Mark C. Gillies

Randomized, Sham-Controlled Trial of Dexamethasone Intravitreal Implant in Patients with Macular Edema Due to Retinal Vein Occlusion

OBJECTIVE To evaluate the safety and efficacy of dexamethasone intravitreal implant (DEX implant; OZURDEX, Allergan, Inc., Irvine, CA) compared with sham in eyes with vision loss due to macular edema (ME) associated with branch retinal vein occlusion (BRVO) or central retinal vein occlusion (CRVO). DESIGN Two identical, multicenter, masked, randomized, 6-month, sham-controlled clinical trials (each of which included patients with BRVO and patients with CRVO). PARTICIPANTS A total of 1267 patients with vision loss due to ME associated with BRVO or CRVO. INTERVENTION A single treatment with DEX implant 0.7 mg (n = 427), DEX implant 0.35 mg (n = 414), or sham (n = 426). MAIN OUTCOME MEASURES The primary outcome measure for the pooled data from the 2 studies was time to achieve a > or =15-letter improvement in best-corrected visual acuity (BCVA). Secondary end points included BCVA, central retinal thickness, and safety. RESULTS After a single administration, the time to achieve a > or =15-letter improvement in BCVA was significantly less in both DEX implant groups compared with sham (P<0.001). The percentage of eyes with a > or =15-letter improvement in BCVA was significantly higher in both DEX implant groups compared with sham at days 30 to 90 (P<0.001). The percentage of eyes with a > or =15-letter loss in BCVA was significantly lower in the DEX implant 0.7-mg group compared with sham at all follow-up visits (P< or =0.036). Improvement in mean BCVA was greater in both DEX implant groups compared with sham at all follow-up visits (P< or =0.006). Improvements in BCVA with DEX implant were seen in patients with BRVO and patients with CRVO, although the patterns of response differed. The percentage of DEX implant-treated eyes with intraocular pressure (IOP) of > or =25 mmHg peaked at 16% at day 60 (both doses) and was not different from sham by day 180. There was no significant between-group difference in the occurrence of cataract or cataract surgery. CONCLUSIONS Dexamethasone intravitreal implant can both reduce the risk of vision loss and improve the speed and incidence of visual improvement in eyes with ME secondary to BRVO or CRVO and may be a useful therapeutic option for eyes with these conditions.

Immunological and aetiological aspects of macular degeneration.

Aetiological and immunological aspects of AMD, a leading cause of blindness in Western countries, have been reviewed. Developmental studies suggest that anatomical features unique to the fovea result in a critical relationship between metabolic demand and blood supply at the macula, which is maintained throughout life. Recent studies show a sufficient degree of consistency in the link between smoking and both dry and wet AMD to regard it as causative. Dry AMD is considered to be the natural endstage of the disease; epidemiological and morphological studies point to choroidal vascular atrophy as the causative event and it is suggested that signals associated with acute vascular compromise lead to the development of subretinal neovascularisation. The relationship between sub-pigment epithelial deposits, including basal laminar deposit, and the pathogenesis of AMD is examined. Much of the literature is consistent with a choroidal origin for the constituents of drusen. The blood-retinal barrier preserves the physiological environment of the neural retina and limits inflammatory responses. The factors, including cytokines, adhesion molecules and the presence of resident immunocompetent cells (microglia), which determine the immune status of the retina are considered. Historical descriptions of the involvement of inflammatory cells are provided, evidence implicating inflammation in the pathogenesis of AMD involving macrophages, giant cells and microglia has been derived from observations of human and animal subretinal neovascular lesions. The role of humoral factors such as anti-retinal autoantibodies and acute phase proteins together with clinical observations has been surveyed. Taken together these data demonstrate the involvement of both cellular and humoral immunity in the pathogenesis of AMD. It remains to be determined to what degree the influence of immunity is causative or contributory in both wet and dry AMD, however, the use of anti-inflammatory agents to ameliorate the condition further indicates the existence of an inflammatory component.

