Preeclampsia and the Retina.

PURPOSE OF REVIEW: This review summarizes key findings relating to the association between preeclampsia and retinal disorders. RECENT FINDINGS: Preeclampsia is a major cause of maternal morbidity. Pregnant women with preeclampsia frequently describe having visual disturbances. Retinal changes can be identified on fundoscopy in most patients with preeclampsia. While retinal pathology secondary to preeclampsia usually resolves postpartum, there is growing evidence that women with preeclampsia have a higher long-term risk of developing retinal disorders after pregnancy. Pregnant women often experience visual changes. While these symptoms may be benign, careful attention should be paid to exclude retinal disorders secondary to preeclampsia. Pregnant women complaining of new-onset or worsening blurry vision, scotomata, diplopia, or photopsia require rapid and thorough evaluation to rule out hypertensive disorders. Management of preeclampsia, including administration of magnesium sulfate and delivery of the fetus, can reverse retinal pathologies in most cases.

Bilateral severe iatrogenic pigmentary glaucoma following laser treatment for cosmetic iris color change.

Purpose: We report a case of bilateral severe pigmentary glaucoma and paracentral acute middle maculopathy (PAMM) following laser treatment for iris color change. Observations: A 32-year-old female presented to our emergency clinic after having undergone 4 sessions of bilateral cosmetic iris laser treatment in Turkey to lighten the color of her dark brown irides. Visual acuity was 20/150 in the right eye (OD) and counting fingers in the left eye (OS) at presentation. Intraocular pressures (IOP) were 50 mmHg in the right eye and 42 mmHg in the left eye, with 4+ free-floating pigmented cells in the anterior chamber. The fundus exam revealed cup-to-disc ratios of 0.5 in the right eye and 0.35 in the left eye and scattered intraretinal hemorrhages in both eyes. The diagnoses of bilateral severe iatrogenic pigmentary glaucoma and PAMM were established. Urgent bilateral fornix-based trabeculectomies with mitomycin C (MMC) 0.05% were performed with an attempt to wash out as much pigment from the anterior chamber as possible. Post-operatively, despite well-controlled IOP and cessation of all glaucoma medications, the patient remains with visual field defects and significant glare. Conclusions and Importance: Photoablative iridoplasty is rarely encountered as a cause of iatrogenic pigmentary glaucoma in North American due to strict regulations against this procedure. However, physicians must be aware of its devastating and life-changing visual sequelae and elicit a careful history in patients with a similar presentation. Our patient demonstrated acute, severe glaucomatous damage from pigmentary dispersion along with PAMM, a newly described complication of this procedure. We strongly advise against this medically unnecessary practice.

Impact of Prenatal Exposure to Opioids, Cocaine, and Cannabis on Eye Disorders in Children.

OBJECTIVES: Prenatal substance exposure is associated with abnormal visual evoked potentials in offspring, but whether ocular abnormalities are present past infancy is unclear. We determined the association between prenatal substance exposure and hospitalizations for eye disorders in childhood. METHODS: We conducted a longitudinal cohort study of 794,099 infants born between 2006 and 2016 in all hospital centers in Quebec, Canada. We identified infants prenatally exposed to opioids, cocaine, cannabis, and other illicit substances and followed them over time to assess eye disorders that required in-hospital treatment, including retinal detachment and breaks, strabismus, and other ocular pathologies. We calculated incidence rates and hazard ratios (HR) with 95% confidence intervals (CI) for the association of prenatal substance exposure with risk of eye disorders, adjusted for patient characteristics. RESULTS: Infants exposed to substances prenatally had a higher incidence of hospitalizations for eye disorders compared with unexposed infants (47.0 vs 32.0 per 10,000 person-years). Prenatal substance exposure was associated with 1.23 times the risk of hospital admission for any eye disorder during childhood compared with no exposure (95% CI 1.04-1.45). Risks were greatest for strabismus (HR 1.55, 95% CI 1.16-2.07) and binocular movement disorders (HR 1.96, 95% CI 1.00-3.83). Opioid use was strongly associated with the risk of ocular muscle disorders (HR 3.15, 95% CI 1.98-5.01). CONCLUSIONS: Prenatal substance exposure is significantly associated with future hospitalizations for eye disorders in childhood. Efforts to minimize substance use in women of reproductive age are needed in light of the current opioid epidemic.

360-degree intra-operative laser retinopexy for the prevention of retinal re-detachment in patients treated with primary pars plana vitrectomy.

