Kathrin Hartmann

Clinical Evaluation and Treatment Accuracy in Diabetic Macular Edema Using Navigated Laser Photocoagulator NAVILAS

PURPOSE To evaluate the clinical use and accuracy of a new retinal navigating laser technology that integrates a scanning slit fundus camera system with fluorescein angiography (FA), color, red-free, and infrared imaging capabilities with a computer steerable therapeutic 532-nm laser. DESIGN Interventional case series. PARTICIPANTS Eighty-six eyes of 61 patients with diabetic retinopathy and macular edema treated by NAVILAS. METHODS The imaging included digital color fundus photographs and FA. The planning included graphically marking future treatment sites (microaneurysms for single-spot focal treatment and areas of diffuse leakage for grid pattern photocoagulation) on the acquired images. The preplanned treatment was visible and overlaid on the live fundus image during the actual photocoagulation. The NAVILAS automatically advances the aiming beam location from one planned treatment site to the next after each photocoagulation spot until all sites are treated. Aiming beam stabilization compensated for patients eye movements. The pretreatment FA with the treatment plan was overlaid on top of the posttreatment color fundus images with the actual laser burns. This allowed treatment accuracy to be calculated. Independent observers evaluated the images to determine if the retinal opacification after treatment overlapped the targeted microaneurysm. MAIN OUTCOME MEASURES Safety and accuracy of laser photocoagulation. RESULTS The images were of very good quality compared with standard fundus cameras, allowing careful delineation of target areas on FA. Toggling from infrared, to monochromatic, to color view allowed evaluation and adjustment of burn intensity during treatment. There were no complications during or after photocoagulation treatment. An analysis of accuracy of 400 random focal targeted spots found that the NAVILAS achieved a microaneurysm hit rate of 92% when the placement of the treatment circle was centered by the operating surgeon on the microaneurysm. The accuracy for the control group analyzing 100 focal spots was significantly lower at 72% (P<0.01). CONCLUSIONS Laser photocoagulation using the NAVILAS system is safe and achieves a higher rate of accuracy in photocoagulation treatments of diabetic retinopathy lesions than standard manual-technique laser treatment. Precise manual preplanning and positioning of the treatment sites by the surgeon is possible, allowing accurate and predictable photocoagulation of these lesions. FINANCIAL DISCLOSURE(S) Proprietary or commercial disclosure may be found after the references.

Scanning Laser Ophthalmoscope Imaging Stabilized Microperimetry In Dry Age-related Macular Degeneration

Purpose: To determine the effect of drusen and geographic atrophy (GA) in dry age-related macular degeneration on retinal sensitivity using an eye tracking scanning laser ophthalmoscope microperimetry. Methods: A total of 44 eyes from 22 patients with dry age-related macular degeneration and drusen and 11 patients with GA were imaged with scanning laser ophthalmoscope microperimetry (OPKO Health, Miami, FL). A custom microperimetry pattern was used to evaluate retinal sensitivity to a Goldmann III size target (108 μm on the retina). The perimetry used a 4-2 stepladder algorithm to determine maximal sensitivity. Microperimetry and optical coherence tomography were performed using a standardized protocol. Twenty-eight eyes with drusen and 16 eyes with GA were analyzed. Results: Retinal sensitivity overlying drusen was significantly reduced compared with the adjacent uninvolved retina. There was a significant correlation between retinal sensitivity and drusen volume, as well as the grading of the photoreceptor inner segment/outer segment junction score. In patients with GA, an absolute scotoma was confirmed. Retinal sensitivity at the margin of GA was significantly decreased compared with the adjacent uninvolved retina. Conclusion: Scanning laser ophthalmoscope microperimetry is able to detect changes in retinal sensitivity in AMD patients overlying drusen and at the margin of GA. It is a useful device to grade focal retinal sensitivity in patients with dry age-related macular degeneration.

