Meningoencephalitis from SARS-CoV-2 infection.

The current global pandemic of COVID-19 disease is caused by a novel coronavirus SARS-CoV-2. This typically causes severe respiratory illness, however, as cases have multiplied across the globe, protean manifestations involving multiple organ systems have been described. We report a case of a 35-year-old woman with meningoencephalitis associated with COVID-19 disease who presented with altered mental status and rhythmic limb movements. Although rare, meningoencephalitis should be considered as a possible manifestation of COVID-19 disease.

Eye-Related Emergency Department Visits and The Opioid Epidemic: a 10-Year Analysis.

PURPOSE: To describe the epidemiology of Emergency Department (ED) visits related to opioid abuse with primary ophthalmic diagnoses in the United States (US). METHODS: This retrospective cross-sectional study used National ED Sample (NEDS) (2006-2015), a representative sample of all US EDs, to analyze and compare the epidemiology of primary ophthalmic diagnoses in opioid abusers and a control group of non-opioid users. National incidence and descriptive statistics were calculated for demographics and prevalent diagnoses. Multivariable logistic regression was used to compare outcomes between primary ophthalmic diagnoses in opioid and non-opioid abusers. RESULTS: An estimated 10,617 visits had a primary ophthalmic diagnosis and an accompanying opioid abuse diagnosis, and the incidence increased from 0.2 in 2006 to 0.6 per 100,000 US population in 2015. Opioid abuse group had more adults (6,747:63.5%) and middle-aged (3,361:31.7%) patients, while in controls adults (7,905,003:40.4%) and children (4,068,534:20.8%) were affected more. Leading etiologies were similar: traumatic and infectious etiologies were most common; however, opioid abuse patients had more severe ophthalmic diagnoses such as orbital fractures (8.4%), orbital cellulitis (7.4%), globe injury (3.4%) and endophthalmitis (3.2%) compared to controls. Patients in the opioid abuse group were also more likely to be admitted (adjusted Odds Ratio [aOR], 28.38 [95% CI, 24.50-32.87]). CONCLUSIONS: In the era of opioid crisis, an increase in ED visits with ophthalmic complaints is seen, with increasing direct and indirect costs on the healthcare system. More research is needed to establish causality and devise strategies to lower this burden.

Comparison of Retinal Layer Thickness in Eyes with Resolved Diabetic Macular Edema Receiving Ranibizumab with Normal Eyes.

PURPOSE: To evaluate the thickness of individual retinal layers in eyes with resolved diabetic macular edema (DME) after treatment with ranibizumab (RBZ). METHODS: Spectral-domain optical coherence tomography (OCT) scans of 25 eyes (25 patients) with DME that had been treated with RBZ (and shown resolution of edema as evident by the absence of fluid in a high-resolution grid placed on the fovea) were acquired using Spectralis HRA + OCTTM. Thickness measurements of individual layers were calculated using papillomacular bundle (PMB), central subfield, and inner- and outer-ring Early Treatment Diabetic Retinopathy Study (ETDRS) grids. Measurements were compared to 45 normal eyes with no known retinal disease. A post-hoc analysis was done correlating visual acuity (VA) with individual retinal layer thickness. RESULTS: Full retinal thickness (FRT) was thinner than normal individuals across all 4 grids. There were similarities and differences among the 4 grids; however, PMB and inner-ring ETDRS grids displayed the most resemblance. The VA significantly correlated with the FRT measured in PMB (p = 0.004), central subfield (p = 0.02), and inner-ring (p = 0.006) ETDRS. CONCLUSIONS: Segmentation of OCT scans revealed significant differences in the overall thickness of the retina and of individual retinal layers in patients with resolved DME. PMB grid showed a stronger correlation between affected retinal layers and VA compared to ETDRS. PMB also showed significance with VA in layers that were shown to be not significant in ETDRS grid.

Loss of Peak Vision in Retinal Vein Occlusion Patients Treated for Macular Edema.

