AMD Update 15 Visualization of Living Rods and Cones

Back in February 2009, I first wrote about David Williams and his research group at the Institute of Optics at the University of Rochester, and their announcement that they had used adaptive optics to image RPE cells in vivo. That report, AMD Update 4: Does Visualizing RPE Cells Hold the Key to Understanding AMD? gave us a first look at how adaptive optics could image some of the retinal cells in the back of the eye in helping to understand how the effect of new drugs and treatments could be visualized in the living eye, providing a diagnostic mechanism to see changes in RPE cells, possibly when applying some of the new retinal treatment techniques.

Well, another group of researchers at  the same Institute of Optics at the University of Rochester, along with colleagues from several other research institutions have done it again. This time using their knowledge of applying adaptive optics to visualizing the much smaller photoreceptor rod cells present in the living eye.

This innovation, described in two papers in the Optical Society's (OSA) open access journal Biomedical Optics Express, will help doctors diagnose degenerative retinal eye disorders sooner, leading to quicker intervention and more effective treatments.

Here is the complete press release from the OSA, describing the two papers recently published:

Historic First Images Of Rod Photoreceptors In The Living Human Eye

Adaptive optics technology likely to spur sight-saving interventions, usher in new era of eye disease research, diagnosis and treatment

08 Jun 2011 

Scientists today reported that the tiny light-sensing cells known as rods have been clearly and directly imaged in the living eye for the first time. Using adaptive optics (AO), the same technology astronomers use to study distant stars and galaxies, scientists can see through the murky distortion of the outer eye, revealing the eye's cellular structure with unprecedented detail. This innovation, described in two papers in the Optical Society's (OSA) open access journal Biomedical Optics Express, will help doctors diagnose degenerative eye disorders sooner, leading to quicker intervention and more effective treatments.

"While therapies are only emerging, the ability to see the cells you are trying to rescue represents a critical first step in the process of restoring sight," says researcher Alfredo Dubra of the University of Rochester in New York, who led the team of researchers from Rochester, Marquette University, and the Medical College of Wisconsin (MCW), Milwaukee. "It's impossible to overemphasize how important early detection is to eye disease."

"One of the major hurdles in detecting retinal disease is that by the time it can be perceived by the patient or detected with clinical tools, significant cellular damage has often already occurred," adds team member Joseph Carroll of MCW.

The breakthrough that is ushering in a new era of eye disease research, diagnosis, and treatment is an improved design of a non-invasive adaptive optics imaging system. Dubra and his colleagues were able to push the device's resolution to its optical limits of nearly 2 microns (a micron is 1/1,000 of a millimeter), or the approximate diameter of a single rod in the human eye.

Rods are much more numerous than cones and are vastly more sensitive to light. With the optical design method successfully demonstrated by Dubra's team, even the smallest cone cells at the center of the retina, known as the foveal center, can be seen very clearly. Rods can be seen clearly in a less central retinal location.

"This is a really exciting breakthrough," says Steve Burns, a professor in the School of Optometry at Indiana University, who is not involved in the Biomedical Optics Express research. "Imaging contiguous rod mosaics will allow us to study the impact of a whole new class of blinding disorders on the retina. Since many of the eye diseases most amenable to intervention affect the rods, this should become a major tool for determining what treatments work best for those disorders."

De-twinkling Stars, Visualizing Rods

In astronomy, adaptive optics is able to correct for the blurring effect of Earth's atmosphere, effectively removing the "twinkling" from starlight and rendering cosmic objects as very sharp points of light. To achieve this correction, the AO system requires a reference point-either a bright, nearby star or an artificial "guide star" produced in the upper atmosphere by lasers mounted on a telescope. By monitoring that reference point, AO systems use a deformable mirror to create the exact but opposite distortion that is happening in the atmosphere. The result is a clearer image with much greater resolution.

Just as light passing through the atmosphere becomes bent and distorted, so too does light passing through the front part of the eye. This distortion is inconsequential on the scale of human vision, but poses a significant barrier in the microscopic realm of medical imaging.

