Convergence insufficiency in patients with post-concussion syndrome is accompanied by a higher symptom load: a cross-sectional study.

OBJECTIVE: To estimate the prevalence of convergence insufficiency (CI) in adult patients with post-concussion syndrome and determine the impact of CI on symptom load. METHODS: Cross-sectional study of 103 patients with neurological symptoms 2-6 months after a concussion. Symptoms were assessed with the Rivermead Post Concussion Symptoms Questionnaire (RPQ), and CI was diagnosed using near point of convergence, vergence facility, and the Convergence Insufficiency Symptom Survey. The RPQ score for patients with and without CI was compared, and sensitivity, specificity, and area under the receiver operating characteristic curve for the two visually related RPQ questions as indicators of CI were calculated. RESULTS: The proportion of patients diagnosed with symptomatic CI was 20.4% (95% confidence interval: 13.1-29.5%). The RPQ score was significantly higher for patients with symptomatic CI both before (p = .01) and after removal of the two visually related questions in the RPQ-questionnaire (p = .03). The two visually related RPQ questions were unable to detect CI. CONCLUSION: In patients with post-concussion syndrome, the load of nonvisual symptoms is higher in the presence of CI. A prospective interventional study on CI is required to study the relationship between CI and other post-concussion symptoms.

Differential effects of purines and prostaglandins on hypoxia induced dilatation of porcine retinal vessels at different branching level ex vivo.

The metabolic pathways leading from hypoxia to retinal vasodilatation can involve effects of both purines and prostaglandins, but the effects of these compounds at different vascular branching levels are unknown. The purpose of the present study was to investigate differential effects of purines and prostaglandins in hypoxia-induced dilatation of retinal arterioles, precapillary arterioles and capillaries ex vivo. Porcine hemiretinas were mounted in a tissue chamber while monitoring temperature, pH, and oxygen tension. The effect of hypoxia on the diameter of larger arterioles, precapillary arterioles and capillaries was studied in the presence of the ecto-nucleotidase inhibitor AOPCP, the nonselective P2 purinoreceptor antagonist PPADS, the A2B adenosine receptor antagonist MRS 1754, the A3 adenosine receptor antagonist MRS 1523, the EP1 receptor antagonist SC-19220, the EP2 receptor antagonist PF-04418948, the EP3 receptor antagonist L-798,106, the EP4 receptor antagonist L-161-982, the prostaglandin synthesis inhibitor ibuprofen, and ibuprofen combined with AOPCP or ATP. Hypoxia-induced dilatation in arterioles was reduced by the A2B adenosine receptor antagonist (p < 0.01) and increased by the EP2 and the EP3 receptor antagonists (p < 0.01 for both comparisons). In precapillary arterioles the dilatation was reduced by the EP2 receptor antagonist (p < 0.04) and increased by the EP1 receptor antagonist (p < 0.03), whereas in capillaries the dilatation was increased by both the A3 adenosine receptor antagonist (p < 0.01), by ibuprofen in combination with the unspecific ecto-nucleotidase inhibitor AOPCP (p = 0.04) and by the prostaglandin EP3 receptor antagonist. Hypoxia-induced dilatation of retinal vessels is influenced by adenosine A2B and A3 receptors, and by the prostaglandin EP1, EP2 and EP3 receptors. The effects mediated by these receptors differ at different branching levels of the resistance vessels.

Porcine models of choroidal neovascularization: A systematic review.

Animal models of choroidal neovascularization (CNV) are extensively used in translational studies of CNV formation and to evaluate angiostatic treatment strategies. However, the current paucity of large animal models compared with rodent models constitutes a knowledge gap regarding the clinical translation of findings. Ocular anatomical and physiological similarities to humans suggest the pig as a relevant model animal. Thus, a systematic survey of porcine CNV models was performed to identify pertinent model parameters and suggest avenues for model standardization and optimization. A systematic search was performed in PubMed and EMBASE on November 28, 2022 for porcine models of CNV. Following inclusion by two investigators, data from the articles were extracted according to a predefined protocol. A total of 14 articles, representing 19 independent porcine CNV models were included. The included models were almost equally divided between laser-induced (53%) and surgically-induced (47%) models. Different specified breeds of domestic pigs (71%) were most commonly used in the studies. All studies used normal animals. Female pigs were reported used in 43% of the studies, while 43% did not report on sex of the animals. Younger pigs were typically used. The surgical models reported consistent CNV induction following mechanical Bruch's membrane rupture. The laser models used variants of the infrared diode laser (40%) or the frequency-doubled Nd:YAG laser (50%). Both lasers enabled successful CNV induction with reported induction rates ranging from 60 to 100%. Collateral damage to the neuroretina was reported for the infrared diode laser. CNV evaluation varied across studies with fluorescein angiography (50%) as the most used in vivo method and retinal sections (71%) as the most used ex vivo method. In interventional studies, quantification of lesions was in general performed between 7 and 14 days. The field of porcine CNV models is relatively small and heterogeneous and almost equally divided between surgically-induced and laser-induced models. Both methods have allowed successful modeling of CNV formation with induction rates comparable to those of non-human primates. However, the field would benefit from standardization of model parameters and reporting. This includes laser parameters and validation of CNV formation as well as methods of CNV evaluation and statistical analysis.

