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October 2014-10-20

Contributor: Dr. Naveen Sankhyan

Coppola G et al. Current role of rufinamide in the treatment of childhood epilepsy: Literature review and treatment guidelines. Eur J Paediatr Neurol 2014 May 28. [Epub ahead of print]

Purpose: The literature on the efficacy and safety of rufinamide in childhood-onset epilepsy syndromes currently includes approximately 600 paediatric patients.

Results: Rufinamide is effective in decreasing the seizure frequency in the Lennox-Gastaut syndrome (LGS), especially tonic and atonic seizures. It might consequently be preferred to other drugs as a second-line treatment for LGS when drop-attacks are frequent. The mean responder rate in the published studies is 38% with seizure freedom achieved in 2.4% of patients. Rufinamide has shown some efficacy in epileptic encephalopathies other than LGS. It can be also effective as adjunctive therapy in children and adolescents with drug-resistant partial seizures. The available data suggest that rufinamide has an acceptable risk/benefit ratio with quite a low risk of aggravating seizures. Common adverse effects (somnolence, nausea and vomiting) are usually mild and self-limiting; they are more frequently observed during titration than in the maintenance phase, suggesting that low escalation rates might be associated with fewer adverse effects. Rufinamide appears to have a favourable cognitive profile compared with other antiepileptic drugs.

Conclusions and comment: This paper summarizes the views of a panel of experienced European epileptologists with regard to the current role of rufinamide in the treatment of childhood epilepsies. Rufinamide is only approved for adjunctive treatment of seizures associated with LGS in children 4 years of age and older. There are very few data on rufinamide treatment at the onset of LGS or early in the course of the disorder; whether early treatment will improve outcome has yet to be determined.

Chiang SS et al. Treatment outcomes of childhood tuberculous meningitis: a systematic review and meta-analysis. Lancet Infect Dis. 2014 Aug 6. pii: S1473-3099(14)70852-7. doi: 10.1016/S1473-3099(14)70852-7. [Epub ahead of print]

Methods: A systematic review and meta-analysis of childhood tuberculous meningitis studies published up to Oct 12, 2012. Included study reports that applied predefined diagnostic criteria and described treatment regimens and outcomes. Pooled risks of death during treatment and neurological sequelae among survivors is presented.

Findings: 19 studies met the inclusion criteria, with reported treatment outcomes for 1636 children. Risk of death was 19·3% (95% CI 14·0-26·1) and probability of survival without neurological sequelae was 36·7% (27·9-46·4). Among survivors, risk of neurological sequelae was 53·9% (95% CI 42·6-64·9). Diagnosis in the most advanced disease stage (3) occurred in 307 (47%) of 657 patients and was associated with worse outcomes than was earlier diagnosis. The most common findings at presentation were cerebrospinal fluid (CSF) leucocytosis (frequency 99·9%, 95% CI 68·5-100·0), CSF lymphocytosis (97·9%, 51·9-100·0), fever (89·8%, 79·8-95·2), and hydrocephalus (86·1%, 68·6-94·6). Frequency of CSF acid-fast-bacilli smear positivity was 8·9% (95% CI 5·0-15·4), and frequency of CSF culture positivity for Mycobacterium tuberculosis was 35·1% (16·8-59·2).

Comment: This is study which collates data of last several decades. This meta-analysis provides the framework to compare emerging data on outcome of TBM. Despite treatment, childhood tuberculous meningitis has very poor outcomes. Poor prognosis and difficult early diagnosis emphasise the importance of preventive therapy for child contacts of patients with tuberculosis and low threshold for empirical treatment of tuberculous meningitis suspects. Implementation of consensus definitions, standardised reporting of data, and high-quality clinical trials are needed to clarify optimum therapy.

Lacosamide in children with refractory status epilepticus. A multicenter Italian experience. Grosso S et al. Eur J Paediatr Neurol. 2014 Sep;18(5):604-8.

Objective: This study aimed to assess the efficacy and tolerability of intravenous (iv) lacosamide (LCM) in children affected by RSE.

Method: Children with RSE who were treated with ivLCM were included in the study. Efficacy was defined as the cessation of seizures after administration of ivLCM, with no need for any further antiepileptic drug. All patients had been unsuccessfully treated following standard protocols before ivLCM was administered.

Results: Eleven children entered the study (mean age: 9.4 years). Etiology was symptomatic in 7 patients (63%). RSE was convulsive (focal or generalized) in 6 patients and nonconvulsive in 5. The mean initial bolus dose of LCM was 8.6 mg/kg. The drug, which was used as a fourth or later option, was effective in stopping RSE in 45% of patients, with seizures terminating within 12 h in three children. No serious adverse events attributable to LCM were reported.

