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Purpose To evaluate safety and successful use of a novel subretinal delivery system and suprachoroidal surgical approach and safety and activity of human umbilical tissue–derived cells (palucorcel) via a novel delivery system in patients with geographic atrophy (GA). Design Multicenter, open-label phase 2b study. Participants Participants were 55 to 90 years with GA secondary to age-related macular degeneration (AMD) and best-corrected visual acuity (BCVA) of 20/80 to 20/800. Exclusion criteria included neovascular AMD in the intervention eye, glaucoma with intraocular pressure of 25 mmHg or more, or other significant ophthalmologic conditions. Methods Participants received a subretinal injection of palucorcel, 3.0 × 105 cells in 50 μl, using the custom-designed delivery system and surgical procedure. Main Outcome Measures Safety assessments included treatment-emergent adverse events (AEs), immunologic assessments, and ophthalmologic evaluations. Efficacy was evaluated as change in mean number of BCVA letters from baseline, proportion of participants gaining 15 BCVA letters or more, and growth rate of GA lesions at 12 months. Results Surgery and palucorcel administration were performed in 21 participants at 8 sites by 8 different surgeons. At baseline, median total area of GA was 13.4 mm2 and median BCVA was 43 letters in the intervention eye. Eye-related AEs occurred in 76% of participants (16/21), including conjunctival hemorrhage (n = 5), retinal hemorrhage (n = 4), and vitreous floaters (n = 4). Most AEs were mild and resolved within 1 month. No serious AEs, no retinal detachment or perforation, and no significant changes in intraocular pressure occurred. At month 12, mean change in BCVA from baseline was –5.9 letters correct (standard deviation, 13.0 letters correct) in the intervention eye and –3.7 letters correct (standard deviation, 9.0 letters correct) in the fellow eye. No participants showed improvement of 15 letters or more in the intervention eye, and 3 participants lost more than 15 letters by month 1. No apparent effect of treatment was observed. Conclusions Palucorcel was delivered successfully to the targeted subretinal site using a novel delivery system and suprachoroidal approach for most participants; however, improvement in GA area, retardation of growth, or visual acuity were not demonstrated.

Quantitative biomarkers for assessing the presence, severity, and progression of age-related macular degeneration (AMD) would benefit research, diagnosis, and treatment. This paper explores development of quantitative biomarkers derived from OCT imagery of the retina. OCT images for approximately 75 patients with Wet AMD, Dry AMD, and no AMD (healthy eyes) were analyzed to identify image features indicative of the patients’ conditions. OCT image features provide a statistical characterization of the retina. Healthy eyes exhibit a layered structure, whereas chaotic patterns indicate the deterioration associated with AMD. Our approach uses wavelet and Frangi filtering, combined with statistical features that do not rely on image segmentation, to assess patient conditions. Classification analysis indicates clear separability of Wet AMD from other conditions, including Dry AMD and healthy retinas. The probability of correct classification of was 95.7%, as determined from cross validation. Similar classification analysis predicts the response of Wet AMD patients to treatment, as measured by the Best Corrected Visual Acuity (BCVA). A statistical model predicts BCVA from the imagery features with R2 = 0.846. Initial analysis of OCT imagery indicates that imagery-derived features can provide useful biomarkers for characterization and quantification of AMD: Accurate assessment of Wet AMD compared to other conditions; image-based prediction of outcome for Wet AMD treatment; and features derived from the OCT imagery accurately predict BCVA; unlike many methods in the literature, our techniques do not rely on segmentation of the OCT image. Next steps include larger scale testing and validation.

Purpose To evaluate the safety and tolerability of and clinical response to a single, subretinal dose of human umbilical tissue–derived cells (palucorcel [CNTO-2476]) in the eyes of adults aged ≥50 years with bilateral geographic atrophy (GA) secondary to age-related macular degeneration (AMD). Design Phase 1/2a, multicenter, open-label, dose-escalation, fellow-eye–controlled study. Methods In the phase 1 portion, eyes were assigned to receive a single, subretinal dose of palucorcel (ranging from 6.0 × 10 4 to 5.6 × 10 5 viable cells). In the phase 2a portion, eyes were assigned to one of 2 palucorcel doses (6.0 × 10 4 or 3.0 × 10 5 cells) determined during the phase 1 portion. The intervention eye was the eye with worse baseline visual acuity. Results A total of 35 eligible subjects underwent at least a partial surgical procedure. Palucorcel was administered in 33 eyes. Overall, 17.1% (6/35) of subjects experienced retinal detachments and 37.1% (13/35) experienced retinal perforations. No episodes of immune rejection or tumor formation were observed. At 1 year, ≥10- and ≥15-letter gains in best-corrected visual acuity were observed in 34.5% (10/29) and 24.1% (7/29) of eyes receiving palucorcel, respectively, and in 3.3% (1/30; for both) of fellow eyes. Conclusions The subretinal delivery procedure in this study was associated with a high rate of retinal perforations (n = 13) and retinal detachments (n = 6). When cells were sequestered in the subretinal space, palucorcel was well tolerated and may be associated with improvements in visual acuity. Larger randomized controlled studies are required to confirm these results. Future studies would require a modified surgical approach.

Purpose of review Stem cell therapy holds great promise for the treatment of retinal diseases. This review summarizes recent advances in stem cell biology, outlines ongoing clinical trials and details the obstacles that must be overcome for stem cell therapy to be a viable treatment for retinal disease. Recent findings Stem cells can now be directed to specific retinal cell fates with high yields and acceptable purity for clinical trials. New stem cell sources have been discovered including induced pluripotent stem cells that can be derived from adult tissues then differentiated into multiple retinal cell types. The initial results of clinical trials of subretinal transplantation of human embryonic stem cell-derived retinal pigment epithelium cells in patients with Stargardt's macular dystrophy and dry age-related macular degeneration showed preliminary safety and possible visual acuity benefits. A phase I trial of intravitreally injected autologous bone marrow-derived mononuclear cells for hereditary retinal dystrophy demonstrated no evidence of toxicity with possible visual acuity benefits but no structural or functional changes. Ongoing trials are examining the trophic effects of undifferentiated umbilical cells for the treatment of geographic atrophy in age-related macular degeneration. Summary Stem cell therapy is a promising treatment under active investigation in multiple retinal diseases. Ongoing clinical trials should yield further insights into the potential for stem cell-based retinal therapies.

Purpose To review the distinctive and shared features of the white dot syndromes, highlighting the clinical findings, diagnostic test results, proposed etiologies, treatments, and prognosis. Design Review. Methods Review of the literature. Results Common white dot syndromes are reviewed, including acute posterior multifocal placoid pigment epitheliopathy, birdshot chorioretinopathy, diffuse unilateral subacute neuroretinitis, multiple evanescent white dot syndrome, multifocal choroiditis with panuveitis, serpiginous choroiditis, and acute zonal occult outer retinopathy. Conclusions The white dot syndromes are a group of disorders characterized by multiple whitish-yellow inflammatory lesions located at the level of the outer retina, retinal pigment epithelium, and choroid. For clinicians and researchers alike, they present significant diagnostic and therapeutic challenges.

