For the past decade, it has been recognized that pediatric low-grade gliomas (LGGs) and glial-neuronal tumors carry distinct molecular alterations with resultant aberrant intracellular signaling in the Ras-mitogen-activated protein kinase pathway. The conclusions and recommendations of a consensus conference of how best to integrate the growing body of molecular genetic information into tumor classifications and, more importantly, for future treatment of pediatric LGGs are summarized here. There is uniform agreement that molecular characterization must be incorporated into classification and is increasingly critical for appropriate management. Molecular-targeted therapies should be integrated expeditiously, but also carefully into the management of these tumors and success measured not only by radiographic responses or stability, but also by functional outcomes. These trials need to be carried out with the caveat that the long-term impact of molecularly targeted therapy on the developing nervous system, especially with long duration treatment, is essentially unknown.

Objective: The goal of the Response Evaluation in Neurofibromatosis and Schwannomatosis Visual Outcomes Committee is to define the best functional outcome measures for future neurofibromatosis type 1 (NF1)-associated optic pathway glioma (OPG) clinical trials. Methods:The committee considered the components of vision, other ophthalmologic parameters affected by OPG, potential biomarkers of visual function, and quality of life measures to arrive at consensus-based, evidence-driven recommendations for objective and measurable functional endpoints for OPG trials.Results: Visual acuity (VA) assessments using consistent quantitative testing methods are recommended as the main functional outcome measure for NF1-OPG clinical trials. Teller acuity cards are recommended for use as the primary VA endpoint, and HOTV as a secondary endpoint once subjects are old enough to complete it. The optic disc should be assessed for pallor, as this appears to be a contributory variable that may affect the interpretation of VA change over time. Given the importance of capturing patient-reported outcomes in clinical trials, evaluating visual quality of life using the Children's Visual Function Questionnaire as a secondary endpoint is also proposed. Conclusions:The use of these key functional endpoints will be essential for evaluating the efficacy of future OPG clinical trials. Neurology ® 2013;81 (Suppl 1):S15-S24 GLOSSARY CVFQ 5 Children's Visual Function Questionnaire; logMAR 5 logarithm of the minimum angle of resolution; MS 5 multiple sclerosis; NF1 5 neurofibromatosis type 1; OCT 5 optical coherence tomography; OPG 5 optic pathway glioma; PFS 5 progression-free survival; QOL 5 quality of life; REiNS 5 Response Evaluation in Neurofibromatosis and Schwannomatosis; RNFL 5 retinal nerve fiber layer; TAC 5 Teller acuity cards; VA 5 visual acuity; VEP 5 visual evoked potential; VF 5 visual field.Optic pathway gliomas (OPG) arise in 15%-20% of children with neurofibromatosis type 1 (NF1), occur preferentially in young children compared with adolescents or adults, and cause vision loss in as many as half of those affected.1 In this regard, the main objective in clinical management of these tumors is preservation of visual function. Although prognostic factors have been identified, there are currently no reliable indicators of future visual loss. This absence of prognostic signs has led clinicians to avoid initiating treatment until visual function has declined. When treatment is indicated, NF1-OPG are typically managed with a combination of carboplatin and vincristine-an approach that has not changed in 15 years. 2To date, OPG clinical trials have focused on imaging outcomes, with tumor response and/or progression-free survival used as measures of treatment success.

Renal medullary carcinoma is an aggressive, chemoresistant tumor. Time from discovery of tumor to patient death is very short and has been altered by a wide variety of chemotherapies and immunotherapies. An unidentified genetic component is likely present.

Optic pathway gliomas (OPGs) occur in 15%-20% of children with neurofibromatosis type 1 (NF1), leading to visual deficits in fewer than half of these individuals. The goal of chemotherapy is to preserve vision, but vision loss in NF1-associated OPG can be unpredictable. Determining which child would benefit from chemotherapy and, equally important, which child is better observed without treatment can be difficult. Unfortunately, despite frequent imaging and ophthalmologic evaluations, some children experience progressive vision loss before treatment. Indications for chemotherapy usually are based on a comprehensive, quantitative assessment of vision, but reliable vision evaluation can be challenging in young children with NF1-OPG. The ability to identify and predict impending vision loss could potentially improve management decisions and visual outcomes. To address this challenge, ophthalmologic, electrophysiologic, and imaging biomarkers of vision in NF1-OPG have been proposed. We review current recommendations for the surveillance of children at risk for NF1-OPG, outline guidelines for initiating therapy, and describe the utility of proposed biomarkers for vision.

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Children and adults with Neurofibromatosis type 1 (NF1), a common autosomal dominant condition, manifest a variety of ophthalmologic conditions. Plexiform neurofibromas involving the eyelid, orbit, periorbital and facial structures (termed OPPN) can result in significant visual loss in children. Equally important, OPPNs can cause significant alteration in physical appearance secondary to proptosis, ptosis, and facial disfigurement, leading to social embarrassment and decreased self-esteem. Despite NF1 being a relatively common disease in which routine ophthalmologic examinations are required, no formal recommendations for clinical care of children with OPPNs exist. While medical and surgical interventions have been reported, there are no agreed upon criteria for when OPPN require therapy and which treatment produces the best outcome. Since a multi-disciplinary team of specialists (oculofacial plastics, pediatric ophthalmology, neuro-ophthalmology, medical genetics and neuro-oncology) direct management decisions, the absence of a uniform outcome measure that represents visual and or aesthetic sequelae complicates the design of evidence based studies and feasible clinical trials. In September 2013, a multi-disciplinary task force, composed of pediatric practitioners from tertiary care centers experienced in caring for children with OPPN, was convened to address the lack of clinical care guidelines for children with OPPN. This consensus statement provides recommendations for ophthalmologic monitoring and outlines treatment indications, forthcoming biologic therapy, while also discussing challenges to performing clinical trials in this complicated condition.

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Left-hemisphere (LH) superiority for speech perception is a fundamental neurocognitive aspect of language, and is particularly strong for consonant perception. Two key theoretical aspects of the LH advantage for consonants remain controversial, however: the processing mode (auditory vs. linguistic) and the developmental basis of the specialization (innate vs. experience dependent). Click consonants offer a unique opportunity to evaluate these theoretical issues. Brief and spectrally complex, oral clicks exemplify the acoustic properties that have been proposed for an auditorily based LH specialization, yet they retain linguistic significance only for listeners whose languages employ them as consonants (e.g., Zulu). Speakers of other languages (e.g., English) perceive these clicks as nonspeech sounds. We assessed Zulu versus English listeners' hemispheric asymmetries for clicks, in and out of syllable context, in a dichotic-listening task. Performance was good for both groups, but only Zulus showed an LH advantage. Thus, linguistic processing and experience both appear to be crucial.