Janet L. Davis

A Variable-dosing Regimen with Intravitreal Ranibizumab for Neovascular Age-related Macular Degeneration: Year 2 of the PrONTO Study

PURPOSE To assess the long-term efficacy of a variable-dosing regimen with ranibizumab in the Prospective Optical Coherence Tomography (OCT) Imaging of Patients with Neovascular Age-Related Macular Degeneration (AMD) Treated with intraOcular Ranibizumab (PrONTO) Study, patients were followed for 2 years. DESIGN A 2-year prospective, uncontrolled, variable-dosing regimen with intravitreal ranibizumab based on OCT. METHODS In this open-label, prospective, single-center, uncontrolled clinical study, AMD patients with neovascularization involving the central fovea and a central retinal thickness (CRT) of at least 300 microm as measured by OCT were enrolled to receive 3 consecutive monthly intravitreal injections of ranibizumab (0.5 mg) [Lucentis; Genentech Inc, South San Francisco, California, USA]. During the first year, retreatment with ranibizumab was performed at each monthly visit if any criterion was fulfilled such as an increase in OCT-CRT of at least 100 microm or a loss of 5 letters or more. During the second year, the retreatment criteria were amended to include retreatment if any qualitative increase in the amount of fluid was detected using OCT. RESULTS Forty patients were enrolled and 37 completed the 2-year study. At month 24, the mean visual acuity (VA) improved by 11.1 letters (P < .001) and the OCT-CRT decreased by 212 microm (P < .001). VA improved by 15 letters or more in 43% of patients. These VA and OCT outcomes were achieved with an average of 9.9 injections over 24 months. CONCLUSIONS The PrONTO Study using an OCT-guided variable-dosing regimen with intravitreal ranibizumab resulted in VA outcomes comparable with the outcomes from the phase III clinical studies, but fewer intravitreal injections were required.

Human embryonic stem cell-derived retinal pigment epithelium in patients with age-related macular degeneration and Stargardt's macular dystrophy: follow-up of two open-label phase 1/2 studies

BACKGROUND Since they were first derived more than three decades ago, embryonic stem cells have been proposed as a source of replacement cells in regenerative medicine, but their plasticity and unlimited capacity for self-renewal raises concerns about their safety, including tumour formation ability, potential immune rejection, and the risk of differentiating into unwanted cell types. We report the medium-term to long-term safety of cells derived from human embryonic stem cells (hESC) transplanted into patients. METHODS In the USA, two prospective phase 1/2 studies were done to assess the primary endpoints safety and tolerability of subretinal transplantation of hESC-derived retinal pigment epithelium in nine patients with Stargardts macular dystrophy (age >18 years) and nine with atrophic age-related macular degeneration (age >55 years). Three dose cohorts (50,000, 100,000, and 150,000 cells) were treated for each eye disorder. Transplanted patients were followed up for a median of 22 months by use of serial systemic, ophthalmic, and imaging examinations. The studies are registered with ClinicalTrials.gov, numbers NCT01345006 (Stargardts macular dystrophy) and NCT01344993 (age-related macular degeneration). FINDINGS There was no evidence of adverse proliferation, rejection, or serious ocular or systemic safety issues related to the transplanted tissue. Adverse events were associated with vitreoretinal surgery and immunosuppression. 13 (72%) of 18 patients had patches of increasing subretinal pigmentation consistent with transplanted retinal pigment epithelium. Best-corrected visual acuity, monitored as part of the safety protocol, improved in ten eyes, improved or remained the same in seven eyes, and decreased by more than ten letters in one eye, whereas the untreated fellow eyes did not show similar improvements in visual acuity. Vision-related quality-of-life measures increased for general and peripheral vision, and near and distance activities, improving by 16-25 points 3-12 months after transplantation in patients with atrophic age-related macular degeneration and 8-20 points in patients with Stargardts macular dystrophy. INTERPRETATION The results of this study provide the first evidence of the medium-term to long-term safety, graft survival, and possible biological activity of pluripotent stem cell progeny in individuals with any disease. Our results suggest that hESC-derived cells could provide a potentially safe new source of cells for the treatment of various unmet medical disorders requiring tissue repair or replacement. FUNDING Advanced Cell Technology.

Short-term safety and efficacy of intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration.

Purpose: To evaluate the safety and efficacy of intravitreal bevacizumab (Avastin, Genentech Inc.) for the treatment of neovascular age-related macular degeneration (ARMD). Methods: A retrospective review was performed on consented patients with neovascular ARMD receiving intravitreal bevacizumab therapy. All patients received intravitreal bevacizumab at baseline with additional monthly injections given at the discretion of the treating physician. At each visit, a routine Snellen visual acuity assessment was performed followed by an ophthalmic examination and optical coherence tomography (OCT) imaging. Results: Fifty–three eyes of 50 patients received an intravitreal bevacizumab injection between May and August 2005. Including the month 3 visit, the average number of injections was 2.3 out of a maximum of 4 injections. No serious drug-related ocular or systemic adverse events were identified. Improvements in visual acuity and central retinal thickness measurements were evident by week 1 and continued through month 3. At month 3, the mean visual acuity improved from 20/160 to 20/125 (P<0.001) and the mean central retinal thickness decreased by 99.6 &mgr;m (P<0.001). Conclusion: Off-label intravitreal bevacizumab therapy for neovascular ARMD was well tolerated over 3 months with improvements in visual acuity and OCT central retinal thickness measurements. While the long-term safety and efficacy of intravitreal bevacizumab remain unknown, these short-term results suggest that intravitreal bevacizumab may be the most cost effective therapy for the treatment of neovascular ARMD.

