Clinical and genetic spectrum of SCN2A-associated episodic ataxia

Background: Pathogenic variants in SCN2A are associated with various neurological disorders including epilepsy, autism spectrum disorder and intellectual disability. Few reports have recently described SCN2A-associated episodic ataxia (EA). Our study identifies its broader clinical and genetic spectrum, and describes pharmacological approaches. Results: We report 21 patients with SCN2A-associated EA, of which 9 are unpublished cases. The large majority of patients present with epileptic seizures (18/21, 86%), often starting within the first three months of life (12/18, 67%). In contrast, onset of episodic ataxia ranged from 10 months to 14 years of age. The frequency of EA episodes ranged from brief, daily events up to 1-2 episodes per year each lasting several weeks. Potential triggers include minor head traumas and sleep deprivation. Cognitive outcome is favorable in most patients with normal or mildly impaired cognitive development in 17/21 patients (81%). No clear genotype-phenotype correlations were identified in this cohort. However, two mutational hotspots were identified, i.e. 7/21 patients (33%) harbor the identical pathogenic variant p.A263V, whereas 5/21 (24%) carry pathogenic variants that affect the S4 segment and its cytoplasmic loop within the domain IV. In addition, we identified six novel pathogenic variants in SCN2A. While acetazolamide was previously reported as beneficial in SCN2A-associated EA in one case, our data show a conflicting response in 8 additional patients treated with acetazolamide: three of them profited from acetazolamide treatment, while 5/8 did not. Conclusions: Our study describes the heterogeneous clinical spectrum of SCN2A-associated EA, identifies two mutational hotspots and shows positive effects of acetazolamide in about 50%. (C) 2019 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.Peer reviewe

Attention in neglect and extinction: Assessing the degree of correspondence between visual and auditory impairments using matched tasks

Claims have been made for associated degrees of impairment on both visual and auditory performance in unilateral neglect and extinction. Since this evidence is primarily based on different tests in each modality, it is difficult to properly quantify the degree of association between performance in vision and audition. The current study compares visual and auditory extinction and temporal order judgments (TOJs) in two cases with clinical visual neglect. Stimuli in both modalities were precisely matched in their temporal and spatial parameters. The results reveal a mixed pattern of association between different auditory tests and their visual counterparts. This suggests that associations between visual and auditory neglect can occur but these are neither obligatory nor pervasive. Instead, our data support models of spatial impairment in neglect and extinction that acknowledge differences in the contribution of spatial information to performance in each modality in responses to changing task demands

Clinical outcomes and patient-matched molecular composition of relapsed medulloblastoma

© 2021 by American Society of Clinical Oncology. Creative Commons Attribution Non-Commercial No Derivatives 4.0 License: https://creativecommons.org/licenses/by-nc-nd/4.0/Purpose: We sought to investigate clinical outcomes of relapsed medulloblastoma and to compare molecular features between patient-matched diagnostic and relapsed tumors. Methods: Children and infants enrolled on either SJMB03 (NCT00085202) or SJYC07 (NCT00602667) trials who experienced medulloblastoma relapse were analyzed for clinical outcomes, including anatomic and temporal patterns of relapse and postrelapse survival. A largely independent, paired molecular cohort was analyzed by DNA methylation array and next-generation sequencing. Results: A total of 72 of 329 (22%) SJMB03 and 52 of 79 (66%) SJYC07 patients experienced relapse with significant representation of Group 3 and wingless tumors. Although most patients exhibited some distal disease (79%), 38% of patients with sonic hedgehog tumors experienced isolated local relapse. Time to relapse and postrelapse survival varied by molecular subgroup with longer latencies for patients with Group 4 tumors. Postrelapse radiation therapy among previously nonirradiated SJYC07 patients was associated with long-term survival. Reirradiation was only temporizing for SJMB03 patients. Among 127 patients with patient-matched tumor pairs, 9 (7%) experienced subsequent nonmedulloblastoma CNS malignancies. Subgroup (96%) and subtype (80%) stabilities were largely maintained among the remainder. Rare subgroup divergence was observed from Group 4 to Group 3 tumors, which is coincident with genetic alterations involving MYC, MYCN, and FBXW7. Subgroup-specific patterns of alteration were identified for driver genes and chromosome arms. Conclusion: Clinical behavior of relapsed medulloblastoma must be contextualized in terms of up-front therapies and molecular classifications. Group 4 tumors exhibit slower biological progression. Utility of radiation at relapse is dependent on patient age and prior treatments. Degree and patterns of molecular conservation at relapse vary by subgroup. Relapse tissue enables verification of molecular targets and identification of occult secondary malignancies.info:eu-repo/semantics/publishedVersio

