Interview of William Sponsel by Katrina Norfleet

Interview of William Sponsel by Katrina Norfleet

May 21, 2014

What is the impact of your research on a broader scale? Please be as specific as possible because this is frequently the main criteria that a reporter will use to determine if a story is needed.

“In glaucoma,a leading cause of irreversible blindness, the small “wires” (axons) in the “video cable” from the eye to the brain (the optic nerve) are progressively lost. As age and other insults to ocular health take their toll on each eye, discrete bundles of the small wires within the larger optic nerve cable are sacrificed so the rest of the axons can continue to carry sight information to the brain. This quiet intentional sacrifice of some wires to save the rest, when there are decreasing resources to support them all (called apoptosis) is analogous to pruning some of the limbs on a stressed fruit tree so the other branches can continue to bear healthy fruit. As it happens, the cellular processused forpruning small optic nerve wires in glaucoma is remarkably similar to the apoptotic mechanism that operates in the brains of people afflicted with Alzheimer’s Disease.

Our new study shows something none of us really knew before, that in eyes afflicted with glaucoma, the brain is actually in charge of the axonal pruning process. This is a big surprise. In glaucoma, the loss of vision in each eye appears to be very haphazard, like a shotgun blast, with horizontal borders that reflect the internal arrangement of the wires within the eye, not the brain. Conversely, neural damage within the brain causedby strokes or tumors produces visual field loss that extends acrosslarge and uniform areas that are almost identical for each eye, following the majorvisual wiring patterns within the brain. These conflicting patterns of damage logically seemed to support the idea that the entire degenerative process in glaucoma must be occurring at random in the individual eyes, without brain involvement. Indeed, as uncontrolled glaucomatous disease progresses, there is little that can be seen to counteract this well-established impression, with areas of permanent visual field loss (where all the axons have died) mixed in arbitrarily with other areas where they are still alive but working poorly.

However, if theocular disease can be totally controlled in patients who have advanced glaucoma in both eyes, something quite remarkable and unexpected can be readily observed. As thepreviously sickaxonsrecover,the remaining scattered areas of permanent visual loss in one eye coincide remarkably well with areas that can still see in the other; the visual fields of the two eyes fitting together like a jigsaw puzzle. This results in a much better bilateral visual field with both eyes open than could possibly arise by chance.

This is exciting news, confirming that even in glaucoma the paired eyes and brain actually work together in a highly coordinated fashion to maintain the best possible binocular visual field. Visual scientists investigatingthe role of the brain in modulating glaucomatous functional damagemay not only help develop treatments for one of the world’s leading causes of blindness, but couldcontribute to the development of future therapies for conserving bilateral cerebral functionin other age-related disorders like Alzheimer’s Disease.”

How did you come to the decision to perform this study?

“Last year we published the results of 100 consecutive patients undergoing a relatively new European glaucoma surgical procedure in whichthe outer two-thirds of the eye’s aqueous humor drainage system can be removed microsurgicallywithout damaging the hundreds of tiny holes of its internal third. This refined surgery typically allows the eye pressure to be reduced to consistently low but safe pressure levels without medication, and minimizes problems with the cornea, lens and macula that might create confusion with subsequent visual field testing. That study was the firstto demonstrate significant and sustained visual field improvement after incisional glaucoma surgery, and the generally improved visual field results were remarkable for their reproducibility 6, 12, and 18 months postoperatively. It was among these bilaterally stabilized patients that complimentary jigsaw patterns became fairly obvious in the paired visual fields. A lot of credit for this important discovery should thus go to the outstanding technicians who performed the visual field testing, because these tests can be tedious, particularly for older patients, and reliable results can only be obtained with an attentive combination of technical perfectionism and good patient rapport.”

Were the results of the study what you expected? Why or why not?

“We were open to any possible outcome from the masked, refined data analyses that were carried out collaboratively with our biomedical engineering colleaguesat the University of Texas – San Antonio. The extent and statistical strength of the jigsaw effect in conserving the binocular visual field among the clinical population turned out to be remarkably strong. We were expecting a greater passive contribution from inherent anatomic symmetry factors that might be expected to enhance bilateral function, but these were not observed. The entire phenomenon appears to be under the meticulous control of the brain.”

What kind of research do you think this study may inspire? What may come next in this line of study?

“We have initiated tomographic structural studies of the retina that reaffirm that the physical loss of axons in these advanced glaucoma patients is bilaterally complimentary, as well. What is really exciting to contemplate is the possibility that analogous structural studies of the brain in individuals with advanced Alzheimer’s might demonstrate similar bilateral conservation of functional zones. Thus far, to our knowledge, no one has actually compared the precise bilateral locations of the lesions that arise within the brains of Alzheimer’s sufferers. Just as the two eyes provide two sets of visual information to our brain, all of our other sensory and motor functions have two matching sets at work, one on each side of the brain. We already know that the cellular mechanisms used for pruning axons in glaucoma and Alzheimer’s are remarkably similar, so it stands to reason that if the brain resists losing the same precise visual function area in both eyes, it may similarly avoid the simultaneous loss of other specific functional areas on both sides of the brain. Like glaucoma damage, the multiple discrete zones of brain injury in Alzheimer’s sufferers appear to arise almost at random, with no apparent rhyme or reason, on both sides of the brain. Various functional imaging methods now exist that could be used tononinvasively investigate any existing tendency for bilaterally coordinated conservation of function in the living brain. Historically, Alzheimer’s post mortem studies havebeen performed on only one brain hemisphere, so any tendency for avoidance of precise overlap of functional zoneloss may have been missed using standard histopathology. If the neurotrophic or neuroprotective factors likely to be responsible for conservation of the bilateral visual field in glaucoma can be discovered and appropriately exploited, similar substances may be of use for treating a wider range of progressive central nervous system neurodegenerations. “

(see also relevant quotes from Ted Maddess, Director of ACEVS in Australia, and from David Calkins, Director of Ocular Research at Vanderbilt, below)

How will your findings improve improve/benefit treatment of glaucoma (i.e., impact on the clinical setting).

