BACKGROUNDSpinal muscular atrophy is an autosomal recessive neuromuscular disorder that is caused by an insufficient level of survival motor neuron (SMN) protein. Nusinersen is an antisense oligonucleotide drug that modifies pre-messenger RNA splicing of the SMN2 gene and thus promotes increased production of full-length SMN protein. METHODSWe conducted a randomized, double-blind, sham-controlled, phase 3 efficacy and safety trial of nusinersen in infants with spinal muscular atrophy. The primary end points were a motor-milestone response (defined according to results on the Hammersmith Infant Neurological Examination) and event-free survival (time to death or the use of permanent assisted ventilation). Secondary end points included overall survival and subgroup analyses of event-free survival according to disease duration at screening. Only the first primary end point was tested in a prespecified interim analysis. To control the overall type I error rate at 0.05, a hierarchical testing strategy was used for the second primary end point and the secondary end points in the final analysis. RESULTSIn the interim analysis, a significantly higher percentage of infants in the nusinersen group than in the control group had a motor-milestone response (21 of 51 infants [41%] vs. 0 of 27 [0%], P<0.001), and this result prompted early termination of the trial. In the final analysis, a significantly higher percentage of infants in the nusinersen group than in the control group had a motor-milestone response (37 of 73 infants [51%] vs. 0 of 37 [0%]), and the likelihood of event-free survival was higher in the nusinersen group than in the control group (hazard ratio for death or the use of permanent assisted ventilation, 0.53; P = 0.005). The likelihood of overall survival was higher in the nusinersen group than in the control group (hazard ratio for death, 0.37; P = 0.004), and infants with a shorter disease duration at screening were more likely than those with a longer disease duration to benefit from nusinersen. The incidence and severity of adverse events were similar in the two groups. CONCLUSIONSAmong infants with spinal muscular atrophy, those who received nusinersen were more likely to be alive and have improvements in motor function than those in the control group. Early treatment may be necessary to maximize the benefit of the drug. (Funded by Biogen and Ionis Pharmaceuticals; ENDEAR ClinicalTrials.gov number, NCT02193074.)

See Cannon (doi: ) for a scientific commentary on this article. Dominant gain-of-function mutations in SCN4A , which encodes the α-subunit of the voltage-gated sodium channel, are a common cause of myotonia and periodic paralysis. Zaharieva et al. now report recessive loss-of-function SCN4A mutations in 11 patents with congenital myopathy. The mutations cause fully non-functional channels or result in reduced channel activity.

Invasive recordings carry a noticeable rate of adverse events but provide invaluable information in delineating the epileptogenic zone. The low incidence of such events among younger children suggests that invasive recordings can be successfully performed with low morbidity in this age group.

SUMMARYPurpose: The present study aims to describe the cognitive profile of children with medically refractory extratemporal epilepsies who undergo focal surgery and to identify determinants for preoperative and postoperative cognitive level. Methods: This is a retrospective cohort study. Children who underwent operations between 1997 and 2008 with a focal lesion in frontal, parietal, or occipital cortices and with a presurgical or postsurgical cognitive evaluation, were eligible for the study. Key Findings: Sixty-six children (53% male) with a mean age of 9.3 ± 8.8 years were enrolled. The overall full-scale IQ (FSIQ) at cognitive testing was 77.4 ± 44.4 before surgery. Children did not show any significant change in their FSIQ after surgery. Duration of presurgical epilepsy, age at epilepsy onset, etiology, and gender were found to be independently associated with lower FSIQ before surgery. Presurgical cognitive level was the only factor independently associated with postsurgical FSIQ. Overall, 51.5% of children who underwent surgery were seizure-free; however, the good postsurgical epilepsy control did not seem to influence the cognitive outcome. Significance: Children with extratemporal lobe epilepsy are below the normal cognitive level range. Intellectual abilities of children undergoing surgery are determined independently by presurgical factors and surgery does not seem to affect the cognitive level in the postsurgical period, even for those who become free from clinical seizures.

ADHD Attention-deficit-hyperactivity disorder ASD Autism spectrum disorder DBD(NOS) disruptive disorders not otherwise specified DSM-IV Diagnostic and Statistical Manual of Mental Disorders (4th edition) ODD ⁄ CD oppositional defiant disorder/conduct disorder AIM To establish the rates and types of psychiatric disorder in children before and after surgery for extratemporal epilepsy. Relationships between psychiatric morbidity and demographic ⁄ clinical variables were examined.METHOD A retrospective case note review of 71 children undergoing extratemporal focal resection for drug resistant epilepsy in a specialist epilepsy surgery programme between 1997 and 2008. Psychiatric diagnoses were derived from pre-and postoperative assessments according to DSM-IV criteria.RESULTS Seventy-one children (38 males, 33 females) were eligible for this study. Mean age (SD)at surgery was 9 (5) years. Frontal resections were performed in 73% of the children, parietal in 17%, and occipital in 10%. Mental health problems were present in 37 of 71 (52%) children preand ⁄ or postoperatively. A similar proportion of children had psychiatric diagnoses pre-and postoperatively: 31 of 71 (44%) and 32 of 71 (45%) respectively.INTERPRETATION Psychopathology is common in children with extratemporal epilepsy. In this sample, the impact of surgery on psychiatric symptoms was not predictable: some children were unchanged, others improved, and others acquired new psychiatric diagnoses postoperatively. Given the high rates of psychiatric disorder in this group of patients, detection and treatment of mental health needs may be important.Children with epilepsy have higher rates of psychiatric disorders than children in the general population. For example, in one epidemiological study, 29% of children with epilepsy had at least one psychiatric diagnosis, more than four times the rate in the general population. This compared with 11.6% in children with chronic physical disorders not involving the brain. 1 Psychiatric diagnoses were found in 58% of children with additional neurological problems as well as epilepsy, a finding replicated in other epidemiological samples.2 Children entering epilepsy surgery programmes are usually examples of this latter group; they almost always have a structural brain abnormality and complex epilepsy, and are, therefore, likely to have high rates of psychiatric disorder. In addition, studies of clinical samples have indicated that the psychosocial impairments in these children are significantly greater than those found in children with other chronic disorders such as diabetes or asthma 3,4 and that mental health problems contribute significantly to the overall impairment experienced by the child and family. 5The best-studied group of patients undergoing epilepsy surgery are those with temporal lobe epilepsy. In children who have undergone temporal lobe resections for epilepsy refractory to medical treatment, a previous study from our group showed that psychopathology was common and a wide range of disorders were seen, in...

