[VASCULAR OPHTHALMIC MANIFESTATIONS IN COVID-19 PATIENTS].

INTRODUCTION: Although COVID-19 is mainly a respiratory disease, recent evidence has emerged of vascular and procoagulant pathologies even in young and otherwise healthy individuals. Ophthalmic manifestations include, among others, visual impairment due to arteritic and venous retinal obstructions, which at times precedes other aspects of the disease. We present two atypical cases of internal carotid dissection (ICAD) and review the different ocular symptoms of ICAD and its association with the COVID-19 pandemic. BACKGROUND: A 43-year-old otherwise healthy man was referred to the Emergency Department with a headache and monocular blurring of vision. A recent fever (2 weeks prior) was noted on anamnesis, in light of absence of available positive PCR test during the illness period, clinical suspicion of COVID-19 was assumed. An initial ophthalmic evaluation found a mild optic nerve function impairment with preserved visual acuity. Computed tomography (CT) showed sinusitis, and an initial diagnosis was made of mild optic neuropathy secondary to sphenoid sinusitis. A few hours after admission, the patient reported deterioration of symptoms and examination revealed no light perception in his right eye and pale edematous optic nerve. Urgent magnetic resonance angiography (MRA) demonstrated right ICAD with no additional findings. The second patient, a 43-year-old man developed an acute event of strabismus, left limb paralysis, and speech difficulties while on a hospital visit for his son. The patient underwent CT of the brain which demonstrated extensive infarction following the distribution of his right cerebral artery. Continued investigation using computed tomography angiography (CTA) demonstrated a dissection of the right internal carotid artery. The patient was positive for COVID-19. DISCUSSION: In this review, we discuss 2 cases of carotid artery dissection presenting with an acute ocular complaint in two otherwise healthy young individuals. Events were suspected to have been provoked by COVID-19 infection. The pathogenesis and mechanisms behind COVID-19 induced coagulopathy are not clear, and several mechanisms have been proposed including endothelial damage and dysfunction. The virus is thought to enter endothelial cells and lead to a pathological procoagulant state. Awareness should be drawn to uncommon signs especially in young adults. Clotting issues can arise and should be treated quickly as they might be life and vision threatening.

Genetic causes of inherited retinal diseases among Israeli Jews of Ethiopian ancestry.

Purpose: This study sought to describe the phenotype frequency and genetic basis of inherited retinal diseases (IRDs) among a nationwide cohort of Israeli Jewish patients of Ethiopian ancestry. Methods: Patients' data-including demographic, clinical, and genetic information-were obtained through members of the Israeli Inherited Retinal Disease Consortium (IIRDC). Genetic analysis was performed by either Sanger sequencing for founder mutations or next-generation sequencing (targeted next-generation sequencing or whole-exome sequencing). Results: Forty-two patients (58% female) from 36 families were included, and their ages ranged from one year to 82 years. Their most common phenotypes were Stargardt disease (36%) and nonsyndromic retinitis pigmentosa (33%), while their most common mode of inheritance was autosomal recessive inheritance. Genetic diagnoses were ascertained for 72% of genetically analyzed patients. The most frequent gene involved was ABCA4. Overall, 16 distinct IRD mutations were identified, nine of which are novel. One of them, ABCA4-c.6077delT, is likely a founder mutation among the studied population. Conclusions: This study is the first to describe IRDs' phenotypic and molecular characteristics in the Ethiopian Jewish community. Most of the identified variants are rare. Our findings can help caregivers with clinical and molecular diagnosis and, we hope, enable adequate therapy in the near future.

Neuroprotective Effect of Azithromycin Following Induction of Optic Nerve Crush in Wild Type and Immunodeficient Mice.

