Yannis M. Paulus

Effect of Pulse Duration on Size and Character of the Lesion in Retinal Photocoagulation

OBJECTIVE To systematically evaluate the effects of laser beam size, power, and pulse duration of 1 to 100 milliseconds on the characteristics of ophthalmoscopically visible retinal coagulation lesions. METHODS A 532-nm Nd:YAG laser was used to irradiate 36 retinas in Dutch Belt rabbits with retinal beam sizes of 66, 132, and 330 mum. Lesions were clinically graded 1 minute after placement, their size measured by digital imaging, and their depth assessed histologically at different time points. RESULTS Retinal lesion size increased linearly with laser power and logarithmically with pulse duration. The width of the therapeutic window, defined by the ratio of the threshold power for producing a rupture to that of a mild coagulation, decreased with decreasing pulse durations. For 132- and 330-mum retinal beam sizes, the therapeutic window declined from 3.9 to 3.0 and 5.4 to 3.7, respectively, as pulse duration decreased from 100 to 20 ms. At pulse durations of 1 millisecond, the therapeutic window decreased to unity, at which point rupture and a mild lesion were equally likely to occur. CONCLUSIONS At shorter pulse durations, the width and axial extent of the retinal lesions are smaller and less dependent on variations in laser power than at longer durations. The width of the therapeutic window, a measure of relative safety, increases with the beam size. CLINICAL RELEVANCE Pulse durations of approximately 20 milliseconds represent an optimal compromise between the favorable impact of speed, higher spatial localization, and reduced collateral damage on one hand, and sufficient width of the therapeutic window (> 3) on the other.

Healing of Retinal Photocoagulation Lesions

PURPOSE To systematically assess the changes in retinal morphology during the healing of retinal photocoagulation lesions of various clinical grades. METHODS Rabbits were irradiated with a 532-nm Nd:YAG laser with a beam diameter of 330 microm at the retinal surface, a power of 175 mW, and pulse durations between 5 and 100 ms. Retinal lesions were clinically graded 1 minute after placement as invisible, barely visible, light, moderate, intense, very intense, and rupture and were assessed histologically at six time points from 1 hour to 4 months. RESULTS At all pulse durations, the width of the retinal lesions decreased over time. At clinical grades of light and more severe (pulse durations, 10-100 ms), retinal scarring stabilized at 1 month at approximately 35% of the initial lesion diameter. Lesions clinically categorized as barely visible and invisible (pulse durations of 7 and 5 ms) exhibited coagulation of the photoreceptor layer but did not result in permanent scarring. In these lesions, photoreceptors completely filled in the damaged areas by 4 months. CONCLUSIONS The decreasing width of the retinal damage zone suggests that photoreceptors migrating from unaffected areas fill in the gap in the photoreceptor layer. Laser photocoagulation parameters can be specified to avoid not only the inner retinal damage, but also permanent disorganization and scarring in the photoreceptor layer. These data may facilitate studies to determine those aspects of laser treatment necessary for beneficial clinical response and those that result in extraneous retinal damage.

Photoacoustic ocular imaging

We developed a photoacoustic ocular imaging device and demonstrated its utility in imaging the deeper layers of the eye including the retina, choroid, and optic nerve. Using safe laser intensity, the photoacoustic system was able to visualize the blood distribution of an enucleated pigs eye and an eye of a living rabbit. Ultrasound images, which were simultaneously acquired, were overlaid on the photoacoustic images to visualize the eyes anatomy. Such a system may be used in the future for early detection and improved management of neovascular ocular diseases, including wet age-related macular degeneration and proliferative diabetic retinopathy.

Wnt signaling promotes Müller cell proliferation and survival after injury.

PURPOSE Müller glia respond to retinal injury by a reactive gliosis, but only rarely do mammalian glial cells re-enter the cell cycle and generate new neurons. In the nonmammalian retina, however, Müller glia act as stem/progenitor cells. Here, we tested the function of Wnt signaling in the postinjury retina, focusing on its ability to influence mammalian Müller cell dedifferentiation, proliferation, and neurogenesis. METHODS A 532 nm frequency doubled neodymium-doped yttrium aluminum garnet (ND:YAG) laser was used to create light burns on the retina of Axin2(LacZ/+) Wnt reporter mice. At various time points after injury, retinas were analyzed for evidence of Wnt signaling as well as glial cell response, proliferation, and apoptosis. Laser injuries also were created in Axin2(LacZ/LacZ) mice, and the effect of potentiated Wnt signaling on retinal repair was assessed. RESULTS A subpopulation of mammalian Müller cells are Wnt responsive and, when Wnt signaling is increased, these cells showed enhanced proliferation in response to injury. In an environment of heightened Wnt signaling, caused by the loss of the Wnt negative regulator Axin2, Müller cells proliferated after injury and adopted the expression patterns of retinal progenitor cells (RPCs). The Wnt-responsive Müller cells also exhibited long-term survival and, in some cases, expressed the rod photoreceptor marker, rhodopsin. CONCLUSIONS The Wnt pathway is activated by retinal injury, and prolonging the endogenous Wnt signal causes a subset of Müller cells to proliferate and dedifferentiate into RPCs. These data raised the possibility that transient amplification of Wnt signaling after retinal damage may unlock the latent regenerative capacity long speculated to reside in mammalian neural tissues.

