Vorinostat, temozolomide or bevacizumab with irradiation and maintenance BEV/TMZ in pediatric high-grade glioma: A Children's Oncology Group Study.

Background: Outcomes for children with high-grade gliomas (HGG) remain poor. This multicenter phase II trial evaluated whether concurrent use of vorinostat or bevacizumab with focal radiotherapy (RT) improved 1-year event-free survival (EFS) compared to temozolomide in children with newly diagnosed HGG who received maintenance temozolomide and bevacizumab. Methods: Patients ≥ 3 and < 22 years with localized, non-brainstem HGG were randomized to receive RT (dose 54-59.4Gy) with vorinostat, temozolomide, or bevacizumab followed by 12 cycles of bevacizumab and temozolomide maintenance therapy. Results: Among 90 patients randomized, the 1-year EFS for concurrent bevacizumab, vorinostat, or temozolomide with RT was 43.8% (±8.8%), 41.4% (±9.2%), and 59.3% (±9.5%), respectively, with no significant difference among treatment arms. Three- and five-year EFS for the entire cohort was 14.8% and 13.4%, respectively, with no significant EFS difference among the chemoradiotherapy arms. IDH mutations were associated with more favorable EFS (P = .03), whereas H3.3 K27M mutations (P = .0045) and alterations in PIK3CA or PTEN (P = .025) were associated with worse outcomes. Patients with telomerase- and alternative lengthening of telomeres (ALT)-negative tumors (n = 4) had an EFS of 100%, significantly greater than those with ALT or telomerase, or both (P = .002). While there was no difference in outcomes based on TERT expression, high TERC expression was associated with inferior survival independent of the telomere maintenance mechanism (P = .0012). Conclusions: Chemoradiotherapy with vorinostat or bevacizumab is not superior to temozolomide in children with newly diagnosed HGG. Patients with telomerase- and ALT-negative tumors had higher EFS suggesting that, if reproduced, mechanism of telomere maintenance should be considered in molecular-risk stratification in future studies.

Comorbidity Burden in a Cohort of Adolescent and Young Adult Patients Diagnosed with Central Nervous System Tumors and Sarcomas.

Purpose: Adolescent and young adult (AYA) oncology patients experience unique biological, behavioral, and socioeconomic challenges, for which provision of care must be tailored. AYAs with central nervous system (CNS) tumors and sarcomas represent a vulnerable population with worse outcomes and potential for serious sequelae from intense multimodal therapy. Comorbidity burden impacts treatment tolerance, adherence, and efficacy, yet has been understudied among these high-risk AYA patients. Methods: Utilizing a validated AYA oncology comorbidity index, we (1) measured comorbid conditions present at diagnosis in AYA-aged patients with CNS tumors and sarcomas and (2) compared baseline comorbidity burden across ascending AYA age groups (15-19, 20-29, and 30-39 years) and with pediatric patients (10-14 years). Results: The cohort included 131 AYAs and 50 pediatric patients. Mean comorbidity score significantly differed between pediatric (0.8) and AYA (1.7) patients, and across ascending age subgroups (0.8 [10-14] < 1.2 [15-19] < 1.7 [20-29] < 2.5 [30-39]). AYAs were significantly more likely than pediatric patients to have ≥2 or ≥3 comorbidities (47% vs. 18%, 24% vs. 6%), with increasing prevalence across ascending age subgroups. Frequency of overweight/obese status, smoking/substance use, obstetric/gynecologic conditions, and cardiovascular comorbidities increased with age. In multivariate analyses adjusting for sex, tumor type, and race, age remained a significant predictor of comorbidity score. Conclusions: AYAs with CNS tumors or sarcomas have a high burden of baseline comorbidities, which increase with age at diagnosis, conferring susceptibility to treatment-related toxicity and mortality. Improving the prognosis for AYAs requires appropriate identification of pre-existing comorbidities and tailoring therapeutic and supportive care accordingly.

Immunohistochemical assessment and clinical, histopathologic, and molecular correlates of membranous somatostatin type-2A receptor expression in high-risk pediatric central nervous system tumors.