This study evaluated the potential neuroprotective effect of azithromycin (AZ) intraperitoneal injections in male C57Bl/6 (wild type, WT) and female NOD scid gamma (NSG) mice subjected to optic nerve crush (ONC) as a model for optic neuropathy. Histologically, reduced apoptosis and improved retinal ganglion cell (RGC) preservation were noted in the AZ-treated mice as shown by TUNEL staining-in the WT mice more than in the NSG mice. The increased microglial activation following ONC was reduced with the AZ treatment. In the molecular analysis of WT and NSG mice, similar trends were detected regarding apoptosis, as well as stress-related and inflammatory markers examining BCL2-associated X (Bax), heme oxygenase 1 (Ho-1), interleukin 1 beta (Il1ß), superoxide dismutase 1 (Sod1), and nuclear factor-kappa B (Nfkb) levels. In the optic nerve, AZ increased the levels of expression of Sod1 and Nfkb only in the WT mice and decreased them in the NSG mice. In the retinas of the WT and NSG mice, the Bax and Ho-1 levels of expression decreased following the AZ treatment, while the Sod1 and Nfkb expression decreased only in the WT mice, and remained stable near the baseline in the NSG mice. Il1ß remained at the baseline in WT mice while it decreased towards the baseline in AZ-treated NSG mice. The neuroprotective effects demonstrated by the reduced RGC apoptosis in AZ-treated WT mice retinae, and in the optic nerves as stress-related and inflammatory gene expression increase. This did not occur in the immunodeficient NSG mice. AZ modulated the inflammatory reaction and microglial activation. The lack of an effect in NSG mice supports the assumption that AZ acts by immunomodulation, which is known to play a role in ONC damage. These findings have implications for the development and repurposing of drugs to preserve RGCs after acute optic neuropathies.

Characterization of Diabetic Retinopathy in Two Mouse Models and Response to a Single Injection of Anti-Vascular Endothelial Growth Factor.

In this study, we characterized diabetic retinopathy in two mouse models and the response to anti-vascular endothelial growth factor (VEGF) injection. The study was conducted in 58 transgenic, non-obese diabetic (NOD) mice with spontaneous type 1 diabetes (n = 30, DMT1-NOD) or chemically induced (n = 28, streptozotocin, STZ-NOD) type 1 diabetes and 20 transgenic db/db mice with type 2 diabetes (DMT2-db/db); 30 NOD and 8 wild-type mice served as controls. Mice were examined at 21 days for vasculopathy, retinal thickness, and expression of genes involved in oxidative stress, angiogenesis, gliosis, and diabetes. The right eye was histologically examined one week after injection of bevacizumab, ranibizumab, saline, or no treatment. Flat mounts revealed microaneurysms and one apparent area of tufts of neovascularization in the diabetic retina. Immunostaining revealed activation of Müller glia and prominent Müller cells. Mean retinal thickness was greater in diabetic mice. RAGE increased and GFAP decreased in DMT1-NOD mice; GFAP and SOX-9 mildly increased in db/db mice. Anti-VEGF treatment led to reduced retinal thickness. Retinas showed vasculopathy and edema in DMT1-NOD and DMT2-db/db mice and activation of Müller glia in DMT1-NOD mice, with some response to anti-VEGF treatment. Given the similarity of diabetic retinopathy in mice and humans, comparisons of type 1 and type 2 diabetic mouse models may assist in the development of new treatment modalities.

Histological and molecular characterization of glaucoma model induced by one or two injections of microbeads to the anterior chamber of mice.

PURPOSE: To characterize glaucoma-induced damage following injections of plastic microbeads into the anterior chamber of mice. METHODS: Mice were divided into three groups: a single plastic microbeads injection (n = 21); two consecutive plastic microbead injections to the right eye at 1-week intervals, 4 of which with two consecutive saline injections in the left eye (n = 15); and an additional control group of two consecutive saline injections at 1-week intervals (n = 6). Intraocular pressure (IOP) was measured weekly. Retinal thickness, ganglion cells (RGCs) and axonal loss, inflammatory and gliosis reactions were measured at week four. Molecular analysis using qRT-PCR in the microbeads injection groups focused on expression levels of inflammation and glaucoma-related genes. RESULTS: Mean IOP following single injection at 4 weeks was significantly elevated compared to baseline in injected eyes (14.5 ± 3.3 mmHg vs. 11.1 ± 2.5 mmHg, respectively, p = 0.003) and not in fellow eyes (13.2 ± 2.9 mmHg vs. 12.2 ± 2.9, respectively, NS). Six (35.3%) bead-injected eyes had IOP ≥ 17 mmHg compared with 2 (11.8%) saline-injected control eyes. Retinal thickness in injected and fellow eyes was 193.7 ± 15.5 µm and 223.9 ± 15.5 µm, respectively (p = 0.03). RGC loss in injected and fellow eyes was 16.0 ± 0.5 and 17.6 ± 0.7 cells per 200 µm, respectively (p = 0.005). Retinal gliosis, axonal loss and inflammatory cell infiltration to the bead-injected eyes were noted. Molecular analysis following double injection showed STAT3 expression decreased in the glaucoma-induced optic nerves (0.69 ± 0.3 vs. 1.16 ± 0.3, p = 0.04), but increased in the glaucoma-induced retinae (p = 0.05) versus saline; retinal IL-1ß decreased significantly (0.04 ± 0.04 vs. 0.36 ± 0.2, p = 0.02). TNF-α, NFkB and SOD-1 expression did not change. CONCLUSION: One/two injections of microbeads elevated IOP, with measurable neuronal damage. An inflammatory response was detected in the injured retina and optic nerve. The therapeutic significance of these findings should be explored.