Purpose To introduce the new approach of inverted pneumatic retinopexy for the management of rhegmatogenous retinal detachments with inferior retinal breaks. Design Retrospective, noncomparative case series. Participants Eleven patients presenting with rhegmatogenous retinal detachments with causative inferior retinal breaks. Intervention Sterile gas/air injection, cryopexy/laser retinopexy, with inverted positioning. Main outcome measures Postoperative primary and final anatomical outcome, visual acuity, and complications. Results Patients were followed for a minimum of 3 months (mean, 5.1 months). Primary retinal reattachment was obtained in 10 of 11(91%) patients. One patient sustained a redetachment secondary to proliferative vitreoretinopathy, resulting in a single operation reattachment rate of 82%. Final reattachment was obtained in 11 of 11 (100%) patients. Mean visual acuity improved about 3 lines from 20/60 to 20/30, with 11 of 11 patients experiencing improvement in their visual acuity. Two patients required an additional surgical procedure to achieve final anatomic success. No new breaks were identified in the postoperative period, and no complications resulted from the pneumatical procedure. Conclusions Inverted pneumatic retinopexy can successfully repair retinal detachments with inferior retinal breaks under appropriate conditions.

Purpose To report our initial experience of limited macular translocation in patients with subfoveal choroidal neovascularization secondary to age-related macular degeneration following photodynamic therapy with verteporfin. Design Interventional case series. Methods Retrospective review of four eyes of four consecutive patients with subfoveal choroidal neovascularization secondary to age-related macular degeneration who underwent effective limited macular translocation following photodynamic therapy. The mean logarithm of minimal angle of resolution preoperative best-corrected visual acuity was 20/190 (range, 20/150 to 20/200), and in all eyes the visual acuity was 20/150 or worse. The major outcome measures were postoperative visual acuity and complications related to the surgery. Results The mean postoperative follow-up was 6.75 months (range, 6–8 months). Postoperative best-corrected visual acuity improved by 2 or more Snellen lines of visual acuity in three of four eyes (75%) and remained within 1 line in one of four eyes (25%). The mean postoperative best-corrected visual acuity was 20/100 (range, 20/40 to 20/150), and in two of the four eyes (50%) the visual acuity achieved was 20/100 or better. No complication was observed. Conclusions Limited macular translocation may be a viable option in patients who have previously undergone photodynamic therapy.

Objectives To introduce and evaluate the infusion and aspiration rates and operative times of the 25-gauge transconjunctival sutureless vitrectomy system (TSV) Design In vitro experimental and comparative interventional study. Participants and controls Twenty eyes of 20 patients underwent a variety of vitreoretinal procedures using the 25-gauge TSV, including idiopathic epiretinal membrane (n = 10), macular hole (n = 4), rhegmatogenous retinal detachment (n = 3), branch retinal vein occlusion (n = 2), diabetic vitreous hemorrhage (n = 1), and 20 cases similar in diagnosis and severity were matched to provide comparison between duration of individual portions of the surgical procedures with the existing 20-gauge vitrectomy system. Methods Description of the 25-gauge TSV is provided; infusion and aspiration rates of the 25-gauge and standard 20-gauge vitrectomy system were measured in vitro using balanced saline solution and porcine vitreous for several levels of aspirating power and bottle height, and operating times of individual portions of surgical procedures were measured for the 25-gauge and 20-gauge vitrectomy system. Main outcome measures Infusion, aspiration rates, and operative times of the 20-gauge and 25-gauge vitrectomy system. Results Infusion and aspiration rates of the 25-gauge TSV system were reduced by an average of 6.9 and 6.6 times, respectively, compared with the 20-gauge system when balanced saline solution was used. The average flow rate of the Storz 25-gauge cutter (at 500 mmHg, 1500 cuts per minute [cpm]) was 40% greater than that of the 20-gauge pneumatic cutter (at 250 mmHg, 750 cpm) but about 2.3 times less than the 20-gauge high-speed cutter (at 250 mmHg, 1500 cpm). Mean total operative time was significantly greater for the 20-gauge high-speed cutter (26 minutes, 7 seconds) than for the 25-gauge vitrectomy system (17 minutes, 17 seconds) ( P = 0.011). Conclusions Although the infusion and aspiration rates of the 25-gauge instruments are lower than those for the 20-gauge high-speed vitrectomy system, the use of 25-gauge TVS may effectively reduce operative times of select cases that do not require the full capability of conventional vitrectomy.

Objective To investigate the construct validity and reliability of the SF-12 with the SF-36 composite scores in patients with retinal diseases. Design Cross-sectional study. Participants One thousand eighty-one patients with retinal disease presenting for care at a tertiary referral university-based retina practice. Methods Each patient completed the SF-36 before his or her initial ocular examination. The SF-12 is based on a subset of 12 items from the SF-36. Main outcome measures Physical Composite Score (PCS) and Mental Composite Score (MCS) as determined by the SF-36 and SF-12. Results Eight hundred thirty-nine (78%) of the participants had scorable PCS and MCS scores on the SF-12. No significant differences were found between the SF-36 and SF-12 for the PCS and MCS overall and stratified by the four most frequently occurring disease categories (all P > 0.20). There were statistically significant differences across the disease categories in the mean PCS scores ( P P = 0.04). The SF-12 PCS and MCS scores were highly correlated with similar indicators (composite scores and subscales) on the SF-36. Conclusions The SF-12 is a valid measure of general health status for ophthalmic research, as long as differences in mental composite scores do not need to be demonstrated between different ocular disease groups. The benefit of reduced administration time makes the SF-12 a recommended general quality-of-life outcomes tool.

Objective To describe the initial experience and to evaluate the safety and feasibility of using the 25-gauge Transconjunctival Sutureless Vitrectomy System (TSV) for a variety of vitreoretinal procedures. Design Retrospective review of a consecutive interventional case series. Participants Thirty-five eyes of 33 patients, including cases of idiopathic epiretinal membrane (12 cases), retinal detachment (6 cases), macular hole (5 cases), branch retinal vein occlusion (4 cases), retinopathy of prematurity (4 cases), persistent diabetic macular edema (1 case), diabetic vitreous hemorrhage (1 case), retained lens material after cataract extraction (1 case), and Norrie disease (1 case). Intervention All patients underwent surgery using the 25-gauge TSV. Main outcome measures Intraocular pressure, visual acuity, and postoperative complications. Results The median preoperative intraocular pressure was 16 mmHg (range, 10–21 mmHg), whereas the median intraocular pressure on the first postoperative day was 12 mmHg (range, 6–28 mmHg). The median intraocular pressure at 1 week and 1 month were both 16 mmHg (range, 10–30 mmHg). Overall, the median preoperative visual acuity was 20/100 (range, 20/30 to hand motions), and the median postoperative visual acuity after a mean follow-up of 14 weeks (range, 1–60 weeks) was 20/60 (range, 20/20–20/150). One eye developed a postoperative retinal detachment. Conclusions The 25-gauge TSV seems to be practical and safe for a variety of vitreoretinal procedures. The concept of transconjunctival surgery has the potential to increase the efficiency of a variety of vitreoretinal surgeries and possibly hasten the postoperative recovery and outcomes in several conditions by simplifying the surgical procedure; minimizing surgically induced trauma; and decreasing the convalescence period, the operating time, and the postoperative inflammatory response.