PURPOSE: To investigate the effect of 360° intra-operative laser retinopexy (ILR) for the prevention of retinal re-detachment in patients treated with pars plana vitrectomy (PPV) for primary rhegmatogenous retinal detachment (RRD). METHODS: A retrospective single-institution cohort study was performed. Consecutive patients with primary uncomplicated RRD who underwent 23-gauge PPV with gas endotamponade between July 2013 and July 2016 were included in the study (n = 151). Two cohorts were compared: one which received laser retinopexy only around identified tears/holes/lattice zones (Control group, n = 86), and one which received additional 360° intra-operative laser retinopexy (360° ILR group, n = 65). RESULTS: Retinal re-detachment was seen in 4/65 eyes (6%) in the 360° ILR group compared to 18/86 eyes (21%) in the control group. In multiple logistic regression, the 360° ILR was associated with a 75% reduction in the odds of retinal re-detachment compared to control (OR = 0.248, 95% CI [0.079-0.772], p = 0.016). There was no statistically significant difference in the incidence of epiretinal membrane formation between the two groups. CONCLUSIONS: Intra-operative 360° laser retinopexy during PPV with gas endotamponade resulted in a significant reduction in the odds of postoperative retinal re-detachment in eyes with uncomplicated primary RRD.

Vascular retinal biomarkers improves the detection of the likely cerebral amyloid status from hyperspectral retinal images.

INTRODUCTION: This study investigates the relationship between retinal image features and ß-amyloid (Aß) burden in the brain with the aim of developing a noninvasive method to predict the deposition of Aß in the brain of patients with Alzheimer's disease. METHODS: Retinal images from 20 cognitively impaired and 26 cognitively unimpaired cases were acquired (3 images per subject) using a hyperspectral retinal camera. The cerebral amyloid status was determined from binary reads by a panel of 3 expert raters on 18F-florbetaben positron-emission tomography (PET) studies. Image features from the hyperspectral retinal images were calculated, including vessels tortuosity and diameter and spatial-spectral texture measures in different retinal anatomical regions. RESULTS: Retinal venules of amyloid-positive subjects (Aß+) showed a higher mean tortuosity compared with the amyloid-negative (Aß-) subjects. Arteriolar diameter of Aß+ subjects was found to be higher than the Aß- subjects in a zone adjacent to the optical nerve head. Furthermore, a significant difference between texture measures built over retinal arterioles and their adjacent regions were observed in Aß+ subjects when compared with the Aß-. A classifier was trained to automatically discriminate subjects combining the extracted features. The classifier could discern Aß+ subjects from Aß- subjects with an accuracy of 85%. DISCUSSION: Significant differences in texture measures were observed in the spectral range 450 to 550 nm which is known as the spectral region known to be affected by scattering from amyloid aggregates in the retina. This study suggests that the inclusion of metrics related to the retinal vasculature and tissue-related textures extracted from vessels and surrounding regions could improve the discrimination performance of the cerebral amyloid status.

Non-invasive in vivo hyperspectral imaging of the retina for potential biomarker use in Alzheimer's disease.

Studies of rodent models of Alzheimer's disease (AD) and of human tissues suggest that the retinal changes that occur in AD, including the accumulation of amyloid beta (Aß), may serve as surrogate markers of brain Aß levels. As Aß has a wavelength-dependent effect on light scatter, we investigate the potential for in vivo retinal hyperspectral imaging to serve as a biomarker of brain Aß. Significant differences in the retinal reflectance spectra are found between individuals with high Aß burden on brain PET imaging and mild cognitive impairment (n = 15), and age-matched PET-negative controls (n = 20). Retinal imaging scores are correlated with brain Aß loads. The findings are validated in an independent cohort, using a second hyperspectral camera. A similar spectral difference is found between control and 5xFAD transgenic mice that accumulate Aß in the brain and retina. These findings indicate that retinal hyperspectral imaging may predict brain Aß load.

Climate and the eye: Case-crossover analysis of retinal detachment after exposure to ambient heat.

