Novel heterozygous PRPH2 variant identified in a patient with spinocerebellar ataxia type 14 and macular dystrophy.

PURPOSE: To report on a patient with spinocerebellar ataxia type 14 (SCA14) and macular dystrophy with identification of a novel PRPH2 variant. METHODS: Case report. RESULTS: A 63-year-old female with molecularly confirmed SCA14 presented with symmetric pigmentary disturbances in a perifoveal distribution resembling a pattern macular dystrophy. She had no history of using medications with recognized toxic macular effects. Subsequent genetic testing confirmed a novel heterozygous missense variant of unknown significance in PRPH2 (PRPH2: c.694 G>A, p.(Ala232Thr)). CONCLUSIONS: To our knowledge, this is the first case of macular dystrophy identified in a patient with SCA14. While it is possible that the macular dystrophy observed in this patient might be an under-reported phenotype associated with SCA14, the pattern of macular changes is consistent with PRPH2-related disorders. The identified missense variant is predicted to be damaging by most in silico models, and the residue is highly conserved, adding support to a dual genetic diagnosis in this case.

RPGR: Deep Phenotyping and Genetic Characterization With Findings Specific to the 3'-end of ORF15.

Purpose: To describe a group of patients with retinitis pigmentosa GTPase regulator (RPGR)-related retinopathy with a tapetal-like retinal sheen and corresponding changes in the reflectivity of the ellipsoid zone on optical coherence tomography (OCT) imaging. Methods: A retrospective case series of 66 patients with a disease-causing variant in RPGR was performed. An expert examiner, masked to patient demographics, clinical evaluations, and specific RPGR variant, analyzed color fundus photographs for the presence of a tapetal-like retinal sheen and assessed OCT images for the presence of an abnormally broad hyper-reflective band in the outer retina. Longitudinal reflectivity profiles were generated and compared with healthy controls. Results: Twelve patients (18.2%) had a retinal sheen on color images that cosegregated with an abnormally broad hyper-reflective ellipsoid zone band on OCT imaging. Three-fourths of these patients were male, had a cone-rod dystrophy, and had pathogenic RPGR variants located toward the 3'-end of ORF15. This group had a different longitudinal reflectivity profile signature compared with controls. After a period of prolonged dark adaptation, the abnormal hyper-reflective band on OCT became less apparent, and the outer retinal layers adopted a more normal appearance. Conclusions: RPGR-related retinopathy should be considered for males presenting with retinal sheen, abnormal ellipsoid zone hyper-reflectivity, and cone or cone-rod dysfunction on ERG, and pursued with molecular testing. Our results have implications for understanding the role of the C-terminal domain encoded by RPGR ORF15 in the phototransduction cascade. Further, the findings may be important to incorporate into both inclusion criteria and outcome measure developments in future RPGR-related cone or cone-rod dystrophy clinical trials.

Central retinal artery occlusion: a retrospective study of disease presentation, treatment, and outcomes.

OBJECTIVE: A central retinal artery occlusion (CRAO) represents a form of ocular stroke with poor visual prognosis. CRAO shares a common pathophysiology with cerebral ischemic stroke but presents unique diagnostic and management challenges leading to variability in clinical practice. This study aims to assess the presentation, treatment, and outcomes of CRAO at a tertiary care centre in Canada over 2 years and elucidate potential areas for improvement in the care of these patients. METHODS: Single-institution retrospective review including 27 patients diagnosed with CRAO from March 2018 to March 2020 in Edmonton, Alberta. RESULTS: Most patients with CRAO presented to eye care providers (14 of 27); others presented to the emergency department (10 of 27) or family physicians (2 of 27). Three patients (11.1%) presented within 4.5 hours of symptom onset. At presentation, 81% of patients had visual acuity of 20/400 or worse in the affected eye. No patients received thrombolysis. The majority of CRAO cases had a nonarteritic etiology (92.6%). All patients had at least one pre-existing vascular risk factor. Forty-eight percent of patients received escalated medical therapy. Ipsilateral carotid stenosis was identified in 5 patients (18.5%); 3 patients required carotid endarterectomy. Two patients were diagnosed with atrial fibrillation. Two patients experienced symptomatic cerebral ischemia within 6 weeks of CRAO. CONCLUSIONS: The majority of patients with CRAO presented to eye care providers, and few present within the potential window for thrombolysis of 4.5 hours, highlighting the need for public awareness strategies. Our cohort highlights the significant rate of systemic comorbidity that exists in these patients.

