Maxwell S. Stem

Neurodegeneration in the pathogenesis of diabetic retinopathy: molecular mechanisms and therapeutic implications.

Diabetic retinopathy (DR), commonly classified as a microvascular complication of diabetes, is now recognized as a neurovascular complication or sensory neuropathy resulting from disruption of the neurovascular unit. Current therapies for DR target the vascular complication of the disease process, including neovascularization and diabetic macular edema. Since neurodegeneration is an early event in the pathogenesis of DR, it will be important to unravel the mechanisms that contribute to neuroretinal cell death in order to develop novel treatments for the early stages of DR. In this review we comment on how inflammation, the metabolic derangements associated with diabetes, loss of neuroprotective factors, and dysregulated glutamate metabolism may contribute to retinal neurodegeneration during diabetes. Promising potential therapies based on these specific aspects of DR pathophysiology are also discussed. Finally, we stress the importance of developing and validating new markers of visual function that can be used to shorten the duration of clinical trials and accelerate the delivery of novel treatments for DR to the public.

A Longitudinal Analysis of Risk Factors Associated with Central Retinal Vein Occlusion

PURPOSE To identify risk factors associated with central retinal vein occlusion (CRVO) among a diverse group of patients throughout the United States. DESIGN Longitudinal cohort study. PARTICIPANTS All beneficiaries aged ≥ 55 years who were continuously enrolled in a managed care network for at least 2 years and who had ≥ 2 visits to an eye care provider from 2001 to 2009. METHODS Insurance billing codes were used to identify individuals with a newly diagnosed CRVO. Multivariable Cox regression was performed to determine the factors associated with CRVO development. MAIN OUTCOME MEASURES Adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) of being diagnosed with CRVO. RESULTS Of the 494 165 enrollees who met the study inclusion criteria, 1302 (0.26%) were diagnosed with CRVO over 5.4 (± 1.8) years. After adjustment for known confounders, blacks had a 58% increased risk of CRVO compared with whites (HR, 1.58; 95% CI, 1.25-1.99), and women had a 25% decreased risk of CRVO compared with men (HR, 0.75; 95% CI, 0.66-0.85). A diagnosis of stroke increased the hazard of CRVO by 44% (HR, 1.44; 95% CI, 1.23-1.68), and hypercoagulable state was associated with a 145% increased CRVO risk (HR, 2.45; 95% CI, 1.40-4.28). Individuals with end-organ damage from hypertension (HTN) or diabetes mellitus (DM) had a 92% (HR, 1.92; 95% CI, 1.52-2.42) and 53% (HR, 1.53; 95% CI, 1.28-1.84) increased risk of CRVO, respectively, relative to those without these conditions. CONCLUSIONS This study confirms that HTN and vascular diseases are important risk factors for CRVO. We also identify black race as being associated with CRVO, which was not well appreciated previously. Furthermore, we show that compared with patients without DM, individuals with end-organ damage from DM have a heightened risk of CRVO, whereas those with uncomplicated DM are not at increased risk of CRVO. This finding may provide a potential explanation for the conflicting reports in the literature on the association between CRVO and DM. Information from analyses such as this can be used to create a risk calculator to identify possible individuals at greatest risk for CRVO.

Multimodal Characterization of Proliferative Diabetic Retinopathy Reveals Alterations in Outer Retinal Function and Structure

