Phenotypic heterogeneity of the mitochondrial DNA A8344G variant presenting with dorsal midbrain syndrome.

Purpose: To describe a neuro-ophthalmic presentation of a phenotypically heterogeneous mitochondrial DNA variant. Observations: A 10-year-old female with gross motor developmental delay, absence seizures and ataxia subacutely developed poor near acuity and asthenopia. She was found to have accommodative insufficiency, impaired supraduction and convergence retraction nystagmus leading to a diagnosis of dorsal midbrain syndrome. Brain MRI showed highly symmetrical lesions involving the dorsal pons. Genetic testing revealed a previously undiagnosed mitochondrial DNA (mtDNA) pathogenic variant, adenine to guanine at nucleopeptide pair 8344 (A8344G). Conclusion and importance: The authors describe a unique, neuro-ophthalmic manifestation of mitochondrial disease in a pediatric patient. This report discusses the phenotypic heterogeneity of the mtDNA A8344G variant, which may include 'stroke-like episodes' involving the brainstem, thus presenting with ophthalmic manifestations.

Quantitative contrast sensitivity test to assess visual function in central serous chorioretinopathy.

BACKGROUND: To characterise the contrast sensitivity function (CSF) in central serous chorioretinopathy (CSCR) compared with healthy controls using novel computerised contrast sensitivity (CS) testing with active learning algorithms. METHODS: Prospective observational study measuring CSF in CSCR eyes and controls using the Manifold Platform (Adaptive Sensory Technology, San Diego, California). Mixed effects multivariate regression models were used. Outcomes included area under the log CSF (AULCSF), CS thresholds at 1, 1.5, 3, 12 and 18 cycles per degree (cpd) and best-corrected visual acuity (BCVA). Associations of contrast outcomes with structural findings on optical coherence tomography (OCT) and subjective symptomatology were investigated. RESULTS: Forty CSCR eyes and 89 controls were included with median BCVA logarithm of median angle of resolution 0.10 (20/25) versus 0.00 (20/20), respectively (p=0.01). When accounting for age, CSCR was associated with significantly reduced median AULCSF (p=0.02, ß=-0.14) and reduced CS thresholds at 6 cpd (p=0.009, ß=-0.18), 12 cpd (p<0.001, ß=-0.23) and 18 cpd (p=0.04, ß=-0.09), versus controls. Within the CSCR group, subjectively perceived visual impairment (N=22) was associated with significantly decreased CS thresholds at all spatial frequencies and in AULCSF compared with asymptomatic CSCR eyes (N=18). Ellipsoid zone attenuation and subfoveal fluid on OCT were associated with decreased AULCSF and CS thresholds specifically at 3, 6 and 12 cpd, whereas presence of extrafoveal fluid at 1.5 and 3 cpd. CONCLUSION: Contrast sensitivity is significantly reduced in CSCR, and strongly correlates with subjective visual impairment. Different structural biomarkers correlate with contrast thresholds reductions at different spatial frequencies.

Active Learning to Characterize the Full Contrast Sensitivity Function in Cataracts.

Background: To characterize contrast sensitivity function (CSF) in cataractous and pseudophakic eyes compared to healthy control eyes using a novel quantitative CSF test with active learning algorithms. Methods: This is a prospective observational study at an academic medical center. CSF was measured in eyes with visually significant cataract, at least 2+ nuclear sclerosis (NS) and visual acuity (VA) ≥ 20/50, in pseudophakic eyes and in healthy controls with no more than 1+ NS and no visual complaints, using the Manifold Contrast Vision Meter. Outcomes included Area under the Log CSF (AULCSF) and CS thresholds at 1, 1.5, 3, 6, 12, and 18 cycles per degree (cpd). A subgroup analysis as performed on cataract eyes with VA ≥ 20/25. Results: A total of 167 eyes were included, 58 eyes in the cataract group, 77 controls, and 32 pseudophakic eyes with respective median AULCSF of 1.053 (0.352) vs 1.228 (0.318) vs 1.256 (0.360). In our multivariate regression model, cataract was associated with significantly reduced AULCSF (P= 0.04, ß= -0.11) and contrast threshold at 6 cpd (P= 0.01, ß= -0.16) compared to controls. Contrast threshold at 6 cpd was significantly reduced even in the subgroup of cataractous eyes with VA ≥ 20/25 (P=0.02, ß=-0.16). Conclusion: The novel qCSF test detected disproportionate significant contrast deficits at 6 cpd in cataract eyes; this remained significant even in the cataractous eyes with VA ≥ 20/25. CSF testing may enhance cataract evaluation and surgical decision-making, particularly in patients with subjective visual complaints despite good VA.

