Electroencephalographic patterns during sleep in children with chromosome 15q11.2-13.1 duplications (Dup15q).

Our objective was to define the EEG features during sleep of children with neurodevelopmental disorders due to copy number gains of 15q11-q13 (Dup15q). We retrospectively reviewed continuous EEG recordings of 42 children with Dup15q (mean age: eight years, 32 with idic15), and data collected included background activity, interictal epileptiform discharges, sleep organization, and ictal activity. Three patterns were recognized: Pattern 1: Alpha­delta sleep was noted in 14 children (33%), not associated with any clinical changes. Pattern 2: Electrical status epilepticus in sleep was noted in 15 children (35%), all diagnosed with treatmentresistant epilepsy. Thirteen of the 15 children had clinical seizures. Pattern 3: Frequent bursts of high amplitude bifrontal predominant, paroxysmal fast activity (12­15 Hz) during non-REM sleep was noted in 15 children (35%). All 15 children had treatment-resistant epilepsy. This is the first report of electroencephalographic patterns during sleep of children with Dup15q reporting alpha-delta rhythms, CSWS, and high amplitude fast frequencies. Alpha-delta rhythms are described in children with dysautonomia and/or mood disorders and CSWS in children with developmental regression. The significance of these findings in cognitive function and epilepsy for the children in our cohort needs to be determined with follow-up studies.

Concordance between Wada, Transcranial Magnetic Stimulation, and Magnetoencephalography for Determining Hemispheric Dominance for Language: A Retrospective Study.

Determination of language hemispheric dominance (HD) in patients undergoing evaluation for epilepsy surgery has traditionally relied on the sodium amobarbital (Wada) test. The emergence of non-invasive methods for determining language laterality has increasingly shown to be a viable alternative. In this study, we assessed the efficacy of transcranial magnetic stimulation (TMS) and magnetoencephalography (MEG), compared to the Wada test, in determining language HD in a sample of 12 patients. TMS-induced speech errors were classified as speech arrest, semantic, or performance errors, and the HD was based on the total number of errors in each hemisphere with equal weighting of all errors (classic) and with a higher weighting of speech arrests and semantic errors (weighted). Using MEG, HD for language was based on the spatial extent of long-latency activity sources localized to receptive language regions. Based on the classic and weighted language laterality index (LI) in 12 patients, TMS was concordant with the Wada in 58.33% and 66.67% of patients, respectively. In eight patients, MEG language mapping was deemed conclusive, with a concordance rate of 75% with the Wada test. Our results indicate that TMS and MEG have moderate and strong agreement, respectively, with the Wada test, suggesting they could be used as non-invasive substitutes.

Presurgical language mapping in bilingual children using transcranial magnetic stimulation: illustrative case.

BACKGROUND: Presurgical mapping of eloquent cortex in young patients undergoing neurosurgery is critical but presents challenges unique to the pediatric population, including motion artifact, noncompliance, and sedation requirements. Furthermore, as bilingualism in children increases, functional mapping of more than one language is becoming increasingly critical. Transcranial magnetic stimulation (TMS), a noninvasive brain stimulation technique, is well suited to evaluate language areas in children since it does not require the patient to remain still during mapping. OBSERVATIONS: A 13-year-old bilingual male with glioblastoma multiforme involving the left parietal lobe and deep occipital white matter underwent preoperative language mapping using magnetic resonance imaging-guided TMS. Language-specific cortices were successfully identified in both hemispheres. TMS findings aided in discussing with the family the risks of postsurgical deficits of tumor resection; postoperatively, the patient had intact bilingual speech and was referred for chemotherapy and radiation. LESSONS: The authors' findings add to the evolving case for preoperative dual language mapping in bilingual neurosurgical candidates. The authors illustrate the feasibility and utility of TMS as a noninvasive functional mapping tool in this child. TMS is safe, effective, and can be used for preoperative mapping of language cortex in bilingual children to aid in surgical planning and discussion with families.

Clinical Utility of Transcranial Magnetic Stimulation (TMS) in the Presurgical Evaluation of Motor, Speech, and Language Functions in Young Children With Refractory Epilepsy or Brain Tumor: Preliminary Evidence.