Comments: A preliminary study of LCM in pediatric RSE, that suggests that LCM might be an effective and well-tolerated AED in children with RSE.

Narzisi A, et al. Non-pharmacological treatments in autism spectrum disorders: an overview on early interventions for pre-schoolers. Curr Clin Pharmacol. 2014 Feb;9(1):17-26.

Abstract: This paper evaluates the current literature on non-pharmacological early interventions (behavior behavioral, developmental and educational approaches) for pre-schoolers (aged 24-71 months) with autism spectrum disorders. Although there lies a significant heterogeneity among the available studies, the present review emphasizes the importance of considering the wide range of interventions through behavioral (behavioral or developmental interventions) and educational continuum according to the suggestions of the recent literature in this field. Furthermore, the present review:
1) outlines the issues about the scientific validity of the treatment outcome studies;
2) describes the findings of different parent-mediated interventions;
3) highlights the importance to use the same outcome measures through the studies to compare findings of different literature contributions; and
4) focuses on the importance to consider pre-treatment variables to identify children who will have better outcomes.
Furthermore, some evidence-based guidelines about clinical management and treatment have also been outlined and summarized in this review. Finally, the review concludes on providing a number of practical recommendations to clinicians working in the field suggesting both the presence of a specialized team and role of an active collaboration of the family to treatment as core milestones for the clinical management.

Chellamuthu et al. High dose (4mg/kg/day) versus usual dose (2mg/kg/day) oral prednisolone for treatment of infantile spasms: An open-label, randomized controlled trial. Epilepsy Res. 2014 Oct;108(8):1378-84.

Objectives: This study aimed to test the hypothesis that high-dose prednisolone (4mg/kg/day) may be more efficacious than usual-dose (2mg/kg/day) prednisolone for spasm resolution at 14-days in children with infantile spasms.

Methods: This was a randomized, open-label-trial conducted at a tertiary-level-hospital from February-2012 to March-2013. Children aged 3-months to 2-years presenting with infantile spasms in clusters (at least 1 cluster/day) with hypsarrhythmia or its variants on EEG were enrolled. The study participants were randomized to receive either high-dose prednisolone (4mg/kg/day) or the usual-dose (2mg/kg/day) prednisolone. The primary outcome measure was the proportion of children who achieved spasm freedom for 48-h at day-14 after treatment initiation as per parental reports in both the groups. The adverse effects were also monitored. The study was registered with the clinicaltrials.gov (ClinicalTrials.gov Identifier: NCT01575639).

Results: Sixty-three children were randomized into the two groups with comparable baseline characteristics. The proportion of children with spasm cessation on day-14 was significantly higher in the high-dose group as compared to the usual-dose group (51.6% vs. 25%, p=0.03). The absolute risk reduction was 26.6% (95% confidence interval 11.5-41.7%) with number needed to treat being 4. The adverse effects were comparable in both the groups.

Conclusions: High-dose prednisolone (4mg/kg/d) was more effective than low-dose prednisolone (2mg/kg/d) in achieving spasm cessation at 14-days (as per parental reports) in children with infantile spasms.

Comments: This is study done in Indian setting with encouraging results. It reports the use of high dose oral steroids in West syndrome. If the authors experience can be replicated elsewhere the high dose steroids can offer an alternative to the more expensive ACTH therapy. The results are particularly relevant to resource constraint setting, because ACTH use is limited for the want of hospital beds, monitoring facilities, trained staff to give IM injections and other problems. The safety and efficacy of high dose steroids on longer use needs to be established.

Morris GL et al. Evidence-based guideline update: vagus nerve stimulation for the treatment of epilepsy: report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology. 2013 Oct 15;81(16):1453-9.

Objective: To evaluate the evidence since the 1999 assessment regarding efficacy and safety of vagus nerve stimulation (VNS) for epilepsy, currently approved as adjunctive therapy for partial-onset seizures in patients >12 years.

Methods: We reviewed the literature and identified relevant published studies. We classified these studies according to the American Academy of Neurology evidence-based methodology.

Results: VNS is associated with a >50% seizure reduction in 55% (95% confidence interval [CI] 50%-59%) of 470 children with partial or generalized epilepsy (13 Class III studies). VNS is associated with a >50% seizure reduction in 55% (95% CI 46%-64%) of 113 patients with Lennox-Gastaut syndrome (LGS) (4 Class III studies). VNS is associated with an increase in ≥ 50% seizure frequency reduction rates of ≈ 7% from 1 to 5 years postimplantation (2 Class III studies). VNS is associated with a significant improvement in standard mood scales in 31 adults with epilepsy (2 Class III studies). Infection risk at the VNS implantation site in children is increased relative to that in adults (odds ratio 3.4, 95% CI 1.0-11.2). VNS is possibly effective for seizures (both partial and generalized) in children, for LGS-associated seizures, and for mood problems in adults with epilepsy. VNS may have improved efficacy over time.

