RP Patients Research Articles

Prevalence Estimates and Genetic Diversity for Autosomal Dominant Retinitis Pigmentosa Due to RHO, c.68C>A (p.P23H) Variant

ObjectiveTo provide the most up-to-date clinical prevalence estimate for autosomal dominant retinitis pigmentosa (adRP) patients due to RHO c.68C>A, (p.P23H) in the United States, supported by two independent approaches; literature based meta-analysis of reported patients and population genetics modeling. DesignSystematic review and meta-analysis plus population genetics modeling. MethodsSystematic review of the literature describing RP patients attributed to RHO variants was conducted to support a meta-analysis used to estimate the clinical prevalence of the RHO P23H patients diagnosed in the US. In parallel, large-scale genetic diversity studies describing the US population and non-European cohorts of the Americas (PAGE II), were evaluated to ascertain the allele frequencies of variant RHO c.68C>A, (p.P23H). The genetic prevalence for variant RHO c.68C>A, (p.P23H) was calculated using Hardy-Weinberg equilibrium. Further demographic data, including age and average age of onset for visual impairment were incorporated into a basic distribution model to estimate clinical prevalence of genetically predisposed persons. ResultsThe estimated clinical prevalence of adRP due to RHO P23H based on literature review was approximately 2000-3000 patients. In comparison the genetic prevalence of persons with RHO c.68C>A, (p.P23H) in the United States was an estimated 6176 (90% CI: 3333-11398) and only half of them are expected to cluster with European genetic ancestry. This variant was found enriched in subgroups of African American or other non-European biogeographic ancestries. Of the estimated 6200 persons carrying this variant in the US, ∼3500 (estimate range: 1900-6500) are expected to show clinical signs of visual impairment as modeled by average age of onset previously reported for patients with this variant. ConclusionsWe utilized two independent approaches to estimate the total number of adRP patients due to RHO c.68C>A, (p.P23H) in the United States; systematic literature review based meta-analysis and population genetics modeling. Both approaches yielded similar, overlapping estimates of adRP patients due to RHO P23H. However, comparison of these estimates provides some indication for a diagnosis gap. Unexpectedly, this variant is present at relatively higher frequency in some predominantly non-European genetic ancestries in the US. While this genetic analysis supports our estimates of clinical prevalence of adRP due to RHO P23H in the United States, it also has implications for diagnosing potential adRP patients due to this variant, raising questions of genotype-phenotype correlation and access to genetic testing.

Predicting Long-Term Clinical Outcomes of Patients With Recurrent Pericarditis

BackgroundRecurrent pericarditis (RP) is a complex condition associated with significant morbidity. Prior studies have evaluated which variables are associated with clinical remission. However, there is currently no established risk-stratification model for predicting outcomes in these patients. ObjectivesWe developed a risk stratification model that can predict long-term outcomes in patients with RP and enable identification of patients with characteristics that portend poor outcomes. MethodsWe retrospectively studied a total of 365 consecutive patients with RP from 2012 to 2019. The primary outcome was clinical remission (CR), defined as cessation of all anti-inflammatory therapy with complete resolution of symptoms. Five machine learning survival models were used to calculate the likelihood of CR within 5 years and stratify patients into high-risk, intermediate-risk, and low-risk groups. ResultsAmong the cohort, the mean age was 46 ± 15 years, and 205 (56%) were women. CR was achieved in 118 (32%) patients. The final model included steroid dependency, total number of recurrences, pericardial late gadolinium enhancement, age, etiology, sex, ejection fraction, and heart rate as the most important parameters. The model predicted the outcome with a C-index of 0.800 on the test set and exhibited a significant ability in stratification of patients into low-risk, intermediate-risk, and high-risk groups (log-rank test; P < 0.0001). ConclusionsWe developed a novel risk-stratification model for predicting CR in RP. Our model can also aid in stratifying patients, with high discriminative ability. The use of an explainable machine learning model can aid physicians in making individualized treatment decision in RP patients.