Introduction: 177Lu-DOTATATE, a radionuclide therapy that binds somatostatin type-2A receptors (SST2A), has demonstrated efficacy in neuroendocrine tumors and evidence of central nervous system (CNS) penetration, supporting potential expansion within pediatric neuro-oncology. Understanding the prevalence of SST2A expression across pediatric CNS tumors is essential to identify patients who may benefit from somatostatin receptor-targeted therapy and to further elucidate the oncogenic role of SST2A. Methods: SST2A immunohistochemistry (IHC) was performed on tumor specimens and interpreted by an experienced pathologist (blinded), utilizing semi-quantitative scoring of membranous expression within viable tumor. Immunoreactive cell percentage was visually scored as 0 (none), 1 (<10%), 2 (10-50%), 3 (51-80%), or 4 (>80%). Staining intensity was scored as 0 (none), 1 (weak), 2 (moderate), or 3 (strong). Combined scores for each specimen were calculated by multiplying percent immunoreactivity and staining intensity values (Range: 0-12). Results: A total of 120 tumor samples from 114 patients were analyzed. Significant differences in SST2A IHC scores were observed across histopathologic diagnoses, with consistently high scores in medulloblastoma (mean ± SD: 7.5 ± 3.6 [n=38]) and meningioma (5.7 ± 3.4 [n=15]), compared to minimal or absent expression in ATRT (0.3 ± 0.6 [n=3]), ETMR (1.0 ± 0 [n=3]), ependymoma (grades I-III; 0.2 ± 0.7 [n=27]), and high-grade glioma (grades III-IV; 0.4 ± 0.7 [n=23]). Pineoblastoma (3.8 ± 1.5 [n=4]) and other embryonal tumors (2.0 ± 4.0 [n=7]) exhibited intermediate, variable expression. Among medulloblastomas, SST2A IHC scores were higher in non-SHH (8.5 ± 3.1) than SHH (5.0 ± 3.3) molecular subgroups (p=0.033). In a subset of paired primary and recurrent specimens from four patients, SST2A IHC scores remained largely unchanged. Discussion: High membranous SST2A expression was demonstrated in medulloblastoma, meningioma, and some rarer embryonal tumors with potential diagnostic, biologic, and therapeutic implications. Somatostatin receptor-targeted therapy such as 177Lu-DOTATATE deserves further investigation in these highly SST2A-expressing pediatric CNS tumors.

Risk of secondary malignant neoplasms in children following proton therapy vs. photon therapy for primary CNS tumors: A systematic review and meta-analysis.

Background: Central nervous system tumors are now the most common primary neoplasms seen in children, and radiation therapy is a key component in management. Secondary malignant neoplasms (SMNs) are rare, but dreaded complications. Proton beam therapy (PBT) can potentially minimize the risk of SMNs compared to conventional photon radiation therapy (RT), and multiple recent studies with mature data have reported the risk of SMNs after PBT. We performed this systematic review and meta-analysis to characterize and compare the incidence of SMNs after proton and photon-based radiation for pediatric CNS tumors. Methods: A systematic search of literature on electronic (PubMed, Cochrane Central, and Embase) databases was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) method. We included studies reporting the incidence and nature of SMNs in pediatric patients with primary CNS tumors. The crude incidence of SMNs and all secondary neoplasms were separately extracted, and the random-effects model was used for pooled analysis and subgroup comparison was performed between studies using photons vs. protons. Results: Twenty-four studies were included for analysis. A total of 418 SMNs were seen in 38,163 patients. The most common SMN were gliomas (40.6%) followed by meningiomas (38.7%), sarcomas (4.8%), and thyroid cancers (4.2%). The median follow-up was 8.8 years [3.3-23.2].The median latency to SMN for photons and protons were 11.9 years [5-23] and 5.9 years [5-6.7], respectively. The pooled incidence of SMNs was 1.8% (95% CI: 1.1%-2.6%, I2 = 94%) with photons and 1.5% (95% CI: 0%-4.5%, I2 = 81%) with protons. The pooled incidence of all SNs was not different [photons: 3.6% (95% CI: 2.5%-4.8%, I2 = 96%) vs. protons: 1.5% (95% CI: 0-4.5%, I2 = 80%); p = 0.21]. Conclusion: We observed similar rates of SMN with PBT at 1.5% compared to 1.8% with photon-based RT for pediatric CNS tumors. We observed a shorter latency to SMN with PBT compared to RT. With increasing use of pencil beam scanning PBT and VMAT, further studies are warranted to evaluate the risk of secondary cancers in patients treated with these newer modalities.

Medulloblastoma in the Modern Era: Review of Contemporary Trials, Molecular Advances, and Updates in Management.

