Purpose: Neurodevelopmental disorders (NDD) caused by protein phosphatase 2A (PP2A) dysfunction have mainly been associated with de novo variants in PPP2R5D and PPP2CA, and more rarely in PPP2R1A. Here, we aimed to better understand the latter by characterizing 30 individuals with de novo and often recurrent variants in this PP2A scaffolding Aα subunit. Methods: Most cases were identified through routine clinical diagnostics. Variants were biochemically characterized for phosphatase activity and interaction with other PP2A subunits. Results: We describe 30 individuals with 16 different variants in PPP2R1A, 21 of whom had variants not previously reported. The severity of developmental delay ranged from mild learning problems to severe intellectual disability (ID) with or without epilepsy. Common features were language delay, hypotonia, and hypermobile joints. Macrocephaly was only seen in individuals without B55α subunit-binding deficit, and these patients had less severe ID and no seizures. Biochemically more disruptive variants with impaired B55α but increased striatin binding were associated with profound ID, epilepsy, corpus callosum hypoplasia, and sometimes microcephaly. Conclusion: We significantly expand the phenotypic spectrum of PPP2R1A-related NDD, revealing a broader clinical presentation of the patients and that the functional consequences of the variants are more diverse than previously reported.

Polyamines are endogenous molecules involved in cell damage following neurological insults, although it is unclear whether polyamines reduce or exacerbate this damage. We used a developmental seizure model in which we exposed Xenopus laevis tadpoles to pentylenetetrazole (PTZ), a known convulsant. We found that, after an initial PTZ exposure, seizure onset times were delayed in response to a second PTZ exposure 4 h later. This protective effect was a result of activity-dependent increases in synthesis of putrescine, the simplest polyamine. Unlike more complex polyamines that directly modulate ion channels, putrescine exerted its effect by altering the balance of excitation to inhibition. Tectal neuron recordings, 4 h after the initial seizure, revealed an elevated frequency of GABAergic spontaneous inhibitory postsynaptic currents. Our data suggest that this effect is mediated by an atypical pathway that converts putrescine into GABA, which then activates presynaptic GABA(B) receptors. Our data suggest that polyamines have a previously unknown neuroprotective role in the developing brain.

Objective Neck-Tongue syndrome (NTS) is characterized by brief attacks of neck or occipital pain, or both, brought out by abrupt head turning and accompanied by ipsilateral tongue symptoms. As the disorder is rare, we undertook a systematic review of the literature to identify all reported cases in order to phenotype clinically the disorder and subsequently inform clinical diagnostic criteria. Methods Two electronic databases were searched using the search term "neck tongue syndrome". All English language references were reviewed in full. Cases were abstracted using a standardized abstraction form and the references of the retrieved articles were reviewed by hand to identify additional references and cases. Conference proceedings from recent headache meetings were searched. We also report six new cases from our centers. Results There were 39 primary cases, 56% of which were female. Mean age (SD) at onset was 16 (12) years. Twenty (53%) experienced neck pain, seven (18%) occipital pain, and 11 (29%) both. Pain was most often sharp or stabbing and severe, lasting several seconds to several minutes. Eleven experienced numbness and/or tingling in the neck/occiput following the pain. Thirty-six had an accompanying tongue sensory disturbance and three a motor/posture disturbance; five had both. Thirteen had other headaches, and four a family history of Neck-Tongue syndrome. Conclusions Neck-Tongue syndrome typically has pediatric or adolescent onset, suggesting that ligamentous laxity during growth and development may facilitate transient subluxation of the lateral atlantoaxial joint with sudden head turning. Familial cases suggest a genetic predisposition in some individuals. Neck-Tongue syndrome should be re-instated in the International Classification of Headache Disorders.