PURPOSE: To evaluate long-term visual and anatomic outcomes in patients with retinal vein occlusion (RVO) treated with anti-vascular endothelial growth factor (VEGF) agents. DESIGN: Prospective, interventional case series. PARTICIPANTS: Patients with central RVO (CRVO) or branch RVO (BRVO). METHODS: Number of anti-VEGF injections and improvement from baseline best-corrected visual acuity (BCVA) and central subfield thickness (CST) were prospectively recorded in 40 eyes of 39 CRVO patients and 50 eyes of 47 BRVO patients. RESULTS: Mean follow-up was 58 months for BRVO and 78 months for CRVO. Within 6 months of last follow-up, 58% of BRVO patients and 75% of CRVO patients required anti-VEGF injections to control edema. Analysis of the course of each patient over time showed that for BRVO patients, BCVA letter score increased by a mean of 24, from baseline of 52 (20/100) to peak of 76 (20/32), and subsequently decreased by 13, to 63 (20/50), at final visit; and for CRVO patients, BCVA letter score increased by a mean of 26, from baseline of 48 (20/100) to peak of 74 (20/32), and subsequently decreased by 18, to 56 (20/80), at last follow-up. Loss from peak BCVA occurred primarily owing to persistent/recurrent edema and related foveal damage. CONCLUSIONS: Patients with RVO showed large improvements in BCVA after initiation of anti-VEGF injections, but in many patients some visual gains were lost over time owing to bouts of recurrent edema. Sustained suppression of VEGF may help to provide optimal outcomes in RVO and reduce treatment burden.

MICROPERIMETRY AS A SCREENING TEST FOR HYDROXYCHLOROQUINE RETINOPATHY: The Hard-Risk-1 Study.

PURPOSE: To assess the sensitivity and specificity of microperimetry as a screening test to detecting hydroxychloroquine retinopathy. METHODS: Retrospective cohort study. Patients with history of hydroxychloroquine use for more than 5 years and with concomitant microperimetry and multifocal electroretinogram testing were retrospectively reviewed. Microperimetry was considered positive if there were three or more contiguous scotoma points in the parafoveal region. Multifocal electroretinogram was used as gold standard and was considered positive if there was an increased R1/R2 ring ratio (>2.5) or reduced R1 absolute amplitude (<9.0). Sensitivity, specificity, positive predictive value, and negative predictive value of microperimetry were calculated. RESULTS: A total of 197 patients were reviewed. Hydroxychloroquine retinopathy was present in 22 (11%) patients. Their mean (SD) age was 54 (14) years, and 96% were women. Their mean (SD) daily dose was 5.7 (1.3) mg/kg, cumulative dose was 2041 (1,548) g, and duration of use was 15 (10) years. Sensitivity, specificity, positive predictive value, and negative predictive value of microperimetry were 73%, 93%, 53%, and 96%, respectively. CONCLUSION: Microperimetry has inferior sensitivity but good specificity in detecting hydroxychloroquine retinopathy (compared with multifocal electroretinogram). As such, it may be a useful ancillary test to exclude retinopathy, especially in high-risk patients or those with conflicting results on different modalities.

Progression of retinitis pigmentosa on multimodal imaging: The PREP-1 study.

IMPORTANCE: It is important to establish reliable outcome measures to detect progression in retinitis pigmentosa (RP). BACKGROUND: To evaluate progression of RP using multimodal imaging, including spectral-domain optical coherence tomography (SD-OCT), fundus autofluorescence (FAF) and microperimetry (MP). DESIGN: Retrospective longitudinal study at a tertiary teaching hospital. PARTICIPANTS: 205 eyes of 106 patients with RP with 1 to 5 y of follow-up. METHODS: Demographics and visual acuity (VA) were recorded, and each modality was graded at baseline and every annual follow-up. SD-OCT was graded for the width of ellipsoid zone (EZ), FAF was graded for the diameter and area of the hyperautofluorescent ring (if present), and MP was graded for mean, central and paracentral sensitivity. Spearman's correlation was used to measure correlations at baseline. Mixed effects models were used to estimate the annual change of each parameter, adjusted for disease duration. MAIN OUTCOME MEASURES: Rate of progression. RESULTS: The median VA at baseline was 75 letters and was positively correlated with mean and central sensitivity (r: 0.372 and 0.394; P = 0.01 for both). All parameters (except paracentral sensitivity) were strongly correlated with each other (r: 0.673-0.991; P < 0.001 for all). The annual rates of change for each parameter were as follows: VA, -2.3 letters (P < 0.001); EZ, -151 µm (P < 0.001); ring diameter, -132 µm (P < 0.001); ring area, -0.4 mm2 (P < 0.001); mean sensitivity, -0.3 dB (P < 0.001); central sensitivity, -0.7 dB (P < 0.001); paracentral sensitivity, -0.4 dB (P < 0.001). CONCLUSIONS AND RELEVANCE: Structural and functional measures are well correlated in RP and can reliably measure disease progression within the course of a year.

