A health terminological system for inherited retinal diseases: Content coverage evaluation and a proposed classification.

PURPOSE: To present a classification of inherited retinal diseases (IRDs) and evaluate its content coverage in comparison with common standard terminology systems. METHODS: In this comparative cross-sectional study, a panel of subject matter experts annotated a list of IRDs based on a comprehensive review of the literature. Then, they leveraged clinical terminologies from various reference sets including Unified Medical Language System (UMLS), Online Mendelian Inheritance in Man (OMIM), International Classification of Diseases (ICD-11), Systematized Nomenclature of Medicine (SNOMED-CT) and Orphanet Rare Disease Ontology (ORDO). RESULTS: Initially, we generated a hierarchical classification of 62 IRD diagnosis concepts in six categories. Subsequently, the classification was extended to 164 IRD diagnoses after adding concepts from various standard terminologies. Finally, 158 concepts were selected to be classified into six categories and genetic subtypes of 412 cases were added to the related concepts. UMLS has the greatest content coverage of 90.51% followed respectively by SNOMED-CT (83.54%), ORDO (81.01%), OMIM (60.76%), and ICD-11 (60.13%). There were 53 IRD concepts (33.54%) that were covered by all five investigated systems. However, 2.53% of the IRD concepts in our classification were not covered by any of the standard terminologies. CONCLUSIONS: This comprehensive classification system was established to organize IRD diseases based on phenotypic and genotypic specifications. It could potentially be used for IRD clinical documentation purposes and could also be considered a preliminary step forward to developing a more robust standard ontology for IRDs or updating available standard terminologies. In comparison, the greatest content coverage of our proposed classification was related to the UMLS Metathesaurus.

Choroidal structure investigated by choroidal vascularity index in patients with inherited retinal diseases.

PURPOSE: To evaluate the choroidal structure in patients with inherited retinal diseases (IRDs) by investigating the choroidal vascularity index (CVI). METHODS: The present study was conducted on 113 IRD patients and 113 sex- and age-matched healthy individuals. Patients' data was extracted from the Iranian National Registry for IRDs (IRDReg®). Total choroidal area (TCA) was determined between retinal pigment epithelium and choroid-scleral junction,1500 microns on either side of the fovea. Luminal area (LA) was considered as the black area corresponding to the choroidal vascular spaces, following Niblack binarization. CVI was calculated as the ratio of the LA to the TCA. CVI and other parameters were compared among different types of IRD and the control group. RESULTS: The IRD diagnosis included retinitis pigmentosa (n = 69), cone-rod dystrophy (n = 15), Usher syndrome (n = 15), Leber congenital amaurosis (n = 9), and Stargardt disease (n = 5). Sixty-one (54.0%) individuals of each of the study and control groups were male. The average CVI was 0.65 ± 0.06 in the IRD patients and 0.70 ± 0.06 in the control group (P < 0.001). Accordingly, the average of TCA and LA were 2.32 ± 0.63 and 1.52 ± 0.44 mm [1] in patients with IRDs, respectively. The measurements for the TCA and the LA were significantly lower in all subtypes of IRD (P-values < 0.05). CONCLUSION: CVI is significantly lower in patients with IRD than in healthy age-matched individuals. Choroidal changes in IRDs may be related to the changes in the lumen of the choroidal vessels rather than the stromal changes.

Assessing the validity of a cross-platform retinal image segmentation tool in normal and diseased retina.

Comparing automated retinal layer segmentation using proprietary software (Heidelberg Spectralis HRA + OCT) and cross-platform Optical Coherence Tomography (OCT) segmentation software (Orion). Image segmentations of normal and diseased (iAMD, DME) eyes were performed using both softwares and then compared to the 'gold standard' of manual segmentation. A qualitative assessment and quantitative (layer volume) comparison of segmentations were performed. Segmented images from the two softwares were graded by two masked graders and in cases with difference, a senior retina specialist made a final independent decisive grading. Cross-platform software was significantly better than the proprietary software in the segmentation of NFL and INL layers in Normal eyes. It generated significantly better segmentation only for NFL in iAMD and for INL and OPL layers in DME eyes. In normal eyes, all retinal layer volumes calculated by the two softwares were moderate-strongly correlated except OUTLY. In iAMD eyes, GCIPL, INL, ONL, INLY, TRV layer volumes were moderate-strongly correlated between softwares. In eyes with DME, all layer volume values were moderate-strongly correlated between softwares. Cross-platform software can be used reliably in research settings to study the retinal layers as it compares well against manual segmentation and the commonly used proprietary software for both normal and diseased eyes.

