Clinical, Genetic and Histopathological Characteristics of CRX-associated Retinal Dystrophies.

PURPOSE: To describe phenotypic, genotypic, and histopathological features of inherited retinal dystrophies associated with the CRX gene (CRX-RDs). DESIGN: Retrospective multicenter cohort study including histopathology. SUBJECTS: Thirty-nine patients from 31 families with pathogenic variants in the CRX gene. METHODS: Clinical data of 152 visits were collected from medical records with a median follow-up time of 9.1 years (IQR, 3.3-15.3 years; range, 0.0-48.8 years). Histopathologic examination of the eye of a 17-year-old patient with advanced early-onset CRX-RD was performed. MAIN OUTCOME MEASURES: Visual acuity, retinal imaging, electroretinography (ERG), genotype-phenotype correlation, and histopathological examination were evaluated. RESULTS: The age at onset ranged from birth to the 8th decade of life. Median visual acuity was 1.00 logMAR (IQR, 0.69-1.48 logMAR; range, 0.06-3.00 logMAR) at a mean age of 52.0 ± 19.9 years (range, 4.6-81.9 years). Sufficient imaging was available for 36 out of 39 patients (92.3%), and all showed degeneration of at least the macula. Out of these 36 patients, 22 (61.1%) had only macular dystrophy. Another 10 patients (27.8%) had additional degeneration beyond the vascular arcades, and 4 patients (11.1%) panretinal degeneration. Two patients (5.1%) had Leber congenital amaurosis (LCA). In total, 21 different disease-associated heterozygous CRX variants were identified (10 missense, 8 frameshift, 2 deletion, 1 deletion-insertion variants). Missense variants in the CRX homeodomain and two variants deleting all functional domains, thus causing haploinsufficiency, generally tended to cause milder late-onset phenotypes. Histopathologic examination of the eye of a 17-year-old patient with advanced early-onset retinal dystrophy due to a heterozygous deletion of exons 3 and 4 of the CRX gene revealed loss of laminar integrity and widespread photoreceptor degeneration especially in the central retina, with extensive loss of photoreceptor nuclei and outer segments. CONCLUSION: This study illustrates the large clinical and genetic heterogenic spectrum of CRX-RDs, ranging from LCA to mild late-onset maculopathy resembling occult macular dystrophy. Haploinsufficiency and missense variants tended to be associated with milder phenotypes. Patients showed degeneration predominantly affecting the central retina on imaging. The histopathological findings also mirror these clinical findings and features similar to previously reported animal models of CRX-RDs.

Pachychoroid disease: review and update.

The pachychoroid disease spectrum is a phenotype characterized by alterations in choroidal vasculature which result in outer retinal and choriocapillaris damage and visual loss. The presence of pachyvessels is one of the key features of the pachychoroid phenotype. Recent imaging studies suggest that pachyvessels may form because of choroidal venous congestion in one or more quadrants. The formation of intervortex anastomosis may function as a compensatory mechanism to dissipate the increased venous pressure, while outflow obstruction has been hypothesized to occur at the site of the vortex vein exiting the sclera. This review aims to summarize recent imaging findings and discuss evolution in the understanding of pathogenesis of the pachychoroid disease spectrum. We have summarized notable treatment trials in central serous chorioretinopathy and polypoidal choroidal vasculopathy and included an update of the current diagnostic and management strategies of the entities that are part of the pachychoroid disease spectrum.

Differential Expression of Sex-Steroid Receptors in the Choroid Aligns With Central Serous Chorioretinopathy Sex Prevalence Across Different Ages.