In 1997, David Williams of the University of Rochester led the group that first demonstrated using AO technology to study the interior of the human eye. In this system, called an adaptive optics ophthalmoscope, a laser creates a reference point that is used to correct the blurring of the image obtained with a fundus camera. Today the fundus camera is commonly replaced by a second laser for imaging, which is known as an adaptive optics scanning laser ophthalmoscope. By moving the laser point across the retina and correcting the distortion along the way, line-by-line an accurate image emerges, in much the same way that a CRT monitor renders an image.

Though earlier AO systems could effectively image cones and have become a mainstay of high-resolution retinal imaging research, the smaller rods, which outnumber cones 20 to 1 in the retina, have eluded clear and contiguous observation in the living eye.

Breakthrough Design

The breakthrough in the design of the AO instrument that led to clearly visualizing rods was, according to Dubra, "embarrassingly simple, and relied on well-known equations and concepts." By simply folding the spherical mirrors that act as lenses in the instrument into a three-dimensional structure, the image quality of the retina was improved sufficiently to clearly resolve the contiguous rod mosaic, as well as the entire cone mosaic at the foveal center.

"By combining careful optical engineering, excellent adaptive optics control, and knowledge of the visual system the authors have made a major advancement in both biomedical imaging and vision science," says Burns.

Improving Patient Care

According to the researchers, their next step is to develop a clinical model that could be widely available. A related task is simplifying and teaching the art of interpreting AO images to guide clinical decisions about diagnosis and treatment.

When that occurs, hopefully in the next 5 to 10 years, doctors will likely be able to routinely peer into a living human eye with such precision and clarity that they will be able to see and evaluate individual rods-and do three things never before possible: accurately describe the physical presentation of specific rod disorders-the "phenotype" of a disease, intervene with early treatment at the first sign of disease, and even determine how individual cells are responding to a specific treatment.

"That's what's really exciting about this imaging device: it can really make a difference in a patient's life," says Carroll. "The ability to now resolve these cells opens up new possibilities for improving care that researchers have been anticipating for a long time-such as using the information in these retinal images to aid in targeting, delivering, and evaluating therapies."


Paper: "Non-invasive imaging of the human rod photoreceptor mosaic using a confocal adaptive optics scanning ophthalmoscope" Biomedical Optics Express, Volume 2, Issue 7, pp. 1864-1876.

Abstract:

The rod photoreceptors are implicated in a number of devastating retinal diseases. However, routine imaging of these cells has remained elusive, even with the advent of adaptive optics imaging. Here, we present the first in vivo images of the contiguous rod photoreceptor mosaic in nine healthy human subjects. The images were collected with three different confocal adaptive optics scanning ophthalmoscopes at two different institutions, using 680 and 775 nm superluminescent diodes for illumination. Estimates of photoreceptor density and rod:cone ratios in the 5°-15° retinal eccentricity range are consistent with histological findings, confirming our ability to resolve the rod mosaic by averaging multiple registered images, without the need for additional image processing. In one subject, we were able to identify the emergence of the first rods at approximately 190 μm from the foveal center, in agreement with previous histological studies. The rod and cone photoreceptor mosaics appear in focus at different retinal depths, with the rod mosaic best focus (i.e., brightest and sharpest) being at least 10 μm shallower than the cones at retinal eccentricities larger than 8°. This study represents an important step in bringing high-resolution imaging to bear on the study of rod disorders.


Paper: "Reflective afocal broadband adaptive optics scanning ophthalmoscope" Biomedical Optics Express, Volume 2, Issue 6, pp. 1757-1768.

Abstract:

A broadband adaptive optics scanning ophthalmoscope (BAOSO) consisting of four afocal telescopes, formed by pairs of off-axis spherical mirrors in a non-planar arrangement, is presented. The non-planar folding of the telescopes is used to simultaneously reduce pupil and image plane astigmatism. The former improves the adaptive optics performance by reducing the root-mean-square (RMS) of the wavefront and the beam wandering due to optical scanning. The latter provides diffraction limited performance over a 3 diopter (D) vergence range. This vergence range allows for the use of any broadband light source(s) in the 450-850 nm wavelength range to simultaneously image any combination of retinal layers. Imaging modalities that could benefit from such a large vergence range are optical coherence tomography (OCT), multi- and hyper-spectral imaging, single- and multi-photon fluorescence. The benefits of the non-planar telescopes in the BAOSO are illustrated by resolving the human foveal photoreceptor mosaic in reflectance using two different superluminescent diodes with 680 and 796 nm peak wavelengths, reaching the eye with a vergence of 0.76 D relative to each other.

