2022

Age-related macular degeneration (AMD) is a leading cause of blindness worldwide. Early to intermediate AMD is characterized by the accumulation of lipid- and protein-rich drusen. Late stages of the disease are characterized by the development of choroidal neovascularization, termed "exudative" or "neovascular AMD," or retinal pigment epithelium (RPE) cell and photoreceptor death, termed "geographic atrophy" (GA) in advanced nonexudative AMD. Although we have effective treatments for exudative AMD in the form of anti-VEGF agents, they have no role for patients with GA. Neuroprotection strategies have emerged as a possible way to slow photoreceptor degeneration and vision loss in patients with GA. These approaches include reduction of oxidative stress, modulation of the visual cycle, reduction of toxic molecules, inhibition of pathologic protein activity, prevention of cellular apoptosis or programmed necrosis (necroptosis), inhibition of inflammation, direct activation of neurotrophic factors, delivery of umbilical tissue-derived cells, and RPE replacement. Despite active investigation in this area and significant promise based on preclinical studies, many clinical studies have not yielded successful results. We discuss selected past and current neuroprotection trials for AMD, highlight the lessons learned from these past studies, and discuss our perspective regarding remaining questions that must be answered before neuroprotection can be successfully applied in the field of AMD research.

Intranasal cocaine abuse can lead to significant sinus and orbital complications, including optic neuropathy. A 46-year-old man with a history of recurrent cocaine-induced sino-orbital inflammation and infection with bony destruction presented with acute, painless, vision loss. Examination revealed no light perception vision. MRI of the orbits demonstrated new restricted diffusion of the right optic nerve on diffusion-weighted imaging and apparent diffusion coefficient sequences, consistent with posterior ischemic optic neuropathy. This is the first among cases of cocaine-induced optic neuropathy in the literature to illustrate ischemic changes on MRI in the optic nerve, highlighting the utility of diffusion-weighted imaging/apparent diffusion coefficient sequences when optic neuropathy is suspected and further suggesting an underlying ischemic etiology in similar cases.

BACKGROUND: To present 2 patients with myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease with unilateral orbital inflammation, optic nerve head edema, and abnormalities of the optic nerve and nerve sheath on imaging. We review the most current literature on this important and uncommon clinical phenotype. METHODS: A case report of 2 patients and a comprehensive review of the relevant literature on orbital inflammation in MOG antibody-associated disease (MOG-AD). RESULTS: Two patients presented with decreased vision and unilateral orbital inflammation. Both had optic nerve head edema and abnormalities of the optic nerve and nerve sheath on imaging. The patients were treated with immunosuppressants and had improvement of vision changes as well as their orbital inflammatory signs. MOG antibody was positive in high titers in both patients. Only 3 other cases of orbital inflammation associated with MOG antibody have been described. In all cases, orbital signs responded rapidly to intravenous methylprednisolone, but the improvement in visual acuity was variable and less robust. CONCLUSION: Orbital inflammation is a unique and underrecognized phenotype of MOG-AD with only a few reports in the literature. In patients who present with vision loss and orbital inflammation, MOG-AD should be considered in the differential.

