RESUMO
PURPOSE: There is an urgent need for a more effective intervention to slow or prevent progression of age-related macular degeneration (AMD) from its early stages to vision-threatening late complications. Subthreshold nanosecond laser (SNL) treatment has shown promise in preclinical studies and a pilot study in intermediate AMD (iAMD) as a potential treatment. We aimed to evaluate the safety of SNL treatment in iAMD and its efficacy for slowing progression to late AMD. DESIGN: The Laser Intervention in Early Stages of Age-Related Macular Degeneration (LEAD) study is a 36-month, multicenter, randomized, sham-controlled trial. PARTICIPANTS: Two hundred ninety-two participants with bilateral large drusen and without OCT signs of atrophy. METHODS: Participants were assigned randomly to receive Retinal Rejuvenation Therapy (2RT®; Ellex Pty Ltd, Adelaide, Australia) SNL or sham treatment to the study eye at 6-monthly intervals. MAIN OUTCOME MEASURES: The primary efficacy outcome was the time to development of late AMD defined by multimodal imaging (MMI). Safety was assessed by adverse events. RESULTS: Overall, progression to late AMD was not slowed significantly with SNL treatment compared with sham treatment (adjusted hazard ratio [HR], 0.61; 95% confidence interval [CI], 0.33-1.14; P = 0.122). However, a post hoc analysis showed evidence of effect modification based on the coexistence of reticular pseudodrusen (RPD; adjusted interaction P = 0.002), where progression was slowed for the 222 participants (76.0%) without coexistent RPD at baseline (adjusted HR, 0.23; 95% CI, 0.09-0.59; P = 0.002), whereas an increased progression rate (adjusted HR, 2.56; 95% CI, 0.80-8.18; P = 0.112) was observed for the 70 participants (24.0%) with RPD with SNL treatment. Differences between the groups in serious adverse events were not significant. CONCLUSIONS: In participants with iAMD without MMI-detected signs of late AMD, no significant difference in the overall progression rate to late AMD between those receiving SNL and sham treatment were observed. However, SNL treatment may have a role in slowing progression for those without coexistent RPD and may be inappropriate in those with RPD, warranting caution when considering treatment in clinical phenotypes with RPD. Our findings provide compelling evidence for further trials of the 2RT® laser, but they should not be extrapolated to other short-pulse lasers.
Assuntos
Neovascularização de Coroide/cirurgia , Fotocoagulação a Laser/métodos , Drusas Retinianas/cirurgia , Degeneração Macular Exsudativa/cirurgia , Idoso , Neovascularização de Coroide/diagnóstico por imagem , Neovascularização de Coroide/fisiopatologia , Progressão da Doença , Método Duplo-Cego , Feminino , Angiofluoresceinografia , Humanos , Masculino , Pessoa de Meia-Idade , Imagem Multimodal , Drusas Retinianas/diagnóstico por imagem , Drusas Retinianas/fisiopatologia , Fatores de Risco , Tomografia de Coerência Óptica , Acuidade Visual/fisiologia , Degeneração Macular Exsudativa/diagnóstico por imagem , Degeneração Macular Exsudativa/fisiopatologiaRESUMO
PURPOSE: To determine the histologic and cellular correlates in the retina and retinal pigment epithelium (RPE) with the presence of optical coherence tomography-defined reticular pseudodrusen (RPD). DESIGN: Observation case using immunocytochemistry of an exenterated eye with immediate fixation after removal. PARTICIPANTS: Two patients, one with confirmed RPD and the other with mid-peripheral drusen, underwent multimethod imaging before exenteration and immediate fixation of the posterior eyecup for high-resolution immunocytochemical analysis. METHODS: Optical coherence tomography (OCT) was compared with high-resolution immunocytochemistry using a range of cellular markers to determine changes in the RPE, photoreceptors, and gliosis. MAIN OUTCOME MEASURES: Correlations of the appearance of reticular pseudodrusen on OCT and immunocytochemical analysis. RESULTS: Reticular pseudodrusen were deposits juxtaposed to photoreceptor outer segments extending through the outer nuclear layer and even beyond the outer limiting membrane. Deposits were rich in vitronectin, photoreceptor-associated proteins, and Iba1-immunoreactive immune cells. In contrast to conventional drusen the lipid stain Oil Red O failed to stain RPD. Cellular analysis revealed that RPD were associated with photoreceptor disruption and loss and localized gliosis. In addition, anomalies in the RPE were observed. CONCLUSIONS: Reticular pseudodrusen represent subretinal deposits that extend through the outer nuclear layer, affect photoreceptor integrity, and are associated with retinal gliosis and RPE damage.