Dexamethasone intravitreal implant in patients with macular edema related to branch or central retinal vein occlusion twelve-month study results

OBJECTIVE To evaluate the safety and efficacy of 1 or 2 treatments with dexamethasone intravitreal implant (DEX implant) over 12 months in eyes with macular edema owing to branch or central retinal vein occlusion (BRVO or CRVO). DESIGN Two identical, multicenter, prospective studies included a randomized, 6-month, double-masked, sham-controlled phase followed by a 6-month open-label extension. PARTICIPANTS We included 1256 patients with vision loss owing to macular edema associated with BRVO or CRVO. METHODS At baseline, patients received DEX implant 0.7 mg (n = 421), DEX implant 0.35 mg (n = 412), or sham (n = 423) in the study eye. At day 180, patients could receive DEX implant 0.7 mg if best-corrected visual acuity (BCVA) was <84 letters or retinal thickness was >250 μm. MAIN OUTCOME MEASURES The primary outcome for the open-label extension was safety; BCVA was also evaluated. RESULTS At day 180, 997 patients received open-label DEX implant. Except for cataract, the incidence of ocular adverse events was similar in patients who received their first or second DEX implant. Over 12 months, cataract progression occurred in 90 of 302 phakic eyes (29.8%) that received 2 DEX implant 0.7 mg injections versus 5 of 88 sham-treated phakic eyes (5.7%); cataract surgery was performed in 4 of 302 (1.3%) and 1 of 88 (1.1%) eyes, respectively. In the group receiving two 0.7-mg DEX implants (n = 341), a ≥ 10-mmHg intraocular pressure (IOP) increase from baseline was observed in (12.6% after the first treatment, and 15.4% after the second). The IOP increases were usually transient and controlled with medication or observation; an additional 10.3% of patients initiated IOP-lowering medications after the second treatment. A ≥ 15-letter improvement in BCVA from baseline was achieved by 30% and 32% of patients 60 days after the first and second DEX implant, respectively. CONCLUSIONS Among patients with macular edema owing to BRVO or CRVO, single and repeated treatment with DEX implant had a favorable safety profile over 12 months. In patients who qualified for and received 2 DEX implant injections, the efficacy and safety of the 2 implants were similar with the exception of cataract progression. FINANCIAL DISCLOSURE(S) Proprietary or commercial disclosure may be found after the references.

Pseudo-endophthalmitis after intravitreal injection of triamcinolone

Aims: To describe an unusual endophthalmitis-like reaction after an intravitreal injection of triamcinolone acetonide in four patients. Methods: Retrospective case series. Results: Four patients are reported with an endophthalmitis-like reaction following an intravitreal injection of triamcinolone acetonide. There was a dense vitreous haze with severe reduction of fundus view in all cases. One case was treated as an infectious endophthalmitis but the vitreous tap showed no evidence of an endophthalmitis and no bacterial or fungal growth in culture. In all four cases, the vitreous haze cleared without specific treatment. The anterior chamber remained quiet in all cases but one, which was examined 30 minutes after the injection, and there was no periorbital inflammation or pain. Conclusion: Pseudo-endophthalmitis after an intravitreal injection of triamcinolone acetonide seems to be a distinct clinical entity that may resolve without specific treatment.

Perifoveal Muller Cell Depletion in a Case of Macular Telangiectasia Type 2

PURPOSE To assess the histopathologic changes in a postmortem sample derived from an eye donor with macular telangiectasia (MacTel) type 2 to gain further insight into the cause of the disease. DESIGN Clinicopathological case report. PARTICIPANTS Postmortem tissue was collected from 5 different donors: 1 MacTel type 2 patient; 1 healthy control; 2 type 2 diabetic patients, 1 with retinopathy and 1 without retinopathy; and 1 patient with unilateral Coats disease. METHODS Macular pigment distribution in the posterior part of freshly dissected eyes was documented by macrophotography. Paraffin sections from both the macular and peripheral regions were assessed using antigen retrieval and immunohistochemistry to study the distribution of cell-specific markers. Blood vessels were visualized with antibodies directed against collagen IV and claudin 5; glial cells with antibodies against glial fibrillary acidic protein (GFAP), vimentin, glutamine synthetase (GS), and retinaldehyde binding protein (RLBP1, also known as CRALBP); microglia with an antibody against allograft inflammatory factor 1 (also known as Iba1); and photoreceptors with antibodies against rhodopsin and opsin. Using anatomic landmarks, the sections then were matched with the macular pigment distribution and a fluorescein angiogram of the patient that was obtained before the patients death. MAIN OUTCOME MEASURES Presence and distribution of macular pigment and cell-specific markers. RESULTS Macular pigment was absent in the macula. Furthermore, abnormally dilated capillaries were identified in a macular region that correlated spatially with regions of fluorescein leakage in an angiogram that was obtained 12 years before death. These telangiectatic vessels displayed a marked reduction of the basement membrane component collagen IV, indicating vascular pathologic features. The presence of GFAP was limited to retinal astrocytes, and no reactive Müller cells were identified. Importantly, reduced immunoreactivity with Müller cell markers (vimentin, GS, and RLBP1) in the macula was observed. The area that lacked Müller cells corresponded with the region of depleted macular pigment. CONCLUSIONS These findings suggest that macular Müller cell loss or dysfunction is a critical component of MacTel type 2, which may have implications for future treatment strategies.