Critical discoveries over the past two decades have transformed our understanding of medulloblastoma from a single entity into a clinically and biologically heterogeneous disease composed of at least four molecularly distinct subgroups with prognostically and therapeutically relevant genomic signatures. Contemporary clinical trials also have provided valuable insight guiding appropriate treatment strategies. Despite therapeutic and biological advances, medulloblastoma patients across the age spectrum experience tumor- and treatment-related morbidity and mortality. Using an updated risk stratification approach integrating both clinical and molecular features, ongoing research seeks to (1) cautiously reduce therapy and mitigate toxicity in low-average risk patients, and (2) thoughtfully intensify treatment with incorporation of novel, biologically guided agents for patients with high-risk disease. Herein, we review important historical and contemporary studies, discuss management updates, and summarize current knowledge of the biological landscape across unique pediatric, infant, young adult, and relapsed medulloblastoma populations.

Volumetric endpoints in diffuse intrinsic pontine glioma: comparison to cross-sectional measures and outcome correlations in the International DIPG/DMG Registry.

BACKGROUND: Cross-sectional tumor measures are traditional clinical trial endpoints; however volumetric measures may better assess tumor growth. We determined the correlation and compared the prognostic impact of cross-sectional and volumetric measures of progressive disease (PD) among patients with DIPG. METHODS: Imaging and clinical data were abstracted from the International DIPG Registry. Tumor volume and cross-sectional product (CP) were measured with mint Lesion™ software using manual contouring. Correlation between CP and volume (segmented and mathematical [ellipsoid] model) thresholds of PD were assessed by linear regression. Landmark analyses determined differences in survival (via log-rank) between patients classified as PD versus non-PD by CP and volumetric measurements at 1, 3, 5, 7, and 9 months postradiotherapy (RT). Hazard ratios (HR) for survival after these time points were calculated by Cox regression. RESULTS: A total of 312 MRIs (46 patients) were analyzed. Comparing change from the previous smallest measure, CP increase of 25% (PD) correlated with a segmented volume increase of 30% (R2 = 0.710), rather than 40% (spherical model extrapolation). CP-determined PD predicted survival at 1 month post-RT (HR = 2.77), but not other time points. Segmented volumetric-determined PD (40% threshold) predicted survival at all imaging timepoints (HRs = 2.57, 2.62, 3.35, 2.71, 16.29), and 30% volumetric PD threshold predicted survival at 1, 3, 5, and 9 month timepoints (HRs = 2.57, 2.62, 4.65, 5.54). Compared to ellipsoid volume, segmented volume demonstrated superior survival associations. CONCLUSIONS: Segmented volumetric assessments of PD correlated better with survival than CP or ellipsoid volume at most time points. Semiautomated tumor volume likely represents a more accurate, prognostically-relevant measure of disease burden in DIPG.

Extraneural Metastases of Diffuse Midline Glioma, H3 K27M-Mutant at Diagnosis: Case Report, Review of the Literature, and Identifying Targetable Alterations.

Extraneural metastases are rare in pediatric high-grade gliomas and little is known about the genomic profiles of tumors that disseminate beyond the central nervous system. We describe a pediatric patient with H3 K27M-mutant diffuse midline glioma of the brain and spine with biopsy-confirmed osseous metastases present at diagnosis and suspected metastatic parenchymal pulmonary disease. Several potentially clinically and/or therapeutically relevant genomic alterations were identified, including H3F3A and TP53 mutations as well as MET, CDK6, EMSY, and PIK3CG amplifications. Sequencing is critical to improve our understanding of the molecular drivers of distant metastases and discover therapeutic targets that penetrate all disease sites.

Accuracy of central neuro-imaging review of DIPG compared with histopathology in the International DIPG Registry.