Ten-year analysis of traumatic open-globe injuries in Edmonton, Canada, from 2009-2018.

OBJECTIVE: To identify and characterize the incidence and correlates of open-globe injuries documented at the Eye Institute of Alberta (EIA) at the Royal Alexandra Hospital in Edmonton. DESIGN: A 10-year single-centre retrospective chart review. METHODS: All patients who underwent traumatic open-globe injury repair at EIA from January 2009-December 2018 were identified using key search terms. Charts were individually assessed for key demographic variables, including mechanism and location of injury. Patterns in open-globe injury incidence over the 10-year period and across demographics were assessed using Poisson regression. Associations between key demographic variables also were analyzed. RESULTS: In total, 551 traumatic open-globe injuries were treated at the EIA from January 2009-December 2018, resulting in an average of 4.63 injuries per month over the 10-year period. Mean patient age was 42 ± 21.56 years. The number of males (n = 442) presenting for open-globe injury repair was 3.9 times higher than that for females (n = 114). Among patients for whom use of eye protection was recorded (n = 186), only 11% reported using eye protection at the time of the trauma. The incidence rate of injuries with zone 3 involvement was significantly higher in males (41.4%) than in females (29.8%). CONCLUSION: Open-globe injuries remain a significant source of ocular morbidity at EIA, averaging just over 1 emergency case a week. Given the strong association with sex and the infrequent use of eye protection, targeted public health strategies are necessary to mitigate the risk of these sight-threatening injuries.

Evolution of focal choroidal excavation in ABCA4-related retinopathy.

Purpose: To report long-term evolution of unilateral focal choroidal excavation in a patient with ABCA4-related retinopathy. Observations: A 51-year-old female with ABCA4-related retinopathy developed a small juxtafoveal defect in Bruch's membrane in a region of macular atrophy in her left eye. In follow-up, the defect widened and subsequently developed into a focal choroidal excavation. Over the next 8 years, serial optical coherence tomography imaging illustrated the conversion of the focal choroidal excavation from conforming subtype into non-conforming subtype with eventual macular hole formation. Conclusions and importance: The long-term follow-up of a patient with serial imaging highlights the potential dynamic nature of focal choroidal excavation in ABCA4-related retinopathy. Progressive retinal degeneration may influence focal choroidal excavation morphology and may promote macular hole formation.

Nonosseous Periocular Manifestations of Langerhans Cell Histiocytosis: A Case Report and Systematic Review.

PURPOSE: Langerhans cell histiocytosis (LCH) is a disorder of dendritic cell proliferation that typically involves bone. It can be diagnostically challenging when LCH presents without bony involvement, leading to delays in diagnosis and treatment. In this study, the periocular manifestations of LCH in cases where the underlying orbital bones are not involved are described through a systematic review. METHODS: A systematic review of the literature was performed to capture all cases of LCH that involved the periocular region but not the underlying orbital bones. These included LCH cases that involved the periocular skin, the ocular surface, and the orbital tissue. The authors also highlight an additional case where LCH presented with periocular edema and multifocal, nodular conjunctival lesions. RESULT: This review illustrates that LCH rarely presents with periocular infiltration without orbital bone involvement. In these atypical cases, LCH can present as an eyelid mass, a chalazion-like lesion, generalized periocular swelling, ocular surface lesions, or infiltration of any orbital structure. Ocular surface LCH has a higher rate of recurrence than other periocular LCH. Orbital LCH can involve any tissue including extraocular muscles, the lacrimal gland, or indistinct areas within the orbit. CONCLUSIONS: LCH is a clinicopathologic diagnosis. Although most cases involve the bone, any soft tissue can be involved. Biopsy is required to confirm the diagnosis of this heterogeneous disease.

PEX6 Mutations in Peroxisomal Biogenesis Disorders: An Usher Syndrome Mimic.