Assuntos
Retina/patologia , Drusas Retinianas/diagnóstico por imagem , Epitélio Pigmentado da Retina/patologia , Tomografia de Coerência Óptica , Idoso de 80 Anos ou mais , Proteínas de Ligação ao Cálcio , Fator H do Complemento/genética , Proteínas de Ligação a DNA/metabolismo , Feminino , Técnica Indireta de Fluorescência para Anticorpo , Gliose/patologia , Humanos , Proteínas dos Microfilamentos , Imagem Multimodal , Receptores Nucleares Órfãos/metabolismo , Polimorfismo de Nucleotídeo Único , Proteínas/genética , Retina/metabolismo , Drusas Retinianas/metabolismo , Drusas Retinianas/patologia , Epitélio Pigmentado da Retina/metabolismo , Vitronectina/metabolismoRESUMO
BACKGROUND: A novel, ultra-low energy nanosecond laser (retinal rejuvenation therapy) has been developed with the aim to slow progression of early age-related macular degeneration (AMD). The safety, changes in fundus characteristics and macular function in a cohort of participants with bilateral intermediate AMD are reported. DESIGN: Prospective non-randomised, pilot intervention study. PARTICIPANTS OR SAMPLES: Subjects with bilateral intermediate AMD (n = 50, aged 50-75 years). METHODS: Ultra-low energy laser pulses applied in 12 spots around the macula of one eye (0.15-0.45 mJ), using 400 µm diameter spot, 3 nanosecond pulse length, 532 nm wavelength and energy titrated to each patient. MAIN OUTCOME MEASURES: Best corrected visual acuity, drusen area and macular sensitivity (flicker perimetry) at baseline and at 3, 6 and 12 months post-laser. RESULTS: Treatment was painless with no clinically visible lesions. No participant developed choroidal neovascularization, while two with thin central retinal thickness at baseline developed atrophy at 12-month follow up. Drusen area was reduced in 44% of treated eyes and 22% of untreated fellow eyes, with changes in drusen and function not being coincident. Improvement in flicker threshold within the central 3° was observed in both the treated and untreated fellow eyes at 3 months post-laser. Of the 11 eyes at greatest risk of progression (flicker defect >15 dB), seven improved sufficiently to be taken out of this high-risk category. CONCLUSIONS: A single unilateral application of nanosecond laser to the macula produced bilateral improvements in macula appearance and function. The nanosecond retinal rejuvenation therapy laser warrants ongoing evaluation as an early intervention for AMD.
Assuntos
Terapia com Luz de Baixa Intensidade/métodos , Degeneração Macular/radioterapia , Retina/fisiologia , Acuidade Visual/fisiologia , Campos Visuais/fisiologia , Idoso , Idoso de 80 Anos ou mais , Feminino , Angiofluoresceinografia , Humanos , Degeneração Macular/fisiopatologia , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Prognóstico , Estudos Prospectivos , Drusas Retinianas/fisiopatologia , Tomografia de Coerência Óptica , Testes de Campo VisualRESUMO
PURPOSE: To evaluate the secondary and exploratory outcomes of the Laser Intervention in Early Stages of Age-Related Macular Degeneration (LEAD) study, a 36-month trial of a subthreshold nanosecond laser (SNL) treatment for slowing the progression to late age-related macular degeneration (AMD) in its early stages. DESIGN: Multicenter, randomized, sham-controlled trial. PARTICIPANTS: Two-hundred ninety-two patients with bilateral large drusen. METHODS: Participants were randomly assigned to receive SNL or sham treatment to the study eye at 6-month intervals. MAIN OUTCOME MEASURES: The secondary outcome measure of the LEAD study was the time to development of late AMD, defined by multimodal imaging in the non-study eye. The exploratory outcome measures were the rate of change in best-corrected visual acuity (BCVA), low-luminance visual acuity, microperimetric mean sensitivity, drusen volume in the study and non-study eyes, and participant-reported outcomes based on the Night Vision Questionnaire and Impact of Vision Impairment questionnaire. RESULTS: Progression to late AMD in the non-study eye was not significantly delayed with SNL treatment (hazard ratio, 0.83; 95% confidence interval, 0.40-1.71; P = 0.611). There was no evidence of effect modification based on the coexistence of reticular pseudodrusen; interaction P = 0.065). There was no significant difference between study groups in the rate of change of low-luminance visual acuity, microperimetric mean sensitivity, and drusen volume in the study or non-study eyes, and Night Vision Questionnaire and Impact of Vision Impairment questionnaire scores (all P ≥ 0.167). The rate of BCVA decline was slightly higher for participants in the SNL group compared with the sham treatment group in the study eye (-0.54 and 0.23 letters/year, respectively; P < 0.001) but not the non-study eye (-0.48 and -0.56 letters/year, respectively; P = 0.628). CONCLUSIONS: Subthreshold nanosecond laser treatment of one eye did not have an effect on delaying progression to late AMD in the fellow eye and did not, in general, have an impact on the exploratory structural, functional, and participant-reported outcomes.
