Benchmarking signal quality and spatiotemporal distribution of interictal spikes in prolonged human iEEG recordings using CorTec wireless brain interchange.

Neuromodulation through implantable pulse generators (IPGs) represents an important treatment approach for neurological disorders. While the field has observed the success of state-of-the-art interventions, such as deep brain stimulation (DBS) or responsive neurostimulation (RNS), implantable systems face various technical challenges, including the restriction of recording from a limited number of brain sites, power management, and limited external access to the assessed neural data in a continuous fashion. To the best of our knowledge, for the first time in this study, we investigated the feasibility of recording human intracranial EEG (iEEG) using a benchtop version of the Brain Interchange (BIC) unit of CorTec, which is a portable, wireless, and externally powered implant with sensing and stimulation capabilities. We developed a MATLAB/SIMULINK-based rapid prototyping environment and a graphical user interface (GUI) to acquire and visualize the iEEG captured from all 32 channels of the BIC unit. We recorded prolonged iEEG (~ 24 h) from three human subjects with externalized depth leads using the BIC and commercially available clinical amplifiers simultaneously in the epilepsy monitoring unit (EMU). The iEEG signal quality of both streams was compared, and the results demonstrated a comparable power spectral density (PSD) in all the systems in the low-frequency band (< 80 Hz). However, notable differences were primarily observed above 100 Hz, where the clinical amplifiers were associated with lower noise floor (BIC-17 dB vs. clinical amplifiers < - 25 dB). We employed an established spike detector to assess and compare the spike rates in each iEEG stream. We observed over 90% conformity between the spikes rates and their spatial distribution captured with BIC and clinical systems. Additionally, we quantified the packet loss characteristic in the iEEG signal during the wireless data transfer and conducted a series of simulations to compare the performance of different interpolation methods for recovering the missing packets in signals at different frequency bands. We noted that simple linear interpolation has the potential to recover the signal and reduce the noise floor with modest packet loss levels reaching up to 10%. Overall, our results indicate that while tethered clinical amplifiers exhibited noticeably better noise floor above 80 Hz, epileptic spikes can still be detected successfully in the iEEG recorded with the externally powered wireless BIC unit opening the road for future closed-loop neuromodulation applications with continuous access to brain activity.

An Initial Experience of Completion Hemispherotomy via Magnetic Resonance-Guided Laser Interstitial Therapy.

INTRODUCTION: In carefully selected patients with medically refractory epilepsy, disconnective hemispherotomy can result in significant seizure freedom; however, incomplete disconnection can result in ongoing seizures and poses a significant challenge. Completion hemispherotomy provides an opportunity to finish the disconnection. We describe the use of magnetic resonance-guided laser interstitial thermal ablation (MRgLITT) for completion hemispherotomy. METHODS: Patients treated with completion hemispherotomy using MRgLITT at our institution were identified. Procedural and seizure outcomes were evaluated retrospectively. RESULTS: Five patients (3 males) underwent six MRgLITT procedures (one child treated twice) for completion hemispherotomy at a median age of 6 years (range 1.8-12.9). Two children had hemimegalencephaly, two had Rasmussen encephalitis, and one had polymicrogyria. All five children had persistent seizures likely secondary to incomplete disconnection after their functional hemispherotomy. The mean time from open hemispherotomy to MRgLITT was 569.5 ± 272.4 days (median 424, range 342-1,095). One patient underwent stereoelectroencephalography before MRgLITT. The mean number of ablation targets was 2.3 ± 0.47 (median 2, range 2-3). The mean length of the procedure was 373 min ± 68.9 (median 374, range 246-475). Four of the five patients were afforded improvement in their neurocognitive functioning and speech performance after ablation, with mean daily seizure frequency at 1 year of 1.03 ± 1.98 (median 0, range 0-5). Two patients achieved Engel Class I outcomes at 1 year after ablation, one was Engel Class III, and two were Engel Class IV. The mean follow-up time was 646.8 ± 179.5 days (median 634, range 384-918). No MRgLITT-related complications occurred. Delayed retreatment (>1 year) occurred in three patients: one child underwent redo ablation and two underwent anatomic hemispherectomy. CONCLUSION: We have demonstrated the feasibility of a minimally invasive approach for completion hemispherotomy using MRgLITT. Delayed retreatment was needed in three patients; thus, further study of this technique with comparison to other surgical techniques is warranted.