Background: The most widely used models of proliferative vitreoretinopathy (PVR) rely on injection of cells into the vitreous of animals. Using retinal pigment epithelial (RPE) cells from human PVR membranes may produce a more accurate model of human PVR. We performed a study to determine whether human RPE cells derived from a single epiretinal membrane (ERM) are capable of inducing the same disease in the rabbit eye, and whether the induced ERMs had cellular components similar to those of human PVR membranes. Methods: Cells were harvested from a human ERM obtained at surgery for PVR. RPE cells were cultured from the membrane and injected into the right eye of 24 New Zealand albino rabbits. The left eyes served as controls. The eyes were examined by indirect ophthalmoscopy over 4 weeks. The enucleated eyes were then examined by means of microscopy and histochemical analysis. Results: By day 7, PVR had developed in all but I of the 24 experimental eyes, with 8 progressing to localized tractional retinal detachment. By day 21, localized tractional retinal detachment had developed in 17 eyes; I eye progressed to extensive tractional retinal detachment by day 28. Immunostaining showed that mostly RPE cells, but also myofibroblasts, glial cells and collagen, were present in the newly formed rabbit PVR membranes. Interpretation: Human RPE cells cultured from a PVR membrane appear to be capable of inducing PVR in rabbits. The resultant ERMs are similar to those formed in human PVR and consist mainly of RPE cells.

AIM—To review the rate of retinal detachment after macular hole surgery in patients who received vitrectomy and scleral buckle versus those who had vitrectomy alone. METHODS—All patient charts and hospital records were examined for patients who underwent vitrectomy surgery for macular hole between September 1993 and June 1997. A total of 326 patients were identified and all were followed for a minimum of 6 months. Clinical records were examined for details of the surgical procedure, visual acuity, hole closure status, adjuvant therapies used, and postoperative retinal attachment status. Relative risks (the ratio of the incidence rate in the exposed to that in the unexposed) with 95% confidence intervals and χ2 tests were calculated to determine which variables were associated with retinal detachment. The primary outcome measure in this review was retinal attachment status. RESULTS—Of 326 eyes which underwent surgery for macular hole during the study period, scleral buckles were utilised in 152 (46.6%) patients. Analysis revealed a detachment rate of 13.2% in patients who did not receive a scleral buckle compared with 5.9% detachment rate in those who did. Analysis of these results indicated a 2.42 times greater risk of developing a retinal detachment in patients without a scleral buckle. Complications related to the use of scleral buckles occurred in two of 152 cases (1.3%) CONCLUSIONS—A reduction in the rate of retinal detachment was noted in patients receiving prophylactic scleral buckles. Those finding suggest a possible beneficial effect of this adjunctive procedure in preventing postoperative retinal detachments. The authors are currently preparing a multicentred, prospective, clinical trial to further study this hypothesis

Purpose: The authors describe the clinical feature of ten patients with a new syndrome characterized by the presence of retinal vasculitis, multiple macroaneurysms, neuro-retinitis, and peripheral capillary nonperfusion. Methods: The authors evaluated ten patients identified to have clinical features compatible with the syndrome of idiopathic retinal vasculitis, aneurysms and neuroretinitis (IRVAN). Clinical examination findings, sequential fundus photographs (when available), fluorescein angiograms, systemic investigations, response to therapy, and visual outcomes were reviewed. Results: Seven eyes of four patients sustained a marked decrease in visual acuity of 20/200 or worse. Visual loss was due to a combination of an exudative maculopathy and sequelae of retinal ischemia. Capillary nonperfusion was seen in all ten patients and was severe enough to warrant panretinal laser photocoagulation in six patients. Systemic investigations were uniformly noncontributory. Oral prednisone appears to have little beneficial effects on patients with this disorder. Conclusions: Patients with IRVAN have characteristic retinal features that readily identify this syndrome. An increased awareness of this rare syndrome may help to identify sight-threatening complications at an earlier stage. The authors caution against extensive medical investigations. Ophthalmology 1995;102:1089-1097

To determine the impact of ranibizumab on driving status, driving ability perception, and having 20/40 vision or better in patients with choroidal neovascularization resulting from age-related macular degeneration (AMD).Phase III, multicenter, randomized clinical trials (Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular Age-Related Macular Degeneration [MARINA] and Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in Age-Related Macular Degeneration [ANCHOR]).One thousand one hundred twenty-six patients with choroidal neovascularization resulting from AMD.Participants were assigned randomly to sham (n=238), 0.3-mg ranibizumab monthly injections (n=238), or 0.5-mg ranibizumab monthly injections (n=240) for 24 months (MARINA), or were randomized to verteporfin photodynamic therapy (PDT; n=143), 0.3-mg ranibizumab monthly injections (n=140), or 0.5-mg ranibizumab monthly injections (n=140) for 24 months (ANCHOR).Self-reported driving status and driving ability perception were assessed as exploratory outcomes at baseline through 24 months after baseline using the 25-item National Eye Institute Visual Function Questionnaire. Best-corrected visual acuity in each eye was assessed monthly through 24 months.At baseline, 68.6% of patients in the MARINA trial and 62.7% of patients in the ANCHOR trial reported driving. Among patients driving at baseline in the MARINA trial 2 years after randomization, 67.2% (95% confidence interval [CI], 59.2-75.2) of sham patients and 78.4% (95% CI, 71.8-85.0) of 0.5-mg patients reported that they were still driving. Among patients driving at baseline in the ANCHOR trial at 2 years after randomization, 71.6% (95% CI, 60.8-82.4) of PDT patients and 91.4% (95% CI, 85.3-97.5) of 0.5-mg patients were still driving. Also in the ANCHOR trial, ranibizumab-treated patients who were not driving at baseline seemed more likely to drive by months 12 and 24 than PDT patients. Perception of driving ability was correlated with improvement in visual acuity (VA) in the better-seeing eye at 12 and 24 months (R2=0.17 and R2=0.20 at 12 and 24 months, respectively [P0.001], in the MARINA trial; R2=0.13 and R2=0.14, respectively [P0.001], in the ANCHOR trial). Visual acuity in one or both eyes 2 years after randomization was more likely to be 20/40 or better in the ranibizumab-treated groups.These results suggest that patients with neovascular AMD treated with ranibizumab are more likely to report driving ability and have vision of at least 20/40 than patients given sham treatment or PDT.Proprietary or commercial disclosure may be found after the references.