Accurate presurgical mapping of motor, speech, and language cortices, while crucial for neurosurgical planning and minimizing post-operative functional deficits, is challenging in young children with neurological disease. In such children, both invasive (cortical stimulation mapping) and non-invasive functional mapping imaging methods (MEG, fMRI) have limited success, often leading to delayed surgery or adverse post-surgical outcomes. We therefore examined the clinical utility of transcranial magnetic stimulation (TMS) in young children who require functional mapping. In a retrospective chart review of TMS studies performed on children with refractory epilepsy or a brain tumor, at our institution, we identified 47 mapping sessions in 36 children 3 years of age or younger, in whom upper and lower extremity motor mapping was attempted; and 13 children 5-6 years old in whom language mapping, using a naming paradigm, was attempted. The primary hand motor cortex was identified in at least one hemisphere in 33 of 36 patients, and in both hemispheres in 27 children. In 17 children, primary leg motor cortex was also successfully identified. The language cortices in temporal regions were successfully mapped in 11 of 13 patients, and in six of them language cortices in frontal regions were also mapped, with most children (n = 5) showing right hemisphere dominance for expressive language. Ten children had a seizure that was consistent with their clinical semiology during or immediately following TMS, none of which required intervention or impeded completion of mapping. Using TMS, both normal motor, speech, and language developmental patterns and apparent disease induced reorganization were demonstrated in this young cohort. The successful localization of motor, speech, and language cortices in young children improved the understanding of the risk-benefit ratio prior to surgery and facilitated surgical planning aimed at preserving motor, speech, and language functions. Post-operatively, motor function was preserved or improved in nine out of 11 children who underwent surgery, as was language function in all seven children who had surgery for lesions near eloquent cortices. We provide feasibility data that TMS is a safe, reliable, and effective tool to map eloquent cortices in young children.

Dravet Syndrome: A Review of Current Management.

Dravet syndrome is a debilitating epileptic encephalopathy of childhood with few treatment options available in the United States before 2018. In the modern era, new genetic testing options will allow diagnosis closer to disease onset. Three new medicines-stiripentol, cannabidiol, and fenfluramine-have documented efficacy and safety as adjunctive therapies for treating pharmacoresistant Dravet syndrome. Early diagnosis resulting in earlier treatment with these and other medications may improve prognosis of long-term outcomes, including less severity of cognitive, motor, and behavioral impairments. New rescue medication formulations can now manage acute seizures and help prevent status epilepticus via intranasal, buccal, and intramuscular routes as opposed to rectal administration. Preventing status epilepticus and generalized tonic-clonic seizures could potentially lower the risk of sudden unexpected death in epilepsy. With this changing landscape in diagnostic and treatment options comes questions and controversies for the practicing clinician, especially as diagnostic techniques outpace clinical treatment strategies. Critical decision points include when to start treatment, what pharmacotherapy combinations to try first, which rescue medication to recommend, and how to advise parents on controversial topics (e.g., immunizations). Given that most patients require polypharmacy, clinicians must be cognizant of drug-drug interactions between new medicines, existing anti-epileptic drugs, and other medications to manage comorbidities and must have an understanding of available therapeutic drug monitoring strategies and pharmacokinetic parameters. This review places new diagnostic, treatment and acute care options into the modern era and provides an overview of the challenges and opportunities facing the pediatric epileptologist in this rapidly changing landscape.

Predicting seizure outcome of vagus nerve stimulation using MEG-based network topology.

Vagus nerve stimulation (VNS) is a low-risk surgical option for patients with drug resistant epilepsy, although it is impossible to predict which patients may respond to VNS treatment. Resting-state magnetoencephalography (rs-MEG) connectivity analysis has been increasingly utilized to investigate the impact of epilepsy on brain networks and identify alteration of these networks after different treatments; however, there is no study to date utilizing this modality to predict the efficacy of VNS treatment. We investigated whether the rs-MEG network topology before VNS implantation can be used to predict efficacy of VNS treatment. Twenty-three patients with epilepsy who had MEG before VNS implantation were included in this study. We also included 89 healthy control subjects from the Human Connectome Project. Using the phase-locking value in the theta, alpha, and beta frequency bands as a measure of rs-MEG functional connectivity, we calculated three global graph measures: modularity, transitivity, and characteristic path length (CPL). Our results revealed that the rs-MEG graph measures were significantly heritable and had an overall good test-retest reliability, and thus these measures may be used as potential biomarkers of the network topology. We found that the modularity and transitivity in VNS responders were significantly larger and smaller, respectively, than those observed in VNS non-responders. We also observed that the modularity and transitivity in three frequency bands and CPL in delta and beta bands were significantly different in controls than those found in responders or non-responders, although the values of the graph measures in controls were closer to those of responders than non-responders. We used the modularity and transitivity as input features of a naïve Bayes classifier, and achieved an accuracy of 87% in classification of non-responders, responders, and controls. The results of this study revealed that MEG-based graph measures are reliable biomarkers, and that these measures may be used to predict seizure outcome of VNS treatment.