Recommendations: VNS may be considered for seizures in children, for LGS-associated seizures, and for improving mood in adults with epilepsy (Level C). VNS may be considered to have improved efficacy over time (Level C). Children should be carefully monitored for site infection after VNS implantation.

Fang Y et al. Randomized-controlled trials of levetiracetam as an adjunctive therapy in epilepsy of multiple seizure types. J Clin Neurosci. 2014 Jan;21(1):55-62.

Abstract: This meta-analysis aimed to systematically collect and synthesize the current evidence regarding the efficacy and tolerability of levetiracetam (LEV) as an adjunctive therapy for adults and children suffering from idiopathic and secondary epilepsy of multiple seizure types. We selected randomized-controlled trials (RCT) of LEV as an adjunctive therapy in epilepsy according to predefined criteria. Outcome measures included a > or =50% reduction in seizure frequency, seizure freedom, and adverse events. Thirteen RCT were analyzed. Results showed that the efficacy of adjunctive LEV was superior to placebo both in achieving > or =50% reduction in seizure frequency (pooled odds ratio [OR] 3.36, 95% confidence interval [CI] 2.78-4.07, Z=12.46; p<0.00001) and seizure freedom (pooled OR 4.72, 95% CI 2.96-7.54, Z=6.50; p<0.00001). The heterogeneity was mild (chi-squared=12.28, I2=2% in > or =50% reduction in seizure frequency, and chi-squared=0.49, I2=0% in seizure freedom). Subgroup analysis suggested similar effects across different dosages in adults. The incidence of adverse reactions was not significantly different between the LEV group and the placebo group. The adverse events of relatively high incidence in the LEV group included somnolence, agitation, dizziness, asthenia, and infection. Incidence of serious adverse reaction such as rash and white blood cells and platelets decreasing was quite low.

Conclusions: A djunctive therapy with LEV was superior to placebo in reducing the frequency of seizures in patients with partial and idiopathic generalized epilepsy with effect in both adults and children, and demonstrated good tolerance in patients with epilepsy.

January 2014


Dr. Jitendra K. Sahu, DM
Assistant Professor, Department of Pediatrics, Postgraduate Institute of Medical Education & Research, Chandigarh

Treatment of infantile spasms with very high dose prednisolone before high dose adrenocorticotropic hormone.

Shaun A. Hussain, Shlomo Shinnar, Grace Kwong, et al.

Authors investigated the short-term response to a standardized hormonal therapy protocol for treatment of infantile spasms. Twenty-seven children with video electroencephalography (EEG)–confirmed infantile spasms received very high dose (8 mg/kg/day, max 60 mg/day) oral prednisolone for 2 weeks. Response (absence of both hypsarrhythmia and spasms) to prednisolone was ascertained by repeat overnight video-EEG. Responders were tapered over 2 weeks and nonresponders were immediately transitioned to high dose (150 IU/m2/day) intramuscular adrenocorticotropic hormone (ACTH) for two additional weeks. Response was again determined by overnight video-EEG after ACTH therapy.

Key Findings: Sixty-three percent (17/27) of patients responded completely to prednisolone. Subsequently, 40% (4/10) of prednisolone nonresponders exhibited a complete response after an additional 2-week course with ACTH. Among 27 subjects with median follow-up of 13.5 months (interquartile range [IQR] 4.8–25.9), 12% (2/17) of prednisolone responders and 50% (2/4) of ACTH responders experienced a relapse between 2 and 9 months after initial response.

Significance: Very high dose prednisolone demonstrated significantly higher efficacy than previously reported for lower doses in prior studies. High dose ACTH may be superior to very high dose prednisolone, and in lieu of a definitive clinical trial, the choice between prednisolone and ACTH for initial treatment of infantile spasms remains controversial.

Pediatric Intracerebral Hemorrhage Score: A Simple Grading Scale for Intracerebral Hemorrhage in Children.

Beslow LA, Ichord RN, Gindville MC, et al. Stroke. 2013 Nov 26. [Epub ahead of print]

The intracerebral hemorrhage (ICH) score is the most commonly used clinical grading scale for outcome prediction after adult ICH. Authors created a similar scale in children to inform clinical care and assist in clinical research. Children, full-term newborns to 18 years, with spontaneous ICH were prospectively enrolled from 2007 to 2012 at 3 centers. The pediatric ICH score was created by identifying factors associated with poor outcome. The score's ability to detect moderate disability or worse and severe disability or death was examined with sensitivity, specificity, and area under the receiver operating characteristic curve.

