Mutations in SCN2A, a gene encoding the voltage-gated sodium channel Nav1.2, have been associated with a spectrum of epilepsies and neurodevelopmental disorders. Here, we report the phenotypes of 71 patients and review 130 previously reported patients. We found that (i) encephalopathies with infantile/childhood onset epilepsies (≥3 months of age) occur almost as often as those with an early infantile onset (<3 months), and are thus more frequent than previously reported; (ii) distinct phenotypes can be seen within the late onset group, including myoclonic-atonic epilepsy (two patients), Lennox-Gastaut not emerging from West syndrome (two patients), and focal epilepsies with an electrical status epilepticus during slow sleep-like EEG pattern (six patients); and (iii) West syndrome constitutes a common phenotype with a major recurring mutation (p.Arg853Gln: two new and four previously reported children). Other known phenotypes include Ohtahara syndrome, epilepsy of infancy with migrating focal seizures, and intellectual disability or autism without epilepsy. To assess the response to antiepileptic therapy, we retrospectively reviewed the treatment regimen and the course of the epilepsy in 66 patients for which well-documented medical information was available. We find that the use of sodium channel blockers was often associated with clinically relevant seizure reduction or seizure freedom in children with early infantile epilepsies (<3 months), whereas other antiepileptic drugs were less effective. In contrast, sodium channel blockers were rarely effective in epilepsies with later onset (≥3 months) and sometimes induced seizure worsening. Regarding the genetic findings, truncating mutations were exclusively seen in patients with late onset epilepsies and lack of response to sodium channel blockers. Functional characterization of four selected missense mutations using whole cell patch-clamping in tsA201 cells-together with data from the literature-suggest that mutations associated with early infantile epilepsy result in increased sodium channel activity with gain-of-function, characterized by slowing of fast inactivation, acceleration of its recovery or increased persistent sodium current. Further, a good response to sodium channel blockers clinically was found to be associated with a relatively small gain-of-function. In contrast, mutations in patients with late-onset forms and an insufficient response to sodium channel blockers were associated with loss-of-function effects, including a depolarizing shift of voltage-dependent activation or a hyperpolarizing shift of channel availability (steady-state inactivation). Our clinical and experimental data suggest a correlation between age at disease onset, response to sodium channel blockers and the functional properties of mutations in children with SCN2A-related epilepsy.

In recent years, several genes have been causally associated with epilepsy. However, making a genetic diagnosis in a patient can still be difficult, since extensive phenotypic and genetic heterogeneity has been observed in many monogenic epilepsies. This study aimed to analyze the genetic basis of a wide spectrum of epilepsies with age of onset spanning from the neonatal period to adulthood. A gene panel targeting 46 epilepsy genes was used on a cohort of 216 patients consecutively referred for panel testing. The patients had a range of different epilepsies from benign neonatal seizures to epileptic encephalopathies (EEs). Potentially causative variants were evaluated by literature and database searches, submitted to bioinformatic prediction algorithms, and validated by Sanger sequencing. If possible, parents were included for segregation analysis. We identified a presumed disease-causing variant in 49 (23%) of the 216 patients. The variants were found in 19 different genes including SCN1A, STXBP1, CDKL5, SCN2A, SCN8A, GABRA1, KCNA2, and STX1B. Patients with neonatal-onset epilepsies had the highest rate of positive findings (57%). The overall yield for patients with EEs was 32%, compared to 17% among patients with generalized epilepsies and 16% in patients with focal or multifocal epilepsies. By the use of a gene panel consisting of 46 epilepsy genes, we were able to find a disease-causing genetic variation in 23% of the analyzed patients. The highest yield was found among patients with neonatal-onset epilepsies and EEs.

