Antiseizure effect of MEK inhibitor in a child with neurofibromatosis type 1-Developmental and epileptic encephalopathy and optic pathway glioma.

BACKGROUND: Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder due to a mutation in NF1 gene, resulting in phenotypically heterogeneous systemic manifestations. Patients with NF1 are prone to develop neoplasms of the central nervous system (CNS) and are particularly at risk for optic pathway gliomas (OPG). Epilepsy is another recognized neurologic complication in patients with NF1, with a prevalence estimated between 4% and 14%. Several case reports and early phase clinical trials have demonstrated that the mitogen-activated protein kinase inhibitors (MEKi) are effective in NF1-low-grade gliomas (LGGs), but their influence on seizure activity in humans has not been established. CASE STUDY: Here, we report a patient with NF1 and developmental and epileptic encephalopathy (DEE) harboring pharmacoresistant tonic seizures, and progressive optic pathway glioma (OPG). By using a MEKi therapy for her OPG, we observed an end to epileptic seizures as well as a significant improvement of interictal EEG abnormalities, despite a lack of tumor reduction. CONCLUSION: MEK inhibitor therapy should be considered for patients with NF1 and refractory epilepsy.

Treatment evaluation by volumetric segmentation in pediatric optic pathway glioma: evaluation of the effect of bevacizumab on intra-tumor components.

PURPOSE: Progressive pediatric optic pathway gliomas (OPGs) are treated by diverse systemic antitumor modalities. Refined insights on the course of intra-tumoral components are limited. METHODS: We performed an exploratory study on the longitudinal volumetric course of different (intra-)tumor components by manual segmentation of MRI at the start and after 3, 6 and 12 months of bevacizumab (BVZ) treatment. RESULTS: Thirty-one patients were treated with BVZ (median 12 months, range: 2-39 months). During treatment the total tumor volume decreased with median 19.9% (range: - 62.3 to + 29.7%; n = 30) within the first 3 months, decreased 19.0% (range: - 68.8 to + 96.1%; n = 28) between start and 6 months and 27.2% (range: -73.4 to + 36.0%; n = 21) between start and 12 months. Intra-tumoral cysts were present in 12 OPGs, all showed a decrease of volume during treatment. The relative contrast enhanced volume of NF1 associated OPG (n = 11) showed an significant reduction compared to OPG with a KIAA1549-BRAF fusion (p < 0.01). Three OPGs progressed during treatment, but were not preceded by an increase of relative contrast enhancement. CONCLUSION: Treatment with BVZ of progressive pediatric OPGs leads to a decrease of both total tumor volume and cystic volume for the majority of OPGs with emphasis on the first three months. NF1 and KIAA1549-BRAF fusion related OPGs showed a different (early) treatment effect regarding the tumor enhancing component on MRI, which did not correlate with tumor volume changes. Future research is necessary to further evaluate these findings and its relevance to clinical outcome parameters.

A nationwide evaluation of bevacizumab-based treatments in pediatric low-grade glioma in the UK: Safety, efficacy, visual morbidity, and outcomes.

BACKGROUND: Bevacizumab is increasingly used in children with pediatric low-grade glioma (PLGG) despite limited evidence. A nationwide UK service evaluation was conducted to provide larger cohort "real life" safety and efficacy data including functional visual outcomes. METHODS: Children receiving bevacizumab-based treatments (BBT) for PLGG (2009-2020) from 11 centers were included. Standardized neuro-radiological (RANO-LGG) and visual (logMAR visual acuity) criteria were used to assess clinical-radiological correlation, survival outcomes and multivariate prognostic analysis. RESULTS: Eighty-eight children with PLGG received BBT either as 3rd line with irinotecan (85%) or alongside 1st/2nd line chemotherapies (15%). Toxicity was limited and minimal. Partial response (PR, 40%), stable disease (SD, 49%), and progressive disease (PD, 11%) were seen during BBT. However, 65% progressed at 8 months (median) from BBT cessation, leading to a radiology-based 3 yr-progression-free survival (PFS) of 29%. Diencephalic syndrome (P = .03) was associated with adverse PFS. Pre-existing visual morbidity included unilateral (25%) or bilateral (11%) blindness. Improvement (29%) or stabilization (49%) of visual acuity was achieved, more often in patients' best eyes. Vision deteriorated during BBT in 14 (22%), with 3-year visual-PFS of 53%; more often in patients' worst eyes. A superior visual outcome (P = .023) was seen in neurofibromatosis type 1-associated optic pathway glioma (OPG). Concordance between visual and radiological responses was 36%; optimized to 48% using only best eye responses. CONCLUSIONS: BBTs provide effective short-term PLGG control and delay further progression, with a better sustained visual (best > worst eye) than radiological response. Further research could optimize the role of BBT toward a potentially sight-saving strategy in OPG.

