Reanalysis of Trio Whole-Genome Sequencing Data Doubles the Yield in Autism Spectrum Disorder: De Novo Variants Present in Half.

Autism spectrum disorder (ASD) is a common condition with lifelong implications. The last decade has seen dramatic improvements in DNA sequencing and related bioinformatics and databases. We analyzed the raw DNA sequencing files on the Variantyx® bioinformatics platform for the last 50 ASD patients evaluated with trio whole-genome sequencing (trio-WGS). "Qualified" variants were defined as coding, rare, and evolutionarily conserved. Primary Diagnostic Variants (PDV), additionally, were present in genes directly linked to ASD and matched clinical correlation. A PDV was identified in 34/50 (68%) of cases, including 25 (50%) cases with heterozygous de novo and 10 (20%) with inherited variants. De novo variants in genes directly associated with ASD were far more likely to be Qualifying than non-Qualifying versus a control group of genes (p = 0.0002), validating that most are indeed disease related. Sequence reanalysis increased diagnostic yield from 28% to 68%, mostly through inclusion of de novo PDVs in genes not yet reported as ASD associated. Thirty-three subjects (66%) had treatment recommendation(s) based on DNA analyses. Our results demonstrate a high yield of trio-WGS for revealing molecular diagnoses in ASD, which is greatly enhanced by reanalyzing DNA sequencing files. In contrast to previous reports, de novo variants dominate the findings, mostly representing novel conditions. This has implications to the cause and rising prevalence of autism.

Whole exome/genome sequencing in cyclic vomiting syndrome reveals multiple candidate genes, suggesting a model of elevated intracellular cations and mitochondrial dysfunction.

Objective: To utilize whole exome or genome sequencing and the scientific literature for identifying candidate genes for cyclic vomiting syndrome (CVS), an idiopathic migraine variant with paroxysmal nausea and vomiting. Methods: A retrospective chart review of 80 unrelated participants, ascertained by a quaternary care CVS specialist, was conducted. Genes associated with paroxysmal symptoms were identified querying the literature for genes associated with dominant cases of intermittent vomiting or both discomfort and disability; among which the raw genetic sequence was reviewed. "Qualifying" variants were defined as coding, rare, and conserved. Additionally, "Key Qualifying" variants were Pathogenic/Likely Pathogenic, or "Clinical" based upon the presence of a corresponding diagnosis. Candidate association to CVS was based on a point system. Results: Thirty-five paroxysmal genes were identified per the literature review. Among these, 12 genes were scored as "Highly likely" (SCN4A, CACNA1A, CACNA1S, RYR2, TRAP1, MEFV) or "Likely" (SCN9A, TNFRSF1A, POLG, SCN10A, POGZ, TRPA1) CVS related. Nine additional genes (OTC, ATP1A3, ATP1A2, GFAP, SLC2A1, TUBB3, PPM1D, CHAMP1, HMBS) had sufficient evidence in the literature but not from our study participants. Candidate status for mitochondrial DNA was confirmed by the literature and our study data. Among the above-listed 22 CVS candidate genes, a Key Qualifying variant was identified in 31/80 (34%), and any Qualifying variant was present in 61/80 (76%) of participants. These findings were highly statistically significant (p < 0.0001, p = 0.004, respectively) compared to an alternative hypothesis/control group regarding brain neurotransmitter receptor genes. Additional, post-analyses, less-intensive review of all genes (exome) outside our paroxysmal genes identified 13 additional genes as "Possibly" CVS related. Conclusion: All 22 CVS candidate genes are associated with either cation transport or energy metabolism (14 directly, 8 indirectly). Our findings suggest a cellular model in which aberrant ion gradients lead to mitochondrial dysfunction, or vice versa, in a pathogenic vicious cycle of cellular hyperexcitability. Among the non-paroxysmal genes identified, 5 are known causes of peripheral neuropathy. Our model is consistent with multiple current hypotheses of CVS.

Lidocaine Ineffectiveness Suggests New Psychopharmacology Drug Target.

