The Michigan Retinal Degeneration Questionnaire: A Patient-Reported Outcome Instrument for Inherited Retinal Degenerations.

PURPOSE: To create a psychometrically validated patient-reported outcome measure for inherited retinal degenerations. DESIGN: Qualitative and quantitative patient-reported outcome (PROs) questionnaire development using item response theory validation. METHODS: One hundred twenty-eight patients with a diagnosis of an inherited retinal degeneration at the Kellogg Eye Center (University of Michigan) were recruited and administered a 166-item questionnaire comprising 7 expert-defined domains. The questionnaire was re-administered 4-16 days later to a subset of 25 participants to assess test-retest variability. Graded response models were fit by Cai's Metropolis-Hastings Robbins-Monro algorithm using the R (version 3.6.3) package mirt. Model data were fit to assess questionnaire dimensionality, to estimate item information, and to score participants. Poorly functioning items were removed, and the model was refit to create the final questionnaire. RESULTS: The psychometrically validated PROs measure was reduced to a 59-item questionnaire measuring 7 unidimesnional domains: central vision, color vision, contrast sensitivity, scotopic function, photopic peripheral vision, mesopic peripheral vision, and photosensitivity. A total of 39 items were removed because of poor factor loading, low item information, poor person-ability differentiation, or high item-level interdependence. This novel questionnaire produces a reliable domain score for person ability that does not show significant test-retest variability across repeated administration. CONCLUSIONS: The final PRO questionnaire, known as the Michigan Retinal Degeneration Questionnaire, is psychometrically validated and available for use in the evaluation of patients with inherited retinal degenerations.

Coats-like Exudative Vitreoretinopathy in Retinitis Pigmentosa: Ocular Manifestations and Treatment Outcomes.

PURPOSE: To provide a comprehensive review of the ocular manifestations, outcomes, and genetic findings in patients with Coats-like retinitis pigmentosa (RP). DESIGN: Multicenter, retrospective, nonconsecutive case series. PARTICIPANTS: Patients with a diagnosis of RP demonstrating Coats-like exudative vitreoretinopathy between January 1, 2008, and October 1, 2019. METHODS: Evaluation of ocular findings at RP diagnosis and at time of presentation of Coats-like exudative vitreoretinopathy, pedigree analysis, genetic testing, retinal imaging, and anatomic outcomes after treatment. MAIN OUTCOME MEASURES: Visual acuity, ophthalmoscopy results, OCT results, fluorescein angiography results, and identification of genetic mutations. RESULTS: Nine patients diagnosed with RP and demonstrating Coats-like exudative vitreoretinopathy were included. Median age at time of RP diagnosis was 8 years (range, 1-22 years), and median age at presentation of Coats-like exudative vitreoretinopathy was 18 years (range, 1-41 years). Seven patients were female, and 2 were male. The genetic cause of disease was identified in 6 patients. Three patients demonstrated Coats-like fundus findings at the time of RP diagnosis. Exudative retinal detachment (ERD) localized to the infratemporal periphery was present in all patients, with bilateral disease observed in 7 patients. In all treated patients, focal laser photocoagulation was used to treat leaking telangiectasias and to limit further ERD expansion. Cystoid macular edema refractory to carbonic anhydrase inhibitor therapy and ultimately amenable to treatment with intravitreal anti-vascular endothelial growth factor injection was observed in 4 patients. CONCLUSIONS: Coats-like vitreoretinopathy is present in up to 5% of all RP patients. The term Coats-like RP is used colloquially to describe this disease state, which can present at the time of RP diagnosis or, more commonly, develops late during the clinical course of patients with longstanding RP. Coats-like RP is distinct from Coats disease in that exudative pathologic features occur exclusively in the setting of a coexisting RP diagnosis, is restricted to the infratemporal retina, can affect both eyes, and does not demonstrate a male gender bias. Given the risk of added vision loss posed by exudative vitreoretinopathy in patients with RP, a heightened awareness of this condition is critical in facilitating timely intervention.

The Michigan Vision-Related Anxiety Questionnaire: A Psychosocial Outcomes Measure for Inherited Retinal Degenerations.

OBJECTIVE: We sought to construct and validate a patient-reported outcome measure for screening and monitoring vision-related anxiety in patients with inherited retinal degenerations. DESIGN: Item-response theory and graded response modeling to quantitatively validate questionnaire items generated from qualitative interviews and patient feedback. METHODS: Patients at the Kellogg Eye Center (University of Michigan, Ann Arbor, Michigan, USA) with a clinical diagnosis of an inherited retinal degeneration (n = 128) participated in an interviewer-administered questionnaire. The questionnaire consisted of 166 items, 26 of which pertained to concepts of "worry" and "anxiety." The subset of vision-related anxiety questions was analyzed by a graded response model using the Cai Metropolis-Hastings Robbins-Monro algorithm in the R software mirt package. Item reduction was performed based on item fit, item information, and item discriminability. To assess test-retest variability, 25 participants completed the questionnaire a second time 4 to 16 days later. RESULTS: The final questionnaire consisted of 14 items divided into 2 unidimensional domains: rod function anxiety and cone function anxiety. The questionnaire exhibited convergent validity with the Patient Health Questionnaire for symptoms of depression and anxiety. This vision-related anxiety questionnaire has high marginal reliability (0.81 for rod-function anxiety, 0.83 for cone-function anxiety) and exhibits minimal test-retest variability (ρ = 0.81 [0.64-0.91] for rod-function anxiety and ρ = 0.83 [0.68-0.92] for cone-function anxiety). CONCLUSIONS: The Michigan Vision-Related Anxiety Questionnaire is a psychometrically validated 14-item patient-reported outcome measure to be used as a psychosocial screening and monitoring tool for patients with inherited retinal degenerations. It can be used in therapeutic clinical trials for measuring the benefit of an investigational therapy on a patient's vision-related anxiety.