Key findings: The pediatric ICH score components include ICH volume >2% to 3.99% of total brain volume (TBV): 1 point; ICH volume ≥4% TBV: 2 points; acute hydrocephalus: 1 point; herniation: 1 point; and infratentorial location: 1 point. The score ranges from 0 to 5. At 3-month follow-up of 60 children, 10 were severely disabled or dead, 30 had moderate disability, and 20 had good recovery. A pediatric ICH score ≥1 predicted moderate disability or worse with a sensitivity of 75% (95% confidence interval [CI], 59% to 87%) and a specificity of 70% (95% CI, 46% to 88%). A pediatric ICH score ≥2 predicted severe disability or death with a sensitivity and specificity of 90% (95% CI, 55% to 99%) and 68% (95% CI, 53% to 80%), respectively. The area under the receiver operating characteristic curve for classifying outcome as severe disability or death was 0.88 (95% CI, 0.78-0.97).

Significance: The pediatric ICH score is a simple clinical grading scale that may ultimately be used for risk stratification, clinical care, and research.

Risk genes associated with pediatric-onset MS but not with monophasic acquired CNS demyelination.

van Pelt ED, Mescheriakova JY, Makhani N, et al. Neurology. 2013 Dec 3;81(23):1996-2001.

Authors investigated whether 57 genetic risk loci recently identified in a large-scale genome-wide association study in adult patients with multiple sclerosis (MS) are also associated with a risk for pediatric-onset MS and whether they can predict MS diagnosis in children presenting with acquired demyelinating syndromes (ADS). Authors included 188 children with ADS, of whom 53 were diagnosed with MS, 466 patients with adult-onset MS, and 2,046 adult controls in our cohort study.

Key findings: Weighted genetic risk scores (wGRS) were calculated to evaluate genetic effects. Mean wGRS was significantly higher for patients with pediatric-onset MS (7.32 ± 0.53) as compared with patients with monophasic ADS (7.10 ± 0.47, p = 0.01) and controls (7.11 ± 0.53, p < 0.01). Authors found no difference in mean wGRS of participants with monophasic ADS (7.10 ± 0.47) and controls (7.11 ± 0.53). The ability of the wGRS for the 57 single nucleotide polymorphisms (SNPs) to discriminate between children with MS and those with monophasic ADS was moderate (area under the curve [AUC] = 0.64), but improved with the addition of sex and HLA-DRB1*15 (AUC = 0.70). The combined effect of 57 SNPs exceeded the effect of HLA-DRB1*15 alone in our risk models for pediatric- and adult-onset MS.

Significance: The previously reported 57 SNPs for adult-onset MS also confer increased susceptibility to pediatric-onset MS, but not to monophasic ADS.

Prognostic factors for subsequent epilepsy in children with febrile seizures.

Pavlidou E, Panteliadis C. Epilepsia. 2013 Dec;54(12):2101-7.

Authors studied prognostic factors that can lead children with FS to epilepsy. Children with a first episode of FS were included. We gathered information about prenatal and perinatal history, family history of FS and epilepsy in first- and second degree relatives, age at the time of the initial FS, dates of FS recurrences, focality, duration of the FS and recurrent episodes within the same febrile illness, height and duration of fever prior to the seizure, cause of the fever, and frequency of febrile illnesses. Patients were seen every 4–6 months and also at each recurrence.

Key Findings: A group of 560 children with a first FS met all entry criteria. Epilepsy was recorded at 5.4%. Statistical analysis was performed between children with epilepsy and those with no afebrile seizure.We analyzed FS recurrences in accordance with the occurrence of epilepsy. From the third FS recurrence and beyond, only focality continued to have prognostic value.

Significance: Main prognostic factors for the development of epilepsy after FS are: (1) complex FS that increased the risk for epilepsy 3.6 times, (2) age at onset of FS beyond the third year of life that raised the risk 3.8 times, (3) positive family history of epilepsy 7.3 times, and (4) multiple episodes of FS about 10 times. Focality at the first and the second FS recurrence increased the risk of epilepsy about 9.7 and 11.7 times, respectively. Focality was the only factor that continued to be significant in further FS recurrences.
August 2013

Contributor: Dr. Naveen Sankhyan, Assistant Professor, Department of Pediatrics, Postgraduate Institute of Medical Education & Research, Chandigarh

Everolimus in Tuberous sclerosis
Franz DN, Belousova E, Sparagana S, et al. Efficacy and safety of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis complex (EXIST-1): a multicentre, randomised, placebo-controlled phase 3 trial.
Lancet. 2013 Jan 12;381(9861):125-32.

