Glaucoma 360 New Horizons – Pt1

I recently attended the 2nd Annual Glaucoma 360: New Horizons Forum. As explained by the organizers, it was created to highlight unmet clinical needs in the field of glaucoma. To do this, the forum is open to academia and industry, bringing together known leaders in science, business, venture capital and the FDA to discuss emerging ideas in the field of glaucoma therapy.  The meeting was held at the Palace Hotel, San Francisco on February 7th, 2013. More information can be found at this link.

In a series of blog entries, I will document the sessions that I found interesting. These postings will be in parts because there was a lot of comment worthy material. Part 1 addresses only the keynote speech.

The keynote was from Dr. Louis Cantor, a renowned Professor of Ophthalmology from Indiana University. The talk was entitled “State of Glaucoma Therapy 2013: Is 13 our lucky number?” His optimism here being based on:

• Central Nervous System (CNS) visual pathway changes support earlier and more aggressive treatment
• Imaging advances allow better definition of the structural changes in the ONH
• Visual function testing becomes more objective and comprehensive
• Neuroprotection becomes a more integral part of our therapeutic strategies
• Surgical devices advances allow for safer and effective procedures

I’ll try and tackle each of these in turn, first reporting what I heard and then adding my own comments.

The first related to structural measurements using MR imaging. It struck me as interesting that, in looking to structural measurement for early intervention, glaucoma specialists were citing a study using MRI. Firstly, there’s limited data supporting such findings. Secondly, for a screening application – i.e., to support early intervention – one might consider cheaper imaging methods. The widespread adoption of MRI screening is highly unlikely. His views stemmed largely from a 2012 IOVS paper by Chen et al., the control set was compared to patients with established primary open-angle glaucoma (POGA), so it is at best a stretch to suggest the suitability to early intervention. The paper shows how different structures in the brain decreased in volume as a result of the glaucomatous damage. Dr. Cantor explained this as: “if you don’t use it you lose it”. Other areas were shown to increase, suggesting a compensation for the loss of sensory input. Consistent was that the cross section area of the optic nerve, which is highly visible and easily measured in MRI, correlated with RNFL thickness loss in being significantly lower than the healthy control group. The authors conclude quite simply that MRI revealed widespread abnormalities in the CNS beyond the visual cortex. Yet, from these findings we cannot tell if a single measurement metric has better discriminatory ability than any other for differentiating glaucomatous patients and normal patients, and certainly not in the case of early glaucoma damage. Dr. Cantor did say that for him, personally, “it supports the argument for earlier and more aggressive treatment”. I tend to disagree as the evidence is simply not there. I also wonder why it is that neuro-ophthalmologists are so interested in the various retinal layers of the eye. The group at Johns Hopkins have shown evidence that, in a retrospective study, the thickness of the inner nuclear layer (INL) could be a useful predictor of disease progression in multiple sclerosis (MS) patients. In some cases, the change in INL preceded indications of abnormality in MRI scans. These measurements are being made using an OCT scanner and automated segmentation software.

I find it astonishing that with all the historical data using OCT for diagnosing ocular diseases and now with the increasing evidence that, as an extension of the CNS, the eye could have clinical value for the management and diagnosis of other neuropathies, glaucoma specialists might now look to MRI.

As an optic neuropathy, structural imaging of the eye using OCT is of course important. So Dr. Cantor’s next topic was using OCT-based measurements of the optic nerve head. We learned that “cupping”, the excavation at the optic nerve caused by atrophy of the nerve fiber layer (NFL), “doesn’t tell us too much and that we really don’t understand the structure of the nerve well, and we really haven’t been able to quantify it very well, yet.” Cupping for sure is not relevant as disc size influences cup size, whereas the measurement of interest is, at the nerve at least, the amount of healthy axons that are exiting the globe at that point. So how do we quantify this? Well, Dr. Cantor cited the recent work of Dr. Bal Chauhan who, based on some earlier work by Dr. Crawford-Downs in Dr. Burgoyne’s lab, define it at the end points of Bruch’s membrane. At the end of last year, Dr. Chauhan’s group published a proposed metric, the Bruch’s membrane opening minimum rim width, that could be used diagnostically, showing higher sensitivity and specificity compared with other metrics. “I think we’re on the cusp of redefining the optic nerve, really what is the neural retinal rim and where it is and what we really need to be looking at in the eye.” Again, I have to show some skepticism here given that such an automated metric was released in a product several years ago, and it has generated a lot more supportive literature. One need only look at this publication to understand how it delineates its measurement of the neural retinal rim using Bruch’s openings, work that was done based on Drs. Doug Anderson and Don Budenz’s guidance. Dr. Chauhan’s metric is illustrated on this web page. Note that this idea was originally published by Boris Považay et al.

And so we moved on to perimetry and how, in Dr. Cantor’s mind, we were “hitting a technological wall in terms of how much we can manipulate the data”. Visual fields only measure differential light sensitivity, which Dr. Cantor considered insufficient as that is not alone sensitive to early damage. That coupled with the difficult patient experience, questions over reliability, the lack of sensitivity and noise in the data justifies looking at alternative metrics. He cited a study using objective perimetry using multifocal visual evoked potentials (VEPs) and correlated this well with standard perimetry.

The motivation here is that objective perimetry may show a better structure-function relationship that standard perimetry. He mentioned that Diopsys were developing this technology, among others. Apparently, the post-processing techniques really remove the variability and subjectivity in the interpretation of the measurements; something that, if proven, will indeed be a good thing– a good thing in part because structure is not really used as endpoints in clinical trials for pharmaceuticals as the relationship is not well enough established. His last word on the subject was: “I think that we are on the cusp, in 2013, of maybe being able to start offering our patients an alternative to the torture test of the visual field”.

The talk then shifted to neuroprotection, referencing in particular the deeper understanding in alpha-2 agonists that act to make the retinal ganglion cells more resistant to damage. Such are in clinical trials now and may offer a more specific way to affect the ganglion cells. (Adrenergic agonists activate muscles in the eye that dilate pupils and, therefore, increase outflow of aqueous fluid.)

Dr. Cantor closed with some comments on minimally invasive glaucoma surgical (MIGS) procedures, nicely summarizing the options and the advances being made through improved technologies, and concluded the talk on an optimistic note that, for all the discussed reasons, 2013 could be “lucky 13” for glaucoma.  Let’s hope so.