Bruch's membrane and choroidal macrophages in early and advanced age-related macular degeneration

Aim To determine the sub-macular Bruchs membrane (BrM) macrophage count and the choroidal and BrM macrophage immunophenotype in normal eyes and in eyes with early and advanced age-related macular degeneration (AMD). Methods BrM macrophages were counted in 125 human eyes (normal, normal aged, early AMD and geographical atrophy), and CD68 and inducible nitric oxide synthase (iNOS) immunohistochemistry was performed on 16 human eyes (normal, normal aged, early AMD, geographical atrophy and disciform scarring). All eyes were examined clinically ante mortem. Results were correlated with histopathological features, including basal laminar deposit and membranous debris, and with clinical fundus appearance. Results CD68+ macrophages were found in the choroid of normal human eyes, and did not express iNOS. Expression of iNOS by choroidal macrophages (as well as endothelial cells and pericytes) was associated with: (1) recruitment of macrophages to BrM in early AMD eyes with soft drusen or thick continuous basal laminar deposit, corresponding to clinically detectable soft drusen or pigment changes; and (2) active disciform scarring. iNOS expression was absent in BrM macrophages, suggesting immunomodulatory differences between the choroid and BrM. The highest BrM macrophage counts were found in eyes with subclinical choroidal neovascularisation. Conclusion The presence of extracellular deposits (soft drusen and thick continuous basal laminar deposit) is associated with macrophage recruitment to BrM and alteration in the immunophenotype of resident choroidal macrophages.

Central serous chorioretinopathy: a review of epidemiology and pathophysiology.

Central serous chorioretinopathy (CSCR) is a common retinal cause of vision loss. This review surveys the epidemiology, risk factors, clinical presentation, natural history and pathophysiology of CSCR. Studies suggest an annual incidence rate of 10 per 100 000 in men, with CSCR occurring six times more commonly in men compared with women. Most acute CSCR cases resolve spontaneously within 2–3 months. Prognosis is highly dependent on presenting visual acuity; patients with initial visual acuities of 6/6 remain at that level, while patients with initial visual acuities of less than 6/9 recover on average two to three Snellen lines over the next few years. The main risk factors for CSCR are systemic corticosteroid use, type A personality, pregnancy and endogenous Cushings syndrome. The pathophysiology of CSCR remains obscure, although disorders in both the choroidal circulation and retinal pigment epithelium are implicated.Central serous chorioretinopathy (CSCR) is a common retinal cause of vision loss. This review surveys the epidemiology, risk factors, clinical presentation, natural history and pathophysiology of CSCR. Studies suggest an annual incidence rate of 10 per 100 000 in men, with CSCR occurring six times more commonly in men compared with women. Most acute CSCR cases resolve spontaneously within 2–3 months. Prognosis is highly dependent on presenting visual acuity; patients with initial visual acuities of 6/6 remain at that level, while patients with initial visual acuities of less than 6/9 recover on average two to three Snellen lines over the next few years. The main risk factors for CSCR are systemic corticosteroid use, type A personality, pregnancy and endogenous Cushings syndrome. The pathophysiology of CSCR remains obscure, although disorders in both the choroidal circulation and retinal pigment epithelium are implicated.