In Tuberous sclerosis complex growth of subependymal giant cell astrocytomas can cause life-threatening symptoms--eg, hydrocephalus, requiring surgery. The researchers assessed the efficacy and safety of everolimus in patients with subependymal giant cell astrocytomas associated with tuberous sclerosis complex. In this double-blind, placebo-controlled, phase 3 trial, patients (aged 0-65 years) in 24 centres were randomly assigned, to oral everolimus 4·5 mg/m(2) per day (titrated to achieve blood trough concentrations of 5-15 ng/mL) or placebo. Eligible patients had a definite diagnosis of TSC and at least one lesion with a diameter of 1 cm or greater, and either serial growth of a subependymal giant cell astrocytoma, a new lesion of 1 cm or greater, or new or worsening hydrocephalus. The primary endpoint was the proportion of patients with confirmed response--ie, reduction in target volume of 50% or greater relative to baseline in subependymal giant cell astrocytomas. Analysis was by intention to treat. 117 patients were randomly assigned to everolimus (n=78) or placebo (n=39). 27 (35%) patients in the everolimus group had at least 50% reduction in the volume of subependymal giant cell astrocytomas versus none in the placebo group (difference 35%, 95% CI 15-52; one-sided exact Cochran-Mantel-Haenszel test, p<0·0001). These results support the use of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis. Additionally, everolimus might represent a disease-modifying treatment for other aspects of tuberous sclerosis.

Anti-NMDA receptor encephalitis

Titulaer MJ, McCracken L, Gabilondo I, et al. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study.

Lancet Neurol. 2013 Feb;12(2):157-65.

Anti-NMDA receptor (NMDAR) encephalitis is an autoimmune disorder in which the use of immunotherapy and the long-term outcome have not been defined. This is possibly the largest series of patients including children with NMDAR. In this multi-institutional observational study, the researchers tested for the presence of NMDAR antibodies in serum or CSF samples of patients with encephalitis between Jan 1, 2007, and Jan 1, 2012. All patients who tested positive for NMDAR antibodies were included in the study; patients were assessed at symptom onset and at months 4, 8, 12, 18, and 24, by use of the modified Rankin scale (mRS). Treatment included first-line immunotherapy (steroids, intravenous immunoglobulin, plasmapheresis), second-line immunotherapy (rituximab, cyclophosphamide), and tumour removal. A total of 577 patients (median age 21 years, range 8 months to 85 years), 211 of whom were children (<18 years) were enrolled. 472 (94%) underwent first-line immunotherapy or tumour removal, resulting in improvement within 4 weeks in 251 (53%). 125 (57%) received second-line immunotherapy that resulted in a better outcome (mRS 0-2) than those who did not (odds ratio [OR] 2·69, CI 1·24-5·80; p=0·012). During the first 24 months, 394 of 501 patients achieved a good outcome and 30 died. At 24 months' follow-up, 203 (81%) of 252 patients had good outcome. Outcomes continued to improve for up to 18 months after symptom onset. Predictors of good outcome were early treatment (0·62, 0·50-0·76; p<0·0001) and no admission to an intensive care unit (0·12, 0·06-0·22; p<0·0001). In 177 children, predictors of good outcome and the magnitude of effect of second-line immunotherapy were similar to those of the entire cohort. The researchers concluded that most patients with anti-NMDAR encephalitis respond to immunotherapy. Second-line immunotherapy is usually effective when first-line treatments fail.

Minocycline in Fragile X

Leigh MJ, Nguyen DV, Mu Y et al. A randomized double-blind, placebo-controlled trial of minocycline in children and adolescents with fragile x syndrome. J Dev Behav Pediatr. 2013 Apr;34(3):147-55.

In this Randomized, double-blind, placebo-controlled, crossover trial in individuals with FXS, aged 3.5 years to 16 years, 66 were randomized. Fifty-five subjects (83.3%) completed at least the first period and 48 (72.7%) completed the full trial. Intention-to-treat analysis demonstrated significantly greater improvements Clinical Global Impression Scale-Improvement after minocycline compared with placebo (2.49 ± 0.13 and 2.97 ± 0.13, respectively, p = .0173) and greater improvement in ad hoc analysis of anxiety and mood-related behaviors on the Visual Analog Scale. Results may be potentially biased by study design weaknesses, including unblinding of subjects when they completed the study, drug-related side effects unblinding, and preliminary efficacy analysis results known to investigators. But the trial may encourage further research for children with fragile X.

