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 process used
for pruning 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 caused by strokes or tumors
produces visual field loss that extends across large and
uniform areas that are almost identical for each eye,
following the major visual 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 the ocular disease can be totally controlled in
patients who have advanced glaucoma in both eyes,
something quite remarkable and unexpected can be readily
observed. As the previously sick axons recover, 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 investigating the role
of the brain in modulating glaucomatous functional
damage may not only help develop treatments for one of
the world’s leading causes of blindness, but could
contribute to the development of future therapies for
conserving bilateral cerebral function in 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 which the outer two-thirds of the
eye’s aqueous humor drainage system can be removed
microsurgically without 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 first to 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 colleagues at 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 to noninvasively investigate any existing tendency
for bilaterally coordinated conservation of function in the
living brain. Historically, Alzheimer’s post mortem studies
have been performed on only one brain hemisphere, so any
tendency for avoidance of precise overlap of functional
zone loss 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 fields in 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 midbrain 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
http://vision.edu.au/
http://neuroscience.anu.edu.au/EIN_CIs/TedMaddess.html
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 factors alluded 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
http://www.psy.vanderbilt.edu/faculty/calkinslab/
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