Brain language networks and cognitive outcomes in children with frontotemporal lobe epilepsy.

Introduction: Pediatric frontal and temporal lobe epilepsies (FLE, TLE) have been associated with language impairments and structural and functional brain alterations. However, there is no clear consensus regarding the specific patterns of cerebral reorganization of language networks in these patients. The current study aims at characterizing the cerebral language networks in children with FLE or TLE, and the association between brain network characteristics and cognitive abilities. Methods: Twenty (20) children with FLE or TLE aged between 6 and 18 years and 29 age- and sex-matched healthy controls underwent a neuropsychological evaluation and a simultaneous functional near-infrared spectroscopy and electroencephalography (fNIRS-EEG) recording at rest and during a receptive language task. EEG was used to identify potential subclinical seizures in patients. We removed these time intervals from the fNIRS signal to investigate language brain networks and not epileptogenic networks. Functional connectivity matrices on fNIRS oxy-hemoglobin concentration changes were computed using cross-correlations between all channels. Results and discussion: Group comparisons of residual matrices (=individual task-based matrix minus individual resting-state matrix) revealed significantly reduced connectivity within the left and between hemispheres, increased connectivity within the right hemisphere and higher right hemispheric local efficiency for the epilepsy group compared to the control group. The epilepsy group had significantly lower cognitive performance in all domains compared to their healthy peers. Epilepsy patients' local network efficiency in the left hemisphere was negatively associated with the estimated IQ (p = 0.014), suggesting that brain reorganization in response to FLE and TLE does not allow for an optimal cognitive development.

Treatment of Refractory Epilepsy With MEK Inhibitor in Patients With RASopathy.

BACKGROUND: Several specific syndromes within the RASopathies spectrum lead to an increased risk of seizures up to developing refractory epileptic encephalopathy. Management remains symptomatic. METHODS: Here we report two patients treated with trametinib, a MEK1-2 inhibitor, as a precision strategy for drug-resistant epilepsy. Patient 1 is a six-year-old girl with cardiofaciocutaneous syndrome (BRAF p.F595L, germline mutation), and Patient 2 is a 14-month-old boy with Schimmelpenning syndrome (KRAS p.G12D, postzygotic somatic mutation). Trametinib was initiated at a dosage of 0.025 mg/kg/day. RESULTS: Patient 1 had multiple seizures per day, multifocal motor to bilateral tonic-clonic. Electroencephalography (EEG) showed a dramatic reduction in EEG discharges three months after trametinib onset, while a marked clinical improvement occurred after about five months, at the same dosage, and the girl is currently seizure-free for more than six months. Patient 2 had left cerebral hemiatrophy leading to right focal motor seizures, multiple per week to multiple per day, since the age of three months. On trametinib, he experienced an early benefit, remaining seizure-free for more than three months. However, after six months we observed recurrence of seizures. After 22 months of treatment, trametinib was discontinued because of a suspected drug-induced inflammatory colitis. After discontinuation, we observed a significant clinical and EEG "rebound effect." CONCLUSIONS: We provide proof of concept that MEK inhibition is a promising approach for the treatment of patients with refractory epilepsy with selected germline and mosaic RASopathies. Future trials are encouraged to better investigate their potentials and limitations.

Pharmacogenetic testing in pediatric neurology: a pragmatic study evaluating clinician and patient perceptions.

Aim: To evaluate clinicians' and patients' perceptions of pharmacogenetic testing in a clinical setting. Materials & methods: This is a pragmatic mixed-method prospective observational study. Hospital pharmacists and neurologists participated in focus groups regarding pharmacogenetic testing; patients who received pharmacogenetic testing and their community pharmacists completed surveys to assess their perception of these tests. Results: Most study participants had a positive view of pharmacogenetic testing. Three major themes were identified from the focus groups: receptiveness to pharmacogenetic testing, pharmacogenetic test characteristics and integrating pharmacogenetic tests into practice. Conclusion: The views reported are encouraging for the eventual implementation of pharmacogenetics in practice. Local integration of these tests is an essential step to improve patient care through personalized medicine.