We studied small vessel disease (SVD) pathology in Familial Alzheimer's disease (FAD) subjects carrying the presenilin 1 (PSEN1) p.Glu280Ala mutation in comparison to those with sporadic Alzheimer's disease (SAD) as a positive control for Alzheimer's pathology and Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) bearing different NOTCH3 mutations, as positive controls for SVD pathology. Upon magnetic resonance imaging (MRI) in life, some FAD showed mild white matter hyperintensities and no further radiologic evidence of SVD. In post-mortem studies, total SVD pathology in cortical areas and basal ganglia was similar in PSEN1 FAD and CADASIL subjects, except for the feature of arteriosclerosis which was higher in CADASIL subjects than in PSEN1 FAD subjects. Further only a few SAD subjects showed a similar degree of SVD pathology as observed in CADASIL. Furthermore, we found significantly enlarged perivascular spaces in vessels devoid of cerebral amyloid angiopathy in FAD compared with SAD and CADASIL subjects. As expected, there was greater fibrinogen-positive perivascular reactivity in CADASIL but similar reactivity in PSEN1 FAD and SAD groups. Fibrinogen immunoreactivity correlated with onset age in the PSEN1 FAD cases, suggesting increased vascular permeability may contribute to cognitive decline. Additionally, we found reduced perivascular expression of PDGFRβ AQP4 in microvessels with enlarged PVS in PSEN1 FAD cases. We demonstrate that there is Aβ-independent SVD pathology in PSEN1 FAD, that was marginally lower than that in CADASIL subjects although not evident by MRI. These observations suggest presence of covert SVD even in PSEN1, contributing to disease progression. As is the case in SAD, these consequences may be preventable by early recognition and actively controlling vascular disease risk, even in familial forms of dementia.

PURPOSE: To assess the prevalence of autoimmune disease (AiD) in patients with primary open-angle glaucoma (POAG) undergoing ophthalmic surgery. DESIGN: Retrospective, cross-sectional study. PARTICIPANTS: Patients with POAG undergoing any ophthalmic surgery and control subjects undergoing cataract surgery at the Massachusetts Eye and Ear from March 2019 to April 2020. METHODS: All available medical records with patient demographics, ocular, and medical conditions were reviewed. Differences in AiD prevalence were assessed and adjusted for covariates using multiple logistic regression. Additionally, a subgroup analysis comparing the POAG patients with and without AiD was performed. MAIN OUTCOME MEASURES: To assess the prevalence of AiD based on the American Autoimmune Related Diseases Association list. RESULTS: A total of 172 patients with POAG and 179 controls were included. The overall prevalence of AiD was 17.4% in the POAG group and 10.1% in the controls (P = 0.044); 6.4% of POAG patients and 3.4% of controls had more than 1 AiD (P = 0.18). The most prevalent AiDs in POAG group were rheumatoid arthritis (4.6%) and psoriasis (4.1%), which were also the most common in controls (2.8% each). In a fully adjusted multiple logistic regression analysis accounting for steroid use, having an AiD was associated with 2.62-fold increased odds of POAG relative to controls (95% confidence interval, 1.27-5.36, P = 0.009); other risk factors for POAG derived from the analysis included age (odds ratio [OR], 1.04, P = 0.006), diabetes mellitus (OR, 2.31, P = 0.008), and non-White ethnicity (OR, 4.75, P < 0.001). In a case-only analysis involving the eye with worse glaucoma, there was no statistical difference in visual field mean deviation or retinal nerve fiber layer (RNFL) thickness in POAG patients with AiD (n = 30) and without AiD (n = 142, P > 0.13, for both). CONCLUSIONS: A higher prevalence of AiD was found in POAG patients compared with control patients undergoing ophthalmic surgery. The presence of AiD was associated with increased risk for POAG after adjusting for covariates. Additional factors may have prevented a difference in RNFL thickness in POAG patients with and without AiD. Autoimmunity should be explored further in the pathogenesis of POAG.

Recessive PJVK mutations that cause a deficiency of pejvakin, a protein expressed in both sensory hair cells and first-order neurons of the inner ear, are an important cause of hereditary hearing impairment. Patients with PJVK mutations garner limited benefits from cochlear implantation; thus, alternative biological therapies may be required to address this clinical difficulty. The synthetic adeno-associated viral vector Anc80L65, with its wide tropism and high transduction efficiency in various inner ear cells, may provide a solution. We delivered the PJVK transgene to the inner ear of Pjvk mutant mice using the synthetic Anc80L65 vector. We observed robust exogenous pejvakin expression in the hair cells and neurons of the cochlea and vestibular organs. Subsequent morphologic and audiologic studies demonstrated significant restoration of spiral ganglion neuron density and hair cells in the cochlea, along with partial recovery of sensorineural hearing impairment. In addition, we observed a recovery of vestibular ganglion neurons and balance function to WT levels. Our study demonstrates the utility of Anc80L65-mediated gene delivery in Pjvk mutant mice and provides insights into the potential of gene therapy for PJVK-related inner ear deficits.

