Joseph I. Maguire

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.

Treatment of Acute Retinal Necrosis

OBJECTIVES To compare outcomes from patients with acute retinal necrosis (ARN) treated in the acyclovir-only era with those treated in the era of newer antiviral therapies, identify variables affecting outcomes in ARN, and evaluate strategies for fellow eye prophylaxis. DESIGN Multicenter, nonrandomized, retrospective, interventional series. PARTICIPANTS A cohort of 58 patients diagnosed with ARN by a retina specialist at 1 of 4 referral centers between 1981 and 2008. The cohort was divided into 2 subgroups: patients treated during the acyclovir-only era (n = 36) and patients treated during the current era of newer antiviral medications (n = 22). INTERVENTION Intravenous, oral, or intravitreal antiviral medications, including acyclovir, valacyclovir, famciclovir, valganciclovir, ganciclovir, and foscarnet; prophylactic laser retinopexy; aspirin; oral steroids. MAIN OUTCOME MEASURES Visual acuity, retinal detachment, and fellow eye involvement. RESULTS A wide range and combination of antiviral agents are currently used for initial and long-term treatment of ARN. Outcomes from the newer antivirals era were similar to those achieved during the acyclovir-only era. In both groups, the incidence of 20/200 or worse visual acuity was 24% per person-year (P = 0.91). The prevalence of retinal detachment was approximately 50% in each group (P = 0.59). No variables, including prophylactic laser retinopexy, were associated with risk of retinal detachment. Two patients (3.4%) developed ARN in the initially unaffected eye. CONCLUSIONS Current treatment trends vary widely, including single agents or combinations of oral, intravenous, and intravitreal agents. Differing strategies did not affect outcomes. The final visual acuity in ARN was generally poor. Retinal detachment was common and could neither be predicted nor prevented. Development of ARN in the unaffected fellow eye occurred rarely. Long-term oral antiviral treatment strategies varied with unclear relative efficacy. FINANCIAL DISCLOSURE(S) Proprietary or commercial disclosure may be found after the references.

Indocyanine green angiography and occult choroidal neovascularization

PURPOSE To evaluate the use of digital indocyanine green (ICG) angiography as an adjunct to fluorescein angiography in the diagnosis and treatment of ill-defined choroidal neovascularization (CNV) associated with age-related macular degeneration (AMD). METHODS The authors retrospectively reviewed all ICG angiograms performed at Wills Eye Hospital from March to July 1992. Included in this study were all cases with exudative manifestations of AMD in which fluorescein angiography showed ill-defined CNV. The initial ICG findings and the clinical outcome of both treated and untreated cases were evaluated through 6 months of follow-up. RESULTS Of the 101 eligible cases, ICG angiography at presentation demonstrated well-defined hyperfluorescence in 40 cases (group 1), ill-defined hyperfluorescence in 43 cases (group 2), mixed pattern of well- and ill-defined hyperfluorescence in 14 cases (group 3), and no abnormalities in 4 cases (group 4). Approximately one half of the cases with well-defined ICG hyperfluorescence (21% of the total) had only extrafoveal changes. Laser photocoagulation treatment based solely on ICG angiogram findings was performed in 19 group 1 cases (extrafoveal hyperfluorescent foci only) and in 8 group 3 cases, with treatment in both groups being directed only to areas of well-defined hyperfluorescence. Successful treatment was achieved in 12 (63%) of 19 cases and in 2 (25%) of 8 cases, respectively. There was a strong correlation between post-treatment persistence or recurrence of ICG hyperfluorescence and treatment failure. CONCLUSIONS Indocyanine green angiography is a valuable diagnostic adjunct to fluorescein angiography in evaluating occult CNV in AMD. In this series, well-defined, extrafoveal ICG hyperfluorescence was identified in 21% of the cases, and preliminary, short-term results suggest that ICG-guided laser treatment is promising in this subgroup.