BACKGROUND: Retinal detachment is an important cause of visual loss, but the association with outdoor heat exposure has not been studied. Our objective was to determine the relationship between acute exposure to high outdoor temperature and risk of retinal detachment. MATERIALS AND METHODS: We analysed 14,302 individuals with inpatient procedures for retinal detachment from April through September between 2006 and 2013 in the province of Quebec, Canada. Using a time-stratified case-crossover study design, we examined the association of retinal detachment with outdoor summer temperature the preceding week. We estimated odds ratios (OR) and 95% confidence intervals (CI) for mean weekly temperature according to subtypes of retinal detachment (traction, serous, rhegmatogenous, breaks), and assessed associations by age and sex. RESULTS: Exposure to elevated temperature the preceding week was associated with a higher likelihood of traction detachment, but not other forms of retinal detachment. Associations were stronger at <75 years of age in both men and women. Relative to 15°C, a mean weekly temperature of 25°C was associated with an OR for traction detachment of 2.71 (95% CI 1.56-4.71) before 55 years, 2.73 (95% CI 1.61-4.64) at 55-64 years, and 1.98 (95% CI 1.30-3.02) at 64-75 years. DISCUSSION: Elevated outdoor temperatures may be associated with an increased risk of traction retinal detachment. In light of climate change, a better understanding of the impact of heat waves on the eye and other sensory organs is needed.

Preeclampsia and Long-term Risk of Maternal Retinal Disorders.

OBJECTIVE: To evaluate whether preeclampsia is associated with risk of maternal retinal disease in the decades after pregnancy. METHODS: We carried out a longitudinal cohort study of 1,108,541 women who delivered neonates in any hospital in Quebec, Canada, between 1989 and 2013. We tracked women for later hospitalizations until March 31, 2014. Preeclampsia was measured at delivery categorized by severity (mild or severe) and onset (before or at 34 weeks or more of gestation). Main outcomes were hospitalizations and inpatient procedures for retinal detachment, retinopathy, or other retinal disorders. We used Cox regression models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) comparing preeclampsia with no preeclampsia adjusting for diabetes and hypertension. RESULTS: Compared with no preeclampsia, women with preeclampsia had a higher incidence of hospitalization for retinal detachment (52.9 compared with 23.9/10,000), retinopathy (60.5 compared with 8.0/10,000), and other retinal disorders (13.3 compared with 7.3/10,000). Preeclampsia was most strongly associated with traction detachments (HR 2.39, 95% CI 1.52-3.74), retinal breaks (HR 2.48, 95% CI 1.40-4.41), and diabetic retinopathy (HR 4.13, 95% CI 3.39-5.04). Severe and early-onset preeclampsia was associated with even higher risk compared with mild or late-onset preeclampsia. CONCLUSION: Preeclampsia, particularly severe or early-onset preeclampsia, is associated with an increased risk of maternal retinal disease in the decades after pregnancy.

Preeclampsia and the risk of cataract extraction in life.

BACKGROUND: Pregnancy-related risk factors for cataract are understudied, including the possibility that preeclampsia increases the risk of cataract later in life. OBJECTIVE: We sought to evaluate the long-term risk of cataract extraction following a preeclamptic pregnancy. STUDY DESIGN: We carried out a historic cohort study of 1,108,541 women who delivered at least 1 infant in any hospital in the province of Quebec, Canada, from 1989 through 2013, including 64,350 with preeclampsia and 5732 with cataract extractions. We categorized preeclampsia by onset time and severity, and followed up women for up to 25 years after delivery. We calculated the incidence of inpatient cataract extraction for women with and without preeclampsia, and used Cox proportional hazard models to estimate hazard ratios and 95% confidence intervals for later risk of cataract extraction, adjusting for age at first delivery, total parity, metabolic disease, asthma, socioeconomic deprivation, and time period. RESULTS: Women with preeclampsia had a higher incidence of cataract extraction compared with no preeclampsia (21.0 vs 15.9/1000) and 1.20 times the risk (95% confidence interval, 1.08-1.34). Women with early-onset preeclampsia had 1.51 times the risk of cataract extraction compared with no preeclampsia (95% confidence interval, 1.14-2.00), whereas women with late-onset preeclampsia had 1.16 times the risk (95% confidence interval, 1.04-1.30). Risk was elevated by about 20% for both severe and mild preeclampsia. Preeclampsia with diabetes was associated with significantly greater risk (hazard ratio, 4.32; 95% confidence interval, 3.60-5.19). CONCLUSION: Women with preeclampsia, particularly preeclampsia of early onset or with diabetes, may have greater risk of cataract later in life. The underlying pathways linking preeclampsia with cataract require further investigation.

Optimal Treatment of Retinal Vein Occlusion: Canadian Expert Consensus.

