Frequency and Distribution of Ophthalmic Surgical Procedures among Patients with Inherited Retinal Diseases.

OBJECTIVE: In this study, we aimed to characterize the frequency and distribution of ocular surgeries in patients with inherited retinal diseases (IRDs) and evaluate associated patient and disease factors. DESIGN: Retrospective cohort. PARTICIPANTS: Subjects aged ≥ 18 years who were followed at the Johns Hopkins Genetic Eye Disease Center. METHODS: We studied a retrospective cohort of patients with an IRD diagnosis to analyze the occurrence of laser and incisional surgeries. Subjects were categorized into 2 groups: central dysfunction (macular/cone/cone-rod dystrophy, "MCCRD group") and panretinal or peripheral dysfunction (retinitis pigmentosa-like, "RP group"). Genetic testing status was recorded. The association of patient and disease factors on the frequency, distribution, and timing of surgeries was analyzed. MAIN OUTCOME MEASURES: Prevalence, prevalence odds ratio (POR), hazard ratio (HR) of ophthalmic procedures by phenotype. RESULTS: A total of 1472 eyes of 736 subjects were evaluated. Among them, 31.3% (n = 230) had undergone ocular surgery, and 78.3% of those (n = 180/230) had a history of more than 1 surgery. A total of 602 surgical procedures were analyzed. Cataract extraction with intraocular lens implantation (CEIOL) was the most common (51.2%), followed by yttrium aluminum garnet capsulotomy, refractive surgery, retinal surgery, and others. Cataract extraction with intraocular lens implantation occurred more frequently in RP than in MCCRD subjects (POR, 2.59; P = 0.002). Retinitis pigmentosa subjects underwent CEIOL at a younger age than patients with MCCRD (HR, 2.11; P < 0.001). CONCLUSIONS: Approximately one-third of patients with IRD had a history of laser or incisional surgery. Cataract extraction with intraocular lens implantation was the most common surgery; its frequency and timing may be associated with the IRD phenotype. This data may inform the design of prospective research. Such efforts may illuminate routine clinical decision-making and contribute to surgical strategy development for cell and gene therapy delivery. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Novel Detection and Restorative Levodopa Treatment for Preclinical Diabetic Retinopathy.

Diabetic retinopathy (DR) is diagnosed clinically by directly viewing retinal vascular changes during ophthalmoscopy or through fundus photographs. However, electroretinography (ERG) studies in humans and rodents have revealed that retinal dysfunction is demonstrable prior to the development of visible vascular defects. Specifically, delays in dark-adapted ERG oscillatory potential (OP) implicit times in response to dim-flash stimuli (<-1.8 log cd · s/m2) occur prior to clinically recognized DR. Animal studies suggest that retinal dopamine deficiency underlies these early functional deficits. In this study, we randomized individuals with diabetes, without clinically detectable retinopathy, to treatment with either low- or high-dose Sinemet (levodopa plus carbidopa) for 2 weeks and compared their ERG findings with those of control subjects (no diabetes). We assessed dim-flash-stimulated OP delays using a novel handheld ERG system (RETeval) at baseline and 2 and 4 weeks. RETeval recordings identified significant OP implicit time delays in individuals with diabetes without retinopathy compared with age-matched control subjects (P < 0.001). After 2 weeks of Sinemet treatment, OP implicit times were restored to control values, and these improvements persisted even after a 2-week washout. We conclude that detection of dim-flash OP delays could provide early detection of DR and that Sinemet treatment may reverse retinal dysfunction.

Validation of a Head-mounted Virtual Reality Visual Field Screening Device.