A randomized, controlled trial of foscarnet in the treatment of cytomegalovirus retinitis in patients with AIDS

OBJECTIVE To evaluate foscarnet sodium in treating cytomegalovirus retinitis in patients with AIDS. PATIENTS Twenty-four previously untreated persons with AIDS and cytomegalovirus retinitis who were at low risk for loss of their visual acuity. INTERVENTION PATIENTS were randomly assigned to receive either no therapy (delayed treatment, control group) or immediate treatment with intravenous foscarnet at a dose of 60 mg/kg body weight three times a day for 3 weeks (induction regimen) followed by a maintenance regimen of 90 mg/kg once a day. MEASUREMENTS PATIENTS were examined weekly until they reached the primary clinical end point, defined as progression of their retinitis border by 750 microns or the development of a new retinal lesion due to cytomegalovirus. Progression was evaluated using retinal photographs by masked readers. Secondary evaluations included changes in visual acuity, cytomegalovirus shedding in the blood and urine, serum levels of human immunodeficiency virus type 1 (HIV-1) p24 antigen, and total CD4 T lymphocyte counts. RESULTS The mean time to progression of retinitis was 3.2 weeks in the control group (n = 11) compared with 13.3 weeks in the treatment group (n = 13) (P less than 0.001). Nine of 13 patients in the treatment group had positive blood cultures for cytomegalovirus at entry and all nine cleared their blood of cytomegalovirus by the end of the induction period (P = 0.004) compared with one of six patients in the control group. No reductions in p24 levels were seen in the control patients compared with a reduction of more than 50% in p24 levels for all four patients on treatment for whom follow-up levels were available. The main adverse effects of foscarnet treatment were seizures (2 of 13 patients), hypomagnesemia (9 of 13), hypocalcemia (11 of 13), and elevations in serum creatinine above 176.8 mumol/L (2.0 mg/dL) (3 of 13). The control patients received an average of 0.2 units of blood per week compared with an average of 0.6 units of blood per week for the patients on treatment. CONCLUSIONS The administration of foscarnet decreases the rate of progression of cytomegalovirus retinitis in persons with AIDS. Its judicious use is likely to prevent loss of vision in these patients. In this study, however, there was little change in visual acuity in patients in either the immediate or delayed treatment group because only patients with non-sight-threatening disease were selected.

Primary Vitreoretinal Lymphoma: A Report from an International Primary Central Nervous System Lymphoma Collaborative Group Symposium

Primary vitreoretinal lymphoma (PVRL), also known as primary intraocular lymphoma, is a rare malignancy typically classified as a diffuse large B-cell lymphoma and most frequently develops in elderly populations. PVRL commonly masquerades as posterior uveitis and has a unique tropism for the retina and central nervous system (CNS). Over 15% of primary CNS lymphoma patients develop intraocular lymphoma, usually occurring in the retina and/or vitreous. Conversely, 65%-90% of PVRL patients develop CNS lymphoma. Consequently, PVRL is often fatal because of ultimate CNS association. Current PVRL animal models are limited and require further development. Typical clinical findings include vitreous cellular infiltration (lymphoma and inflammatory cells) and subretinal tumor infiltration as determined using dilated fundoscopy, fluorescent angiography, and optical coherent tomography. Currently, PVRL is most often diagnosed using both histology to identify lymphoma cells in the vitreous or retina and immunohistochemistry to indicate monoclonality. Additional adjuncts in diagnosing PVRL exist, including elevation of interleukin-10 levels in ocular fluids and detection of Ig(H) or T-cell receptor gene rearrangements in malignant cells. The optimal therapy for PVRL is not defined and requires the combined effort of oncologists and ophthalmologists. PVRL is sensitive to radiation therapy and exhibits high responsiveness to intravitreal methotrexate or rituximab. Although systemic chemotherapy alone can result in high response rates in patients with PVRL, there is a high relapse rate. Because of the disease rarity, international, multicenter, collaborative efforts are required to better understand the biology and pathogenesis of PVRL as well as to define both diagnostic markers and optimal therapies.

Decrease in the Risk of Bilateral Acute Retinal Necrosis by Acyclovir Therapy

We reviewed the course of 54 patients who had unilateral acute retinal necrosis at initial examination. Thirty-one patients were treated with acyclovir, whereas 23 were not. Of the 31 patients treated with acyclovir, 27 (87.1%) had fellow eyes that remained disease-free throughout a median follow-up of 12 months. Of the 23 patients not treated with acyclovir, seven (30.4%) had fellow eyes that remained disease-free throughout a median follow-up of 11 months. Survival analysis indicated that the fellow eyes of the group of patients treated with acyclovir were more likely to remain disease-free than the fellow eyes of the group not treated with acyclovir (P = .0013). Two years after initial onset, the proportion of fellow eyes that remained disease-free was 75.3% for the group treated with acyclovir and 35.1% for the group not treated with acyclovir. These results suggest that acyclovir treatment reduces the risk of involvement of the fellow eye in patients with acute retinal necrosis.