Dose-dependent seizure control with MEK inhibitor therapy for progressive glioma in a child with neurofibromatosis type 1.

BACKGROUND: Low-grade gliomas (LGGs) occurring in children can result in many different neurologic complications, including seizures. MEK inhibitors are increasingly being used to treat LGG, but their effect on associated neurologic symptoms has not been established. RESULTS: Here, we report a patient with neurofibromatosis type 1 (NF1), medically refractory epilepsy (MRE), and an extensive optic pathway glioma (OPG) who developed dose-dependent seizure control while being treated with selumetinib. Seizure frequency rebounded after dose reduction for cardiac toxicity, then improved, and finally ceased after restarting full dosing, allowing confidence in the cause of improvement. CONCLUSION: Selumetinib may have promise in epilepsy management in other children with NF1 or LGG.

Visual Outcomes of Optic Pathway Glioma Treated With Chemotherapy in Neurofibromatosis Type 1.

PURPOSE: To analyze the visual outcomes following chemotherapy for optic pathway glioma in children with neurofibromatosis type 1. METHODS: This was a retrospective cohort study of 58 children with optic pathway glioma between 2003 and 2019. Best corrected visual acuity (BCVA) at diagnosis and at the last follow-up visit were analyzed. Correlation tests were performed to determine whether the final BCVA was predicted by the initial BCVA, initial Dodge stage, or retinal nerve fiber layer (RNFL) thickness stability. The first-line chemotherapy regimen included vincristine plus carboplatin (2003 to 2016) and vinblastine (since 2017). RESULTS: Twenty-four children (41%) received chemotherapy. The median age at diagnosis was 3 years, and 61% of the children were female. From the first visit to the last follow-up visit, there was a statistically significant difference in mean BCVA in eyes in the no treatment group (P = .034) but not in eyes in the chemotherapy group (P = .824). A moderate and weak positive correlation was found (r = 0.58 and r = 0.29, respectively). At the last follow-up visit, BCVA remained stable in 73% and improved in 27% of eyes in the no treatment group, and BCVA worsened in 25%, remained stable in 62%, and improved in 13% of eyes in the chemotherapy group. At the last follow-up visit, BCVA and Dodge stage had a weak negative correlation (r = -0.06 and r = -0.17, respectively). A negative moderate correlation was identified between RNFL thickness and BCVA at the last follow-up visit (r = -0.48 in the no treatment group and r = -0.46 in the chemotherapy group). CONCLUSIONS: Children treated with chemotherapy had worse BCVA, although the treatment arrested the decline or improved BCVA in 75% of the patients with no major side effects. [J Pediatr Ophthalmol Strabismus. 2022;59(2):128-135.].

Early radiotherapy preserves vision in sporadic optic pathway glioma.