Ocular candidiasis: a review

Aims: To review the epidemiology, diagnosis and changing treatment paradigm of ocular candidiasis, and report current prevalence rates and risk factors at one inpatient hospital. Design: Retrospective review; systematic literature review. Methods: All Wills Eye Institute inpatient ophthalmology consultations from Thomas Jefferson University Hospital were retrospectively reviewed between June 2006 and November 2006. All consultations for candidaemia were included. The outcome variables included chorioretinitis, endophthalmitis, visual symptoms and Candida speciation. The ophthalmic literature was reviewed using PubMed. Keywords included Candida, candidaemia, chorioretinitis, vitritis and endophthalmitis. Bibliographies were manually searched. Results: Three of the 38 consultations for candidaemia (7.9%) had chorioretinitis. There were no cases of vitritis or endophthalmitis. The presence of symptoms, or the inability to articulate symptoms, was significantly associated with risk of ocular candidiasis (p = 0.003). All three cases of chorioretinitis had positive blood cultures for Candida albicans (p = 0.089) and were treated with oral fluconazole. Conclusions: Various factors have led to the increasing prevalence of inpatient candidaemia. Risk factors for ocular involvement include albicans species and the presence of, or inability to articulate, visual symptoms. For those without abnormal findings on initial examination, a subsequent retinal examination should be performed in 2 weeks, particularly if new symptoms develop or if the patient is unable to relay symptoms. Patients with chorioretinitis should be treated with systemic antifungal agents. For those with vitritis or endophthalmitis, particularly if worsening on systemic therapy alone, intravitreal antifungal medications or early vitrectomy should be considered.

Retinal pigment epithelial tears after intravitreal bevacizumab injection for exudative age-related macular degeneration

Purpose:  To determine the incidence of and the risk factors for the development of retinal pigment epithelial (RPE) tears after intravitreal bevacizumab (Avastin) injection for the treatment of exudative age‐related macular degeneration (AMD).

The competency of pars plana vitrectomy incisions: a comparative histologic and spectrophotometric analysis.

PURPOSE To compare the relative competency of pars plana vitrectomy (PPV) sclerotomies. DESIGN Laboratory investigation. METHODS PPV was performed in human cadaveric eyes using 20-gauge (20 G), 23-gauge (23 G), and 25-gauge (25 G) instrumentation. India ink was applied over a sclerotomy site while the intraocular pressure was varied. The presence of India ink particles (IIPs) along incisions was evaluated by histologic analysis. Spectrophotometric absorbance levels of vitreous aspirates were measured. RESULTS PPV was performed in a control eye and two eyes, each using standard 20 G, standard 23 G, perpendicular 25 G, and beveled 25 G instrumentation incisions. IIPs were not detected in the 20 G incisions either on histology or by spectrophotometry. IIPs were detected along the entire incision length in one of two eyes with 23 G sclerotomies and confirmed by spectrophotometry. IIPs were detected along the entire incision length in one of two eyes with 25 G perpendicular sclerotomies and confirmed by spectrophotometry in both eyes. IIPs were noted partially along the length in one of the two beveled 25 G eyes, but not detected in either eye by spectrophotometry. CONCLUSIONS During the early postoperative period, sutureless vitrectomy incisions may allow entry of ocular surface fluid. These findings may provide a pathophysiologic mechanism for the reported increased risk of endophthalmitis in small-gauge vitrectomy surgery.

Characteristics of endophthalmitis in patients with the Boston keratoprosthesis.