Epilepsy Surgery in Young Children With Tuberous Sclerosis Complex: A Novel Hybrid Multimodal Surgical Approach.

BACKGROUND: Surgery has become integral in treating children with tuberous sclerosis complex (TSC)-related drug-resistant epilepsy (DRE). OBJECTIVE: To describe outcomes of a multimodal diagnostic and therapeutic approach comprising invasive intracranial monitoring and surgical treatment and compare the complementary techniques of open resection and magnetic resonance-guided laser interstitial thermal therapy. METHODS: Clinical and radiographic data were prospectively collected for pediatric patients undergoing surgical evaluation for TSC-related DRE at our tertiary academic hospital. Seizure freedom, developmental improvement, and Engel class were compared. RESULTS: Thirty-eight patients (20 females) underwent treatment in January 2016 to April 2019. Thirty-five underwent phase II invasive monitoring with intracranial electrodes: 24 stereoencephalography, 9 craniotomy for grid/electrode placement, and 2 grids + stereoencephalography. With the multimodal approach, 33/38 patients (87%) achieved >50% seizure freedom of the targeted seizure type after initial treatment; 6/9 requiring secondary treatment and 2/2 requiring a third treatment achieved >50% freedom. The median Engel class was II at last follow-up (1.65 years), and 55% of patients were Engel class I/II. The mean age was lower for children undergoing open resection (2.4 vs 4.9 years, P = .04). Rates of >50% reduction in seizures (86% open resection vs 88% laser interstitial thermal therapy) and developmental improvement (86% open resection vs 83% magnetic resonance-guided laser interstitial thermal therapy) were similar. CONCLUSION: This hybrid approach of using both open surgical and minimally invasive techniques is safe and effective in treating DRE secondary to TSC. Clinical trials focused on treatment method with longer follow-up are needed to determine the optimal candidates for each approach and compare the treatment modalities more effectively.

A sparse representation strategy to eliminate pseudo-HFO events from intracranial EEG for seizure onset zone localization.

Objective.High-frequency oscillations (HFOs) are considered a biomarker of the epileptogenic zone in intracranial EEG recordings. However, automated HFO detectors confound true oscillations with spurious events caused by the presence of artifacts.Approach.We hypothesized that, unlike pseudo-HFOs with sharp transients or arbitrary shapes, real HFOs have a signal characteristic that can be represented using a small number of oscillatory bases. Based on this hypothesis using a sparse representation framework, this study introduces a new classification approach to distinguish true HFOs from the pseudo-events that mislead seizure onset zone (SOZ) localization. Moreover, we further classified the HFOs into ripples and fast ripples by introducing an adaptive reconstruction scheme using sparse representation. By visualizing the raw waveforms and time-frequency representation of events recorded from 16 patients, three experts labeled 6400 candidate events that passed an initial amplitude-threshold-based HFO detector. We formed a redundant analytical multiscale dictionary built from smooth oscillatory Gabor atoms and represented each event with orthogonal matching pursuit by using a small number of dictionary elements. We used the approximation error and residual signal at each iteration to extract features that can distinguish the HFOs from any type of artifact regardless of their corresponding source. We validated our model on sixteen subjects with thirty minutes of continuous interictal intracranial EEG recording from each.Main results.We showed that the accuracy of SOZ detection after applying our method was significantly improved. In particular, we achieved a 96.65% classification accuracy in labeled events and a 17.57% improvement in SOZ detection on continuous data. Our sparse representation framework can also distinguish between ripples and fast ripples.Significance.We show that by using a sparse representation approach we can remove the pseudo-HFOs from the pool of events and improve the reliability of detected HFOs in large data sets and minimize manual artifact elimination.