Accuracy of the Heidelberg Spectralis in the alignment between near-infrared image and tomographic scan in a model eye: a multicenter study

PURPOSE To evaluate temporal changes and predictors of accuracy in the alignment between simultaneous near-infrared image and optical coherence tomography (OCT) scan on the Heidelberg Spectralis using a model eye. DESIGN Laboratory investigation. METHODS After calibrating the device, 6 sites performed weekly testing of the alignment for 12 weeks using a model eye. The maximum error was compared with multiple variables to evaluate predictors of inaccurate alignment. Variables included the number of weekly scanned patients, total number of OCT scans and B-scans performed, room temperature and its variation, and working time of the scanning laser. A 4-week extension study was subsequently performed to analyze short-term changes in the alignment. RESULTS The average maximum error in the alignment was 15 ± 6 μm; the greatest error was 35 μm. The error increased significantly at week 1 (P = .01), specifically after the second imaging study (P < .05); reached a maximum after the eighth patient (P < .001); and then varied randomly over time. Predictors for inaccurate alignment were temperature variation and scans per patient (P < .001). For each 1 unit of increase in temperature variation, the estimated increase in maximum error was 1.26 μm. For the average number of scans per patient, each increase of 1 unit increased the error by 0.34 μm. CONCLUSION Overall, the accuracy of the Heidelberg Spectralis was excellent. The greatest error happened in the first week after calibration, and specifically after the second imaging study. To improve the accuracy, room temperature should be kept stable and unnecessary scans should be avoided. The alignment of the device does not need to be checked on a regular basis in the clinical setting, but it should be checked after every other patient for more precise research purposes.

Hydrosilylated porous silicon particles function as an intravitreal drug delivery system for daunorubicin.

PURPOSE To evaluate in vivo ocular safety of an intravitreal hydrosilylated porous silicon (pSi) drug delivery system along with the payload of daunorubicin (DNR). METHODS pSi microparticles were prepared from the electrochemical etching of highly doped, p-type Si wafers and an organic linker was attached to the Si-H terminated inner surface of the particles by thermal hydrosilylation of undecylenic acid. DNR was bound to the carboxy terminus of the linker as a drug-loading strategy. DNR release from hydrosilylated pSi particles was confirmed in the excised rabbit vitreous using liquid chromatography-electrospray ionization-multistage mass spectrometry. Both empty and DNR-loaded hydrosilylated pSi particles were injected into the rabbit vitreous and the degradation and safety were studied for 6 months. RESULTS The mean pSi particle size was 30×46×15 μm with an average pore size of 15 nm. Drug loading was determined as 22 μg per 1 mg of pSi particles. An ex vivo drug release study showed that intact DNR was detected in the rabbit vitreous. An in vivo ocular toxicity study did not reveal clinical or pathological evidence of any toxicity during a 6-month observation. Hydrosilylated pSi particles, either empty or loaded with DNR, demonstrated a slow elimination kinetics from the rabbit vitreous without ocular toxicity. CONCLUSIONS Hydrosilylated pSi particles can host a large quantity of DNR by a covalent loading strategy and DNR can be slowly released into the vitreous without ocular toxicity, which would appear if an equivalent quantity of free drug was injected.

Effect Of Change In Drusen Evolution On Photoreceptor Inner Segment/outer Segment Junction

Purpose: To evaluate the integrity of photoreceptor inner segment/outer segment (IS/OS) junction after change of drusen size in age-related macular degeneration using spectral-domain optical coherence tomography. Methods: Drusen volume raster scans were performed with the Spectralis spectral-domain optical coherence tomography (Heidelberg Engineering) through 2,624 drusen in 14 eyes with clinically dry age-related macular degeneration, which had been longitudinally followed-up between 23 and 28 months without intervention (mean, 26.3 months). All eyes had Early Treatment Diabetic Retinopathy Study visual acuity. A total of 416 of 2,624 drusen were analyzed. Results: Of 416 drusen, 83 (20%) were found to have regressed spontaneously (Group A), 212 (51%) showed no change in size (Group B), and 121 (29%) progressed (Group C). Mean drusen size of all drusen was 63.7 ± 25.7 &mgr;m. Cross-sectional analysis of drusen morphology showed a correlation between drusen size and disrupted IS/OS junction/photoreceptor integrity (r = −0.48, P < 0.001). Of the drusen that regressed over time, there was intact IS/OS junction integrity. Even drusen that caused a major disruption showed IS/OS restoration in 74% of the drusen (P < 0.001). Conclusion: Progression of drusen shows structural disruption of the IS/OS junction. After drusen regression, the IS/OS junction is either able to restore as drusen regress or was artifactitiously compressed and not initially visible because of the initial drusen compression of the IS/OS junctional line. Therefore, drusen evolution may play an important role in affecting the photoreceptor IS/OS junction integrity.