BACKGROUND: The availability of new therapeutic approaches, particularly intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapies, has prompted significant changes to the established treatment paradigms for retinal vein occlusion (RVO). Better visual outcomes and significantly lower rates of adverse events have been noted in multiple large randomized clinical trials and have led to a new standard of care for this sight-threatening condition. OBJECTIVE: To develop an expert consensus for the management of RVO and associated complications in the context of recent clinical evidence. METHODS: The development of a Canadian expert consensus for optimal treatment began with a review of clinical evidence, daily practice, and existing treatment guidelines and algorithms. The expert clinicians (11 Canadian retina specialists) met on February 1, 2014, in Toronto to discuss their findings and to propose strategies for consensus. RESULTS: The result of this expert panel is a consensus proposal for Canadian ophthalmologists and retina specialists treating patients presenting with RVO. Treatment algorithms specific to branch and central RVO (BRVO and CRVO) were also developed. CONCLUSIONS: The consensus provides guidelines to aid clinicians in managing RVO and associated complications in their daily practice. In summary, laser remains the therapy of choice when neovascularization secondary to RVO is detected. Adjunctive anti-VEGF could be considered in managing neovascularization secondary to RVO in cases of vitreous hemorrhage. Intravitreal anti-VEGF should be considered for symptomatic visual loss associated with center-involving macular edema on optical coherence tomography. Patients with BRVO and a suboptimal response to anti-VEGF could be treated with grid laser, and those with CRVO and an inadequate response to anti-VEGF may be candidates for intravitreal steroids.

Retinal detachments after Boston Keratoprosthesis: incidence, predisposing factors, and visual outcomes.

PURPOSE: To determine the rates, predisposing factors, and visual outcomes of retinal detachment (RD) after Boston Keratoprosthesis (KPro) implantation. METHODS: In this noncomparative, interventional case series, the medical records of 170 patients (205 eyes) who underwent Boston type 1 and type 2 KPro implantation at the Massachusetts Eye and Ear Infirmary between April 1993 and June 2009 were retrospectively reviewed. Incidence and annual rates of RD were calculated, and the roles of possible predictive factors for RD after KPro were investigated. Main outcome measures were rates of and risk factors for RD, visual acuity after RD, and surgical outcomes after repair. RESULTS: Sterile vitritis and autoimmune systemic disease significantly predisposed patients to RD after KPro placement. Of patients who developed RD after implantation, 50% progressed to visual acuity of no light perception despite surgical repair. CONCLUSIONS: Inflammation plays a major role in RD development after KPro implantation. Patients with predisposing factors should be advised of the high rates of RD and comanaged with a vitreoretinal specialist.

A novel function of p53: a gatekeeper of retinal detachment.

Proliferative vitreoretinopathy (PVR) is a blinding disease associated with rhegmatogenous retinal detachment, for which there is no satisfactory treatment. Surgery helps in many cases, but, to our knowledge, there are no pharmacological approaches to reduce PVR risk. We report that suppressing expression of p53 was a required event in two assays of PVR (namely, platelet-derived growth factor receptor α-mediated contraction of cells in a collagen gel and retinal detachment in an animal model of PVR). Furthermore, preventing the decline in the level of p53 with agents such as Nutlin-3 protected from retinal detachment, which is the most vision-compromising component of PVR. Finally, Nutlin-3 may be effective in the clinical setting because it prevented human PVR vitreous-induced contraction of cells isolated from a patient PVR membrane. These studies identify Nutlin-3 as a potential PVR prophylaxis.

A novel strategy to develop therapeutic approaches to prevent proliferative vitreoretinopathy.

Proliferative vitreoretinopathy (PVR) thwarts the repair of rhegmatogenous retinal detachments. Currently, there is no effective prevention for PVR. Platelet-derived growth factor receptor α (PDGFRα) is associated with PVR in humans and strongly promotes experimental PVR driven by multiple vitreal growth factors outside the PDGF family. We sought to identify vitreal factors required for experimental PVR and to establish a potential approach to prevent PVR. Vitreous was obtained from normal rabbits or those in which PVR was either developing or stabilized. Normal vitreous contained substantial levels of growth factors and cytokines, which changed quantitatively and/or qualitatively as PVR progressed and stabilized. Neutralizing a subset of these agents in rabbit vitreous eliminated their ability to induce PVR-relevant signaling and cellular responses. A single intravitreal injection of neutralizing reagents for this subset prevented experimental PVR. To identify growth factors and cytokines likely driving PVR in humans, we subjected vitreous from patients with or without PVR to a similar series of analyses. This analysis accurately identified those agents required for vitreous-induced contraction of cells from a patient PVR membrane. We conclude that combination therapy encompassing a subset of vitreal growth factors and cytokines is a potential approach to prevent PVR.