PURPOSE To identify changes in retinal function and structure in persons with proliferative diabetic retinopathy (PDR), including the effects of panretinal photocoagulation (PRP). DESIGN Cross-sectional study. PARTICIPANTS Thirty adults who underwent PRP for PDR, 15 adults with untreated PDR, and 15 age-matched controls. METHODS Contrast sensitivity, frequency doubling perimetry (FDP), Humphrey visual fields, photostress recovery, and dark adaptation were assessed. Fundus photography and macular spectral-domain optical coherence tomography (SD OCT) were performed. To quantify retinal layer thicknesses, SD OCT scans were segmented semiautomatically. MAIN OUTCOME MEASURES Visual function measures were compared among patients with PDR and PRP, untreated patients with PDR, and controls. Mean retinal layer thicknesses were compared between groups. Correlation analyses were performed to evaluate associations between visual function measures and retinal layer thicknesses. RESULTS A significant reduction of FDP mean deviation (MD) was exhibited in PRP-treated patients with PDR (MD ± standard deviation, -8.20±5.76 dB; P < 0.0001) and untreated patients (-5.48±4.48 dB; P < 0.0001) relative to controls (1.07±2.50 dB). Reduced log contrast sensitivity compared with controls (1.80±0.14) also was observed in both PRP-treated patients (1.42±0.17; P < 0.0001) and untreated patients (1.56±0.20; P = 0.001) with PDR. Compared with controls, patients treated with PRP demonstrated increased photostress recovery time (151.02±104.43 vs. 70.64±47.14 seconds; P = 0.001) and dark adaptation speed (12.80±5.15 vs. 9.74±2.56 minutes; P = 0.022). Patients who underwent PRP had diffusely thickened nerve fiber layers (P = 0.024) and diffusely thinned retinal pigment epithelium (RPE) layers (P = 0.009) versus controls. Untreated patients with PDR also had diffusely thinned RPE layers (P = 0.031) compared with controls. CONCLUSIONS Patients with untreated PDR exhibited inner retinal dysfunction, as evidenced by reduced contrast sensitivity and FDP performance, accompanied by alterations in inner and outer retinal structure. Patients who underwent PRP had more profound changes in outer retinal structure and function. Distinguishing the effects of PDR and PRP may guide the development of restorative vision therapies for patients with advanced diabetic retinopathy.

Risk Factors Associated with Developing Branch Retinal Vein Occlusion Among Enrollees in a United States Managed Care Plan

PURPOSE To determine risk factors associated with development of a branch retinal vein occlusion (BRVO) among a large group of managed-care plan beneficiaries in the United States. DESIGN Retrospective, longitudinal cohort study. PARTICIPANTS All beneficiaries age ≥55 years continuously enrolled for ≥2 years in a managed care network from 2001-2009 who had ≥2 visits to an eye care provider. METHODS Multivariable Cox regression analyses identified sociodemographic factors, ocular and nonocular conditions associated with incident BRVO. MAIN OUTCOME MEASURES Hazard of incident BRVO with 95% confidence interval (CI). RESULTS Of the 492,488 enrollees who met inclusion criteria, 2283 (0.5%) developed incident BRVO. After adjustment for confounding factors, blacks (adjusted hazard ratio [aHR], 1.43; CI, 1.19-1.73; P = 0.0001) had a 43% increased hazard of BRVO relative to non-Hispanic whites. Enrollees with hypertension (HTN) alone (aHR, 1.78; CI, 1.36-2.32; P < 0.0001) or HTN along with other metabolic syndrome components (diabetes mellitus [DM] and hyperlipidemia; aHR, 1.44; CI, 1.12-1.84; P = 0.005) had an increased hazard of developing a BRVO compared with those with none of these conditions. Disease severity was important; enrollees with end-organ damage caused by HTN had a 107% increased hazard of developing BRVO compared with enrollees without HTN (aHR, 2.07; CI, 1.75-2.45; P < 0.0001). Although there was no association between DM without end-organ damage and BRVO (aHR, 0.92; CI, 0.81-1.04; P = 0.2), individuals with end-organ damage from DM had a 36% increased hazard of BRVO (aHR, 1.36; CI, 1.18-1.57; P < 0.0001) compared with those without DM. Although cerebrovascular accident was associated with an increased hazard of developing BRVO (aHR, 1.34; CI, 1.19-1.52; P < 0.0001), other diseases of the vascular system (deep venous thrombosis/pulmonary embolism, peripheral vascular disease, hypercoagulable state, myocardial infarction) or anticoagulant use did not increase the risk of BRVO (P > 0.10 for all comparisons). CONCLUSIONS Both HTN and end-organ damage from DM contribute to arteriosclerosis, atherosclerosis, and endothelial dysfunction, which seem to be major risk factors for BRVO. Ophthalmologists should emphasize to patients and their primary physicians the importance of effectively managing systemic medical conditions associated with BRVO.