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Objectives: To describe the impact of effusion volume, viscosity, and purulence on the audiologic profiles of children with otitis media with effusion. Design: Fifty-one ears from children between the ages of 8 months and 11 years who had a diagnosis of otitis media with effusion and were scheduled for tympanostomy tube placement were recruited from medical clinics. The control group consisted of 17 ears from children between the ages of 10 months and 11 years without a recent history of otitis media and were recruited from a database of research volunteers. Participants received a comprehensive audiologic testing battery consisting of tympanometry, otoacoustic emissions, behavioral audiometric thresholds, and auditory brainstem response testing. For children with otitis media, this testing battery occurred 1 to 2 days before surgery. Middle ear effusions were characterized and collected on the day of surgery during tympanostomy tube placement from ears with otitis media with effusion. The comprehensive audiologic testing battery was completed postoperatively as well for most participants. Results: Effusion volume, categorized in each ear as clear, partial, or full, effected the audiologic results. Ears with full effusions had moderate hearing losses, few to no measurable otoacoustic emissions, and delayed Wave V latencies. Ears with partial effusions and clear ears both had slight to mild hearing losses and normal Wave V latencies, though ears with partial effusions had fewer measurable otoacoustic emissions than clear ears. Normal-hearing control ears with no recent history of otitis media with effusion demonstrated normal audiometric thresholds, present otoacoustic emissions, and normal Wave V latencies. Repeat postoperative testing demonstrated improvements in audiologic testing results for all of the otitis media with effusion volume groups, with no significant differences remaining between the three otitis media with effusion groups. However, significant differences between otitis media with effusion ears and normal-hearing control ears persisted postoperatively, with otitis media with effusion ears demonstrating significantly poorer audiometric thresholds and reduced otoacoustic emissions as compared to normal control ears. The effect of effusion viscosity and purulence could not be systematically evaluated because minimal variability in effusion viscosity and purulence was observed in our sample, with nearly all effusions being mucoid and nonpurulent. Conclusions: Effusion volume observed at the time of tympanostomy tube surgery was found to play a significant role in outcomes and responses on a range of audiologic tests that compose the standard clinical pediatric audiologic assessment battery. Full middle ear effusions were associated with a moderate hearing loss, and few to no measurable otoacoustic emissions were detected. Ears with a recent diagnosis of otitis media with effusion but clear at the time of tympanostomy tube placement had less hearing loss and a greater number of present otoacoustic emissions than ears with full or partial effusions but were still found to have poorer hearing sensitivity than the healthy control ears. Differences between ears with otitis media with effusion and healthy control ears persisted on postoperative assessments of otoacoustic emissions and audiometric thresholds, though there were no remaining effects of the presurgical effusion volume group.

BACKGROUND Migraine is common in children and adolescents and can be disabling. Being able to predict which patients will respond to triptans based on their clinical phenotype would be helpful. Adult data suggest cranial autonomic symptoms (CAS) and aura predict triptan response. This study examined clinical predictors of triptan response in pediatric migraineurs. METHODS This retrospective chart review study included all patients <18 years old with migraine who were seen at the University of California, San Francisco Headache Center in 2014. Univariate Chi-squared analyses were performed, followed by multivariate logistic regression modeling. RESULTS Of 127 pediatric migraineurs, 70 (55%) had chronic migraine and 24 (19%) had aura. The majority (55%) had at least one CAS. Of 65 with triptan outcome data, 47 (73%) benefitted from a triptan. In univariate analyses, triptan benefit was seen in: 65% with chronic migraine vs. 88% with episodic migraine (p=0.048), 67% with aura vs. 74% without (p=0.66), and 70% of those with CAS vs. 74% without (p=0.76). In a multivariate logistic regression model, chronic migraine (CM), aura, and CAS were not statistically significant predictors of triptan benefit: CM: 0.25 (0.06–1.04)); aura: 0.65 (0.09–4.45); CAS: 0.75 (0.22–2.52). CONCLUSIONS In univariate analysis, those with chronic migraine were less likely to benefit from triptans. In contrast to what has been seen in adults, CAS and aura did not predict triptan response, though small sample size limited power. Larger pediatric studies are needed and future pediatric triptan trials should provide response rates stratified by clinical variables such as aura.

Introduction. The developing world continues to face challenges in closing the large treatment gap for epilepsy, due to a high burden of disease and few experienced providers to manage the condition. Children with epilepsy are susceptible to higher rates of developmental impairments and refractory disease due to delays or absence of appropriate management as a result. We demonstrated that a structured education intervention on pediatric epilepsy can improve knowledge, confidence, and impact clinical practice of first level providers in Zambia. Methods. Three first-level facilities across Zambia were included. After initial pilot versions and revisions, the final course was implemented at each site. Pre- and post-intervention knowledge and confidence assessments were performed. Additionally, chart reviews were conducted prior to intervention and 4 months after completion of training at each site to assess change on management. Results. Twenty-three of the original 24 participants from all 3 sites completed the training; 48% clinical officers, 43% nurses, 9% other expertise. Of the 15 concepts tested by knowledge assessment, 12 showed trends in improvement, 7 of which were significant ( P < .05). Chart reviews demonstrated significant improvement in documentation of seizure description ( P = .008), seizure frequency ( P = .00), and possible causes of seizures/epilepsy ( P = .034). Discussion. Key elements of success to this program included hands on clinical skills building and case-based teaching, development of a program with direct and ongoing input from the target audience, and inclusion of assessments to monitor impact on clinical practice. Future studies looking at health outcomes are necessary to determine sustained impact.

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