Implementation of a registry and open access genetic testing program for inherited retinal diseases within a non-profit foundation.

The Foundation Fighting Blindness is a 50-year old 501c(3) non-profit organization dedicated to supporting the development of treatments and cures for people affected by the inherited retinal diseases (IRD), a group of clinical diagnoses that include orphan diseases such as retinitis pigmentosa, Usher syndrome, and Stargardt disease, among others. Over $760 M has been raised and invested in preclinical and clinical research and resources. Key resources include a multi-national clinical consortium, an international patient registry with over 15,700 members that is expanding rapidly, and an open access genetic testing program that provides no cost comprehensive genetic testing to people clinically diagnosed with an IRD living in the United States. These programs are described with particular focus on the challenges and outcomes of establishing the registry and genetic testing program.

Rapid visual field constriction in a patient with retinitis pigmentosa and pituitary adenoma.

PURPOSE: To report a case of pituitary adenoma in a patient with retinitis pigmentosa (RP) and consequent rapid constriction of the visual field in each eye, which is atypical for either of these pathologies. OBSERVATIONS: A 45-year old male, with a long-standing history of RP, presented with rapid vision loss over 3 months. Examination revealed a severe drop in visual acuity and significant progression of concentric visual field constriction in each eye compared to 3 months prior. MRI revealed a pituitary macroadenoma compressing the optic chiasm. The patient underwent endoscopic trans-sphenoidal resection of the tumor and experienced partial recovery of visual acuity but not visual field. CONCLUSIONS AND IMPORTANCE: The visual field deficit in this patient was atypical for pituitary adenoma or optic neuropathy. The pattern was most consistent with RP, but the rate of progression was not. In a patient with chiasmal pathology in the setting of pre-existing retinopathy, visual field progression may not be limited exclusively to the bitemporal regions. Rapid constriction of the visual field in a patient with RP should prompt a work-up for alternative etiologies which includes neuro-imaging.

X-Chromosome Inactivation Is a Biomarker of Clinical Severity in Female Carriers of RPGR-Associated X-Linked Retinitis Pigmentosa.

PURPOSE: X-linked retinitis pigmentosa can manifest in female carriers with widely variable severity, whereas others remain unaffected. The contribution of X-chromosome inactivation (XCI) to phenotypic variation has been postulated but not demonstrated. Furthermore, the impact of genotype and genetic modifiers has been demonstrated in affected males but has not been well established in female carriers. The purpose of this study was to describe the scope of clinical phenotype in female carriers with mutations in RPGR and quantify the contribution of genotype, genetic modifiers, and XCI to phenotypic severity. DESIGN: Cohort study. PARTICIPANTS: Seventy-seven female carriers with RPGR mutations from 41 pedigrees. METHODS: Coding single nucleotide polymorphisms were sequenced in candidate genetic modifier genes encoding known RPGR-interacting proteins. X-chromosome inactivation ratios were determined in genomic DNA isolated from blood (n = 42) and saliva (n = 20) using methylation status of X-linked polymorphic repeats. These genetic data were compared with disease severity based on quantitative clinical parameters. MAIN OUTCOME MEASURES: Visual acuity, Humphrey visual field (HVF) results, full-field electroretinography results, and dark adaptation. RESULTS: Most individuals at all ages were mildly affected or unaffected, whereas those who progressed to moderate or severe vision loss were older than 30 years. RPGR genotype was not associated with clinical severity. The D1264N variant in RPGRIP1L was associated with more severe disease. Skewed XCI toward inactivation of the normal RPGR allele was associated with more severe disease. The XCI ratio in both blood and saliva was a predictor of visual function as measured by HVF diameter, rod amplitude, flicker amplitude, and flicker implicit time. For carriers with extreme XCI skewing of 80:20 or more, 57% were affected severely compared with 8% for those with XCI of less than 80:20 (P = 0.002). CONCLUSIONS: Female carriers with mutations in RPGR demonstrate widely variable clinical severity. X-chromosome inactivation ratios correlate with clinical severity and may serve as a predictor of clinically significant disease. Because RPGR gene therapy trials are underway, a future imperative exists to determine which carriers require intervention and when to intervene. X-chromosome inactivation analysis may be useful for identifying candidates for early intervention.