Clinical and molecular findings in children with retinitis pigmentosa

ABSTRACT Purpose To study the clinical and genetic features of a cohort of RP children. Methods We identified 46 RP patients with pathogenic or likely pathogenic mutations among 96 patients with a clinical diagnosis of retinitis pigmentosa. All of the patients underwent comprehensive clinical examinations and genetic testing. A retrospective study was conducted on 46 children with retinitis pigmentosa. The genetic and clinical characteristics of children with different genotypes were analyzed. Results Among the 46 children, 13 inherited X-linked gene mutations, including 9 RPGR and 4 RP2 mutations. There were 10 cases of autosomal dominant genes and 23 cases of autosomal recessive genes. XLRP accounted for a larger proportion of children, as observed in previous studies on RP. We found that RPGR genes were the most commonly mutated genes in RP children. The most frequently mutated gene was RPGR (9.3%), followed by RP2 (4.2%) and RPE65 (4.2%). Forty-six patients had mutations in 21 different genes, 19 of which were novel mutations. Most children with XLRP have a high degree of myopia, poor vision, and severe clinical symptoms. Frameshift mutations were more common in XLRP, followed by nonsense mutations. The onset of XLRP is relatively serious since childhood. Most children with ADRP have relatively good visual acuity and mild clinical symptoms, and missense mutations are common. The clinical manifestations of ARRP in children are more severe than those of ADRP in children but milder than those of XLRP in children, and missense mutations are common. The manifestations of RPE65 mutations are also severe and appear early. Conclusions Our results revealed that XLRP gene mutations were more common in children than in adults, as observed in previous studies on RP. The proportion of RP children with ADRP is relatively small. The new findings in our study polished the spectrum of novel mutations and the proportions of different genotypes in pediatric patients. The onset of XLRP occurred earlier. The genes with a high incidence in children were all relatively severe gene types of RP. This comprehensive database may provide essential information regarding the initial stage of RP.

Comparative Outcomes of Robotic Versus Open Proctectomy for Rectal Cancer at High Risk of Positive Circumferential Resection Margin.

Concerns persist regarding the effectiveness of robotic proctectomy when compared with open proctectomy for locally advanced rectal cancer with a high risk of circumferential resection margin involvement. Comparison of surrogate cancer outcomes following robotic versus open proctectomy in this subpopulation. Retrospective cohort study. Three academic hospitals (Mayo Clinic Arizona, Florida, and Rochester) through the Mayo Data Explorer platform. Patients at high risk of circumferential resection margin involvement were selected based on the magnetic resonance imaging-based definition from Mercury I and II trials. Rate of pathologic circumferential resection margin involvement (≤1 mm), mesorectal grading, rate of distal margin involvement. Out of 413 patients, 125 (30%) underwent open and 288 (70%) robotic proctectomy. Open proctectomy was significantly associated with a greater proportion of cT4 tumors (39.3% vs. 24.8%, p = 0.021), multivisceral/concomitant resections (40.8% vs. 18.4%, p < 0.001) and less frequent total neoadjuvant therapy use (17.1% vs. 47.1%, p = 0.001). Robotic proctectomy was less commonly associated with pathologic circumferential resection margin involvement (7.3% vs. 17.6%, p = 0.002), including after adjustment for cT stage, neoadjuvant therapy, and multivisceral resection (OR 0.326, 95% CI, 0.157-0.670, p = 0.002). Propensity score-matching on 66 patients per group and related multivariable analysis no longer indicated any reduction of circumferential positive margin rate associated with robotic surgery (p = 0.86 and p = 0.18). Mesorectal grading was comparable (incomplete mesorectum in 6% RP patients vs. 11.8% OP patients, p = 0.327). All cases had negative distal resection margins. Retrospective design. In patients with locally advanced rectal cancer at high risk of circumferential resection margin involvement, robotic proctectomy is an effective approach and could be pursued when technically possible as an alternative to open proctectomy. See Video Abstract.

Clinical value of Tc-99m MDP SPECT/CT bone imaging for early diagnosis of Relapsing Polychondritis: a report of 5 cases

BackgroundRelapsing Polychondritis(RP) is a rare rheumatic immune disease. As with most diseases, if intervention is delayed, the patient’s prognosis is worse. Currently, the diagnostic criteria used in clinical practice do not include CT, PET/CT, SPECT/CT and other new imaging examinations that have developed rapidly in recent years. However, these examinations have some special manifestations for RP, which can help clinicians diagnose RP earlier and distinguish it from other diseases.Case presentationThese five RP patients all had respiratory symptoms such as cough and wheezing as the first symptom, which could not be diagnosed in time according to the previous diagnostic criteria. The clinical data of the five patients are listed in Table 1. The relatively specific manifestations of SPECT/CT examination provided clinicians with very valuable clues to help them advance the diagnosis time.ConclusionsThe application of SPECT/CT bone imaging in early diagnosing RP proves to be effective, enabling clinicians to intervene promptly and enhance the overall well-being and quality of life for individuals affected by this condition.