Retinal adherence and fibrillary surface changes correlate with surgical difficulty of epiretinal membrane removal.

PURPOSE To correlate surgical difficulty of epiretinal membrane (ERM) removal with characteristics of ERM adherence seen by spectral-domain optical coherence tomography (SD-OCT). DESIGN Prospective observational case series. METHODS Surgical difficulty was correlated with extent of ERM adherence by SD-OCT using masked observers in consecutive eyes undergoing ERM removal (N=31). Surgical videos were analyzed and difficulty of ERM removal (grade 1-3) was determined in 4 quadrants as well as the fovea by consensus of observers masked to SD-OCT findings. Extent of ERM adhesion was categorized (focal, broad, or complete) by masked observers using SD-OCT. The presence of fibrillary changes between the ERM and retinal nerve fiber layer (RNFL) was also evaluated. Surgical difficulty of ERM removal for each quadrant and fovea was compared to extent of ERM adherence and presence of fibrillary changes. RESULTS Assessment of ERM adherence using SD-OCT between masked observers was highly concordant (kappa=0.9178). Surgical difficulty of ERM removal was strongly associated with more extensive ERM adherence to the retina observed by SD-OCT. Complete ERM adherence correlated with an 8.6-fold increased surgical difficulty of ERM removal compared to focal adherence (P<.0001). The presence of fibrillary changes between the ERM and RNFL also correlated with a 25.5-fold increased difficulty of surgical removal compared to the absence of fibrillary changes (P<.0001). CONCLUSION Extent of ERM-retinal adhesion and presence of fibrillary changes determined by SD-OCT provide reliable preoperative assessment of surgical difficulty. Furthermore, SD-OCT analysis may help localize surgically advantageous coordinates to initiate ERM removal.

Treatment of optic neuritis with erythropoietin (TONE): a randomised, double-blind, placebo-controlled trial—study protocol

Introduction Optic neuritis leads to degeneration of retinal ganglion cells whose axons form the optic nerve. The standard treatment is a methylprednisolone pulse therapy. This treatment slightly shortens the time of recovery but does not prevent neurodegeneration and persistent visual impairment. In a phase II trial performed in preparation of this study, we have shown that erythropoietin protects global retinal nerve fibre layer thickness (RNFLT-G) in acute optic neuritis; however, the preparatory trial was not powered to show effects on visual function. Methods and analysis Treatment of Optic Neuritis with Erythropoietin (TONE) is a national, randomised, double-blind, placebo-controlled, multicentre trial with two parallel arms. The primary objective is to determine the efficacy of erythropoietin compared to placebo given add-on to methylprednisolone as assessed by measurements of RNFLT-G and low-contrast visual acuity in the affected eye 6 months after randomisation. Inclusion criteria are a first episode of optic neuritis with decreased visual acuity to ≤0.5 (decimal system) and an onset of symptoms within 10 days prior to inclusion. The most important exclusion criteria are history of optic neuritis or multiple sclerosis or any ocular disease (affected or non-affected eye), significant hyperopia, myopia or astigmatism, elevated blood pressure, thrombotic events or malignancy. After randomisation, patients either receive 33 000 international units human recombinant erythropoietin intravenously for 3 consecutive days or placebo (0.9% saline) administered intravenously. With an estimated power of 80%, the calculated sample size is 100 patients. The trial started in September 2014 with a planned recruitment period of 30 months. Ethics and dissemination TONE has been approved by the Central Ethics Commission in Freiburg (194/14) and the German Federal Institute for Drugs and Medical Devices (61-3910-4039831). It complies with the Declaration of Helsinki, local laws and ICH-GCP. Trial registration number NCT01962571.