Sex-Specific Changes in Choroid Vasculature Among Patients with Schizophrenia and Bipolar Disorder.

Purpose: While structural changes within the retina of psychosis patients have been established, no detailed studies of choroidal microvasculature in these patients have been performed. Given evidence of microvascular disruption in psychosis patients, this study sought to determine whether there exists evidence of microvascular disruption in the choroids in these patients. Methods: Fifty-six subjects (20 controls and 36 psychosis patients) were recruited from April 2018 to February 2020. Five were excluded due to imaging artifact or missing demographic information. Swept-source optical coherence tomography angiography (SS-OCTA) images were obtained. Choroid vascular enface images (12 mm × 9mm) were exported every 2.6 µm from Bruch's membrane to the choroid-scleral interface from Topcon to ImageJ. The images were binarized using Otsu's method, signal from the optic disk and retinal vasculature was removed, and average choroid vascular density (CVD) was calculated as the average of percent area occupied by choroidal vasculature across images in the stack. Choroid vascular volume (CVV) was calculated as the CVD multiplied by maximum CT and image area. During image analysis, study staff were blinded to the phenotype of the study subjects. Results: Compared with same-sex controls, male psychiatric patients had significantly lower CVD. Compared with same-sex controls, female psychiatric patients had significantly lower maximum CT with correspondingly decreased CVV, after adjusting for age. When all psychiatric patients were compared with all healthy controls, no significant differences in CT, CVD, or CVV were noted. Conclusion: These results suggest that the pathogenesis of psychotic illness affects choroidal microvasculature in a sex-specific manner.

Retinal microvasculature and vasoreactivity changes in hypertension using optical coherence tomography-angiography.

PURPOSE: To evaluate the retinal vasculature and vasoreactivity of patients with hypertension (HTN) using spectral domain optical coherence tomography angiography (SD-OCTA). METHODS: Patients with and without a diagnosis of HTN were included in this cross-sectional observational study. All eyes were imaged with SD-OCTA using 3 mm × 3 mm and 6 mm × 6 mm centered on both the fovea and optic disk. A second 6 mm × 6 mm scan was taken after a 30 s breath-hold. Vessel density (VD), vessel skeletonized density (VSD), and fractal dimension (FD) were calculated using customized MATLAB scripts. Vessel diameter index (VDI) was obtained by taking the ratio of VD to VSD. Vasoreactivity was measured by subtracting the VD or VSD before and after breath-hold (∆VD, ∆VSD). RESULTS: Twenty-three eyes with HTN (17 patients) and 17 control eyes (15 patients) were included. In the 6 mm × 6 mm angiogram centered on fovea, the superficial capillary plexus (SCP) VD (ß = - 0.029, p = 0.012), VSD (ß = - 0.004, p = 0.043) and the choriocapillaris VD (ß = - 0.021, p = 0.030) were significantly decreased in HTN compared to control eyes. Similarly, FD was decreased in both the SCP (ß = - 0.012, p = 0.013) and choriocapillaris (ß = - 0.009, p = 0.030). In the 3 mm × 3 mm angiogram centered on optic disk, SCP VDI (ß = - 0.364, p = 0.034) was decreased. ∆VD and ∆VSD were both reduced in the DCP (ß = - 0.034, p = 0.032; ß = - 0.013, p = 0.043) and ∆VSD was elevated in the choriocapillaris of HTN eyes (ß = 0.004, p = 0.032). CONCLUSIONS: The study used SD-OCTA to show significant differences in the retinal vasculature of hypertensive patients. It was also the first to demonstrate the potential of OCT-A to investigate retinal vascular reactivity in patients with HTN.