Genetic tests can help predict patients' response to medication. This study aimed to evaluate clinicians' and patients' perceptions of these genetic tests. Pediatric patients, with epilepsy, were tested and completed a survey to assess their perception of these tests. A survey was also completed by their community pharmacists, and virtual discussion groups were held with hospital pharmacists and neurologists. Most participants had a positive view of these tests, with three major themes identified from the discussion groups: receptiveness to testing, test characteristics and integration of tests into practice. The views reported are encouraging for the eventual implementation of these tests in practice, an essential step to improve patient care through personalized medicine.

Recognition of Psychogenic Versus Epileptic Seizures Based on Videos.

OBJECTIVE: Ictal semiology interpretation for differentiating psychogenic nonepileptic seizures (PNESs) and epileptic seizures (ESs) is important for the institution of appropriate treatment. Our objective was to assess the ability of different health care professionals (HCPs) or students to distinguish PNES from ES based on video-recorded seizure semiology. METHODS: This study was designed following the Standards for Reporting of Diagnostic Accuracy Studies (STARD) guidelines. We showed in a random mix 36 videos of PNES or ES (18 each) and asked 558 participants to classify each seizure. The diagnostic accuracy of various groups of HCPs or students for PNES versus ES was assessed, as well as the effect of patient age and sex. Measures of diagnostic accuracy included sensitivity, specificity, and area under the curve (AUC). RESULTS: The descending order of diagnostic accuracy (AUC) was the following (p ≤ 0.001): (1) neurologists and epileptologists; (2) neurology residents; (3) other specialists and nurses with experience in epilepsy; and (4) undergraduate medical students. Although there was a strong trend toward statistical difference, with AUC 95% confidence intervals (CIs) that were not overlapping, between epileptologists (95% CI 93, 97) compared to neurologists (95% CI 88, 91), and neurologists compared to electroencephalography technicians (95% CI 82, 87), multiple pairwise comparisons with the conservative Tukey-Kramer honest significant difference test revealed no statistical difference (p = 0.25 and 0.1, respectively). Patient age and sex did not have an effect on diagnostic accuracy in neurology specialists. CONCLUSION: Visual recognition of PNES by HCPs or students varies overall proportionately with the level of expertise in the field of neurology/epilepsy.

What is the optimal duration for vigabatrin monotherapy in patients with infantile spasms: 6 months or longer?

Vigabatrin (VGB) is approved as monotherapy for pediatric patients with Infantile Spasms (IS). Duration of VGB use should be limited because of the risk of retinal and neurotoxicity, but the optimal length of treatment is unknown. Our study aimed to determine the risk of spasms relapse after 6 months of VGB as first-line therapy in IS patients deemed VGB good responders. The participants were 44 infants with IS who demonstrated both absence of clinical spasms and hypsarrhythmia four weeks after starting VGB, obtained from two cohorts: 29 patients from a multicenter prospective cohort and 15 patients from a retrospective single-center cohort. We divided them post hoc into two groups according to the duration of VGB treatment: 6-month group (n=34) and >6-month group (n=10) and compared outcome between the two groups. No patient in either group had a relapse of spasms. For patients with non-identified etiology (NIE) in the 6 months treatment group, no other seizure types were observed. Late epilepsy, in the form of focal seizures, emerged in only 5/37 patients (3/30 in the 6-month treatment group; 2/7 in the extended treatment group); all within the first 6-9 months after VGB initiation. Our study provides substantial evidence that a shortened VGB course of 6 months could be sufficient to treat and prevent relapse of spasms in children with IS, particularly those with NIE.

Cognitive outcome in children with infantile spasms using a standardized treatment protocol. A five-year longitudinal study.

AIM: To evaluate the long-term developmental trajectory of children with infantile spasms (IS) and identify the clinical protective and risk factors associated with their cognitive outcome. METHODS: We analyzed the five-year follow-up results of 41 children (13 female) from the previously published cohort (n = 68) recruited in a multicenter randomized controlled trial for 2-years, examining the effect of an adjunctive therapy (Flunarizine) on standardized IS treatment. The children were subsequently monitored in an open-label study for additional 3 years.  The Vineland Adaptive Behavior Scale, second edition, and either the Stanford-Binet Intelligence Scale, Fifth Edition (SB5) or the Bayley Scales of Infant Development, second edition (BSID-II) were used as cognitive outcome measures. RESULTS: Etiology was the strongest predictor of outcome. Children with no identified etiology (NIE) showed a progressive improvement of cognitive functions, mostly occurring between 2 and 5 years post-diagnosis.  Conversely, symptomatic etiology was predictive of poorer cognitive outcome. Developmental delay, other seizure types (before and after IS diagnosis), and persistent electroencephalographic abnormalities following treatment were predictive of poor cognitive outcome. INTERPRETATION: Given the 5-year cognitive improvement, children with IS should undergo a developmental assessment before school entry. Factors influencing their cognitive outcome emphasize the importance of thorough investigation and evidence-based treatment.