Purpose: To determine the characteristics of endophthalmitis in patients with the Boston keratoprosthesis. Methods: Retrospective chart review of 4 out of 35 patients who underwent implantation of the Boston keratoprosthesis on the Wills Eye Cornea service between 2001 and 2007 and developed infectious endophthalmitis. Results: All 4 patients had keratoprosthesis surgery due to previous corneal transplant failure. The incidence of endophthalmitis was 11.4%. All patients were on topical antibiotic prophylaxis with a fluoroquinolone and 1 of the 4 patients was also using vancomycin drops. All 4 patients underwent a tap and inject and were admitted for intensive intravenous and topical antibiotics for 3 to 7 days. Culture positive results were found in 3 of the 4 vitreous samples: 2 coagulase-negative Staphylococcus, and 1 Pseudomonas and Staphylococcus aureus. Minimum Inhibitory Concentration data showed high resistance to fourth-generation fluoroquinolone antibiotics in all isolates. All patients recovered significant vision, except 1 patient who developed fluctuating vision secondary to vitreoretinal traction bands, which developed secondary to the endophthalmitis. Conclusion: Endophthalmitis can occur after Boston keratoprosthesis at a significant rate, even in low-risk patients on prophylactic antibiotic drops. Given our experience with these patients and vancomycin, we recommend its prophylactic use. The increasing resistance of gram-positive organisms to fluoroquinolones and the need for close patient follow-up to encourage adherence to preventive regimens are further supported in this report.

Optical Coherence Tomography Angiography and En Face Optical Coherence Tomography Features of Paracentral Acute Middle Maculopathy

PURPOSE To characterize the optical coherence tomography (OCT) angiography, en face OCT, and microperimetry features of paracentral acute middle maculopathy in both the acute phase and after resolution, and to propose a classification of distinct subtypes of this entity. DESIGN Retrospective observational case series. METHODS Clinical histories, high-resolution digital color imaging, spectral-domain OCT images, fluorescein angiography, OCT angiography images, and en face OCT images of 16 patients with paracentral acute middle maculopathy were evaluated. Microperimetry was available in 6 patients. RESULTS The most common referring diagnoses were isolated branch retinal arterial occlusion (5/16), combined central retinal vein and cilioretinal artery occlusion (4/16), and isolated central retinal vein occlusion (4/16). All patients demonstrated hyperreflective plaque-like lesions at the level of the inner nuclear layer on spectral-domain OCT, with no fluorescein angiographic correlate. OCT angiography demonstrated variable areas of capillary dropout within the superficial and deep retinal capillary plexi in these areas. En face OCT highlighted confluent areas of middle retina hyperreflectivity corresponding to these lesions. Three distinct en face OCT patterns were observed: arteriolar, fern-like, and globular. Microperimetry demonstrated relative scotomas mapping to the area of middle retinal hyperreflectivity seen on en face OCT. CONCLUSIONS Paracentral acute middle maculopathy may be best evaluated with the use of en face OCT imaging, which corresponds to subjective and objective visual field defects. En face OCT appearance may be used to classify paracentral acute maculopathy into distinct subtypes.

Treatment of foveal pigment epithelial detachments with contiguous extrafoveal choroidal neovascular membranes.

Fourteen eyes of 14 patients who had subfoveal retinal pigment epithelial detachments and extrafoveal contiguous choroidal neovascular membranes associated with age-related macular degeneration underwent laser photo-coagulation treatment directed solely to their choroidal neovascular membrane. In eight of 14 eyes (57%), photocoagulation treatment resulted in closure of the choroidal neovascular membrane with subsequent collapse of the pigment epithelial detachment. Six of the eight eyes also had visual improvement. In six of 14 eyes (43%), the neovascular membrane eventually progressed into the fovea with resultant visual loss. The results of our study suggest that photocoagulation of extrafoveal choroidal neovascular membranes associated with foveal detachments of the retinal pigment epithelium may preserve and even improve visual function in affected patients.

Spectral Domain Optical Coherence Tomographic Findings of Occult Macular Dystrophy

Occult macular dystrophy is a rare macular disorder in which patients have bilaterally decreased visual acuity without any significant ophthalmoscopic findings. Using spectral domain optical coherence tomography, the authors found a defect in the junction between the inner and outer segments of the foveal photoreceptors in a patient with occult macular dystrophy.