AIMS: To compare the efficacy of diabetic retinal neovascularisation (NV) detection using the widefield swept-source optical coherence tomography angiography (WF SS-OCTA) vitreoretinal interface (VRI) Angio slab and SS-OCT VRI Structure slab. METHODS: A prospective, observational study was performed at Massachusetts Eye and Ear from January 2019 to June 2020. Patients with proliferative diabetic retinopathy (PDR), patients with non-proliferative diabetic retinopathy and patients with diabetes but without diabetic retinopathy were included. All patients were imaged with WF SS-OCTA using the 12×12 mm Angio scan protocol centred on the fovea and optic disc. The en-face SS-OCTA VRI Angio slab and SS-OCT VRI Structure slab were evaluated for the presence or absence of NV. SS-OCTA B-scan was used to classify NV according to cross-sectional morphology (forward, tabletop or flat). All statistical analyses were performed using SPSS V.26.0. RESULTS: One hundred and forty-two eyes of 89 participants were included in the study. VRI Angio detected NV at higher rates compared with VRI Structure (p<0.05). Combining VRI Angio and Structure improved detection rates compared with VRI Angio alone (p<0.05). Due to segmentation errors of the internal limiting membrane, NV with flat morphological classification had lower rates of detection on VRI Angio compared with NV with forward and tabletop morphology (p<0.05). CONCLUSIONS: WF SS-OCTA 12×12 mm VRI Angio and SS-OCT VRI Structure imaging centred on the fovea and optic disc detected NV with high sensitivity and low false positives. The VRI slab may be useful to diagnose and monitor PDR in clinical practice.

BACKGROUND/AIMS: To determine whether timing of ophthalmic screening influences prevalence of neonatal fundus haemorrhages. We compared the prevalence of fundus haemorrhages in two populations: term newborns screened early (less than 72 hours) and preterm newborns screened late (4-11 weeks). Additionally, we reviewed the literature on timing and prevalence of newborn haemorrhages. METHODS: Retrospective observational cohort study. Infants who underwent wide-angle ophthalmic digital imaging over one overlapping year in the Newborn Eye Screen Testing (NEST) or Stanford University Network for Diagnosis of Retinopathy of Prematurity (SUNDROP) programme were included. The PubMed database was filtered to include English-language articles dating back to 1950. Nine articles were selected for review based on inclusion of the prevalence of newborn fundus haemorrhages at multiple time points. RESULTS: A total of 202 patients received early imaging in the NEST cohort and 73 patients received late imaging in the SUNDROP cohort. In the NEST cohort, 20.2% of newborns had haemorrhages. In contrast, we found haemorrhages in only one case or 1.4% of the SUNDROP cohort. Using prevalence data from nine additional studies, we developed a predicted probabilities model of newborn haemorrhages. Per this model, the probability of seeing a haemorrhage if you screen an infant at 1 hour is 18.8%, at 2 weeks is 2.9% and at 1 month is 0.28%. CONCLUSION: We found a significant difference in the prevalence of fundus haemorrhages between the early-screened NEST cohort and the late-screened, preterm SUNDROP cohort. Likely, this difference is due to the transient nature of most newborn haemorrhages.