Abstract 7669: Use of computational pathology to predict biochemical recurrence in prostate cancer (Pca) (Rp) patients following radical prostatectomy: Evaluation in low decipher risk category

Abstract Background: Current tools for predicting prostate cancer biochemical recurrence (BCR) after RP often depend on parameters determined by pathologists, such as tumor grade, which is known to vary between reviewers. Genomic risk classifiers provide useful information but require substantial tissue, are costly, and are not commonly accessible in many medical centers. The study presents an artificial intelligence (AI) model for automated risk assessment of biochemical recurrence (BCR) by analyzing nuclear morphologic patterns from Pca archival H&amp;E slides. Nuclear morphometric features are essential for disease diagnosis and gaining insights into cellular functions. Specifically, we sought to evaluate whether the computational pathology approach could provide additional granular risk stratification within the low-risk group identified by Decipher. Methods: The study employed two cohorts from the University of Pennsylvania D1 and D2. D1 comprised 180 patients, while D2 comprised 175 patients, including 63 individuals from the Decipher low-risk group. None of the patients in either cohort had received any pre-operative treatments. Within the Decipher cohort, a tumor segmentation model was created using the U-net deep learning network. The HoVer-Net model was used to both segment and classify nuclei. The feature extracted included a combination of nuclear texture and quantitative measurements of the spatial arrangement of nuclei. The eleven most significant features, selected via the least absolute shrinkage and selection operator (LASSO), were utilized to build a Cox regression model for predicting the risk of BCR in D1. In D2, patients were classified as either low-risk or high-risk for BCR based on the median risk score derived from D1. Results: Patients from D1 identified as high risk by the AI model experienced shorter survival, with a median BCR time of 27 months, in contrast to 55 months for those classified as low risk. The AI model demonstrated significant prognostic value for BCR in both D1 (HR = 6.82, 95% confidence interval [CI]: 3.54-13.12, p &amp;lt; 0.0019), and D2 (HR = 2.72, 95% CI: 1.53-4.82, p &amp;lt; 0.0032). Furthermore, the model effectively stratified the Decipher low-risk group in D2 into distinct low and high-risk categories (HR = 4.52, 95% confidence interval [CI]: 1.70-12.05, p &amp;lt; 0.0085). The most prognostic features identified included five related to nuclei shape diversity (Minor Axis Length, Eccentricity, Equivalent Diameter, Solidity, and Circularity) in conjunction with nine nuclear texture features. Conclusions: The AI model's findings suggest that a digital image-based prognostic classifier for prostate cancer could serve as an alternative or complementary method to molecular-based companion risk tests. Additional, independent multi-site and prospective validation of these findings are warranted. Citation Format: Kamal Hammouda, Tilak Pathak, Tuomas Mirtti, Priti Lal, Shilpa Gupta, Anant Madabhushi. Use of computational pathology to predict biochemical recurrence in prostate cancer (Pca) (Rp) patients following radical prostatectomy: Evaluation in low decipher risk category [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7669.

Modeling autosomal dominant retinitis pigmentosa by using patient-specific retinal organoids with a class-3 RHO mutation

Rhodopsin-mediated autosomal dominant retinitis pigmentosa (RHO-adRP) causes progressive vision loss and is potentially incurable, accounting for 25% of adRP cases. Studies on RHO-adRP mechanism were at large based on the biochemical and cellular properties, especially class-3. Nonetheless, the absence of an appropriate model for class-3 RHO-adRP has impeded comprehensive exploration. Here, induced pluripotent stem cells (iPSCs) were generated from a healthy control and two sibling RP patients with the same point mutation, c.403C>T (p.R135W). The first three-dimensional (3D) retinal organoid model of a class-3 RHO point mutation from patient-derived iPSCs was generated. Significant defects were observed in rod photoreceptors in terms of localization, morphology, transcriptional profiling and single cell resolution, to better understand the human disease resulting from RHO mutations from a developmental perspective. This first human model of class-3 RHO-adRP provides a representation of patient's retina in vitro and displays features of RHO-adRP retinal organoids relevant for therapeutic development.

Association of extended core sampling with delayed intervention and pathologic outcomes for active surveillance patients A population-based analysis.

