Faculty Bibliography

PURPOSE/OBJECTIVE:To compare retinal toxicity as measured by electroretinogram, ocular, and patient survival in retinoblastoma treated with intravitreal melphalan at two concentrations (25 vs. 30 µg). METHODS:Single-center, retrospective analysis of retinoblastoma eyes receiving 25-µg or 30-µg intravitreal melphalan from September 2012 to January 2019. Ocular toxicity was measured by electroretinogram of evaluable injections in 449 injections in 136 eyes. A repeated-measures linear mixed model with a random intercept and slope was applied to account for repeated measures for each eye. RESULTS:Average decline in electroretinogram after each additional injection was -4.9 µV (95% confidence interval -6.3 to -3.4); electroretinogram declined by -4.6 µV (95% confidence interval -7.0 to -2.2) after 25-µg injections and -5.2 µV (95% confidence interval -6.6 to -3.8) after 30-µg injections (P = 0.66). Injection at a new clock site hour was associated with a -3.91-µV lower average (95% confidence interval -7.8 to -0.04). CONCLUSION/CONCLUSIONS:Electroretinogram-measured toxicity in retinoblastoma eyes treated with intravitreal injections was not found to be different across 25-µg and 30-µg injections. There were no cases of extraocular extension or metastatic deaths in our patient population.

BACKGROUND:This study aimed to identify best practices for treating 13q deletion syndrome (13q-) patients with retinoblastoma in the era of super-selective ophthalmic artery chemosurgery (OAC) and intravitreal injection therapy (IVIT). METHODS:Retrospective study of 21 eyes from 14 patients with retinoblastoma and 13q- who were treated at Memorial Sloan Kettering Cancer Center (MSKCC) between May 2006 and May 2020, with a mean follow up of 3.7 years. Ocular survival, patient survival, and treatment toxicities were assessed. RESULTS:Nine of the 12 eyes that underwent OAC/IVIT at MSKCC have been progression free for at least 1 year since their last treatments. Fifteen out of 26 OAC cycles resulted in grade 3-4 hematologic toxicity. There was one death from sepsis in the setting of intravenous chemotherapy (IVC) for metastatic disease that occurred after OAC/IVIT therapy. The 2-year Kaplan-Meier ocular survival estimate for the whole cohort was 75% and for the eyes that received OAC or IVIT at MSKCC 83%. For OAC hematologic toxicities, one platelet transfusion and two filgrastim doses were administered, and one patient was hospitalized for neutropenic fevers. CONCLUSIONS:The majority of 13q- eyes treated with OAC/IVIT-based regimens can be cured, and there were no deaths related to complications from OAC or IVIT. 13q- Patients did have increased risk of systemic treatment complications, even from super-selective chemotherapies. Despite these toxicities, only one patient developed febrile neutropenia, one patient required a blood product transfusion, and two patients received filgrastim for both OAC and IVC complications. PRÉCIS: Children with 13q deletion syndrome with retinoblastoma managed with intra-arterial and intravitreal chemotherapy have excellent patient and ocular survival with acceptable toxicity.

PURPOSE/OBJECTIVE:The electroretinogram (ERG) has proven to be useful in the evaluation and monitoring of patients with posterior uveitis. ERG oscillatory potentials (OPs) are sometimes reduced in many uveitic eyes with otherwise grossly normal ERG responses. This study compares ERG parameters, including OPs, between patients with birdshot chorioretinopathy, other posterior uveitis, and controls. METHODS:This was a retrospective case-control study. Sixty-four patients seen at a clinical practice had a total of 93 visits during which ERG was performed on both eyes. ERG data from 93 age-matched controls were also collected. Root-mean-squared (RMS) energy of the OPs was calculated using Fourier analysis for 88 patients and 88 age-matched controls for whom complete data were available. Photopic flicker amplitudes, photopic flicker latencies, scotopic b-wave amplitudes, and OP RMS values were compared between patients and controls. Diagnostic performance was assessed using receiver operating characteristic (ROC) curves. RESULTS:The mean ages of patients and controls were 55.9 ± 10.8 (SD) years and 55.1 ± 11.5, respectively. 83% of the patients had a diagnosis of BCR. The mean OP RMS value was significantly different in patients (15.6 µV ± 9.7 µV) versus control eyes (33.0 µV ± 12.7 µV), p < 0.001. Area under the ROC curves (AUROC) was 0.75 for photopic flicker amplitudes, 0.77 for photopic flicker latencies, 0.72 for scotopic b-wave amplitudes, and 0.88 for OP RMS. AUROC was significantly different between OP RMS and photopic flicker amplitudes (p < 0.001), between OP RMS and flicker latencies (p = 0.0032), and between OP RMS and scotopic b-wave amplitudes (p < 0.0001). CONCLUSION/CONCLUSIONS:Analysis of OPs shows greater sensitivity and specificity in the diagnosis and evaluation of patients with birdshot chorioretinopathy than photopic and scotopic ERG amplitudes and photopic flicker latencies.