AIM: To describe survival and neonatal morbidities in infants born before 24 weeks of gestation during a 12-year period. METHODS: Data were retrieved from national registries and validated in medical files of infants born before 24 weeks of gestation 2007-2018 in Sweden. Temporal changes were evaluated. RESULTS: In 2007-2018, 282 live births were recorded at 22 weeks and 460 at 23 weeks of gestation. Survival to discharge from hospital of infants born alive at 22 and 23 weeks increased from 20% to 38% (p = 0.006) and from 45% to 67% (p < 0.001) respectively. Caesarean section increased from 12% to 22% (p = 0.038) for infants born at 22 weeks. Neonatal morbidity rates in infants alive at 40 weeks of postmenstrual age (n = 399) were unchanged except for an increase in necrotising enterocolitis from 0 to 33% (p = 0.017) in infants born at 22 weeks of gestation. Bronchopulmonary dysplasia was more common in boys than girls, 90% versus 82% (p = 0.044). The number of infants surviving to 40 weeks doubled over time. CONCLUSION: Increased survival of infants born before 24 weeks of gestation resulted in increasing numbers of very immature infants with severe neonatal morbidities likely to have a negative impact on long-term outcome.

Corneal transplantation is the most common form of tissue transplantation. The success of corneal transplantation mainly relies on the integrity of corneal endothelial cells (CEnCs), which maintain tissue transparency by pumping out excess water from the cornea. After transplantation, the rate of CEnC loss far exceeds that seen with normal aging, which can threaten sight. The underlying mechanisms are poorly understood. Alpha-melanocyte-stimulating hormone (α-MSH) is a neuropeptide that is constitutively found in the aqueous humor with both cytoprotective and immunomodulatory effects. The curent study found high expression of melanocortin 1 receptor (MC1R), the receptor for α-MSH, on CEnCs. The effect of α-MSH/MC1R signaling on endothelial function and allograft survival in vitro and in vivo was investigated using MC1R signaling-deficient mice (Mc1re/e mice with a nonfunctional MC1R). Herein, the results indicate that in addition to its well-known immunomodulatory effect, α-MSH has cytoprotective effects on CEnCs after corneal transplantation, and the loss of MC1R signaling significantly decreases long-term graft survival in vivo. In conclusion, α-MSH/MC1R signaling is critical for CEnC function and graft survival after corneal transplantation.

The SARS-CoV-2 pandemic has had a disastrous impact on global health. Although some vaccine candidates have been effective in combating SARS-CoV-2, logistical, economical, and sociological aspects still limit vaccine access globally. Recently, we reported on two room-temperature stable AAV-based COVID-19 vaccines that induced potent and protective immunogenicity following a single injection in murine and primate models. Obesity and old age are associated with increased mortality in COVID-19, as well as reduced immunogenicity and efficacy of vaccines. Here, we investigated the effectiveness of the AAVCOVID vaccine candidates in murine models of obesity and aging. Results demonstrate that obesity did not significantly alter the immunogenicity of either vaccine candidate. In aged mice, vaccine immunogenicity was impaired. These results suggest that AAV-based vaccines may have limitations in older populations and may be equally applicable in obese and non-obese populations.