Disorganisation of retinal inner layers is associated with reduced contrast sensitivity in retinal vein occlusion.

BACKGROUND/AIMS: To determine if disorganisation of retinal inner layers (DRIL) is associated with reduced contrast sensitivity (CS) in patients with retinal vein occlusion (RVO) with a history of macular oedema (ME). METHODS: Prospective, observational cohort study. Patients with a history of ME secondary to central retinal vein occlusion (CRVO) or branch retinal vein occlusion (BRVO) from October 2017 to July 2019 at a single institution were included. Patients underwent complete ophthalmic examination, spectral domain optical coherence tomography (SD-OCT) and CS testing using the quick contrast sensitivity function (qCSF) method. Eyes with coexisting macular disease were excluded. SD-OCT images were analysed for presence and extent of DRIL, intraretinal fluid (IRF), subretinal fluid (SRF), hyperreflective foci, epiretinal membrane (ERM), external limiting membrane (ELM) disruption, ellipsoid zone (EZ) disruption, central macular thickness (CMT) and central foveal thickness (CFT). Multivariable mixed-effect linear regressions were performed for the area under the log contrast sensitivity function (AULCSF) using Stata (StataCorp). P values <0.05 were considered significant. RESULTS: 58 visits from 31 patients were included (1.9±1.2 visits per patient). 29 (50%) were for CRVO. The average age was 63.9±10.5 years. On multivariable analysis, DRIL extent (p<0.001), CMT (p=0.007), CFT (p=0.024) and moderate cataract (p=0.001) were significantly associated with worse AULCSF. CONCLUSIONS: DRIL extent is associated with reduced CS in eyes with ME secondary to RVO. DRIL is an imaging feature that has important implications for visual function.

BILATERAL EPIRETINAL MEMBRANE FORMATION AFTER INTRAVITREAL INJECTIONS OF AUTOLOGOUS MESENCHYMAL STEM CELLS.

PURPOSE: The authors describe a case of new bilateral epiretinal membranes and vitreous cells after intravitreal and sub-Tenon's injections of bone marrow-derived stem cells. METHODS: A case report of a 43-year-old man with OPA-1 autosomal dominant optic atrophy who self-enrolled in a stem cell therapy clinical trial and received simultaneous bilateral intravitreal and sub-Tenon's injections of bone marrow-derived stem cells. RESULTS: Within one month of receiving the injections, the patient developed epiretinal membranes and vitreous cells in both eyes, seen with optical coherence tomography. CONCLUSION: Stem cell therapy has been gaining popularity as a potential intervention for progressive retinal and optic nerve diseases; however, the mechanism of action of bone marrow-derived stem cells is still not well understood and may result in unintended cell differentiation.

Contrast sensitivity function in patients with macular disease and good visual acuity.

INTRODUCTION: Contrast sensitivity function (CSF) may better estimate a patient's visual function compared with visual acuity (VA). Our study evaluates the quick CSF (qCSF) method to measure visual function in eyes with macular disease and good letter acuity. METHODS: Patients with maculopathies (retinal vein occlusion, macula-off retinal detachment, dry age-related macular degeneration and wet age-related macular degeneration) and good letter acuity (VA ≥20/30) were included. The qCSF method uses an intelligent algorithm to measure CSF across multiple spatial frequencies. All maculopathy eyes combined and individual macular disease groups were compared with healthy control eyes. Main outcomes included area under the log CSF (AULCSF) and six CS thresholds ranging from 1 cycle per degree (cpd) to 18 cpd. RESULTS: 151 eyes with maculopathy and 93 control eyes with VA ≥20/30 were included. The presence of a maculopathy was associated with significant reduction in AULCSF (ß: -0.174; p<0.001) and CS thresholds at all spatial frequencies except for 18 cpd (ß: -0.094 to -0.200 log CS, all p<0.01) compared with controls. Reductions in CS thresholds were most notable at low and intermediate spatial frequencies (1.5 cpd, 3 cpd and 6 cpd). CONCLUSION: CSF measured with the qCSF active learning method was found to be significantly reduced in eyes affected by macular disease despite good VA compared with healthy control eyes. The qCSF method is a promising clinical tool to quantify subtle visual deficits that may otherwise go unrecognised by current testing methods.