Macular telangiectasia type 2

Macular telangiectasia type 2 is a bilateral disease of unknown cause with characteristic alterations of the macular capillary network and neurosensory atrophy. Its prevalence may be underestimated and has recently been shown to be as high as 0.1% in persons 40 years and older. Biomicroscopy may show reduced retinal transparency, crystalline deposits, mildly ectatic capillaries, blunted venules, retinal pigment plaques, foveal atrophy, and neovascular complexes. Fluorescein angiography shows telangiectatic capillaries predominantly temporal to the foveola in the early phase and a diffuse hyperfluorescence in the late phase. High-resolution optical coherence tomography (OCT) may reveal disruption of the photoreceptor inner segment-outer segment border, hyporeflective cavities at the level of the inner or outer retina, and atrophy of the retina in later stages. Macular telangiectasia type 2 shows a unique depletion of the macular pigment in the central retina and recent therapeutic trials showed that such depleted areas cannot re-accumulate lutein and zeaxanthin after oral supplementation. There have been various therapeutic approaches with limited or no efficacy. Recent clinical trials with compounds that block vascular endothelial growth factor (VEGF) have established the role of VEGF in the pathophysiology of the disease, but have not shown significant efficacy, at least for the non-neovascular disease stages. Recent progress in structure-function correlation may help to develop surrogate outcome measures for future clinical trials. In this review article, we summarize the current knowledge on macular telangiectasia type 2, including the epidemiology, the genetics, the clinical findings, the staging and the differential diagnosis of the disease. Findings using retinal imaging are discussed, including fluorescein angiography, OCT, adaptive optics imaging, confocal scanning laser ophthalmoscopy, and fundus autofluorescence, as are the findings using visual function testing including visual acuity and fundus-controlled microperimetry. We provide an overview of the therapeutic approaches for both non-neovascular and neovascular disease stages and provide a perspective of future directions including animal models and potential therapeutic approaches.

A Randomized Clinical Trial of Intravitreal Bevacizumab versus Intravitreal Dexamethasone for Diabetic Macular Edema: The BEVORDEX Study

OBJECTIVE To report the 12-month results of the first head-to-head comparison of a dexamethasone implant (Ozurdex; Allergan, Inc., Irvine, CA) versus bevacizumab (Avastin; Genentech, South San Francisco, CA) for center-involving diabetic macular edema (DME). DESIGN Phase 2, prospective, multicenter, randomized, single-masked clinical trial (clinicaltrials.gov identifier NCT01298076). PARTICIPANTS We enrolled 88 eyes of 61 patients with center-involving DME. METHODS Forty-two eyes were randomized to receive bevacizumab every 4 weeks and 46 eyes were randomized to receive a dexamethasone implant every 16 weeks, both pro re nata. Results were analyzed using linear regression with generalized estimation equation methods to account for between-eye correlation. MAIN OUTCOME MEASURES The primary outcome was the proportion of eyes that improved vision by 10 logarithm of minimum angle of resolution letters. Secondary outcomes included mean change in best-corrected visual acuity (BCVA), change in central macular thickness (CMT), injection frequency, and adverse events. Patient-reported outcomes were measured using the Impact of Vision Impairment (IVI) questionnaire. RESULTS Improvement in BCVA of 10 or more letters was found in 17 of 42 eyes (40%) treated with bevacizumab compared with 19 of 46 dexamethasone implant-treated eyes (41%; P = 0.83). None of the 42 bevacizumab eyes lost 10 letters or more, whereas 5 of 46 (11%) dexamethasone implant eyes did, mostly because of cataract. Mean CMT decreased by 122 μm for bevacizumab eyes and by 187 μm for dexamethasone implant eyes (P = 0.015). Bevacizumab-treated eyes received a mean of 8.6 injections compared with 2.7 injections for dexamethasone implant eyes. Significant improvement in IVI scores occurred for both treatment groups. CONCLUSIONS Dexamethasone implant achieved similar rates of visual acuity improvement compared with bevacizumab for DME, with superior anatomic outcomes and fewer injections. Both treatments were associated with improvement in visual quality-of-life scores. However, more dexamethasone implant-treated eyes lost vision, mainly because of cataract.

Conditional Müller Cell Ablation Causes Independent Neuronal and Vascular Pathologies in a Novel Transgenic Model

Müller cells are the major glia of the retina that serve numerous functions essential to retinal homeostasis, yet the contribution of Müller glial dysfunction to retinal diseases remains largely unknown. We have developed a transgenic model using a portion of the regulatory region of the retinaldehyde binding protein 1 gene for conditional Müller cell ablation and the consequences of primary Müller cell dysfunction have been studied in adult mice. We found that selective ablation of Müller cells led to photoreceptor apoptosis, vascular telangiectasis, blood–retinal barrier breakdown and, later, intraretinal neovascularization. These changes were accompanied by impaired retinal function and an imbalance between vascular endothelial growth factor-A (VEGF-A) and pigment epithelium-derived factor. Intravitreal injection of ciliary neurotrophic factor inhibited photoreceptor injury but had no effect on the vasculopathy. Conversely, inhibition of VEGF-A activity attenuated vascular leak but did not protect photoreceptors. Our findings show that Müller glial deficiency may be an important upstream cause of retinal neuronal and vascular pathologies in retinal diseases. Combined neuroprotective and anti-angiogenic therapies may be required to treat Müller cell deficiency in retinal diseases and in other parts of the CNS associated with glial dysfunction.