Shortest Distance From Fovea to Subfoveal Hemorrhage Border Is Important in Patients With Neovascular Age-related Macular Degeneration.

PURPOSE: To identify factors influencing visual outcome in patients with neovascular age-related macular degeneration (NVAMD) and subfoveal hemorrhage (SFH) treated with anti-vascular endothelial growth factor (VEGF) agents. DESIGN: Retrospective case series. METHODS: Anti-VEGF-treated eyes with SFH > 1 disc area (DA) were identified (n = 16) and changes in visual acuity (VA) and central subfield thickness (CST) from baseline to last follow-up, along with SFH area, thickness, minimum distance from fovea to SFH border, and time to resolution, were determined. RESULTS: At baseline, mean (± standard error of the mean) size and thickness of SFH were 14.9 ± 2.8 DA and 386.6 ± 46.9 µm, and mean Snellen VA and CST were 20/250 and 591.7 ± 57.0 µm. Median follow-up was 47.6 months. While more than 50% of patients had VA ≤ 20/200 at baseline and all time points through week 48, the percentage of patients with VA ≥ 20/50 increased to 30%-40% at months 6 and 12 and remained stable through month 48. Spearman rank correlation demonstrated 2 independent variables that correlated with good visual outcome, smaller area of SFH at baseline (r = -0.630; P = .009), and high frequency of anti-VEGF injections (r = 0.646; P = .007). In exceptional patients with good visual outcome despite large baseline SFH, shortest distance between the fovea and hemorrhage border significantly correlated with baseline VA (r = -0.503, P = .047) and final VA (r = -0.575, P = .02). CONCLUSIONS: Patients with NVAMD and thick SFH, but short distance between fovea and uninvolved retina, can have good visual outcomes when given frequent anti-VEGF injections.

Progression of Retinitis Pigmentosa as Measured on Microperimetry: The PREP-1 Study.

PURPOSE: To evaluate yearly progression of retinitis pigmentosa (RP) using microperimetry (MP) performed on Nidek MP1 (NAVIS Software v1.7; Nidek Technologies, Padova, Italy). DESIGN: Retrospective longitudinal study. PARTICIPANTS: RP patients with consecutive MP tests (using the same test settings). METHODS: Data were collected as part of the Photoreceptor Cell Death in Retinitis Pigmentosa Retrospective (PREP-1) study. Visual acuity, fixation stability, mean sensitivity, and regional sensitivity were assessed at baseline and at yearly follow-up appointments. Regional sensitivity was calculated based on 2 methods. Method 1 involved topographical division into central macula (CM) and paracentral macula (PM). Method 2 involved functional division into the edge of scotoma (ES) and the seeing retina (SR). Linear mixed-effects models were used to assess the annual rate of change for each parameter, adjusted for disease duration. MAIN OUTCOME MEASURES: Annual rate of change of visual acuity, fixation stability, and retinal sensitivities (mean sensitivity and regional sensitivities using methods 1 and 2). RESULTS: In total, 75 eyes of 39 patients (median age, 56 y; males, 57%) with a follow-up period ranging from 1 to 4 years were reviewed. Visual acuity at baseline was positively correlated with all retinal sensitivity parameters, most strongly with CM sensitivity (r = 0.545, P < 0.001). There was no change in visual acuity (P = 0.075) or fixation stability (P = 0.371) per year. All retinal sensitivity parameters had a significant decline per year (P < 0.001), with a decline of 0.4 decibel (dB) for mean sensitivity, 0.6 dB for CM, 0.3 dB for PM, 1.3 dB for ES, and 1.1 dB for SR. Method 2 identified the greatest number of cases, with a significant decline in regional sensitivity. CONCLUSION: MP can detect significant changes in regional sensitivity over a 1-year period in patients with RP, even as visual acuity and fixation remain stable. An individualized approach to analyzing retinal sensitivity derived from MP may offer a useful outcome measure for future clinical trials.