Differential reduction in corneal nerve fiber length in patients with type 1 or type 2 diabetes mellitus.

AIM To examine the relationship between corneal nerve fiber length (CNFL) and diabetic neuropathy (DN) status in patients with type 1 or type 2 diabetes mellitus (DM). METHODS In this cross-sectional study, we examined 25 diabetic patients without DN, 10 patients with mild DN, 8 patients with severe DN, and 9 controls without diabetes. DN status was assigned based on a combination of clinical symptoms, signs, and electrophysiological testing. Patients underwent corneal confocal microscopy (CCM) of the sub-basal nerve plexus. Post-hoc analysis of the CCM images was performed to quantify the average CNFL, and ANOVA was used to assess for differences in CNFL. RESULTS All 25 subjects without DN had type 1 DM, and subjects with DN had type 2 DM. Participants with severe DN had significantly lower CNFL (12.5±6.1mm/mm(2)) compared to controls (20.7±2.2mm/mm(2)) (p=0.009). However, lower CNFL was also found in participants with type 1 DM who did not have DN (15.1±4.7mm/mm(2)) relative to controls (p=0.033). CONCLUSIONS CCM of the sub-basal nerve plexus may be an indicator of early peripheral nerve degeneration in type 1 DM. Type of diabetes, in addition to degree of neuropathy, may influence the extent of corneal nerve damage.

Glucose variability and inner retinal sensory neuropathy in persons with type 1 diabetes mellitus

PurposeTo quantify early neuroretinal alterations in patients with type 1 diabetes mellitus (T1DM) and to assess whether glycemic variability contributes to alterations in neuroretinal structure or function.MethodsThirty patients with T1DM and 51 controls underwent comprehensive ophthalmic examination and assessment of retinal function or structure with frequency doubling perimetry (FDP), contrast sensitivity, dark adaptation, fundus photography, and optical coherence tomography (OCT). Diabetic participants wore a subcutaneous continuous glucose monitor for 5 days, from which makers of glycemic variability including the low blood glucose index (LGBI) and area under the curve (AUC) for hypoglycemia were derived.ResultsSixteen patients had no diabetic retinopathy (DR), and 14 had mild or moderate DR. Log contrast sensitivity for the DM group was significantly reduced (mean±SD=1.63±0.06) compared with controls (1.77±0.13, P<0.001). OCT analysis revealed that the inner temporal inner nuclear layer (INL) was thinner in patients with T1DM (34.9±2.8 μm) compared with controls (36.5±2.9 μm) (P=0.023), although this effect lost statistical significance after application of the Bonferroni correction for multiple comparisons. Both markers of glycemic variability, the AUC for hypoglycemia (R=−0.458, P=0.006) and LGBI (R=−0.473, P=0.004), were negatively correlated with inner temporal INL thickness.ConclusionsPatients with T1DM and no to moderate DR exhibit alterations in inner retinal structure and function. Increased glycemic variability correlates with retinal thinning on OCT imaging, suggesting that fluctuations in blood glucose may contribute to neurodegeneration.

The effects of diabetic retinopathy and pan-retinal photocoagulation on photoreceptor cell function as assessed by dark adaptometry