PURPOSE To compare the effectiveness of three consecutive intravitreal injections of bevacizumab (Avastin) and ranibizumab (Lucentis) in patients with treatment-naive neovascular age-related macular degeneration. METHODS This is a retrospective comparative study of qualifying consecutively treated patients (n = 176) with new-onset subfoveal choroidal neovascularization presenting at 6 retina referral centers. Patients were treated with 3 consecutive monthly injections of ranibizumab (0.5 mg) or 3 injections of bevacizumab every 6 weeks (1.25 mg) as determined by physician and patient preference. Ophthalmologic evaluations included monthly visual acuity measurements, ocular examinations, and optical coherence tomography imaging at each visit. RESULTS A 29.2% reduction in the mean central foveal thickness measurement through optical coherence tomography was found in the ranibizumab-treated patients versus a 20.9% reduction in the bevacizumab-treated patients (P

To examine the effects of ranibizumab on the National Eye Institute Visual Function Questionnaire-25 (NEI VFQ-25) scores in neovascular age-related macular degeneration (AMD) according to whether the study eye was the better- or worse-seeing eye at baseline.Within 2 randomized, double-masked clinical trials (MARINA and ANCHOR), the NEI VFQ-25 was administered at 0, 1, 2, 3, 6, 9, 12, 18, and 24 months.We included 646 MARINA and 379 ANCHOR patients.Patients were randomized 1:1:1 to monthly intravitreal ranibizumab (0.3 or 0.5 mg) or control (sham injections for MARINA; photodynamic therapy [PDT] with verteporfin for ANCHOR).Mean change from baseline in NEI VFQ-25 scores at 12 and 24 months.Across all treatment arms, 21% to 38% of enrolled eyes were the better-seeing eye. At the 24-month follow-up visit, mean change in composite scores with ranibizumab seemed to be better than control for both better-seeing eyes (8.4 [95% confidence interval (CI), 5.2-11.6], 7.5 [95% CI, 3.7-11.4], and -9.4 [95% CI, -12.5 to -6.3] for the 0.3-mg, 0.5-mg, and sham groups, respectively) and worse-seeing eyes (1.7 [95% CI, -1.1 to 4.4], 1.7 [95% CI, -0.7 to 4.1], and -5.4 [95% CI, -7.9 to -2.8] for the 0.3-mg, 0.5-mg, and sham groups, respectively) in MARINA, as well as the better-seeing eye in ANCHOR (11.3 [95% CI, 5.3-17.3], 13.3 [95% CI, 7.7-19.0], and -2.7 [95% CI, -9.0 to 3.7] for the 0.3-mg, 0.5-mg, and PDT groups, respectively). When the worse-seeing eye was treated in ANCHOR, such differences could not be detected at 24 months (1.3 [95% CI, -1.7 to 4.2], 2.6 [95% CI, -1.1 to 6.3], and 0.1 [95% CI, -3.5 to 3.7] for the 0.3-mg, 0.5-mg, and PDT groups, respectively).Analysis of patient perception of vision-related function in phase III trials evaluating ranibizumab for neovascular AMD demonstrates improved patient-reported outcomes regardless of whether the treated eye is the better- or worse-seeing eye at onset of treatment, and supports treatment of such lesions with ranibizumab, even those in the worse-seeing eye.Proprietary or commercial disclosure may be found after the references.

Objective To compare patient-reported visual function in those with neovascular age-related macular degeneration treated with ranibizumab or verteporfin photodynamic therapy (PDT). Design Multicenter, double-masked, phase 3 trial (ANCHOR). Participants were randomized in a 1:1:1 ratio to receive 0.3 or 0.5 mg of intravitreal ranibizumab plus sham verteporfin or sham injections plus active verteporfin monthly. The National Eye Institute Visual Function Questionnaire-25 (NEI VFQ-25) was administered at baseline and 1, 2, 3, 6, 9, 12, 18, and 24 months. Main Outcome Measure Mean change from baseline in NEI VFQ-25 scores at 12 months. Results At 12 months, patients treated with ranibizumab (0.3 mg [n = 137] or 0.5 mg [n = 139]) had mean improvements in NEI VFQ-25 composite scores of 5.9 (95% confidence interval [CI], 3.6 to 8.3) and 8.1 (95% CI, 5.3 to 10.8) points, respectively; patients treated with PDT (n = 142) had a mean improvement of 2.2 points (95% CI, −0.3 to 4.7; vs 0.5 mg of ranibizumab, P P = .003). At each dose through 24 months, patients treated with ranibizumab were more likely to improve in most subscales, including the prespecified subscales (near activities, distance activities, and vision-specific dependency). Conclusions Patients treated with ranibizumab were more likely to report clinically meaningful improvements in visual function through 24 months compared with those treated with verteporfin PDT. Application to Clinical Practice Ranibizumab treatment in neovascular age-related macular degeneration can improve patient-reported visual function. Trial Registration clinicaltrials.gov Identifier:NCT00061594

To review the clinical features, disease progression, and effects of treatment on idiopathic retinitis, vasculitis, aneurysms, and neuroretinitis (IRVAN).Retrospective interventional case series.Ten patients with IRVAN originally reported in 1995 and 12 additional patients identified since the original series.Patients in the series had testing that may have included fluorescein angiography, indocyanine green angiography, and systemic evaluation. Treatments included panretinal laser photocoagulation, cryotherapy, vitrectomy surgery, and injection of periocular or intravitreal steroids.Initial visual acuity (VA), initial stage at diagnosis, clinical course, surgical intervention, final VA, and complications of disease.A total of 44 eyes of 22 patients were studied; 9 eyes had reached stage 1 or 2 disease at last follow-up, 17 had reached stage 3, and 12 had reached stage 4 or 5. At the time of last follow-up, 14 eyes had maintained 20/20 vision, 15 had between 20/40 and 20/200 vision, and 9 had 20/300 vision or worse. Later stages of retinal ischemia are associated with worse VA. Thirty-two of 38 followed eyes were treated. Twenty-five were treated initially with panretinal laser photocoagulation. The clinical course of each eye after initiation of panretinal laser photocoagulation was evaluated with respect to the final VA and stage of ischemic retinopathy at the initiation of treatment. Panretinal laser photocoagulation was initiated in 3 eyes at stage 2, 16 at stage 3, 5 at stage 4, and 1 at stage 5. Seven eyes underwent grid laser retinal photocoagulation of the macula for macular edema.Idiopathic retinitis, vasculitis, aneurysms, and neuroretinitis is an isolated retinal vascular disease that can progress rapidly to severe vision loss due to ischemic sequelae despite treatment with panretinal laser photocoagulation. Based on our review of the largest cohort of IRVAN patients, early panretinal laser photocoagulation should be considered when angiographic evidence of widespread retinal nonperfusion is present, and before (or shortly after) the development of neovascularization. A functional staging system is proposed to improve treatment paradigms.