The papers appear as part of a special feature issue of Biomedical Optics Express on "Cellular Imaging of the Retina."

Laser Treaments for AMD Show Promise

An edited version of this column, along with an accompanying table listing the market participants, was published in the January 15, 2000 issue of Ocular Surgery News.

Treatments for AMD, Even Prevention, are on the Horizon

Irving J. Arons
Managing Director
Spectrum Consulting

This year, as reported at the 1999 AAO Meeting in Orlando, for the first time it appears that one or more methods for stopping the progress of age-related macular degeneration (AMD) and, perhaps, even to improve vision for those who suffer from the disease, is on the horizon. And in an even bigger leap of faith, additional clinical work is being undertaken to determine if this terrible disease can be stopped before it progresses to the final stages that causes legal blindness.

What is AMD?

AMD is a progressive degenerative condition that damages the macula, the small central part of the retina in the back of the eye which provides central vision, and currently affects approximately 15 million people in the U.S., and at least double that in the rest of the world. Loss of central vision robs a person of the ability to perform tasks which require fine focus, such as reading, watching TV, or seeing faces. AMD can occur in two forms, the "dry" (non-exudative) form and the "wet" (exudative) form, and both can coexist in the same patient. The dry form, accounting for between 85% to 90% of AMD, is typically characterized by a build-up of drusen, white to yellow deposits underneath the retina in the macula that initially results in minimal visual symptoms. With time, vision may gradually deteriorate, depending upon drusen type, size, quantity, and location. More importantly, the presence of drusen constitutes a risk factor to develop severe vision loss due to the development of geographic atrophy or the development of the exudative (wet) form of AMD, accounting for approximately 10% to 15% of all AMD, but 90% of severe vision loss (legal blindness) in those over the age of 50.

The wet form is typically characterized by a proliferation of abnormal blood vessels (i.e., choroidal neovascularization [CNV]) underneath the macula and results in a more rapid and profound loss of central vision. About 1.5 million to 2.5 million American people (approximately 10% to 15% of all AMD cases) currently have the wet form, which accounts for the vast majority of AMD patients who are legally blind. AMD is the leading cause of blindness in the U.S. for all age groups. For persons 65 to 74 years of age, the prevalence approaches 30%. In the U.S., the current annual incidence of AMD is approximately 2 million people, 200,000 to 300,000 of whom have the wet form. It is expected that both the incidence and prevalence of AMD will increase substantially with the aging of the population.

Treatments for Wet AMD: Laser Photocoagulation

Currently, there is no clinically proven interventional therapy for dry AMD while a minority (about 15%) of patients with the wet form of AMD can be treated using laser photocoagulation, which works to close and stop progression of the bleeding CNV vessels. Photocoagulation usually causes the immediate further loss of visual acuity due to the thermal damage done to the overlying retina, and can only be applied to those patients, with "classic", well-demarcated CNV lesions. In spite of these deficiencies, laser photocoagulation is widely employed, principally because it is the only treatment option available for sufferers of wet AMD. Approximately 42,000 laser photocoagulations were performed last year, used in less than 2% of eyes with AMD. Thus there is a need for a treatment modality suitable for a large segment of AMD patients that selectively closes the choroidal neovessels with out damaging overlying neurosensory retina and without causing further loss of vision. The photodynamic therapy (PDT) approach appears to be one such treatment.