Objectives: The mechanism of many neuropsychiatric disorders remains unknown, but the ineffectiveness of the sodium channel blocker lidocaine has been suggested to be a biomarker for Attention Deficit Hyperactivity Disorder (ADHD) and a severe form of Premenstrual Syndrome (PMS) that is considered psychiatric. We conducted single-arm double-blind clinical trials to test whether lidocaine ineffectiveness can be used as a biomarker to identify people with these conditions and provide a clue as to the molecular mechanism and potential psychopharmacological intervention. Experimental Design: We developed a noninvasive taste test for lidocaine ineffectiveness, validated by comparing lidocaine injections to pain testing in 12 subjects, and assessed it in individuals with ADHD and PMS. Principal Observations: Lidocaine ineffectiveness had a strong association in women with ADHD + PMS in a sample of 53 subjects and controls (p < 0.001). Conclusions: These results suggest the possibility of the biological understanding of the combination of ADHD and PMS that is characteristic of the psychiatric disorder Premenstrual Dysphoric Disorder (PMDD). These results and comparison to family pedigrees of a neuromuscular channelopathy with overlapping symptoms suggest the possibility that the clinical phenotype in PMDD is produced by sensory overstimulation, and amenable to molecular understanding and treatment.

High-Density EEG in Current Clinical Practice and Opportunities for the Future.

SUMMARY: High-density EEG (HD-EEG) recordings use a higher spatial sampling of scalp electrodes than a standard 10-20 low-density EEG montage. Although several studies have demonstrated improved localization of the epileptogenic cortex using HD-EEG, widespread implementation is impeded by cost, setup and interpretation time, and lack of specific or sufficient procedural billing codes. Despite these barriers, HD-EEG has been in use at several institutions for years. These centers have noted utility in a variety of clinical scenarios where increased spatial resolution from HD-EEG has been required, justifying the extra time and cost. We share select scenarios from several centers, using different recording techniques and software, where HD-EEG provided information above and beyond the standard low-density EEG. We include seven cases where HD-EEG contributed directly to current clinical care of epilepsy patients and highlight two novel techniques which suggest potential opportunities to improve future clinical care. Cases illustrate how HD-EEG allows clinicians to: case 1-lateralize falsely generalized interictal epileptiform discharges; case 2-improve localization of falsely generalized epileptic spasms; cases 3 and 4-improve localization of interictal epileptiform discharges in anatomic regions below the circumferential limit of standard low-density EEG coverage; case 5-improve noninvasive localization of the seizure onset zone in lesional epilepsy; cases 6 and 7-improve localization of the seizure onset zone to guide invasive investigation near eloquent cortex; case 8-identify epileptic fast oscillations; and case 9-map language cortex. Together, these nine cases illustrate that using both visual analysis and advanced techniques, HD-EEG can play an important role in clinical management.

The variability of SMARCA4-related Coffin-Siris syndrome: Do nonsense candidate variants add to milder phenotypes?

SMARCA4 encodes a central ATPase subunit in the BRG1-/BRM-associated factors (BAF) or polybromo-associated BAF (PBAF) complex in humans, which is responsible in part for chromatin remodeling and transcriptional regulation. Variants in this and other genes encoding BAF/PBAF complexes have been implicated in Coffin-Siris Syndrome, a multiple congenital anomaly syndrome classically characterized by learning and developmental differences, coarse facial features, hypertrichosis, and underdevelopment of the fifth digits/nails of the hands and feet. Individuals with SMARCA4 variants have been previously reported and appear to display a variable phenotype. We describe here a cohort of 15 unrelated individuals with SMARCA4 variants from the Coffin-Siris syndrome/BAF pathway disorders registry who further display variability in severity and degrees of learning impairment and health issues. Within this cohort, we also report two individuals with novel nonsense variants who appear to have a phenotype of milder learning/behavioral differences and no organ-system involvement.

The SOFIA Study: Negative Multi-center Study of Low Dose Fluoxetine on Repetitive Behaviors in Children and Adolescents with Autistic Disorder.

