A Retrospective Longitudinal Study of 460 Patients with ABCA4-Associated Retinal Disease.

PURPOSE: To investigate the distribution of genotypes and natural history of ABCA4-associated retinal disease in a large cohort of patients seen at a single institution. DESIGN: Retrospective, single-institution cohort review. PARTICIPANTS: Patients seen at the University of Iowa between November 1986 and August 2022 clinically suspected to have disease caused by sequence variations in ABCA4. METHODS: DNA samples from participants were subjected to a tiered testing strategy progressing from allele-specific screening to whole genome sequencing. Charts were reviewed, and clinical data were tabulated. The pathogenic severity of the most common alleles was estimated by studying groups of patients who shared 1 allele. Groups of patients with shared genotypes were reviewed for evidence of modifying factor effects. MAIN OUTCOME MEASURES: Age at first uncorrectable vision loss, best-corrected visual acuity, and the area of the I2e isopter of the Goldmann visual field. RESULTS: A total of 460 patients from 390 families demonstrated convincing clinical features of ABCA4-associated retinal disease. Complete genotypes were identified in 399 patients, and partial genotypes were identified in 61. The median age at first vision loss was 16 years (range, 4-76 years). Two hundred sixty-five families (68%) harbored a unique genotype, and no more than 10 patients shared any single genotype. Review of the patients with shared genotypes revealed evidence of modifying factors that in several cases resulted in a > 15-year difference in age at first vision loss. Two hundred forty-one different alleles were identified among the members of this cohort, and 161 of these (67%) were found in only a single individual. CONCLUSIONS: ABCA4-associated retinal disease ranges from a very severe photoreceptor disease with an onset before 5 years of age to a late-onset retinal pigment epithelium-based condition resembling pattern dystrophy. Modifying factors frequently impact the ABCA4 disease phenotype to a degree that is similar in magnitude to the detectable ABCA4 alleles themselves. It is likely that most patients in any cohort will harbor a unique genotype. The latter observations taken together suggest that patients' clinical findings in most cases will be more useful for predicting their clinical course than their genotype. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Portable wide-field digital imaging for screening of neonatal visual impairment causes in Rio de Janeiro, Brazil: a budget impact analysis.

OBJECTIVE: To estimate the budget impact of portable wide-field digital imaging incorporation on screening neonatal causes of childhood blindness and visual impairment in Rio de Janeiro, Brazil. DESIGN: Budget impact analysis. SETTING: Rio de Janeiro, Brazil. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was the direct cost of indirect binocular ophthalmoscopy, red reflex test and portable wide-field digital image screening comprising all babies born in Rio de Janeiro's government maternity wards. The secondary outcome was the budget impact of implementing portable wide-field digital image screening in Rio de Janeiro, Brazil. RESULTS: Considering 100% coverage of maternity wards, the total budget impact between 2020 and 2024 would be US$3 820 706.04, ranging from US$3 139 844.34 to US$6 099 510.35. The additional cost would be US$3 124 457.28, ranging from US$2 714 492.26 to US$4 880 608.63. CONCLUSION: The cost of universal digital imaging screening corresponds to less than 1% of the government health budget of the city of Rio de Janeiro. The information provided in this study may help government decision-makers evaluate the feasibility of implementing this new strategy in the municipal setting. Further health economic evaluations should be performed to verify the affordability of the implementation of this screening strategy in the Brazilian scenario, taking into account scarce human resources.

Cost-Utility Analysis of Wide-Field Imaging as an Auxiliary Technology for Retinopathy of Prematurity Care in Brazil.

Purpose: To evaluate the cost-utility of wide-field imaging (WFI) as a complementary technology for retinopathy of prematurity (ROP) screening from the Brazilian Unified Health System's perspective. Introduction: ROP is one of the leading causes of avoidable childhood blindness worldwide, especially in middle-income countries. The current ROP screening involves indirect binocular ophthalmoscopy (IBO) by ROP expert ophthalmologists. However, there is still insufficient ROP screening coverage. An alternative screening strategy is the combination of WFI with IBO. Methods: A cost-utility analysis was performed using a deterministic decision-tree simulation model to estimate incremental cost-utility for ROP care. Two screening strategies were compared: (1) IBO and (2) combination of WFI of all eligible preterm infants and IBO for type 2 ROP or worse and for non-readable images. Eligible population included preterm infants <32 weeks of gestational age or birth weight equal to or <1,500 g. The temporal horizon was lifetime. Visual outcome data was converted to utility, and the health benefits were estimated on quality-adjusted life-years (QALY). Incremental cost per QALY gained was calculated from the health system perspective. Costs were estimated considering equipment, maintenance, consumables, and staff. A micro-costing approach was used for WFI. Two technician nurses were trained for imaging execution and had their time evaluated. Two ROP expert ophthalmologists had their time evaluated for imaging reading. One-way sensitivity analysis and probabilistic sensitivity analysis were performed. Results: Combined screening strategy resulted in a cost-effective program considering 90% ROP screening coverage. Costs per examination: (1) screening with IBO: US dollar (US $) 34.36; (2) screening with combination: US $58.20; (3) laser treatment: US $642.09; (4) long-term follow-up: ranged from US $69.33 to 286.91, based on the infant's visual function. Incremental cost per QALY gained was US $1,746.99/QALY per infant screened with the combination strategy. One-way sensitivity analysis resulted in cost-effectiveness for all parameters. Probabilistic sensitivity analyses yielded a 100% probability of combination being cost-effective in a willingness-to-pay threshold of US $1,800/QALY. Conclusion: The combined strategy for ROP screening was cost-effective. It enhances access for appropriate ROP care in middle-income countries and dminishes opportunity costs for ophthalmologists.