Insular Magnetoencephalography Dipole Clusters in Patients With Refractory Focal Epilepsy.

PURPOSE: The clinical significance of magnetoencephalography (MEG) dipole clusters in the insular region in patients with focal epilepsy, when present in conjunction with MEG dipole clusters in other regions of the brain is not known. METHODS: All patients (adult and pediatric) with MEG dipole clusters involving the insula were retrospectively evaluated. Patients who underwent any form of surgical intervention were included in the study. Data obtained included age, sex, seizure characteristics, MRI brain, EEG, MEG, intracranial EEG, type of intervention, and seizure outcomes. RESULTS: Twenty-four patients (12 adults and 12 pediatric) were included. Eight patients had one staged intervention and 16 had intracranial evaluation. Ten of 11 patients (91%) with insular coverage by stereotactic EEG had interictal insular spikes, and 5 of 11 patients (45%) had ictal onset from the insula. Combined Engel (I & II) outcomes were seen in five patients with resections/ablations involving the insula MEG dipole clusters as compared with eight patients where the insular MEG dipole clusters were not resected/ablated. CONCLUSIONS: Insular MEG dipole clusters identified on surface MEG correlated with interictal spikes in intracranial stereotactic electrode contacts in the insula. The presence of insular MEG dipole clusters, however, does not definitively imply a primary insular onset epilepsy.

Establishing functional brain networks using a nonlinear partial directed coherence method to predict epileptic seizures.

BACKGROUND: Epilepsy is a neurological disorder characterized by unpredictable seizures that can lead to severe health problems. EEG techniques have shown to be advantageous for studying and predicting epileptic seizures, thanks to their cost-effectiveness, non-invasiveness, portability and the capability for long-term monitoring. Linear and non-linear EEG analysis methods have been developed for the effective prediction of seizure onset, however both methods remain blind to underlying alterations of the structural and functional brain networks associated with epileptic seizures. Such information is employed in this study to develop novel method for epileptic seizure prediction. NEW METHODS: In this study, nonlinear partial directed coherence (NPDC) was employed as measure of functional brain networks (FBNs) and analyzed to reveal the directional flow of epilepsy-linked brain activity. A novel prediction strategy was then developed for the prediction of epileptic seizures by introducing extracted network features to an extreme learning machine (ELM). RESULTS: Results show that the proposed method achieved favorable performance across all subjects and in all EEG frequency bands, with best accuracy of 89.2% in beta band and an optimal prediction time of 1356.4 s in delta bands, which outperforms currently available approaches. COMPARISON WITH EXISTING METHODS: Our NPDC based on FBNs methods approach surpasses the accuracy of pure graph theory and pure non-linear methods with a significantly increased prediction time. CONCLUSIONS: The findings of this study demonstrate that the proposed prediction strategy is suitable for the prediction of seizure onset.

Phenotypic characterization of individuals with SYNGAP1 pathogenic variants reveals a potential correlation between posterior dominant rhythm and developmental progression.