Purpose ERGs have been traditionally recorded using corneal electrodes, which can be difficult for some patients to tolerate. In the last several years, adhesive skin electrodes have gained in acceptance. We have previously reported on the clinical usefulness of qualitative interpretation of ERG recordings using skin electrodes for a wide spectrum of retinal disorders, as well as a preliminary estimate of the quantitative comparison of simultaneous ERG recordings using contact lens and adhesive skin electrodes to compare the differences in signal strength. In the present report, we update our quantitative findings. Methods The study was Institutional Review Board approved. 89 subjects who were referred for full-field ERG testing for multiple clinical indications were drawn from the practice of one of the authors (SEB). Informed consent was obtained from patients or their accompanying parent. ERGs (obtained according to ISCEV standards) were recorded simultaneously from both eyes with ERG-jet corneal contact lens electrodes and LKC Technologies Sensor Strip adhesive skin electrodes using multi-channel instrumentation (Diagnosys LLC, Espion3). A-wave and b-wave amplitudes and implicit times were compared between the two electrode types. Results Waveform morphologies obtained with skin electrodes were similar to those obtained with contact lens electrodes. Regression coefficients (conversion factors) for a-wave and b-wave amplitudes under both photopic and scotopic conditions were tightly clustered: DA 0.01 b-wave: 0.368; DA 3.0 a-wave: 0.343; DA 3.0 b- wave: 0.360; LA 3.0 a-wave: 0.256; LA 3.0 b-wave: 0.325; 30-Hz flicker peak-to-peak: 0.384. Regression coefficients for implicit times were nearly equal to 1.0, indicating comparable latencies for recordings from skin electrodes and contact lens electrodes: DA 0.01 b-wave: 0.971; DA 3.0 a-wave: 0.926; DA 3.0 b-wave: 0.996; LA 3.0 a-wave: 0.967; LA 3.0 b-wave: 0.964. The regression coefficient for the entire amplitude data set was 0.336, with an overall correlation between skin electrode and contact lens electrode amplitudes of 0.799. The regression coefficient for the entire implicit time data set was 0.980, with an overall correlation between skin electrode and contact lens electrode implicit times of 0.96. Conclusion Our best estimate for the conversion factor between ERG amplitudes recorded with adhesive skin electrodes and contact lens electrodes is 0.336 (amplitudes with skin electrodes are about 1/3 the amplitudes recorded simultaneously from the same eyes with contact lens electrodes) with a high correlation between skin electrode and contact lens electrode amplitudes. Implicit times are nearly identical for the two electrode types.