Identifying seizure onset zone from electrocorticographic recordings: A machine learning approach based on phase locking value.

PURPOSE: Using a novel technique based on phase locking value (PLV), we investigated the potential for features extracted from electrocorticographic (ECoG) recordings to serve as biomarkers to identify the seizure onset zone (SOZ). METHODS: We computed the PLV between the phase of the amplitude of high gamma activity (80-150Hz) and the phase of lower frequency rhythms (4-30Hz) from ECoG recordings obtained from 10 patients with epilepsy (21 seizures). We extracted five features from the PLV and used a machine learning approach based on logistic regression to build a model that classifies electrodes as SOZ or non-SOZ. RESULTS: More than 96% of electrodes identified as the SOZ by our algorithm were within the resected area in six seizure-free patients. In four non-seizure-free patients, more than 31% of the identified SOZ electrodes by our algorithm were outside the resected area. In addition, we observed that the seizure outcome in non-seizure-free patients correlated with the number of non-resected SOZ electrodes identified by our algorithm. CONCLUSION: This machine learning approach, based on features extracted from the PLV, effectively identified electrodes within the SOZ. The approach has the potential to assist clinicians in surgical decision-making when pre-surgical intracranial recordings are utilized.

Epilepsy in 22q11.2 Deletion Syndrome: A Case Series and Literature Review.

BACKGROUND: The 22q11.2 deletion syndrome affects multiple organ systems, and the neurological manifestations are an important aspect of this disorder. Many are aware of cardiac anomalies associated with this uncommon genetic disorder. However, the different types of seizures, electroencephalography (EEG), and brain magnetic resonance imaging (MRI) findings seen in this condition are not appreciated. METHODS: Medical records of four patients with epilepsy due to 22q11.2 deletion syndrome were retrospectively reviewed for documentation of seizure types, EEG, and brain MRI findings. In addition, we also did a literature review of previously reported individuals with unprovoked seizures in this condition. RESULTS: A review of all published cases including our patients reveals that focal epilepsy (39 of 88, 44%) is the most common type followed by genetic generalized epilepsy (24 of 88, 27%). Diffuse cerebral atrophy and polymicrogyria were the most frequent MRI findings. CONCLUSIONS: Patients with structural brain abnormalities, especially polymicrogyria and associated epilepsy should have a chromosomal microarray (CMA) performed to screen for the 22q11.2 deletion syndrome. Focal epilepsy and genetic generalized epilepsy are the most frequent epilepsy types reported in this condition.

Vagus Nerve Stimulation in Intractable Epilepsy Associated With SCN1A Gene Abnormalities.

Mutations in the SCN1A gene cause a spectrum of epilepsy syndromes. There are 2 syndromes that are on the severe end of this spectrum. The classic severe form, Dravet syndrome, is an epileptic encephalopathy of childhood, causing cognitive decline as well as intractable seizures. Severe Myoclonic Epilepsy of Infancy-Borderline (SMEIB) is a term used to include cases with similar severities as those with Dravet syndrome, but lacking a single feature of classic severe myoclonic epilepsy of infancy. Vagus nerve stimulation is a nonpharmacologic treatment for intractable epilepsy. A retrospective review was conducted of patients with deleterious SCN1A mutations who had vagus nerve stimulation placement for treatment of their intractable epilepsy. These children had onset of their epilepsy between 3 and 29 months of age. Seizure control was assessed 6 months after implantation. Twenty patients are included in the study, with 12 implanted at our institution. Nine of the 12 patients implanted at our institution, who had confirmed pre- and post-implantation seizure assessments, showed improvement in seizure control, which was defined as >50% reduction in generalized tonic-clonic seizures, and 4 of those 12 reported improvement in cognitive or speech development. Seven of the 8 patients not implanted at our institution reported subjective benefit, with 4 relating "marked improvement" or seizure freedom. Vagus nerve stimulation appears to impart a benefit to children with deleterious SCN1A gene abnormalities associated with intractable epilepsy.