Magnetic resonance arterial spin labeling (ASL) at 3 Tesla has been investigated as a quantitative technique for measuring regional cerebral perfusion (RCP) in newborn infants. RCP values were measured in 49 healthy neonates: 32 preterm infants born before 34 wk of gestation and 17 term-born neonates. Examinations were performed on unsedated infants at postmenstrual age of 39 -40 wk in both groups. Due to motion, reliable data were obtained from 23 preterm and 6 term infants. Perfusion in the basal ganglia (39 and 30 mL/100 g/min for preterm and term neonates, respectively) was significantly higher (p Ͻ 0.0001) than in cortical gray matter (19 and 16 mL/100 g/min) and white matter (15 and 10 mL/100 g/min), both in preterm neonates at term-equivalent age and in term neonates. Perfusion was significantly higher (p ϭ 0.01) in the preterm group than in the term infants, indicating that RCP may be influenced by developmental and postnatal ages. This study demonstrates, for the first time, that noninvasive ASL at 3T may be used to measure RCP in healthy unsedated preterm and term neonates. ASL is, therefore, a viable tool that will allow serial studies of RCP in high-risk neonates. H igh-risk neonates, either infants born prematurely or asphyxiated infants born at term, have a vulnerable cerebral circulation (1). Impaired autoregulation of the CBF and thus cerebral perfusion contributes to some extent to the development of brain damage in those infants (2-4). Other mechanisms, as inflammation-mediated perfusion disturbances might also be implicated in brain damage development (5), however, this point has not yet been demonstrated.Studies of the cerebral circulation have previously been performed using different invasive methods as xenon clearance (1,6), positron emission tomography (PET) (7,8), and SPECT (9). Noninvasive approaches for estimating global CBF, e.g. Doppler ultrasonography and NIRS (10) have been used achieving only a limited use (11). NIRS as a cot-side method for measuring CBF was described in the late 1980s (12) but has not yet become a routine application, probably because methodological limitations are a problem in quantitative NIRS perfusion measurements. However, quantitative measurements of CBF in neonates have recently been performed with sonographic flowmetry of carotid and vertebral arteries (13)(14)(15)(16). From these studies, it is known that global CBF increases with PMA; however, quantitative regional brain perfusion data and the influence of postnatal age beyond the first 2 wk of life (16) are not yet available on healthy neonates.In recent years, a noninvasive magnetic resonance (MR) method for accurately measuring regional brain perfusion has been developed (17). MR-Atrial spin labeling (ASL) is a completely noninvasive MR technique that enables accurate maps of RCP to be acquired in a few minutes. As this MR method is noninvasive and safe, even in very young infants, the measurements may be repeated, e.g. for monitoring changes in perfusion or response to treatment.The basic...

The purpose of this study was to determine whether visual stimulation in sleeping infants and young children can be examined by functional magnetic resonance imaging. We studied 17 children, aged 3 d to 48 mo, and three healthy adults. Visual stimulation was performed with 8-Hz flickering light through the sleeping childs' closed eyelids. Functional magnetic resonance imaging was performed with a gradient echoplanar sequence in a l.5-T magnetic resonance scanner. Six subjects were excluded because of movement artifacts; the youngest infant showed no response. In 10 children, we could demonstrate areas of signal decrease during visual stimulation in the occipital cortex (mean decrease 2.21%), contrary to the signal increase observed in the adult controls (mean increase 2.82%). This decrease may be due to a higher proportional increase in oxygen extraction compared with increase in cerebral blood flow during activation. The different response patterns in young children and adults can reflect developmental or behavioral differences. Localization of the activation seemed to be age-dependent. In the older children and the adults, it encompassed the whole length of the calcarine sulcus, whereas it was restricted to the anterior and medial part of the calcarine sulcus in the younger infants. This may reflect a different functional organization of the young child's visual cortex or the on-going retinal development.