Combined systematic plus targeted biopsy sampling improves detection of clinically significant prostate cancer (PCa). Our objective was to evaluate whether extended core sampling at initial biopsy in active surveillance (AS) patients is associated with subsequent AS discontinuation and pathologic outcomes. National Comprehensive Cancer Network (NCCN) low- and favorable-intermediate-risk (FIR) AS patients diagnosed between 2010 and 2015 were identified from the Surveillance, Epidemiology, and End Results (SEER) Prostate with Watchful Waiting database. Prostate biopsy sampling was operationalized as: standard (10-12 cores), extended (13-20 cores), or super-extended (21+ cores). Sensitivity analyses using differing cutoffs was performed. Outcomes included delayed definitive intervention (radical prostatectomy [RP]/radiotherapy) and pathologic upgrading and/or downgrading in delayed RP patients. Multivariable logistic regression modelling adjusted for sociodemographic/oncologic variables was performed. This cohort included 42 459 patients (low-risk: 28 411; FIR:14 048); 25-29% and 3-5% of patients underwent extended and super-extended core sampling, respectively, at diagnosis. Extended core sampling was associated with decreased odds of definitive intervention in low (odds ratio [OR] 0.89, p=0.003) and grade group 2 (GG2) FIR (OR 0.83, p=0.002) patients. Super-extended sampling was associated with decreased odds of definitive intervention in prostate-specific antigen (PSA) 10-20 FIR patients (OR 0.65, p=0.02). Super-extended sampling was associated with decreased odds of upgrading to ≥GG2 disease in low-risk (OR 0.45, p=0.032) and to ≥GG3 disease in GG2 FIR patients (OR 0.67, p=0.044). This population-based analysis demonstrates that extended/super-extended sampling at diagnosis is associated with significantly decreased odds of AS discontinuation and pathologic upgrading in low/FIR AS patients. This highlights the significance of extended tissue sampling at initial biopsy to appropriately risk-stratify AS patients and minimize AS discontinuation rates.

Genetic profile of syndromic retinitis pigmentosa in Portugal

PurposeRetinitis pigmentosa (RP) comprises a genetically and clinically heterogeneous group of inherited retinal degenerations, where 20–30% of patients exhibit extra-ocular manifestations (syndromic RP). Understanding the genetic profile of RP has important implications for disease prognosis and genetic counseling. This study aimed to characterize the genetic profile of syndromic RP in Portugal.MethodsMulticenter, retrospective cohort study. Six Portuguese healthcare providers identified patients with a clinical diagnosis of syndromic RP and available genetic testing results. All patients had been previously subjected to a detailed ophthalmologic examination and clinically oriented genetic testing. Genetic variants were classified according to the American College of Medical Genetics and Genomics; only likely pathogenic or pathogenic variants were considered relevant for disease etiology.ResultsOne hundred and twenty-two patients (53.3% males) from 100 families were included. Usher syndrome was the most frequent diagnosis (62.0%), followed by Bardet-Biedl (19.0%) and Senior-Løken syndromes (7.0%). Deleterious variants were identified in 86/100 families for a diagnostic yield of 86.0% (87.1% for Usher and 94.7% for Bardet-Biedl). A total of 81 genetic variants were identified in 25 different genes, 22 of which are novel. USH2A and MYO7A were responsible for most type II and type I Usher syndrome cases, respectively. BBS1 variants were the cause of Bardet-Biedl syndrome in 52.6% of families. Best-corrected visual acuity (BCVA) records were available at baseline and last visit for 99 patients (198 eyes), with a median follow-up of 62.0 months. The mean BCVA was 56.5 ETDRS letters at baseline (Snellen equivalent ~ 20/80), declining to 44.9 ETDRS letters (Snellen equivalent ~ 20/125) at the last available follow-up (p < 0.001).ConclusionThis is the first multicenter study depicting the genetic profile of syndromic RP in Portugal, thus contributing toward a better understanding of this heterogeneous disease group. Usher and Bardet-Biedl syndromes were found to be the most common types of syndromic RP in this large Portuguese cohort. A high diagnostic yield was obtained, highlighting current genetic testing capabilities in providing a molecular diagnosis to most affected individuals. This has major implications in determining disease-related prognosis and providing targeted genetic counseling for syndromic RP patients in Portugal.

Genotypes and clinical features of RHO-associated retinitis pigmentosa in a Japanese population.