Safety and efficacy of 0.01% and 0.1% low-dose atropine eye drop regimens for reduction of myopia progression in Danish children: a randomized clinical trial examining one-year effect and safety.

BACKGROUND: To investigate the efficacy and safety of 0.1% and 0.01% low-dose atropine eye drops in reducing myopia progression in Danish children. METHODS: Investigator-initiated, placebo-controlled, double-masked, randomized clinical trial. Ninety-seven six- to twelve-year old myopic participants were randomized to 0.1% loading dose for six months followed by 0.01% for six months (loading dose group, Number (N) = 33), 0.01% for twelve months (0.01% group, N = 32) or vehicle for twelve months (placebo, N = 32). Primary outcomes were axial length and spherical equivalent refraction. Secondary outcomes included adverse events and reactions, choroidal thickness and ocular biometry. Outcomes were measured at baseline and three-month intervals. Data was analyzed with linear-mixed model analysis according to intention-to-treat. RESULTS: Mean axial elongation was 0.10 mm less (95% confidence interval (CI): 0.17; 0.02, adjusted-p = 0.06) in the 0.1% loading dose and 0.07 mm less (95% CI: 0.15; 0.00, adjusted-p = 0.16) in the 0.01% group at twelve months compared to placebo. Mean spherical equivalent refraction progression was 0.24 D (95% CI: 0.05; 0.42) less in the loading dose and 0.19 D (95% CI: 0.00; 0.38) less in the 0.01% groups at twelve months, compared to placebo (adjusted-p = 0.06 and 0.14, respectively). A total of 108 adverse events were reported during the initial six-month loading dose period, primarily in the loading dose group, and 14 were reported in the six months following dose switching, all deemed mild except two serious adverse events, unrelated to the intervention. CONCLUSIONS: Low-dose atropine eye drops are safe over twelve months in otherwise healthy children. There may be a modest but clinically relevant reduction in myopia progression in Danish children after twelve months treatment, but the effect was statistically non-significant after multiple comparisons adjustment. After dose-switching at six months the loading dose group approached the 0.01% group, potentially indicating an early "rebound-effect". TRIAL REGISTRATION: this study was registered in the European Clinical Trials Database (EudraCT, number: 2018-001286-16) 05/11/2018 and first posted at www. CLINICALTRIALS: gov (NCT03911271) 11/04/2019, prior to initiation.

Similarities and differences in systemic risk factors for retinal artery occlusion and retinal vein occlusion: A nationwide case-control study.

BACKGROUND: To investigate the relationship between risk factors for retinal artery occlusion (RAO) and retinal vein occlusion (RVO) and thereby identify similarities and differences between the two types of retinal vascular occlusions. METHODS: In this case-control study, 5708 patients with RAO were included and matched with three patients with RVO each. The patients with RVO were matched on sex and age at index date. All patients, personal information, diagnoses, and prescriptions were obtained from the Danish nationwide registries. Adjusted conditional logistic regression was used to investigate the association of RAO and RVO with the included risk factors. RESULTS: RAO was stronger associated with arterial hypertension, heart failure, ischemic heart disease, peripheral artery disease, and stroke than RVO, with effect measures ranging from 1.10 to 2.21. RVO was associated with cataract and glaucoma with effect measures of 0.80 (95% CI 0.73-0.87) and 0.65 (95% CI 0.56-0.76), respectively. CONCLUSION: Differences in the level of associations with the included risk factors suggests differences in the pathophysiologies of the two diseases. The main pathophysiology associated with RAO was atherosclerosis, whereas the main pathophysiology associated with RVO was changes in the pressure gradients of the eyes.