Fluoxetine is a selective serotonin reuptake inhibitor (SSRI) that reduces obsessive-compulsive symptoms. There is limited evidence supporting its efficacy for repetitive behaviors (RRBs) in autistic spectrum disorder (ASD). We conducted a randomized controlled trial (RCT) of fluoxetine in 158 individuals with ASD (5-17 years). Following 14 treatment weeks (mean dose 11.8 mg/day), no significant differences were noted on the Children's Yale-Brown Obsessive Compulsive Scale; the proportion of responders was similar (fluoxetine: 36%; placebo: 41%). There were similar rates of AEs (e.g., insomnia, diarrhea, vomiting); high rates of activation were reported in both groups (fluoxetine: 42%; placebo: 45%). Overly cautious dosing/duration may have prevented attainment of a therapeutic level. Results are consistent with other SSRI RCTs treating RRBs in ASD.Trial Registration: clinicaltrials.gov Identifier: NCT00515320.

Child neurology in the 21st century: More than the sum of our RVUs.

In September 2017, the Child Neurology Society (CNS) convened a special task force to review the practice of child neurology in the United States. This was deemed a necessity by our membership, as our colleagues expressed discouragement and burnout by the increase in workload without additional resources; reliance on work relative value units (wRVUs) as the sole basis of compensation; a push by administrators for providers to see more patients with less allotted time; and lack of administrative, educational, and research support. The CNS Task Force designed and distributed a survey to multiple academic divisions of various sizes, as well as to private practices. Our findings were strikingly similar across different practices, demonstrating high workloads, lack of resources, poor electronic medical record support, and high provider symptoms of fatigue and burnout. From the results, the CNS Task Force has concluded that wRVUs cannot be the sole basis of compensation for child neurology. We have also made several specific recommendations for alleviating the current situation, including innovative ways to fund child neurology as well as ways to enhance job satisfaction.

Safety and Tolerability of Adjunctive Eslicarbazepine Acetate in Pediatric Patients (Aged 4-17 Years) With Focal Seizures.

OBJECTIVE: To evaluate the safety and tolerability of adjunctive eslicarbazepine acetate (ESL) in pediatric patients (aged 4-17 years) with refractory focal seizures. METHODS: Pooled safety data from patients aged 4-17 years in Study 208 (NCT01527513) and Study 305 (NCT00988156) were analyzed. Both were randomized, double-blind, placebo-controlled studies of ESL as adjunctive treatment in pediatric patients with refractory focal seizures receiving 1 or 2 antiepileptic drugs. Incidences of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), TEAEs leading to discontinuation, and TEAEs of special interest were evaluated. RESULTS: The safety population comprised 362 patients (placebo, n = 160; ESL, n = 202). The overall incidence of TEAEs was similar between the ESL (67.8%) and placebo groups (65.6%), with no clear dose-response relationship. The most frequently reported TEAEs with ESL were headache, somnolence, vomiting, and diplopia. Overall incidences of SAEs and TEAEs leading to discontinuation were higher with ESL versus placebo (9.9% vs 5.0% and 5.9% vs 2.5%, respectively). The majority of SAEs with ESL occurred in Study 305. Two deaths were reported, 1 with ESL (0.5%) due to cluster seizures (resulting in herniation of the cerebellar tonsils) and 1 with placebo (0.6%) due to asphyxia. TEAEs related to allergic reaction, hyponatremia, hypothyroidism, cytopenia, seizure exacerbation, cognitive dysfunction, psychiatric disorders, or suicide occurred infrequently (<9%). CONCLUSION: Adjunctive ESL was generally well tolerated in children aged 4-17 years with focal seizures. The safety profile of ESL in children was comparable to that observed in adults.

Revisiting Lithium: Utility for Behavioral Stabilization in Adolescents and Adults with Autism Spectrum Disorder.

Objectives: To examine the efficacy of lithium as a mood stabilizer for patients with autism spectrum disorder (ASD). Experimental Design: A retrospective chart review was performed that examined the use of both extended and immediate release lithium carbonate in patients with ASD that were treated at a single clinical center (CNNH NeuroHealth). Clinical Global Impression (CGI) scales were used to quantify baseline severity of ASD and mood symptoms as well as improvement after treatment with lithium carbonate. Principle Observations: Our retrospective chart review found that 73.7% (n = 14) of patients with ASD and concomitant maladaptive behaviors experienced "improvement" (CGI-I rating ≤ 3) with the addition of lithium to their treatment regimen. Those with comorbid "ADHD" phenotype were most predictive of an efficacious response (p = 0.038, Odds Ratio 12.2). Conclusions: Lithium carbonate is a viable, efficacious and well tolerated alternative to various neuroleptics and other psychotropic medications for use as a mood stabilizer for patients with ASD.