PURPOSE: Serum lipids are modifiable, routinely collected blood test features associated with cardiovascular health. We examined the association of commonly collected serum lipid measures (total cholesterol [TC], high-density lipoprotein cholesterol [HDL-C], low-density lipoprotein cholesterol [LDL-C], and triglycerides) with intraocular pressure (IOP). DESIGN: Cross-sectional study in the UK Biobank and European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk cohorts. PARTICIPANTS: We included 94 323 participants from the UK Biobank (mean age, 57 years) and 6230 participants from the EPIC-Norfolk (mean age, 68 years) cohorts with data on TC, HDL-C, LDL-C, and triglycerides collected between 2006 and 2009. METHODS: Multivariate linear regression adjusting for demographic, lifestyle, anthropometric, medical, and ophthalmic covariables was used to examine the associations of serum lipids with corneal-compensated IOP (IOPcc). MAIN OUTCOME MEASURES: Corneal-compensated IOP. RESULTS: Higher levels of TC, HDL-C, and LDL-C were associated independently with higher IOPcc in both cohorts after adjustment for key demographic, medical, and lifestyle factors. For each 1-standard deviation increase in TC, HDL-C, and LDL-C, IOPcc was higher by 0.09 mmHg (95% confidence interval [CI], 0.06-0.11 mmHg; P < 0.001), 0.11 mmHg (95% CI, 0.08-0.13 mmHg; P < 0.001), and 0.07 mmHg (95% CI, 0.05-0.09 mmHg; P < 0.001), respectively, in the UK Biobank cohort. In the EPIC-Norfolk cohort, each 1-standard deviation increase in TC, HDL-C, and LDL-C was associated with a higher IOPcc by 0.19 mmHg (95% CI, 0.07-0.31 mmHg; P = 0.001), 0.14 mmHg (95% CI, 0.03-0.25 mmHg; P = 0.016), and 0.17 mmHg (95% CI, 0.06-0.29 mmHg; P = 0.003). An inverse association between triglyceride levels and IOP in the UK Biobank (-0.05 mmHg; 95% CI, -0.08 to -0.03; P < 0.001) was not replicated in the EPIC-Norfolk cohort (P = 0.30). CONCLUSIONS: Our findings suggest that serum TC, HDL-C, and LDL-C are associated positively with IOP in 2 United Kingdom cohorts and that triglyceride levels may be associated negatively. Future research is required to assess whether these associations are causal in nature.

TOPIC: This systematic review summarizes evidence for associations between female reproductive factors (age at menarche, parity, oral contraceptive [OC] use, age at menopause, and postmenopausal hormone [PMH] use) and intraocular pressure (IOP) or open-angle glaucoma (OAG). CLINICAL RELEVANCE: Understanding the associations between female reproductive factors and glaucoma may shed light on the disease pathogenesis and aid clinical prediction and personalized treatment strategies. Importantly, some factors are modifiable, which may lead to new therapies. METHODS: Two reviewers independently extracted articles in MEDLINE, Embase, Cochrane Database of Systematic Reviews, and Cochrane Central Register of Controlled Trials databases to identify relevant studies. Eligibility criteria included studies with human subjects aged > 18 years; a measured outcome of either IOP or OAG; a cohort, case-control, cross-sectional, or randomized controlled trial design; a reported measure of association, such as the hazard ratio, relative risk, odds ratio, or mean difference, with an associated confidence interval; and a measured exposure of at least 1 of the following variables: age at menarche, parity, OC use, age at menopause, or PMH use. RESULTS: We included a total of 27 studies. Substantial differences in study designs, exposure and treatment levels, treatment durations, and variable reporting precluded a meaningful quantitative synthesis of the identified studies. Overall, relatively consistent associations between PMH use and a lower IOP were identified. Estrogen-only PMH use may be associated with lower OAG risk, which may be modified by race. No significant associations were found with combined estrogen-and-progesterone PMH use. No strong associations between parity or age at menarche and glaucoma were found, but a younger age at menopause was associated with an increased glaucoma risk, and adverse associations were identified with a longer duration of OC use, though no overall association with OC use was found. CONCLUSIONS: The association between PMH use and lower IOP or OAG risk is a potentially clinically relevant and modifiable risk factor and should be investigated further, although this needs to be interpreted in the context of a high risk of bias across included studies. Future research should examine associations with IOP specifically and how the relationship between genetic factors and OAG risks may be influenced by female reproductive factors.