Purpose To evaluate the diagnostic yield and clinical impact of the SPARK/Invitae 248 gene panel in patients with known or suspected inherited degenerative retinal disease, in comparison with traditional clinical assessments including ERG testing. Methods Patients were drawn from the clinical practices of the authors. Genetic screening was provided by means of the SPARK/Invitae 248-gene panel at no charge to patients. Over the past year, results are available for 18 patients. Clinical diagnoses were Best vitelliform dystrophy (definite in one patient, suspected in three patients); retinitis pigmentosa (five affected patients, one likely female carrier); possible Stargardt disease (five patients); and one each with Leber congenital amaurosis, choroideremia, nyctalopia, and Norrie disease. Results Of the 18 studies returned, results were deemed by Invitae ''Positive'' in nine and ''Uncertain'' in nine. The genetic diagnosis agreed with the clinical diagnosis in eight cases (including two patients diagnosed with retinitis pigmentosa with homozygous mutations in USH2A, and one patient with the diagnosis of retinitis pigmentosa with compound heterozygotic mutations in NR2E3, which is also associated with enhanced S-cone syndrome). One patient with macular degeneration of uncertain etiology had a deletion in TPP1, which codes for ceroid lipofuscinosis. The remaining nine patients all returned heterozygous mutations considered ''variations of uncertain significance'' (VUS) ranging from two to eight different genes. Heterozygous VUS in ABCA4 were noted in two patients with the clinical diagnosis of Stargardt disease and in one with the clinical diagnosis of Best disease. Conclusion The SPARK/Invitae 248-gene panel provided a genetic diagnosis consistent with the clinical diagnosis in about half of cases and was diagnostic in one case where the clinical diagnosis was unclear. Retinitis pigmentosa and Stargardt disease were the most common genetic diagnoses. No cases of Leber congenital amaurosis were detected by genetic testing which had been misdiagnosed clinically.

OBJECTIVE:Intravitreal melphalan injections are commonly used in the treatment for intraocular retinoblastoma. This study compares retinal toxicity and ocular survival between two formulations, with and without propylene glycol (Alkeran vs. Evomela, respectively). METHODS:A retrospective cohort study of retinoblastoma patients who received intravitreal injections of Alkeran and Evomela at 30 μg from September 2012 to January 2019 at a single tertiary care center were enrolled. Retinal toxicity was measured using electroretinogram (ERG) and compared using a multivariate analysis of 338 injections in 101 eyes of 96 patients. Ocular survival of 163 eyes in 150 patients was compared across formulations using Cox proportional hazards model. Eyes were censored at the time a patient received a dose other than 30 μg. RESULTS:Overall, ERG decline (mean, 95% CI) for each injection was -5.58 μV (-7.17, -3.99). No significant differences in ERG decrement were found between Alkeran (with alcohol) -5.52uV (-6.99, -4.05). and Evomela (without alcohol) -5.65uV (-8.31 to -2.98) formulations (p = 0.93). Ocular survival at 24 months was 93.6% (95% CI 86.2, 97.1) with alcohol and 91.7% (95% CI 53.9, 98.8) without alcohol. The hazard ratio (HR) for without vs with alcohol was 0.50 (95% CI 0.06 to 4.07); no significant difference in ocular survival was found between formulations (p = 0.52). CONCLUSIONS AND RELEVANCE/CONCLUSIONS:No differences were found in retinal toxicity and ocular survival between 30 μg intravitreal injections of Alkeran or Evomela for intraocular retinoblastoma. Given the increased stability of Evomela, intravitreal treatment could be expanded to centers without the ability to supply Alkeran due to its shorter safety window; however, Alkeran is less expensive. For those with existing infrastructure, Alkeran is a comparable, cost-effective alternative.