Side Effects of Brolucizumab.

Age-related macular degeneration and its complication, subretinal neovascularization, are common causes of progressive, irreversible impairment of central vision. Anti-vascular endothelial growth factor (anti-VEGF) therapy has improved the visual outcome and provided an evolution in the treatment of retinal disease. The current four anti-VEGF drugs - pegaptanib, ranibizumab, aflibercept, and bevacizumab - have been administered for many years. A new anti-VEGF agent, brolucizumab, was approved by the U.S. Food and Drug Administration (FDA) in late 2019 for the treatment of wet age-related macular degeneration. Brolucizumab is a novel single-chain fragment variable antibody that inhibits all isoforms of VEGF-A and has been suggested to have more tissue penetration. Despite all the benefits, there are some reports of serious side effects that need to be understood in managing patients. Brolucizumab has been reported to cause occlusive retinal vasculitis in the setting of intraocular inflammation, which has not been seen in other anti-VEGF medications. A PubMed and Scopus search was performed and all article types were included. In the present article, we have reviewed the reported side effects of brolucizumab.

CHARACTERIZING THE NATURAL HISTORY OF FOVEAL-SPARING ATROPHIC LATE-ONSET RETINAL DEGENERATION.

PURPOSE: To identify quantifiable markers of disease progression in patients with foveal-sparing atrophic late-onset retinal degeneration using fundus autofluorescence and spectral-domain optical coherence tomography imaging. METHODS: Natural history study evaluating patients within a 3-year interval. Disease progression was assessed based on the area of retinal atrophy, macular topographic distribution of lesions, retinal and choroidal thickness and volume, and choroidal vascularity index. RESULTS: Twenty-four eyes (12 individuals) were included for fundus autofluorescence, and 31 eyes (16 individuals) for spectral-domain optical coherence tomography studies. Measurements were symmetrical between eyes of the same patient. The area of atrophy significantly enlarged (P = 0.002), with a growth rate of 2.67 mm2/year (SD: 2.13; square rooted: 0.57 mm/year, SD = 0.34). Baseline area of atrophy and progression both correlated with age. Most atrophic lesions were found in the temporal macula and progressed nasally at follow-up. Central choroidal and retinal thicknesses and volume in late-onset retinal degeneration cases were significantly reduced compared with controls, but only central retinal thickness decreased significantly at follow-up. CONCLUSION: This study identifies the area of atrophy and central retinal thickness, but not chorioretinal volume or choroidal thickness, as markers of short-term progression in late-onset retinal degeneration. These findings may be useful for disease monitoring and late-onset retinal degeneration interventional studies.

REPLACEMENT OF LIDOCAINE GEL WITH TOPICAL PROPARACAINE ANESTHESIA FOR ROUTINE INTRAVITREAL INJECTIONS: A Comparative Study.

PURPOSE: Lidocaine gel was suggested to be highly effective in providing anesthesia for intravitreal injections but adverse effects include a possibility of making sterilization of the conjunctiva difficult. Hence, we wished to determine the effect of using 0.5% proparacaine drops alone over the use of 3.5% lidocaine hydrochloride gel anesthesia during office-based intravitreal injections. METHODOLOGY: This was a case-control study in patients who came routinely to the clinic for antivascular endothelial growth factor injections. Eyes were treated with one of two anesthesia modalities. A total of 216 injections in 120 patients were reviewed. One group (N = 107) underwent anesthesia with 0.5% proparacaine drops, and the control group (N = 109) received 3.5% lidocaine gel. The pain perceived after injection was graded using the numerical rating scale, and score was immediately recorded by the "masked" injecting physician. RESULTS: The mean pain score (±SD) for the proparacaine-only group versus gel group was 1.97 (±1.17) versus 1.76 (±0.92), P value = 0.3174. There was no statistical difference between the 2 groups. CONCLUSION: 3.5% lidocaine gel is not superior to 0.5% proparacaine drops as patients attained good pain control and excellent rates of overall satisfaction with proparacaine drops alone.

Accuracy of Different Topographic Instruments in Calculating Corneal Power after Myopic Photorefractive Keratectomy.