Photodynamic Therapy for Wet AMD

Most of the AMD news to date, has been on the ongoing studies of photodynamic therapy to stop the progress of classic wet AMD, those lesions that are well defined, leak heavily, and cause the most rapid deterioration of vision. Several studies are underway, with the QLT PhotoTherapuetics' team (Ciba Vision for marketing and Coherent and Carl Zeiss with the activating lasers) in the lead. QLT's PMA for Visudyne therapy recently won recommendation for approval from the FDA's Ophthalmic Drug Advisory Panel. Following behind is the Miravant team (Pharmacia & Upjohn as the marketer, and IRIDEX's Iris Medical as the laser supplier), and then Pharmacyclics (with marketing partner Alcon Laboratories, and probably Diomed as the laser supplier). FDA final approval of QLT's Visudyne injection therapy might be in hand before this article reaches print, most likely in the first quarter of 2000. Miravant's Photopoint therapy has completed enrollment of patients in its Phase III clinical trial, with a PMA expected to be filed sometime in 2000 or 2001. Pharmacyclics' Optrin therapy is even further behind, still running Phase I/II clinical trials. (Others in preclinical trials include Nippon Chemical and Toyo Kogyo, in association with Lederle Japan.) (See the table below for a listing of the players and the drugs/lasers involved.)

In the PDT approach, a photosensitizer is administered intravenously, which selectively accumulates in the neovascularized tissue. A dose of carefully calculated laser light is administered directly to the lesions, which activates the photosensitizer causing death to the cells and destroying the vessels. It is important to note that the effect of PDT treatment is photochemical and there is no accompanying thermal reactions. Although the results are a stoppage of blood leakage from the disruption of the vessels, according to the results seen in the TAP study (Treatment of Age-Related Macular Degeneration with Photodynamic Therapy), as reported at the Vitreoretinal Update '99 meeting held just prior to the AAO, the effect appears to be temporary, and as many as four treatments per year may be needed. However, there are indications that the recurrance of bleeding should lessen with time. The problem is the cost of the treatment. Visudyne is expected to be priced at about $1200 per dose, and with the surgeon and facility fee added in, a single treatment could cost as much as $2000, or $8000 per year. But, the results of the TAP study indicate that visual acuity, contrast sensitivity, and angiographic outcomes are better in verteporfin-treated eyes, than those receiving a placebo. Verteporfin therapy can safely reduce the risk of vision loss in eyes with predominantly classic CNV lesions. However, vertoporfin therapy does not appear effective for occult CNV, typically poorly defined and diffuse lesions with less leakage, the most common form, which accounts for over 70% of all "wet" AMD. In anecdotal information picked up at the AAO meeting, even though the cost appears high, most of the retinal surgeons we spoke with, expect to use the PDT approach with most of their wet AMD patients, rather than laser photocoagulation.

Newer Laser Treatments for Wet AMD

However, there are several emerging new laser treatments for AMD currently undergoing clinical trials. A few are for the treatment of wet AMD, and at least two for the prophylactic treatments of patients with high-risk drusen in the pre-neovascularization stage of dry AMD, to prevent or delay CNV.

One prospective randomized, placebo-controlled, multicenter clinical trial underway to treat wet AMD patients with subfoveal occult choroidal neovascular membranes (CNVM) with a low intensity laser is the "Transpupillary Thermotherapy for Choroidal Neovascularization" (The TTT4CNV Clinical Trial), sponsored by IRIDEX. This study uses the Iris Medical OcuLight Slx 810 nm diode laser in its unique long-pulse/large-spot size mode, known as "Transpupillary Thermotherapy (TTT), to close the CNVM without collateral damage to the overlying central retina. The laser is used to induce localized hyperthermia, but below the coagulative threshold, to close the choroidal vessels. In a recently published study Elias Reichel, MD of The New England Eye Center (Boston) noted that in a small sample of eyes (16 eyes of 15 patients), 75% of TTT patients experienced improved or stable visual acuity post therapy. Another small study, presented at this year's AAO meeting by Richard Newsome, MD, performed at the King's College Hospital in London, UK, showed that after an average of 6.5 months follow-up after the TTT treatment, the CNV resolved in 71% of treated eyes and visual acuity stabilized in 86% of treated eyes.

Iridex is also involved in a second laser photocoagulation study for the indirect closure of subfoveal occult or classic CNVM through the laser treatment of the extrafoveal feeder vessels. This treatment, uses dynamic high-speed indocyanine green (ICG) dye-enhanced angiography to identify and localize the tiny feeder vessels, and the same OcuLight Slx 810 nm diode laser, to treat them with a train of repetitive infrared laser pulses. In an initial study, reported by Bert Glaser, MD, at the Vitreoretinal Update meeting preceding the AAO, over 80% of the feeder vessels treated were closed one day following treatment, with the patients noting a subjective improvement in vision and minimal side effects. The company is in the process of considering undertaking a multi-center study of this procedure.

