Staring Spells: How to Distinguish Epileptic Seizures from Nonepileptic Staring.

OBJECTIVE: To determine the nature of staring spells and factors distinguishing epileptic from nonepileptic staring spells, we studied the clinical and demographic features of children with staring spells referred to a regional new-onset seizure clinic. STUDY DESIGN: Our retrospective chart review encompassed 2818 consecutive patients evaluated in the new-onset seizure clinic between September 22, 2015, and March 19, 2018. We identified 121 patients with newly presenting staring spells. RESULTS: Sixty-two of 121 (51%) children were diagnosed with nonepileptic staring spells and 59 (49%) with epileptic seizures (24 with absence epilepsy, 35 with focal epilepsy). Patients with nonepileptic staring spells were younger (4.8 vs 7.1 years, P = .001) and more likely to have developmental delay (P = .005) than the seizure group. There was an 8.9-month delay on average from the onset of staring spells to the new-onset seizure clinic visit. The emergency department was a referral source for 80% (28/35) of focal seizures. In children with focal seizures, the staring spells typically lasted >1minute (29/35, 83%), whereas only 19 of 62 (31%) of children with nonepileptic staring spells had events lasting this long (P = .04). All children had a routine electroencephalography (EEG) on the day of new-onset seizure clinic visit. EEG was diagnostic in 100% (24/24) of absence seizures and 51% (18/35) of focal seizures. CONCLUSIONS: In children presenting with staring spells, the differential diagnosis of epileptic staring spells vs nonepileptic staring spells can be made by history and routine EEG. Staring was as likely to be epileptic as nonepileptic spells. Younger children with developmental delay were more likely to have nonepileptic events. Our simple approach based on event duration, postictal symptoms, and EEG allowed identification of epileptic staring on first visit to new-onset seizure clinic but requires validation in future prospective studies including long-term video EEG monitoring and follow-up.

Creatine transporter deficiency impairs stress adaptation and brain energetics homeostasis.

The creatine transporter (CrT) maintains brain creatine (Cr) levels, but the effects of its deficiency on energetics adaptation under stress remain unclear. There are also no effective treatments for CrT deficiency, the second most common cause of X-linked intellectual disabilities. Herein, we examined the consequences of CrT deficiency in brain energetics and stress-adaptation responses plus the effects of intranasal Cr supplementation. We found that CrT-deficient (CrT-/y) mice harbored dendritic spine and synaptic dysgenesis. Nurtured newborn CrT-/y mice maintained baseline brain ATP levels, with a trend toward signaling imbalance between the p-AMPK/autophagy and mTOR pathways. Starvation elevated the signaling imbalance and reduced brain ATP levels in P3 CrT-/y mice. Similarly, CrT-/y neurons and P10 CrT-/y mice showed an imbalance between autophagy and mTOR signaling pathways and greater susceptibility to cerebral hypoxia-ischemia and ischemic insults. Notably, intranasal administration of Cr after cerebral ischemia increased the brain Cr/N-acetylaspartate ratio, partially averted the signaling imbalance, and reduced infarct size more potently than intraperitoneal Cr injection. These findings suggest important functions for CrT and Cr in preserving the homeostasis of brain energetics in stress conditions. Moreover, intranasal Cr supplementation may be an effective treatment for congenital CrT deficiency and acute brain injury.

Evaluation of pediatric patients in new-onset seizure clinic (NOSc).

AIM: We evaluated the clinical and demographic features of children presenting with unprovoked seizures at a regional new-onset seizure clinic (NOSc). METHODS: We retrospectively reviewed charts of 492 consecutive patients evaluated in the NOSc at the Childrne's Healthcare of Atlanta RESULTS: Nonepileptic events (NEE) were diagnosed in 102 (24%) and epileptic seizures in the remaining 326 (76%). Patients with NEE were younger than patients with epileptic seizure (5.0 vs. 7.4 years). Except for headache which occurred more frequently in NEE (14% vs. 6%), frequencies of comorbidities were similar in groups with NEE and epileptic seizure. Electroencephalogram (EEG) was performed in 98%, and finding was abnormal in 51%. Brain magnetic resonance imaging (MRI) was performed in 55%, and finding was abnormal in 15%. An electroclinical epilepsy syndrome was diagnosed in 42%. Antiseizure medication was started in 25% with first seizure and in 77% with recurrent seizures. INTERPRETATION: For children with newly-presenting seizures, a regional NOSc provided efficient, timely diagnosis and appropriate evaluations and treatment. Timely recognition of NEE resulted in fewer unnecessary evaluations and treatment for a quarter of referred patients whereas identification of the specific types of seizures and epilepsy allowed appropriate use, including deferral, of neuroimaging and guided treatment selection.