[ACUTE VISION LOSS ASSOCIATED WITH HYPEREOSINOPHILIC SYNDROME].

INTRODUCTION: Hypereosinophilic syndrome (HES) is a rare disorder, in which eosinophilic toxins damage capillary and coronary endothelium and neuronal axons, at different target organs; 12% of patients experience stroke as a result of endothelial dysfunction, cardiomyopathy with secondary embolism, hyperviscosity and hypercoagulability. The treatment target is to lower the eosinophil count and shorten its tissue survival time. Supportive care and anticoagulants are given as required. We report a case of myocarditis, respiratory failure and cortical blindness due to rapidly deteriorating HES. The case demonstrates how early recognition and appropriate treatment can reduce tissue toxicity and functional loss due to hypereosinophilic syndrome.

A nationwide genetic analysis of inherited retinal diseases in Israel as assessed by the Israeli inherited retinal disease consortium (IIRDC).

Inherited retinal diseases (IRDs) cause visual loss due to dysfunction or progressive degeneration of photoreceptors. These diseases show marked phenotypic and genetic heterogeneity. The Israeli IRD consortium (IIRDC) was established in 2013 with the goal of performing clinical and genetic mapping of the majority of Israeli IRD patients. To date, we recruited 2,420 families including 3,413 individuals with IRDs. On the basis of our estimation, these patients represent approximately 40% of Israeli IRD patients. To the best of our knowledge, this is, by far, the largest reported IRD cohort, and one of the first studies addressing the genetic analysis of IRD patients on a nationwide scale. The most common inheritance pattern in our cohort is autosomal recessive (60% of families). The most common retinal phenotype is retinitis pigmentosa (43%), followed by Stargardt disease and cone/cone-rod dystrophy. We identified the cause of disease in 56% of the families. Overall, 605 distinct mutations were identified, of which 12% represent prevalent founder mutations. The most frequently mutated genes were ABCA4, USH2A, FAM161A, CNGA3, and EYS. The results of this study have important implications for molecular diagnosis, genetic screening, and counseling, as well as for the development of new therapeutic strategies for retinal diseases.

Proptosis due to intraorbital space-occupying lesions in children.

PURPOSE: To report the 10-year experience of two tertiary medical centers with children presenting with proptosis due to an intraorbital space-occupying lesion. METHODS: Patients were identified by file review. Data were collected on demographics, findings on ophthalmologic and imaging evaluations, etiology, treatment, and outcome. RESULTS: Nineteen children (7 male) were included. Eleven patients had optic nerve glioma, including 9 with substantially decreased visual acuity. Treatment consisted of chemotherapy alone or with radiation, resection or anti-VEGF agents, MEK inhibitor, or observation only (n = 1). Visual and cosmetic outcomes were poor in all cases. Outcome for arteriovenous malformations was good following corticosteroid treatment (n = 1), but catheterization led to persistent proptosis and fluctuating visual acuity (n = 1). Compound capillary hemangioma (n = 1) was treated with laser and systemic beta blockers with satisfactory results. Rhabdomyosarcoma had a good prognosis in one patient treated with resection and radiation but was fatal in another even after chemotherapy. Juvenile xanthogranuloma, frontal bone osteoma, and localized hypertrophic neuropathy of the supraorbital nerve (n = 1 each) were treated by resection with good visual and cosmetic outcomes. CONCLUSIONS: Proptosis accompanied by visual loss is an uncommon presentation in children and suggests an orbital tumor. We found that visual outcome was better when the nerve was not involved by tumor. Optic nerve glioma was the most common cause and failed to respond to various treatments. Catheterization for arteriovenous malformation did not prevent proptosis, and final visual acuity fluctuated. Surgery for rhabdomyosarcoma and xanthogranuloma led to remission with preservation of vision in 2 of 3 cases.