ATP induced calcium signaling activity in perivascular cells differ at different vascular branch levels in the porcine retina.

BACKGROUND: The purine adenosine triphosphate (ATP) plays a significant role in retinal blood flow regulation and recent evidence suggests that the vasoactive effect of the compound differs in vessels at different branching level. However, the cellular basis for the regulation of retinal blood flow mediated by ATP has only been scarcely studied. METHODS: Perfused porcine hemiretinas (n = 60) were loaded with the calcium-sensitive fluorophore Oregon Green ex vivo. Spontaneous oscillations in fluorescence were studied in perivascular cells at five different vascular branching levels ranging from the main arteriole to the capillaries, before and after the addition of intra- and extravascular ATP alone or in the presence of a P2-purinergic receptor antagonist. RESULTS: Intravascular ATP induced an overall significant (p < 0.01) constriction of (mean ± SD) -9.79 ± 13.40% and extravascular ATP an overall significant (p < 0.01) dilatation of (mean ± SD) 19.62 ± 13.47%. Spontaneous oscillations of fluorescence in perivascular cells were significantly more intense around third order arterioles than around vessels at both lower and higher branching levels (p < 0.05 for all comparisons). ATP increased intracellular fluorescence in perivascular cells of first and second order arterioles after extravascular application, and the increase correlated with the accompanying vasodilatation (p < 0.03). Blocking of P2-receptors reduced oscillating fluorescence in pre-capillary arterioles secondary to intravascular ATP (p = 0.03). CONCLUSIONS: Spontaneous oscillations of calcium-sensitive fluorescence in perivascular retinal cells differ at different vascular branching levels. Extravascular ATP increases fluorescence in cells around the larger retinal arterioles exposed to the retinal surface. Future studies should investigate calcium signaling activity in perivascular retinal cells during interventions that simulate retinal pathology such as hypoxia.

Prevalence of Macular Microcystoid Lacunae in Autosomal Dominant Optic Atrophy Assessed With Adaptive Optics.

BACKGROUND: To assess the prevalence of macular microcystoid lacunae in patients with autosomal dominant optic atrophy (ADOA) and its association with visual function and inner retinal morphology. METHODS: The study included 140 participants with ADOA, with a mean age of 44 (SD ±19, range 7-82) years. Study participants with a genetically verified sequence variant in the OPA1 gene were examined with best-corrected visual acuity, contrast sensitivity, optical coherence tomography (Spectralis, Heidelberg) and adaptive optics fundus photography (rtx1, Imagine Eyes). Optically empty microcystoid spaces in the ganglion cell layer and inner plexiform layer were mapped by inspection of the 2 sets of images. Data were analyzed with a mixed model adjusted for age and sex with family and individual as random effect. RESULTS: Microcystoid lacunae were present in 32 of 140 participants (23%) including 18 males and 14 females. Microcystoid lacunae were associated with younger age ( P = 0.0503) and a smaller nerve fiber layer volume ( P = 0.035). No association was found between presence of microcystoid lacunae and visual acuity ( P = 0.2), contrast sensitivity ( P = 0.8), axial length ( P = 0.7), or ganglion cell layer volume ( P = 0.2). The analysis showed moderately reduced visual acuity in patients with microcystoid lacunae. Normal and severely impaired visual function were seen only in participants without microcystoid lacunae. CONCLUSION: In ADOA, macular microcystoid lacunae were found in 23% of the study participants and tended to be present in younger participants with moderate visual acuity reduction and a smaller nerve fiber layer volume. Further studies are needed to investigate whether cavities left by dead ganglion cells are predictors of decrease in visual function.

Similarities and Differences in Systemic Risk Factors for Retinal Artery Occlusion and Stroke: A Nationwide Case-Control Study.