PURPOSE: To compare the corneal power measurements obtained using different topographic instruments after myopic photorefractive keratectomy (PRK). METHODS: Patients with myopia who were candidates for corneal refractive surgery were sequentially included. Pre-PRK and six months post-PRK corneal powers were measured using Javal manual keratometer, Orbscan II, Galilei, Tomey TMS4, and EyeSys 2000 topographers. Measured values were compared with those obtained using the clinical history method (CHM). RESULTS: This study included 66 eyes of 33 patients. The lowest keratometric measurements were obtained using the Galilei topographer (42.98 ± 1.69 diopters, D) and the highest measurements were obtained using the Javal manual keratometer (43.96 ± 1.54 D) preoperatively. The same order was observed postoperatively. Effective refractive power (EffRP) measured using EyeSys was most similar to the values obtained using CHM (ICC, intraclass correlation coefficient = 0.951), followed by the total corneal power measured using the Galilei system (ICC = 0.943). The values obtained using the adjusted EffRP formula (EffRP - 0.015*Δ Refraction - 0.05) were more consistent with the values obtained using CHM (ICC = 0.954) compared to those obtained with the adjusted average central corneal power formula measured using the Tomey system (ICC = 0.919). CONCLUSION: Post-PRK corneal powers measured using the adjusted EffRP formula were the most similar to values obtained using CHM.

Ocular Safety of Intravitreal Connective Tissue Growth Factor Neutralizing Antibody.

PURPOSE: To detect the safety of intravitreal injection of anti-connective tissue growth factor (CTGF) (IVAC) in rat eyes in order to apply this neutralizing antibody for experimental animal studies. METHODS: Forty-five Lister Hooded male pigmented rats were divided into five groups that received IVAC (2 µl) corresponding to the doses of 10 (B), 20 (C), 50 (D), and 100 µg/ml (E), equal to 1.25, 2.5, 6.25, and 12.5 µg/ml of antibody concentration in rat vitreous, respectively. The sham group (A) received 2 µl of normal saline. Full field electroretinography (ERG) was performed at baseline and on days 7 and 28 after IVAC. The animals were euthanized and the corresponding eyes were subjected to routine histopathology, immunohistochemistry for glial fibrillary acidic protein (GFAP), and terminal transferase dUTP nick end-labeling (TUNEL) assay. RESULTS: Scotopic rod b-wave amplitude and maximal combined b-wave amplitude were 111.89 ± 71.2 and 178.57 ± 55.58 µV, respectively, at baseline which significantly reduced to 79.31 ± 52.59 and 128.73 ± 41.61 µV, respectively, after 28 days in group E (p < 0.05). There was no significant reduction of amplitudes in other groups with lower doses of anti-CTGF antibody. Retinal ganglion cells were significantly decreased in group E as compared to other groups. GFAP immune reactivity was not significant in any of the groups. TUNEL test showed inner retinal neural cell apoptosis only in group E. CONCLUSIONS: ERG, histopathologic, and apoptotic assays revealed no toxic effects of 10-50 µg/ml of IVAC in rat eyes. Using 100 µg/ml IVAC led to a significant toxic effect in terms of functional, histopathologic, and TUNEL findings.

Comparison between Two Scheimpflug Anterior Segment Analyzers.

PURPOSE: To compare the anterior segment indices measured by two Scheimpflug camera machines; Galilei and Pentacam. METHODS: In this observational case series, the anterior segment indices of myopic healthy subjects seeking for refractive surgery were measured by Pentacam and Galilei on the same day. Analyzed parameters were anterior and posterior best fit spheres (BFS), axial curvature, true corneal power, central corneal thickness (CCT), anterior chamber (AC) depth, AC volume, AC angle, and pupil diameter. RESULTS: This study included 176 eyes of 88 participants. Mean radius of the anterior BFS was 7.79 ± 0.34 mm versus 7.75 ± 0.39 mm measured by Pentacam and Galilei, respectively (r = 0.877, P < 0.001). Corresponding values for the mean radius of posterior BFS were 6.42 ± 0.32 and 6.47 ± 0.38 mm, respectively (r = 0.879, P < 0.001). Anterior corneal mean power was 43.8 ± 1.9 diopters (D) with Pentacam and 43.8 ± 2.4 D with Galilei (r = 0.905,P < 0.001). Posterior corneal mean power was measured - 6.3 ± 0.3 and - 6.3 ± 0.4 D using Pentacam and Galilei, respectively (r = 0.873, P < 0.001). True corneal power was 43.9 ± 1.9 D with Pentacam and 43.5 ± 2.3 D with Galilei (r = 0.909, P < 0.001). CCT was 537 ± 44 and 553 ± 51 µm measured by Pentacam and Galilei, respectively (r = 0.796, P < 0.001). AC depth measurements using Pentacam and Galilei were 3.29 ± 0.4 and 3.3 ± 0.38 mm (P < 0.001), respectively; AC volume was 207 ± 50 and 129 ± 39 mm3≥ (P = 0.004), and AC angle was 39.7 ± 9.2 and 54.2 ± 5.2 degrees (P = 0.051), respectively. Average pupil diameter was measured 3.91 ± 1.77 mm by Pentacam and 3.34 ± 0.89 mm by Galilei (P = 0.018). CONCLUSIONS: There was a significant correlation between the Pentacam and Galilei in all measured parameters except AC angle, AC volume, and average pupil diameter.