Purpose: Peroxisomal biogenesis disorders (PBDs) represent a spectrum of conditions that result in vision loss, sensorineural hearing loss, neurologic dysfunction, and other abnormalities resulting from aberrant peroxisomal function caused by mutations in PEX genes. With no treatments currently available, we sought to investigate the disease mechanism in a patient with a PBD caused by defects in PEX6 and to probe whether overexpression of PEX6 could restore peroxisome function and potentially offer therapeutic benefit. Design: Laboratory-based study. Participants: A 12-year-old boy sought treatment with hearing loss and retinopathy. After negative results in an Usher syndrome panel, targeted genetic testing revealed compound heterozygous mutations in PEX6. These included a 14-nucleotide deletion (c.802_815del: p.(Asp268Cysfs∗8)) and a milder missense variant (c.35T→C:(p.Phe12Ser)). Methods: Patient-derived skin fibroblasts were cultured, and a PEX6 knockout cell line was developed using clustered regularly interspaced short palindromic repeats and Cas9 technology in HEK293T cells to emulate a more severe disease phenotype. Immunoblot analysis of whole cell lysates was performed to assess peroxisome number. Immunofluorescence studies used antibodies against components of the peroxisomal protein import pathway to interrogate the effects of mutations in PEX6 on protein trafficking. Main Outcome Measures: Primary outcome measures were peroxisome abundance and matrix protein import. Results: Peroxisome number was not significantly different between control fibroblasts and patient fibroblasts; however, fewer peroxisomes were observed in PEX6 knockout cells compared with wild-type cells (P = 0.04). Analysis by immunofluorescent microscopy showed significantly impaired peroxisomal targeting signal 1- and peroxisomal targeting signal 2-mediated matrix protein import in both patient fibroblasts and PEX6 knockout cells. Overexpressing PEX6 resulted in improved matrix protein import in PEX6 knockout cells. Conclusions: Mutations in PEX6 were responsible for combined hearing loss and retinopathy in our patient. The primary peroxisomal defect in our patient's skin fibroblasts was impaired peroxisomal protein import as opposed to reduction in the number of peroxisomes. Genetic strategies that introduce wild-type PEX6 into cells deficient in PEX6 protein show promise in restoring peroxisome function. Future studies of patient-specific induced pluripotent stem cell-derived retinal pigment epithelium cells may clarify the role of PEX6 in the retina and the potential for gene therapy in these patients.

Severe retinal degeneration in a patient with Canavan disease.

Background: Canavan disease is an autosomal recessive, neurodegenerative disorder caused by mutations in ASPA, a gene encoding the enzyme aspartoacylase. Patients present with macrocephaly, developmental delay, hypotonia, vision impairment and accumulation of N-acetylaspartic acid. Progressive white matter changes occur in the central nervous system. The disorder is often fatal in early childhood, but milder forms exist. Materials and methods: Case report. Results: We present the case of a 31-year-old male with mild/juvenile Canavan disease who had severe vision loss due to a retinal degeneration resembling retinitis pigmentosa. Prior to this case, vision loss in Canavan disease had been attributed to optic atrophy based on fundoscopic evidence of optic nerve pallor. Investigations for an alternative cause for our patient's retinal degeneration were non-revealing. Conclusion: We wonder if retinal degeneration may not have been previously recognized as a feature of Canavan disease. We highlight findings from animal models of Canavan disease to further support the association between Canavan disease and retinal degeneration.

PHACOVITRECTOMY FOR PRIMARY RHEGMATOGENOUS RETINAL DETACHMENT REPAIR: A Retrospective Review.