Purpose The pathophysiology of vision loss in persons with diabetic retinopathy (DR) is complex and incompletely defined. We hypothesized that retinal pigment epithelium (RPE) and rod and cone photoreceptor dysfunction, as measured by dark adaptometry, would increase with severity of DR, and that pan-retinal photocoagulation (PRP) would exacerbate this dysfunction. Methods Dark adaptation (DA) was measured in subjects with diabetes mellitus and healthy controls. Dark adaptation was measured at 5° superior to the fovea following a flash bleach, and the data were analyzed to yield cone and rod sensitivity curves. Retinal layer thicknesses were quantified using spectral-domain optical coherence tomography (OCT). Results The sample consisted of 23 controls and 73 diabetic subjects. Subjects with moderate nonproliferative diabetic retinopathy (NPDR) exhibited significant impairment of rod recovery rate compared with control subjects (P = 0.04). Cone sensitivity was impaired in subjects with proliferative diabetic retinopathy (PDR) (type 1 diabetes mellitus [T1DM]: P = 0.0047; type 2 diabetes mellitus [T2DM]: P < 0.001). Subjects with untreated PDR compared with subjects treated with PRP exhibited similar rod recovery rates and cone sensitivities. Thinner RPE as assessed by OCT was associated with slower rod recovery and lower cone sensitivity, and thinner photoreceptor inner segment/outer segment layer was associated with lower cone sensitivity. Conclusions The results suggest that RPE and photoreceptor cell dysfunction, as assessed by cone sensitivity level and rod- and RPE-mediated dark adaptation, progresses with worsening DR, and rod recovery dysfunction occurs earlier than cone dysfunction. Function was preserved following PRP. The findings suggest multiple defects in retinoid function and provide potential points to improve visual function in persons with PDR.

Acute anterior uveitis following intravitreal bevacizumab but not subsequent ranibizumab

Purpose Previous reports have identified noninfectious uveitis as a potential sequela following both intravitreal bevacizumab and ranibizumab injections. We present two unique cases of acute anterior uveitis following intravitreal bevacizumab that did not occur with subsequent ranibizumab injections. Methods Case report. Conclusion These cases may reflect differences in the etiology of anterior uveitis following intravitreal bevacizumab and ranibizumab. Given these differences, it may be reasonable to offer ranibizumab to patients who have experienced presumed bevacizumab-induced anterior uveitis.

Successful salvage therapy of Fusarium endophthalmitis secondary to keratitis: An interventional case series

Purpose To describe a combination of treatment modalities used for the successful eradication of Fusarium endophthalmitis. Design Interventional case series. Participants Three consecutive patients with keratitis-associated Fusarium endophthalmitis. Methods After failure of traditional management options, a combination of intravitreal and long-term, high-dose systemic voriconazole, topical antifungal medications, and surgical intervention, with penetrating keratoplasty, lensectomy, and endoscopic-guided pars plana vitrectomy, was administered to each patient. Results All three cases achieved full resolution of the infection, with a final Snellen visual acuity score of 20/50 to 20/70. Conclusions An aggressive combination of therapeutic modalities, including the removal of subiris abscesses, might be needed for the successful resolution of Fusarium endophthalmitis.

Patient-centered and visual quality outcomes of premium cataract surgery: a systematic review

Purpose Over 8 million cataract surgeries are performed in the United States and the European Union annually, with many patients choosing to pay out of pocket for premium options including premium intraocular lens implants (IOLs) or laser-assisted cataract surgery (LACS). This report provides a systematic review evaluating patient-centered and visual quality outcomes comparing standard monofocal IOLs to premium cataract surgery options. Methods PubMed and EMBASE were searched for publications published between January 1, 1980, and September 18, 2016, on multifocal, accommodative, and toric IOLs, monovision, and LACS, which reported on 1) dysphotopsias, 2) contrast sensitivity, 3) spectacle independence, 4) vision-related quality of life or patient satisfaction, and 5) IOL exchange. Results Multifocal lenses achieved higher rates of spectacle independence compared to monofocal lenses but also had higher reported frequency of dysphotopsia and worse contrast sensitivity, especially with low light or glare. Accommodative lenses were not associated with reduced contrast sensitivity or more dysphotopsia but had only modest improvements in spectacle independence compared to monofocal lenses. Studies of monovision did not target a sufficiently myopic outcome in the near-vision eye to achieve the full potential for spectacle independence. Patients reported high levels of overall satisfaction regardless of implanted IOL. No studies correlated patient-reported outcomes with patient expectations. Conclusions Studies are needed to thoroughly compare patient-reported outcomes with concomitant patient expectations. In light of the substantial patient costs for premium options, patients and their surgeons will benefit from a better understanding of which surgical options best meet patients’ expectations and how those expectations can be impacted by premium versus monofocal—including monovision—options.