BACKGROUND: Eyelid warming is an important treatment for meibomian gland dysfunction (MGD). Specialized chambered devices, using warm moist air have been developed. PURPOSE: To critically evaluate the literature on the safety and efficacy of chambered warm moist air devices in MGD treatment and pinpoint areas of future research. METHODS: PubMed and Embase were searched on 06 June 2021. The search term was '(warm OR heat OR steam OR goggle OR spectacle OR moist air) AND (meibomian OR MGD OR blepharitis OR eyelid OR dry eye OR DED)'. All relevant articles with available English full text were included. RESULTS: Eighteen articles assessing the application of chambered warm moist air eyelid warming devices were identified. In single-application studies, steam-based eyelid warming increased the eyelid temperature and improved symptoms, lipid layer thickness, and tear film breakup time (TBUT). In treatment studies, the steam-based devices improved TBUT and symptom scores. However, in the only randomized controlled trial (RCT) comparing chambered steam-based heat to hot towel treatment, there was no difference between groups for the primary outcome measure; the proportion of subjects noting symptom improvement after 4 weeks. CONCLUSION: Currently available chambered warm moist air eyelid warming devices are safe and effective at raising eyelid temperature to therapeutic levels and improving signs and symptoms of dry eye. However, it is not clear if they provide a greater benefit than other eyelid warming therapies. Further well-conducted RCTs comparing moist and dry heat devices should be conducted on patients across the range of DED severities and subtype spectrum.

OBJECTIVE: To investigate the clinical and magnetic resonance imaging (MRI) characteristics of patients with varicella zoster virus (VZV) reactivation involving the cranial nerves and central nervous system (CNS). METHODS: This is a retrospective, multi-center case-series of 37 patients with VZV infection affecting the cranial nerves and CNS. RESULTS: The median age was 71 years [IQR 51.5-76]; 21 (57%) were men. Cerebrospinal fluid (CSF) was available in 24/37 (65%); median CSF white blood cell count was 11 [IQR 2-23] cells/μL and protein was 45.5 [IQR 34.5-75.5] mg/dL. VZV polymerase chain reaction (PCR) assays were positive in 6/21 (29%) CSF and 8/9 (89%) ocular samples. Clinical involvement included the optic nerve in 12 (32%), other cranial nerves in 20 (54%), brain parenchyma in 12 (32%) and spinal cord or nerve roots in 4 (11%). Twenty-seven/28 immunocompetent patients' MRIs were available for review (96%). Of the 27, 18 had T1 postcontrast fat saturated sequences without motion artifact to evaluate for cranial nerve enhancement and optic perineuritis (OPN). Eight/18 (44%) demonstrated OPN. All 8 experienced vision loss: 3 optic neuritis, 1 acute retinal necrosis, and 3 CNS vasculitis with 1 central and 1 branch retinal artery occlusion and 1 uveitis. Diplopic patients had cranial nerve and cavernous sinus enhancement. All immunosuppressed patients were imaged. Seven/9 (88%) had extensive neuraxis involvement, including encephalitis, vasculitis and transverse myelitis; one case had OPN. CONCLUSION: OPN is a frequent manifestation in VZV-associated vision loss among immunocompetent patients. Immunosuppressed patients had greater neuraxis involvement. Optimizing MRI protocols may improve early diagnosis in VZV reactivation.

In this study, we report a case of multifocal choroiditis that was successfully treated with adalimumab monotherapy. A 25-year-old male presented with a history of bilateral multifocal choroiditis which was resistant to a combination of azathioprine, valacyclovir, and prednisone. Dilated fundoscopy revealed small creamy-yellow lesions around the arcades in both eyes (OU). Indocyanine green angiography (ICGA) revealed active hypocyanescent lesions around the arcades and macula OU. Valacyclovir was stopped, adalimumab subcutaneous injections biweekly were added to the regimen, and prednisone was tapered after the second adalimumab loading dose. At 3-month follow-up, ocular examination and ICGA were unremarkable OU. After 30 months of remission, azathioprine was tapered and stopped. After 40 months of remission, adalimumab was tapered and stopped. Four months after stopping adalimumab injections, the patient returned with new floaters in his right eye (OD). ICGA and macular optical coherence tomography detected active lesions OU. The patient was restarted on adalimumab subcutaneous injections as monotherapy. At 3-month follow-up visit, his symptoms had resolved, and ICGA showed resolution of the lesions OD and improvement of the lesions in the left eye (OS). He has been in remission for 6 months at the time of writing since restarting adalimumab monotherapy. We conclude from this study that long-term adalimumab monotherapy can be employed effectively and safely in the re-treatment of patients with multifocal choroiditis resistant to other immunomodulatory therapy even after successful tapering and discontinuation of concurrent therapies.