Detailed clinical characterisation, unique features and natural history of autosomal recessive RDH12-associated retinal degeneration.

BACKGROUND: Defects in retinol dehydrogenase 12 (RDH12) account for 3.4%-10.5 % of Leber congenital amaurosis and early-onset severe retinal dystrophy (EOSRD) and are a potential target for gene therapy. Clinical trials in inherited retinal diseases have unique challenges, and natural history studies are critical to successful trial design. The purpose of this study was to characterise the natural history of RDH12-associated retinal degeneration. METHODS: A retrospective chart review was performed in individuals with retinal degeneration and two likely disease-causing variants in RDH12. RESULTS: 57 subjects were enrolled from nine countries. 33 subjects had clinical records available from childhood. The data revealed an EOSRD, with average age of onset of 4.1 years. Macular atrophy was a universal clinical finding in all subjects, as young as 2 years of age. Scotopic and photopic electroretinography (ERG) responses were markedly reduced in all subjects, and a non-recordable ERG was documented as young as 1 year of age. Assessment of visual acuity, visual field and optical coherence tomography revealed severe loss of function and structure in the majority of subjects after the age of 10 years. Widefield imaging in 23 subjects revealed a unique, variegated watercolour-like pattern of atrophy in 13 subjects and sparing of the peripapillary area in 18 subjects. CONCLUSIONS: This study includes the largest collection of phenotypic data from children with RDH12-associated EOSRD and provides a comprehensive description of the timeline of vision loss in this severe, early-onset condition. These findings will help identify patients with RDH12-associated retinal degeneration and will inform future design of therapeutic trials.

Contrast sensitivity deficits in patients with mutation-proven inherited retinal degenerations.

BACKGROUND: Patients with retinal diseases frequently complain of poor visual function even when visual acuity is relatively unaffected. This clinical finding has been attributed to deficits in contrast sensitivity (CS). The purpose of our study was to evaluate the CS in patients with clinical and genetic diagnosis of inherited retinal degeneration (IRD) and relatively preserved visual acuity. METHODS: Seventeen patients (30 eyes) with IRD and visual acuity of 20/40 or better, and 18 controls (18 eyes) without any ocular condition underwent slit lamp examination, visual acuity testing via standard Snellen chart testing, CS testing via the Quick Contrast Sensitivity Function (QCSF), and Spectral Domain Optical Coherence Tomography (SD-OCT). CS were measured at 1.0, 1.5, 3.0, 6.0, 12.0, and 18.0 cycles per degree (cpd). T tests with general estimated equations were used to compare CS between groups. Wald chi square followed by pairwise comparisons was used to compare CS between multiple groups. RESULTS: We included 12 patients with rod-cone dystrophy (RCD), 3 patients with Stargardt disease (STGD) and 2 patients with Best disease. Patients with IRD had significantly worse CS than controls (p < 0.001) in all spatial frequencies. Patients with STGD had more marked deficits in CS than patients with Best disease (p < 0.001) and RCD (p < 0.001) despite having similar visual acuities. CONCLUSION: Patients with IRD, especially patients with STGD with relatively preserved visual acuity have marked deficits in CS when measured across a range of spatial frequencies. We recommend that clinical trials for STGD incorporate CS measured over a range of spatial frequencies as a secondary clinical endpoint for monitoring visual function. CS may provide an explanation for complaints of visual dysfunction when visual acuity is not significantly altered.

Retinal detachment and infantile-onset glaucoma in Stickler syndrome associated with known and novel COL2A1 mutations.

BACKGROUND: Few reports on surgical outcomes after retinal detachment in Stickler syndrome exist. Also, infantile-onset glaucoma associated with Stickler syndrome has been rarely reported and no reports exist that examine outcomes after glaucoma surgery. This study describes the clinical and genetic associations and the long-term outcomes of retinal detachment repair or glaucoma surgery in patients with Stickler syndrome. MATERIALS AND METHODS: Retrospective, single-center, case series of patients with Stickler syndrome. Demographics, clinical features, genetic mutations, and long-term surgical outcomes of eyes that experienced retinal detachment or diagnosed with infantile-onset glaucoma were assessed. RESULTS: Fifteen patients were identified with a mean age of 13 years at presentation and followed for a mean of 6 years. Two-thirds were male. Genetic analysis was performed as part of routine examination in nine patients from eight families. All were identified as having variants in COL2A1, three of which were novel. Six eyes of six patients experienced retinal detachment. Fifty percent of eyes without prophylactic laser treatment experienced retinal detachment, whereas only 5% of eyes that underwent prophylactic therapy detached. Despite surgical intervention for retinal detachment, five eyes became phthisical. Five eyes of three patients were diagnosed with infantile-onset glaucoma. All five eyes required multiple glaucoma surgeries, and three eyes became phthisical. CONCLUSIONS: This study illustrates the surgical challenges encountered in patients with Stickler syndrome. Additionally, infantile-onset glaucoma may be more prevalent than previously reported and presents a challenge in terms of management. A multidisciplinary approach is recommended to provide optimal care to these patients.