BACKGROUND: Sporadic optic pathway/hypothalamic gliomas represent a unique entity within pediatric low-grade glioma. Despite favorable survival, location makes treatment difficult and local progression debilitating. This study is a longitudinal assessment of visual acuity (VA) among children treated within the last 2 decades. METHODS: Clinical characteristics were abstracted for patients treated from 2000 to 2018 at Texas Children's Cancer Center in Houston. Ophthalmologic data taken at 3- to 6-month intervals were examined with age-appropriate VA metrics converted to the LogMAR (logarithm of the minimum angle of resolution) scale. Kaplan-Meier blindness-free survival (BFS) curves, calculated as time-to-bilateral functional blindness (LogMAR ≥0.8 in both eyes), were calculated for patients receiving early radiation therapy (RT; upfront or as first-line salvage treatment) or chemotherapy (CT) and evaluated using the log-rank test. RESULTS: Thirty-eight patients with a median follow-up of 8.5 years (range, 2-17 years) were identified. Median age at diagnosis was 3 years (interquartile range, <1-6 years). Early RT was administered in 11 patients (29%). Twenty-seven patients (71%) were treated primarily with CT, initiated at a median age of 3.5 years (range, <1-11 years). Eight patients in the CT group did eventually require RT secondary to VA loss and following multiple lines of CT. Median age at RT for all patients was 11 years (range, 3-17 years). BFS rates were 81% at 5 years and 60% at 8 years for CT and 100% at 5 and 8 years for early RT (P = .017). CONCLUSIONS: In a contemporary cohort, early RT, defined as initial or first-line salvage therapy, was found to have superior BFS for appropriately selected patients with sporadic optic pathway/hypothalamic gliomas. LAY SUMMARY: Children with low-grade brain tumors of the optic pathway generally have excellent long-term survival; however, given the location of these tumors, there can commonly be threatened vision if the tumor grows. Although radiation is generally deferred in children on the basis of legitimate concerns regarding the effects on the developing brain, it may represent a vision-preserving therapy for well-selected older patients.

A phase II trial of selumetinib in children with recurrent optic pathway and hypothalamic low-grade glioma without NF1: a Pediatric Brain Tumor Consortium study.

BACKGROUND: Pediatric low-grade gliomas (pLGGs) are the most common childhood brain tumor. Progression-free survival (PFS) is much lower than overall survival, emphasizing the need for alternative treatments. Sporadic (without neurofibromatosis type 1) optic pathway and hypothalamic gliomas (OPHGs) are often multiply recurrent and cause significant visual deficits. Recently, there has been a prioritization of functional outcomes. METHODS: We present results from children with recurrent/progressive OPHGs treated on a PBTC (Pediatric Brain Tumor Consortium) phase II trial evaluating efficacy of selumetinib (AZD6244, ARRY-142886) a MEK-1/2 inhibitor. Stratum 4 of PBTC-029 included patients with sporadic recurrent/progressive OPHGs treated with selumetinib at the recommended phase II dose (25mg/m2/dose BID) for a maximum of 26 courses. RESULTS: Twenty-five eligible and evaluable patients were enrolled with a median of 4 (1-11) previous therapies. Six of 25 (24%) had partial response, 14/25 (56%) had stable disease, and 5 (20%) had progressive disease while on treatment. The median treatment courses were 26 (2-26); 14/25 patients completed all 26 courses. Two-year PFS was 78 ± 8.5%. Nineteen of 25 patients were evaluable for visual acuity which improved in 4/19 patients (21%), was stable in 13/19 (68%), and worsened in 2/19 (11%). Five of 19 patients (26%) had improved visual fields and 14/19 (74%) were stable. The most common toxicities were grade 1/2 CPK elevation, anemia, diarrhea, headache, nausea/emesis, fatigue, AST and ALT increase, hypoalbuminemia, and rash. CONCLUSIONS: Selumetinib was tolerable and led to responses and prolonged disease stability in children with recurrent/progressive OPHGs based upon radiographic response, PFS, and visual outcomes.

Visual outcomes following everolimus targeted therapy for neurofibromatosis type 1-associated optic pathway gliomas in children.