BACKGROUND: Diffuse intrinsic pontine glioma (DIPG) remains a clinico-radiologic diagnosis without routine tissue acquisition. Reliable imaging distinction between DIPG and other pontine tumors with potentially more favorable prognoses and treatment considerations is essential. METHODS: Cases submitted to the International DIPG registry (IDIPGR) with histopathologic and/or radiologic data were analyzed. Central imaging review was performed on diagnostic brain MRIs (if available) by two neuro-radiologists. Imaging features suggestive of alternative diagnoses included nonpontine origin, <50% pontine involvement, focally exophytic morphology, sharply defined margins, and/or marked diffusion restriction throughout. RESULTS: Among 286 patients with pathology from biopsy and/or autopsy, 23 (8%) had histologic diagnoses inconsistent with DIPG, most commonly nondiffuse low-grade gliomas and embryonal tumors. Among 569 patients with centrally-reviewed diagnostic MRIs, 40 (7%) were classified as non-DIPG, alternative diagnosis suspected. The combined analysis included 151 patients with both histopathology and centrally-reviewed MRI. Of 77 patients with imaging classified as characteristic of DIPG, 76 (99%) had histopathologic diagnoses consistent with DIPG (infiltrating grade II-IV gliomas). Of 57 patients classified as likely DIPG with some unusual imaging features, 55 (96%) had histopathologic diagnoses consistent with DIPG. Of 17 patients with imaging features suggestive of an alternative diagnosis, eight (47%) had histopathologic diagnoses inconsistent with DIPG (remaining patients were excluded due to nonpontine tumor origin). Association between central neuro-imaging review impression and histopathology was significant (p < 0.001), and central neuro-imaging impression was prognostic of overall survival. CONCLUSIONS: The accuracy and important role of central neuro-imaging review in confirming the diagnosis of DIPG is demonstrated.

A pilot radiogenomic study of DIPG reveals distinct subgroups with unique clinical trajectories and therapeutic targets.

An adequate understanding of the relationships between radiographic and genomic features in diffuse intrinsic pontine glioma (DIPG) is essential, especially in the absence of universal biopsy, to further characterize the molecular heterogeneity of this disease and determine which patients are most likely to respond to biologically-driven therapies. Here, a radiogenomics analytic approach was applied to a cohort of 28 patients with DIPG. Tumor size and imaging characteristics from all available serial MRIs were evaluated by a neuro-radiologist, and patients were divided into three radiographic response groups (partial response [PR], stable disease [SD], progressive disease [PD]) based on MRI within 2 months of radiotherapy (RT) completion. Whole genome and RNA sequencing were performed on autopsy tumor specimens. We report several key, therapeutically-relevant findings: (1) Certain radiologic features on first and subsequent post-RT MRIs are associated with worse overall survival, including PD following irradiation as well as present, new, and/or increasing peripheral ring enhancement, necrosis, and diffusion restriction. (2) Upregulation of EMT-related genes and distant tumor spread at autopsy are observed in a subset of DIPG patients who exhibit poorer radiographic response to irradiation and/or higher likelihood of harboring H3F3A mutations, suggesting possible benefit of upfront craniospinal irradiation. (3) Additional genetic aberrations were identified, including DYNC1LI1 mutations in a subgroup of patients with PR on post-RT MRI; further investigation into potential roles in DIPG tumorigenesis and/or treatment sensitivity is necessary. (4) Whereas most DIPG tumors have an immunologically "cold" microenvironment, there appears to be a subset which harbor a more inflammatory genomic profile and/or higher mutational burden, with a trend toward improved overall survival and more favorable radiographic response to irradiation, in whom immunotherapy should be considered. This study has begun elucidating relationships between post-RT radiographic response with DIPG molecular profiles, revealing radiogenomically distinct subgroups with unique clinical trajectories and therapeutic targets.

Trametinib-associated Hyponatremia in a Child With Low-grade Glioma is Not Seen Following Treatment With Alternative MEK Inhibitor.

Molecularly targeted therapy with MEK inhibitors has been increasingly incorporated into the treatment of pediatric low-grade gliomas, but this promising therapy is associated with distinctive and specific toxicities. Understanding life-threatening MEK inhibitor toxicities and their management is critical to MEK inhibitor safety, especially among young children. This report describes severe hyponatremia associated with trametinib in an infant with progressive low-grade glioma without underlying endocrine dysfunction, which recurred despite significant dose reduction. Therapy with an alternative MEK inhibitor, binimetinib, provided excellent tumor response without hyponatremia, suggesting that some toxicities may be avoided by changing MEK inhibitor agents within the same class.

Characterizing temporal genomic heterogeneity in pediatric low-grade gliomas.