To evaluate the safety and efficacy of 25-gauge instrumentation for a variety of vitreoretinal conditions on previously nonvitrectomized eyes.Single-center, retrospective, interventional case series.One-hundred forty eyes of 140 patients were evaluated at the Doheny Retina Institute from July 2002 to July 2003.All patients underwent surgical procedures using the Millennium 25-gauge Transconjunctival Standard Vitrectomy system. Twenty eyes (14.3%) underwent procedures without vitrectomy.Postoperative visual acuity (VA), intraocular pressure, surgical time, postoperative inflammation, complications, and number of sutured sites.No intraoperative complications were noted. No cases required conversion to 20-gauge machines. Ten cases (7.1%) involved single-site sclerotomy suture placement due to bleb formation at the conclusion of the procedure, but 5 of these entry sites were enlarged to facilitate larger instrumentation for tissue manipulation. Median VA improved from 20/250 (logarithm of the minimum angle of resolution, 1.08+/-0.47) preoperatively to 20/60 (0.47+/-0.30) (P0.0001) at final visit. Mean follow-up was 33.8+/-9.7 weeks, and all eyes were observed for a minimum of 12 weeks. Mean total surgical time was 17.4+/-6.9 minutes. Intraocular pressures remained stable throughout the postoperative course. Five eyes (3.8%) presented on day 1 with shallow choroidal detachments, but all resolved by day 7, and none required volume infusion during the postoperative period. All but one of these cases was within the first 50 procedures performed. No detectable inflammation was noted in any eyes by 4 weeks postoperatively. No case of retinal detachment or endophthalmitis was recorded.Transconjunctival surgery using 25-gauge instrumentation may hasten postoperative recovery by decreasing overall surgical time and postoperative inflammation. Procedures requiring minimal intraocular manipulation did not require sutures and, thus, may be better suited for this surgical modality.

Purpose To evaluate the effects of subfoveal choroidal neovascularization secondary to age-related macular degeneration on functional parameters obtained by scanning laser ophthalmoscope microperimetry. Design Retrospective observational case series and cross-sectional study. Methods At the Doheny Retina Institute and Wilmer Eye Institute a consecutive series of 179 eyes of 175 patients with subfoveal choroidal neovascularization secondary to age-related macular degeneration was studied. The onset of visual symptoms, best-corrected visual acuity, fluorescein angiography, evaluation of fundus microperimetry and fixation pattern using the Rodenstock scanning laser ophthalmoscope were obtained for each patient. The main outcome measures were central retinal sensitivity and fixation pattern (fixation location and fixation stability) in eyes with subfoveal choroidal neovascularization and their relationship to the length of disease, type and characteristics of choroidal neovascularization, and visual acuity. Results Of 179 eyes, 135 (75%) had central fixation, 27 (15%) had poor central fixation, and 17 (9%) had predominantly eccentric fixation. Seventy-six eyes (42%) had stable fixation, 70 eyes (39%) had relatively unstable fixation, and 33 eyes (18%) had unstable fixation. In 50 eyes (28%) a dense central scotoma was noted. Eighty-nine of 100 eyes (89%) with length of symptoms of less than 3 months had predominantly central fixation and 58 (58%) had stable fixation; 14 of 34 eyes (41%) with length of symptoms of more than 6 months had predominantly central fixation, and 5 eyes (15%) had stable fixation. In 15 eyes of patients who elected not to receive treatment, successive scanning laser ophthalmoscope microperimetry were obtained over time (follow-up of 18 months after onset of symptoms). Three months or less after the onset of symptoms, 13 eyes (87.7%) had predominantly central fixation and 9 eyes (60%) had stable fixation. More than 3 months and 6 months or less after the onset of symptoms, 10 eyes (66.7%) had predominantly central fixation and 7 eyes (46.7%) had stable fixation. This trend was further demonstrated in eyes more than 6 months after the onset of symptoms. Conclusions We conclude that the sequence of events leading to visual function deterioration appears to involve an initial mild decrease in central retinal sensitivity and visual acuity followed by progressive fixation instability and, ultimately, development of an absolute central scotoma with totally eccentric fixation. Increased length of disease is associated with worse fixation pattern and retinal sensitivity deterioration as assessed by scanning laser ophthalmoscope microperimetry. A better understanding of the characteristics of visual loss assessed by fixation pattern evaluation and microperimetry in age-related macular degeneration may help optimize timing, patient selection, and treatment options in eyes with this condition.

To introduce the new approach of inverted pneumatic retinopexy for the management of rhegmatogenous retinal detachments with inferior retinal breaks.Retrospective, noncomparative case series.Eleven patients presenting with rhegmatogenous retinal detachments with causative inferior retinal breaks.Sterile gas/air injection, cryopexy/laser retinopexy, with inverted positioning.Postoperative primary and final anatomical outcome, visual acuity, and complications.Patients were followed for a minimum of 3 months (mean, 5.1 months). Primary retinal reattachment was obtained in 10 of 11(91%) patients. One patient sustained a redetachment secondary to proliferative vitreoretinopathy, resulting in a single operation reattachment rate of 82%. Final reattachment was obtained in 11 of 11 (100%) patients. Mean visual acuity improved about 3 lines from 20/60 to 20/30, with 11 of 11 patients experiencing improvement in their visual acuity. Two patients required an additional surgical procedure to achieve final anatomic success. No new breaks were identified in the postoperative period, and no complications resulted from the pneumatical procedure.Inverted pneumatic retinopexy can successfully repair retinal detachments with inferior retinal breaks under appropriate conditions.

To introduce and evaluate the infusion and aspiration rates and operative times of the 25-gauge transconjunctival sutureless vitrectomy system (TSV) DESIGN: In vitro experimental and comparative interventional study.Twenty eyes of 20 patients underwent a variety of vitreoretinal procedures using the 25-gauge TSV, including idiopathic epiretinal membrane (n = 10), macular hole (n = 4), rhegmatogenous retinal detachment (n = 3), branch retinal vein occlusion (n = 2), diabetic vitreous hemorrhage (n = 1), and 20 cases similar in diagnosis and severity were matched to provide comparison between duration of individual portions of the surgical procedures with the existing 20-gauge vitrectomy system.Description of the 25-gauge TSV is provided; infusion and aspiration rates of the 25-gauge and standard 20-gauge vitrectomy system were measured in vitro using balanced saline solution and porcine vitreous for several levels of aspirating power and bottle height, and operating times of individual portions of surgical procedures were measured for the 25-gauge and 20-gauge vitrectomy system.Infusion, aspiration rates, and operative times of the 20-gauge and 25-gauge vitrectomy system.Infusion and aspiration rates of the 25-gauge TSV system were reduced by an average of 6.9 and 6.6 times, respectively, compared with the 20-gauge system when balanced saline solution was used. The average flow rate of the Storz 25-gauge cutter (at 500 mmHg, 1500 cuts per minute [cpm]) was 40% greater than that of the 20-gauge pneumatic cutter (at 250 mmHg, 750 cpm) but about 2.3 times less than the 20-gauge high-speed cutter (at 250 mmHg, 1500 cpm). Mean total operative time was significantly greater for the 20-gauge high-speed cutter (26 minutes, 7 seconds) than for the 25-gauge vitrectomy system (17 minutes, 17 seconds) (P = 0.011).Although the infusion and aspiration rates of the 25-gauge instruments are lower than those for the 20-gauge high-speed vitrectomy system, the use of 25-gauge TVS may effectively reduce operative times of select cases that do not require the full capability of conventional vitrectomy.