PURPOSE: To analyze the single surgery success rate and anterior segment complications related to phacoemulsification and intraocular lens implantation in a series of patients undergoing phacovitrectomy for all types of primary rhegmatogenous retinal detachment. METHODS: We performed a retrospective interventional case series on 302 eyes undergoing phacovitrectomy for primary rhegmatogenous retinal detachment repair between November 1, 2016, and February 2, 2019, in Edmonton, Canada. Primary outcomes included single surgery retinal reattachment rate and anterior segment complications. Secondary outcomes included the effects of proliferative vitreoretinopathy and macula and/or peripheral internal limiting membrane peeling on the rate of surgical success. RESULTS: The single surgery success rate of phacovitrectomy for all types of primary rhegmatogenous retinal detachment was 85.1%. The presence of proliferative vitreoretinopathy was associated with lower surgical success (odds ratio, 0.33; P = 0.01). Macular internal limiting membrane peeling was associated with higher surgical success (odds ratio, 2.4; P = 0.05). Anterior segment complications included posterior capsular opacification (28.8%), posterior synechiae (10.9%), and posterior capsular rupture (2.3%). CONCLUSION: Phacovitrectomy is a safe and effective treatment option for the primary repair of rhegmatogenous retinal detachments. This study provides evidence to support the safe incorporation of phacoemulsification and intraocular lens implantation with retinal surgery.

A diagnostic approach to syndromic retinal dystrophies with intellectual disability.

Inherited retinal dystrophies are a group of monogenic disorders that, as a whole, contribute significantly to the burden of ocular disease in both pediatric and adult patients. In their syndromic forms, retinal dystrophies can be observed in association with intellectual disability, frequently alongside other systemic manifestations. There are now over 80 genes implicated in syndromic retinal dystrophies with intellectual disability. Identifying and accurately characterizing these disorders allows the clinician to narrow the differential diagnosis, evaluate for relevant associated features, arrive at a timely and accurate diagnosis, and address both sight-threatening ocular manifestations and morbidity-causing systemic manifestations. The co-occurrence of retinal dystrophy and intellectual disability in an individual can be challenging to investigate, diagnose, and counsel given the considerable phenotypic and genotypic heterogeneity that exists within this broad group of disorders. We performed a review of the current literature and propose an algorithm to facilitate the evaluation, and clinical and mechanistic classification, of these individuals.

Improved electroretinographic responses following dietary intervention in a patient with Refsum disease.

Refsum disease is a rare inherited metabolic disorder arising from a defect in peroxisomal metabolism. Patients lack the functional enzyme phytanoyl-CoA hydroxylase, resulting in perturbed alpha oxidation of fatty acids. Phytanic acid accumulates in nervous and adipose tissue and leads to several disease phenotypes including early-onset retinal degeneration, hearing loss, peripheral neuropathy, anosmia, and cerebellar ataxia, among others. Currently, restricting dietary phytanic acid is the only means of altering the chronic sequelae and the disease course. While dietary intervention has been demonstrated to improve peripheral neuropathy, ichthyosis, and ataxia, there have been no reports of improved retinal function in patients with Refsum disease. We describe the case of a 51-year-old patient with molecularly and biochemically confirmed Refsum disease who underwent electroretinography before and after beginning a phytanic acid-restricted diet. His post-intervention 30 Hz flicker electroretinogram demonstrated significantly improved waveform amplitudes and implicit times, suggesting improved retinal function. Thus, we propose that the possibility exists for some visual recovery in these patients and we highlight the utility of performing standardized electroretinography to assess treatment response in Refsum disease.

Diffuse Pigmented Lesions in the Outer Retina: An Unusual Fundus Appearance.

Purpose: This report describes and provides a differential diagnosis for a patient with unusual bilateral retinal pigmented lesions. Methods: A 40-year-old woman was found to have multiple flat, gray lesions scattered across her fundi, becoming larger and more confluent toward the periphery. There were small drusenlike deposits in her foveae. The hyperpigmented lesions demonstrated hypoautofluorescence with thickening of the retinal pigment epithelium and disruption of the overlying layers on optical coherence tomography (OCT). Full-field electroretinography revealed generalized reduced a- and b-wave amplitudes. Results: Chest x-ray, breast ultrasound, mammography, and pelvic ultrasound findings were negative for malignant etiologic factors. Panel testing results for hereditary retinal dystrophy were negative. Conclusions: Although the clinical and OCT appearance of the lesions is similar to congenital grouped pigmentation, the symmetric and bilateral nature of ocular findings coupled with electroretinographic changes suggest a possible retinal dystrophy. This case adds to the phenotypic diversity of pigmented fundus lesions.

Combination Treatment with Rituximab and Bortezomib in a Patient with Non-Paraneoplastic Autoimmune Retinopathy.