BACKGROUND: The SYNGAP1 gene encodes for a small GTPase-regulating protein critical to dendritic spine maturation and synaptic plasticity. Mutations have recently been identified to cause a breadth of neurodevelopmental disorders including autism, intellectual disability, and epilepsy. The purpose of this work is to define the phenotypic spectrum of SYNGAP1 gene mutations and identify potential biomarkers of clinical severity and developmental progression. METHODS: A retrospective clinical data analysis of individuals with SYNGAP1 mutations was conducted. Data included genetic diagnosis, clinical history and examinations, neurophysiologic data, neuroimaging, and serial neurodevelopmental/behavioral assessments. All patients were seen longitudinally within a 6-year period; data analysis was completed on June 30, 2018. Records for all individuals diagnosed with deleterious SYNGAP1 variants (by clinical sequencing or exome sequencing panels) were reviewed. RESULTS: Fifteen individuals (53% male) with seventeen unique SYNGAP1 mutations are reported. Mean age at genetic diagnosis was 65.9 months (28-174 months). All individuals had epilepsy, with atypical absence seizures being the most common semiology (60%). EEG abnormalities included intermittent rhythmic delta activity (60%), slow or absent posterior dominant rhythm (87%), and epileptiform activity (93%), with generalized discharges being more common than focal. Neuroimaging revealed nonspecific abnormalities (53%). Neurodevelopmental evaluation revealed impairment in all individuals, with gross motor function being the least affected. Autism spectrum disorder was diagnosed in 73% and aggression in 60% of cases. Analysis of biomarkers revealed a trend toward a moderate positive correlation between visual-perceptual/fine motor/adaptive skills and language development, with posterior dominant rhythm on electroencephalogram (EEG), independent of age. No other neurophysiology-development associations or correlations were identified. CONCLUSIONS: A broad spectrum of neurologic and neurodevelopmental features are found with pathogenic variants of SYNGAP1. An abnormal posterior dominant rhythm on EEG correlated with abnormal developmental progression, providing a possible prognostic biomarker.

Stereotyped high-frequency oscillations discriminate seizure onset zones and critical functional cortex in focal epilepsy.

High-frequency oscillations in local field potentials recorded with intracranial EEG are putative biomarkers of seizure onset zones in epileptic brain. However, localized 80-500 Hz oscillations can also be recorded from normal and non-epileptic cerebral structures. When defined only by rate or frequency, physiological high-frequency oscillations are indistinguishable from pathological ones, which limit their application in epilepsy presurgical planning. We hypothesized that pathological high-frequency oscillations occur in a repetitive fashion with a similar waveform morphology that specifically indicates seizure onset zones. We investigated the waveform patterns of automatically detected high-frequency oscillations in 13 epilepsy patients and five control subjects, with an average of 73 subdural and intracerebral electrodes recorded per patient. The repetitive oscillatory waveforms were identified by using a pipeline of unsupervised machine learning techniques and were then correlated with independently clinician-defined seizure onset zones. Consistently in all patients, the stereotypical high-frequency oscillations with the highest degree of waveform similarity were localized within the seizure onset zones only, whereas the channels generating high-frequency oscillations embedded in random waveforms were found in the functional regions independent from the epileptogenic locations. The repetitive waveform pattern was more evident in fast ripples compared to ripples, suggesting a potential association between waveform repetition and the underlying pathological network. Our findings provided a new tool for the interpretation of pathological high-frequency oscillations that can be efficiently applied to distinguish seizure onset zones from functionally important sites, which is a critical step towards the translation of these signature events into valid clinical biomarkers.awx374media15721572971001.

High-frequency oscillations detected in ECoG recordings correlate with cavernous malformation and seizure-free outcome in a child with focal epilepsy: A case report.

Epilepsy associated with cavernous malformation (CM) often requires surgical resection of seizure focus to achieve seizure-free outcome. High-frequency oscillations (HFOs) in intracranial electroencephalogram (EEG) are reported as potential biomarkers of epileptogenic regions, but to our knowledge there are no data on the existence of HFOs in CM-caused epilepsy. Here we report our experience of the identification of the seizure focus in a 3-year-old pediatric patient with intractable epilepsy associated with CM. The electrocorticographic recordings were obtained from a 64-contact grid over 2 days in the epilepsy monitoring unit (EMU). The spatial distribution of HFOs and epileptic spikes were estimated from recording segments right after the electrode placement, during sleep and awake states separately. The HFO distribution showed consistency with the perilesional region; the location of spikes varied over days and did not correlate with the lesion. The HFO spatial distribution was more compact in sleep state and pinpointed the contacts sitting on the CM border. Following the resection of the CM and the hemosiderin ring, the patient became seizure-free. This is the first report describing HFOs in a pediatric patient with intractable epilepsy associated with CM and shows their potential in identifying the seizure focus.

Epilepsy is associated with ventricular alterations following convulsive status epilepticus in children.