Data for visual acuity (VA) after treatment of neurofibromatosis type 1-associated optic pathway gliomas (NF1-OPGs) are limited. We retrospectively collected VA, converted to logMAR, before and after targeted therapy with everolimus for NF1-OPG, and compared to radiologic outcomes (14/18 with NF1-OPG, 25 eyes [three without quantifiable vision]). Upon completion of treatment, VA was stable in 19 eyes, improved in four eyes, and worsened in two eyes; visual and radiologic outcomes were discordant. In summary, the majority of children with NF1-OPG exhibited stabilization of their VA after everolimus treatment. A larger, prospective study will help delineate visual outcomes after targeted therapy.

Visual field outcomes in children treated for neurofibromatosis type 1-associated optic pathway gliomas: a multicenter retrospective study.

BACKGROUND: Optic pathway gliomas associated with neurofibromatosis type 1 (NF1-OPGs) may adversely affect visual acuity, but data regarding visual field (VF) outcomes after treatment in children are limited. The purpose of this study was to investigate the effects of NF1-OPGs on VF function in a large cohort of children after treatment with chemotherapy. METHODS: We performed a retrospective, international, multicenter study of VF outcomes in patients treated with chemotherapy for NF1-OPGs. RESULTS: A total of 25 participants underwent VF testing using formal perimetric techniques. At the end of treatment, 19 participants (76%) had persistent VF deficits. Formal VF testing was available for 16 participants (64%) at initiation and completion of treatment. Of the 16 children who underwent VF testing at initiation and completion of treatment, 7 (44%) showed stability of VF changes, 3 (19%) showed improvement of VF function, and 6 (38%) had worsening of VFs. Improvement or worsening of VF outcome did not always correlate with visual acuity outcome. Posterior tumor location involving the optic tracts and radiations was associated with more frequent and more profound VF defects. CONCLUSIONS: In our study cohort, children undergoing initial chemotherapy for NF1-OPGs had a high prevalence of VF loss, which could be independent of visual acuity loss. A larger, prospective study is necessary to fully determine the prevalence of VF loss and the effects of chemotherapy on VF outcomes in children with NF1-OPGs.

Visual field fluctuations correlating with the menstrual cycle in a patient with optic pathway glioma.

Optic pathway gliomas are commonly associated with vision loss in children. We describe an 18-year-old woman with neurofibromatosis, type 1 and an optic nerve glioma who showed reproducible visual field defects that worsened midmenstrual cycle and returned to baseline during menses. To our knowledge, this is the first reported case of visual field fluctuations in a patient with an optic nerve glioma that correlated with her menstrual cycle.

Bevacizumab for optic pathway glioma with worsening visual field in absence of imaging progression: 2 case reports and literature review.

Children with optic pathway gliomas (OPGs) frequently suffer from problems of visual function resulting from tumors. Previous reports showed that bevacizumab improved visual function in patients with OPG via tumor response to treatment. In these two case reports, we show that bevacizumab improved visual field without tumor response as seen in imaging. Both, a 10-year-old girl and a 6-year-old boy, had previous history of treatment with platinum-based chemotherapy. They had visual deterioration without tumor progression on MR imaging. Bevacizumab effectively and immediately improved visual field in both patients without imaging response of OPG. We emphasize that bevacizumab should be considered for patients with OPGs having visual deterioration without tumor progression.

Comparison of multi-shot and single shot echo-planar diffusion tensor techniques for the optic pathway in patients with neurofibromatosis type 1.