Expression of PDGFRα is a determinant of the PVR potential of ARPE19 cells.

PURPOSE: Previous studies indicate that the expression of platelet-derived growth factor (PDGF) receptor α (PDGFRα) dramatically increases the ability of fibroblasts to induce experimental proliferative vitreoretinopathy (PVR). The purpose of this study was to determine whether PDGFRα contributed to the PVR potential of retinal pigment epithelial (RPE) cells, one of the most abundant cell types in PVR membranes. METHODS: PDGFRα expression in human ARPE19 cells was increased or decreased by stably expressing the PDGFRα cDNA or short hairpin (sh) RNA directed at PDGFRα, respectively. The level of PDGFRα expression in the resulting panel of cell lines was either barely detectable (KD), standard (similar to the level of primary RPE cells), or overexpressed approximately 80-fold. Western blot analysis was used to assess the level of p53 and the activation state of PDGFRα and Akt. The following cellular responses were monitored: proliferation, apoptosis, and contraction. The PVR potential of cells was tested in a rabbit model of PVR in which cells were coinjected with platelet-rich plasma into the vitreous. RESULTS: Comparison of KD and overexpressing cells indicated that high-level expression of PDGFRα dramatically augmented signaling events, cellular responses, and the PVR potential of ARPE19 cells. However, all these outcomes were also significantly increased, albeit not as robustly, by PDGFRα expression to the level typically present in RPE cells. CONCLUSIONS: Even though RPE cells express substantially less PDGFRα than fibroblasts, it significantly boosts PVR-related signaling events, cellular responses, and the PVR potential of ARPE19 cells. These studies suggest that inhibiting activation, signaling, or both by PDGFRα has the potential to prevent the development of PVR.

Pharmacologic vitreolysis.

It is now well recognized that vitreous plays an important role in the pathogenesis of various retinal disorders. In many instances it can be addressed with pars plana vitrectomy, although this approach, like any surgery, has its limitations. The search for alternatives or adjunct to surgery has led to the development of pharmacologic vitreolysis. The use of intravitreal agents to alter the vitreous in order to reduce or eliminate its role in disease seems promising. The purpose of this article is to summarize the present knowledge on pharmacologic vitreolysis. A review of the different agents used and of ongoing trials will be presented. Also, current understanding of vitreous structure and its interaction with the retina will be discussed.

Recent developments in our understanding of how platelet-derived growth factor (PDGF) and its receptors contribute to proliferative vitreoretinopathy.

Proliferative vitreoretinopathy, a disease process occurring in the setting of a rhegmatogenous retinal detachment, is thought to develop as a result of exposure of retinal cells to vitreous. Vitreous contains many growth factors, and platelet-derived growth factor (PDGF) has been considered a major contributor to PVR. Evaluation of both PDGF and PDGF receptors (PDGFRs) as potential therapeutic targets in the context of a rabbit model of PVR revealed that PDGFR-based approaches protected from PVR, whereas neutralizing PDGFs was a much less effective strategy. The basis for these observations appears to reflect that fact that the PDGFR could be activated by a wide spectrum of vitreal agents that are outside of the PDGF family. Furthermore, blocking signaling events by which the non-PDGFs indirectly activated PDGF alpha receptor (PDGFRalpha) protected rabbits from developing PVR. These studies demonstrate that the best therapeutic targets for PVR are not PDGFs, but PDGFRalpha and certain signaling events required for indirectly activating PDGFRalpha.

Pigment dispersion and recurrent hyphema associated with in-the-bag lens implantation.

We present the case of a patient who experienced recurrent episodes of blurry vision and eye pain after uneventful cataract extraction and in-the-bag intraocular lens (IOL) implantation. Examination revealed a microhyphema and signs of pigment dispersion. Iris transillumination was seen overlying areas where the IOL optic was not covered by the anterior capsule. Anterior segment optical coherence tomography confirmed iris indentation by the IOL optic, which was alleviated by performing laser peripheral iridotomy. This case shows that IOLs in the capsular bag can erode the posterior surface of the iris and that an adequately sized capsulorhexis should be performed to ensure anterior capsule coverage. Laser peripheral iridotomy should be considered when significant posterior iris bowing is observed.