Neuroinflammatory Disease as an Isolated Manifestation of Hemophagocytic Lymphohistiocytosis.

Isolated neuroinflammatory disease has been described in case reports of familial hemophagocytic lymphohistiocytosis (FHL), but the clinical spectrum of disease manifestations, response to therapy and prognosis remain poorly defined. We combined an international survey with a literature search to identify FHL patients with (i) initial presentation with isolated neurological symptoms; (ii) absence of cytopenia and splenomegaly at presentation; and (iii) systemic HLH features no earlier than 3 months after neurological presentation. Thirty-eight (20 unreported) patients were identified with initial diagnoses including acute demyelinating encephalopathy, leukoencephalopathy, CNS vasculitis, multiple sclerosis, and encephalitis. Median age at presentation was 6.5 years, most commonly with ataxia/gait disturbance (75%) and seizures (53%). Diffuse multifocal white matter changes (79%) and cerebellar involvement (61%) were common MRI findings. CSF cell count and protein were increased in 22/29 and 15/29 patients, respectively. Fourteen patients progressed to systemic inflammatory disease fulfilling HLH-2004 criteria at a mean of 36.9 months after initial neurological presentation. Mutations were detected in PRF1 in 23 patients (61%), RAB27A in 10 (26%), UNC13D in 3 (8%), LYST in 1 (3%), and STXBP2 in 1 (3%) with a mean interval to diagnosis of 28.3 months. Among 19 patients who underwent HSCT, 11 neurologically improved, 4 were stable, one relapsed, and 3 died. Among 14 non-transplanted patients, only 3 improved or had stable disease, one relapsed, and 10 died. Isolated CNS-HLH is a rare and often overlooked cause of inflammatory brain disease. HLH-directed therapy followed by HSCT seems to improve survival and outcome.

Seizures in Pediatric Patients With Primary Brain Tumors.

BACKGROUND: Seizures are one of the most common symptoms of pediatric brain tumors. The purpose of this study was to define seizures related to primary central nervous system tumors and to identify risk factors predictive of seizure occurrence and recurrence. METHODS: We reviewed the records of children treated from January 1, 2004, to January 1, 2018 and collected data including age, gender, tumor location, histology, extent of initial resection, seizure characteristics, treatment modalities, recurrence, and seizure control. A binomial logistic regression was performed to determine the risk factors of seizure occurrence. RESULTS: During the observation period, 348 children were diagnosed with a primary brain tumor. The median age at diagnosis was 7.8 years, and the median follow-up interval was 3.9 years. There were 196 boys (56.3%). In our cohort, a total of 70 children (20.1%) experienced seizures. Most of them (64.3%) had cortical tumors. All patients with dysembryoplastic neuroepithelial tumors and 81.8% of patients with glioneuronal tumors presented seizures. Risk factors associated with an increased risk for seizures included cortical location, tumor recurrence, and age at diagnosis. Thirty-nine (86.7%) patients with seizures at diagnosis were seizure free at last follow-up (Engel 1). Significantly more patients (69.6%) with a gross total resection were withdrawn from their antiepileptic drugs when compared with those with subtotal resection (27.3%, P = 0.007). CONCLUSIONS: Our study is the largest cohort in children with tumor-related seizures and brings new insight in terms of seizure risk according to tumor types and evolution following treatment.

Mutations in ACTL6B Cause Neurodevelopmental Deficits and Epilepsy and Lead to Loss of Dendrites in Human Neurons.