The co-occurrence of rare non-ocular phenotypes in patients with inherited retinal degenerations.

Purpose: To describe the coexistence of additional non-ocular genetic diseases in patients diagnosed with inherited retinal degenerations (IRDs). Methods: The study was based on a retrospective chart review of patients diagnosed with IRD and additional rare systemic diseases. The chart review included the ophthalmic and genetic aspects of each patient. The ophthalmic examination included best-corrected visual acuity, biomicroscopic examination, cycloplegic refraction, retinal imaging (fundus photos, optical coherence tomography, and fundus autofluorescence), and electroretinography. Genetic testing included homozygosity mapping, whole exome sequencing, and Sanger sequencing. Results: Fifteen index cases diagnosed with IRDs and one or more rare systemic diseases were identified. Six of the families were consanguineous. Of six patients with complete molecular diagnosis, four (66%) had pathogenic variants in two autosomal recessive (AR) disease genes, and of the total pathogenic variants identified, AR mutations were the most common (16/22, 72%). One patient was diagnosed with mutations in three different genes, underlying three distinct genetic conditions. Nine patients could have had an incorrect clinical diagnosis based on the clinical evaluation only (e.g., retinitis pigmentosa and hearing loss could have been diagnosed as Usher syndrome). Conclusions: The common working paradigm for the ophthalmologist is combining the different symptoms observed in a patient into one unifying diagnosis. However, IRD is a strikingly heterogeneous condition, and may coincide with other genetic (and non-genetic) rare conditions. Establishing a correct diagnosis is important for the patients and their family members, as it enables prediction of disease prognosis, aids in tailoring the correct follow-up and treatment, and allows patients to pursue prenatal counseling and reproductive planning.

Likelihood of Diagnosing Neuroblastoma in Isolated Horner Syndrome.

BACKGROUND: The need for an extensive evaluation for neuroblastoma in children with Horner syndrome is controversial. METHODS: A retrospective study design was used. The cohort included 47 children with anisocoria who were diagnosed with Horner syndrome and 135 children with neuroblastoma evaluated at a pediatric medical center between 2007 and 2015. To detect neuroblastoma, patients with Horner syndrome underwent brain and cervical MRI, abdominal ultrasound, and/or measurement of urinary vanillylmandelic acid (VMA). The neuroblastoma group was evaluated for signs/symptoms of Horner syndrome at the time of diagnosis. RESULTS: Seven patients with Horner syndrome were lost to follow-up, and the findings of the remaining 40 were categorized according to the age of the patient. Horner syndrome most frequently was idiopathic (58%), and in only 1 patient did the discovery of neuroblastoma precede the appearance of Horner syndrome. In the 21 patients aged 1-18 years, Horner syndrome was acquired in 15 patients and congenital in 6. The most common etiology was trauma (62%). Imaging was performed in 14 patients and VMA testing in 13. Neuroblastoma was diagnosed in 5 patients; in none was it related to Horner syndrome. In the 135 patients with neuroblastoma, most of the tumors were diagnosed at Stage 4 (60%) or Stage 3 (30%) with 53% originating in the abdomen. In one patient (0.74%) with signs/symptoms of Horner syndrome at diagnosis of neuroblastoma, the tumor had been identified prenatally and the diagnosis confirmed by imaging postnatally. CONCLUSIONS: The absence of occult neuroblastoma in children with Horner syndrome and of signs/symptoms of Horner syndrome in the children diagnosed with neuroblastoma suggests that Horner syndrome might not be as frequent a cause of neuroblastoma as previously thought. We recommend that full investigation for neuroblastoma be reserved for suspicious cases associated with additional systemic signs or symptoms.