Purpose: The purpose of this study was to investigate the presence of sex-steroid receptors in human choroidal tissue across different ages and sex, aiming to better understand the pronounced sex difference in central serous chorioretinopathy (CSC) occurrence. Methods: Paraffin-embedded enucleated eyes of 14 premenopausal women, 15 postmenopausal women, 10 young men (<45 years), and 10 older men (>60 years) were used. A clinically certified immunostaining was performed to detect the presence of the androgen receptor (AR), progesterone receptor (PR; isoform A and B), and estrogen receptor (ERα). The stained slides were scored in a blinded manner for positive endothelial cells and stromal cells in consecutive sections of the same choroidal region. Results: Our analysis revealed the presence of AR, PR, and ERα in endothelial cells and stromal cells of choroidal tissue. The mean proportion of AR-positive endothelial cells was higher in young men (46% ± 0.15) compared to aged-matched women (29% ± 0.12; P < 0.05, 95% confidence interval [CI]). Premenopausal women showed markedly lower mean proportion of ERα (5% ± 0.02) and PR-positive endothelial cells (2% ± 0.01) compared to postmenopausal women (15% ± 0.07 and 19% ± 0.13; both P < 0.05, 95% CI), young men (13% ± 0.04 and 21% ± 0.10; both P < 0.05, 95% CI), and older men (18% ± 0.09 and 27% ± 0.14; both P < 0.05, 95% CI). Mean PR-positive stromal cells were also less present in premenopausal women (12% ± 0.07) than in other groups. Conclusions: The number of sex-steroid receptors in the choroidal tissue differs between men and women across different ages, which aligns with the prevalence patterns of CSC in men and postmenopausal women.

Genetic Testing of Patients with Inherited Retinal Diseases in the European Countries. An International Survey by the European Vision Institute.

INTRODUCTION: The purpose of this project was to explore the current standards of clinical care genetic testing and counseling for patients with inherited retinal diseases (IRDs) from the perspective of leading experts in selected European countries. Also, to gather opinions on current bottlenecks and future solutions to improve patient care. METHODS: On the initiative of the European Vision Institute, a survey questionnaire with 41 questions was designed and sent to experts in the field from ten European countries. Each participant was asked to answer with reference to the situation in their own country. RESULTS: Sixteen questionnaires were collected by November 2023. IRD genetic tests are performed in clinical care settings for 80% or more of tested patients in 9 countries, and the costs of genetic tests in clinical care are covered by the public health service to the extent of 90% or more in 8 countries. The median proportion of patients who are genetically tested, the median rate of genetically solved patients among those who are tested, and the median proportion of patients receiving counseling are 51-70%, 61-80% and 61-80%, respectively. Improving the education of healthcare professionals who facilitate patient referrals to specialised centres, improving access of patients to more thorough genotyping, and increasing the number of available counselors were the most advocated solutions. CONCLUSION: There is a significant proportion of IRD patients who are not genetically tested, whose genetic testing is inconclusive, or who do not receive counseling. Educational programs, greater availability of state-of-the-art genotyping and genetic counselors could improve healthcare for IRD patients.

A cohort study of 19 patients with gyrate atrophy of the choroid and retina (GACR).

PURPOSE: Gyrate atrophy of the choroid and retina (GACR) is an autosomal recessive inherited metabolic disorder (IMD) characterised by progressive retinal degeneration, leading to severe visual impairment. The rapid developments in ophthalmic genetic therapies warrant knowledge on clinical phenotype of eligible diseases such as GACR to define future therapeutic parameters in clinical trials. METHODS: Retrospective chart analysis was performed in nineteen patients. Data were analysed using IBM SPSS Statistics version 28.0.1.1. RESULTS: Nineteen patients were included with a mean age of 32.6 years (range 8-58). Mean age at onset of ophthalmic symptoms was 7.9 years (range 3-16). Median logMAR of visual acuity at inclusion was 0.26 (range -0.18-3.00). Mean age at cataract surgery was 28.8 years (n = 11 patients). Mean spherical equivalent of the refractive error was -8.96 (range -20.87 to -2.25). Cystoid maculopathy was present in 68% of patients, with a loss of integrity of the foveal ellipsoid zone (EZ) in 24/38 eyes. Of the 14 patients treated with dietary protein restriction, the four patients who started the diet before age 10 showed most benefit. CONCLUSION: This study demonstrates the severe ophthalmic disease course associated with GACR, as well as possible benefit of early dietary treatment. In addition to visual loss, patients experience severe myopia, early-onset cataract, and CME. There is a loss of foveal EZ integrity at a young age, emphasising the need for early diagnosis enabling current and future therapeutic interventions.