BACKGROUND: Retinal artery occlusion (RAO) has been considered a stroke equivalent. This study compares risk factor profiles for thromboembolism among patients with RAO and stroke, respectively. METHODS: This case-control study is based on 5683 RAO patients entered in the Danish National Patient Register between 1st of January 2000 and 31st of December 2018. Cases were matched on sex, year of birth, and age at event with 28,415 stroke patients. The Danish nationwide registries were used to collect information about age, sex, previous diagnoses, and drug prescriptions. Adjusted conditional logistic regression models were used to investigate the association between hypothesised risk factors and the patient outcome. RESULTS: For atrial fibrillation, a substantially stronger association to stroke was found, with an odds ratio (OR) of 0.52 (95% CI: 0.47-0.58) when comparing RAO patients with stroke patients. RAO was stronger associated with arterial hypertension, peripheral artery disease, retinal vein occlusion, cataract, and glaucoma with OR's ranging from 1.21-11.70. The identified effect measures reached equivalence or was close to equivalence for diabetes, heart failure, ischemic heart disease, and renal disease. CONCLUSION: The differences in risk factor profiles between RAO and stroke suggests differences in the pathophysiology of the two diseases. These variations in pathophysiologies between the two diseases may indicate that different interventions are needed to ensure the optimal long-term prognosis for the patients.

Increasing metabolic variability increases the risk for vitrectomy in proliferative diabetic retinopathy.

PURPOSE: Proliferative diabetic retinopathy (PDR) can be treated by retinal photocoagulation, but in some cases, the treatment is initiated too late or is insufficient so that the disease advances to a stage requiring vitrectomy. There is a need to identify risk factors that can predict if patients with PDR will develop complications in need for vitrectomy. METHODS: Survival analysis with death as competing risk was used to study systemic risk factors for PDR progression to a complication in need for vitrectomy in right eyes of all 1288 diabetic patients from the Aarhus area, Denmark, who had developed proliferative retinopathy in the right eye during the 25 years period from 1 July 1994 until 1 July 2019. RESULTS: The overall cumulative incidence of reaching a vitrectomy end point in the right eye was 24.1% (n = 311). In 9.3% (n = 120) of the patients where vitrectomy had been performed together with the first photocoagulation, the age of onset of diabetes was significantly higher (p < 0.0001), the diabetes duration longer (p < 0.035) and BMI higher (p < 0.01) than in the patients who had been vitrectomized later than the first photocoagulation. The risk for vitrectomy was significantly increased by high variability of HbA1c before the development of PDR (p < 0.0001), but not by other parameters known to increase the risk for developing PDR. CONCLUSION: Increasing variability of HbA1c before the development of PDR increases the risk for progression to a complication in need of vitrectomy. The need for vitrectomy is unaffected by other risk factors known to increase the risk for developing PDR.

Clinical risk factors for retinal artery occlusions: a nationwide case-control study.

PURPOSE: This study seeks to examine potential risk factors for the development of retinal artery occlusions (RAO). METHODS: We used data obtained from Danish nationwide registries to evaluate potential risk factors for RAO present up to 5 years prior to the RAO diagnosis. The study included 5312 patients diagnosed with RAO registered in the Danish National Patient Register and 26,560 controls assessed from the general population matched on sex and age at index date. Adjusted conditional logistic regression was used to estimate the odds ratio of included risk factors for RAO diagnosis. We conducted supplementary analyses stratified on sex and age, and on RAO subtype. In addition, interaction analyses were performed between strata in the stratified analyses. RESULTS: Risk factors associated with the development of RAO included diabetes, arterial hypertension, ischemic heart disease, peripheral artery disease, stroke, renal disease, cataract, and glaucoma, with ORs ranging from 1.33 to 4.94. Atrial fibrillation and sleep apnea yielded effect measures close to equivalence. The presence of a risk factor was generally associated with higher odds of RAO among the population ≤ 55 of age. Arterial hypertension was stronger associated with RAO in male patients than in female patients. The association with arterial hypertension was stronger for CRAO than for BRAO subtype. CONCLUSION: The investigated risk factors suggest that atherosclerosis and conditions changing the intraocular pressure are involved in the pathophysiology of RAO.

Systemic risk factors contribute differently to the development of proliferative diabetic retinopathy and clinically significant macular oedema.