Recent discoveries have provided valuable insight into the genomic landscape of pediatric low-grade gliomas (LGGs) at diagnosis, facilitating molecularly targeted treatment. However, little is known about their temporal and therapy-related genomic heterogeneity. An adequate understanding of the evolution of pediatric LGGs' genomic profiles over time is critically important in guiding decisions about targeted therapeutics and diagnostic biopsy at recurrence. Fluorescence in situ hybridization, mutation-specific immunohistochemistry, and/or targeted sequencing were performed on paired tumor samples from primary diagnostic and subsequent surgeries. Ninety-four tumor samples from 45 patients (41 with two specimens, four with three specimens) from three institutions underwent testing. Conservation of BRAF fusion, BRAFV600E mutation, and FGFR1 rearrangement status was observed in 100%, 98%, and 96% of paired specimens, respectively. No loss or gain of IDH1 mutations or NTRK2, MYB, or MYBL1 rearrangements were detected over time. Histologic diagnosis remained the same in all tumors, with no acquired H3K27M mutations or malignant transformation. Changes in CDKN2A deletion status at recurrence occurred in 11 patients (42%), with acquisition of hemizygous CDKN2A deletion in seven and loss in four. Shorter time to progression and shorter time to subsequent surgery were observed among patients with acquired CDKN2A deletions compared to patients without acquisition of this alteration [median time to progression: 5.5 versus 16.0 months (p = 0.048); median time to next surgery: 17.0 months versus 29.0 months (p = 0.031)]. Most targetable genetic aberrations in pediatric LGGs, including BRAF alterations, are conserved at recurrence and following chemotherapy or irradiation. However, changes in CDKN2A deletion status over time were demonstrated. Acquisition of CDKN2A deletion may define a higher risk subgroup of pediatric LGGs with a poorer prognosis. Given the potential for targeted therapies for tumors harboring CDKN2A deletions, biopsy at recurrence may be indicated in certain patients, especially those with rapid progression.

Online Simulated Cases Assess Retention of Virtual Neighborhood Tour Curriculum.

Background Learning to identify and address social determinants of health (SDH) is a crucial component of pediatric residency training. A virtual tour of an impoverished neighborhood previously demonstrated efficacy in increasing residents' self-assessed knowledge and competence, but its impact on performance has not yet been reported. Online simulated cases are emerging as feasible assessment tools to measure trainees' skills across various healthcare settings. We developed online simulated cases to evaluate residents' retention of the virtual tour's key SDH-related learning objectives 1 month after completing this curriculum. Methods Three online simulated cases with interpolated open-ended questions were created to assess residents' ability to identify SDH, recommend appropriate resources, and display empathy. Scoring rubrics to objectively evaluate responses were developed and borderline scores were decided by a team of educators. Results 19 residents participated. Mean scores for all cases exceeded pre-established borderline scores (statistically significant in two of the three cases). More than 90% of residents identified relevant SDH in the primary care and emergency department cases. Ninety-five percent of residents recommended appropriate resources in all cases, and 89% displayed empathy. Discussion Residents' performance in online simulated cases demonstrated retention and application of the virtual tour's learning objectives, including recognizing SDH, offering appropriate resources, and displaying empathy, which supports the long-term effectiveness of the virtual tour curriculum to train pediatricians about SDH. Online simulated cases provided a standardized and cost-effective way to measure residents' skills related to curricular uptake, suggesting that this assessment approach may be adapted to evaluate other educational interventions.

Stress, Depression, and Quality of Life Among Caregivers of Children With Osteogenesis Imperfecta.

INTRODUCTION: The purpose of this study was to evaluate stress, depressive symptoms, and quality of life (QOL) among caregivers of children with osteogenesis imperfecta (OI) and to determine if associations exist with patient disease-related characteristics. METHODS: Psychosocial outcomes were evaluated in 33 caregivers of 31 patients with OI using the Pediatric Inventory for Parents (assessing stress), PedsQL Family Impact Module (assessing QOL), and Center for Epidemiologic Studies Depression Scale (assessing depressive symptoms). RESULTS: Higher levels of patient pain and lower patient physical functioning were significantly associated with both higher caregiver stress and poorer QOL (p < .05). Center for Epidemiologic Studies Depression Scale scores were not associated with patient pain or physical functioning. DISCUSSION: Parents caring for children with OI with higher levels of pain and/or lower physical functioning are at higher risk of suffering from increased stress and poorer QOL. Interventions should be developed to screen for and target these at-risk caregiver groups with resources and support.

Cyclic bisphosphonate therapy reduces pain and improves physical functioning in children with osteogenesis imperfecta.