Analysis of optical coherence tomography biomarker probability detection in central serous chorioretinopathy by using an artificial intelligence-based biomarker detector.

AIM: To adopt a novel artificial intelligence (AI) optical coherence tomography (OCT)-based program to identify the presence of biomarkers associated with central serous chorioretinopathy (CSC) and whether these can differentiate between acute and chronic central serous chorioretinopathy (aCSC and cCSC). METHODS: Multicenter, observational study with a retrospective design enrolling treatment-naïve patients with aCSC and cCSC. The diagnosis of aCSC and cCSC was established with multimodal imaging and for the current study subsequent follow-up visits were also considered. Baseline OCTs were analyzed by an AI-based platform (Discovery® OCT Fluid and Biomarker Detector, RetinAI AG, Switzerland). This software allows to detect several different biomarkers in each single OCT scan, including subretinal fluid (SRF), intraretinal fluid (IRF), hyperreflective foci (HF) and flat irregular pigment epithelium detachment (FIPED). The presence of SRF was considered as a necessary inclusion criterion for performing biomarker analysis and OCT slabs without SRF presence were excluded from the analysis. RESULTS: Overall, 160 eyes of 144 patients with CSC were enrolled, out of which 100 (62.5%) eyes were diagnosed with cCSC and 60 eyes (34.5%) with aCSC. In the OCT slabs showing presence of SRF the presence of biomarkers was found to be clinically relevant (> 50%) for HF and FIPED in aCSC and cCSC. HF had an average percentage of 81% (± 20) in the cCSC group and 81% (± 15) in the aCSC group (p = 0.4295) and FIPED had a mean percentage of 88% (± 18) in cCSC vs. 89% (± 15) in the aCSC (p = 0.3197). CONCLUSION: We demonstrate that HF and FIPED are OCT biomarkers positively associated with CSC when present at baseline. While both HF and FIPED biomarkers could aid in CSC diagnosis, they could not distinguish between aCSC and cCSC at the first visit. AI-assisted biomarker detection shows promise for reducing invasive imaging needs, but further validation through longitudinal studies is needed.

Mitochondrial retinopathies and optic neuropathies: The impact of retinal imaging on modern understanding of pathogenesis, diagnosis, and management.

Advancements in ocular imaging have significantly broadened our comprehension of mitochondrial retinopathies and optic neuropathies by examining the structural and pathological aspects of the retina and optic nerve in these conditions. This article aims to review the prominent imaging characteristics associated with mitochondrial retinopathies and optic neuropathies, aiming to deepen our insight into their pathogenesis and clinical features. Preceding this exploration, the article provides a detailed overview of the crucial genetic and clinical features, which is essential for the proper interpretation of in vivo imaging. More importantly, we will provide a critical analysis on how these imaging modalities could serve as biomarkers for characterization and monitoring, as well as in guiding treatment decisions. However, these imaging methods have limitations, which will be discussed along with potential strategies to mitigate them. Lastly, the article will emphasize the potential advantages and future integration of imaging techniques in evaluating patients with mitochondrial eye disorders, considering the prospects of emerging gene therapies.

Rare genetic variation in VE-PTP is associated with central serous chorioretinopathy, venous dysfunction and glaucoma.

Central serous chorioretinopathy (CSC) is a fluid maculopathy whose etiology is not well understood. Abnormal choroidal veins in CSC patients have been shown to have similarities with varicose veins. To identify potential mechanisms, we analyzed genotype data from 1,477 CSC patients and 455,449 controls in FinnGen. We identified an association for a low-frequency (AF=0.5%) missense variant (rs113791087) in the gene encoding vascular endothelial protein tyrosine phosphatase (VE-PTP) (OR=2.85, P=4.5×10-9). This was confirmed in a meta-analysis of 2,452 CSC patients and 865,767 controls from 4 studies (OR=3.06, P=7.4×10-15). Rs113791087 was associated with a 56% higher prevalence of retinal abnormalities (35.3% vs 22.6%, P=8.0×10-4) in 708 UK Biobank participants and, surprisingly, with varicose veins (OR=1.31, P=2.3×10-11) and glaucoma (OR=0.82, P=6.9×10-9). Predicted loss-of-function variants in VEPTP, though rare in number, were associated with CSC in All of Us (OR=17.10, P=0.018). These findings highlight the significance of VE-PTP in diverse ocular and systemic vascular diseases.

