Douglas R. Lazzaro

Inner Retinal Layer Thinning in Parkinson Disease

OBJECTIVE To quantify retinal thickness in patients with Parkinson disease (PD). METHODS Forty-five eyes of 24 PD patients and 31 eyes of 17 control subjects underwent a comprehensive ophthalmologic examination. We used optical coherence tomography to examine retinal thickness, separately quantifying the inner and outer retinal layers. Intraocular pressure was measured by Goldmann applanation tonometry. RESULTS The mean (SD) ages of the patients with PD and healthy subjects were 64.0 (6.5) years vs 63.5 (10.7) years (P = .77). The mean (SD) intraocular pressure was 13.6 (+/-2.7) mm Hg in the PD patients. No difference was found in either the superior or inferior outer retinal layer thickness of PD vs control eyes. The mean (SD) superior inner retinal layer thickness of PD vs control eyes was 88.79 (11.3) microm vs 103.5 (24.3) microm (P = .01), and the mean inferior inner retinal layer thickness was 89.83 (11.1) microm vs 104.0 (23.5) microm (P = .01). CONCLUSIONS The inner retinal layer is significantly thinner in PD patients than in healthy subjects. Idiopathic PD, distinct from glaucoma, needs to be considered in the differential diagnosis of retinal nerve fiber layer thinning.

Peters anomaly: review of the literature.

Purpose: Peters anomaly is a rare dramatic finding at birth and can be associated with other systemic malformations. We performed a literature review of multiple case reports and case series to better define the common characteristics and unusual findings associated with Peters anomaly. Methods: A representative case is discussed followed by a literature review of multiple case reports and case series. The literature search was conducted for the years 1969 to 2009. Cases and case series were included in the review of published English ophthalmic literature. Cases were excluded if no information was reported on ocular and systemic malformations or if no information was reported on surgical interventions or outcomes. In addition, if cases did not report laterality of the lesion, they were excluded from the review. Fifty-eight cases were found that fit the above criteria, and the relevant cases were reviewed to better characterize the systemic malformations, interventions, and outcomes associated with Peters anomaly reported in the literature. Results: Fifty-eight cases of Peters anomaly were reviewed. Of those cases reporting sex, 56% were men and 44% of cases were women. In terms of laterality, 67.2% of cases were bilateral versus 32.8% of cases that were unilateral. Moreover, bilateral cases of Peters anomaly were associated with a higher rate of systemic malformations (71.8%) versus unilateral Peters anomaly (36.8%). This difference was significant (P < 0.03 by Fischer exact test). In the 15 eyes where results of penetrating keratoplasty were reported, the overall success rate was 53%. However, the success rate was significantly higher in patients with Peters anomaly type I (87.5%), as opposed to those patients with Peters anomaly type II (14.2%) (P < 0.02 by Fischer exact test). Discussion: The clinical features, epidemiology, genetics, complications, and treatments of Peters anomaly are presented. Cornea specialists who care for pediatric patients should be aware of the common and uncommon associations with Peters anomaly. Although bilateral Peters anomaly is much more commonly associated with systemic malformations, we believe that all patients with Peters anomaly should be screened for systemic malformations by both pediatricians and geneticists and undergo chromosomal analysis and molecular genetic testing.

Circadian rhythm dysfunction in glaucoma: A hypothesis.

The absence of circadian zeitgebers in the social environment causes circadian misalignment, which is often associated with sleep disturbances. Circadian misalignment, defined as a mismatch between the sleep-wake cycle and the timing of the circadian system, can occur either because of inadequate exposure to the light-dark cycle, the most important synchronizer of the circadian system, or reduction in light transmission resulting from ophthalmic diseases (e.g., senile miosis, cataract, diabetic retinopathy, macular degeneration, retinitis pigmentosa, and glaucoma). We propose that glaucoma may be the primary ocular disease that directly compromises photic input to the circadian time-keeping system because of inherent ganglion cell death. Glaucomatous damage to the ganglion cell layer might be particularly harmful to melanopsin. According to histologic and circadian data, a subset of intrinsically photoresponsive retinal ganglion cells, expressing melanopsin and cryptochromes, entrain the endogenous circadian system via transduction of photic input to the thalamus, projecting either to the suprachiasmatic nucleus or the lateral geniculate nucleus. Glaucoma provides a unique opportunity to explore whether in fact light transmission to the circadian system is compromised as a result of ganglion cell loss.