PURPOSE: To describe outcomes of combined rituximab and bortezomib treatment for non-paraneoplastic autoimmune retinopathy. CASE: A 37-year-old female developed photopsias and reduced vision. Electroretinography, optical coherence tomography, and positive serum anti-retinal antibodies were consistent with autoimmune retinopathy. A negative malignancy work-up specified her non-paraneoplastic presentation. Given absence of response to periocular steroids, azathioprine, and methotrexate, a combination of rituximab and bortezomib was initiated as fifth-line therapy. RESULTS: There was no significant improvement in the patient's symptoms or visual function following treatment. The full field electroretinogram amplitudes were reduced with progressive outer retinal degeneration evident on optical coherence tomography. Post-treatment anti-retinal antibody testing demonstrated the persistence of antibodies and revealed additional antibodies not previously detected. CONCLUSION: Combined rituximab and bortezomib treatment did not result in significant clinical improvement and there was evidence of disease progression. Further prospective studies are required to assess the efficacy of immunotherapy in patients with autoimmune retinopathy.

An analysis of strabismus reoperations in Northern Alberta, Canada from 1995 to 2015.

OBJECTIVE: To report the reoperation rate in a large group of pediatric and adult strabismus patients over a 21-year period in Northern Alberta, Canada. METHODS: A retrospective review of 6177 strabismus surgeries from July 1995 to June 2015 on 5125 pediatric and adult patients was conducted to determine the reoperation rate at a single major referral centre. A set of guidelines was implemented in November 2014 recommending delaying reintervention for at least 12 weeks from the initial surgery, with specific exceptions. RESULTS: The historical strabismus reoperation rate over a 21-year period was 15.7%. Of those surgeries requiring reoperation, 77.7% required only 1 reoperation, 17.1% required 2 reoperations, 3.1% required 3 reoperations, and 2.1% required 4 or more reoperations. The mean time between surgeries for patients undergoing reoperation was 2.3 years and the median time was 1.0 years. CONCLUSIONS: Our study provides insight into the strabismus reoperation rate and the number of subsequent surgeries performed for patients over a 21-year period. Although preoperative ocular alignment, comorbidities, and the status of the operative eye modify the probability of reoperation, our results from a large cohort of patients provide an impression of the rate of reoperation and may be of benefit in the preoperative counseling of patients. Furthermore, we highlight the scarcity of guidelines for the appropriate timing of reoperation. The implementation of specific guidelines may encourage future investigation into trends in reoperation over time and promote ways to avoid unnecessary surgeries, lower health care costs to stakeholders, and ultimately improve patient care.

Analysis of penetrating keratoplasty in Northern Alberta, Canada, from 2000 to 2015.

OBJECTIVE: To study indications for penetrating keratoplasty (PK) at a single site. The trends in the causative organisms for infectious keratitis requiring surgery were also evaluated. DESIGN: Retrospective observational study. PARTICIPANTS: A total of 1181 eyes of 935 patients undergoing PK between January 2000 and December 2015 in Northern Alberta, Canada. METHODS: Indications for PK were evaluated over the 16-year study period, and the trends in these indications were compared over 5-year intervals. The microbiology of infectious keratitis cases requiring surgery was similarly evaluated. RESULTS: The most common indications for PK from 2000 to 2015 were keratoconus (23%), re-graft (22%), and corneal scar (12%). There was a decline in the percent of total surgeries done for Fuchs' dystrophy (p = 1.1 × 10-3) and pseudophakic bullous keratopathy (p = 5.6 × 10-5), whereas a corresponding increase in keratoconus (p = 3.2 × 10-5), trauma (p = 2.1 × 10-3), and infectious keratitis cases (p = 0.010) was observed. The most common causes for infectious keratitis cases were viral (45%), bacterial (18%), parasitic (11%), and fungal (9%). There was a significant increase in the percent of infectious keratitis cases due to a viral etiology from 2005 to 2010 (p = 6.4 × 10-3). CONCLUSIONS: The indications for PK are comparable with other centres in North America. Nearly half of all infectious keratitis cases requiring surgery are viral. The increase in viral cases requiring surgery may reflect improved diagnostics or recurrent cases.