To report the genotypes and clinical features of RHO-associated retinitis pigmentosa (RHO-RP) in the Kyushu region of Japan. Retrospective, single-center study. Sixteen RP patients with pathogenic RHO variants seen at Kyushu University Hospital were investigated. Clinical data including age, best-corrected visual acuity (BCVA) in logarithm of the minimum angle of resolution (logMAR) units, visual field, fundus photography, and optical coherence tomography were retrospectively obtained. Visual outcomes were compared between classical and sector phenotypes and among genetic variants. The mean age at the first visit was 54.0 ± 15.7 years, with a mean follow-up of 7.6 ± 4.0 years. Fourteen patients (87.5%) showed the classical RP phenotype, of whom four were associated with p.[Pro23Leu] and two had p.[Pro347Leu] variants. In addition, two patients with the sector phenotype harbored p.[Ala164Val] variants. Among the classical RHO-RP patients, the mean BCVA decreased from 0.60 to 1.08 logMAR over the follow-up period (7.4 ± 4.1 years) whereas BCVA was preserved at 0.04 logMAR in sector RHO-RP patients (9.0 ± 3.0 years). Genotype-to-phenotype analysis demonstrated that p.[Pro347Leu] was associated with severe vision loss at an earlier age. Macular complications such as epiretinal membrane and cystoid macular edema were observed in 5 classical RHO-RP patients. p.[Pro23Leu], but not p.[Pro23His], was a frequent variant causing RHO-RP in the Kyushu region of Japan. As reported in previous studies, patients with the p.[Pro347Leu] variant showed a more severe phenotype, and variants causing sector RHO-RP were associated with a good prognosis.

Unilateral Macular hole in a patient with Retinitis Pigmentosa treated with cover flap technique with the use of platelet-rich plasma under air tamponade: case report.

The purpose of the study is to show the excellent anatomical result of the inverted flap-assisted technique with PRP under air for retinitis pigmentosa complicated with macular hole. A 32-year-old woman, previously diagnosed with retinitis pigmentosa, was referred to our department complaining of decreased central vision in her LEFT eye for 4 weeks. At the time of presentation, the optical coherence tomography and fundoscopy examination showed the presence of a macular hole of 620 microns in diameter. The closure of the macular hole was observed after the surgical procedure, but endophthalmitis occurred 5 days postoperatively. In our presented case, the cover flap-assisted technique with PRP under air for retinitis pigmentosa complicated with macular hole resulted in excellent anatomical outcomes with unremarkable visual recovery. The physiopathology of full-thickness macular holes in RP patients remains still not fully elucidated. Pars plana vitrectomy with the adjunct of highly concentrated P-PRP have shown successful results.

Clinical Characteristics and Genetic Variants of a Large Cohort of Patients with Retinitis Pigmentosa Using Multimodal Imaging and Next Generation Sequencing

This retrospective study identifies patients with RP at the Inherited Retinal Disease Clinic at the University of Minnesota (UMN)/M Health System who had genetic testing via next generation sequencing. A database was curated to record history and examination, genetic findings, and ocular imaging. Causative pathogenic and likely pathogenic variants were recorded. Disease status was further characterized by ocular coherence tomography (OCT) and fundus autofluorescence (AF). Our study cohort included a total of 199 patients evaluated between 1 May 2015–5 August 2022. The cohort included 151 patients with non-syndromic RP and 48 with syndromic RP. Presenting symptoms included nyctalopia (85.4%) photosensitivity/hemeralopia (60.5%), and decreased color vision (55.8%). On average, 38.9% had visual acuity of worse than 20/80. Ellipsoid zone band width on OCT scan of less than 1500 μm was noted in 73.6%. Ninety-nine percent had fundus autofluorescence (AF) findings of a hypo- or hyper-fluorescent ring within the macula and/or peripheral hypo-AF. Of the 127 subjects who underwent genetic testing, a diagnostic pathogenic and/or likely pathogenic variant was identified in 67 (52.8%) patients—33.3% of syndromic RP and 66.6% of non-syndromic RP patients had a diagnostic gene variant identified. It was found that 23.6% of the cohort had negative genetic testing results or only variants of uncertain significance identified, which were deemed as non-diagnostic. We concluded that patients with RP often present with advanced disease. In our population, next generation sequencing panels identified a genotype consistent with the exam in just over half the patients. Additional work will be needed to identify the underlying genetic etiology for the remainder.