The Matricellular Protein Cysteine-rich Protein 61 (CCN1/Cyr61) Enhances Physiological Adaptation of Retinal Vessels and Reduces Pathological Neovascularization Associated with Ischemic Retinopathy

Retinal vascular damages are the cardinal hallmarks of retinopathy of prematurity (ROP), a leading cause of vision impairment and blindness in childhood. Both angiogenesis and vasculogenesis are disrupted in the hyperoxia-induced vaso-obliteration phase, and recapitulated, although aberrantly, in the subsequent ischemia-induced neovessel formation phase of ROP. Yet, whereas the histopathological features of ROP are well characterized, many key modulators with a therapeutic potential remain unknown. The CCN1 protein also known as cysteine-rich protein 61 (Cyr61) is a dynamically expressed, matricellular protein required for proper angiogenesis and vasculogenesis during development. The expression of CCN1 becomes abnormally reduced during the hyperoxic and ischemic phases of ROP modeled in the mouse eye with oxygen-induced retinopathy (OIR). Lentivirus-mediated re-expression of CCN1 enhanced physiological adaptation of the retinal vasculature to hyperoxia and reduced pathological angiogenesis following ischemia. Remarkably, injection into the vitreous of OIR mice of hematopoietic stem cells (HSCs) engineered to express CCN1 harnessed ischemia-induced neovessel outgrowth without adversely affecting the physiological adaptation of retinal vessels to hyperoxia. In vitro exposure of HSCs to recombinant CCN1 induced integrin-dependent cell adhesion, migration, and expression of specific endothelial cell markers as well as many components of the Wnt signaling pathway including Wnt ligands, their receptors, inhibitors, and downstream targets. CCN1-induced Wnt signaling mediated, at least in part, adhesion and endothelial differentiation of cultured HSCs, and inhibition of Wnt signaling interfered with normalization of the retinal vasculature induced by CCN1-primed HSCs in OIR mice. These newly identified functions of CCN1 suggest its possible therapeutic utility in ischemic retinopathy.

Daily illumination exposure and melatonin: influence of ophthalmic dysfunction and sleep duration.

Background Ocular pathology lessens lights efficacy to maintain optimal circadian entrainment. We examined whether ophthalmic dysfunction explains unique variance in melatonin excretion of older adults over and above the variance explained by daily illumination, medical, and sociodemographic factors. We also examined whether ophthalmic dysfunction influences relationships between ambient illumination and melatonin. Methods Thirty older adults (mean age = 69 years; Blacks = 42% and Whites = 58%) of both genders participated in the study. Demographic and health data were collected at baseline. Participants underwent eye exams at SUNY Downstate Medical Center, wore an actigraph to monitor illumination and sleep, and collected urine specimens to estimate aMT6s concentrations. Results Hierarchical regression analysis showed that illumination factors explained 29% of the variance in aMT6s mesor. The proportion of variance explained by ophthalmic factors, sleep duration, and race was 10%, 2%, and 2%, respectively. Illumination factors explained 19% of the variance in aMT6s acrophase. The proportion of variance explained by ophthalmic factors, sleep duration, and race was 11%; 17%; and 2%, respectively. Controlling for sleep duration and race reduced the correlations between illumination and melatonin, whereas controlling for ophthalmic factors did not. Conclusion Ophthalmic exams showed that elevated intraocular pressure and large cup-to-disk ratios were independently associated with earlier melatonin timing. Lower illumination exposure also had independent associations with earlier melatonin timing. Conceivably, ophthalmic and illumination factors might have an additive effect on the timing of melatonin excretion, which in turn might predispose individuals to experience early morning awakenings.

Hydrogen Peroxide Accumulation in the Choroid During Intermittent Hypoxia Increases Risk of Severe Oxygen-Induced Retinopathy in Neonatal Rats

PURPOSE Extremely low gestational age neonates (ELGANs) requiring oxygen therapy often experience frequent episodes of intermittent hypoxia (IH) and are at high risk for severe retinopathy of prematurity (ROP). Using an established model for oxygen-induced retinopathy (OIR), we examined the hypothesis that there is a critical number of daily brief IH episodes which will result in irreversible retinal oxidative damage. METHODS Newborn rats were exposed to increasing daily clustered IH episodes (12% O₂ with 50% O₂) from postnatal day (P) 0 to P7 or P0 to P14, or placed in room air (RA) until P21 following 7- or 14-day IH. RA littermates at P7, P14, and P21 served as controls. A group exposed to constant 50% O₂ (CH) served as a second control. Blood gases, eye opening at P14, retinal, and choroidal oxidative stress and lipid peroxidation (8-isoPGF(2α)), oxidants (H₂O₂) and antioxidants (catalase and SOD), retinal pathology (adenosine diphosphatase (ADPase)-stained retinal flatmounts), and mitochondria-related genes were assessed. RESULTS pO₂ levels were higher with increasing IH episodes and remained elevated during the reoxygenation period. High SO₂ levels were associated with most severe OIR. Levels of all measured biomarkers peaked with six IH episodes and decreased with 8 to 12 episodes. H₂O₂ accumulated in the choroid during the reoxygenation period with irreversible retinal damage. CONCLUSIONS Our data suggest that six is the maximum number of IH episodes that the retina can sustain. Accumulation of H₂O₂ in the choroid may result in high levels being delivered to the entire retina, ultimately resulting in irreversible retinal oxidative damage.