Perspectives and Update on the Global Shortage of Verteporfin (Visudyne®).

An ongoing global shortage of verteporfin (Visudyne®) limits the treatment possibilities for several chorioretinal diseases, including central serous chorioretinopathy, choroidal hemangioma, and polypoidal choroidal vasculopathy. Verteporfin is required to perform photodynamic therapy in these ocular diseases. Therefore, the current situation has a substantial impact on eye care worldwide. The worldwide supply of verteporfin appears to be manufactured by a single factory, which is situated in the United States. The distribution of verteporfin is done by different companies for different regions of the world. Official communication on the shortage by the responsible companies has been scarce and over the past years several promises with regards to resolution of the shortage have not been fulfilled. The delivery of new batches of verteporfin is at irregular intervals, unpredictable, and may not be fairly balanced between different regions or countries in the world. To ensure a fair distribution of available verteporfin within a country, several measures can be taken. In the Netherlands, a national committee, consisting of ophthalmologists, is in place to arrange this. On the European level, the European Union and European Medicine Agency have plans to monitor medicine shortages more closely and to intervene if necessary. With a more intensified monitoring and regulation of medicine supplies, future impending shortages may be prevented. Remarkably, the amount of medicine shortages is increasing, having a significant and sometimes irreversible impact on patient care. Thus, efforts should be undertaken to minimize the consequences and, whenever possible, to prevent future medicine shortages.

Retinal Dystrophies Associated With Peripherin-2: Genetic Spectrum and Novel Clinical Observations in 241 Patients.

Purpose: To describe the clinical, electrophysiological and genetic spectrum of inherited retinal diseases associated with variants in the PRPH2 gene. Methods: A total of 241 patients from 168 families across 15 sites in 9 countries with pathogenic or likely pathogenic variants in PRPH2 were included. Records were reviewed for age at symptom onset, visual acuity, full-field ERG, fundus colour photography, fundus autofluorescence (FAF), and SD-OCT. Images were graded into six phenotypes. Statistical analyses were performed to determine genotype-phenotype correlations. Results: The median age at symptom onset was 40 years (range, 4-78 years). FAF phenotypes included normal (5%), butterfly pattern dystrophy, or vitelliform macular dystrophy (11%), central areolar choroidal dystrophy (28%), pseudo-Stargardt pattern dystrophy (41%), and retinitis pigmentosa (25%). Symptom onset was earlier in retinitis pigmentosa as compared with pseudo-Stargardt pattern dystrophy (34 vs 44 years; P = 0.004). The median visual acuity was 0.18 logMAR (interquartile range, 0-0.54 logMAR) and 0.18 logMAR (interquartile range 0-0.42 logMAR) in the right and left eyes, respectively. ERG showed a significantly reduced amplitude across all components (P < 0.001) and a peak time delay in the light-adapted 30-Hz flicker and single-flash b-wave (P < 0.001). Twenty-two variants were novel. The central areolar choroidal dystrophy phenotype was associated with 13 missense variants. The remaining variants showed marked phenotypic variability. Conclusions: We described six distinct FAF phenotypes associated with variants in the PRPH2 gene. One FAF phenotype may have multiple ERG phenotypes, demonstrating a discordance between structure and function. Given the vast spectrum of PRPH2 disease our findings are useful for future clinical trials.

Leber's hereditary optic neuropathy like disease in MT-ATP6 variant m.8969G>A.