Corneal characteristics in patients with retinitis pigmentosa

BackgroundTo evaluate corneal topography and specular microscopic findings in patients with retinitis pigmentosa. MethodsOne hundred and two eyes of 51 patients with retinitis pigmentosa and 60 eyes of 30 healty subjects were included in our study. A detailed ophthalmological examination involving best corrected visual acuity (BCVA) was performed. A rotating Scheimpflug imaging system, was used to evaluate all eyes for topographic and aberrometrics parameters. Specular microscopy measurements were also noted. ResultsThe retinitis pigmentosa group consisted of 51 patients (29 male and 22 female, mean age of 35.61±13.55 (18–65) years and the control group also consisted of 30 healty subjects (29 male and 22 female, mean age of 33.67±9.92 (20–58) years. There was no difference between the groups in terms of age (p = 0.624) and gender (p = 0.375). Spherical equivalents were higher in the RP group (p<0.001). Central keratoconus index (CKI) (p<0.001), Belin Ambrosio enhanced ectasia display total deviation value (BAD-D) (p = 0.003), index of surface variance (ISV) (p<0.001), index of vertical asymmetry (IVA) (p<0.001), Ambrosio related thickness (ART max) (p = 0.018), index of height asymmetry (IHA) (p = 0.009), index of height decentration (IHD) (p<0.001), maximum anterior elevation (p<0.001), front elevation in thin location (p = 0.05), progression index average (p = 0.015), root mean square (RMS) total (p = 0.010) and RMS-higher order aberration (RMS-HOA) (p<0.001) values were higher in RP group. There was a weak negative correlation between BCVA and ART max measurements (r=-0.256, p = 0.009) in RP group. We detected keratoconus-suspect in 6 eyes and clinically manifest keratoconus in one eye in the RP group. ConclusionsPatients with retinitis pigmentosa may have corneal morphological disorders that may affect vision. In our study, corneal topographic pathologies including keratoconus and possible keratoconus were detected in RP patients.

Edi Mod Spectral Domain Optical Coherence Tomography Evaluation of The Choroid in Retinitis Pigmentosa: A Case-Control Study

Objective: The evaluation of choroidal thickness measurements became possible after the developments in optical coherence tomography (OCT) technology. This study aimed to evaluate choroidal features in Retinitis Pigmentosa subjects with EDI (Enhanced depth imaging) mode spectral domain optical coherence tomography (SD-OCT). Material and Method: A hundred and three eyes of 54 RP subjects underwent scanning with EDI-OCT for central retinal and choroidal thickness measurements and were compared with 40 healthy controls. Submacular choroidal thickness measurements were obtained beneath the fovea and at 500 µm intervals for 2.5 mm nasal and temporal to the center of the fovea. Results: Mean subfoveal choroidal thickness measurements were 253.2±74.9 µm in RP patients and 336.2±91.7 µm in control (p&lt;0.0001). There was no correlation between subfoveal choroidal thickness and visual acuity in RP patients. The choroid had an irregular shape in 85 % of RP patients. The thickest point of the choroid was not subfoveal as in healthy eyes, and excessive nasal thinning of the choroid was observed in 93 % of RP patients. Conclusion: Submacular choroidal thickness was significantly reduced but did not correlate with the visual acuity in RP patients.

Choroidal vascular index in cystoid macular edema associated with retinitis pigmentosa

BackgroundRetinitis pigmentosa (RP) is an inherited degenerative disease characterized by night blindness (nyctalopia), visual field defects, and varying degrees of vision loss. Choroid tissue has an essential role in the pathophysiology of many chorioretinal diseases. The choroidal vascularity index (CVI) is a choroidal parameter obtained as the ratio of the luminal choroidal area to the total choroidal area. The study aimed to compare the CVI of RP patients with and without CME with each other and with healthy individualsAU: Please confirm that the provided email ''ademoztel@hotmail.com" is the correct address for official communication, else provide an alternate e-mail address to replace the existing one.. MethodsA retrospective, comparative study of 76 eyes of 76 RP patients and 60 right eyes of 60 healthy subjects was conducted. The patients were divided into two groups: those with and those without cystoid macular edema (CME). The images were obtained using enhanced depth imaging optical coherence tomography (EDI-OCT). CVI was calculated by using the binarization method with ImageJ software. ResultsThe mean CVI was significantly lower in RP patients compared to the control group (0.61±0.05 and 0.65±0.02, respectively, p<0.01). The mean CVI in RP patients with CME was significantly lower than in those without CME (0.60±0.54 and 0.63±0.35, respectively, p=0.01) The CVI was positively correlated with subfoveal choroidal thickness (r=0.74, p=0.001), central macular thickness (r=0.27, p<0.001) and visual acuity (logMAR) (r=-0.23 p=0.03) in RP patients. ConclusionsThe CVI is lower in RP patients with CME than in patients without CME and in RP patients compared to healthy subjects, indicating an ocular vascular involvement in the pathophysiology of the disease and the pathogenesis of RP-associated cystoid macular edema.