Primary intraocular lymphoma: a review

Primary intraocular lymphoma (PIOL) is a rare, non-Hodgkin lymphoma considered to be a subtype of primary central nervous system lymphoma. We describe a 65-year-old woman who presented to the Hematology/Oncology Clinic at Scripps Clinic, La Jolla, California, who was diagnosed with bilateral PIOL without systemic disease. She enjoyed a 16-month remission but ultimately recurred in the brain. We reviewed the literature and present a discussion of the diagnostic criteria for PIOL and current strategies for treating PIOL in immunocompetent patients.

Restoration of retinal layers after epiretinal membrane peeling

Purpose: To evaluate the morphologic restoration of retinal anatomy after surgery for epiretinal membrane (ERM) peeling using spectral domain optical coherence tomography. Correlation of retinal structure with visual outcome. Design: Retrospective consecutive case series. Methods: Thirty-four consecutive eyes with ERM underwent surgery with 1 year follow-up examination. Spectral domain optical coherence tomography scans were analyzed preoperatively and 1, 3, 6, 9, and 12 months postoperative. Best-corrected visual acuity (BCVA) using Early Treatment Diabetic Retinopathy Study charts was measured at each visit. Results: All eyes showed a significant improvement of BCVA after ERM peeling (P = 0.002). The time point of BCVA and retinal restoration seen on spectral domain optical coherence tomography occurred simultaneously and varied between individuals (occurrence of BCVA: mean, 4.82 months; retinal restoration: mean, 4.24 months). At 3 months, the retinal anatomical restoration rate was 70% and 88% at 6 months. Conclusion: Restoration of the retinal anatomical structure predominantly occurs within the first 3 months post-ERM peeling. An improvement of BCVA and anatomical retinal restoration after ERM removal varies in individuals. If retinal layers fully restore in their anatomical structure, BCVA improves at the same time point.

Intraocular Safety and Pharmacokinetics of Hexadecyloxypropyl-Cidofovir (HDP-CDV) as a Long-lasting Intravitreal Antiviral Drug

PURPOSE To evaluate the intraocular safety and pharmacokinetics of hexadecyloxypropyl-cidofovir (HDP-CDV), the hydrolysis product of HDP-cyclic-CDV, a long-lasting intravitreal cidofovir prodrug for cytomegalovirus (CMV) retinitis. METHODS HDP-cyclic-CDV was suspended in phosphate-buffered saline (PBS) at 37°C and formation of HDP-CDV was monitored by high-performance liquid chromatography (HPLC) analysis for 30 weeks. The safety and pharmacokinetics of HDP-CDV intravitreal injections were studied using New Zealand Red rabbits and (14)C labeled HDP-CDV. Ocular tissues from five time points (1, 3, 7, 14, and 35 days) were analyzed by scintillation counting and HPLC to characterize the pharmacokinetics. RESULTS During the hydrolysis study, approximately 35% of the HDP-cyclic-CDV was converted to HDP-CDV. Evaluation of safety found no toxicity after intravitreal injection of HDP-CDV up to 28 μg/eye. Intravitreal pharmacokinetics of HDP-CDV in the retina, choroid, and vitreous followed a two-phase elimination process and elimination half-lives of 8.4 days (retina), 6.9 days (choroid), and 6.2 days (vitreous). In the retina, cidofovir and an unknown metabolite were detected in the first 2 weeks, and the maximum metabolite concentrations were present 48 hours after the maximum HDP-CDV concentration. CONCLUSIONS HDP-cyclic CDV, under simulated physiologic conditions, slowly converts to HDP-CDV, another potent anti-CMV prodrug that may be taken up by retinal cells and metabolized further to the active antiviral metabolite, cidofovir diphosphate. Taken together, these observations help to explain the ability of a single intravitreal dose of HDP-cyclic-CDV to prevent viral retinitis for up to 68 days in a rabbit model.