FCD Focal cortical dysplasiaAIM The aim of the study was to describe seizure outcome following surgery for focal extratemporal epilepsy and identify factors associated with prolonged postsurgical freedom from seizures.METHOD In this retrospective cohort study, children with drug-resistant focal extratemporal epilepsy were treated surgically and followed up in a single tertiary care centre between 1997 and 2008.RESULTS Eighty children were identified for inclusion in the study (42 males, 38 females; median age 9y 1mo, range 3mo-18y 7mo). The aetiology was identified as focal cortical dysplasia (n=37), low-grade tumour (n=22), tuberous sclerosis (n=9), or non-specific (n=12). Children were followed for a median of 3 years 1 month (range 8mo-10y 7mo) after surgery. Overall, at last follow-up, 50% of the children had been completely seizure free since surgery (Engel class Ia); of these 40 individuals, 15 had discontinued all antiepileptic drugs. Several presurgical factors were associated with a favourable outcome. However, after controlling for confounding factors, aetiology appeared to be the only determinant of long-term seizure outcome as non-specific lesion pathology was associated with seizure recurrence (hazard ratio 10.43; 95% confidence interval 3.26-33.39).INTERPRETATION In 50% of cases, children with surgically treated drug-resistant extratemporal epilepsies have an excellent long-term outcome. The aetiology of the epileptogenic lesion appears to be the only significant determinant of surgical outcome in this population of children. It is difficult to correctly identify non-specific pathology on presurgical magnetic resonance imaging.About 20% of surgical procedures for drug-resistant epilepsy in childhood involve focal resection of areas outside the temporal lobe.1 Although surgical resection for an extratemporal focus is less likely to achieve seizure freedom than temporal lobe resections, improved presurgical diagnostics and patient selection in the last decades appear to have improved the selection and seizure outcome of focal extratemporal resections, as reported in recent case series.2,3 Forty to 70% of children with extratemporal epilepsies could become seizure free after surgery, and this would have a significant impact on the quality of life for these children, especially considering that remission from epilepsy is unlikely to be achieved by medications alone.4,5 However, current literature is limited and only a few, small descriptive series have been published, in which the outcomes and populations were inconsistent and follow-up was mostly short term. [6][7][8] Our purpose was to study a large surgical population of children with focal extratemporal epilepsies, to describe their seizure outcome, and to identify which factors were independently associated with long-term postsurgical seizure freedom. METHOD ParticipantsAll children who had undergone focal resection for drug-resistant epilepsy involving the frontal, parietal, or occipital cortices, confined to one lobe, at Great Ormond Street Hosp...

Tuberous sclerosis complex (TSC) is an inherited disorder resulting from mutations in one of two genes, TSC1 (Hamartin) and TSC2 (Tuberin). These two proteins form a cytosolic complex that inhibits the mTOR pathway that controls cell growth and proliferation. Pathologically, abnormalities of neuronal migration, cellular differentiation and excessive cellular proliferation all contribute to the formation of the different brain lesions of TSC. Seizure is the most common presenting symptom. Seizures can be present in the first year of life and up to one third of children develop infantile spasms. Seizures usually have a focal or multifocal origin, are often resistant to antiepileptic drugs and have a negative impact on the neurocognitive development. Vigabatrin has proved to be effective against infantile spasms due to TSC. New evidence suggests that it is possible to noninvasively identify using multimodality techniques, TSC children who are likely to become seizure-free following surgical treatment. Understanding the mechanisms of epileptogenesis and the possible role of the mTOR pathway in this process might increase the availability of novel and targeted therapies.

Autosomal recessive mutations in the ECEL1 gene have recently been associated with a wide phenotypic spectrum including severe congenital contractural syndromes and distal arthrogryposis type 5D (DA5D). Here, we describe four novel families with ECEL1 gene mutations, reporting 15 years of follow-up for four patients and detailed muscle pathological description for three individuals. In particular, we observed mild myopathic features, prominent core-like areas in one individual, and presence of nCAM positive fibres in three patients from 2 unrelated families suggesting a possible problem with innervation. Our findings expand current knowledge concerning the phenotypic and pathological spectrum associated with ECEL1 gene mutations and may suggest novel insights regarding the underlying pathomechanism of the disease.