Endogenous aspergillus endophthalmitis: Clinical features and treatment outcomes

OBJECTIVE This study evaluated the clinical features and treatment outcomes in patients with endogenous Aspergillus endophthalmitis. DESIGN The study design was a multicenter retrospective chart review. PARTICIPANTS Ten patients (12 eyes) with culture-proven endogenous Aspergillus endophthalmitis treated by 1 of the authors were studied. INTERVENTION Intravitreous amphotericin B injection, pars plana vitrectomy, systemic amphotericin B therapy, and oral anti-fungal therapy were performed. MAIN OUTCOME MEASURES Elimination of endogenous Aspergillus endophthalmitis and Snellen visual acuity, best corrected, were measured. RESULTS All patients had a 1- to 3-day history of pain and marked loss of visual acuity in the involved eyes. Varying degrees of vitritis was present in all 12 eyes. In 8 of 12 eyes, a central macular chorioretinal inflammatory lesion was present. Four patients (six eyes) had associated pulmonary diseases and were receiving concurrent steroid therapy. One of these patients with chronic asthma also was abusing intravenous drugs. Overall, six patients (six eyes) had a history of intravenous drug abuse, whereas a seventh patient (one eye) was suspected of abusing intravenous drugs. Blood cultures and echocardiograms were negative for systemic aspergillosis. Management consisted of a pars plana vitrectomy in 10 of 12 eyes. Intravitreous amphotericin B was administered in 11 of 12 eyes. Systemic amphotericin B therapy was used in eight patients. One patient was treated with oral antifungal agents. In three eyes without central macular involvement, final visual acuities were 20/25 to 20/200. In eight eyes with initial central macular involvement, final visual acuities were 20/400 in three eyes and 5/200 or less in four eyes. Two painful eyes with marked inflammation, hypotony, and retinal detachment were enucleated. CONCLUSIONS Endogenous Aspergillus endophthalmitis usually has an acute onset of intraocular inflammation and often has a characteristic chorioretinal lesion located in the macula. Although treatment with pars plana vitrectomy and intravitreous amphotericin B is capable of eliminating the ocular infection, the visual outcome generally is poor, especially when there is direct macular involvement.

Mutations Conferring Ganciclovir Resistance in a Cohort of Patients with Acquired Immunodeficiency Syndrome and Cytomegalovirus Retinitis

Cytomegalovirus (CMV) retinitis is among the most common opportunistic infections in patients with acquired immunodeficiency syndrome. In a prospective study of 210 patients with CMV retinitis, 26 were identified as having either a phenotypic or a genotypic ganciclovir-resistant isolate from either blood or urine cultures. For blood culture isolates with an IC(50) >6.0 microm for ganciclovir, the sensitivity and specificity for detecting a UL97 mutation were 95% and 98%, respectively, whereas for an IC(50) >8.0 microM they were 79% and 99%, respectively. Although there were trade-offs between the 2 thresholds for blood culture isolates, for urine culture isolates an IC(50) >8.0 microM appeared to be better at identifying genotypic resistance. UL97 mutations identified in both the blood and urine cultures of individual patients were identical in 87.5% of cases. High-level ganciclovir resistance (IC(50), >30 microM) typically, but not invariably, was associated with a mutation in both the UL97 and UL54 genes.

Endophthalmitis after intravitreal anti-vascular endothelial growth factor antagonists: A six-year experience at a university referral center

Purpose: To assess the rate of infectious endophthalmitis and to describe the clinical and microbiological features of eyes that develop clinically suspected endophthalmitis after an intravitreal injection of vascular endothelial growth factor antagonists. Methods: The medical records of patients undergoing intravitreal injections of anti-vascular endothelial growth factor agents from January 1, 2005, through December 31, 2010, at a single university referral center and associated satellite clinics were retrospectively analyzed to determine the rate of infectious endophthalmitis after intravitreal anti-vascular endothelial growth factor injections. Results: Twelve cases (11 patients) of clinically suspected endophthalmitis were identified after a total of 60,322 injections (0.02%; 95% confidence interval, 0.0114%-0.0348%). Of the 12 cases, 11 presented within 3 days of the injection. Of the 7 culture-positive cases, 5 were because of Streptococcus species. In 4 of the 5 Streptococcus cases, final visual acuity was hand motions or worse. The rate of clinically suspected endophthalmitis was 0.018% after bevacizumab and 0.027% after ranibizumab injections. Conclusion: A very low rate of endophthalmitis after intravitreal injections of anti-vascular endothelial growth factor agents was observed. Patients typically presented within 3 days of injection. Streptococcus species was the most common bacteria isolated, and it was generally associated with poor visual outcomes.

Idiopathic retinal vasculitis, aneurysms, and neuro-retinitis

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