AIMS/HYPOTHESIS: The purpose of screening for diabetic retinopathy is to detect either of the two sight-threatening complications: proliferative diabetic retinopathy (PDR) or clinically significant diabetic macular oedema (DME). The aim of the study was to evaluate whether systemic risk factors affect the risk of developing these two complications differently. METHODS: Survival analysis with death as a competing risk was used to describe the effect of sex, age and time of onset of diabetes, systolic (SBP) and diastolic (DBP) BPs, and the weighted exposure and CV of HbA1c for the development of PDR and DME from all 2773 patients treated for diabetic retinopathy in a defined population from the Aarhus area, Denmark, between 1 July 1994 and 1 July 2019. RESULTS: Increasing HbA1c above normal increased the risk of developing both PDR and DME (p < 0.04), and values below normal increased the risk of developing PDR (p < 0.013). Increasing DBP increased the risk of developing both PDR and DME (p < 0.0001), whereas increasing SBP increased the risk of developing DME (p < 0.0001), but not PDR (p > 0.08). The risk of developing PDR increased with decreasing age of onset of diabetes (p < 0.0001), whereas the risk of developing DME was maximal for a known onset of diabetes at about 30 years of age and decreased significantly for both lower and higher ages of onset (p < 0.0001). The risk of developing both PDR and DME was lower in women than in men (p < 0.004) and was reduced with lower variability of repeated HbA1c measurements (p < 0.0001). CONCLUSIONS/INTERPRETATION: Systemic risk factors such as metabolic regulation, arterial BP and the age of onset of diabetes contribute differently to the development of PDR and DME. The overall risk of developing treatment-requiring diabetic retinopathy should be calculated from the risks of reaching each of the two complications separately.

Dilatation of Retinal Arterioles Induced by Topical Dorzolamide for One Week Is Impaired in Patients with Type 1 Diabetes and Mild Retinopathy.

BACKGROUND: Diabetic retinopathy is characterised by morphological lesions in the retina secondary to disturbances in retinal blood flow. Previous studies have shown that the carbonic anhydrase inhibitor (CAI) dorzolamide can induce immediate dilatation of retinal arterioles and a sustained increase in retinal blood flow in primary open-angle glaucoma. However, the effect of sustained treatment with CAI on retinal arterioles in normal persons and in patients with diabetic retinopathy is unknown. METHODS: The Dynamic Vessel Analyzer was used to assess the baseline diameter and the diameter response of retinal arterioles during an increase in arterial blood pressure induced by isometric exercise and during flicker stimulation before and 2 h, 24 h and 1 week after onset of topical treatment with dorzolamide. At each examination the diameter responses were studied before and during breathing in of a hypercapnic gas mixture. RESULTS: Treatment with dorzolamide for 1 week significantly increased the diameter of retinal arterioles in normal persons, and breathing in of a hypercapnic gas mixture reduced this response. The pathological vasodilatation and reduced retinal autoregulation in patients with diabetic retinopathy were unaffected by dorzolamide and hypercapnia. CONCLUSIONS: The study suggests a lack of relevance of CAI for the treatment of pathological vasodilatation in early diabetic retinopathy.

The vasodilating effect of glucose differs among vessels at different branching level in the porcine retina ex vivo.

Diabetic retinopathy is characterized by retinal lesions related to disturbances in retinal blood flow. The metabolic dysregulation in diabetes involves hyperglycemia which in both clinical and experimental studies has been shown to induce dilatation of larger retinal vessels, which has been suggested to be mediated by nitric oxide (NO). However, the effects of glucose on the diameter of smaller retinal vessels that are the site of development of diabetic retinopathy are unknown. Diameter changes in porcine retinal arterioles, pre-capillary arterioles and capillaries were studied ex vivo during acute changes in intraluminal glucose concentrations that mimicked changes in plasma glucose in diabetic patients. The experiments were repeated during blocking of NO-synthesis. Intravascular application of 2 mM glucose dilated arterioles and capillaries significantly, while 20 mM glucose dilated precapillary arterioles significantly. Intravascular application of 20 mM glucose dilated precapillary arterioles previously exposed to 2 mM glucose, while no significant diameter changes were observed after application of 2 mM glucose in vessels previously exposed to 20 mM glucose. No diameter changes were observed after application of 5.5 mM glucose in vessels previously exposed to both 2 mM and 20 mM glucose in either order. There was no significant difference between the diameter responses in the absence and presence of NO-synthesis blocker. Glucose induced dilatation of porcine precapillary arterioles ex vivo differs from the response in larger arterioles and capillaries, and the response is unaffected by the blocking of NO-synthesis. This may have implications for understanding the pathophysiology of diseases in the retinal microcirculation, such as diabetic retinopathy.

Reduced baseline diameter and contraction of peripheral retinal arterioles immediately after remote ischemia in diabetic patients.