[THE ISRAELI INHERITED RETINAL DISEASES CONSORTIUM (IIRDC)- CLINICAL-GENETIC MAPPING AND FUTURE PERSPECTIVES].

INTRODUCTION: The sense of vision is highly important for humans and its loss markedly affects function and quality of life. Many inherited retinal diseases (IRDs) cause visual loss due to dysfunction or progressive degeneration of photoreceptor cells. These diseases show clinical and genetic heterogeneity. AIMS: The Israeli IRD consortium (IIRDC) was established with the goal of performing clinical and genetic mapping of IRDs in the Israeli population. METHODS: Clinical evaluation is carried out at electroretinography (ERG) centers and ophthalmology departments, where the patients undergo a comprehensive eye exam, including testing of visual acuity, refractive error, imaging techniques and ERG tests. Genetic analysis is performed using Sanger sequencing, analysis of founder mutations, and whole exome sequencing. RESULTS: We recruited over 2,000 families including more than 3,000 individuals with IRDs. The most common inheritance pattern is autosomal recessive (65% of families). The most common retinal phenotype is retinitis pigmentosa (RP- 45% of families), followed by cone/cone-rod dystrophy, Stargardt Disease and Usher syndrome. We identified the cause of disease in 51% of families, mainly due to mutations in ABCA4, USH2A, FAM161A, CNGA3, and EYS. IIRDC researchers were involved in the identification of 16 novel IRD genes. In parallel, IIRDC members are involved in the development of therapeutic modalities for these currently incurable diseases. CONCLUSIONS: IIRDC works in close collaborative efforts aiming to continue and recruit for the genotype - phenotype study from the vast majority of Israeli IRD families, to identify all disease-causing mutations, and to tailor therapeutic interventions to each IRD patient.

Exome sequencing identified a novel de novo OPA1 mutation in a consanguineous family presenting with optic atrophy.

Inherited optic neuropathies are a heterogeneous group of disorders characterized by mild to severe visual loss, colour vision deficit, central or paracentral visual field defects and optic disc pallor. Optic atrophies can be classified into isolated or non-syndromic and syndromic forms. While multiple modes of inheritance have been reported, autosomal dominant optic atrophy and mitochondrial inherited Leber's hereditary optic neuropathy are the most common forms. Optic atrophy type 1, caused by mutations in the OPA1 gene is believed to be the most common hereditary optic neuropathy, and most patients inherit a mutation from an affected parent. In this study we used whole-exome sequencing to investigate the genetic aetiology in a patient affected with isolated optic atrophy. Since the proband was the only affected individual in his extended family, and was a product of consanguineous marriage, homozygosity mapping followed by whole-exome sequencing were pursued. Exome results identified a novel de novo OPA1 mutation in the proband. We conclude, that though de novo OPA1 mutations are uncommon, testing of common optic atrophy-associated genes such as mitochondrial mutations and OPA1 gene sequencing should be performed first in single individuals presenting with optic neuropathy, even when dominant inheritance is not apparent.

Difficulty in Distinguishing Posterior Reversible Encephalopathy Syndrome, Hypoxic-Ischemic Insult, and Acute Toxic Leukoencephalopathy in Children.

AIM: This study aims to describe our experience of unique pediatric neurological cases and associated difficulty in differentiating posterior reversible encephalopathy syndrome (PRES) from hypoxic-ischemic insult (HII), and acute toxic leukoencephalopathy (ATL). METHODS: The study included three children with a clinical picture suggestive of PRES, HII, and ATL of different etiologies who were diagnosed and treated at a tertiary pediatric medical center in 2011 to 2014. RESULTS: All patients presented with blindness following seizures with asphyxia/aspiration in a syndromatic child, too-rapid lipid infusion in a child with acute lymphoblastic leukemia, and repeated vomiting in a child with cerebral palsy, hydrocephalus, and malfunction of ventriculoperitoneal shunt. All patients had cortical blindness and high-signal foci in the cortical and subcortical regions on magnetic resonance imaging. All children improved. CONCLUSIONS: Familiarity with the clinical and radiological characteristics of neurological conditions leading to reversible cortical blindness is essential for diagnosis and management. Distinguishing PRES from HII and ATL can be challenging. Our cases most likely combined these etiologies, with the first patient diagnosed with PRES with HII, the second with PRES with ATL, and the third with focal HII. Given the diversity of the findings and the unclear prognostic significance, studies of the pathophysiology of PRES are warranted.