PRéCIS:: The C3 fields analyzer (CFA) is a moderately reliable perimeter preferred by patients to standard perimetry. While it does not approximate the gold standard, it was sensitive and specific for clinically defined glaucoma (area under the receiving operator characteristic curve=0.77 to 0.86). PURPOSE: Testing the visual field is a vital sign for diagnosing and managing glaucoma. The current gold standard, the Humphrey visual field analyzer (HFA), is large, expensive and can be uncomfortable for some patients. The current study investigated the CFA, a virtual reality head-mounted visual field testing device, as a possible subjective field test for glaucoma screening and eventually glaucoma monitoring. PATIENTS AND METHODS: The CFA presented stimuli in the same 54 positions as the HFA 24-2 SITA Standard test using a suprathreshold algorithm approximating an 18 dB deficit. A total of 157 patients (both controls and glaucoma patients) at the Aravind Eye Hospital, Pondicherry, India, were tested with both devices. RESULTS: The number of stimuli missed on the CFA correlated with HFA mean deviation (r=0.62, P<0.001), and with pattern standard deviation (r=0.36, P<0.001). The area under the receiving operator characteristic curve was 0.77±0.06 for mild glaucoma (HFA mean deviation ≥-6 dB) and 0.86±0.04 for moderate-advanced glaucoma (HFA mean deviation <-6 dB). Patients with an 18 dB or worse deficit at a point in the visual field on the HFA failed to see the CFA stimulus at the same position 38% of the time. CONCLUSIONS: While the CFA did not reliably identify deficits that matched the HFA, it was moderately effective at identifying glaucoma subjects. Further refinements to the device will be required to improve point by point testing performance and screening performance.

Low-Intensity Exercise in Mice Is Sufficient to Protect Retinal Function During Light-Induced Retinal Degeneration.

Purpose: We previously reported that a specific treadmill running exercise regimen protects against light-induced retinal degeneration (LIRD) in mice. We hypothesized that this protective effect varies with running intensity. To test this, mice undergoing LIRD were run at different treadmill speeds and retinal function was assessed. Methods: BALB/c mice were assigned to LIRD groups at varying treadmill speeds-0, 5, 10, or 20 m/min labeled inactive, low, medium, and high, respectively-and compared with naïve mice exposed to standard lighting (50 lux; naïve). Following 2 weeks of exercise, a subset of mice were exposed to toxic light (10,000 lux; LIRD) for 4 hours. After 5 additional days of exercise, retinal function was assessed by ERG. Corticosterone levels in serum and cathepsin B (CTSB) protein levels in muscle, brain, serum, and retina were measured. The retinal gene expression of complement factor 1qa (C1qa) and CTSB were measured. Results: The low+LIRD and medium+LIRD exercise groups had greater a- and b-wave ERG amplitudes when compared with the inactive+LIRD group (P < 0.02). The high+LIRD mice only differed from the inactive+LIRD mice in their dark-adapted b-waves. Serum corticosterone increased in the high+LIRD mice (P < 0.006). Retinal CTSB protein levels were higher in the low+LIRD versus high+LIRD mice (P < 0.004) but were otherwise unchanged. Exercise of any intensity decreased C1qa gene expression. Conclusions: Faster running did not additionally protect against LIRD, but it did increase serum corticosterone, suggesting stress-induced limits to exercise benefits. Unexpectedly, exercise did not increase CTSB proteins levels in muscle or serum, suggesting that it may not mediate exercise effects. Our results have implications for the use of low-intensity exercise as a vision loss treatment.

Faster emergence behavior from ketamine/xylazine anesthesia with atipamezole versus yohimbine.

Recent interest in reversal of the hypnotic effects of anesthesia has mainly focused on overcoming a surge in GABA-mediated inhibitory signaling through activation of subcortical arousal circuits or antagonizing GABA receptors. Here we examine the reversal of anesthesia produced from non-GABA agents ketamine/xylazine and the effects of antagonists of adrenoreceptors. These antagonists vary in selectivity and produce temporally unique waking behavior post-anesthesia. We compared two antagonists with differential selectivity for α1- vs. α2-receptors, yohimbine (YOH, 1:40 selectivity) and atipamezole (ATI, 1:8500). Adult mice received intraperitoneal injections of either YOH (4.3 mg/kg), ATI (0.4 mg/kg), or saline after achieving sustained loss of righting following injection of ketamine/xylazine (ketamine: 65.0 mg/kg; xylazine: 9.9 mg/kg). Behaviors indicative of the post-anesthesia, re-animation sequence were carefully monitored and the timing of each behavior relative to anesthesia induction was compared. Both YOH and ATI hastened behaviors indicative of emergence, but ATI was faster than YOH to produce certain behaviors, including whisker movement (YOH: 21.9±1.5 min, ATI: 17.5±0.5 min, p = 0.004) and return of righting reflex (RORR) (YOH: 40.6±8.8 min, ATI: 26.0±1.2 min, p<0.001). Interestingly, although YOH administration hastened early behavioral markers of emergence relative to saline (whisking), the completion of the emergence sequence (time from first marker to appearance of RORR) was delayed with YOH. We attribute this effect to antagonism of α1 receptors by yohimbine. Also notable was the failure of either antagonist to hasten the re-establishment of coordinated motor behavior (e.g., attempts to remove adhesive tape on the forepaw placed during anesthesia) relative to the end of emergence (RORR). In total, our work suggests that in addition to pharmacokinetic effects, re-establishment of normal waking behaviors after anesthesia involves neuronal circuits dependent on time and/or activity.