Pharmacologic synergism of ocular ketorolac and systemic caffeine citrate in rat oxygen-induced retinopathy

Background:Caffeine or ketorolac decrease the risk of retinopathy of prematurity and may act synergistically to improve beneficial effect. Combination of caffeine (Caff) and ketorolac (Keto) to prevent oxygen-induced retinopathy was studied.Methods:Newborn rats exposed to room air (RA) or intermittent hypoxia (IH) consisting of 12% O2 during hyperoxia (50% O2) from birth (P0) had single daily IP injections of Caff from P0-P13 or saline; and/or ocular Keto (Acuvail, 0.45% ophthalmic solution) administered subcutaneously over the eyes from P5-P7. Pups were studied at P14 or placed in RA for recovery from IH (IHR) until P21. Eyes were examined for neovascularization, histopathology, growth factors, and VEGF-signaling genes.Results:Severe retinal damage noted during IHR in the untreated groups evidenced by hemorrhage, neovascularization, and oxygen-induced retinopathy (OIR) pathologies were prevented with Keto/Caff treatment. Keto and/or Caff treatment in IH also promoted retinal neural development evidenced by eye opening (92%, P < 0.001 vs. 31% in the placebo-treated IH group). No corneal pathologies were noted with Keto.Conclusion.Caff or Keto given individually reduced retinal neovascularization, but the two drugs given together prevented severe OIR.

The effect of positional changes on intraocular pressure during sleep in patients with and without glaucoma.

Purpose:To determine whether sleeping at a 20-degree head-up position decreases nocturnal intraocular pressure (IOP) compared with lying supine (flat) in patients with and without glaucoma. Design:Prospective, nonrandomized comparative case series. Materials and Methods:Thirty patients were recruited based on self-reported disease status with 15 glaucoma and 15 nonglaucoma patients; a total of 60 eyes were tested. Patients were evaluated in a sleep laboratory on 2 separate nights, lying flat 1 night and lying on a wedge pillow at a 20-degree head-up position another night. Baseline IOP was measured during the awake period (10 PM), then measured at 2-hour intervals during the sleep period (12, 2, 4, and 6 AM). Results:IOP measurements during the 10 PM awake period did not significantly differ between the 2 positions (P=0.55). During the sleep period (12 to 6 AM), the mean IOP was 1.51 mm Hg lower in the 20-degree head-up position when compared with the flat position (95% confidence interval, 0.99 to 2.04 mm Hg), with an average drop of 1.56 and 1.47 mm Hg in glaucoma and nonglaucoma patients, respectively. This corresponds to a 9.33% and 8.67% IOP reduction in glaucoma and nonglaucoma patients, respectively. Twenty-five of 30 patients (83.3%) had lower mean IOPs in the 20-degree head-up position. Mean IOP reduction was >10% for 11 of 30 patients (36.7%) when sleeping in the head-up position. Conclusions:The 20-degree head-up position correlates with lower nocturnal IOP as compared with the supine position in glaucoma and nonglaucoma patients. No significant difference in IOP reduction was observed in glaucoma patients when compared with nonglaucoma patients.

Case report: spontaneous Stenotrophomonas maltophilia keratitis in a diabetic patient.

Objectives: To report a rare case of spontaneous Stenotrophomonas maltophilia keratitis in a diabetic patient. Methods: A case report of this rare ulcerative keratitis case with an extensive review of the literature. Results: The patients corneal infiltrate was successfully cultured and a rare ocular organism identified. The patients presentation and course and the response to empiric treatment are discussed. Conclusions: Consideration of the antibiotic combination chosen here can be considered in the treatment of S. maltophilia keratitis after appropriate cultures are taken and the organism isolated.

Repair of necrotizing scleritis in ulcerative colitis with processed pericardium and a Prokera amniotic membrane graft.

Objectives: To demonstrate an unusual case of necrotizing scleritis in ulcerative colitis successfully managed by a combination of a Prokera implant and processed pericardium. Methods: A case report of a novel approach to treat scleral melts that may be seen in several clinical situations. Results: The dual use of amniotic membrane material (Prokera) with processed tuttoplast for necrotizing scleritis salvaged the eye without the need for enucleation while also preserving most of the vision. Conclusions: Consideration of the combined method discussed in this article should be considered in the treatment of severe scleromalacia seen in inflammatory cases of the eye.