Laser Therapy for Dry AMD

But, perhaps even more exciting than the studies underway to treat wet AMD, are the two studies being undertaken by IRIDEX and the one by the National Eye Institute (NEI) to prophylactically treat patients at risk with drusen secondary to dry AMD. The idea is to attack the disease much earlier in its course to reduce drusen, stabilize of improve vision and possibly prevent or delay the progression to the exudative form. The first is a therapeutic treatment to reduce drusen for vision improvement. An article in the November issue of Ophthalmology, entitled "Therapeutic Benefits of Infrared (810 nm) Diode Laser Macular Grid Photocoagulation in Prophylactic Treatment of Nonexudative Age-Related Macular Degeneration", by Joseph Olk, MD, of the Retina Center of St. Louis, et al, discusses the 2-year clinical pilot trial in detail. The findings showed evidence that laser therapy resolved the drusen and improved vision. This study used both visible laser burns and subthreshold (invisible) laser treatments to determine if the effects on the reduction/elimination of drusen would improve/stabilize visual acuity and reduce/delay the incidence of CNV. Results of the pilot study showed resorption of drusen in 68% of treated eyes and visual acuity improvement in 24% of a subset of treated eyes after a single treatment. One purpose of the pilot study was to determine the appropriate laser dose to be used in a follow-up prophylactic study, described below. (There is some evidence that the therapeutic approach is effective, while there is no evidence yet that the prophylactic approach is effective.)

The second IRIDEX-sponsored trial, the "Prophylactic Treatment of Age-Related Macular Degeneration" (PTAMD) trial, following up on the results obtained with the subthreshold treatments done in the study above, is designed to more definitively evaluate the prophylactic treatment of high-risk drusen-evident patients using minimal, gentle, subthreshold micropulse 810 nm laser treatments placed in a grid surrounding the drusen, to halt or delay progression from the dry form of AMD to the wet form. The PTAMD trial is currently in its second year, with over 400 patients participating, of an anticipated 1000 to 1300 to be enrolled. Study results are anticipated in about three years.

And the NEI-sponsored study, called "Complications of Age-Related Macular Degeneration Prevention Trial" (CAPT), is to determine if low intensity argon laser treatment prophylactically decreases vision loss for people at risk for severe AMD. Twenty-four selected sites across the country are participating in the CAPT trial. It is designed to assess the safety and effectiveness of low intensity laser light to prevent disease progression and loss of vision in people who are at risk for severe AMD. The CAPT study will enroll a total of 1000 patients at 24 clinical centers across the United States during an 18-month period. The trial is expected to last at least five years.

Unanswered Questions

An important question, yet to be answered, is who will do the needed diagnosis to determine who is eligible for treatment to prevent this disease. In today's managed care environment, the retinal specialist who has the laser and diagnostic tools to treat the early stages of the disease rarely sees the patients at risk. They are usually seen by the general ophthalmologist. Will he/she be motivated to look for the very early signs of AMD to get his/her patients into a prophylactic or early treatment program. Perhaps, as the word is spread that such treatments are available, and with the advent of the internet, a more educated consumer/patient will know to ask the right questions, and to demand the appropriate treatments. Only time will tell, but the next few years will be very interesting in the diagnosis and treatment of AMD.

NeoVista Epi retinal Strontium 90 Treatment for AMD Update

In mid-June, NeoVista announced the initiation of its CABERNET (Cnv secondary to AMD treated with BEta RadiatioN Epiretinal Therapy) clinical trial for the treatment of subfoveal choroidal neovascularization associated with age-related macular degeneration (AMD).

The CABERNET study will employ the company’s Epi-Rad90 ophthalmic system to deliver Strontium 90 directly to the retina (using an outpatient partial vitrectomy), along with an injection of an anti-VEGF agent (Lucentis) at the time of surgery, followed by a second injection of Lucentis 30 days thereafter. The control arm of the study will utilize Lucentis injections alone.

The company noted that it was following the PIER regimen for Lucentis in the control arm, which represents 3 initial monthly injections and then quarterly after that. There is also a rescue plan in place for those patients who begin reverting back to worsening VA. They chose to follow this path, as PIER is the only trial that treated all types of CNV, thus providing them the broadest possible label.