Purpose: To describe a case with Leber's hereditary optic neuropathy (LHON) like optic atrophy in the presence of MT-ATP6 gene variant m.8969G > A. Observations: A 20-year-old patient with a history of mild developmental delay, mild cognitive impairment, and positional tremor presented with subacute painless visual loss over a few weeks. Mitochondrial genome sequencing revealed a variant in MT-ATP6, m.8969G > A (p.Ser148Asn). This variant was previously reported in association with mitochondrial myopathy, lactic acidosis, and sideroblastic anemia (MLASA) and with nephropathy, followed by brain atrophy, muscle weakness and arrhythmias, but not with optic atrophy. Conclusions and importance: Rare variants in MT-ATP6 can also cause LHON like optic atrophy. It is important to perform further genetic analysis of mitochondrial DNA in genetically unsolved cases suspected of Leber's hereditary optic neuropathy to confirm the clinical diagnosis.

Utilization of automated cilia analysis to characterize novel INPP5E variants in patients with non-syndromic retinitis pigmentosa.

INPP5E encodes inositol polyphosphate-5-phosphatase E, an enzyme involved in regulating the phosphatidylinositol (PIP) makeup of the primary cilium membrane. Pathogenic variants in INPP5E hence cause a variety of ciliopathies: genetic disorders caused by dysfunctional cilia. While the majority of these disorders are syndromic, such as the neuronal ciliopathy Joubert syndrome, in some cases patients will present with an isolated phenotype-most commonly non-syndromic retinitis pigmentosa (RP). Here, we report two novel variants in INPP5E identified in two patients with non-syndromic RP: patient 1 with compound heterozygous variants (c.1516C > T, p.(Q506*), and c.847G > A, p.(A283T)) and patient 2 with a homozygous variant (c.1073C > T, p.(P358L)). To determine whether these variants were causative for the phenotype in the patients, automated ciliary phenotyping of patient-derived dermal fibroblasts was performed for percent ciliation, cilium length, retrograde IFT trafficking, and INPP5E localization. In both patients, a decrease in ciliary length and loss of INPP5E localization in the primary cilia were seen. With these molecular findings, we can confirm functionally that the novel variants in INPP5E are causative for the RP phenotypes seen in both patients. Additionally, this study demonstrates the usefulness of utilizing ciliary phenotyping as an assistant in ciliopathy diagnosis and phenotyping.

Mutations in NSUN3, a Mitochondrial Methyl Transferase Gene, Cause Inherited Optic Neuropathy.

Inherited optic neuropathies (IONs) are rare genetic diseases characterized by progressive visual loss due the atrophy of optic nerves. The standard diagnostic workup involving next-generation sequencing panels has a diagnostic yield of about forty percent. In the other 60% of the patients with a clinical diagnosis of ION, the underlying genetic variants remain unknown. In this case study, we describe a potentially new disease-associated gene, NSUN3, for IONs. The proband was a young woman with consanguineous parents. She presented with bilateral optic atrophy and nystagmus at the age of seven years. Genetic testing revealed the homozygous variant c.349_352dup p.(Ala118Glufs*45) in NSUN3, with a segregation in the family compatible with autosomal recessive inheritance. Additional functional analysis showed decreased NSUN3 mRNA levels, slightly diminished mitochondrial complex IV levels, and decreased cell respiration rates in patient fibroblasts compared to healthy controls. In conclusion, pathogenic variants in NSUN3 can cause optic neuropathy. Trio whole-exome sequencing should be considered as a diagnostic strategy in ION cases where standard diagnostic analysis does not reveal disease-causing variants.

Systematic study of ophthalmological findings in 10 patients with PEX1-mediated Zellweger spectrum disorder.