Emerging Antiepileptic Drugs for Severe Pediatric Epilepsies.

The medical management of the epilepsy syndromes of early childhood (eg, infantile spasms, Dravet syndrome, and Lennox-Gastaut syndrome) is challenging; and requires careful evaluation, classification, and treatment. Pharmacologic therapy continues to be the mainstay of management for these children, and as such it is important for the clinician to be familiar with the role of new antiepileptic drugs. This article reports the clinical trial data and personal experience in treating the severe epilepsies of childhood with the recently Food and Drug Administration-approved new antiepileptic drugs (vigabatrin, rufinamide, perampanel, and clobazam) and those in clinical trials (cannabidiol, stiripentol, and fenfluramine). Genetic research has also identified an increasing number of pediatric developmental and seizure disorders that are possibly treatable with targeted drug therapies, focused on correcting underlying neural dysfunction. We highlight recent genetic advances, and how they affect our treatment of some of the genetic epilepsies, and speculate on the use of targeted genetic treatment (precision medicine) in the future.

SmartWatch by SmartMonitor: Assessment of Seizure Detection Efficacy for Various Seizure Types in Children, a Large Prospective Single-Center Study.

INTRODUCTION: Patients with epilepsy and their caregivers are constantly burdened with the possibility of a seizure and its consequences, such as accidents, injuries, and sudden unexplained death in epilepsy. It is the unpredictable nature of seizures that often affects both patients with seizures and their caregivers, limits independence, and hinders quality of life. There are several types of motion detectors on the market, each with varying degrees of sensitivity. MATERIAL AND METHODS: We prospectively tested the SmartWatch, a wrist-worn monitor, on children, adolescents, and young adults with various types of seizures in an epilepsy monitoring unit. Confirmation of seizure type and if there was rhythmic upper extremity jerking associated with the seizure was determined by review of the video electroencephalograph. This was compared with the standard detection system of the watch. RESULTS: This study analyzed a total of 191 seizures in 41 patients aged 5-41 years. Fifty-one of the seizures were generalized tonic-clonic. Forty-seven of the seizures had a rhythmic arm movement component. The SmartWatch detected 30 seizures (16%) of the total, 16 (31%) of the generalized tonic-clonic seizures, and 16 (34%) seizures associated with rhythmic arm movements. DISCUSSION: Overall, only a minority of generalized tonic-clonic seizures or seizures with rhythmic movements were detected, highlighting the need for an effective seizure detection device.

Enalapril dosage in steroid-resistant nephrotic syndrome.

We have examined, in a randomized crossover trial, the antiproteinuric effect of treatment with low- (0.2 mg/kg daily) and high-dose (0.6 mg/kg daily) enalapril in 25 consecutive patients with steroid-resistant nephrotic syndrome (SRNS). Patients in group A ( n=11) received enalapril at low doses for 8 weeks, followed by 2 weeks of washout and then at high doses for 8 weeks. Those in group B ( n=14) initially received enalapril at high and then low doses. Patients continued to receive treatment with tapering doses of prednisolone; none received concomitant therapy with daily oral or intravenous steroids, alkylating agents, cyclosporine, non-steroidal anti-inflammatory drugs, and other antihypertensive medications. The urine albumin-to-creatinine (Ua/Uc) ratio and the percentage reduction were determined for each phase of therapy. Baseline clinical, biochemical, and histological features were comparable in the two groups. In the first phase, treatment with low-dose enalapril (group A) resulted in median 34.8% Ua/Uc reduction compared with 62.9% with high doses (group B) ( P<0.01). High-dose enalapril was associated with a significant reduction in Ua/Uc ratio in both groups. The combined median Ua/Uc (95% confidence interval) reduction in the low-dose phase was 33% (-10.3% to 72.4%) and in the high-dose 52% (15.4%-70.4%) ( P<0.05). The median Ua/Uc ratio at the end of 20 weeks was 1.1 and 1.8 in groups A and B, respectively ( P>0.05). Systolic and diastolic blood pressure reductions were similar in both groups. No period or carry-over effect was found. Prolonged treatment with enalapril thus resulted in a dose-related reduction in nephrotic-range proteinuria. Titration of the dose of enalapril may be a useful strategy for achieving substantial reduction of proteinuria in children with SRNS.