Neuroprotective effects of intraocular bone marrow‐derived mononuclear cell transplants in inherited retinal degenerations

AbstractInherited retinal degenerations are diseases characterized by photoreceptor loss secondary to genetic defects. At present, only a minority are susceptible of genetic treatment and therefore are a frequent cause of blindness in infancy and adulthood.Retinitis Pigmentosa (RP) is the most frequent inherited retinal degeneration. This disease has a prevalence of around 1 in 4000 individuals and is caused by mutations in more than 300 genes. RP is characterized by progressive loss of photoreceptors, rods and then cones that may die secondarily to rod loss.The rats P23H and Royal college of Surgeon (RCS) are two well characterized animal models of RP because they bear genetic defects observed in RP patients. The P23H rat suffers an autosomal dominant mutation of the rhodopsin gene that causes protein misfolding and endoplasmic reticulum stress in rods, which die first followed by cones. The RCS rat has a mutation of MERTK gene, that impedes the normal photoreceptor outer segment phagocytosis by RPE cells thus causing simultaneous rod and cone degeneration.Therapies for inherited photoreceptor degeneration aim to prevent or delay death of the photoreceptors, or in specific circumstances try to replace them.The Bone marrow derived‐mononuclear cells (BM‐MNCs) are a mononuclear CD34+ subpopulation of bone marrow‐derived cells that can be separated from the other cellular fractions of the bone marrow aspirate using a Ficoll density gradient‐based protocol. The BM‐MNCs is a mixture of specific bone marrow cell subtypes in which is possible to find cells: Lin+, Lin−, CD34+, c‐Kit+, CD133+ or Sca‐1+ HSCs, endothelial precursor cells, and Mesenchymal Stem Cells.BM‐MNCs transplantation has shown promising results in different animal models of neuronal degeneration, including inherited photoreceptor degenerations.In our studies we have performed a syngeneic intravitreal or subretinal transplantation of BM‐MNCs in a P23H‐1 and RCS rats, and we have documented that both increase photoreceptor survival. They also improve the morphology of the photoreceptors outer segment, decrease synaptic degeneration in the outer plexiform layer and reduce glial fibrillary acidic protein (GFAP) expression in Müller cells. However, the transplanted cells did not penetrate the retina, only survived for up to 15 days, and did not modify microglial cell activation and migration or the electroretinographic responses. Their beneficial effects are maybe due to a paracrine trophic effect achieved through release of neurotrophic, anti‐angiogenic and/or immunomodulatory factors.In conclusion, the intra ocular transplantation BM‐MNCs shows photoreceptor neuroprotective actions in inherited retinal degenerations. These cells may have the potential to slow down photoreceptor loss, and therefore could be indicated for treatment of the early stages of photoreceptor degenerations.

Progressive accumulation of cytoplasmic aggregates in PRPF31 retinal pigment epithelium cells interferes with cell survival

Progressive accumulation of cytoplasmic aggregates in PRPF31 retinal pigment epithelium cells interferes with cell survival

The medaka mutant deficient in eyes shut homolog exhibits opsin transport defects and enhanced autophagy in retinal photoreceptors.