“We have already seen the calming psychological effect these new findings can have on surgically stabilized patients who were previously very worried about going blind when shown their isolated right and left eye visual fields. They become far less perplexed and reassured when allowed to see their typically much better composite binocular visual field. It would be relatively straightforward to modify existing equipment to allow for the performance of simultaneous binocular visual fieldsin addition to standard right eye and left eye testing. This would allow doctors to monitor the relative efficiency of the brain in conserving bilateral function in different patients. In some patients with circulatory or diabetic problems, the bilateral conservation mechanism may work less well than it does in other glaucoma patients. Addressing coexisting circulatory or metabolic issues may help better conserve useful vision for these patients.“

William Eric Sponsel, MB ChB, MD, FRANZCO

Ophthalmic Surgeon and Research Director, WESMDPA

Professor of Visual Science, UIW Rosenberg School of Optometry

Adjunct Professor of Biomedical Engineering, UTSA

Co-Investigator; ARC Centre of Excellence in Vision Science

…

Comments from other investigators (coauthors Ted Maddess and Matt Reilly, and groundbreaking basic science researcher David Calkins)

Comment from Ted Maddess

“From my perspective the main points would be that there had been some evidence from primates and humans for involvement of the mid-brain and visual cortex in glaucoma (mainly Y Yucel et al.), but it was not known if the damage in the brain was simply the result of death of optic nerve fibres, or whether the brain exercised some control over the death of optic nerve cells. So, it was a chicken and egg problem. Some recent evidence from a mouse model of glaucoma (D Calkins et al.) suggested the possibly that following injury to the optic nerve cells in the eye that the brain controlled a pruning of those cells at its end of the nerve, which ultimately caused the injured cells to die. Our paper is the first evidence in humans that the brain plays a part in pruning optic nerve cells.

We don’t know if the binocular jigsaw effect is a planned or unplanned consequence of brain control, but it does suggest a new target for therapy directed at slowing the pruning. The spatial distribution of damage to optic nerve cells does suggest that the point of initial injury is often near where the nerve exists the eye ball, the so called optic nerve head. The optic nerve head has therefore been the focus of much research in glaucoma. If the brain is actively trying to maintain the best binocular field, and not just producing the jigsaw effect accidentally, that would imply some neuro-protective substance is at work preventing unwanted pruning. So in addition to trying to slow the pruning process that hypothetical neuro-trophic substance might be another target for research into future treatments for glaucoma. Since glaucoma has much in common with other important neurodegenerative disorders, our research may say something generally about connections of other nerves within the brain and what controls their maintenance.”

Professor Ted Maddess

Director, ARC Centre of Excellence in Vision Science (ACEVS)

Australian National University, Canberra, Australia

tel 011 61 2 6125 4099 fax 011 61 6125 9532

Comment by David Calkins

“It is gratifying scientifically when different approaches from different groups converge on similar conclusions. As we move forward studying interactions between the retina, optic projection and brain, it is our sincere expectation that new treatment strategies will emerge from rigorous mechanistic studies.

This clinical research focuses on patients with fairly advanced disease where many axons have already been lost. The situation in early and mid-stage glaucoma may be even more amenable to treatment and recovery than has been traditionally assumed. Our basic science work has demonstrated that axons undergo functional deficits in transport at central brain sites well before any structural loss of axons and their axon terminals. Indeed, we found no evidence of actual pruning of axon synapses until much, much later. Similarly, projection neurons in the brain persisted much longer, as well. Thus long before any "axonal pruning" occurs there is "axonal dysfunction." This is consistent with the partial recovery of more diffuse overlapping visual field defects observed by Prof. Sponsel that helped unmask the more permanent interlocking jigsaw patterns once the eyes of his severely affected patients had been surgically stabilized.

In response to axonal dysfunction, the brain targets demonstrate upregulation of BDNF (one of the trophic factorsalluded to by Prof. Maddess in his comments above) in very focal locations that correspond retinotopically to the sites of axon dysfunction specifically (Crish et al 2013, Neuroscience). Again, this is the antithesis of pruning and correlates temporally with the persistence of axon synapses demonstrated in Crish et al 2010, PNAS. So as we proceed with our future research we intend to focus on identifying and rescuing dysfunctional axons long before they reach the point of apoptotic “pruning.”

David J. Calkins, Ph.D.

The Denis M. O'Day Professor of Ophthalmology and Visual Sciences

Vice-Chairman and Director for Research

The Vanderbilt Eye Institute

Vanderbilt University Medical Center

11435 MRB IV

2215B Garland Avenue

Nashville, Tennessee 37232

Tel: (615) 936-6412;Fax: (615) 936-6410

Comment by Matt Reilly

“The clinicians can much more ably comment on the treatment implications of these findings than I can, but I wanted to pass along my excitement for being a part of this research team. The combination of clinical and biomedical engineering expertise allowed us to take what started out as a strange, serendipitous clinical observation and find that it was a highly significant change in the way we think about glaucoma. No one on the team could have taken this finding to the point of publication without close collaboration. We are currently reaching out to neurologists and psychiatrists to extend our study to neurodegenerative conditions in the brain. If the brain really is doing something to retain function, this would open the door to new therapeutic modalities.”

Matthew Reilly PhD

Asst. Professor, Department of Biomedical Engineering

University of Texas – San Antonio