Epidemiology of traumatic brain injury-associated epilepsy and early use of anti-epilepsy drugs: An analysis of insurance claims data, 2004-2014.

BACKGROUND: About 2.8 million TBI-related emergency department visits, hospitalizations and deaths occurred in 2013 in the United States. Post-traumatic epilepsy (PTE) can be a disabling, life-long outcome of TBI. OBJECTIVES: The purpose of this study is to address the probability of developing PTE within 9 years after TBI, the risk factors associated with PTE, the prevalence of anti-epileptic drug (AEDs) use, and the effectiveness of using AEDs prophylactically after TBI to prevent the development of PTE. METHODS: Using MarketScan® databases covering commercial, Medicare Supplemental, and multi-state Medicaid enrollees from 2004 to 2014, we examined the incidence of early seizures (within seven days after TBI) and cumulative incidence of PTE, the hazard ratios (HR) of PTE by age, gender, TBI severity, early seizure and AED use (carbamazepine, clonazepam, divalproex sodium, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, phenytoin, pregabalin, topiramate, acetazolamide). We used backward selection to build the final Cox proportional hazard model and conducted multivariable survival analysis to obtain estimates of crude and adjusted HR (cHRs, aHRs) of PTE and 95% confidence intervals (CI). RESULTS: The incidence of early seizure among TBI patients in our study was 0.5%. The cumulative incidence of PTE increased from 1.0% in one year to 4.0% in nine years. Most patients with TBI (93%) were not prescribed any AED. Gender was not associated with PTE. The risk of PTE was higher for individuals with older age, early seizures, and more severe TBI. Only individuals using prophylactic acetazolamide had significantly lower risk of PTE (aHR = 0.6, CI 0.4-0.9) compared to those not using any AED. CONCLUSION: The probability of developing PTE increased within the study period. The risk of developing PTE significantly increased with age, early seizure and TBI severity. Most of the individuals did not receive AED after TBI. There was no evidence suggesting AEDs helped to prevent PTE with the possible exception of acetazolamide. However, further studies may be needed to test the efficacy of acetazolamide in preventing PTE.

Language and social functioning in children and adolescents with epilepsy.

Individuals with epilepsy have difficulties with social function that are not adequately accounted for by seizure severity or frequency. This study examined the relationship between language ability and social functioning in 193 children with epilepsy over a period of 36months following their first recognized seizure. The findings show that children with persistent seizures have poorer language function, even at the onset of their seizures, than do their healthy siblings, children with no recurrent seizures, and children with recurrent but not persistent seizures. They continue to demonstrate poorer language function 36months later. This poor language function is associated with declining social competence. Intervention aimed at improving social competence should include consideration of potential language deficits that accompany epilepsy and social difficulty.

Design and implementation of the first randomized controlled trial of coenzyme CoQ10 in children with primary mitochondrial diseases.

We report the design and implementation of the first phase 3 trial of CoenzymeQ10 (CoQ10) in children with genetic mitochondrial diseases. A novel, rigorous set of eligibility criteria was established. The trial, which remains open to recruitment, continues to address multiple challenges to the recruitment of patients, including widely condoned empiric use of CoQ10 by individuals with proven or suspected mitochondrial disease and skepticism among professional and lay mitochondrial disease communities about participating in placebo-controlled trials. These attitudes represent significant barriers to the ethical and scientific evaluation--and ultimate approval--of nutritional and pharmacological therapies for patients with life-threatening inborn errors of energy metabolism.

Cyclocreatine treatment improves cognition in mice with creatine transporter deficiency.