Corneal profile in primary congenital glaucoma.

PURPOSE: To investigate biomechanical and ultrastructural corneal parameters and ocular biometrics in the affected eyes of patients with unilateral primary congenital glaucoma (PCG) as compared to unaffected fellow eyes and age-matched healthy controls. METHODS: A total of 12 patients with treated unilateral PCG and 10 normal subjects were evaluated. LENSTAR was performed to determine biometric parameters; the ocular response analyser was employed to determine biomechanical properties and slit-scanning confocal microscopy was used for evaluation of corneal ultrastucture. RESULTS: Axial length was significantly higher and mean keratometry in affected eyes was significantly flatter in affected eyes as compared to fellow eyes and normal controls (p < 0.05), and a negative correlation was present between axial length and mean keratometry (p < 0.05). Mean aqueous depth and anterior chamber depth were increased in affected eyes as compared to fellow eyes and normal controls (p < 0.05). There was no significant difference in central corneal thickness (CCT) among affected eyes, fellow eyes and normal controls. Corneal hysteresis (CH) was significantly reduced in affected eyes (p < 0.05) and corneal resistance factor (CRF) was also reduced in the affected eyes as compared to fellow eyes and normal controls, although not statistically significant. Mean endothelial cell density was reduced in the affected eyes compared to fellow eyes and normal controls (p < 0.05). CONCLUSION: Corneal biometrics, biomechanical parameters and ultrastructural features are altered in eyes affected with PCG despite clinically normal and clear corneas. These findings should be considered in the preoperative assessment of intraocular or corneal surgery in these patients.

Intravitreal bevacizumab role in the treatment of macular edema secondary to retinal vasoproliferative tumor in a patient with neurofibromatosis type 1.

Objective: To report a case of neurofibromatosis-1 (NF-1) with retinal vasoproliferative tumor (RVPT) and macular edema and exudation that was successfully treated with intravitreal bevacizumab (IVB). Method: A retrospective case report of patient with neurofibromatosis, retinal vasoproliferative tumor and macular edema who received three monthly intravitreal injections of bevacizumab. Optical coherence tomography (OCT) and fluorescein angiography (FAG) before and three months after treatment were done. Results: Macular edema and exudation of the right eye was effectively resolved with IVB injection and vascularity of RVPT significantly decreased after treatment with IVB. Conclusion: Macular edema and exudation secondary to RVPT in patients with NF-1 could be successfully treated with IVB.

Trends in Indications and Techniques of Corneal Transplantation in Iran from 2006 to 2013; an 8-year Review.

PURPOSE: To report changing trends in indications and techniques of corneal transplantation in Iran. METHODS: We reviewed eye bank records of 47,129 patients who had undergone corneal transplantation between 2006 and 2013 at different eye centers throughout Iran. RESULTS: The most common indication for corneal transplantation was keratoconus (KCN, n = 21,350 eyes, 45.3%), followed by bullous keratopathy (BK, n = 8,566 eyes, 18.2%), corneal opacity and scar (COS, n = 7,158 eyes, 15.2%), graft failure (n = 3,252 eyes, 6.9%), corneal dystrophies (n = 2,553 eyes, 5.4%), and infectious keratitis (n = 2,238 eyes, 4.7%). Over the study period, there was a significant increase in the frequency of BK (P = 0.001) and graft failure (P = 0.025), and a significant decrease in the relative frequency of COS (P = 0.012). The prevalence of KCN (P = 0.172), infectious keratitis (P = 0.107), and corneal dystrophies (P = 0.836) remained unchanged. The most common technique of corneal transplantation was penetrating keratoplasty (PKP, n = 33,476 eyes, 71.0%), followed by deep anterior lamellar keratoplasty (DALK, n = 8,363 eyes, 17.7%), Descemet's stripping automated endothelial keratoplasty (DSAEK, n = 3,516 eyes, 7.5%), tectonic (n = 1752, 3.7%), and keratolimbal allograft (KLAL, n = 19 eyes, 0.1%). Regarding the shift in surgical techniques, a significant increase was observed in DSAEK (P < 0.001), whereas PKP was significantly decreased (P = 0.005) over the 8-year period. No significant change was seen in the rates of DALK (P = 0.354), tectonic graft (P > 0.999) and KLAL (P = 0.151). CONCLUSION: KCN was the most common indication and PKP was the most prevalent technique used for corneal transplantation. Significant changes in surgical techniques were observed over the past 8 years; DSAEK demonstrated an increasing trend while PKP showed a decrease.