BACKGROUND: Children with osteogenesis imperfecta (OI) experience pain and impaired physical functioning. The longitudinal effect of cyclic bisphosphonate treatment on these symptoms has not been described. We serially evaluated pain and functioning in pediatric patients with OI treated with intravenous bisphosphonate therapy. METHODS: Pain and physical functioning were assessed at multiple time-points over two infusion cycles in 22 OI patients (median age 10 years [range 2-21 years]; 8 girls) receiving cyclic intravenous bisphosphonate therapy. Pain was assessed using the FACES® visual analogue scale; physical functioning, including self-care, was assessed using the PedsQL™ Generic Core inventory. RESULTS: Pain scores decreased significantly immediately following infusion and remained reduced at 4 weeks post-infusion, increasing before and decreasing again after subsequent infusion (F = 25.00, p < 0.001). Physical functioning scaled scores improved 4 weeks after infusion and declined before subsequent infusion across patients (F = 10.87, p = 0.007). Exploratory analyses indicated significantly different effects between mild and moderate-severe OI types for pain, but not for physical functioning. No fractures occurred during the study. CONCLUSION: In children with OI, cyclic intravenous bisphosphonate therapy transiently reduces pain and improves functional abilities. Pain relief occurs immediately following infusion with functional improvements observed 4 weeks later. Both pain and physical functioning return to pretreatment levels by the subsequent infusion.

Modernizing Training on Social Determinants of Health: A Virtual Neighborhood Tour is Noninferior to an in-Person Experience.

Using innovative technology to teach about social determinants of health might address current training barriers related to standardization, sustainability, and scalability. A virtual tour of an impoverished neighborhood that used 360° videos was noninferior to the previous in-person experience.

Autofluorescence imaging and spectral-domain optical coherence tomography in incomplete congenital stationary night blindness and comparison with retinitis pigmentosa.

PURPOSE: To test the hypothesis that the evaluation of retinal structure can have diagnostic value in differentiating between incomplete congenital stationary night blindness (CSNB2) and retinitis pigmentosa (RP). To compare retinal thickness differences between patients with CSNB2 and myopic controls. DESIGN: Prospective cross-sectional study. METHODS: Ten eyes of 5 patients diagnosed with CSNB2 (4 X-linked recessive, 1 autosomal recessive) and 6 eyes of 3 patients with RP (2 autosomal dominant, 1 autosomal recessive) were evaluated with spectral-domain optical coherence tomography (SD OCT) and fundus autofluorescence (FAF). Diagnoses of CSNB2 and RP were confirmed by full-field electroretinography (ERG). Manual segmentation of retinal layers, aided by a computer program, was performed by 2 professional segmenters on SD OCT images of all CSNB2 patients and 4 age-similar, normal myopic controls. Seven patients were screened for mutations with congenital stationary night blindness and RP genotyping arrays. RESULTS: Patients with CSNB2 had specific findings on SD OCT and FAF that were distinct from those found in RP. CSNB2 patients showed qualitatively normal SD OCT results with preserved photoreceptor inner segment/outer segment junction, whereas this junction was lost in RP patients. In addition, CSNB2 patients had normal FAF images, whereas patients with RP demonstrated a ring of increased autofluorescence around the macula. On SD OCT segmentation, the inner and outer retinal layers of both X-linked recessive and autosomal recessive CSNB2 patients were thinner compared with those of normal myopic controls, with means generally outside of normal 95% confidence intervals. The only layers that demonstrated similar thickness between CSNB2 patients and the controls were the retinal nerve fiber layer and, temporal to the fovea, the combined outer segment layer and retinal pigment epithelium. A proband and his 2 affected brothers from a family segregating X-linked recessive CSNB2 had a mutation, p.R614X, in the gene encoding calcium channel, α 1F subunit. CONCLUSIONS: CSNB2 patients (X-linked recessive and autosomal recessive) had significantly thinner retinas than myopic controls. However, they demonstrated qualitatively normal SD OCT and FAF images, and therefore can be differentiated from RP patients with these techniques. Although ERG testing remains the gold standard for the diagnosis of these conditions, FAF and SD OCT systems are more widely available to community ophthalmologists, offer shorter acquisition times, and, unlike ERG, can be performed on the same day as the initial clinic visit. Therefore, as a supplement to ERG and genetic testing, we advocate the use of FAF and SD OCT in the examination of patients with CSNB2 and RP.

Transition zones between healthy and diseased retina in choroideremia (CHM) and Stargardt disease (STGD) as compared to retinitis pigmentosa (RP).