We identified individuals with variations in ACTL6B, a component of the chromatin remodeling machinery including the BAF complex. Ten individuals harbored bi-allelic mutations and presented with global developmental delay, epileptic encephalopathy, and spasticity, and ten individuals with de novo heterozygous mutations displayed intellectual disability, ambulation deficits, severe language impairment, hypotonia, Rett-like stereotypies, and minor facial dysmorphisms (wide mouth, diastema, bulbous nose). Nine of these ten unrelated individuals had the identical de novo c.1027G>A (p.Gly343Arg) mutation. Human-derived neurons were generated that recaptured ACTL6B expression patterns in development from progenitor cell to post-mitotic neuron, validating the use of this model. Engineered knock-out of ACTL6B in wild-type human neurons resulted in profound deficits in dendrite development, a result recapitulated in two individuals with different bi-allelic mutations, and reversed on clonal genetic repair or exogenous expression of ACTL6B. Whole-transcriptome analyses and whole-genomic profiling of the BAF complex in wild-type and bi-allelic mutant ACTL6B neural progenitor cells and neurons revealed increased genomic binding of the BAF complex in ACTL6B mutants, with corresponding transcriptional changes in several genes including TPPP and FSCN1, suggesting that altered regulation of some cytoskeletal genes contribute to altered dendrite development. Assessment of bi-alleic and heterozygous ACTL6B mutations on an ACTL6B knock-out human background demonstrated that bi-allelic mutations mimic engineered deletion deficits while heterozygous mutations do not, suggesting that the former are loss of function and the latter are gain of function. These results reveal a role for ACTL6B in neurodevelopment and implicate another component of chromatin remodeling machinery in brain disease.

Intracranial hypertension following sacrifice of occipital and marginal sinuses during posterior fossa decompression for Chiari I malformation: case report.

The occipital and marginal sinuses, when present, must be sacrificed in order to open the dura in most posterior fossa surgeries in the pediatric population, including posterior fossa decompression for Type I Chiari malformation (CM-I) with duraplasty. Apart from the immediate risk of hemorrhage, the voluntary occlusion of this structure is almost universally well tolerated. The authors report a case of intracranial hypertension following the sacrifice of occipital and marginal sinuses following posterior fossa decompression with duraplasty for CM-I. The specific draining pattern variant of the occipital and marginal sinuses leading to this complication as well as avoidance and management strategies of this condition are discussed.

Atypical juvenile presentation of GM2 gangliosidosis AB in a patient compound-heterozygote for c.259G > T and c.164C > T mutations in the GM2A gene.

GM2-gangliosidosis, AB variant is an extremely rare autosomal recessive inherited disorder caused by mutations in the GM2A gene that encodes GM2 ganglioside activator protein (GM2AP). GM2AP is necessary for solubilisation of GM2 ganglioside in endolysosomes and its presentation to ß-hexosaminidase A. Conversely GM2AP deficiency impairs lysosomal catabolism of GM2 ganglioside, leading to its storage in cells and tissues. We describe a 9-year-old child with an unusual juvenile clinical onset of GM2-gangliosidosis AB. At the age of 3 years he presented with global developmental delay, progressive epilepsy, intellectual disability, axial hypertonia, spasticity, seizures and ataxia, but without the macular cherry-red spots typical for GM2 gangliosidosis. Brain MRI detected a rapid onset of diffuse atrophy, whereas whole exome sequencing showed that the patient is a compound heterozygote for two mutations in GM2A: a novel nonsense mutation, c.259G > T (p.E87X) and a missense mutation c.164C > T (p.P55L) that was recently identified in homozygosity in patients of a Saudi family with a progressive chorea-dementia syndrome. Western blot analysis showed an absence of GM2AP in cultured fibroblasts from the patient, suggesting that both mutations interfere with the synthesis and/or folding of the protein. Finally, impaired catabolism of GM2 ganglioside in the patient's fibroblasts was demonstrated by metabolic labeling with fluorescently labeled GM1 ganglioside and by immunohistochemistry with anti-GM2 and anti-GM3 antibodies. Our observation expands the molecular and clinical spectrum of molecular defects linked to GM2-gangliosidosis and suggests novel diagnostic approach by whole exome sequencing and perhaps ganglioside analysis in cultured patient's cells.

Periictal activity in cooled asphyxiated neonates with seizures.