PURPOSE: This cross-sectional study describes the ophthalmological and general phenotype of 10 patients from six different families with a comparatively mild form of Zellweger spectrum disorder (ZSD), a rare peroxisomal disorder. METHODS: Ophthalmological assessment included best-corrected visual acuity (BCVA), perimetry, microperimetry, ophthalmoscopy, fundus photography, spectral-domain optical coherence tomography (SD-OCT), and fundus autofluorescence (FAF) imaging. Medical records were reviewed for medical history and systemic manifestations of ZSD. RESULTS: Nine patients were homozygous for c.2528 G > A (p.Gly843Asp) variants in PEX1 and one patient was compound heterozygous for c.2528 G>A (p.Gly843Asp) and c.2097_2098insT (p.Ile700TyrfsTer42) in PEX1. Median age was 22.6 years (interquartile range (IQR): 15.9 - 29.9 years) at the most recent examination, with a median symptom duration of 22.1 years. Symptom onset was variable with presentations of hearing loss (n = 7) or nyctalopia/reduced visual acuity (n = 3) at a median age of 6 months (IQR: 1.9-8.3 months). BCVA (median of 0.8 logMAR; IQR: 0.6-0.9 logMAR) remained stable over 10.8 years and all patients were hyperopic. Fundus examination revealed a variable retinitis pigmentosa (RP)-like phenotype with rounded hyperpigmentations as most prominent feature in six out of nine patients. Electroretinography, visual field measurements, and microperimetry further established the RP-like phenotype. Multimodal imaging revealed significant intraretinal fluid cavities on SD-OCT and a remarkable pattern of hyperautofluorescent abnormalities on FAF in all patients. CONCLUSION: This study highlights the ophthalmological phenotype resembling RP with moderate to severe visual impairment in patients with mild ZSD. These findings can aid ophthalmologists in diagnosing, counselling, and managing patients with mild ZSD.

Choroidal hyperpermeability patterns correlate with disease severity in central serous chorioretinopathy: CERTAIN study report 2.

PURPOSE: Choroidal vascular hyperpermeability (CVH) on indocyanine green angiography (ICGA) is a hallmark feature of central serous chorioretinopathy (CSC). We identified three distinct CVH phenotypes in CSC: uni-focal indistinct signs of choroidal hyperpermeability (uni-FISH) with one focal area of CVH, multiple areas of focal CVH (multi-FISH), and diffuse hyperpermeability covering most of the posterior pole (DISH). This report investigates the distribution of these phenotypes and their association with signs of disease chronicity. METHODS: The CERTAIN study is a monocentric, retrospective study on consecutive CSC patients referred to a large tertiary referral centre that underwent ultra-widefield (UWF) and 55° ICGA. Two independent graders assessed CVH patterns based on mid- to late-phase UWF and 55° ICGA with a third grader acting as referee. RESULTS: Of the 167 eyes of 91 patients included in this study, 43 (26%) showed uni-FISH, 87 (52%) multi-FISH, and 34 (20%) showed DISH based on UWF ICGA. Median age (40 vs. 45 vs. 57; p < 0.001) and logMAR visual acuity (0 vs. 0 vs. 0.1, p < 0.001) differed significantly in-between groups, as did the occurrence of cystoid retinal degeneration (PCRD; 0% vs. 1% vs. 18%, p < 0.001) or diffuse atrophic RPE alterations (DARA; 0% vs. 17% vs. 29%, p < 0.001). The same was true when grading was based on 55° ICGA. CONCLUSIONS: The CVH patterns of uni-FISH, multi-FISH, and DISH are typical of CSC. These patterns correlate with established signs of CSC chronicity. Their predictive role in treatment response and prognosis remains to be evaluated.

The Analysis of Embryoid Body Formation and Its Role in Retinal Organoid Development.

Within the last decade, a wide variety of protocols have emerged for the generation of retinal organoids. A subset of studies have compared protocols based on stem cell source, the physical features of the microenvironment, and both internal and external signals, all features that influence embryoid body and retinal organoid formation. Most of these comparisons have focused on the effect of signaling pathways on retinal organoid development. In this study, our aim is to understand whether starting cell conditions, specifically those involved in embryoid body formation, affect the development of retinal organoids in terms of differentiation capacity and reproducibility. To investigate this, we used the popular 3D floating culture method to generate retinal organoids from stem cells. This method starts with either small clumps of stem cells generated from larger clones (clumps protocol, CP) or with an aggregation of single cells (single cells protocol, SCP). Using histological analysis and gene-expression comparison, we found a retention of the pluripotency capacity on embryoid bodies generated through the SCP compared to the CP. Nonetheless, these early developmental differences seem not to impact the final retinal organoid formation, suggesting a potential compensatory mechanism during the neurosphere stage. This study not only facilitates an in-depth exploration of embryoid body development but also provides valuable insights for the selection of the most suitable protocol in order to study retinal development and to model inherited retinal disorders in vitro.