Prenatal valproate and autism risk

Christensen J, Grønborg TK, Sørensen MJ, et al. Prenatal valproate exposure and risk of autism spectrum disorders and childhood autism.
JAMA. 2013 Apr 24;309(16):1696-703.

In this Population-based study of all children born alive in Denmark from 1996 to 2006. The maternal use of valproate during pregnancy was associated with significantly increased risk of autism spectrum disorder and childhood autism in the offspring, even after adjusting for maternal epilepsy. For women of childbearing potential who use antiepileptic medications, these findings must be balanced against the treatment benefits for women who require valproate for epilepsy control.

Magnesium sulphate to prevent cerebral palsy

Crowther CA, Middleton PF, Wilkinson D et al. Magnesium sulphate at 30 to 34 weeks' gestational age: neuroprotection trial (MAGENTA)--study protocol.
BMC Pregnancy Childbirth. 2013 Apr 9;13:91.

Magnesium sulphate is currently recommended for neuroprotection of preterm infants for women at risk of preterm birth at less than 30 weeks' gestation, based on high quality evidence of benefit. However there remains uncertainty as to whether these benefits apply at higher gestational ages. The aim of this randomised controlled trial is to assess whether giving magnesium sulphate compared with placebo to women immediately prior to preterm birth between 30 and 34 weeks' gestation reduces the risk of death or cerebral palsy in their children at two years' corrected age. Given the magnitude of the protective effect in the systematic review, the ongoing uncertainty about benefits at later gestational ages, the serious health and cost consequences of cerebral palsy for the child, family and society, a trial of magnesium sulphate for women at risk of preterm birth between 30 to 34 weeks' gestation is both important and relevant for clinical practice globally. This paper is the detailed description of the trial design which is ongoing, similar trials are needed for prevention of cerebral palsy from resource constrained setting like ours.

May 2013

Contributor: Dr. Jitendra K Sahu

A comparative study of Ethosuximide, valproic acid, and lamotrigine in childhood absence epilepsy

Epilepsia. 2013 Jan;54(1):141-55

There is conflict in literature regarding optimal initial monotherapy for children with newly diagnosed childhood absence epilepsy (CAE). This study is landmark study in childhood absence epilepsy due to its robust study design, large sample size and 12 months outcome. The study was double-blind, randomized controlled clinical trial comparing the efficacy, tolerability, and neuropsychological effects of ethosuximide, valproic acid, and lamotrigine in children with newly diagnosed CAE. In this report, the main effectiveness outcome was the freedom from failure rate 12 months after randomization and included a video-EEG assessment. The main cognitive outcome was the percentage of subjects experiencing attentional dysfunction at the month 12 visit. A total of 453 children were enrolled and randomized. By 12 months after starting therapy, only 37% of all enrolled subjects were free from treatment failure on their first medication. As initial monotherapy, the superior effectiveness of ethosuximide and valproic acid compared to lamotrigine in controlling seizures without intolerable adverse events noted at 16-20 weeks persisted at 12 months. The valproic acid cohort experienced a higher rate of adverse events leading to drug discontinuation as well as significant negative effects on attentional measures that were not seen in the ethosuximide cohort. These 12-month outcome data coupled with the study's prespecified decision-making algorithm indicate that ethosuximide is the optimal initial empirical monotherapy for CAE. This is the first randomized controlled trial meeting International League Against Epilepsy (ILAE) criteria for class I evidence for CAE (or for any type of generalized seizure in adults or children).

Effects of hyperbaric oxygen on motor function in children with cerebral palsy

Ann Neurol. 2012 Nov;72(5):695-703

Here, Lacey DJ et al conducted a randomized, double-blind, controlled clinical trial to determine whether hyperbaric oxygen (HBO) improves gross motor function in children with cerebral palsy. Forty-nine children aged 3 to 8 years with spastic cerebral palsy were randomized to 40 treatments of HBO (100% oxygen at 1.5atm) or hyperbaric air (HBA, 14% oxygen at 1.5atm) over an 8-week period. The primary outcome was the Gross Motor Function Measure (GMFM) global score. Other outcomes included the Pediatric Evaluation of Disability Inventory (PEDI). Assessments were made before and immediately, 3 months, and 6 months after the treatment period. Forty-six children (24 HBO, 22 HBA) were analyzed at the second interim analysis, which was scheduled to take place when at least half of the required number of patients in each group had completed pre- and post-treatment testing. No changes occurred in the GMFM from pre- to post-treatment in either group or between groups. Statistically significant increases occurred in both groups on the PEDI, with no difference between groups. The study was stopped because the calculated conditional probability of obtaining a difference between groups if the study continued to the end was only between 0.5% and 1.6%. HBO was not effective in improving GMFM scores, and was no more effective than HBA in improving PEDI scores. These results do not support use of HBO as a therapy for cerebral palsy in young children who did not have neonatal hypoxic-ischemic encephalopathy.