Relative neuroprotective effects hyperbaric oxygen treatment and TLR4 knockout in a mouse model of temporary middle cerebral artery occlusion.

PURPOSE: To examine the effects of hyperbaric oxygen (HBO) therapy and knockout of toll-like receptor 4 (TLR4) on the outcome of temporary middle cerebral artery occlusion (MCAO) in a mouse model. MATERIALS AND METHODS: MCAO was induced in anesthetized male C57Bl/6 mice (WT) and TLR4 knockout mice (TLR4(-/-)) using an intra-arterial filament method. After 30 or 90 min, the filament was removed, and the mice were given either no treatment (WT and TLR4(-/-) groups) or HBO (WT only). Mice were euthanized 24 h after MCAO, and the brain infarct area was examined using 2,3,5-triphenyltetrazolium chloride (TTC) staining. RESULTS: In the WT group, without treatment, lesion volume was 120 ± 13 mm(3) in the mice subjected to 30 min' MCAO and 173 ± 23 mm(3) in the mice subjected to 90 min' MCAO. Respective values with HBO treatment were 66.5 ± 36.7 mm(3) and 53.2 ± 17.2 mm(3). The difference was significant only for 90-minute MCAO (p < 0.01, nonparametric test). In the TLR4(-/-) group (all untreated), lesion volume was 95.9 ± 17.9 after 90 min of MCAO, which was significantly lower than in the untreated WT animals (p < 0.05, nonparametric test). CONCLUSIONS: A single treatment of HBO immediately after MCAO followed by 24 h' reperfusion significantly reduces edema and may improve perfusion. TLR4 knockout protects mice from MCAO damage, but to a lesser extent than HBO treatment.

Toll-like receptor-4 knockout mice are more resistant to optic nerve crush damage than wild-type mice.

BACKGROUND: This study aims to investigate the role of the inflammatory response following optic nerve crush (ONC) in knockout mice for the toll-like receptor-4 gene (TLR4-/-) compared to wild-type (WT) mice. METHODS: ONC was induced in TLR4-/- and C57BL6 WT mice. Histological sections of the retina and optic nerve were analysed on days 1, 3 or 21 after injury. Molecular analysis with real-time quantitative polymerase chain reaction was used to study the expression of CD45, tumour necrosis-alpha (TNF-α) and glial fibrillary acidic protein, as well as retinal ganglion cell (RGC) markers THY-1 and Brn3b. RESULTS: There was a 25.5% and 38% loss in the RGC layer of the ONC-injured eyes of the TLR4-/- and the WT mice, respectively (with 27% and 9% of the remaining cells positive for Brn3a, respectively). Mean levels of Thy-1 and Brn3b were higher in the TLR4-/- mice. CD45 and Iba1 staining revealed infiltration of inflammatory cells into the injured nerve and retina in both groups. Molecular analysis of the optic nerve on day 1 showed increased TNF-α expression and reduced CD45 and GFAP expression; on day 3, CD45 reverted to baseline but GFAP remained low; on day 21, all 3 markers were at baseline in the TLR4-/- group and decreased in the WT group. CONCLUSION: Inflammation plays a major role in the response to ONC injury. Reduced levels of inflammation are associated with improved RGC preservation. The increase in TNF-α and reduction in CD45 in both TLR4-/- and WT mice may indicate the presence of an alternative pathway for induction of RGC death.

Parainfectious optic neuritis: manifestations in children vs adults.