Central serous chorioretinopathy: An evidence-based treatment guideline.

Central serous chorioretinopathy (CSC) is a relatively common disease that causes vision loss due to macular subretinal fluid leakage and it is often associated with reduced vision-related quality of life. In CSC, the leakage of subretinal fluid through defects in the retinal pigment epithelial layer's outer blood-retina barrier appears to occur secondary to choroidal abnormalities and dysfunction. The treatment of CSC is currently the subject of controversy, although recent data obtained from several large randomized controlled trials provide a wealth of new information that can be used to establish a treatment algorithm. Here, we provide a comprehensive overview of our current understanding regarding the pathogenesis of CSC, current therapeutic strategies, and an evidence-based treatment guideline for CSC. In acute CSC, treatment can often be deferred for up to 3-4 months after diagnosis; however, early treatment with either half-dose or half-fluence photodynamic therapy (PDT) with the photosensitive dye verteporfin may be beneficial in selected cases. In chronic CSC, half-dose or half-fluence PDT, which targets the abnormal choroid, should be considered the preferred treatment. If PDT is unavailable, chronic CSC with focal, non-central leakage on angiography may be treated using conventional laser photocoagulation. CSC with concurrent macular neovascularization should be treated with half-dose/half-fluence PDT and/or intravitreal injections of an anti-vascular endothelial growth factor compound. Given the current shortage of verteporfin and the paucity of evidence supporting the efficacy of other treatment options, future studies-ideally, well-designed randomized controlled trials-are needed in order to evaluate new treatment options for CSC.

Vision on gyrate atrophy: why treat the eye?

In the April issue of this Journal, Boffa and coworkers put forward a new therapeutic approach for Gyrate Atrophy of the Choroid and Retina (GACR; OMIM 258870) (Boffa et al, 2023). The authors propose to apply gene therapy to the liver for GACR, a metabolic disease primarily affecting eyesight due to retinal degeneration. Their vision is enthusiastically supported by a News and Views comment in the same issue (Seker Yilmaz and Gissen, 2023). However, based on disease pathology, patient's needs, ethical considerations, therapeutic developmental time lines, and current state of the art of gene therapy for liver and eye, we have a different view on this issue: We argue below that local treatment of the eye is the preferred option for GACR.

The Road towards Gene Therapy for X-Linked Juvenile Retinoschisis: A Systematic Review of Preclinical Gene Therapy in Cell-Based and Rodent Models of XLRS.