The CABERNET clinical trial will include 30 clinical sites, with 20 in the U.S., and 10 spread across Europe, Israel, and South America. The study will involve 495 patients followed for 2 years; 330 receiving the 24 Gy dosage of Strontium-90 plus Lucentis, and 165 receiving only the Lucentis injections.

In addition to the information about the start of the CABERNET study, the company also sent along information updating its previously reported results of both its Radiation Only feasability study, now out to 18 months, with vision holding at +6.4 letters (as shown below in Graph 1), and 9 month data on its Concomitant Study, which utilized two injections of Avastin along with a treatment of Strontium-90. These results are shown in Graph 2 below.

Graph 1.

Graph 2.

(See my February 14, 2007 report for the full initial story.)

These updated results were reported by the company at the recent (May 30 – June 2nd) Macular Society Meeting held in London. The nine-month Concomitant Study results show equivalent results to the ANCHOR Study, which applied monthly doses of Lucentis to patients over a 2 year period.

As a result of this updated data and the start of the CABERNET study, the following key questions were posed to the company:

1) The Epi-Rad90 arm of the feasability study appears to be showing increased VA, especially in months 9 - 12. Although the results decreased again (according to your reports) out to month 18. Is there any thought of performing a second treatment of radiation, or adding an injection of anti-VEGF agent at the two-year period?

Given that radiation alone is likely not to have the same efficacy as concomitant treatment over a 2-year period, we must wait to learn the 2 year results of both arms for proper comparison. As for the possibility of a second radiation treatment, this is an opportunity that will require much investigation. At this stage of our existence, we are not able to investigate all opportunities presented us and realize that concluding the CABERNET trail must remain our first priority.

2) The Concomitant Study arm results appear to be leveling off after 6 months. Would another shot of Avastin at, say 9 months, be expected to show further improvements?

Time will tell. We will likely see an increase in cataract formation in the treated group in the first year post-op. Post-cataract procedure exams showed an increase in VA again between 9 and 12 months in the Radiation Only Study. As you know, cataract formation is a common occurrence in patients undergoing vitrectomy. Our procedure has shown a much lower incidence of cataract procedure than standard Vitrectomy outcomes. We believe this is due to the use of a partial versus complete Vitrectomy. Another point to make; many of those eligible for our procedure will have likely already had cataract surgery due to natural change.

3) Is OCT inspection of the retina part of the followup examinations – similar to the PRONTO Study?

We are utilizing both OCT and FA (fluorescein angiogram) in CABERNET via assigned Reading Centers. In our feasibility studies, OCT and FA were utilized. For CABERNET rescue requirements, one component of judging whether or not to re-inject will be the OCT image analysis.

(A writeup of the PRONTO Study is shown in a separate report – see Two-Year Results of the PRONTO Study on this web site.)



For Information Only:

The MARINA study enrolled patients with occult and minimally classic choroidal neovascularization (CNV), the form of CNV found in most patients with wet AMD, while the ANCHOR study enrolled patients with predominantly classic CNV.

MARINA (Minimally classic/occult trial of the Anti-VEGF antibody Ranibizumab (Lucentis) In the treatment of Neovascular AMD) was a Phase III randomized, multi-center, double-masked, sham-controlled study of 716 patients in the United States with minimally classic or occult wet AMD who were randomized 1:1:1 to receive intravitreal ranibizumab injections (0.3 mg or 0.5 mg) or a control regimen once a month for two years. The control regimen consisted of a sham injection, meaning the treating physician prepared and anesthetized the patient’s eye but did not perform an injection.

ANCHOR (ANti-VEGF Antibody for the Treatment of Predominantly Classic CHORoidal Neovascularization in AMD) was a Phase III randomized, multi-center, double-masked, active-treatment controlled study comparing two different doses of Lucentis to verteporfin (Visudyne) photodynamic therapy (PDT) in 423 patients with predominantly classic wet AMD in the United States, Europe and Australia. Patients were randomized 1:1:1 to receive intravitreal ranibizumab injections (0.3 mg or 0.5 mg) once a month or PDT every three months for two years.