Eye Findings in Infants With Suspected or Confirmed Antenatal Zika Virus Exposure.

: media-1vid110.1542/5804915134001PEDS-VA_2018-1104Video Abstract OBJECTIVES: To characterize ophthalmic manifestations of confirmed or suspected antenatal Zika virus (ZIKV) exposure. METHODS: Infants with antenatal ZIKV exposure were referred for evaluation during the 2015-2016 Rio de Janeiro outbreak. Mothers with symptomatic ZIKV infection during pregnancy and/or infants with microcephaly or other findings that were suggestive of suspected antenatal exposure were tested with reverse transcriptase polymerase chain reaction (RT-PCR). Complete eye examinations were performed by pediatric ophthalmologists between January 2016 and February 2017. The main outcome measure was eye abnormalities in RT-PCR-positive and suspected (ie, not tested or RT-PCR-negative) antenatal ZIKV cases. RESULTS: Of 224 infants, 189 had RT-PCR testing performed. Of 189 patients, 156 had positive RT-PCR results in their blood, urine, and/or placenta. Of 224 infants, 90 had central nervous system (CNS) abnormalities, including microcephaly (62 infants). Eye abnormalities were present in 57 of 224 (25.4%) infants. Optic nerve (44 of 57; 77.2%) and retina abnormalities (37 of 57; 64.9%) were the most common. The group with suspected ZIKV infection (68 infants) had proportionally more eye (36.8% vs 20.5%; P = .022) and CNS abnormalities (68.3% vs 28.1%; P = .008), likely because of referral patterns. Eye abnormalities consistent with ZIKV infection were clinically comparable in both RT-PCR-positive and unconfirmed groups, including 4 RT-PCR-positive infants of 5 without any CNS abnormalities. CONCLUSIONS: Similar eye manifestations were identified regardless of laboratory confirmation. Well-appearing infants were also found to have eye abnormalities. Therefore, all infants born after ZIKV outbreaks should be universally screened for eye abnormalities.

Visual function in infants with antenatal Zika virus exposure.

PURPOSE: To report the findings of a cross-sectional study of visual function in infants with confirmed or suspected antenatal Zika virus (ZIKV) infection seen at a single referral center in Rio de Janeiro. METHODS: Infants were examined following the ZIKV outbreak period at Instituto Fernandes Figueira/FIOCRUZ. Visual function was considered abnormal if an infant could not fix and follow a standardized high-contrast target (10 cm) by 3-6 months of age. Visual function and associations with structural eye abnormalities, central nervous system (CNS) abnormalities, microcephaly, and nystagmus were assessed. Sensitivity and specificity of screening criteria for structural eye abnormalities was assessed. RESULTS: A total of 173 infants met inclusion criteria. Abnormal visual function was found in 52 infants (30.0%) and was significantly associated with eye abnormalities (40/52; OR = 44.2; 95% CI, 16.6-117.6), CNS abnormalities (50/52; OR = 64.0; 95% CI, 14.7-277.6), microcephaly (44/52; OR = 31.5; 95% CI, 12.7-77.8), and nystagmus (26/52; OR = 120.0; 95% CI, 15.6-924.5). Using microcephaly as screening criteria for the detection of eye abnormalities provided a sensitivity of 88.9% (95% CI, 76.0-96.3) and specificity of 82.8% (95% CI, 75.1-88.9). Using both abnormal visual function and microcephaly increased sensitivity to 100% (95% CI, 92.1-100.0) and decreased specificity to 80.5% (95% CI, 72.5-86.9). CONCLUSIONS: Infants with suspected antenatal ZIKV infection and reduced visual function should be referred to an ophthalmologist. Visual function assessments are helpful in screening for antenatal ZIKV exposure in resource-limited settings and can identify infants who may benefit from visual habilitation.