PURPOSE: Diffusion tensor imaging (DTI) may be helpful in assessing optic pathway integrity as a marker for treatment in neurofibromatosis type 1 (NF1) patients with optic gliomas (OG). However, susceptibility artifacts are common in typical single-shot echo planar imaging (ssDTI). A readout-segmented multi-shot EPI technique (rsDTI) was utilized to minimize susceptibility distortions of the skull base and improve quantitative metrics. METHODS: Healthy controls, children with NF1 without OG, and NF1 with OG ± visual symptoms were included. All subjects were scanned with both rsDTI and ssDTI sequences sequentially. Diffusion metrics and deterministic fiber tracking were calculated. Tract count, volume, and length were also compared by a two-factor mixed ANOVA. RESULTS: Five healthy controls, 7 NF1 children without OG, and 12 NF1 children with OG were imaged. Six OG patients had visual symptoms. Four subjects had no detectable optic pathway fibers on ssDTI due to susceptibility, for which rsDTI was able to delineate. Tract count (p < 0.001), tract volume (p < 0.001), and FA (P < 0.001) were significantly higher for rsDTI versus ssDTI for all subjects. MD (p < 0.001) and RD (p < 0.001) were significantly lower for rsDTI vs ssDTI. Finally, MD, AD, and RD had a significantly lower difference in NF1 children with visual symptoms compared to NF1 children without visual symptoms only on ssDTI scans. CONCLUSION: DTI with readout-segmented multi-shot EPI technique can better visualize the optic pathway and allow more confident measurements of anisotropy in NF1 patients. This is shown by a significant increase in FA, tract count, and volume with rsDTI versus ssDTI.

Marked functional recovery and imaging response of refractory optic pathway glioma to BRAFV600E inhibitor therapy: a report of two cases.

BACKGROUND: Despite appropriate therapeutic interventions, progressive optic pathway glioma (OPG) in children may result in loss of vision and other neurologic morbidities. Molecularly targeted therapy against the MAP kinase pathway holds promise in improving outcomes while resulting in lower treatment-related toxicities. We report two children with refractory OPG who had a substantial and early reversal of their neurologic deficits and an impressive imaging response of their tumor to BRAFV600E inhibition therapy. METHODS: Two children with OPG (BRAFV600E-mutated pilocytic astrocytoma) who did not respond to at least one frontline therapy were treated with the oral BRAFV600E inhibitor vemurafenib. RESULTS: Both children had substantial visual compromise before start of therapy, with one child additionally having motor deficits. Both had an early improvement in their vision, and the second child showed a demonstrable improvement in motor weakness. This was accompanied by a decrease in tumor size, which was sustained at 6 months from therapy. Neither child had significant toxicities except for mild skin sensitivity to vemurafenib. CONCLUSIONS: BRAFV600E inhibitor therapy can potentially reverse visual and neurologic decline associated with progressive OPG. The clinico-radiologic response appears to be prompt and marked. Ongoing clinical trials using BRAFV600E inhibitors can help confirm these early promising findings.

Analysis of Survival Prognosis for Children with Symptomatic Optic Pathway Gliomas Who Received Surgery.

OBJECTIVE: The feasibility and prognosis of surgical treatment for children with optic pathway gliomas (OPGs) is controversial. Therefore this study attempted to evaluate the effects of surgery and discuss prognostic factors related to the survival of children with symptomatic OPGs. MATERIALS AND METHODS: One-hundred twenty-five children diagnosed with OPGs underwent surgery in the Department of Neurosurgery, Beijing Tiantan Hospital from 2003-2016. In this retrospective study, their demographics, clinical characteristics, treatments, and survival outcomes were investigated and summarized. RESULTS: Among the 125 patients, the 5-year overall survival (OS) rate and progression-free survival (PFS) rate were 84.1% and 70.6%, respectively. In the univariate analysis, patients who received postoperative radiotherapy (RT) after surgery had significantly better 5-year OS and PFS rates than patients who did not receive RT (P < 0.001 for both comparisons), patients who were 3 years old had better PFS rates than younger patients (P < 0.001), and patients with endocrinology symptoms had significantly worse PFS rates than patients with other symptoms (P = 0.049). In the multiple regression analysis, postoperative treatment with RT and tumors with a lower pathologic grade were better predictors of OS. An age older than 3 years and postoperative treatment with RT were better predictors of PFS. CONCLUSIONS: Surgery is safe and feasible for children with large volumes of OPGs and symptoms of functional impairment and obstructive hydrocephalus. Furthermore, adjuvant RT after surgery may significantly improve OS and PFS. The pathologic grade is an independent prognostic factor for OS, and the age at diagnosis is an independent prognostic factor for PFS.