Pediatric uveitis accounts for 5-10% of all uveitis. Uveitis in children differs from adult uveitis in that it is commonly asymptomatic and can become chronic and cause damage to ocular structures. The diagnosis might be delayed for multiple reasons, including the preverbal age and difficulties in examining young children. Pediatric uveitis may be infectious or noninfectious in etiology. The etiology of noninfectious uveitis is presumed to be autoimmune or autoinflammatory. The most common causes of uveitis in this age group are idiopathic and juvenile idiopathic arthritis-associated uveitis. The stepladder approach for the treatment of pediatric uveitis is based on expert opinion and algorithms proposed by multidisciplinary panels. Uveitis morbidities in pediatric patients include cataract, glaucoma, and amblyopia. Pediatric patients with uveitis should be frequently examined until remission is achieved. Once in remission, the interval between follow-up visits can be extended; however, it is recommended that even after remission the child should be seen every 8-12 weeks depending on the history of uveitis and the medications used. Close follow up is also necessary as uveitis can flare up during immunomodulatory therapy. It is crucial to measure the impact of uveitis, its treatment, and its complications on the child and the child's family. Visual acuity can be considered as an acceptable criterion for assessing visual function. Additionally, the number of cells in the anterior chamber can be a measure of disease activity. We review different aspects of pediatric uveitis. We discuss the mechanisms of noninfectious uveitis, including autoimmune and autoinflammatory etiologies, and the risks of developing uveitis in children with systemic rheumatologic diseases. We address the risk factors for developing morbidities, the Standardization of Uveitis Nomenclature (SUN) criteria for timing and anatomical classifications, and describe a stepladder approach in the treatment of pediatric uveitis based on expert opinion and algorithms proposed by multi-disciplinary panels. In this review article, We describe the most common entities for each type of anatomical classification and complications of uveitis for the pediatric population. Additionally, we address monitoring of children with uveitis and evaluation of Quality of Life.

OBJECTIVE: To determine whether individuals with type 1 diabetes (T1D) who develop any retinopathy at any time prior to 5 years of diabetes duration have an increased subsequent risk for further progression of retinopathy or onset of proliferative diabetic retinopathy (PDR), clinically significant macular edema (CSME), diabetes-related retinal photocoagulation, or anti-vascular endothelial growth factor injections. Additionally, to determine the influence of HbA1c and other risk factors in these individuals. RESEARCH DESIGN AND METHODS: Diabetic retinopathy (DR) was assessed longitudinally using standardized stereoscopic seven-field fundus photography at time intervals of 6 months to 4 years. Early-onset DR (EDR) was defined as onset prior to 5 years of T1D duration. Cox models assessed the associations of EDR with subsequent risk of outcomes. RESULTS: In unadjusted models, individuals with EDR (n = 484) had an increased subsequent risk of PDR (hazard ratio [HR] 1.51 [95% CI 1.12, 2.02], P = 0.006), CSME (HR 1.44 [1.10, 1.88], P = 0.008), and diabetes-related retinal photocoagulation (HR 1.48 [1.12, 1.96], P = 0.006) compared with individuals without EDR (n = 369). These associations remained significant when adjusted for HbA1c, but only the association with PDR remained significant after adjustment for age, duration of T1D, HbA1c, sex, systolic/diastolic blood pressure, pulse, use of ACE inhibitors, albumin excretion rate, and estimated glomerular filtration rate (HR 1.47 [95% CI 1.04, 2.06], P = 0.028). CONCLUSIONS: These data suggest that individuals with any sign of retinopathy within the first 5 years of T1D onset may be at higher risk of long-term development of advanced DR, especially PDR. Identification of early-onset DR may influence prognosis and help guide therapeutic management to reduce the risk of future visual loss in these individuals.