Role of ventral hippocampal NMDA receptors in anxiolytic-like effect of morphine.

The possible role of ventral hippocampal N-methyl-d-aspartate (NMDA) receptors on morphine-induced anxiolytic-like behavior in an elevated plus maze (EPM) task was investigated in the present study. Adult male mice (7 per group) with cannulas aimed at the ventral hippocampus (VH) received NMDA or a competitive NMDA receptor antagonist D-AP5 with or without morphine and 30min later were subjected to an EPM task. Intraperitoneal injection (i.p.) of morphine (3-9mg/kg) increased the percentage of open arm time (%OAT) and open arm entries (%OAE), which suggested an anxiolytic-like effect. Intra-VH microinjection of NMDA (0.5-1µg/mouse) with an ineffective dose of morphine (3mg/kg, i.p.) significantly increased %OAT and %OAE. However, microinjections of the same doses of NMDA into the VH in the absence of morphine had no effect on %OAT and %OAE. Intra-VH microinjection of D-AP5 (0.5-2µg/mouse) decreased the anxiolytic-like effect of morphine, while intra-VH microinjection of the same doses of D-AP5 alone increased %OAT and %OAE, which indicated an anxiolytic response. Furthermore, intra-VH microinjection of D-AP5 reversed the effect of NMDA response to the administration of a lower morphine dose as seen in the EPM task. It should be noted that intra-VH microinjection of D-AP5 plus NMDA, 5min before morphine increased locomotor activity, while other treatments had no effect on this parameter. The results suggest that VH-NMDA receptors participate in the mediation of morphine-induced anxiolytic-like behavior.

Dorsal hippocampal dopamine receptors are involved in mediating ethanol state-dependent memory.

In the present study, the effects of bilateral injections of dopaminergic agents into the hippocampal CA1 regions (intra-CA1) on ethanol (EtOH) state-dependent memory were examined in mice. A single-trial step-down passive avoidance task was used for the assessment of memory retention in adult male NMRI mice. Pre-training intra-peritoneal (i.p.) administration of EtOH (0.25, 0.5 and 1 g/kg) dose dependently induced impairment of memory retention. Pre-test administration of EtOH (0.5 g/kg)-induced state-dependent retrieval of the memory acquired under pre-training EtOH (0.5 g/kg) influence. Intra-CA1 administration of the dopamine D(1) receptor agonist, SKF 38393 (0.5, 1 and 2 g/mouse) or the dopamine D(2) receptor agonist, quinpirole (0.25, 0.5 and 1 microg/mouse) alone cannot affect memory retention. While, pre-test intra-CA1 injection of SKF 38393 (2 microg/mouse, intra-CA1) or quinpirole (0.25, 0.5 and 1 microg/mouse, intra-CA1) improved pre-training EtOH (0.5 g/kg)-induced retrieval impairment. Moreover, pre-test administration of SKF 38393 (0.5, 1 and 2 microg/mouse, intra-CA1) or quinpirole (0.5 and 1 microg/mouse, intra-CA1) with an ineffective dose of EtOH (0.25 g/kg) significantly restored the retrieval and induced EtOH state-dependent memory. Furthermore, pre-training injection of the dopamine D(1) receptor antagonist, SCH 23390 (4 microg/mouse), but not the dopamine D(2) receptor antagonist, sulpiride, into the CA1 regions suppressed the learning of a single-trial passive avoidance task. Pre-test intra-CA1 injection of SCH 23390 (2 and 4 microg/mouse, intra-CA1) or sulpiride (2.5 and 5 microg/mouse, intra-CA1) 5 min before the administration of EtOH (0.5 g/kg, i.p.) dose dependently inhibited EtOH state-dependent memory. These findings implicate the involvement of a dorsal hippocampal dopaminergic mechanism in EtOH state-dependent memory and also it can be concluded that there may be a cross-state dependency between EtOH and dopamine.