Eyes shut homolog (EYS) encodes a proteoglycan and the human mutation causes retinitis pigmentosa type 25 (RP25) with progressive retinal degeneration. RP25 most frequently affects autosomal recessive RP patients with many ethnic backgrounds. Although studies using RP models have facilitated the development of therapeutic medications, Eys has been lost in rodent model animals. Here we examined the roles for Eys in the maintenance of photoreceptor structure and function by generating eys-null medaka fish using the CRISPR-Cas9 system. Medaka EYS protein was present near the connecting cilium of wild-type photoreceptors, while it was absent from the eys-/- retina. The mutant larvae exhibited a reduced visual motor response compared with wild-type. In contrast to reported eys-deficient zebrafish at the similar stage, no retinal cell death was detected in the 8-month post-hatching (8-mph) medaka eys mutant. Immunohistochemistry showed a significant reduction in the length of cone outer segments (OSs), retention of OS proteins in the inner segments of photoreceptors, and abnormal filamentous actin network at the base of cone OSs in the mutant retina by 8 mph. Electron microscopy revealed aberrant structure of calyceal processes, numerous vesiculation and lamellar interruptions, and autophagosomes in the eys-mutant cone photoreceptors. In situ hybridization showed an autophagy component gene, gabarap, was ectopically expressed in the eys-null retina. These results suggest eys is required for regeneration of OS, especially of cone photoreceptors, and transport of OS proteins by regulating actin filaments. Enhanced autophagy may delay the progression of retinal degeneration when lacking EYS in the medaka retina.

Modulation of flash ERGs by dynamic backgrounds

PurposeThe aim of this study was to characterize the signal processing mechanisms that lead to an ERG response and to use this characterization for obtaining more robust responses in patients who display feeble responses with standard recordings. We studied the influence of sinusoidally modulating backgrounds on flash ERGs and the relationship between the ERG components’ amplitudes and the momentary Weber fraction of the flash stimulus.MethodsERG recordings were performed in nine healthy subjects and three RP patients. In four normal subjects, we measured the response to flashes (500 cd/m2, 1 ms duration) on a steady background (50 cd/m2) and on a sine wave (50 cd/m2 mean luminance) modulating background at 1, 5, 10, and 25 Hz temporal frequencies. The flashes were delivered at eight different phases (0–315° in a step of 45°) during the modulating background sine wave. The responses to the backgrounds were also recorded and subtracted from the responses to flash plus modulating backgrounds to obtain the flash ERGs at the different phases. The recordings in the remaining five normal subjects and the RP patients were performed with a subset of these stimuli.ResultsThe flash ERGs were strongly modulated by the backgrounds particularly at low frequencies and were enhanced when the momentary Weber fraction was large. The amplitudes of the components could be described by the Weber fraction plus a saturating nonlinearity and a delay in the processing of background luminance. The strength of the modulation decreased with increasing peak time of the component. Furthermore the background luminance delay was positively correlated with the peak time. The effect was also present in RP patients.ConclusionsA sine wave background of about 1 Hz can be used to enhance ERG responses. Weber fraction of the flashes is an adequate quantification of stimulus for describing the amplitudes of the ERGs. The data provide basic information on how background luminance is processed in ERG generating mechanisms. The response enhancement can be used in clinical applications to obtain a more robust comparison between normal and patient data.

Immunological consequences of compromised ocular immune privilege accelerate retinal degeneration in retinitis pigmentosa

BackgroundRetinitis pigmentosa (RP) is a hereditary retinal disease which leads to visual impairment. The onset and progression of RP has physiological consequences that affects the ocular environment. Some of the key non-genetic factors which hasten the retinal degeneration in RP include oxidative stress, hypoxia and ocular inflammation. In this study, we investigated the status of the ocular immune privilege during retinal degeneration and the effect of ocular immune changes on the peripheral immune system in RP. We assessed the peripheral blood mononuclear cell stimulation by retinal antigens and their immune response status in RP patients. Subsequently, we examined alterations in ocular immune privilege machineries which may contribute to ocular inflammation and disease progression in rd1 mouse model.ResultsIn RP patients, we observed a suppressed anti-inflammatory response to self-retinal antigens, thereby indicating a deviated response to self-antigens. The ocular milieu in rd1 mouse model indicated a significant decrease in immune suppressive ligands and cytokine TGF-B1, and higher pro-inflammatory ocular protein levels. Further, blood–retinal-barrier breakdown due to decrease in the expression of tight junction proteins was observed. The retinal breach potentiated pro-inflammatory peripheral immune activation against retinal antigens and caused infiltration of the peripheral immune cells into the ocular tissue.ConclusionsOur studies with RP patients and rd1 mouse model suggest that immunological consequences in RP is a contributing factor in the progression of retinal degeneration. The ocular inflammation in the RP alters the ocular immune privilege mechanisms and peripheral immune response. These aberrations in turn create an auto-reactive immune environment and accelerate retinal degeneration.