Adjunctive Perampanel Oral Suspension in Pediatric Patients From ≥2 to <12 Years of Age With Epilepsy: Pharmacokinetics, Safety, Tolerability, and Efficacy.

Study 232, an open-label pilot study with an extension phase, evaluated the pharmacokinetics and preliminary safety/tolerability and efficacy of adjunctive perampanel oral suspension (≤0.18 mg/kg/d) in epilepsy patients aged ≥2 to <12 years. Patients were grouped into cohorts 1 (aged ≥7 to <12 years) and 2 (aged ≥2 to <7 years). The Core Study included pretreatment (≤2 weeks) and treatment phases (7-week titration; 4-week maintenance; 4-week follow-up [for those not entering the extension]). The extension phase consisted of 41-week maintenance and 4-week follow-up periods. Pharmacokinetic data were pooled with adolescent pharmacokinetic data from phase II/III studies. Population pharmacokinetic analysis showed that perampanel pharmacokinetics was independent of age, weight, or liver function, suggesting age- or weight-based dosing is not required and that the same dose can be given to adults and children to achieve exposures shown to be efficacious. Perampanel was well tolerated and efficacious for ≤52 weeks.

Evolution in the Understanding of Autism Spectrum Disorder: Historical Perspective.

The study of the evolution in the diagnosis and treatment of autism is a lesson in the dangers of medical beliefs or doctrines that are not grounded in medical science. The early descriptions of autism suggested that it was the result of childhood psychoses or psychodynamic disturbances of parent-child relationships. This flawed conceptualization of autism spectrum disorders (ASD) gave way to advances in medical science, which have established ASD as a neurobiological disorder of early brain development. There are many genetic, epigenetic, metabolic, hormonal, immunological, neuroanatomical and neurophysiological etiologies of ASD, as well as an array of gastrointestinal and other systemic co-morbid disorders. Thus, ASD are a biologically heterogeneous population with extensive neurodiversity. Early identification and understanding of ASD is crucial; interventions at younger ages are associated with improved outcomes. The advent of understanding the biological sub-phenotypes of ASD, along with targeted medical therapies, coupled with a multimodal therapeutic approach that encompasses behavioral, educational, social, speech, occupational, creative arts, and other forms of therapies has created a new and exciting era for individuals with ASD and their families: "personalized" and "precision" medical care based upon underlying biological sub-phenotypes and clinical profiles. For many individuals and their families dealing with the scourge of autism, their long and frustrating diagnostic journey is beginning to come to an end, with a hope for improved outcomes and quality of life.

Child Neurology Recruitment and Training: Views of Residents and Child Neurologists From the 2015 AAP/CNS Workforce Survey.

BACKGROUND: To assess and compare resident and practicing child neurologists' attitudes regarding recruitment and residency training in child neurology. METHODS: A joint task force of the American Academy of Pediatrics and the Child Neurology Society conducted an electronic survey of child neurology residents (n = 305), practicing child neurologists (n = 1290), and neurodevelopmental disabilities specialists (n = 30) in 2015. Descriptive and multivariate analyses were performed. RESULTS: Response rates were 32% for residents (n = 97; 36% male; 65% Caucasian) and 40% for practitioners (n = 523; 63% male; 80% Caucasian; 30% lifetime certification). Regarding recruitment, 70% (n = 372) attributed difficulties recruiting medical students to insufficient early exposure. Although 68% (n = 364) reported that their medical school required a neurology clerkship, just 28% (n = 152) reported a child neurology component. Regarding residency curriculum, respondents supported increased training emphasis for genetics, neurodevelopmental disabilities, and multiple other subspecialty areas. Major changes in board certification requirements were supported, with 73% (n = 363) favoring reduced adult neurology training (strongest predictors: fewer years since medical school P = 0.003; and among practicing child neurologists, working more half-day clinics per week P = 0.005). Furthermore, 58% (n = 289) favored an option to reduce total training to 4 years, with 1 year of general pediatrics. Eighty-two percent (n = 448) would definitely or probably choose child neurology again. CONCLUSIONS: These findings provide support for recruitment efforts emphasizing early exposure of medical students to child neurology. Increased subspecialty exposure and an option for major changes in board certification requirements are favored by a significant number of respondents.