Current and emerging treatment strategies for children with progressive chiasmatic-hypothalamic glioma diagnosed as infants: a web-based survey.

Treatment of infant hypothalamic chiasmatic glioma (iCHG) is challenging, about 30% of the children progress during chemotherapy. Despite subsequent treatments the 5 year overall-survival rate is only 70%. This study investigates treatment strategies currently applied for progressive iCHG. A web-based questionnaire was sent out to the members of the SIOPE Brain Tumour Group asking for current second and third line strategies at progression during and after the end of first line therapy. The questionnaire was answered by 47 paediatric oncologists from 15 countries. iCHG progressing during first line therapy with carboplatin-vincristine would be considered for treatment with alternative chemotherapy by 17 (36%) and with surgery plus chemotherapy by 27 respondents (58%). Components suggested for second line were vinblastine (62%), cisplatin (34%) and cyclophosphamide (26%). For third line therapy bevacizumab (BVZ) was considered as suitable by respondents in 53% (often with irinotecan 40%) and vinblastine by 34% respectively. Experience with BVZ in CHG is shown by 53% of respondents regarding at least 95 patients (median treated 1-5 patients per respondent at any age) with a median BVZ administration over 12 months. Effectiveness was reported varying between stable disease and regression while complications were rarely stated (proteinuria, hypertension, bleeding). BVZ would be available to 85% of respondents as therapeutic option for iCHG patients. Multiple anti-neoplastic drug regimens are applied for progressive iCHG, partly considered in combination with surgery if safely feasible. BVZ is commonly used at a satisfactory level in third line, mainly combined with irinotecan.

Defining the temporal course of murine neurofibromatosis-1 optic gliomagenesis reveals a therapeutic window to attenuate retinal dysfunction.

Background: Optic gliomas arising in the neurofibromatosis type 1 (NF1) cancer predisposition syndrome cause reduced visual acuity in 30%-50% of affected children. Since human specimens are rare, genetically engineered mouse (GEM) models have been successfully employed for preclinical therapeutic discovery and validation. However, the sequence of cellular and molecular events that culminate in retinal dysfunction and vision loss has not been fully defined relevant to potential neuroprotective treatment strategies. Methods: Nf1flox/mut GFAP-Cre (FMC) mice and age-matched Nf1flox/flox (FF) controls were euthanized at defined intervals from 2 weeks to 24 weeks of age. Optic nerve volumes were measured, and optic nerves/retinae analyzed by immunohistochemistry. Optical coherence tomography (OCT) was performed on anesthetized mice. FMC mice were treated with lovastatin from 12 to 16 weeks of age. Results: The earliest event in tumorigenesis was a persistent elevation in proliferation (4 wk), which preceded sustained microglia numbers and incremental increases in S100+ glial cells. Microglia activation, as evidenced by increased interleukin (IL)-1ß expression and morphologic changes, coincided with axonal injury and retinal ganglion cell (RGC) apoptosis (6 wk). RGC loss and retinal nerve fiber layer (RNFL) thinning then ensued (9 wk), as revealed by direct measurements and live-animal OCT. Lovastatin administration at 12 weeks prevented further RGC loss and RNFL thinning both immediately and 8 weeks after treatment completion. Conclusion: By defining the chronology of the cellular and molecular events associated with optic glioma pathogenesis, we demonstrate critical periods for neuroprotective intervention and visual preservation, as well as establish OCT as an accurate biomarker of RGC loss.

High-Dose Intravenous Vitamin C Treatment of a Child with Neurofibromatosis Type 1 and Optic Pathway Glioma: A Case Report.