To describe the initial experience and to evaluate the safety and feasibility of using the 25-gauge Transconjunctival Sutureless Vitrectomy System (TSV) for a variety of vitreoretinal procedures.Retrospective review of a consecutive interventional case series.Thirty-five eyes of 33 patients, including cases of idiopathic epiretinal membrane (12 cases), retinal detachment (6 cases), macular hole (5 cases), branch retinal vein occlusion (4 cases), retinopathy of prematurity (4 cases), persistent diabetic macular edema (1 case), diabetic vitreous hemorrhage (1 case), retained lens material after cataract extraction (1 case), and Norrie disease (1 case).All patients underwent surgery using the 25-gauge TSV.Intraocular pressure, visual acuity, and postoperative complications.The median preoperative intraocular pressure was 16 mmHg (range, 10-21 mmHg), whereas the median intraocular pressure on the first postoperative day was 12 mmHg (range, 6-28 mmHg). The median intraocular pressure at 1 week and 1 month were both 16 mmHg (range, 10-30 mmHg). Overall, the median preoperative visual acuity was 20/100 (range, 20/30 to hand motions), and the median postoperative visual acuity after a mean follow-up of 14 weeks (range, 1-60 weeks) was 20/60 (range, 20/20-20/150). One eye developed a postoperative retinal detachment.The 25-gauge TSV seems to be practical and safe for a variety of vitreoretinal procedures. The concept of transconjunctival surgery has the potential to increase the efficiency of a variety of vitreoretinal surgeries and possibly hasten the postoperative recovery and outcomes in several conditions by simplifying the surgical procedure; minimizing surgically induced trauma; and decreasing the convalescence period, the operating time, and the postoperative inflammatory response.

Objectives To evaluate the use of the scanning laser ophthalmoscope (SLO) as a predictor for potential visual improvement in eyes with subfoveal choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD) undergoing limited macular translocation. Design Retrospective noncomparative case series. Participants Consecutive series of 71 eyes of 70 patients with subfoveal CNV secondary to AMD that underwent effective and uncomplicated limited macular translocation at the Wilmer Ophthalmological Institute. Methods Evaluation of the fundus microperimetry and fixation pattern was conducted on all patients using the Rodenstock scanning laser ophthalmoscope (G. Rodenstock Instrument GmbH, Munich, Germany) within 72 hours before surgery. Main outcome measures Sensitivity and specificity in addition to positive and negative predictive values of SLO findings for visual outcome after macular translocation. Results Stable fixation presented the highest positive predictive value for visual acuity equal to or better than 20/100 (30 of 33=0.91), and predominantly eccentric fixation had the highest negative predictive value for visual acuity worse than 20/100 (7 of 9=0.78). Sensitivity was higher for the presence of predominantly central fixation (42 of 48=0.87), and specificity was higher for relatively unstable/unstable fixation (20 of 23=0.87). Conclusions Eyes with stable and central fixation (without dense central scotoma) good preoperative visual acuity, and short length of symptoms are those with the greatest chance to achieve good vision after macular translocation. The knowledge of the fixation and microperimetry pattern enables better understanding of the macular function in eyes with AMD and may be useful for evaluation of baseline retinal cell viability. Incorporation of these testing modalities may help to optimize patient selection for macular translocation or other future techniques aimed at rescuing photoreceptors.

Objective To investigate the validity of the visual function index (VF-14) in assessing visual function in patients with age-related macular degeneration (AMD). Design Prospective noncomparative observational case series. Participants One hundred fifty-nine consecutive patients attending a sole practitioner's academic retina-only clinic from May 1998 through August 1998 and from May 1999 through August 1999. Main outcome measures Correlations were calculated between the VF-14 scores and the medical outcomes study 36-item short form (SF-36), weighted comorbidity scale, visual acuity and clinical AMD severity (stage), and vision self-assessment scales. Documentation of the severity of macular degeneration was performed by a sole examiner. Results There was a moderately strong correlation between visual acuity and trouble with vision ( r = 0.51), satisfaction with vision ( r = −0.50), and overall quality of vision ( r = −0.56). A strong correlation was noted between VF-14 score and patients' self-rating of amount of trouble with vision ( r = −0.67), satisfaction with vision ( r = 0.62), and overall quality of vision ( r = 0.67). In comparison, correlations between SF-36 score and patients' self-rating of amount of trouble with vision, satisfaction with vision, and overall quality of vision ranged from r = 0.37 to r = −0.40. Linear regression analysis for the overall study population indicated that AMD severity was not an independently significant predictor of VF-14 score after adjusting for visual acuity. However, among patients with 20/20 vision in the better eye, AMD severity was an independently significant predictor of VF-14 score after adjusting for visual acuity in the worse eye. Conclusions The VF-14 exhibits a considerable degree of validity as a measure of functional impairment in patients with AMD. Age-related macular degeneration severity was an independently significant predictor of VF-14 score in the group of patients with 20/20 vision in the better eye, but this did not hold true for the overall study population. Age-related macular degeneration is associated with substantial impairment in reported visual function.

Objective To test the validity of the Visual Function Index (VF-14) in patients with retinal disease. Design A self-administered questionnaire package in association with clinical examination findings. Participants Consecutive patients attending the Vancouver General Hospital Eye Care Centre, Vancouver, British Columbia, retina clinic between May 1 and August 15, 1998. Main Outcome Measures Responses to the questionnaire package as they relate to global self-assessment scales and visual acuity. In addition, correlations were calculated between the VF-14, the 36-Item Short-Form Health Survey, a Weighted Comorbidity Scale, and visual acuity scores. Results Five hundred forty-seven patients were given the questionnaire package to complete. The VF-14 demonstrated a moderately strong positive association with patient self-rating of amount of trouble, satisfaction, and overall quality of vision. Correlations between the 36-Item Short-Form Health Survey, visual acuity, and the global scales were mild to moderate. The VF-14 was moderately correlated with visual acuity in the better and the worse eyes. Conclusions This study provides support for the validity of the VF-14 as a measure of functional impairment in patients with retinal disease. Once responsiveness has been measured and an analysis of disease subtypes has been carried out, the VF-14 will be ready for inclusion in clinical trials to evaluate patients' functional ability. Further implementation and development of this outcome measure will better our understanding of the utility of the functional assessment format for patients with retinal disease.