PURPOSE: Seizures are common in critically ill neonates. Both seizures and antiepileptic treatments may lead to short term complications and worsen the outcomes. Predicting the risks of seizure reoccurrence could enable individual treatment regimens and better outcomes. We aimed to identify EEG signatures of seizure reoccurrence by investigating periictal electrographic features and spectral power characteristics in hypothermic neonates with hypoxic-ischemic encephalopathy (HIE) with or without reoccurrence of seizures on rewarming. METHODS: We recruited five consecutive HIE neonates, submitted to continuous EEG monitoring, with high seizure burden (>20% per hour) while undergoing therapeutic hypothermia. Two of them had reoccurrence of seizures on rewarming. We performed quantitative analysis of fifteen artifact-free consecutive seizures to appreciate spectral power changes between the interictal, preictal and ictal periods, separately for each patient. Visual analysis allowed description of electrographic features associated with ictal events. RESULTS: Every patient demonstrated a significant increase in overall spectral power from the interictal to preictal and ictal periods (p<0.01). Alpha power increase was more pronounced in the two patients with reoccurrence of seizures on rewarming and significant when comparing both interictal-to-preictal and interictal-to-ictal periods. This alpha activity increase could be also appreciated using visual analysis and distinguished neonates with and without seizure reoccurrence. CONCLUSION: This distinct alpha activity preceding ictal onset could represent a biomarker of propensity for seizure reoccurrence in neonates. Future studies should be performed to confirm whether quantitative periictal characteristics and electrographic features allow predicting the risks of seizure reoccurrence in HIE neonates and other critically ill patients.

Rewarming affects EEG background in term newborns with hypoxic-ischemic encephalopathy undergoing therapeutic hypothermia.

OBJECTIVE: To investigate how rewarming impacts the evolution of EEG background in neonates with hypoxic-ischemic encephalopathy (HIE) undergoing therapeutic hypothermia (TH). METHODS: We recruited a retrospective cohort of 15 consecutive newborns with moderate (9) and severe (6) HIE monitored with a continuous EEG during TH and at least 12h after its end. EEG background was analyzed using conventional visual and quantitative EEG analysis methods including EEG discontinuity, absolute and relative spectral magnitudes. One patient with seizures on rewarming was excluded from analyses. RESULTS: Visual and quantitative analyses demonstrated significant changes in EEG background from pre- to post-rewarming, characterized by an increased EEG discontinuity, more pronounced in newborns with severe compared to moderate HIE. Neonates with moderate HIE also had an increase in the relative magnitude of slower delta and a decrease in higher frequency theta and alpha waves with rewarming. CONCLUSIONS: Rewarming affects EEG background in HIE newborns undergoing TH, which may represent a transient adaptive response or reflect an evolving brain injury. SIGNIFICANCE: EEG background impairment induced by rewarming may represent a biomarker of evolving encephalopathy in HIE newborns undergoing TH and underscores the importance of continuously monitoring the brain health in critically ill neonates.

Efficacy and safety of lacosamide as an adjunctive therapy for refractory focal epilepsy in paediatric patients: a retrospective single-centre study.

AIM: Lacosamide is an antiepileptic drug approved for the treatment of focal epilepsy in adult patients. The aim of this observational study was to review our centre's experience with lacosamide and to characterize its effectiveness and tolerability as an adjunctive antiepileptic drug in a retrospective cohort of children with refractory focal epilepsy. METHODS: We retrospectively reviewed the medical records of 22 patients who received lacosamide from November 2009 to April 2014 at the CHU Ste-Justine, University of Montreal. Treatment responders were defined as children with a ≥50% reduction in seizure frequency compared to baseline, and this was determined three months after the initiation of treatment and at the last follow-up visit. RESULTS: We included 14 boys and eight girls with a mean age of 12.9 years (SD: 5.2; range: 5.2-20.7 years) at the initiation of treatment. The average length of follow-up was 11.9 months. Patients had previously received an average of 7.5 antiepileptic drugs. The mean number of concomitant antiepileptic drugs was 2.3. The mean initial and maintenance doses were 2.9 and 8.4 mg/kg/d, respectively. Thirteen (59%) and ten (45%) patients were responders after three months of treatment and at the last follow-up visit, respectively. One became seizure-free. Adverse effects were reported in 11 patients and none were severe. Responders and non-responders were identical with respect to all studied parameters except gender, with the proportion of responders being greater in girls than in boys (75% vs 29%; p=0.035). CONCLUSION: Our study adds evidence that lacosamide appears to be a safe and effective adjunctive therapy for children with refractory focal epilepsy.