Dynamics of retinal photocoagulation and rupture

In laser retinal photocoagulation, short (<20 ms) pulses have been found to reduce thermal damage to the inner retina, decrease treatment time, and minimize pain. However, the safe therapeutic window (defined as the ratio of power for producing a rupture to that of mild coagulation) decreases with shorter exposures. To quantify the extent of retinal heating and maximize the therapeutic window, a computational model of millisecond retinal photocoagulation and rupture was developed. Optical attenuation of 532-nm laser light in ocular tissues was measured, including retinal pigment epithelial (RPE) pigmentation and cell-size variability. Threshold powers for vaporization and RPE damage were measured with pulse durations ranging from 1 to 200 ms. A finite element model of retinal heating inferred that vaporization (rupture) takes place at 180-190 degrees C. RPE damage was accurately described by the Arrhenius model with activation energy of 340 kJ/mol. Computed photocoagulation lesion width increased logarithmically with pulse duration, in agreement with histological findings. The model will allow for the optimization of beam parameters to increase the width of the therapeutic window for short exposures.

Selective retinal therapy with microsecond exposures using a continuous line scanning laser.

Purpose: To evaluate the safety, selectivity, and healing of retinal lesions created using a continuous line scanning laser. Methods: A 532-nm Nd:YAG laser (PASCAL) with retinal beam diameters of 40 μm and 66 μm was applied to 60 eyes of 30 Dutch-belted rabbits. Retinal exposure duration varied from 15 μs to 60 μs. Lesions were acutely assessed by ophthalmoscopy and fluorescein angiography. Retinal pigment epithelial (RPE) flatmounts were evaluated with live-dead fluorescent assay. Histological analysis was performed at 7 time points from 1 hour to 2 months. Results: The ratios of the threshold of rupture and of ophthalmoscopic visibility to fluorescein angiography visibility (measures of safety and selectivity) increased with decreasing duration and beam diameter. Fluorescein angiography and live-dead fluorescent assay yielded similar thresholds of RPE damage. Above the ophthalmoscopic visibility threshold, histology showed focal RPE damage and photoreceptor loss at 1 day, without inner retinal effects. By 1 week, photoreceptor and RPE continuity was restored. By 1 month, photoreceptors appeared normal. Conclusion: Retinal therapy with a fast scanning continuous laser achieves selective targeting of the RPE and, at higher power, of the photoreceptors without permanent scarring or inner retinal damage. Continuous scanning laser can treat large retinal areas within standard eye fixation time.

Restoration of Retinal Structure and Function after Selective Photocoagulation

CNS neurons change their connectivity to accommodate a changing environment, form memories, or respond to injury. Plasticity in the adult mammalian retina after injury or disease was thought to be limited to restructuring resulting in abnormal retinal anatomy and function. Here we report that neurons in the mammalian retina change their connectivity and restore normal retinal anatomy and function after injury. Patches of photoreceptors in the rabbit retina were destroyed by selective laser photocoagulation, leaving retinal inner neurons (bipolar, amacrine, horizontal, ganglion cells) intact. Photoreceptors located outside of the damaged zone migrated to make new functional connections with deafferented bipolar cells located inside the lesion. The new connections restored ON and OFF responses in deafferented ganglion cells. This finding extends the previously perceived limits of restorative plasticity in the adult retina and allows for new approaches to retinal laser therapy free of current detrimental side effects such as scotomata and scarring.

IgG4-positive Sclerosing Orbital Inflammation Involving the Conjunctiva: A Case Report

Purpose: To describe IgG4-positive sclerosing orbital inflammation with prominent conjunctival and scleral involvement. Design: Case report. Methods: Clinical, radiologic, and pathologic correlation. Results: A 66-year-old man presented with right eye redness and irritation. Examination revealed unilateral scleritis and nongranulomatous anterior uveitis with elevated p-ANCA and CRP. Orbital CT scan showed inferotemporal scleral thickening. Biopsy revealed sclerosis and IgG4-positive plasma cells in the conjunctiva and inferior rectus. Conclusions: IgG4-mediated sclerosing inflammation is well-recognized in the orbit and adnexa, particularly the lacrimal gland. Scleritis with anterior uveitis should be recognized as a possible presentation for this entity, which has important systemic associations.

Therapeutic window of retinal photocoagulation with green (532-nm) and yellow (577-nm) lasers.

BACKGROUND AND OBJECTIVE The 577-nm (yellow) laser provides an alternative to the 532-nm (green) laser in retinal photocoagulation, with potential benefits in macular treatment and through ocular opacities. To assess relative risk of thermomechanical rupture of Bruchs membrane with yellow laser in photocoagulation, the therapeutic window, the ratio of threshold powers for mild coagulation and rupture, was measured. MATERIALS AND METHODS Retinal coagulation and rupture thresholds, visualized ophthalmoscopically, were measured with 577- and 532-nm lasers using 10- to 100-ms pulses in 34 rabbit eyes. Lesions at 1 and 7 days were assessed histologically. RESULTS Coagulation threshold with yellow laser was 26% lower than with green laser. The therapeutic window increased linearly with log-duration for both wavelengths with a difference in parallel-slope intercept of 0.36 ± 0.20, corresponding to 8% to 15% wider therapeutic window for yellow wavelength. CONCLUSION The therapeutic window of retinal photocoagulation in rabbits at 577 nm is slightly wider than at 532 nm, whereas histologically the lesions are similar.

Resolution of Persistent Exudative Retinal Detachment in a Case of Sturge-Weber Syndrome with Anti-VEGF Administration

Purpose: Report the resolution of a persistent exudative retinal detachment in a patient with Sturge-Weber syndrome following intravitreal pegaptanib injection. Design: Case report. Methods: A 13-year-old male with Sturge-Weber syndrome presented with a choroidal hemangioma associated with an exudative retinal detachment that failed to resolve 6 months after external beam radiation therapy. Results: A single intravitreal pegaptanib injection resulted in 50% resolution of the detachment within 1 week and complete resolution within a month. Despite anatomic success, vision remained poor. Conclusions: VEGF likely plays a role in the pathogenesis of Sturge-Weber choroidal hemangioma-associated exudative retinal detachment and offers potential treatment.