Recent advances in molecular genetics have led to a better understanding of mitochondrially inherited diseases. Mitochondrial encephalomyopathy overlap syndrome is one such group of diseases in which ocular abnormalities are frequently manifest. The authors describe the clinical, molecular genetic, and pathologic findings of two patients with the mitochondrial encephalomyopathy overlap syndrome. The patients shared a similar clinical course with features overlapping the three traditionally distinct clinical phenotypes (the Kearns-Sayre syndrome; the syndrome of mitochondrial encephalopathy, lactic acidosis, and stroke [MELAS], and the syndrome of myoclonus, epilepsy, and ragged red fibers [MERRF]). The patients had identical mitochondrial DNA mutations (at nucleotide position 3243) and had similar ultrastructural abnormalities, including abundant enlarged mitochondria with "whorled" and "tubular" cristae. These abnormal mitochondria appeared to be preferentially distributed in cells with high metabolic activity (retinal pigment epithelium, corneal endothelium, and extraocular muscles).

Objective To examine the effects of ranibizumab on the National Eye Institute Visual Function Questionnaire-25 (NEI VFQ-25) scores in neovascular age-related macular degeneration (AMD) according to whether the study eye was the better- or worse-seeing eye at baseline. Design Within 2 randomized, double-masked clinical trials (MARINA and ANCHOR), the NEI VFQ-25 was administered at 0, 1, 2, 3, 6, 9, 12, 18, and 24 months. Participants We included 646 MARINA and 379 ANCHOR patients. Intervention Patients were randomized 1:1:1 to monthly intravitreal ranibizumab (0.3 or 0.5 mg) or control (sham injections for MARINA; photodynamic therapy [PDT] with verteporfin for ANCHOR). Main Outcome Measures Mean change from baseline in NEI VFQ-25 scores at 12 and 24 months. Results Across all treatment arms, 21% to 38% of enrolled eyes were the better-seeing eye. At the 24-month follow-up visit, mean change in composite scores with ranibizumab seemed to be better than control for both better-seeing eyes (8.4 [95% confidence interval (CI), 5.2–11.6], 7.5 [95% CI, 3.7–11.4], and −9.4 [95% CI, −12.5 to −6.3] for the 0.3-mg, 0.5-mg, and sham groups, respectively) and worse-seeing eyes (1.7 [95% CI, −1.1 to 4.4], 1.7 [95% CI, −0.7 to 4.1], and −5.4 [95% CI, −7.9 to −2.8] for the 0.3-mg, 0.5-mg, and sham groups, respectively) in MARINA, as well as the better-seeing eye in ANCHOR (11.3 [95% CI, 5.3–17.3], 13.3 [95% CI, 7.7–19.0], and −2.7 [95% CI, −9.0 to 3.7] for the 0.3-mg, 0.5-mg, and PDT groups, respectively). When the worse-seeing eye was treated in ANCHOR, such differences could not be detected at 24 months (1.3 [95% CI, −1.7 to 4.2], 2.6 [95% CI, −1.1 to 6.3], and 0.1 [95% CI, −3.5 to 3.7] for the 0.3-mg, 0.5-mg, and PDT groups, respectively). Conclusions Analysis of patient perception of vision-related function in phase III trials evaluating ranibizumab for neovascular AMD demonstrates improved patient-reported outcomes regardless of whether the treated eye is the better- or worse-seeing eye at onset of treatment, and supports treatment of such lesions with ranibizumab, even those in the worse-seeing eye. Financial Disclosure(s) Proprietary or commercial disclosure may be found after the references.

To study the regulation of the multiple forms of erythromycin N-demethylase, we determined the influence of sex and inducer treatment on this mixed-function oxidase activity in adult Wistar rats injected intraperitoneally once daily for 4 days with dexamethasone, pregnenolone-16α-carbonitrile, phenobarbital, or 2% Tween 80 (control). Based on the results from a computer curve-fitting procedure (ENZFITTER) as well as Eadie–Hofstee and Lineweaver–Burk plots, at least two forms of erythromycin N-demethylase were present in control, dexamethasone, pregnenolone-16α-carbonitrile, and phenobarbital-treated male rats and in control and dexamethasone-treated female rats. Only a high-affinity form was apparent in pregneno-lone-16α-carbonitrile and phenobarbital-treated female rats. Therefore, more than one form of erythromycin N-demethylase exists in hepatic microsomes from adult rats, depending on sex and inducer treatment. As well, at a substrate concentration commonly used in the erythromycin N-demethylase assay, the relative contribution of the high- and low-affinity forms to the enzyme activity varies with sex and inducer treatment.Key words: erythromycin N-demethylase, dexamethasone, pregnenolone-16α-carbonitrile, phenobarbital, mixed-function oxidase.

To examine the effects of ranibizumab on patient-reported visual function using the National Eye Institute Visual Function Questionnaire 25 (NEI VFQ-25) in patients with neovascular age-related macular degeneration (AMD).In MARINA, a randomized, double-masked clinical trial, 716 patients with AMD with recent disease progression and minimally classic or occult with no classic lesion component were randomized 1:1:1 to monthly intravitreal ranibizumab (0.3 or 0.5 mg) or sham injections. The NEI VFQ-25 was administered at 0, 1, 2, 3, 6, 9, 12, 18, and 24 months. Main Outcome Measure Mean change from baseline in NEI VFQ-25 scores at 12 and 24 months.At 12 months, ranibizumab-treated patients (0.3 mg [n = 238] and 0.5 mg [n = 240]) had mean improvements in NEI VFQ-25 composite scores of +5.2 (95% confidence interval [CI], 3.5 to 6.9) and +5.6 (95% CI, 3.9 to 7.4), respectively; sham-injected patients (n = 238) had a mean decline of -2.8 (95% CI, -4.6 to -1.1; P.001 vs each dose). Ranibizumab-treated patients were more likely to improve in near activities, distance activities, and vision-specific dependency through 24 months.In MARINA, ranibizumab-treated patients were more likely than sham-treated patients to report visual function improvements at 12 and 24 months.Treatment of neovascular AMD with ranibizumab can improve patient-reported visual function in a meaningful way compared with sham treatments.clinicaltrials.gov Identifier: NCT00056836.

Purpose To review the clinical features, disease progression, and effects of treatment on idiopathic retinitis, vasculitis, aneurysms, and neuroretinitis (IRVAN). Design Retrospective interventional case series. Participants Ten patients with IRVAN originally reported in 1995 and 12 additional patients identified since the original series. Intervention Patients in the series had testing that may have included fluorescein angiography, indocyanine green angiography, and systemic evaluation. Treatments included panretinal laser photocoagulation, cryotherapy, vitrectomy surgery, and injection of periocular or intravitreal steroids. Main Outcome Measures Initial visual acuity (VA), initial stage at diagnosis, clinical course, surgical intervention, final VA, and complications of disease. Results A total of 44 eyes of 22 patients were studied; 9 eyes had reached stage 1 or 2 disease at last follow-up, 17 had reached stage 3, and 12 had reached stage 4 or 5. At the time of last follow-up, 14 eyes had maintained 20/20 vision, 15 had between 20/40 and 20/200 vision, and 9 had 20/300 vision or worse. Later stages of retinal ischemia are associated with worse VA. Thirty-two of 38 followed eyes were treated. Twenty-five were treated initially with panretinal laser photocoagulation. The clinical course of each eye after initiation of panretinal laser photocoagulation was evaluated with respect to the final VA and stage of ischemic retinopathy at the initiation of treatment. Panretinal laser photocoagulation was initiated in 3 eyes at stage 2, 16 at stage 3, 5 at stage 4, and 1 at stage 5. Seven eyes underwent grid laser retinal photocoagulation of the macula for macular edema. Conclusions Idiopathic retinitis, vasculitis, aneurysms, and neuroretinitis is an isolated retinal vascular disease that can progress rapidly to severe vision loss due to ischemic sequelae despite treatment with panretinal laser photocoagulation. Based on our review of the largest cohort of IRVAN patients, early panretinal laser photocoagulation should be considered when angiographic evidence of widespread retinal nonperfusion is present, and before (or shortly after) the development of neovascularization. A functional staging system is proposed to improve treatment paradigms.