Recovery From Central Nervous System Acute Demyelination in Children.

BACKGROUND: Few prospective studies have systematically evaluated the extent of recovery from incident acquired demyelinating syndromes (ADS) of the central nervous system in children. METHODS: In a national cohort study of pediatric ADS, severity of the incident attack and extent of recovery by 12 months were evaluated. Annual evaluations were used to determine current diagnoses (monophasic ADS or multiple sclerosis [MS]) and new deficits. RESULTS: Of 283 children, 244 (86%) required hospitalization for a median (interquartile range [IQR]) of 6 (3-10) days, and 184 had moderate or severe deficits; 41 children were profoundly encephalopathic, 129 were unable to ambulate independently, and 59 with optic neuritis (ON) had moderately or severely impaired vision. Those with transverse myelitis (TM) and patients with monophasic disease were more likely to have moderate or severe deficits at onset. Twenty-seven children (10%) did not experience full neurologic recovery from their incident attack; 12 have severe residual deficits. Monophasic illness, TM, and moderate or severe deficits at onset were associated with poor recovery. After a median (IQR) follow-up of 5.06 (3.41-6.97) years, 59 children (21%) were diagnosed with MS; all recovered fully from their incident ADS attacks, although 6 subsequently acquired irreversible deficits after a median (IQR) observation period of 5.93 (4.01-7.02) years. CONCLUSIONS: ADS is a serious illness, with 86% of affected Canadian children requiring hospitalization. More than 90% of children recovered physically from their ADS event, including those children experiencing onset of MS. However, permanent visual or spinal cord impairment occurred in some children with ON or TM.

CACNA1A haploinsufficiency causes cognitive impairment, autism and epileptic encephalopathy with mild cerebellar symptoms.

CACNA1A loss-of-function mutations classically present as episodic ataxia type 2 (EA2), with brief episodes of ataxia and nystagmus, or with progressive spinocerebellar ataxia (SCA6). A minority of patients carrying CACNA1A mutations develops epilepsy. Non-motor symptoms associated with these mutations are often overlooked. In this study, we report 16 affected individuals from four unrelated families presenting with a spectrum of cognitive impairment including intellectual deficiency, executive dysfunction, ADHD and/or autism, as well as childhood-onset epileptic encephalopathy with refractory absence epilepsy, febrile seizures, downbeat nystagmus and episodic ataxia. Sequencing revealed one CACNA1A gene deletion, two deleterious CACNA1A point mutations including one known stop-gain and one new frameshift variant and a new splice-site variant. This report illustrates the phenotypic heterogeneity of CACNA1A loss-of-function mutations and stresses the cognitive and epileptic manifestations caused by the loss of CaV2.1 channels function, presumably affecting cerebellar, cortical and limbic networks.

The genetic landscape of infantile spasms.

Infantile spasms (IS) is an early-onset epileptic encephalopathy of unknown etiology in ∼40% of patients. We hypothesized that unexplained IS cases represent a large collection of rare single-gene disorders. We investigated 44 children with unexplained IS using comparative genomic hybridisation arrays (aCGH) (n = 44) followed by targeted sequencing of 35 known epilepsy genes (n = 8) or whole-exome sequencing (WES) of familial trios (n = 18) to search for rare inherited or de novo mutations. aCGH analysis revealed de novo variants in 7% of patients (n = 3/44), including a distal 16p11.2 duplication, a 15q11.1q13.1 tetrasomy and a 2q21.3-q22.2 deletion. Furthermore, it identified a pathogenic maternally inherited Xp11.2 duplication. Targeted sequencing was informative for ARX (n = 1/14) and STXBP1 (n = 1/8). In contrast, sequencing of a panel of 35 known epileptic encephalopathy genes (n = 8) did not identify further mutations. Finally, WES (n = 18) was very informative, with an excess of de novo mutations identified in genes predicted to be involved in neurodevelopmental processes and/or known to be intolerant to functional variations. Several pathogenic mutations were identified, including de novo mutations in STXBP1, CASK and ALG13, as well as recessive mutations in PNPO and ADSL, together explaining 28% of cases (5/18). In addition, WES identified 1-3 de novo variants in 64% of remaining probands, pointing to several interesting candidate genes. Our results indicate that IS are genetically heterogeneous with a major contribution of de novo mutations and that WES is significantly superior to targeted re-sequencing in identifying detrimental genetic variants involved in IS.