Intravitreous injection of AAV2-sFLT01 in patients with advanced neovascular age-related macular degeneration: a phase 1, open-label trial.

BACKGROUND: Long-term intraocular injections of vascular endothelial growth factor (VEGF)-neutralising proteins can preserve central vision in many patients with neovascular age-related macular degeneration. We tested the safety and tolerability of a single intravitreous injection of an AAV2 vector expressing the VEGF-neutralising protein sFLT01 in patients with advanced neovascular age-related macular degeneration. METHODS: This was a phase 1, open-label, dose-escalating study done at four outpatient retina clinics in the USA. Patients were assigned to each cohort in order of enrolment, with the first three patients being assigned to and completing the first cohort before filling positions in the following treatment groups. Patients aged 50 years or older with neovascular age-related macular degeneration and a baseline best-corrected visual acuity score of 20/100 or less in the study eye were enrolled in four dose-ranging cohorts (cohort 1, 2 × 108 vector genomes (vg); cohort 2, 2 × 109 vg; cohort 3, 6 × 109 vg; and cohort 4, 2 × 1010 vg, n=3 per cohort) and one maximum tolerated dose cohort (cohort 5, 2 × 1010 vg, n=7) and followed up for 52 weeks. The primary objective of the study was to assess the safety and tolerability of a single intravitreous injection of AAV2-sFLT01, through the measurement of eye-related adverse events. This trial is registered with ClinicalTrials.gov, number NCT01024998. FINDINGS: 19 patients with advanced neovascular age-related macular degeneration were enrolled in the study between May 18, 2010, and July 14, 2014. All patients completed the 52-week trial period. Two patients in cohort 4 (2 × 1010 vg) experienced adverse events that were possibly study-drug related: pyrexia and intraocular inflammation that resolved with a topical steroid. Five of ten patients who received 2 × 1010 vg had aqueous humour concentrations of sFLT01 that peaked at 32·7-112·0 ng/mL (mean 73·7 ng/mL, SD 30·5) by week 26 with a slight decrease to a mean of 53·2 ng/mL at week 52 (SD 17·1). At baseline, four of these five patients were negative for anti-AAV2 serum antibodies and the fifth had a very low titre (1:100) of anti-AAV2 antibodies, whereas four of the five non-expressers of sFLT01 had titres of 1:400 or greater. In 11 of 19 patients with intraretinal or subretinal fluid at baseline judged to be reversible, six showed substantial fluid reduction and improvement in vision, whereas five showed no fluid reduction. One patient in cohort 5 showed a large decrease in vision between weeks 26 and 52 that was not thought to be vector-related. INTERPRETATION: Intravitreous injection of AAV2-sFLT01 seemed to be safe and well tolerated at all doses. Additional studies are needed to identify sources of variability in expression and anti-permeability activity, including the potential effect of baseline anti-AAV2 serum antibodies. FUNDING: Sanofi Genzyme, Framingham, MA, USA.

Increased Frequency of Topical Steroids Provides Benefit in Patients With Recalcitrant Postsurgical Macular Edema.