PURPOSE: Remote ischemic conditioning (RIC) implies that transient ischemia in one organ can affect blood flow and protect from ischemia in another remote organ such as the retina. The purpose of the present study was to investigate the effect of RIC on the diameter of retinal arterioles in patients with diabetic retinopathy and whether this effect differs among peripheral and macular vessels. METHODS: In twenty type 1 diabetes patients aged 20-31 years, the Dynamic Vessel Analyzer (DVA) was used to measure diameters of peripheral and macular arterioles during rest, isometric exercise, and flicker stimulation. Measurements were obtained before, immediately after, and 1 h after RIC, and were compared to responses obtained from normal persons. RESULTS: The reduced baseline diameter (p < 0.009) and contraction of peripheral retinal arterioles during isometric exercise (p = 0.025) observed immediately after RIC in normal persons were absent in the studied diabetic patients. CONCLUSIONS: RIC affects the diameter of peripheral but not macular arterioles in normal persons, but the response is abolished in diabetic patients. TRIAL REGISTRATION: NCT03906383.

Extracellular l-arginine Enhances Relaxations Induced by Opening of Calcium-Activated SKCa Channels in Porcine Retinal Arteriole.

We investigated whether the substrate for nitric oxide (NO) production, extracellular l-arginine, contributes to relaxations induced by activating small (SKCa) conductance Ca2+-activated potassium channels. In endothelial cells, acetylcholine increased 3H-l-arginine uptake, while blocking the SKCa and the intermediate (IKCa) conductance Ca2+-activated potassium channels reduced l-arginine uptake. A blocker of the y+ transporter system, l-lysine also blocked 3H-l-arginine uptake. Immunostaining showed co-localization of endothelial NO synthase (eNOS), SKCa3, and the cationic amino acid transporter (CAT-1) protein of the y+ transporter system in the endothelium. An opener of SKCa channels, cyclohexyl-[2-(3,5-dimethyl-pyrazol-1-yl)-6-methyl-pyrimidin-4-yl]-amine (CyPPA) induced large currents in endothelial cells, and concentration-dependently relaxed porcine retinal arterioles. In the presence of l-arginine, concentration-response curves for CyPPA were leftward shifted, an effect unaltered in the presence of low sodium, but blocked by l-lysine in the retinal arterioles. Our findings suggest that SKCa channel activity regulates l-arginine uptake through the y+ transporter system, and we propose that in vasculature affected by endothelial dysfunction, l-arginine administration requires the targeting of additional mechanisms such as SKCa channels to restore endothelium-dependent vasodilatation.

Correction to: The CAPOS mutation in ATP1A3 alters Na/K-ATPase function and results in auditory neuropathy which has implications for management.

The following information was inadvertently omitted in the original publication.

The CAPOS mutation in ATP1A3 alters Na/K-ATPase function and results in auditory neuropathy which has implications for management.

Cerebellar ataxia, areflexia, pes cavus, optic atrophy and sensorineural hearing impairment (CAPOS) is a rare clinically distinct syndrome caused by a single dominant missense mutation, c.2452G>A, p.Glu818Lys, in ATP1A3, encoding the neuron-specific alpha subunit of the Na+/K+-ATPase α3. Allelic mutations cause the neurological diseases rapid dystonia Parkinsonism and alternating hemiplegia of childhood, disorders which do not encompass hearing or visual impairment. We present detailed clinical phenotypic information in 18 genetically confirmed patients from 11 families (10 previously unreported) from Denmark, Sweden, UK and Germany indicating a specific type of hearing impairment-auditory neuropathy (AN). All patients were clinically suspected of CAPOS and had hearing problems. In this retrospective analysis of audiological data, we show for the first time that cochlear outer hair cell activity was preserved as shown by the presence of otoacoustic emissions and cochlear microphonic potentials, but the auditory brainstem responses were grossly abnormal, likely reflecting neural dyssynchrony. Poor speech perception was observed, especially in noise, which was beyond the hearing level obtained in the pure tone audiograms in several of the patients presented here. Molecular modelling and in vitro electrophysiological studies of the specific CAPOS mutation were performed. Heterologous expression studies of α3 with the p.Glu818Lys mutation affects sodium binding to, and release from, the sodium-specific site in the pump, the third ion-binding site. Molecular dynamics simulations confirm that the structure of the C-terminal region is affected. In conclusion, we demonstrate for the first time evidence for auditory neuropathy in CAPOS syndrome, which may reflect impaired propagation of electrical impulses along the spiral ganglion neurons. This has implications for diagnosis and patient management. Auditory neuropathy is difficult to treat with conventional hearing aids, but preliminary improvement in speech perception in some patients suggests that cochlear implantation may be effective in CAPOS patients.