Mutations in DOCK7 in individuals with epileptic encephalopathy and cortical blindness.

Epileptic encephalopathies are increasingly thought to be of genetic origin, although the exact etiology remains uncertain in many cases. We describe here three girls from two nonconsanguineous families affected by a clinical entity characterized by dysmorphic features, early-onset intractable epilepsy, intellectual disability, and cortical blindness. In individuals from each family, brain imaging also showed specific changes, including an abnormally marked pontobulbar sulcus and abnormal signals (T2 hyperintensities) and atrophy in the occipital lobe. Exome sequencing performed in the first family did not reveal any gene with rare homozygous variants shared by both affected siblings. It did, however, show one gene, DOCK7, with two rare heterozygous variants (c.2510delA [p.Asp837Alafs(∗)48] and c.3709C>T [p.Arg1237(∗)]) found in both affected sisters. Exome sequencing performed in the proband of the second family also showed the presence of two rare heterozygous variants (c.983C>G [p.Ser328(∗)] and c.6232G>T [p.Glu2078(∗)]) in DOCK7. Sanger sequencing confirmed that all three individuals are compound heterozygotes for these truncating mutations in DOCK7. These mutations have not been observed in public SNP databases and are predicted to abolish domains critical for DOCK7 function. DOCK7 codes for a Rac guanine nucleotide exchange factor that has been implicated in the genesis and polarization of newborn pyramidal neurons and in the morphological differentiation of GABAergic interneurons in the developing cortex. All together, these observations suggest that loss of DOCK7 function causes a syndromic form of epileptic encephalopathy by affecting multiple neuronal processes.

Diagnosis of migraine in the pediatric emergency department.

BACKGROUND: Migraine criteria lack sensitivity in children and are not designed to be used in the emergency department. This study's aim was to compare the diagnosis of migraine in children with moderate to severe headache made by pediatric emergency physicians to the International Classification of Headache Disorders II migraine criteria with annotation for children and a new criteria, the Irma emergency department criteria, using the neurologist's diagnosis as the gold standard. METHODS: This was part of a prospective study with a convenience sample of patients <18 years old, diagnosed with migraine by pediatric emergency physicians and treated with intravenous medication due to severity of symptoms. A standardized questionnaire on the patient's present and past headaches description was completed by the patient and his or her family during their stay in the emergency department. Each patient was assessed by a pediatric neurologist within 3 months to confirm the final diagnosis. RESULTS: Between July 2007 and July 2009, 79 children completed a questionnaire. Of these, 11 were not evaluated by the neurologist (eight never reported for follow-up and three were not referred). Of the remaining, four had another final diagnosis, leaving 64 (94%) patients with confirmed diagnoses of migraine. Among these patients, 29 (45%) had headaches that fulfilled the International Classification of Headache Disorders II migraine criteria with annotation for children and 55 (86%) fulfilled the new criteria, the Irma emergency department criteria. CONCLUSIONS: Physicians' clinical judgment performed better than the published migraine criteria, which did not have adequate sensitivity to be of use to pediatric emergency physicians.

Psychogenic nonepileptic seizures.

Psychogenic nonepileptic seizures (PNES) are clinical events resembling epileptic seizures but lacking abnormal cortical electrical discharges. They are involuntary manifestations of a psychological distress. PNES are less frequent in the pediatric population than in adults, they represent from 3.5 to 9% of patients admitted for prolonged video-EEG (PV-EEG). Diagnosis is rarely made on history only and PV-EEG is mandatory to obtain a definitive diagnosis. Children as young as 5 years can present with PNES. They are more frequent in girls except in school age children where boys are identically or more represented than girls. PNES can either present with subtle signs, even unresponsiveness, or prominent motor activity. Major differential diagnosis is absences, day dreaming, and complex partial seizures including hyperkinetic frontal seizures. PNES are usually rapidly registered during PV-EEG and provocative methods have not been thoroughly studied in children. Major risk factors are psychological stressors, such as school or family problems. Psychiatric conditions are less frequent than in adults though they should be looked for. Prognosis is better than in adults, and most children become PNES-free. There are no guidelines for treatment, however stressors should be addressed. In general, it should be clearly explained that PNES are not epileptic seizures.