Purpose : The Goldmann-Weekers Dark Adaptometer (GWDA), the historic "gold standard" for clinical measurement of dark adaptation, has been out of production for decades, and few working instruments remain available for clinical use. We compared a new alternative, the Dark Adaptation module for the Espion3/Colordome with the GWDA. Methods : Adapting lights were measured with an IL 1700 photometer. Adaptation curves of normal volunteers were obtained on the GWDA after a 5-minute bleach, and using various protocols for the Espion3/Colordome as provided by the manufacturer. Subjects gave informed consent under approval from the NYU Langone IRB. Results : The adapting luminance of the GWDA was 1019 cd/m2; the adapting luminance of the Espion3/ColorDome was 542 cd/m2 for a nominal luminance setting of 500 cd/m2. GWDA adaptation curves featured an initial threshold near 0 dB, a cone-mediated adaptation phase with 2 log units of adaptation over 5-10 minutes, followed by a cone-rod break and second, rod-mediated adaptation phase showing an additional 2 log units of adaptation of the next 10 minutes. The original Espion3/ColorDome protocol showed an initial threshold of -2.- to -3.0 dB, followed by an adaptation of less than 0.6 dB over the next 5-10 minutes, followed by a rod-cone break and a subsequent rod-mediated adaptation of 2 log units over the next 10 minutes. Subsequent protocols, including a masking attachment for the ColorDome and flickering test lights in lieu of simple brief flashes produced adapdtation curves very similar to those from the GWDA, but with initial thressholds between -2 and -3 dB. An option on the Espion3/ColorDome to test adaptation with alternating red and green test lights worked well, showing a cone adaptation curve (response to red lights) matching the cone limb of the white light curve, but with no later rod limb, and a curve in response to green test lights which closely tracked the white light adaptation curve. Conclusions : The Epions3/ColorDome is a satisfactory alternative to the GWDA. Adaptation curves are similar, though the initial threshold displaced downward by 2 to 3 dB. The red-green test light paradigm clearly distinguishes between cone and rod adaptation processes

BACKGROUND/AIMS/OBJECTIVE:Ophthalmic artery chemosurgery (OAC) has changed the face of retinoblastoma treatment and led to a higher rate of globe salvage. The introduction of intravitreal chemotherapy (IVitC) has further enhanced globe salvage with increased success in treatment of intravitreal seeds. Our group has seen success at treating non-vitreous disease that is refractory to OAC using IVitC. This study was undertaken to quantify and report on this success. METHODS:test, respectively. RESULTS:Fifty-six eyes from 52 retinoblastoma patients were identified. There were no disease-related or treatment-related deaths. One patient developed a second primary malignancy (pinealoblastoma) and subsequent leptomeningeal spread. Ninety-eight per cent of the eyes showed clinical regression. Recurrence was seen in 14.3%. Of the recurrences, five occurred in retinal tumours and three in subretinal seeds. The Kaplan-Meier estimated risk of recurrence in all patients treated was 83.5% (95% CI 7.9 to 14.1) at 10 months. The mean change in ERG over treatment course was -17.7 μV. CONCLUSIONS:Intravitreal chemotherapy is successful for the treatment of subretinal seeds and recurrent retinal tumours and could be considered as adjunctive therapy in globe-sparing treatment of retinoblastoma.

IMPORTANCE/OBJECTIVE:Predictions of visual outcomes are useful in clinical and family decisions regarding treatment for retinoblastoma. Very little has been published on the association of post-treatment visual acuity with pre-treatment electroretinography (ERG), which can be performed on infants too young to reliably quantify visual acuity. OBJECTIVE:To report associations of pre-treatment ERG with post-treatment visual acuity in eyes with advanced retinoblastoma treated with ophthalmic artery chemosurgery (OAC). DESIGN/METHODS:Retrospective case-control study of eyes treated from 2006 through 2017, with mean follow-up of 51 months (range 2.3-150 months). SETTING/METHODS:Single large academic center. PARTICIPANTS/METHODS:Group D and E eyes treated with OAC at Memorial Sloan Kettering Cancer Center with recorded visual acuity and ERG (30Hz flicker). MAIN OUTCOME AND MEASURE/UNASSIGNED:Snellen visual acuity (uncorrected) compared to initial 30Hz flicker ERG. RESULTS:This study included 157 Group D and E eyes. Results of the Jonckheere-Terpstra test for trend were statistically significant and indicated that eyes with lower pre-treatment ERG readings tended to have more visual impairment post-treatment. Among eyes with initial ERG 75+ μV, 11 of 32 eyes (34%) had visual acuity 20/40 or better. Among eyes with ERG 0 μV, 44 of 46 (96%) had visual acuity of 20/200 or worse. CONCLUSIONS AND RELEVANCE/CONCLUSIONS:Eyes with advanced intraocular retinoblastoma treated with OAC can achieve excellent visual acuity, but poor ERG at initial visit is associated with poor visual acuity after treatment in the majority of eyes. Expectations regarding visual potential may influence decisions about treatment.