Incidence and risk factors for neovascular age-related macular degeneration in the fellow eye.

PURPOSE: The epidemiology, risk factors, and the effect of anti-VEGF treatment on neovascular age-related macular degeneration (nAMD) have primarily been studied in the first eye developing the disease. The understanding of pathophysiology and planning of follow-up examinations can be improved by knowledge of incidence and risk factors for development of the disease in the fellow eye. METHODS: In a prospective observational cohort study, epidemiological and clinical risk factors for the development of nAMD in the fellow eye among 2516 patients consecutively diagnosed with the disease from a population of 0.9 million citizens during a period of more than 10 years were studied. RESULTS: nAMD had been diagnosed in the fellow eye of 541 (21.5%) of the patients. The incidence of fellow-eye involvement increased from approximately 5% in patients initially presenting with bilateral disease to approximately 28% more than 6 years after the diagnosis in the first eye. Visual acuity (VA) was higher and central retinal thickness (CRT) was lower in fellow eyes with nAMD diagnosed later than the first eye. Male gender, increasing leakage area, and peripapillary location of the subretinal neovascular membrane in the first eye reduced the risk of developing disease in the fellow eye. CONCLUSIONS: The planning of follow-up examinations of patients diagnosed with nAMD in one eye should consider that the risk of fellow-eye involvement is higher within the first 6 years, in women, and when the leakage area in the first eye is small and not located peripapillary.

ARTERIAL OXYGEN SATURATION IN NEOVASCULARIZATIONS IN PROLIFERATIVE DIABETIC RETINOPATHY.

PURPOSE: Retinal neovascularizations in proliferative diabetic retinopathy have been proposed to develop from larger retinal venules. However, angiographic evidence suggests that the new vessels may originate from both arterioles and venules, and the vitreous oxygen tension near retinal neovascularizations is similar to that of retinal arterioles. An assessment of the oxygen saturation in neovascularizations may help characterizing the vascular origin of these vessels in proliferative diabetic retinopathy. METHODS: Dual wavelength oximetry was used to study the oxygen saturation in arterioles, venules, and retinal neovascularizations in 40 eyes from 40 patients with proliferative diabetic retinopathy. RESULTS: The oxygen saturation was significantly lower in retinal venules than in arterioles and neovascularizations (P < 0.0001), and after a correction for the influence of vessel diameter, there was no significant difference between the oxygen saturation in retinal arterioles and neovascularizations (P = 0.71). Age at onset and duration of diabetes mellitus contributed significantly to the variation in oxygen saturation of the venules, whereas none of the clinical background parameters contributed to the variation in oxygen saturation in arterioles and neovascularizations. CONCLUSION: The oxygen saturation in retinal neovascularizations in proliferative diabetic retinopathy is similar to that of the arterioles. Neovascularizations may act as shunts to bypass areas of capillary occlusion.

Spatial distribution of early red lesions is a risk factor for development of vision-threatening diabetic retinopathy.

AIMS/HYPOTHESIS: Diabetic retinopathy is characterised by morphological lesions related to disturbances in retinal blood flow. It has previously been shown that the early development of retinal lesions temporal to the fovea may predict the development of treatment-requiring diabetic maculopathy. The aim of this study was to map accurately the area where lesions could predict progression to vision-threatening retinopathy. METHODS: The predictive value of the location of the earliest red lesions representing haemorrhages and/or microaneurysms was studied by comparing their occurrence in a group of individuals later developing vision-threatening diabetic retinopathy with that in a group matched with respect to diabetes type, age, sex and age of onset of diabetes mellitus who did not develop vision-threatening diabetic retinopathy during a similar observation period. RESULTS: The probability of progression to vision-threatening diabetic retinopathy was higher in a circular area temporal to the fovea, and the occurrence of the first lesions in this area was predictive of the development of vision-threatening diabetic retinopathy. The calculated peak value showed that the risk of progression was 39.5% higher than the average. There was no significant difference in the early distribution of lesions in participants later developing diabetic maculopathy or proliferative diabetic retinopathy. CONCLUSIONS/INTERPRETATION: The location of early red lesions in diabetic retinopathy is predictive of whether or not individuals will later develop vision-threatening diabetic retinopathy. This evidence should be incorporated into risk models used to recommend control intervals in screening programmes for diabetic retinopathy.