The second-largest cause of X-linked mental retardation is a deficiency in creatine transporter (CRT; encoded by SLC6A8), which leads to speech and language disorders with severe cognitive impairment. This syndrome, caused by the absence of creatine in the brain, is currently untreatable because CRT is required for creatine entry into brain cells. Here, we developed a brain-specific Slc6a8 knockout mouse (Slc6a8-/y) as an animal model of human CRT deficiency in order to explore potential therapies for this syndrome. The phenotype of the Slc6a8-/y mouse was comparable to that of human patients. We successfully treated the Slc6a8-/y mice with the creatine analog cyclocreatine. Brain cyclocreatine and cyclocreatine phosphate were detected after 9 weeks of cyclocreatine treatment in Slc6a8-/y mice, in contrast to the same mice treated with creatine or placebo. Cyclocreatine-treated Slc6a8-/y mice also exhibited a profound improvement in cognitive abilities, as seen with novel object recognition as well as spatial learning and memory tests. Thus, cyclocreatine appears promising as a potential therapy for CRT deficiency.

Importance of muscle light microscopic mitochondrial subsarcolemmal aggregates in the diagnosis of respiratory chain deficiency.

The purpose of this study was to evaluate relationships between subsarcolemmal mitochondrial aggregates and electron transport chain deficiencies in skeletal muscle with the objective of establishing an association between mitochondrial accumulation and electron transport chain complex deficiency. We conducted a large-scale, retrospective study to evaluate factors associated with subsarcolemmal mitochondrial aggregates (percent) in pediatric patients who received muscle biopsies for suspected respiratory chain disorders. Patients were included if they had histochemical stains for assessment of mitochondrial pathology and had biochemical testing for muscle electron transport chain complex activities. Significant positive bivariate correlations (n = 337) were found between subsarcolemmal mitochondrial aggregate percentage and electron transport chain complexes II, IV, I + III, and II + III activities. Evaluation showed that a cutoff value of > 2% subsarcolemmal mitochondrial aggregates had poor overall diagnostic accuracy (mean, 32%), compared with a < 5% cutoff (mean, 60%). To better evaluate the effects of subsarcolemmal mitochondrial aggregates percentages, patients were stratified according to lower one-third (group 1, n = 120 plus ties) and upper one-third (group 2, n = 115 plus ties) of subsarcolemmal mitochondrial aggregates values. Although only minor clinical and pathologic differences were observed, group 1 participants had significantly lower electron transport chain complex activities than group 2 for all enzymes except complex III. Logistic regression showed over 2-fold greater odds of deficiency for electron transport chain complexes I + III (P = .01) and II + III (P = .03) for group 1 participants compared with group 2. We conclude that, contrary to the previous > 2.0% subsarcolemmal mitochondrial aggregates cutoff for respiratory chain disorder, patients with a low subsarcolemmal mitochondrial aggregates percentage (≤4%) are significantly more likely to have electron transport chain complex deficiency than patients with increased subsarcolemmal mitochondrial aggregates percentage (≥10%). This morphological approach for assessment of mitochondrial proliferation may assist clinicians to select further testing to rule out an electron transport chain complex deficiency in children by other methods, including direct biochemical testing of electron transport chain complex activities, measurement of muscle coenzyme Q10 content, or evaluation for a mitochondrial DNA depletion syndrome.

Ictal MEG onset source localization compared to intracranial EEG and outcome: improved epilepsy presurgical evaluation in pediatrics.

PURPOSE: Magnetoencephalography (MEG) has been shown a useful diagnostic tool for presurgical evaluation of pediatric medically intractable partial epilepsy as MEG source localization has been shown to improve the likelihood of seizure onset zone (SOZ) sampling during subsequent evaluation with intracranial EEG (ICEEG). We investigated whether ictal MEG onset source localization further improves results of interictal MEG in defining the SOZ. METHODS: We identified 20 pediatric patients with one habitual seizure during MEG recordings between October 2007 and April 2011. MEG was recorded with sampling rates of 600Hz and 4000Hz for 10 and 2min respectively. Continuous head localization (CHL) was applied. Source localization analyses were applied using multiple algorithms, both at the beginning of ictal onset and for interictal MEG discharges. Ictal MEG onsets were identified by visual inspection and power spectrum using short-time Fourier transform (STFT). Source localizations were compared with ICEEG, surgical procedure and outcome. KEY FINDINGS: Eight patients met all inclusion criteria. Five of the 8 patients (63%) had concordant ictal MEG onset source localization and interictal MEG discharge source localizations in the same lobe, but the source of ictal MEG onset was closer to the SOZ defined by ICEEG. SIGNIFICANCE: Although the capture of seizures during MEG recording is challenging, the source localization for ictal MEG onset proved to be a useful tool for presurgical evaluation in our pediatric population with medically intractable epilepsy.