OBJECTIVE: Convulsive status epilepticus can exert profound cardiovascular effects in adults including ventricular depolarization-repolarization abnormalities. Whether status epilepticus adversely affects ventricular electrical properties in children is less understood. Therefore, we sought to characterize ventricular alterations and the associated clinical factors in children following convulsive status epilepticus. METHODS: We conducted a 2-year retrospective, case-control study. Children between 1 month and 21 years of age were included if they were admitted to the pediatric intensive care unit with primary diagnosis of convulsive status epilepticus and had 12-lead electrocardiogram (ECG) within 24 hours of admission. Children with heart disease, ion channelopathy, or on vasoactive medications were excluded. Age-matched control subjects had no history of seizures or epilepsy. The primary outcome was ventricular abnormalities represented by ST segment changes, abnormal T wave, QRS axis deviation, and corrected QT (QTc) interval prolongation. The secondary outcomes included QT/RR relationship, beat-to-beat QTc interval variability, ECG interval measurement between groups, and clinical factors associated with ECG abnormalities. RESULTS: Of 317 eligible children, 59 met the inclusion criteria. History of epilepsy was present in 31 children (epileptic) and absent in 28 children (non-epileptic). Compared with the control subjects (n = 31), the status epilepticus groups were more likely to have an abnormal ECG with overall odds ratio of 3.8 and 7.0 for the non-epileptic and the epileptic groups respectively. Simple linear regression analysis demonstrated that children with epilepsy exhibited impaired dependence and adaptation of the QT interval on heart rate. Beat-to-beat QTc interval variability, a marker of ventricular repolarization instability, was increased in children with epilepsy. SIGNIFICANCE: Convulsive status epilepticus can adversely affect ventricular electrical properties and stability in children, especially those with epilepsy. These findings suggest that children with epilepsy may be particularly vulnerable to seizure-induced arrhythmias. Therefore postictal cardiac surveillance may be warranted in this population.

The spectrum of epilepsy and electroencephalographic abnormalities due to SHANK3 loss-of-function mutations.

OBJECTIVE: The coincidence of autism with epilepsy is 27% in those individuals with intellectual disability.1 Individuals with loss-of-function mutations in SHANK3 have intellectual disability, autism, and variably, epilepsy.2-5 The spectrum of seizure semiologies and electroencephalography (EEG) abnormalities has never been investigated in detail. With the recent report that SHANK3 mutations are present in approximately 2% of individuals with moderate to severe intellectual disabilities and 1% of individuals with autism, determining the spectrum of seizure semiologies and electrographic abnormalities will be critical for medical practitioners to appropriately counsel the families of patients with SHANK3 mutations. METHODS: A retrospective chart review was performed of all individuals treated at the Blue Bird Circle Clinic for Child Neurology who have been identified as having either a chromosome 22q13 microdeletion encompassing SHANK3 or a loss-of-function mutation in SHANK3 identified through whole-exome sequencing. For each subject, the presence or absence of seizures, seizure semiology, frequency, age of onset, and efficacy of therapy were determined. Electroencephalography studies were reviewed by a board certified neurophysiologist. Neuroimaging was reviewed by both a board certified pediatric neuroradiologist and child neurologist. RESULTS: There is a wide spectrum of seizure semiologies, frequencies, and severity in individuals with SHANK3 mutations. There are no specific EEG abnormalities found in our cohort, and EEG abnormalities were present in individuals diagnosed with epilepsy and those without history of a clinical seizure. SIGNIFICANCE: All individuals with a mutation in SHANK3 should be evaluated for epilepsy due to the high prevalence of seizures in this population. The most common semiology is atypical absence seizure, which can be challenging to identify due to comorbid intellectual disability in individuals with SHANK3 mutations; however, no consistent seizure semiology, neuroimaging findings, or EEG findings were present in the majority of individuals with SHANK3 mutations.

Long-Term Durability of Carpentier-Edwards Magna Ease Valve: A One Billion Cycle In Vitro Study.