Active Learning of Contrast Sensitivity to Assess Visual Function in Macula-off Retinal Detachment.

PURPOSE: To characterize the contrast sensitivity function (CSF) in patients with successful repair of macula-off rhegmatogenous retinal detachment (RD) using an adaptive computerized contrast testing device. METHODS: CSF was prospectively measured in macula-off RD patients following successful repair and age-matched controls at W. K. Kellogg Eye Center and Massachusetts Eye and Ear, employing the active learning device Manifold Contrast Vision Meter (Adaptive Sensory Technology, San Diego, CA). Outcome measures included average area under the CSF curve (AULCSF), CS thresholds at 1-18 cycles per degree (cpd) and best correctd visual acuity (BCVA) in RD eyes fellow eyes and controls. A sub-analysis was performed in eyes with BCVA of 20/30 or better. RESULTS: Twenty-three macula-off RD eyes status post repair, fellow healthy eyes and 45 age-matched control eyes underwent CSF testing. The mean BCVA of the 23 RD eyes was 0.250 logMAR, significantly reduced compared to fellow eyes 0.032 (p<0.001) and controls 0.026 (p< 0.00001). There was a statistically significant reduction in AULCSF in RD eyes compared to the fellow eyes (p<0.0001) and to age-matched controls (Z-score -0.90, p<0.0001) and CSF reduction across all spatial frequencies. In the 15 RD eyes with BCVA of 20/30 or better, the mean CSF was significantly reduced compared to fellow eyes (p=0.0158) and controls (p=0.0453). CONCLUSIONS: CSF in macula-off RD eyes following repair was significantly reduced compared to fellow eyes and age-matched controls. CSF seems to be a promising visual function endpoint with potential applications in the clinical practice and future clinical trials.

Retinal Imaging Findings in Carriers With PSEN1-Associated Early-Onset Familial Alzheimer Disease Before Onset of Cognitive Symptoms.

Importance: Individuals with autosomal dominant mutations for Alzheimer disease are valuable in determining biomarkers present prior to the onset of cognitive decline, improving the ability to diagnose Alzheimer disease as early as possible. Optical coherence tomography (OCT) has surfaced as a potential noninvasive technique capable of analyzing central nervous system tissues for biomarkers of Alzheimer disease. Objective: To evaluate whether OCT can detect early retinal alterations in carriers of the presenilin 1 (PSEN1 [OMIM 104311]) E280A mutation who are cognitively unimpaired. Design, Setting, and Participants: A cross-sectional imaging study conducted from July 13, 2015, to September 16, 2020, included 10 carriers of the PSEN1 E280A mutation who were cognitively unimpaired and 10 healthy noncarrier family members, all leveraged from a homogenous Colombian kindred. Statistical analysis was conducted from September 9, 2017, to September 16, 2020. Main Outcomes and Measures: Mixed-effects multiple linear regression was performed to compare the thickness values of the whole retina and individual retinal layers on OCT scans between mutation carriers and noncarriers. Simple linear-effects and mixed-effects multiple linear regression models were used to assess whether age was an effect modifier for PSEN1 mutation of amyloid ß levels and retinal thickness, respectively. Fundus photographs were used to compare the number of arterial and venous branch points, arterial and venous tortuosity, and fractal dimension. Results: This study included 10 carriers of the PSEN1 E280A mutation who were cognitively unimpaired (7 women [70%]; mean [SD] age, 36.3 [8.1] years) and 10 healthy noncarrier family members (7 women [70%]; mean [SD] age, 36.4 [8.2] years). Compared with noncarrier controls, PSEN1 mutation carriers who were cognitively unimpaired had a generalized decrease in thickness of the whole retina as well as individual layers detected on OCT scans, with the inner nuclear layer (outer superior quadrant, ß = -3.06; P = .007; outer inferior quadrant, ß = -2.60; P = .02), outer plexiform layer (outer superior quadrant, ß = -3.44; P = .03), and outer nuclear layer (central quadrant, ß = -8.61; P = .03; inner nasal quadrant, ß = -8.39; P = .04; inner temporal quadrant, ß = -9.39; P = .02) showing the greatest amount of statistically significant thinning. Age was a significant effect modifier for the association between PSEN1 mutation and amyloid ß levels in cortical regions (ß = 0.03; P = .001) but not for the association between PSEN1 mutation and retinal thickness. No statistical difference was detected in any of the vascular parameters studied. Conclusions and Relevance: These findings suggest that OCT can detect functional and morphologic changes in the retina of carriers of familial Alzheimer disease who are cognitively unimpaired several years before clinical onset, suggesting that OCT findings and retinal vascular parameters may be biomarkers prior to the onset of cognitive decline.