Aberrant high-gamma oscillations in the somatosensory cortex of children with cerebral palsy: a meg study.

OBJECTIVE: Our study is to investigate somatosensory dysfunction in children with spastic cerebral palsy (CP) using magnetoencephalography (MEG) and synthetic aperture magnetometry (SAM). METHODS: Six children with spastic CP and six age- and gender-matched typically developing children were studied using a 275-channel MEG system while their left and right index fingers were stimulated in random order. The latency and amplitude of somatosensory evoked magnetic fields were analyzed at sensor level. The patterns of high-gamma oscillations were investigated with SAM at source level. RESULTS: In comparison to the children with typical development, the latency of the first response of somatosensory evoked magnetic fields (SEFs) in the children with spastic CP was significantly delayed (p<0.05). High-gamma oscillations were identified in the somatosensory cortex in both children with CP and typical developing children. Interestingly, children with spastic CP had significantly higher incidence of ipsilateral activation in the somatosensory cortex following right and left finger stimulation, compared to typically developing children (p=0.05). CONCLUSION: The results suggest that children with spastic CP have a measurable delay of SEFs and high-gamma oscillations. The high rates of ipsilateral cortical activation imply the impairments of functional lateralization in the developing brain. This is the first MEG study to demonstrate abnormal high-gamma oscillations of somatosensory cortices representing the finger in children with spastic CP.

Enzyme inducing antiepileptic drugs are associated with mitochondrial proliferation and increased cytochrome c oxidase activity in muscle of children with epilepsy.

PURPOSE: To evaluate the effects of epilepsy-related factors associated with mitochondrial pathology and function in skeletal muscle of children with suspected mitochondrial disorders. METHODS: This case-control study evaluated patients and age-matched controls with muscle biopsies at Cincinnati Children's Hospital Medical Center obtained between January, 2000 and December, 2008. RESULTS: A total of 65 epilepsy patients and 65 age-matched controls met the inclusion criteria. No significant clinical, pathological, or biochemical differences were found between the epilepsy and control groups. Treatment resistance was associated with decreased electron transport chain (ETC) complex II+III activity compared to treatment-responsive patients. Only patients receiving enzyme inducer antiepileptic drugs (AEDs) had ETC complex activities equivalent to or greater than other study groups. Robust regression modeling found a significant effect between percentage of myofibers with subsarcolemmal mitochondrial aggregates (SSMA) and ETC complex IV activity for the enzyme inducer AED group. Least squares regression showed that only complex IV/citrate synthase ratio was strongly correlated with SSMA percentage for the enzyme inducer AED group. As far as we can determine this is the first study to show an association between enzyme inducer AED treatment and enhanced ETC complex IV activity. CONCLUSIONS: In skeletal muscle mitochondrial density, assessed by SSMA percentage, and ETC complex IV activity are positively correlated in patients receiving enzyme inducer AED treatment.

Neuromagnetic measures of word processing in bilinguals and monolinguals.

OBJECTIVE: This study aimed to use magnetoencephalography (MEG) to examine the question of whether Mandarin-English bilingual speakers recruit the same cortical areas or develop distinct language-specific networks without overlaps for word processing. METHODS: Eight healthy Mandarin-English bilingual adults and eight healthy English monolingual adults were scanned while single-word paradigms were audio-visually presented. RESULTS: Our results showed significantly stronger beta-band power suppression in the right inferior parietal lobe (IPL) covering the supramarginal gyrus (BA 40) and angular gyrus (BA 39) for bilinguals when processing Mandarin versus English. Moreover, there were no significant differences between bilinguals and monolinguals in the left inferior frontal cortex (LIFC, BA 44/45) when both were processing their first language. CONCLUSIONS: These results support the view that Mandarin-English bilinguals have a shared neural system for word processing in both the first and second language, which is highly similar to monolinguals', but with stronger right hemisphere involvement. SIGNIFICANCE: To our knowledge, this is the first MEG study to investigate the spatio-temporal and frequency characteristics between bilinguals and monolinguals, which provides us a new angle to better understand the language system in bilinguals' and monolingual's brain.