The child neurology clinical workforce in 2015: Report of the AAP/CNS Joint Taskforce.

OBJECTIVES: More than a decade has passed since the last major workforce survey of child neurologists in the United States; thus, a reassessment of the child neurology workforce is needed, along with an inaugural assessment of a new related field, neurodevelopmental disabilities. METHODS: The American Academy of Pediatrics and the Child Neurology Society conducted an electronic survey in 2015 of child neurologists and neurodevelopmental disabilities specialists. RESULTS: The majority of respondents participate in maintenance of certification, practice in academic medical centers, and offer subspecialty care. EEG reading and epilepsy care are common subspecialty practice areas, although many child neurologists have not had formal training in this field. In keeping with broader trends, medical school debts are substantially higher than in the past and will often take many years to pay off. Although a broad majority would choose these fields again, there are widespread dissatisfactions with compensation and benefits given the length of training and the complexity of care provided, and frustrations with mounting regulatory and administrative stresses that interfere with clinical practice. CONCLUSIONS: Although not unique to child neurology and neurodevelopmental disabilities, such issues may present barriers for the recruitment of trainees into these fields. Creative approaches to enhance the recruitment of the next generation of child neurologists and neurodevelopmental disabilities specialists will benefit society, especially in light of all the exciting new treatments under development for an array of chronic childhood neurologic disorders.

Stimulant Medications and Cognition, Behavior and Quality of Life in Children and Youth with HIV.

BACKGROUND: Limited empirical investigation exists into longitudinal changes in cognition, behavior or quality of life (QOL) in children with perinatal HIV who are prescribed stimulants. METHODS: This study was an analysis of longitudinal data from children age 3-19 years, with perinatal HIV infection, with and without prescriptions for stimulant medications [prescription (PG) and comparison (CG) groups, respectively], matched on age, availability of CD4% and outcome measures of cognition, behavior and QOL. Generalized estimating equation models were used to evaluate effects of stimulant exposure on change in measured outcomes over 3 years of follow-up, adjusting for baseline levels of outcomes and relevant covariates. RESULTS: Children in both the PG (n = 132) and the CG (n = 392) obtained mean verbal and performance (nonverbal) intelligence quotients (VIQ and PIQ, respectively) in the low-average range for age. At baseline, those in PG demonstrated more frequent signs of hyperactivity, impulsivity and conduct and learning problems than those in CG (P ≤ 0.003 in unadjusted analyses). At follow-up, after adjustment for baseline functioning and other relevant covariates, there were no significant changes from baseline in VIQ or PIQ. Stimulant prescription use, however, was associated with worsening symptoms of hyperactivity (P = 0.01), impulsivity (P = 0.04), learning problems (P < 0.001) and worsening of perceived health status (P < 0.001). CONCLUSIONS: The results suggest expectations for behavioral improvement may not align well with long-term effects of stimulant prescription use on behavior and QOL in children with HIV. Further research is necessary to determine if there are subsets of children who may benefit from stimulant therapy.

A long-term open-label extension study assessing cognition and behavior, tolerability, safety, and efficacy of adjunctive levetiracetam in children aged 4 to 16 years with partial-onset seizures.

