reflects their bacterial origin.” Each mitochondrion carries multiple copies of mtDNA, the mutations of which are associated with diseases such as LHON and the cellular apoptosis they cause.

The authors said that understanding the role of mitochondria is likely the key to understanding the pathogenesis of a variety of ophthalmologic degenerative diseases.

“Control of mitochondrial mediated apoptosis will become a holy grail in general,” they said.

From LHON to optic neuritis

Many neuro-ophthalmic diseases fall under the category of mitochondrial diseases, said John R. Guy, MD. At the University of Florida, where he is Dean’s Distinguished Professor in Neuro-Ophthalmology, Dr. Guy has investigated specific gene expressions in LHON and the role of mutated mitochondrial DNA. He presented this work at this year’s Association for Research in Vision and Ophthalmology meeting.

He also looked at the role of mitochondria in neurodegeneration in experimental animal models of multiple sclerosis and presented that information at this year’s meeting of the American Academy of Neurology.

He said his studies provide further evidence for the role of mitochondria in neurodegeneration, suggesting that protecting nerve cells against oxidative stress could prevent apoptosis in optic neuritis.

His work has also helped to debunk earlier theories regarding cellular death, he told Ocular Surgery News in a telephone interview.

“It used to be thought that it was loss of myelin, the rubber coating around the axons, that was a cause of optic neuritis,” he explained. “Now people are finding that it’s actually loss of axons, which is why a lot of people don’t recover. The problem is trying to figure out which ones don’t recover so you can apply your treatments early, because after they’ve lost their axons there’s nothing you can do to make it grow back again.”

He said the field of neuro-ophthalmology has come a long way from the work done in the landmark Optic Neuritis Treatment Trial, which built a foundation for understanding the disease’s symptoms and risk factors.

OCT and neuro-ophthalmology

Advances in the field of neuro-ophthalmology are not limited to molecular and genetic research. Recently developed imaging techniques now allow physicians to identify patients at risk for neurologic diseases and to identify relationships between vision loss and the state of the retinal nerve fiber layer (RNFL).

Peter J. Savino

Specifically, optical coherence tomography (OCT) is showing its value for research in this area, said OSN Neuro-Sciences Section Member Peter J. Savino, MD.

“What we are now interested in as neuro-ophthalmologists is that these machines, particularly the OCT, can measure the nerve fiber layer in the back of the eye. So you can in vivo look at the retina, look at the nerve fiber layer of the retina, look at the various other layers of the retina, and follow this in certain diseases,” Dr. Savino said.

The imaging modality may also be useful for evaluating the efficacy of treatments, he said. A study recently published in Ophthalmology showed that OCT measurements of the RNFL can be used as clinical outcome measures in patients with multiple sclerosis, Dr. Savino said.

“That’s important when you realize you can lose a whole lot of nerve fibers before you develop a visual field defect,” he said.

As knowledge of neuro-ophthalmic diseases has grown, neuro-ophthalmologists have become increasingly reliant on techniques such as OCT imaging, Dr. Savino noted.

“Now more and more neuro-ophthalmologists won’t practice without this technology,” he said.

Treatment options

Despite the advances in the field of neuro-ophthalmology, few or no treatment options exist for many neuro-ophthalmic diseases. But researchers are hopeful, particularly those studying LHON.

“I will be disappointed if we don’t see a treatment for Leber’s in the next 5 years,” Dr. Sadun said.

In the search for neuroprotective agents to stop the process of apoptosis, LHON provides the best opportunity to evaluate treatments, he said.

“The best place to test neuroprotection is in a disease where you have apoptosis and you know when it’s going to happen,” he said.

For more information:

• Alfredo A. Sadun, MD, PhD, can be reached at Doheny Eye Institute, University of Southern California, 1450 San Pablo St., Los Angeles, CA 90033; (323) 442-6417; fax: (323) 442-6407; e-mail: asadun@usc.edu.
• John R. Guy, MD, can be reached at the Department of Ophthalmology, University of Florida, Box 100284 JHMHSC, Gainesville, FL 32610-0001; 352-392-3451; e-mail: johnguy@eye.ufl.edu.
• Peter J. Savino, MD, can be reached at Wills Eye Hospital, Neuro-Ophthalmology Service, 840 Walnut Street, Philadelphia, PA 19107; 215-928-3130; fax: 215-592-1923; e-mail: pjsavino@aol.com.

References:

• Carelli V, Achilli A, Valentino ML, et al. Haplogroup effects and recombination of mitochondrial DNA: novel clues from the analysis of Leber hereditary optic neuropathy pedigrees. Am J Hum Genet. 2006;78(4):564-74.
• Fisher JB, Jacobs DA, Markowitz CE, et al. Relation of visual function to retinal nerve fiber layer thickness in multiple sclerosis. Ophthalmology. 2006; 113(2):324-32.
• Guy J, Qi X, et al. Rescue of a mitochondrial deficiency causing Leber Hereditary Optic Neuropathy. Ann Neurol. 2002;52(5):529-530.
• Quiros PA, Torres RJ, Salomao S, et al. Colour vision defects in asymptomatic carriers of the Leber’s hereditary optic neuropathy (LHON) mtDNA 11778 mutation from a large Brazilian LHON pedigree: a case-control study. Br J Ophthalmol. 2006;90(2):150-3.
• Sadun AA, Carelli V. The role of mitochondria in health, ageing, and diseases affecting vision. Br J Ophthalmol. 2006;90(7):809-810.

• Jared Schultz is an OSN Staff Writer who covers all aspects of ophthalmology. He focuses geographically on Europe and the Asia-Pacific region.