X-linked juvenile retinoschisis (XLRS) is an early-onset progressive inherited retinopathy affecting males. It is characterized by abnormalities in the macula, with formation of cystoid retinal cavities, frequently accompanied by splitting of the retinal layers, impaired synaptic transmission of visual signals, and associated loss of visual acuity. XLRS is caused by loss-of-function mutations in the retinoschisin gene located on the X chromosome (RS1, MIM 30083). While proof-of-concept studies for gene augmentation therapy have been promising in in vitro and rodent models, clinical trials in XLRS patients have not been successful thus far. We performed a systematic literature investigation using search strings related to XLRS and gene therapy in in vivo and in vitro models. Three rounds of screening (title/abstract, full text and qualitative) were performed by two independent reviewers until consensus was reached. Characteristics related to study design and intervention were extracted from all studies. Results were divided into studies using (1) viral and (2) non-viral therapies. All in vivo rodent studies that used viral vectors were assessed for quality and risk of bias using the SYRCLE's risk-of-bias tool. Studies using alternative and non-viral delivery techniques, either in vivo or in vitro, were extracted and reviewed qualitatively, given the diverse and dispersed nature of the information. For in-depth analysis of in vivo studies using viral vectors, outcome data for optical coherence tomography (OCT), immunohistopathology and electroretinography (ERG) were extracted. Meta-analyses were performed on the effect of recombinant adeno-associated viral vector (AAV)-mediated gene augmentation therapies on a- and b-wave amplitude as well as the ratio between b- and a-wave amplitudes (b/a-ratio) extracted from ERG data. Subgroup analyses and meta-regression were performed for model, dose, age at injection, follow-up time point and delivery method. Between-study heterogeneity was assessed with a Chi-square test of homogeneity (I2). We identified 25 studies that target RS1 and met our search string. A total of 19 of these studies reported rodent viral methods in vivo. Six of the 25 studies used non-viral or alternative delivery methods, either in vitro or in vivo. Of these, five studies described non-viral methods and one study described an alternative delivery method. The 19 aforementioned in vivo studies were assessed for risk of bias and quality assessments and showed inconsistency in reporting. This resulted in an unclear risk of bias in most included studies. All 19 studies used AAVs to deliver intact human or murine RS1 in rodent models for XLRS. Meta-analyses of a-wave amplitude, b-wave amplitude, and b/a-ratio showed that, overall, AAV-mediated gene augmentation therapy significantly ameliorated the disease phenotype on these parameters. Subgroup analyses and meta-regression showed significant correlations between b-wave amplitude effect size and dose, although between-study heterogeneity was high. This systematic review reiterates the high potential for gene therapy in XLRS, while highlighting the importance of careful preclinical study design and reporting. The establishment of a systematic approach in these studies is essential to effectively translate this knowledge into novel and improved treatment alternatives.

Efficacy of Carbonic Anhydrase Inhibitors on Cystoid Fluid Collections and Visual Acuity in Patients with X-Linked Retinoschisis.

PURPOSE: To date, there is no standard treatment regimen for carbonic anhydrase inhibitors (CAIs) in X-linked retinoschisis (XLRS) patients. This retrospective study aims to evaluate the efficacy of CAIs on visual acuity and cystoid fluid collections (CFC) in XRLS patients in Dutch and Belgian tertiary referral centers. DESIGN: Retrospective cohort study. PARTICIPANTS: Forty-two patients with XLRS. METHODS: In total, 42 patients were enrolled. To be included, patients had to have previous treatment with an oral CAI (acetazolamide), a topical CAI (brinzolamide/dorzolamide), or a combination of an oral and a topical CAI for at least 4 consecutive weeks. We evaluated the effect of the CAI on best-corrected visual acuity (BCVA) and central foveal thickness (CFT) on OCT. MAIN OUTCOME MEASURES: Central foveal thickness and BCVA. RESULTS: The median age at the baseline visit of the patients in this cohort study was 14.7 (range, 43.6) years, with a median (interquartile range [IQR]) follow-up period of 4.0 (2.2-5.2) years. During the follow-up period, 25 patients were treated once with an oral CAI (60%), 24 patients were treated once with a topical CAI (57%), and 11 patients were treated once with a combination of both topical and oral CAI (26%). We observed a significant reduction of CFT for oral CAI by 14.37 µm per 100 mg per day (P < 0.001; 95% confidence interval [CI], -19.62 to -9.10 µm) and for topical CAI by 7.52 µm per drop per day (P = 0.017; 95% CI, -13.67 to -1.32 µm). The visual acuity changed significantly while on treatment with oral CAI by -0.0059 logMAR per 100 mg (P = 0.008; 95% CI, -0.010 to -0.0013 logMAR). Seven patients (17%) had side effects leading to treatment discontinuation. CONCLUSIONS: Our data indicate that treatment with (oral) CAI may be beneficial for short-term management of CFC in patients with XLRS. Despite a significant reduction in CFT, the change in visual acuity was modest and not of clinical significance. Nonetheless, the anatomic improvement of the central retina in these patients may be of value to create an optimal retinal condition for future potential treatment options such as gene therapy. FINANCIAL DISCLOSURE(S): The authors have no proprietary or commercial interest in any materials discussed in this article.