PURPOSE: To compare standard and frequent topical steroids for postsurgical macular edema (ME). DESIGN: Randomized clinical trial. METHODS: Subjects with postsurgical ME stratified into post-cataract surgery ME (PCSME) and post-other surgery ME (POSME) were randomized to ketorolac 4 times a day (qid) + 1% prednisolone acetate (PA) every hour while awake (q1hWA, Group 1) or qid (Group 2). Mean change from baseline best-corrected visual acuity (BCVA) was determined at week 12, after which group 2 subjects with persistent edema were crossed over to PA q1hWA. RESULTS: Twenty-two subjects (13 PCSME and 9 POSME) were randomized to Group 1 and 20 (12 PCSME and 8 POSME) to Group 2. At week 12, change from baseline BCVA (ETDRS letters) in Group 1 vs 2 was +11.6 vs +8.5 (P = .32) and for subgroups was +10.6 vs +7.8 (P = .23) for PCSME and +13.1 vs +9.4 (P = .47) for POSME. Mean change from baseline central subfield thickness (CST, µm) at week 12 in Group 1 vs 2 was -100.8 vs -63.9 (P = .30). Mean change from baseline intraocular pressure was +2.6 vs +1.7 mm Hg (P = .52). Eight subjects in Group 2 with residual ME at week 12 were switched to PA q1hWA and at week 24, the mean changes from week 12 BCVA and CST were +7.0 letters (P = .01) and -108.25 µm (P = .04). CONCLUSIONS: Our data suggest that patients with postsurgical ME should initially be treated with ketorolac and PA qid, but if edema does not resolve after 12 weeks, a switch to ketorolac qid and PA q1hWA may provide benefit.

Pro-permeability Factors in Diabetic Macular Edema; the Diabetic Macular Edema Treated With Ozurdex Trial.

PURPOSE: The Diabetic Macular Edema Treated with Ozurdex (DMEO) Trial measured aqueous pro-permeability factors (PPFs) in diabetic macular edema (DME) patients before and after injection of dexamethasone implant or vascular endothelial growth factor (VEGF)-neutralizing protein and correlated changes in levels with changes in excess foveal thickness (EFT) to identify potential PPFs contributing to DME. DESIGN: Prospective, randomized crossover clinical trial. METHODS: Twenty DME patients randomized to dexamethasone implant or VEGF-neutralizing protein had aqueous taps and spectral-domain optical coherence tomography (SDOCT) at baseline and every 4 weeks for 28 weeks. Aqueous levels of 55 vasoactive proteins were measured with protein array. Crossover at week 16 provided changes in protein levels after each intervention in all 20 patients. RESULTS: After dexamethasone implant there was significant correlation between changes in levels of 13 vasoactive proteins with changes in EFT, including 3 known PPFs: angiopoietin-2 (r = 0.40, P = .001), hepatocyte growth factor (HGF; r = 0.31, P = .02), and endocrine gland-VEGF (EG-VEGF, r = 0.43, P < .001). Reduction of prolactin, insulin-like growth factor binding protein-3, and matrix metalloproteinase-9 correlated with edema reduction after injection of a VEGF-neutralizing protein as well as dexamethasone implant, suggesting their modulation is likely secondary to changes in edema rather than causative. CONCLUSIONS: Correlation of edema reduction with reduction in the PPFs angiopoietin-2, HGF, and EG-VEGF provides potential insight into the multifactorial molecular mechanism by which dexamethasone implants reduce edema and suggest that additional study is needed to investigate the contributions of these 3 factors to chronic DME.

Enhanced Benefit in Diabetic Macular Edema from AKB-9778 Tie2 Activation Combined with Vascular Endothelial Growth Factor Suppression.