BACKGROUND: Durability and hemodynamic performance are top considerations in selecting a valve for valve replacement surgery. This study was conducted in order to evaluate the long-term mechanical durability and hydrodynamic performance of the Carpentier-Edwards PERIMOUNT Magna Ease Bioprostheses, through 1 billion cycles (equivalent to 25 years). METHODS: In vitro valve hydrodynamic performance, durability, and quantitative flow visualization were conducted in accordance with ISO 5840:2005 heart valve standard. The study valves were subjected to accelerated valve cycling to an equivalent of 25 years of wear. Hydrodynamic evaluations at intervals of 100 million cycles (2.5 years) were performed on the study valves. New uncycled Magna Ease valves were used as hydrodynamic controls in this study. A quantitative assessment of the fluid motion downstream of the control and study valves was performed using particle image velocimetry. The results between the test and control valves were compared to assess valve performance after an equivalent of 25 years of wear. RESULTS: All study valves met the ISO 5840 requirements for effective orifice area, 1.81 ± 0.06 cm(2) and 2.06 ± 0.17 cm(2), and regurgitant fraction, 1.11% ± 0.87% and 2.5% ± 2.34%, for the 21 mm and 23 mm study valves, respectively. The flow characterization of the control valves and the billion-cycle valves demonstrated that the valves exhibited similar flow characteristics. The velocity and shear stress fields were similar between the control and study valves. CONCLUSIONS: The Magna Ease valves demonstrated excellent durability and hydrodynamic performance after an equivalent of 25 years of simulated in vitro wear. All study valves successfully endured 1 billion cycles of simulated wear, 5 times longer than the standard requirement for a tissue valve as stipulated in ISO 5840.

Application of envelope trend to analyze early EEG changes in the frontal regions during intracarotid amobarbital procedure in children.

BACKGROUND: Intracarotid amobarbital procedure (IAP) is acknowledged as the gold standard test for language lateralization. EEG is performed routinely during IAP to monitor the anesthetization of a brain hemisphere. Here, we studied the correlation between the early EEG changes using envelope trend and the clinical outcome of IAP. METHOD: Fifty consecutive patients underwent IAP at Texas Children's Hospital (2004-2009). Intracarotid amobarbital procedure was considered "complete" or "incomplete" based on the outcome if the procedure was completed or aborted due to behavior changes. Envelope trend was used to calculate the median EEG amplitude changes within the first 60s of IAP. Statistical analysis was performed to determine the role of EEG changes and clinical features on the procedure outcome. RESULTS: Only 30 IAP-EEG files were available for review. Amobarbital was administered at the dose of 60-150mg (mean: 110±20). The intracarotid amobarbital procedure was recorded as complete in 23 patients and incomplete in 7 patients. EEG changes occurred within the first few seconds following amobarbital injection. Following amobarbital injection, focal slowing was present in the ipsilateral frontal region or both ipsilateral and contralateral frontal regions. Elapsed time to the first EEG change or duration and change in median EEG amplitude in the ipsilateral frontal regions were indifferent between the complete and incomplete groups (p>0.05). However, the median amplitude changes between the ipsilateral and contralateral frontal regions within each group were found significant only in the complete group (p<0.05), suggesting ipsilateral without contralateral frontal slowing. Other than age at the time of IAP (p=0.03), none of the other clinical features correlated with the clinical outcome of IAP (p>0.05). CONCLUSION: Early EEG changes during IAP using envelope trend may predict successful completion of the IAP test. Younger children are at risk of behavioral changes during IAP.

Infantile spasms and hyperekplexia associated with isolated sulfite oxidase deficiency.