The objective of this study was to assess cognition and behavior in children (4-16 years; n = 103) with partial-onset seizures using the Leiter-R International Performance Scale and Achenbach Child Behavior Checklist. The study was a multicenter, open-label, noncomparative 48-week extension study (NCT00152516) of adjunctive levetiracetam (20-100 mg/kg/d, mean 50.2 mg/kg/d). Improvement from baseline in Leiter-R Memory Screen composite score at weeks 24 and 48 (mean [SD] change, +4.8 [12.6] and +4.5 [15.3]) was similar to changes observed with levetiracetam and placebo in a prior study. Child Behavior Checklist Syndrome scores improved from baseline at weeks 24 and 48 (total problems mean [SD] change, -9.3 [22.2] and -10.4 [23.4]). Adjunctive levetiracetam was well tolerated (most frequently reported central nervous system-related treatment-emergent adverse events: headache [24.3%], aggression [7.8%], irritability [7.8%]). Of the patients, 4.9% discontinued because of treatment-emergent adverse events. Levetiracetam provided good and sustained seizure control (median percentage reduction from baseline in partial-onset seizure frequency/wk during maintenance: 86.4%); 24.7% of patients had continuous seizure freedom from all seizure types for ≥40 weeks. In children, adjunctive levetiracetam was associated with long-term stability in cognitive functioning and improvement in emotional/behavioral functioning over time.

The use of second-generation antipsychotics and the changes in physical growth in children and adolescents with perinatally acquired HIV.

Second-generation antipsychotics (SGAs) are increasingly prescribed to treat psychiatric symptoms in pediatric patients infected with HIV. We examined the relationship between prescribed SGAs and physical growth in a cohort of youth with perinatally acquired HIV-1 infection. Pediatric AIDS Clinical Trials Group (PACTG), Protocol 219C (P219C), a multicenter, longitudinal observational study of children and adolescents perinatally exposed to HIV, was conducted from September 2000 until May 2007. The analysis included P219C participants who were perinatally HIV-infected, 3-18 years old, prescribed first SGA for at least 1 month, and had available baseline data prior to starting first SGA. Each participant prescribed an SGA was matched (based on gender, age, Tanner stage, baseline body mass index [BMI] z score) with 1-3 controls without antipsychotic prescriptions. The main outcomes were short-term (approximately 6 months) and long-term (approximately 2 years) changes in BMI z scores from baseline. There were 236 participants in the short-term and 198 in the long-term analysis. In linear regression models, youth with SGA prescriptions had increased BMI z scores relative to youth without antipsychotic prescriptions, for all SGAs (short-term increase = 0.192, p = 0.003; long-term increase = 0.350, p < 0.001), and for risperidone alone (short-term = 0.239, p = 0.002; long-term = 0.360, p = 0.001). Participants receiving both protease inhibitors (PIs) and SGAs showed especially large increases. These findings suggest that growth should be carefully monitored in youth with perinatally acquired HIV who are prescribed SGAs. Future research should investigate the interaction between PIs and SGAs in children and adolescents with perinatally acquired HIV infection.

Impact of medications prescribed for treatment of attention-deficit hyperactivity disorder on physical growth in children and adolescents with HIV.

OBJECTIVE: To examine the relationships between physical growth and medications prescribed for symptoms of attention-deficit hyperactivity disorder in children with HIV. METHODS: Analysis of data from children with perinatally acquired HIV (N = 2251; age 3-19 years), with and without prescriptions for stimulant and nonstimulant medications used to treat attention-deficit hyperactivity disorder, in a long-term observational study. Height and weight measurements were transformed to z scores and compared across medication groups. Changes in z scores during a 2-year interval were compared using multiple linear regression models adjusting for selected covariates. RESULTS: Participants with (n = 215) and without (n = 2036) prescriptions were shorter than expected based on US age and gender norms (p < .001). Children without prescriptions weighed less at baseline than children in the general population (p < .001) but gained height and weight at a faster rate (p < .001). Children prescribed stimulants were similar to population norms in baseline weight; their height and weight growth velocities were comparable with the general population and children without prescriptions (for weight, p = .511 and .100, respectively). Children prescribed nonstimulants had the lowest baseline height but were similar to population norms in baseline weight. Their height and weight growth velocities were comparable with the general population but significantly slower than children without prescriptions (p = .01 and .02, respectively). CONCLUSION: The use of stimulants to treat symptoms of attention-deficit hyperactivity disorder does not significantly exacerbate the potential for growth delay in children with HIV and may afford opportunities for interventions that promote physical growth. Prospective studies are needed to confirm these findings.

Neurocognitive effects of adjunctive levetiracetam in children with partial-onset seizures: a randomized, double-blind, placebo-controlled, noninferiority trial.