PURPOSE: To describe the structural changes across the transition zone (TZ) in choroideremia (CHM) and Stargardt disease (STGD) and to compare these to the TZ in retinitis pigmentosa (RP). METHODS: Frequency-domain (Fd)OCT line scans were obtained from seven patients with CHM, 20 with STGD, and 12 with RP and compared with those of 30 previously studied controls. A computer-aided manual segmentation procedure was used to determine the thicknesses of the outer segment (OS) layer, the outer nuclear layer plus outer plexiform layer (ONL+), the retinal pigment epithelium plus Bruch's membrane (RPE+BM), and the outer retina (OR). RESULTS: The TZ, while consistent within patient groups, showed differences across disease groups. In particular, (1) OS loss occurred before ONL+ loss in CHM and RP, whereas ONL+ loss occurred before OS loss in STGD; (2) ONL+ was preserved over a wider region of the retina in CHM than in RP; (3) RPE+BM remained normal across the RP TZ, but was typically thinned in CHM. In some CHM patients, it was abnormally thin in regions with normal OS and ONL+ thickness. In STGD, RPE+BM was thinned by the end of the TZ; and (4) the disappearances of the IS/OS and OLM were more abrupt in CHM and STGD than in RP. CONCLUSIONS: On fdOCT scans, patients with RP, CHM, and STGD all have a TZ between relatively healthy and severely affected retina. The patterns of changes in the receptor layers are similar within a disease category, but different across categories. The findings suggest that the pattern of progression of each disease is distinct and may offer clues for strategies in the development of future therapies.

Quantification of peripapillary sparing and macular involvement in Stargardt disease (STGD1).

PURPOSE: To quantify and compare structure and function across the macula and peripapillary area in Stargardt disease (STGD1). METHODS: Twenty-seven patients (27 eyes) and 12 age-similar controls (12 eyes) were studied. Patients were classified on the basis of full-field electroretinogram (ERG) results: Fundus autofluorescence (FAF) and spectral domain-optical coherence tomography (SD-OCT) horizontal line scans were obtained through the fovea and peripapillary area. The thicknesses of the outer nuclear layer plus outer plexiform layer (ONL+), outer segment (OS), and retinal pigment epithelium (RPE) were measured through the fovea, and peripapillary areas from 1° to 4° temporal to the optic disc edge using a computer-aided, manual segmentation technique. Visual sensitivities in the central 10° were assessed using microperimetry and related to retinal layer thicknesses. RESULTS: Compared to the central macula, the differences between controls and patients in ONL+, OS, and RPE layer thicknesses were less in the nasal and temporal macula. Relative sparing of the ONL+ and/or OS layers was detected in the nasal (i.e., peripapillary) macula in 8 of 13 patients with extramacular disease on FAF; relative functional sparing was also detected in this subgroup. All 14 patients with disease confined to the central macula, as detected on FAF, showed ONL+ and OS layer thinning in regions of normal RPE thickness. CONCLUSIONS: Relative peripapillary sparing was detected in STGD1 patients with extramacular disease on FAF. Photoreceptor thinning may precede RPE degeneration in STGD1.

The transition zone between healthy and diseased retina in patients with retinitis pigmentosa.

PURPOSE: To describe the structural changes in the transition zone from relatively healthy retinal regions to severely affected regions in patients with retinitis pigmentosa (RP) using frequency domain optical coherence tomography (fdOCT). METHODS: FdOCT line scans of the horizontal meridian were obtained from one eye of 13 patients with RP and 30 control subjects. The patients had normal or near normal foveal sensitivities and visual field diameters ≥10°. Using a computer-aided manual segmentation procedure, the locations at which the outer segment (OS) and outer nuclear layer plus outer plexiform layer (ONL+) thicknesses fell below the 95% confidence interval of the controls were measured, as were the locations at which the OS layer disappeared and the locations at which the ONL+ was reduced to an asymptotically small thickness. RESULTS: The progression from healthy to severely affected regions followed a common pattern in most patients. Region A, the central region including the foveal center, had normal OS and ONL+ thickness. Region B had abnormal OS but normal ONL+ thickness. Region C had abnormal but measurable OS and ONL+ thicknesses. In Region D, the OS layer disappeared, as did the IS/OS line, and the ONL+ thickness decreased further. In Region E, the ONL+ reached an asymptotic thickness. CONCLUSIONS: The structural changes in the transition zone followed an orderly progression from a thinning of the OS layer, to a thinning of the ONL+, to a loss of the OS layer, to an ONL+ reduced to an asymptotically small level.