Therapeutic impact of cytoreductive surgery and irradiation of posterior fossa ependymoma in the molecular era: a retrospective multicohort analysis

PURPOSE: Posterior fossa ependymoma comprises two distinct molecular variants termed EPN_PFA and EPN_PFB that have a distinct biology and natural history. The therapeutic value of cytoreductive surgery and radiation therapy for posterior fossa ependymoma after accounting for molecular subgroup is not known. METHODS: Four independent nonoverlapping retrospective cohorts of posterior fossa ependymomas (n = 820) were profiled using genome-wide methylation arrays. Risk stratification models were designed based on known clinical and newly described molecular biomarkers identified by multivariable Cox proportional hazards analyses. RESULTS: Molecular subgroup is a powerful independent predictor of outcome even when accounting for age or treatment regimen. Incompletely resected EPN_PFA ependymomas have a dismal prognosis, with a 5-year progression-free survival ranging from 26.1% to 56.8% across all four cohorts. Although first-line (adjuvant) radiation is clearly beneficial for completely resected EPN_PFA, a substantial proportion of patients with EPN_PFB can be cured with surgery alone, and patients with relapsed EPN_PFB can often be treated successfully with delayed external-beam irradiation. CONCLUSION: The most impactful biomarker for posterior fossa ependymoma is molecular subgroup affiliation, independent of other demographic or treatment variables. However, both EPN_PFA and EPN_PFB still benefit from increased extent of resection, with the survival rates being particularly poor for subtotally resected EPN_PFA, even with adjuvant radiation therapy. Patients with EPN_PFB who undergo gross total resection are at lower risk for relapse and should be considered for inclusion in a randomized clinical trial of observation alone with radiation reserved for those who experience recurrence

Therapeutic Impact of Cytoreductive Surgery and Irradiation of Posterior Fossa Ependymoma in the Molecular Era: A Retrospective Multicohort Analysis

Posterior fossa ependymoma comprises two distinct molecular variants termed EPN_PFA and EPN_PFB that have a distinct biology and natural history. The therapeutic value of cytoreductive surgery and radiation therapy for posterior fossa ependymoma after accounting for molecular subgroup is not known

ICAR: endoscopic skull‐base surgery

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Binaural factors in auditory continuity

Presented at the 8th International Conference on Auditory Display (ICAD), Kyoto, Japan, July 2-5, 2002.Auditory continuity is a powerful illusion which has implications for the efficient coding of sound. Although auditory continuity has been studied extensively as a monaural phenomenon, there have been few reports of the influence of binaural factors. Hartmann [1] and Kashino & Warren [2] report that when a tone alternates with a noise, the continuity threshold of the tone is lower when the tone and noise differ in their interaural timing. Here we aconfirm the binaural contribution to continuity continuity using Huggins pitch [3]. We alternate a Huggins-pitch noise (target) with a negative-phase Schroeder complex (inducer) and find that pulsation thresholds are lower when listeners judge continuity of the pitch percept within the Huggins noise, than when they judge continuity of the noise itself. We also demonstrate that binaural continuity is determined by the relative ITDs of the targe and inducer rather than by their perceived spatial positions and introduce a simple model to account for our findings, which assumes that the tone is heard as pulsating if there is a detectable dip in the output of either of three channels: two monaural [4] and one binaural channel

Auditory Objects of attention: the role of interaural time-differences

The role of interaural time difference (ITD) in perceptual grouping and selective attention was explored in three experiments. Experiment 1 showed that listeners can use small differences in ITD between two sentences to say which of two, short, constant, target words was part of the attended sentence, in the absence of talker or fundamental frequency differences. Experiments 2 and 3 showed that listeners do not explicitly track components that share a common ITD. Their inability to segregate a harmonic from a target vowel by a difference in ITD was not substantially changed by the vowel being placed in a sentence context, where the sentence shared the same ITD as the rest of the vowel. The results indicate that, in following a particular auditory sound source over time, listeners attend to perceived auditory objects at particular azimuthal positions rather than attending explicitly to those frequency components that share a common ITD