BACKGROUND In neurofibromatosis type 1 (NF1) disease, the loss of the tumor suppressor function of the neurofibromin gene leads to proliferation of neural tumors. In children, the most frequently identified tumor is the optic pathway glioma. CASE REPORT We describe the case of a 5-year-old child who was diagnosed with NF1 and optic pathway tumor onset at the age of 14 months. Because of the tumor progression, chemotherapy with carboplatin and vincristine was prescribed at this early age and continued for one year. As the progression of disease continued after chemotherapy, the child, at the age of 2.8 years, was started on high-dose intravenous vitamin C (IVC) treatment (7-15 grams per week) for 30 months. After 30 months, the results of IVC treatments demonstrated reduction and stabilization of the tumors in the optic chiasm, hypothalamus, and left optic nerve according to radiographic imaging. The right-sided optic nerve mass seen before IVC treatment disappeared by the end of the treatment. CONCLUSIONS This case highlights the positive effects of treating NF1 glioma with IVC. Additional studies are necessary to evaluate the role of high-dose IVC in glioma treatment.

Optic pathway glioma in children: 10 years of experience in a single institution.

Optic pathway glioma (OPG) is a rare brain tumor that occurs more commonly during early childhood and is frequently associated with neurofibromatosis type 1 (NF1). In this study, our aim was to describe the characteristics, management, and outcome of patients with OPG. We retrospectively analyzed the clinical charts of all children diagnosed with OPG at our institution from 2003 to 2013. Twenty children (11 boys and 9 girls, median age: 5 and 3/12 years; NF1: 15/20) were diagnosed with OPG. The diagnosis was based on magnetic resonance imaging (MRI) findings. A biopsy was useful in 3 patients. The main reason for seeking medical advice was decreased vision (7/20 patients), whereas in 10/20 patients, the diagnosis was established during the routine follow-up for their NF1. Fifteen patients demonstrated MRI findings of optic nerve involvement and/or chiasmal tumor, whereas in 5 children, postchiasmal structures were also involved. Sixteen patients (16/20) received carboplatin-based regimens, whereas 4/20 patients were only under close observation. Six patients showed deterioration of visual acuity and/or imaging findings at the end of treatment and/or during their follow-up. Three of them (3/6) underwent tumor resection, whereas 1 (1/6) received radiation treatment. None of our patients had total blindness from both eyes. Half of our patients were diagnosed during follow-up for their NF1, the incidence of which was high in our group. Our data suggest that chemotherapy helps in the preservation of vision in the majority of children.

Nerve growth factor improves visual loss in childhood optic gliomas: a randomized, double-blind, phase II clinical trial.

Paediatric optic pathway gliomas are low-grade brain tumours characterized by slow progression and invalidating visual loss. Presently there is no strategy to prevent visual loss in this kind of tumour. This study evaluated the effects of nerve growth factor administration in protecting visual function in patients with optic pathway glioma-related visual impairment. A prospective randomized double-blind phase II clinical trial was conducted in 18 optic pathway glioma patients, aged from 2 to 23 years, with stable disease and severe visual loss. Ten patients were randomly assigned to receive a single 10-day course of 0.5 mg murine nerve growth factor as eye drops, while eight patients received placebo. All patients were evaluated before and after treatment, testing visual acuity, visual field, visual-evoked potentials, optic coherence tomography, electroretinographic photopic negative response, and magnetic resonance imaging. Post-treatment evaluations were repeated at 15, 30, 90, and 180 days Brain magnetic resonance imaging was performed at baseline and at 180 days. Treatment with nerve growth factor led to statistically significant improvements in objective electrophysiological parameters (electroretinographic photopic negative response amplitude at 180 days and visual-evoked potentials at 30 days), which were not observed in placebo-treated patients. Furthermore, in patients in whom visual fields could still be measured, visual field worsening was only observed in placebo-treated cases, while three of four nerve growth factor-treated subjects showed significant visual field enlargement. This corresponded to improved visually guided behaviour, as reported by the patients and/or the caregivers. There was no evidence of side effects related to nerve growth factor treatment. Nerve growth factor eye drop administration appears a safe, easy and effective strategy for the treatment of visual loss associated with optic pathway gliomas.