IMPORTANCE: Isolated sulfite oxidase deficiency (ISOD) causes severe intellectual disability, epilepsy, and shortened life expectancy. Intractable seizures are invariable in children with ISOD; however, to our knowledge, infantile spasms with a corresponding hypsarrhythmia pattern on electroencephalogram have never been reported. In addition, the nonepileptic paroxysmal movement disorder hyperekplexia has not previously been reported with ISOD. OBSERVATIONS: We describe an infant with ISOD who initially presented with neonatal seizures, diffusion restriction noted on magnetic resonance imaging, and elevated serum S-sulfocysteine consistent with ISOD. A homozygous mutation in the SUOX gene was identified, confirming the diagnosis. Uniquely, this patient developed a profound accentuated startle response that did not have a corresponding electrographic change on electroencephalogram consistent with hyperekplexia. This was followed by a change in the child's electroencephalogram to the chaotic pattern of hypsarrhythmia and brief tonic seizures with attenuation of the hypsarrhythmia pattern characteristic of infantile spasms. CONCLUSIONS AND RELEVANCE: The evolution of seizures associated with ISOD is poorly characterized because of the small number of patients. We report what we believe to be the first case of a child with ISOD who developed infantile spasms and hyperekplexia. This expands the phenotypes associated with ISOD and also should caution clinicians to not assume that all abnormal movements are seizures.

Vitamin-responsive epileptic encephalopathies in children.

Untreated epileptic encephalopathies in children may potentially have disastrous outcomes. Treatment with antiepileptic drugs (AEDs) often may not control the seizures, and even if they do, this measure is only symptomatic and not specific. It is especially valuable to identify potential underlying conditions that have specific treatments. Only a few conditions have definitive treatments that can potentially modify the natural course of disease. In this paper, we discuss the few such conditions that are responsive to vitamin or vitamin derivatives.

The electroencephalogram in neonatal maple syrup urine disease: a case report.

Untreated maple syrup urine disease (MSUD) leads to encephalopathy in neonates and causes abnormalities on the electroencephalogram (EEG). A case is presented of MSUD with unique features consisting of a comb-like rhythm before the therapy and its disappearance with therapy is presented. This case illustrates the potential use of the EEG in the identification of this specific cause of a neonatal encephalopathy.

TGFBR2 deletion in a 20-month-old female with developmental delay and microcephaly.

To date, over 70 mutations in the TGFBR2 gene have been reported in patients with Loeys-Dietz syndrome (LDS), Marfan syndrome type 2 (MFS2), or other hereditary thoracic aortic aneurysms and dissections. Whereas almost all of mutations analyzed thus far are predicted to disrupt the constitutively active C-terminal serine/threonine kinase domain of TGFBR2, mounting evidence suggests that the molecular mechanism underlying these diseases is more complex than simple haploinsufficiency. Using exon-targeted oligonucleotide array comparative genomic hybridization, we identified an ∼896 kb deletion of TGFBR2 in a 20-month-old female with microcephaly and global developmental delay, but no stigmata of LDS. FISH analysis showed no evidence of this deletion in the parental peripheral blood samples; however, somatic mosaicism was detected using PCR in the paternal DNA from peripheral blood lymphocytes and lymphoblasts. Our data suggest that TGFBR2 haploinsufficiency may cause a phenotype, which is distinct from LDS. Moreover, we propose that somatic mosaicism below the detection threshold of FISH analysis in asymptomatic parents of children with genomic disorders may be more common than previously recognized.

Newer anticonvulsant medications in pediatric neurology.

OPINION STATEMENT: Antiepileptic drugs (AEDs) are the mainstay of treatment for recurrent seizures. Uncontrolled seizures may cause medical, developmental, and psychological disturbances. The medical practitioner should thus strive to eliminate or minimize seizures. Treatment advances in epilepsy include 1) identification of the basic mechanisms of epilepsy and action of AEDs, 2) the introduction of new AEDs, and 3) the use of neurostimulation, including vagus nerve stimulation. Treatment with AEDs involves balancing each AED's efficacy against its side effects. In some patients, effective AEDs must be discontinued because of intolerable side effects. Although all AEDs have a proven efficacy, the choice of AEDs should be based on better efficacy for individual seizure types or epilepsy syndromes. Side effects also differ from drug to drug and must be taken into account. This article focuses on studies and expert opinion consensus to guide the choice of AEDs.