Measuring Contrast Sensitivity Function With Active Learning in Retinal Vein Occlusion: A New Endpoint of Visual Function.

BACKGROUND AND OBJECTIVE: To characterize contrast sensitivity function (CSF) in patients with retinal vein occlusion (RVO) compared to age-matched controls using novel computerized contrast sensitivity (CS) testing with active learning algorithms. PATIENTS AND METHODS: CSF was prospectively measured in RVO patients with visual acuity (VA) greater than 20/200 and age-matched controls using the novel Manifold Contrast Vision Meter implementing quantitative CSF testing. Outcomes included area under the Log CSF (AULCSF), contrast acuity (CA), and CS thresholds at 1, 1.5, 3, 12, and 18 cycles per degree (cpd). A sub-analysis was performed on RVO eyes with good acuity (VA ≥ 20/30). RESULTS: Twenty-two eyes with RVO and 63 control eyes were included. Mean AULCSF (± standard deviation) in RVO eyes was 0.817 (0.28) compared to 1.217 (0.28) in controls (P < .0001). Mean contrast acuity in the RVO group was 1.054 (0.19) versus 1.286 ± 0.16 in controls (P < .0001). For individual spatial frequencies, CS loss at 6.0 cpd was most prominent in the RVO group. In 10 RVO eyes with VA of 20/30 or greater, mean AULCSF was 0.978 versus 1.217 in control eyes. (P = .008). CONCLUSIONS: CSF in eyes with RVO was found to be significantly reduced compared to age-matched controls. CSF seems to be a promising visual function endpoint with potential applications in clinical practice and future clinical trials. [Ophthalmic Surg Lasers Imaging Retina. 2020;51:392-400.].

Retinal layer abnormalities and their association with clinical and brain measures in psychotic disorders: A preliminary study.

Studies utilizing optical coherence tomography (OCT) in psychosis have identified abnormalities in retinal cytoarchitecture. We aim to analyze retinal layer topography in psychosis and its correlation with clinical and imaging parameters. Macular retinal images were obtained via OCT in psychosis probands (n = 25) and healthy controls (HC, n = 15). Clinical, cognitive and structural MRI data were collected from participants. No thinning was noted for the retinal nerve fiber, ganglion cell or inner plexiform layers. We found significant thinning in the right inner temporal, right central, and left inner superior quadrants of the outer nuclear layer (ONL) in probands compared to HC. Thickening of the outer plexiform layer (OPL) was observed in the right inner temporal, left inner superior, and left inner temporal quadrants. The right inner temporal and left inner superior quadrants of both the OPL and ONL showed significant inverse correlations. Retinal pigment epithelium thinning correlated with worse mania symptoms, and thinning in the ONL was associated with worse cognitive function. ONL thinning was also associated with smaller total brain and white matter volume. Our findings suggest that outer retinal layers may provide additional insights into the pathophysiology of psychosis, possibly reflecting synaptic or inflammatory aberrations that lead to retinal pathologies.

CLOSURE OF SMALL MACULAR HOLES USING VITRECTOMY SURGERY WITH INTERNAL LIMITING MEMBRANE PEELING WITHOUT THE USE OF INTRAOCULAR GAS TAMPONADE: BROADENING THE UNDERSTANDING OF THE MACULAR HOLE PATHOPHYSIOLOGY.