IMPORTANCE Human papillomavirus (HPV) infections cause anogenital cancers and warts. The 9-valent HPV vaccine provides protection against 7 high-risk types of HPV responsible for 90% of cervical cancers and 2 other HPV types accounting for 90% of genital warts.OBJECTIVE To determine whether HPV type-specific antibody responses would be noninferior among girls and boys aged 9 to 14 years after receiving 2 doses of the 9-valent HPV vaccine compared with adolescent girls and young women aged 16 to 26 years receiving 3 doses. DESIGN, SETTING, AND PARTICIPANTS Open-label, noninferiority, immunogenicity trial conducted at 52 ambulatory care sites in 15 countries. The study was initiated on December 16, 2013, with the last participant visit for this report on June 19, 2015. Five cohorts were enrolled: (1) girls aged 9 to 14 years to receive 2 doses 6 months apart (n = 301); (2) boys aged 9 to 14 years to receive 2 doses 6 months apart (n = 301); (3) girls and boys aged 9 to 14 years to receive 2 doses 12 months apart (n = 301); (4) girls aged 9 to 14 years to receive 3 doses over 6 months (n = 301); and (5) a control group of adolescent girls and young women aged 16 to 26 years to receive 3 doses over 6 months (n = 314).INTERVENTIONS Two doses of the 9-valent HPV vaccine administered 6 or 12 months apart or 3 doses administered over 6 months. MAIN OUTCOMES AND MEASURESThe primary end point was prespecified as the antibody response against each HPV type assessed 1 month after the last dose using a competitive immunoassay. Each of the three 2-dose regimens was compared with the standard 3-dose schedule in adolescent girls and young women using a noninferiority margin of 0.67 for the ratio of the antibody geometric mean titers. RESULTSOf the 1518 participants (753 girls [mean age, 11.4 years]; 451 boys [mean age, 11.5 years]; and 314 adolescent girls and young women [mean age, 21.0 years]), 1474 completed the study and data from 1377 were analyzed. At 4 weeks after the last dose, HPV antibody responses in girls and boys given 2 doses were noninferior to HPV antibody responses in adolescent girls and young women given 3 doses (P < .001 for each HPV type). Compared with adolescent girls and young women who received 3 doses over 6 months, the 1-sided 97.5% CIs for the ratio of HPV antibody geometric mean titers at 1 month after the last dose across the 9 HPV subtypes ranged from 1.36 to ϱ to 2.50 to ϱ for girls who received 2 doses 6 months apart; from 1.37 to ϱ to 2.55 to ϱ for boys who received 2 doses 6 months apart; and from 1.61 to ϱ to 5.36 to ϱ for girls and boys who received 2 doses 12 months apart.CONCLUSIONS AND RELEVANCE Among girls and boys aged 9 to 14 years receiving 2-dose regimens of a 9-valent HPV vaccine separated by 6 or 12 months, immunogenicity 4 weeks after the last dose was noninferior to a 3-dose regimen in a cohort of adolescent girls and young women. Further research is needed to assess persistence of antibody responses and effects on clinical outcomes.

Modified Atkins diet (MAD) is a less restrictive variety of the classical ketogenic diet (KD), used for treating patients with medically resistant epilepsy. There are only few reports comparing the two types of diets in terms of seizure reduction and tolerability. We compared the effect of a MAD evaluated prospectively on 33 consecutive children with medically resistant epilepsy, with a group of 50 patients, previously treated with KD. Patients who had >50% seizure reduction were considered responders. After 3 months on the MAD, 17 patients (52%) were responders, including 14 (42%) who had >90% seizure reduction. After 6 months, 13 patients (39%) were responders. Seventeen patients (52%) remained on the MAD at least 12 months with excellent overall tolerance and compliance, including 9 patients (27%) who were responders, 4 of them (12%) having >90% seizure reduction. Although there was a trend for higher incidence of responders in the KD group, this failed to reach the level of significance: after 6 months 39% on MAD and 60% on KD were responders. However, this trend was not observed when the two groups were adjusted for difference in age (patients in the MAD group were older than the KD group). In conclusion, our experience suggests that the MAD is similarly effective as the KD in reducing seizure frequency in children with medically resistant epilepsy.

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(Abstracted from JAMA 2016;316:2411–2421) Diseases caused by human papillomavirus (HPV) infections are a substantial health care burden in both the developing and developed world.