Creatine transporter (CrT; Slc6a8) knockout mice as a model of human CrT deficiency.

Mutations in the creatine (Cr) transporter (CrT; Slc6a8) gene lead to absence of brain Cr and intellectual disabilities, loss of speech, and behavioral abnormalities. To date, no mouse model of CrT deficiency exists in which to understand and develop treatments for this condition. The purpose of this study was to generate a mouse model of human CrT deficiency. We created mice with exons 2-4 of Slc6a8 flanked by loxP sites and crossed these to Cre:CMV mice to create a line of ubiquitous CrT knockout expressing mice. Mice were tested for learning and memory deficits and assayed for Cr and neurotransmitter levels. Male CrT(⁻/y) (affected) mice lack Cr in the brain and muscle with significant reductions of Cr in other tissues including heart and testes. CrT(⁻/y) mice showed increased path length during acquisition and reversal learning in the Morris water maze. During probe trials, CrT(⁻/y) mice showed increased average distance from the platform site. CrT(⁻/y) mice showed reduced novel object recognition and conditioned fear memory compared to CrT(+/y). CrT(⁻/y) mice had increased serotonin and 5-hydroxyindole acetic acid in the hippocampus and prefrontal cortex. Ubiquitous CrT knockout mice have learning and memory deficits resembling human CrT deficiency and this model should be useful in understanding this disorder.

High gamma oscillations of sensorimotor cortex during unilateral movement in the developing brain: a MEG study.

Recent studies in adults have found consistent contralateral high gamma activities in the sensorimotor cortex during unilateral finger movement. However, no study has reported on this same phenomenon in children. We hypothesized that contralateral high gamma activities also exist in children during unilateral finger movement. Sixty normal children (6-17 years old) were studied with a 275-channel MEG system combined with synthetic aperture magnetometry (SAM). Sixty participants displayed consistently contralateral event-related synchronization (C-ERS) within high gamma band (65-150 Hz) in the primary motor cortices (M1) of both hemispheres. Interestingly, nineteen younger children displayed ipsilateral event-related synchronization (I-ERS) within the high gamma band (65-150 Hz) just during their left finger movement. Both I-ERS and C-ERS were localized in M1. The incidence of I-ERS showed a significant decrease with age. Males had significantly higher odds of having ipsilateral activity compared to females. Noteworthy, high gamma C-ERS appeared consistently, while high gamma I-ERS changed with age. The asymmetrical patterns of neuromagnetic activities in the children's brain might represent the maturational lateralization and/or specialization of motor function. In conclusion, the present results have demonstrated that contralateral high-gamma neuromagnetic activities are potential biomarkers for the accurate localization of the primary motor cortex in children. In addition, the interesting finding of the ipsilateral high-gamma neuromagnetic activities opens a new window for us to understand the developmental changes of the hemispherical functional lateralization in the motor system.

Neuromagnetic evidence of impaired cortical auditory processing in pediatric intractable epilepsy.

PURPOSE: We aimed to determine the changes in neural correlates of auditory information processing such as auditory detection, encoding, and sensory discrimination in pediatric patients with intractable epilepsy. METHODS: In this magnetoencephalography (MEG) study, 10 patients and 10 age- and gender-matched healthy controls were investigated with the multi-feature mismatch negativity (MMN) paradigm. Latencies and amplitudes of M100, M150, M200, and MMN event-related fields were evaluated. RESULTS: All event-related fields in response to standard stimuli (M100, M150 and M200) and responses to occasional five deviant sounds, deviating from the standard stimuli either in duration, frequency, intensity, location, or by including a silent gap were reduced in amplitude in epilepsy patients compared with healthy controls. CONCLUSIONS: Our study suggests that auditory information processing is impaired in patients with drug-resistant epilepsy, being evident both in stimulus feature encoding (as reflected by changes of early event-related components, e.g., M100) and in cortical sound discrimination (as reflected by MMNm). The neural changes involving diminished M100 as well as MMNms for all five deviant sound types suggest wide-spread auditory information processing impairments in these patients.