Assuntos
Terapia a Laser/métodos , Degeneração Macular/cirurgia , Drusas Retinianas/cirurgia , Acuidade Visual , Idoso , Idoso de 80 Anos ou mais , Feminino , Angiofluoresceinografia , Seguimentos , Fundo de Olho , Humanos , Macula Lutea/patologia , Degeneração Macular/complicações , Degeneração Macular/diagnóstico , Masculino , Pessoa de Meia-Idade , Drusas Retinianas/diagnóstico , Drusas Retinianas/etiologia , Resultado do TratamentoRESUMO
PURPOSE: The Laser Intervention in Early Stages of Age-Related Macular Degeneration (LEAD) study is an investigation of the safety and efficacy of subthreshold nanosecond laser treatment to slow the progression of intermediate age-related macular degeneration (AMD). This report presents the novel study design and baseline characteristics. DESIGN: Multicenter, double-masked, randomized controlled, medical device feasibility clinical trial. PARTICIPANTS: Persons with bilateral drusen >125 µm within 1500 µm of the fovea, monocular best-corrected visual acuity (BCVA) ≥20/40, and microperimetric retinal sensitivity of <25 decibels (dB) in at least 1 location within central 6° in 1 eye. Signs of late AMD; choroidal neovascularization or geographic atrophy, or anatomic end points defined on multimodal imaging (MMI) as fundus autofluorescence-defined atrophy, spectral-domain OCT (SD-OCT)-defined atrophy, or nascent GA excluded participation. METHODS: Participants were randomized to nanosecond or sham laser treatment. Twelve laser or sham spots are applied to the macular region of the study eye. Participants are reviewed in visits every 6 months with functional testing and MMI for 36 months and are re-treated at each visit (until 30 months) if an end point is not reached in the study eye. MAIN OUTCOME MEASURES: Progression to late AMD or MMI-defined anatomic end points in the study eye. RESULTS: A total of 292 participants across 6 centers were enrolled, with 145 participants randomized to arm 1 and 147 participants randomized to arm 2. Population characteristics at baseline were as follows: median age 70 years, 73% female, 90% Anglo-Saxon, and 3% current smokers. Baseline ocular characteristics of the study eyes were BCVA of 83 letters (20/25); low luminance visual acuity (LLVA) of 68 letters (20/50); hyperpigmentation, 33%; reticular pseudodrusen, 23%; square root drusen area (SD-OCT), 0.77 mm; square root drusen area (color photographs), 0.92 mm; cube root drusen volume (SD-OCT), 0.26 mm; average retinal sensitivity, 26 dB; and worst point retinal sensitivity, 20 dB. Only lutein supplement use was significantly different between treatment arms. CONCLUSIONS: The LEAD study uses novel inclusion/exclusion criteria and end points in an attempt to optimize our study design. Risk characteristics for progression to study end points are equally distributed between treatment arms.
RESUMO
PURPOSE: To investigate the prevalence of specific reading disability in children with functional amblyopia and to explore the relationship between the two. METHODS: In this prospective study, 20 consecutive children, aged 6 to 15 years (mean 8 +/-1.99 years), and diagnosed with amblyopia underwent a vision and reading assessment. The orthoptic examination included the assessment of participants' visual acuity, ocular motility and binocular functions. Specific reading disability was diagnosed using the Wide Range Achievement Test (WRAT III Reading Subtest). Intelligence, phonological awareness, rapid automatized naming (RAN), and the ability to read pseudo or nonsense words was also assessed using various psycho-linguistic reading tests. RESULTS: The prevalence of specific reading disability in this small series of amblyopic children was found to be 5% (n=1/20). This was even less than that reported in the local Victoria general population (16%). The type of amblyopia appeared related to phonological awareness (p=0.018) and decoding words (p=0.024), those with anisometropic amblyopia performing significantly better on these tasks than the strabismic amblyopes. The presence of binocular vision functions was also related to decoding words; those with binocular single vision performed better than those with suppression and lacking single binocular vision (p=0.007). Generally, amblyopic children also showed a lower RAN score when compared to phonological awareness score. There was no statistically significant difference for the severity of amblyopia (p=>0.05). CONCLUSIONS: In this very small pilot series, reading disorders were relatively rare in children with amblyopia. However, strabismic amblyopia and presence of suppression may have an adverse effect on phonological skills. In addition, amblyopia may be associated with a deficit in RAN. Further research is needed and planned to gain a better understanding about the relationship between amblyopia and reading ability.