BACKGROUND: Parainfectious optic neuritis may appear at any age. The aim of our report was to compare the clinical manifestations and outcomes of this form of optic neuritis between children and adults. METHODS: The study sample consisted of all patients diagnosed with parainfectious optic neuritis evaluated by 2 neuro-ophthalmology services between 2005 and 2012. Data were collected retrospectively from the medical files. Findings were compared between patients aged 0-18 years and 19 years or older. RESULTS: Ten children (50% female) and 8 adults (50% female) met the study criteria. Mean duration of follow-up was 29.4 months (range, 2-72 months) in the pediatric group and 14.2 months (range, 5-80 months) in the adult group. Respective rates of bilateral disease were 50% and 38%, and all patients had optic disc swelling. The associated pathogen was identified in 60% of the pediatric group, mainly Mycoplasma pneumoniae, and 75% of the adult group, in which no microorganism predominated. The interval from the febrile illness to symptom onset was 6 days (range, 1-14 days) in the pediatric group and 19.5 days (range, 14-30 days) in the adult group. Acute disseminated encephalomyelitis (ADEM) was diagnosed in 40% (4/10) of the children and none of the adults. Final visual outcome was 20/30 or better in all patients. There was a higher frequency of bilateral disease in prepubescent vs postpubescent children. CONCLUSIONS: Parainfectious optic neuritis is associated with a favorable visual prognosis regardless of age. Children tend to manifest visual symptoms sooner after the antecedent infectious illness and more often bilaterally and in conjunction with ADEM. The causative agent is isolated less frequently in children compared with adults.

Nationwide Prevalence of Inherited Retinal Diseases in the Israeli Population.

Importance: Data regarding the prevalence of various inherited retinal diseases (IRDs) are limited and vary across populations; moreover, nationwide prevalence studies may be limited to a specific IRD phenotype, potentially leading to inaccurate prevalence estimations. Therefore, nationwide prevalence data are needed. Objective: To determine the prevalence of 67 IRD phenotypes in the Israeli population. Design, Setting, and Participants: This cohort study collected nationwide data regarding the number of individuals affected with IRD phenotypes assessed in 10 clinical and academic centers in Israel as part of the research activity of the Israeli inherited retinal disease consortium. Data were collected in May 2023 on 9396 individuals residing in Israel who were diagnosed by an ophthalmologist with an IRD using either electroretinography or retinal imaging where included. Individuals with retinal diseases known to have a nonmendelian basis or without a clear genetic basis and those who were reported as deceased at the time of data collection were excluded from this study. Main Outcomes and Measures: Prevalence of 67 IRD phenotypes. Results: Among the 9396 participants in our cohort, the most common IRD in Israel was retinitis pigmentosa with a disease prevalence of approximately 1:2400 individuals, followed by cone-rod dystrophy (approximately 1:14 000), Stargardt disease (approximately 1:16 000), Usher syndrome (approximately 1:16,000), and congenital stationary night blindness (approximately 1:18 000). The prevalence of all IRDs combined was 1:1043 individuals. Conclusions and Relevance: The current study provides large prevalence dataset of 67 IRD phenotypes, some of which are extremely rare, with only a single identified case. This analysis highlights the potential importance of performing additional nationwide prevalence studies to potentially assist with determining the prevalence of IRDs worldwide.

Best Disease: Global Mutations Review, Genotype-Phenotype Correlation, and Prevalence Analysis in the Israeli Population.

Purpose: To review all reported disease-causing mutations in BEST1, perform genotype-phenotype correlation, and estimate disease prevalence in the Israeli population. Methods: Medical records of patients diagnosed with Best disease and allied diseases from nine Israeli medical centers over the past 20 years were collected, as were clinical data including ocular findings, electrophysiology results, and retina imaging. Mutation detection involved mainly whole exome sequencing and candidate gene analysis. Demographic data were obtained from the Israeli Bureau of Statistics (January 2023). A bibliometric study was also conducted to gather mutation data from online sources. Results: A total of 134 patients were clinically diagnosed with Best disease and related conditions. The estimated prevalence of Best disease was calculated to be 1 in 127,000, with higher rates among Arab Muslims (1 in 76,000) than Jews (1 in 145,000). Genetic causes were identified in 76 individuals (57%), primarily showing autosomal-dominant inheritance due to BEST1 mutations (58 patients). Critical conserved domains were identified consisting of a high percentage of dominant missense mutations, primarily in transmembrane domains and the intracellular region (Ca2+ binding domain) of the BEST1 protein. Conclusions: This study represents the largest cohort of patients with Best disease reported in Israel and globally. The prevalence in Israel is akin to that in Denmark but is lower than that in the United States. Critical conserved domains within the BEST1 protein are pivotal for normal functioning, and even minor missense alterations in these areas lead to a dominant disease manifestation. Genetic testing is indispensable as the gold standard for Best disease diagnosis due to the variable clinical presentation of the disease.