Central cloudy corneal dystrophy of Francois was first described in 1955 by J. Francois; its pathophysiology remains unknown. An 80-year-old woman with bilateral central cloudy corneal dystrophy of Francois was examined after having undergone a combined penetrating keratoplasty and cataract extraction. The corneal button was obtained. Light microscopy revealed stromal staining for acid mucopolysaccharide. Transmission electron microscopy revealed extracellular vacuoles, some of which had fibrillogranular material and electron-dense deposits. Fibrillogranular material was present in and around some keratocytes. Numerous endothelial vacuoles contained light-staining fibrillogranular material and round electron-dense granules. Our findings suggest that the opacities in patients with central cloudy corneal dystrophy of Francois are due to the extracellular accumulation of mucopolysaccharide and lipidlike material. Further studies are needed to elucidate the nature of these deposits.

Diffuse unilateral subacute neuro-retinitis (DUSN) is a clinical syndrome characterized by unilateral visual loss and associated in the early stages with vitritis, papillitis, retinal vasculitis, and recurrent crops of gray-white outer retinal lesions. With time, visual loss may be progressive, with secondary development of optic atrophy, retinal vessel narrowing, and retinal pigment epithelium (RPE) degeneration.1-3Evidence suggests that DUSN is caused by an intraretinal nematode of 2 different sizes. The smaller nematode, measuring 400 to 700 μm in length, appears to be endemic to the southeastern United States, the Caribbean islands, and Brazil. The larger nematode, measuring 1500 to 2000 μm in length, has been described in the northern midwestern United States.3,4 In this report, we describe 3 cases of DUSN in Canada that represent different stages along the clinical spectrum of early to late DUSN. In the first 2 cases, both from Vancouver, British Columbia, subretinal nematodes

Background: Conjunctival intraepithelial neoplasia has traditionally been found at the limbus in elderly individuals. Recently, this ocular tumor has been observed in younger patients. Objective: To investigate the potential association of human immunodeficiency virus infection with the emergence of this atypical presentation of conjunctival intraepithelial neoplasia. Design, Setting, and Participants: Records of patients at the Bascom Palmer Eye Institute (Miami, Fla) in whom conjunctival intraepithelial neoplasia was diagnosed between January 1, 1991, and December 31, 1993, were reviewed. Attempts were made to contact those patients younger than 50 years for clinical evaluation and human immunodeficiency virus serologic testing. Results: Conjunctival intraepithelial neoplasia was diagnosed in 73 patients during the study period. Of the nine patients younger than 50 years, six were available for serologic testing. Three (50%) of these individuals were found to be positive for human immunodeficiency virus. Conclusion: Human immunodeficiency virus testing and counseling should be considered in patients younger than 50 years in whom conjunctival intraepithelial neoplasia is diagnosed.

This study evaluated a nomogram designed to identify a subgroup of the patients whose serum phenytoin concentrations are near steady state at a given time after initiation of therapy. A sample of 95 adult subjects with reported values of Vmax and Km was pooled from the literature, and computer simulations of phenytoin accumulation for 15 days after initiation of phenytoin acid at 300 mg/day were performed. Simulated serum concentrations on days 5, 10, and 15 were used to identify subjects who were predicted by the nomogram to be at greater than or equal to 83% of steady state, and these results were compared with those expected from the Michaelis-Menten model. In the simulations, 42, 62, and 66 subjects reached greater than or equal to 83% of steady state by days 5, 10, and 15, respectively. The nomogram correctly identified 13 (31.0%), 33 (53.2%), and 43 (65.2%) of these individuals, respectively. The frequency of erroneous predictions was low, even in subjects whose Km and volume of distribution were outside the limits set in the development of the nomogram. Use of a nomogram such as this would help a subgroup of patients to attain a desired serum phenytoin concentration earlier in therapy and with fewer serum phenytoin determinations than would otherwise be required. It would also prevent premature increases in phenytoin dose in patients whose serum concentration is still rising.

Cimetidine, a substituted imidazole, is an inhibitor of hepatic cytochrome P-450-mediated drug metabolism in rats and humans. We investigated the effect of cimetidine on phenobarbital induction of hepatic microsomal aminopyrine N-demethylase activity in the rat. Phenobarbital induction of aminopyrine N-demethylase was log-linear in the range of 1–6 mg/kg/day and the ED50 was approximately 3 mg/kg/day. Cimetidine 75 mg/kg (four times a day) attenuated the induction of aminopyrine N-demethylase activity by 58% in low dose (3 mg/kg/day) but not in high dose (40 mg/kg/day) phenobarbital treated rats. This result could not be explained by residual inhibition of enzyme activity by cimetidine and suggests that cimetidine affects the induction of hepatic cytochrome P-450 by low dose phenobarbital.

Steady-state serum phenytoin concentration (Css) is known to increase nonlinearly with dose, but it is less well recognized that the rate of phenytoin accumulation is also dose dependent. This stimulation study estimated the extent and rate of phenytoin accumulation in a sample of 95 adult subjects, with known values of Vmax and Km, pooled from the literature. Simulations were done using a Michaelis-Menten model and phenytoin sodium doses of 200, 300, and 400 mg/day. The distributions of Css and the time required to reach 90% of steady state (T90) became increasingly positively skewed as dose was increased. The T90 and Css were positively correlated (r greater than or equal to 0.8880, p less than 0.00001) and subjects reached 90% or more of Css more slowly as the initial phenytoin dose was increased. At an initial dose of 300 mg/day of phenytoin sodium, mean Css was 11.0 +/- 9.10 micrograms/ml (median, 7.62 micrograms/ml), and mean T90 was 12.2 +/- 15.4 days (median, 5.98 days). Only 25.3% of the subjects would be expected to achieve therapeutic serum concentrations (10-20 micrograms/ml) on this dose, and 88.4% would reach 0.9 Css within 30 days. Phenytoin dosage must be individualized to achieve concentrations of 10-20 micrograms/ml. Multiple serum phenytoin determinations during the first 30 days or more are required to determine that steady state has been reached, but these need not be done more often than once a week.