Análise de impacto orçamentário da incorporação da retinografia digital portátil para a triagem de doenças oculares causadoras de deficiência visual infantil

Objetivo: Estimar o impacto orçamentário da incorporação da retinografia digital portátil para a triagem de doenças causadoras de baixa visão e cegueira infantis no município do Rio de Janeiro. Métodos: Apenas os custos diretos através da técnica de microcusto dos modelos de triagem no cenário atual (oftalmoscopia binocular indireta e teste do reflexo vermelho) e do cenário alternativo (retinografia digital portátil) foram calculados para a análise do impacto orçamentário total e incremental. A população de referência corresponde a todos os nascidos vivos em maternidades públicas no município do Rio de Janeiro. O horizonte temporal é de cinco anos (2020 a 2024) e foram utilizados três cenários alternativos (cobertura de 100, 75 e 50% das maternidades) para a difusão da nova tecnologia. Por fim, foi realizada uma análise de sensibilidade para testar a influência de parâmetros de incerteza do modelo nos resultados do impacto orçamentário. Resultado: No cenário de 100% de cobertura, o impacto orçamentário total esperado entre 2020-2024 seria de R$ 14.958.162,91 podendo variar entre R$ 12.167.161,22 e R$ 23.549.785,30. Esses valores correspondem a um custo adicional aos cofres públicos entre R$ 10.491.273,99 a R$ 18.747.312,54, com um custo esperado de R$ 12.422.314,20. Conclusão: O custo para a implementação da retinografia digital portátil para rastreio de doenças causadoras de deficiência visual infantil representa menos de 1% do orçamento do SUS destinado ao município do Rio de Janeiro. Os achados do presente estudo podem auxiliar o gestor de saúde a avaliar a viabilidade da implementação da nova tecnologia a nível municipal.

Análise de impacto orçamentário da incorporação da retinografia digital portátil para a triagem de doenças oculares causadoras de deficiência visual infantil / Analysis of the budgetary impact of incorporating portable digital retinography for screening eye diseases that cause visual impairment in children

Objetivo: Estimar o impacto orçamentário da incorporação da retinografia digital portátil para a triagem de doenças causadoras de baixa visão e cegueira infantis no município do Rio de Janeiro. Métodos: Apenas os custos diretos através da técnica de microcusto dos modelos de triagem no cenário atual (oftalmoscopia binocular indireta e teste do reflexo vermelho) e do cenário alternativo (retinografia digital portátil) foram calculados para a análise do impacto orçamentário total e incremental. A população de referência corresponde a todos os nascidos vivos em maternidades públicas no município do Rio de Janeiro. O horizonte temporal é de cinco anos (2020 a 2024) e foram utilizados três cenários alternativos (cobertura de 100, 75 e 50% das maternidades) para a difusão da nova tecnologia. Por fim, foi realizada uma análise de sensibilidade para testar a influência de parâmetros de incerteza do modelo nos resultados do impacto orçamentário. Resultado: No cenário de 100% de cobertura, o impacto orçamentário total esperado entre 2020-2024 seria de R$ 14.958.162,91 podendo variar entre R$ 12.167.161,22 e R$ 23.549.785,30. Esses valores correspondem a um custo adicional aos cofres públicos entre R$ 10.491.273,99 a R$ 18.747.312,54, com um custo esperado de R$ 12.422.314,20. Conclusão: O custo para a implementação da retinografia digital portátil para rastreio de doenças causadoras de deficiência visual infantil representa menos de 1% do orçamento do SUS destinado ao município do Rio de Janeiro. Os achados do presente estudo podem auxiliar o gestor de saúde a avaliar a viabilidade da implementação da nova tecnologia a nível municipal.

Purpose: To estimate the budgetary impact of portable digital retinography incorporation for screening of neonatal causes of childhood low vision and blindness in Rio de Janeiro, Brazil Methods: For the budgetary impact analysis, a microcosting technique was performed. Direct costs of screening models in the current scenario (indirect ophthalmoscopy and red reflex test) and in the alternative scenario (digital imaging screening) were calculated. The eligible population is all live births in Rio de Janeiro's government maternity wards. The time horizon will be five years (2020 to 2024) and three alternative scenarios (100, 75 and 50% coverrage) for the diffusion of the technology were used. Finally, uncertainty analyses was be performed to test the impact of different input parameter values on the outcomes of the budget-impact analysis. Results: Considering coverage of 100% of maternity wards, the total budgetary impact between 2020-2024 would range from R$ 12,167,161.22 to R$ 23,549,785.30, with an expected value of R$ 14,958,162.91. Additional cost ranged from R$ 10,491,273.99 to R$ 18,747,312.54, with an expected value of R$ 11,232,019.80. The cost per exam would be R$ 57.15. Conclusion: The cost of universal digital imaging retinography screening corresponds to less than 1% of the public health budget of Rio de Janeiro city. The information provided in this paper may help the budget holder to evaluate the feasibility of implementing the new technology at the municipal setting.