Genetic heterogeneity and consanguinity lead to a "double hit": homozygous mutations of MYO7A and PDE6B in a patient with retinitis pigmentosa.

PURPOSE: Retinitis pigmentosa (RP), the most genetically heterogeneous disorder in humans, actually represents a group of pigmentary retinopathies characterized by night blindness followed by visual-field loss. RP can appear as either syndromic or nonsyndromic. One of the most common forms of syndromic RP is Usher syndrome, characterized by the combination of RP, hearing loss, and vestibular dysfunction. METHODS: The underlying cause of the appearance of syndromic and nonsyndromic RP in three siblings from a consanguineous Israeli Muslim Arab family was studied with whole-genome homozygosity mapping followed by whole exome sequencing. RESULTS: THE FAMILY WAS FOUND TO SEGREGATE NOVEL MUTATIONS OF TWO DIFFERENT GENES: myosin VIIA (MYO7A), which causes type 1 Usher syndrome, and phosphodiesterase 6B, cyclic guanosine monophosphate-specific, rod, beta (PDE6B), which causes nonsyndromic RP. One affected child was homozygous for both mutations. Since the retinal phenotype seen in this patient results from overlapping pathologies, one might expect to find severe retinal degeneration. Indeed, he was diagnosed with RP based on an abnormal electroretinogram (ERG) at a young age (9 months). However, this early diagnosis may be biased, as two of his older siblings had already been diagnosed, leading to increased awareness. At the age of 32 months, he had relatively good vision with normal visual fields. Further testing of visual function and structure at different ages in the three siblings is needed to determine whether the two RP-causing genes mutated in this youngest sibling confer increased disease severity. CONCLUSIONS: This report further supports the genetic heterogeneity of RP, and demonstrates how consanguinity could increase intrafamilial clustering of multiple hereditary diseases. Moreover, this report provides a unique opportunity to study the clinical implications of the coexistence of pathogenic mutations in two RP-causative genes in a human patient.

Ocular Torsion in Children with Horizontal Strabismus or Orthophoria.

PURPOSE: To report the rate of ocular torsion in children with horizontal strabismus or orthophoria. METHODS: A retrospective study design was used. Nineteen children were included in the study, including seven girls, aged 4-16 years. All patients were examined for strabismus and 12 were scheduled for surgical intervention. All participants had digital fundus photos (DRSplus, Padova, Italy) of both eyes at presentation, and 5 of 12 also had fundus photos following the strabismus operation. Patient files were reviewed for age, demographic data, type of strabismus, clinical symptoms and signs, orthoptic exams, subjective and objective reports of torsion, inferior oblique overaction, and V pattern. Fundus photos were analyzed for torsion by ImageJ software [ImageJ 1.54f, National Institute of Health, USA]. The disc-foveal angle was calculated for ocular torsion. Disc-foveal angle was defined as the angle formed between a line passing through the center of the optic disc to the fovea and another horizontal line passing through the center of the optic disc, using fundus photographs. RESULTS: Of the 19 children, 18 had horizontal strabismus: 9 with exotropia and 9 with esotropia. One child was orthophoric with torsional strabismus. Inferior oblique overaction was detected in all but 3 children, while V pattern was documented in 10. Visual acuity was reduced (under 6/12) in four eyes of four children. None were symptomatic for ocular torsion. Although extorsion was documented clinically in 3 of 19 children, it was measurable on fundus photos in all patients before surgery with a mean of 8.7 ± 8.5 degrees and 8.5 ± 9.7 degrees in the right and left eyes, respectively. The mean extorsion in both eyes was 19.7 ± 10.1 degrees and improved to a mean of 15.3 ± 7.9 degrees in the children who were operated on and had documented postoperative fundus photographs. CONCLUSIONS: Extorsion was detected on fundus photos at a significantly higher rate than in clinical examination. Notably, inferior oblique overaction was mainly associated with torsion. This study demonstrated that torsion is underdiagnosed in clinical examinations, as the children are often asymptomatic, but fundus photos which are easily obtained can improve its detection.