PURPOSE: Evaluate potential neurocognitive effects of adjunctive levetiracetam in children with inadequately controlled partial-onset seizures (POS). METHODS: Randomized, double-blind, placebo-controlled, noninferiority safety study. Children (4-16 years; IQ > or =65) with > or =1 POS during 4 weeks before screening despite taking 1-2 antiepileptic drugs (AEDs) were randomized (2:1) to levetiracetam (20-60 mg/kg/day) or placebo for 12 weeks. RESULTS: Ninety-nine patients were randomized with 98 (levetiracetam 64, placebo 34) in intent-to-treat (ITT) and 73 (levetiracetam 46, placebo 27) in per protocol (PP) populations. Primary cognitive assessment was the Leiter International Performance Scale-Revised Attention and Memory Battery with the memory screen composite score change from baseline as the primary endpoint. PP Least Square Mean [LSM (standard error)] were 5.36 (1.78) for levetiracetam; 5.17 (2.33) for placebo; difference [two-sided 90% confidence interval (CI)] 0.19 (-4.69, 5.08). Levetiracetam was noninferior to placebo because the 90% CI lower bound was greater than the defined noninferiority margin (-9.0). There were no statistically significant differences between groups in Wide Range Assessment of Memory and Learning-2 indexes and Leiter-R Examiner's Rating Scale scores. Median reductions from baseline in weekly POS frequency were 91.5% versus 26.5% for levetiracetam versus placebo; > or =50% responder rates: 62.5% versus 41.2%; seizure freedom rates: 46.9% versus 8.8% (ITT). Adverse events were reported by 89.1% levetiracetam-treated and 85.3% placebo-treated patients; those reported by > or =10% levetiracetam patients and more often with levetiracetam were headache, nasopharyngitis, fatigue, vomiting, somnolence, and aggression. DISCUSSION: Neurocognitive effects were no different in pediatric patients with POS treated with adjunctive levetiracetam or placebo. Levetiracetam was effective and well tolerated.

The underrecognized epilepsy spectrum: the effects of levetiracetam on neuropsychological functioning in relation to subclinical spike production.

The purpose of this prospective, open-label pilot study was to determine whether treatment with levetiracetam improves neuropsychological functioning in children and adolescents who have evidence of subclinical spike production associated with attention and learning difficulties. Six participants (mean age 9.8 years) were treated with levetiracetam up to 40 mg/kg per day and evaluated using neuropsychological (Wide Range Assessment of Memory and Learning, Second Edition), academic (Wechsler Individual Achievement Test, Second Edition, Abbreviated), and electroencephalographic assessments at baseline and after 10 weeks of treatment. Statistically significant improvements on indexes of the Wide Range Assessment of Memory and Learning, Second Edition were observed in 4 participants after 10 weeks. No statistically significant differences were observed for the Wechsler Individual Achievement Test, Second Edition, Abbreviated. Concomitant spike suppression was observed. Levetiracetam was generally well tolerated. A subset of patients exists with attention and learning problems that have associated aberrant cortical electrical activity without clinical seizures and associated neuropsychological deficits that may improve after treatment with levetiracetam.

Atomoxetine treatment of ADHD in children with comorbid Tourette syndrome.

OBJECTIVE: This study examines changes in severity of tics and ADHD during atomoxetine treatment in ADHD patients with Tourette syndrome (TS). METHOD: Subjects (7-17 years old) with ADHD (Diagnostic and Statistical Manual of Mental Disorders, DSM-IV) and TS were randomly assigned to double-blind treatment with placebo (n = 56) or atomoxetine (0.5-1.5 mg/kg/day, n = 61) for approximately 18 weeks. RESULTS: Atomoxetine subjects showed significantly greater improvement on ADHD symptom measures. Treatment was also associated with significantly greater reduction of tic severity on two of three measures. Significant increases were seen in mean pulse rate and rates of treatment-emergent nausea, decreased appetite, and decreased body weight. No other clinically relevant treatment differences were observed in any other vital sign, adverse event, laboratory parameter, or electrocardiographic measure. CONCLUSION: Atomoxetine is efficacious for treatment of ADHD and its use appears well tolerated in ADHD patients with comorbid TS.