TrkB signalling pathway mediates the protective effects of exercise in the diabetic rat retina.

Diabetic retinopathy is a leading cause of vision loss. Treatment options for early retinopathy are sparse. Exercise protects dying photoreceptors in models of retinal degeneration, thereby preserving vision. We tested the protective effects of exercise on retinal and cognitive deficits in a type 1 diabetes model and determined whether the TrkB pathway mediates this effect. Hyperglycaemia was induced in Long Evans rats via streptozotocin injection (STZ; 100 mg/kg). Following confirmed hyperglycaemia, both control and diabetic rats underwent treadmill exercise for 30 min, 5 days/week at 0 m/min (inactive groups) or 15 m/min (active groups) for 8 weeks. A TrkB receptor antagonist (ANA-12), or vehicle, was injected 2.5 h before exercise training. We measured spatial frequency and contrast sensitivity using optokinetic tracking biweekly post-STZ; retinal function using electroretinography at 4 and 8 weeks; and cognitive function and exploratory behaviour using Y-maze at 8 weeks. Retinal neurotrophin-4 was measured using ELISA. Compared with non-diabetic controls, diabetic rats showed significantly reduced spatial frequency and contrast sensitivity, delayed electroretinogram oscillatory potential and flicker implicit times and reduced cognitive function and exploratory behaviour. Exercise interventions significantly delayed the appearance of all deficits, except for exploratory behaviour. Treatment with ANA-12 significantly reduced this protection, suggesting a TrkB-mediated mechanism. Despite this, no changes in retinal neurotrohin-4 were observed with diabetes or exercise. Exercise protected against early visual and cognitive dysfunction in diabetic rats, suggesting that exercise interventions started after hyperglycaemia diagnosis may be a beneficial treatment. The translational potential is high, given that exercise treatment is non-invasive, patient controlled and inexpensive.

Dopamine Deficiency Mediates Early Rod-Driven Inner Retinal Dysfunction in Diabetic Mice.

Purpose: Electroretinograms (ERGs) are abnormal in diabetic retinas before the appearance of vascular lesions, providing a possible biomarker for diabetic vision loss. Previously, we reported that decreased retinal dopamine (DA) levels in diabetic rodents contributed to early visual and retinal dysfunction. In the current study, we examined whether oscillatory potentials (OPs) could serve as a potential marker for detecting early inner retinal dysfunction due to retinal DA deficiency. Methods: Retinal function was tested with dark-adapted ERGs, taken at 3, 4, and 5 weeks after diabetes induction with streptozotocin. Electrical responses were analyzed and correlations were made with previously reported retinal DA levels. The effect of restoring systemic DA levels or removing DA from the retina in diabetic mice on OPs was assessed using L-3,4-dihydroxyphenylalanine (L-DOPA) treatments and retina-specific tyrosine hydroxylase (Th) knockout mice (rTHKO), respectively. Results: Diabetic animals had significantly delayed OPs compared to control animals in response to dim, but not bright, flash stimuli. L-DOPA treatment preserved OP implicit time in diabetic mice. Diabetic rTHKO mice had further delayed OPs compared to diabetic mice with normal retinal Th, with L-DOPA treatment also providing benefit. Decreasing retinal DA levels significantly correlated with increasing OP delays mediated by rod pathways. Conclusions: Our data suggest that inner retinal dysfunction in early-stage diabetes is mediated by rod-pathway deficits and DA deficiencies. OP delays may be used to determine the earliest functional deficits in diabetic retinopathy and to establish an early treatment window for DA therapies that may prevent progressive vision loss.