White matter abnormalities in children and adolescents with temporal lobe epilepsy.

BACKGROUND AND PURPOSE: The widespread propagation of synchronized neuronal firing in seizure disorders may affect cortical and subcortical brain regions. Diffusion tensor imaging (DTI) can noninvasively quantify white matter integrity. The purpose of this study was to investigate the abnormal changes of white matter in children and adolescents with focal temporal lobe epilepsy (TLE) using DTI. MATERIALS AND METHODS: Eight patients with clinically diagnosed TLE and eight age- and sex-matched healthy controls were studied. DTI images were obtained with a 3-T magnetic resonance imaging scanner. The epileptic foci were localized with magnetoencephalography. Fractional anisotropy (FA), mean diffusivity (MD), parallel (λ(||)) and perpendicular (λ(⊥)) diffusivities in the genu of the corpus callosum, splenium of the corpus callosum (SCC), external capsule (EC), anterior limbs of the internal capsule (AIC), and the posterior limbs of the internal capsule (PIC) were calculated. The DTI parameters between patients and controls were statistically compared. Correlations of these DTI parameters of each selected structure with age of seizure onset and duration of epilepsy were analysed. RESULTS: In comparison to controls, both patients' seizure ipsilateral and contralateral had significantly lower FA in the AIC; PIC and SCC and higher MD, λ(||) and λ(⊥) in the EC, AIC, PIC and SCC. The MD, λ(||) and λ(⊥) were significantly correlated with age of seizure onset in the EC and PIC. λ(||) was significantly correlated with the duration of epilepsy in the EC and PIC. CONCLUSION: The results of the present study indicate that children and adolescents with TLE had significant abnormalities in the white matter in the hemisphere with seizure foci. Furthermore, these abnormalities may extend to the other brain hemisphere. The age of seizure onset and duration of epilepsy may be important factors in determining the extent of influence of children and adolescents TLE on white matter.

Self-esteem and symptoms of depression in children with seizures: relationships with neuropsychological functioning and family variables over time.

PURPOSE: To test over time the relationships of neuropsychological functioning to mental health in children following a first recognized seizure and, of primary importance, to determine if the strength of these relationships differs based on risk and protective factors. METHODS: In a larger prospective study, 135 children with a first seizure (ages 8-14 years) and 73 healthy sibling controls completed neuropsychological testing at baseline and 36 months. Structured telephone interviews were used to obtain data from children on mental health and family environment; major caregiving parents provided data on demographic and family variables. Data analyses included correlation coefficients and linear regression models. RESULTS: Children with seizures showed an overall trend for improvement in mental health. More children with seizures than siblings had declines in processing speed. Declines in neuropsychological functioning were correlated with worse mental health. With regard to risk and protective factors, higher parent education protected against decline in self-esteem related to decline in processing speed. Better family functioning and greater parental support protected against decline in self-esteem related to decrease in verbal memory and learning. Older child age protected against increase in depressive symptoms related to decline in processing speed. DISCUSSION: Seizure onset had a negative impact on mental health in children with declines in cognitive functioning except for older children and those with more family resources. Children should be assessed for declines in processing speed and, if found, those subgroups of children with less educated or more anxious parents and those in less supportive families should be targeted for interventions.

The effect of temperament and neuropsychological functioning on behavior problems in children with new-onset seizures.

The present study is part of a larger project that seeks to identify factors that predict children's behavioral, social, and cognitive adaptation to epilepsy. Children with seizures are more likely to have internalizing and externalizing behavior problems than either healthy children or children with other chronic illnesses. The present research examines risk factors for behavior problems. Early temperament and neuropsychological functioning, specifically executive function and language abilities, are evaluated as unique and moderating predictors of adverse behavioral outcomes in 229 children with a first recognized seizure. Parents assessed temperament, children were administered neuropsychological tests, and teachers evaluated behavior 36 months after seizure onset. Results revealed that early temperament and neuropsychological functioning, specifically executive function, predicted behavioral outcomes 3 years after seizure onset.