Recurrence risk of congenital malformations in infants exposed to antiepileptic drugs in utero

Epilepsia. 2013 Jan;54(1):165-71

Use of antiepileptic drugs in pregnancy is associated with congenital malformations and developmental delay. Previous studies have suggested that women who have had one child with a congenital malformation are at increased risk of having other children with malformations. Here, researchers sought to confirm the magnitude of risk in a large cohort drawn from the United Kingdom Epilepsy and Pregnancy Register. The United Kingdom Epilepsy and Pregnancy Register is a prospective, observational registration and follow-up study set up to determine the relative safety of antiepileptic drugs in pregnancy. Outcome data were available for 1,534 pregnancies born to 719 mothers. For women whose first child had a congenital malformation there was a 16.8% risk of having another child with a congenital malformation, compared with 9.8% for women whose first child did not have a malformation (relative risk 1.73, 95% confidence interval [CI] 1.01–2.96). The risk for recurrence was 50% for women who had had two previous children with a congenital malformation. There was a trend toward a higher risk for recurrent malformations in pregnancies exposed to valproate (21.9%, relative risk 1.47, 95% CI 0.68–3.20) and topiramate (50%, relative risk 4.50, 95% CI 0.97–20.82), but not for other drugs such as carbamazepine and lamotrigine. Recurrence risks were also higher for pregnancies exposed to polytherapy regimens and for those where the dose of antiepileptic drug treatment had been increased after the first pregnancy.

Fetal antiepileptic drug exposure and cognitive outcomes at age 6 years (NEAD study): a prospective observational study

Meador KJ et al. Lancet Neurol 2013; 12: 244–52

This multicentre, prospective observational study from UK and USA evaluated the effects of maternal AEDs (Valproate, Phenytoin, Carbamazepine and Lamotrigene) on children’s cognition at 6 years of age (Neurodevelopmental Effects of Antiepileptic Drugs-NEAD study). The IQ of children was (in the descending order) highest with Phenytoin, followed by Lamotrigene, Carbamazepine and Valproate (Lowest). Children exposed to Valproate were noted to have poor verbal and memory abilities compared with all other AEDs, and poorer non-verbal and executive functions compared with Lamotrigene. Fetal Valproate exposure also appears to have dose-dependent effects with higher levels associated with lower abilities in multiple domains.

Clinical, neurological, and electrophysiological features of nodding syndrome in Kitgum, Uganda: an observational case series

Sejvar JJ et al. Lancet Neurol 2013; 12: 166–74

Nodding syndrome, epidemic epilepsy was earlier reported from Sudan and Tanzania. But, this is the larger case-series of 23 previously healthy children (age 7-15 years). The head nodding spells were paroxysmal, characterized as atonic seizures on EEG (generalized electrodecrement) with paraspinal surface EMG (two cases). Six of the twelve children showed cognitive decline on follow-up, with MRI showing diffuse cerebral and cerebellar atrophy and normal CSF examinations.

December 2012

Contributor: Dr. Ramesh Konanki

Early onset absence epilepsy: 1 in 10 cases is caused by GLUT1 deficiency

Todor Arsov et al. Epilepsia 2012;53 (12): e204-7

In the recent years, there is increasing evidence to suggest that early-onset absence epilepsy (EOAE) is a distinct epilepsy syndrome, not yet recognized in ILAE classification. Of more interest is the fact that, nearly 10-13% of these cases are the result of GLUT1 deficiency. Adding to the publications in past 4-5 years, this new case series of 55 patients with EOAE found that SLC2A1 mutations responsible for glucose transporter deficiency were found in 7 patients (13%). The same group had reported 4 patients with GLUT1 deficiency from another cohort of 34 patients with EOAE in 2009 (Suls A et al. Ann Neurol. 2009 Sep;66(3):415-9). This finding has important treatment and genetic counselling implications as GLUT1 deficiency syndrome has excellent response to ketogenic diet.