PURPOSE: To determine whether small macular hole closure can be achieved with 25-G vitrectomy surgery with internal limiting membrane peeling without the use of intraocular gas tamponade or facedown positioning. METHODS: 25-G vitrectomy surgery with internal limiting membrane peeling without the use of intraocular gas tamponade or positioning was performed on 20 eyes with a small (<400-µm diameter), full-thickness macular hole. RESULTS: In 17 of 20 eyes (85%), the hole had closed. Three holes had closed by Postoperative Day 1, 13 holes by Postoperative Week 1, 16 holes by Postoperative Week 2, and 17 holes by Postoperative Week 6. At Postoperative Month 1, vision improved in 16 of 17 eyes in which the macular hole had closed. One hole that had not closed at the first postoperative week and two holes that had not closed at the third postoperative week required follow-up surgery with intraocular gas tamponade and facedown positioning, after which the hole closed. The mean preoperative visual acuity was 0.626 logMAR (20/85), and the mean postoperative visual acuity after 1 month was 0.392 logMAR (20/50) (P < 0.001). CONCLUSION: Vitrectomy surgery with internal limiting membrane peeling without the use of gas tamponade or positioning can achieve closure of small macular holes.

Intensive multidisciplinary weight management in patients with type 1 diabetes and obesity: A one-year retrospective matched cohort study.

AIMS: Recent studies report that approximately 50% of patients with type 1 diabetes (T1D) are overweight or obese. This work studies the effects of intensive multidisciplinary weight management (IMWM) in patients with T1D and obesity. METHODS: We retrospectively evaluated 68 patients with T1D and obesity who enrolled in a 12-week IMWM program (IMWM cohort: mean age, 42 ± 11 years; HbA1c, 8.3% ± 1.0%; body weight, 104.3 ± 18.2 kg; BMI, 36.2 ± 4.9 kg/m2 ). We matched them 1:1 with a similar cohort of patients receiving standard care (SC cohort: mean age, 42 ± 12 years; HbA1c, 8.3% ± 1.0%; body weight, 102.4 ± 17.9 kg; BMI, 36.1 ± 4.7 kg/m2 ). Data were collected at baseline and at 12 months. RESULTS: Participants in the IMWM cohort had a body weight change of -6.6 ± 1.8 kg or -6.4% ± 1.6% of their initial body weight, while participants in the SC cohort had no change (P < 0.01 for group*time interaction). Participants in the IMWM cohort had a change in HbA1c of -0.4% ± 0.1% from baseline (P < 0.01), while participants in the SC cohort had no change. There was no difference in glycaemic control between cohorts at 12 months. Total daily insulin dose changed by -5.9 ± 1.8 units/d from baseline in the IMWM cohort while there was no change in the SC cohort (P < 0.01 for group*time interaction). CONCLUSIONS: In comparison to standard care, patients with T1D and obesity who participated in an IMWM programme achieved significant weight loss and significant reduction in daily insulin dose at 1 year. Weight reduction was associated with improvements in glycaemic control compared to baseline.

Weight Management in Patients with Type 1 Diabetes and Obesity.

PURPOSE OF REVIEW: Patients with type 1 diabetes (T1D) are typically viewed as lean individuals. However, recent reports showed that their obesity rate surpassed that of the general population. Patients with T1D who show clinical signs of type 2 diabetes such as obesity and insulin resistance are considered to have "double diabetes." This review explains the mechanisms of weight gain in patients with T1D and how to manage it. RECENT FINDINGS: Weight management in T1D can be successfully achieved in real-world clinical practice. Nutrition therapy includes reducing energy intake and providing a structured nutrition plan that is lower in carbohydrates and glycemic index and higher in fiber and lean protein. The exercise plan should include combination stretching as well as aerobic and resistance exercises to maintain muscle mass. Dynamic adjustment of insulin doses is necessary during weight management. Addition of anti-obesity medications may be considered. If medical weight reduction is not achieved, bariatric surgery may also be considered.