PURPOSE: To assess the effect of AKB-9778 alone or in combination with ranibizumab in subjects with diabetic macular edema (DME). DESIGN: A phase IIa, randomized, placebo- and sham injection-controlled, double-masked clinical trial. PARTICIPANTS: Subjects (n = 144) with decreased vision from DME and central subfield thickness (CST) ≥325 µm measured by spectral-domain optical coherence tomography (SD OCT) enrolled at 36 sites. METHODS: Subjects were randomized to (1) AKB-9778 monotherapy: subcutaneous AKB-9778 15 mg twice per day (BID) + monthly sham intraocular injections; (2) combination therapy: subcutaneous AKB-9778 15 mg BID + monthly 0.3 mg ranibizumab; or (3) ranibizumab monotherapy: subcutaneous placebo injections BID + monthly 0.3 mg ranibizumab. Best-corrected visual acuity (BCVA) and CST were measured at baseline and every 4 weeks. MAIN OUTCOME MEASURES: Primary outcome measure was mean change from baseline CST at week 12. Other outcomes included BCVA, safety assessments, and Diabetic Retinopathy Severity Score (DRSS). RESULTS: At week 12, mean change from baseline CST was significantly greater in the combination group (-164.4±24.2 µm) compared with the ranibizumab monotherapy group (-110.4±17.2 µm; P = 0.008) and was 6.2±13.0 µm in the AKB-9778 monotherapy group. Mean CST at week 12 and percentage of eyes with resolved edema was 340.0±11.2 µm and 29.2%, respectively, in the combination group versus 392.1±17.1 µm and 17.0%, respectively, in the ranibizumab monotherapy group. Mean change from baseline BCVA (letters) was 6.3±1.3 in the combination group, 5.7±1.2 in the ranibizumab monotherapy group, and 1.5±1.2 in the AKB-9778 monotherapy group. The percentage of study eyes that gained ≥10 or ≥15 letters was 8.7% and 4.3%, respectively, in the AKB-9778 monotherapy group, 29.8% and 17.0%, respectively, in the ranibizumab monotherapy group, and 35.4% and 20.8%, respectively, in the combination group. Improvements in DRSS in study eyes were similar across groups, and the percentage of qualified fellow eyes with a ≥2-step change was 11.4% in all AKB-9778-treated subjects compared with 4.2% in the ranibizumab monotherapy group. AKB-9778 was well tolerated, with no clear by-treatment differences in adverse events. CONCLUSIONS: Activation of Tie2 by subcutaneous injections of AKB-9778 combined with suppression of vascular endothelial growth factor (VEGF) causes a significantly greater reduction in DME than that seen with suppression of VEGF alone.

Changes in Retinal Nonperfusion Associated with Suppression of Vascular Endothelial Growth Factor in Retinal Vein Occlusion.

PURPOSE: To assess changes in retinal nonperfusion (RNP) in patients with retinal vein occlusion (RVO) treated with ranibizumab. DESIGN: Secondary outcome measure in randomized double-masked controlled clinical trial. PARTICIPANTS: Thirty-nine patients with central RVO (CRVO) and 42 with branch RVO (BRVO). METHODS: Subjects were randomized to 0.5 or 2.0 mg ranibizumab every month for 6 months and then were re-randomized to pro re nata (PRN) groups receiving either ranibizumab plus scatter laser photocoagulation or ranibizumab alone for an additional 30 months. MAIN OUTCOME MEASURES: Comparison of percentage of patients with increased or decreased area of RNP in patients with RVO treated with 0.5 versus 2.0 mg ranibizumab, during monthly injections versus ranibizumab PRN, and in patients treated with ranibizumab PRN versus ranibizumab PRN plus laser. RESULTS: In RVO patients given monthly injections of 0.5 or 2.0 mg ranibizumab for 6 months, there was no significant difference in the percentage who showed reduction or increase in the area of RNP. However, regardless of dose, during the 6-month period of monthly injections, a higher percentage of patients showed a reduction in area of RNP and a lower percentage showed an increase in area of RNP compared with subsequent periods of ranibizumab PRN treatment. After the 6-month period of monthly injections, BRVO patients, but not CRVO patients, randomized to ranibizumab PRN plus laser showed significantly less progression of RNP compared with patients treated with ranibizumab PRN. CONCLUSIONS: Regardless of dose (0.5 or 2.0 mg), monthly ranibizumab injections promote improvement and reduce progression of RNP compared with PRN injections. The addition of scatter photocoagulation to ranibizumab PRN may reduce progression of RNP in patients with BRVO, but a statistically significant reduction was not seen in patients with CRVO.