Extreme delta brush: A unique EEG pattern in adults with anti-NMDA receptor encephalitis

Schmitt SE et al. Neurology 2012;79: 1094–1100

The authors of this study evaluated continuous EEG of adult patients with anti-NMDA receptor encephalitis and tried to identify any “specific patterns” associated with/unique to this entity. Seven of 23 patients had EEG pattern termed as “extreme delta brush” by the authors. The presence of this EEG finding is said to be associated with a more protracted course of disease (prolonged hospitalization and worse scores on modified Rankin scale. Recognition of this finding in patients with suspected autoimmune encephalitis early in the course might help in suspecting anti-NMDA receptor encephalitis even before the antibody test results are available and help in early initiation of specific therapy. It is not known whether this EEG finding is seen in children or specific to adults or patients with neoplasm-related encephalitis.

Migraine and migraine subtypes in preadolescent children: Association with school performance

Arruda MA, Bigal ME. Neurology 2012;79:1881–1888

This is a population-based study of Brazilian children assessing school performance of children with migraine in comparison to those without headache. Among the large sample of 5671 children aged 5-12 years, the prevalence of migraine (all subtypes included) was about 27%. The authors report that, school performance is more likely to be poor in children with episodic migraine and chronic migraine compared to controls. The school performance was significantly associated with severity, duration and frequency of headaches, presence of nausea, use of analgesics and scores of mental health. The findings of this study calls for better efforts at recognizing the migraine in school-going children providing early, appropriate therapy and continuing care. The Pediatricians and Pediatric neurologists should not ignore the impact of poor headache control on school performance.

EPNS/SFNP guideline on the anticoagulant treatment of cerebral sinovenous thrombosis in children and neonates

Lebas A et al. European journal of paediatric neurology 16 (2012) e219-e228

The literature review for the guidelines is quiet extensive. The guidelines have been prepared for neonates and children separately, and tried to answer important clinical queries like tolerability, efficacy, and duration of anticoagulation. The data suggests that anticoagulation in children is tolerated well and efficacious. The duration of anticoagulation depends upon the age, risk factors identified, and recanalization of venous sinus. In children, level B evidence suggests that it probably reduces risk of death and sequelae, whereas in neonates the evidence is less strong to make recommendations. The guidelines conclude that, it is reasonable to start anticoagulation in children with sinovenous thrombosis, continue for 3-6 months; further therapy to be decided individually based on the risk factors and recanalization.

Evidence-based guideline update: Steroids and antivirals for Bell palsy Report of the Guideline Development Subcommittee of the American Academy of Neurology

Neurology 2012;79:2209-2213

The guidelines reviewed the articles since 2001 for effectiveness, safety and tolerability of steroids and antivirals for new-onset Bell’s palsy. The population is mainly adults. The evidence suggests that use of steroids increases the probability of recovery. Addition of antivirals to steroids does not seem to significantly increase the chances of recovery in comparison steroids alone. The duration of steroids ranged from 5-20 days.

Critical determinants of the epilepsy treatment gap: A cross-national analysis in resource-limited settings

Ana-Claire L. Meyer et al. Epilepsia 2012; 53(12): 2178-85

For those with interest in community neurology and epidemiology, this systematic review focused on which resources determine treatment gap for epilepsy in the resource-constrained settings. This data from 47 studies comprising 8,285 individuals from 24 countries shows the factors associated with higher risk of untreated epilepsy: rural location; those associated with lower risk of untreated epilepsy: higher physician density, presence of an association for epilepsy, and presence of postgraduate neurology training program in the region.
Upcoming events
2nd AOCN Masterclass in Pediatric Neurology for Postgraduates

Place: New delhi
Date: 4th February 2018
Course coordinators: Dr. JS Koushik, Dr. Suvasini Sharma and Dr. Rekha Mittal
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Manipal Genetics Update V on Genomics of Neurodevelopmental Disorders
is to be held on 9th and 10th of February, 2018 at Kasturba Medical College, Manipal, India. This conference brings together international and national experts to highlight the latest advances in the area of neurodevelopmental and neurogenetics research.

Date: 9th and 10th of February, 2018 Venue: Kasturba Medical College, Manipal, India.
More details are available on http://www.manipalgeneticsupdate.com
Amrita Masterclass: Neonatal brain, Seizures and Development

Place: Amrita Institute of Medical Sciences, Kochi
Date: 10-11 February 2018
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The 15th International Child Neurology Congress (ICNC), will be held in Mumbai, between 15th-18th November 2018.

The ICNC 2018 is being jointly organized by the Association of Child Neurology (AOCN) and the Child Neurology Group in association with International Child Neurology Association (ICNA). The theme of the conference will be: "Protect the developing brain".
Venue: Hotal Grand Hyatt, Kalina, Mumbai, India
Date: 15-18 November 2018
For more details go to the conference website: www.icnc2018mumbai.com