Faculty Bibliography

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/METHODS: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/CONCLUSIONS: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.

Our objective is to characterize the long-term course of Glut1 deficiency syndrome. Longitudinal outcome measures, including Columbia Neurological Scores, neuropsychological tests, and adaptive behavior reports, were collected for 13 participants with Glut1 deficiency syndrome who had been followed for an average of 14.2 (range = 8.9-23.6) years. A parent questionnaire assessed manifestations throughout development. The 6-Minute Walk Test captured gait disturbances and triggered paroxysmal exertional dyskinesia. All longitudinal outcomes remained stable over time. Epilepsy dominated infancy and improved during childhood. Dystonia emerged during childhood or adolescence. Earlier introduction of the ketogenic diet correlated with better long-term outcomes on some measures. Percent-predicted 6-Minute Walk Test distance correlated significantly with Columbia Neurological Scores. We conclude that Glut1 deficiency syndrome is a chronic condition, dominated by epilepsy in infancy and by movement disorders thereafter. Dietary treatment in the first postnatal months may effect improved outcomes, emphasizing the importance of early diagnosis and treatment.

RATIONALE/BACKGROUND:(18)F fluorodeoxyglucose positron emission tomography ((18)F FDG-PET) facilitates examination of glucose metabolism. Previously, we described regional cerebral glucose hypometabolism using (18)F FDG-PET in patients with Glucose transporter 1 Deficiency Syndrome (Glut1 DS). We now expand this observation in Glut1 DS using quantitative image analysis to identify the epileptic network based on the regional distribution of glucose hypometabolism. METHODS:(18)F FDG-PET scans of 16 Glut1 DS patients and 7 healthy participants were examined using Statistical parametric Mapping (SPM). Summed images were preprocessed for statistical analysis using MATLAB 7.1 and SPM 2 software. Region of interest (ROI) analysis was performed to validate SPM results. RESULTS:Visual analysis of the (18)F FDG-PET images demonstrated prominent regional glucose hypometabolism in the thalamus, neocortical regions and cerebellum bilaterally. Group comparison using SPM analysis confirmed that the regional distribution of glucose hypo-metabolism was present in thalamus, cerebellum, temporal cortex and central lobule. Two mildly affected patients without epilepsy had hypometabolism in cerebellum, inferior frontal cortex, and temporal lobe, but not thalamus. Glucose hypometabolism did not correlate with age at the time of PET imaging, head circumference, CSF glucose concentration at the time of diagnosis, RBC glucose uptake, or CNS score. CONCLUSION/CONCLUSIONS:Quantitative analysis of (18)F FDG-PET imaging in Glut1 DS patients confirmed that hypometabolism was present symmetrically in thalamus, cerebellum, frontal and temporal cortex. The hypometabolism in thalamus correlated with the clinical history of epilepsy.

PURPOSE/OBJECTIVE:Generalized periodic epileptiform discharges (GPDs) are a specific periodic EEG pattern, reported as having a poor clinical outcome. The incidence and clinical implications of this EEG pattern in children are not known. In this study, we examined the clinical features of children with GPDs. METHODS:EEG-video monitoring reports of children with critical illness in the intensive care unit were retrospectively reviewed to detect GPDs. The clinical history, hospital course and seizure characteristics were reviewed and outcome was based on the clinical findings at hospital discharge. RESULTS:Twenty one children (age 2-18 years) were identified with GPDs. The most common underlying etiology was encephalitis (N=11). At the time of EEG, a continuous intravenous infusion (cIV) of an anticonvulsant drug was used to treat refractory status epilepticus (RSE). Non-convulsive seizures (NCS) were identified in 15, and clinical seizures in 13 children after GPDs were detected. GPDs occurred after a dose reduction in the cIV in 43%. Neuroimaging done in 16 children showed an acute change in 13/16 (81%) and chronic changes in 2/16 (13%). Five children (23%) died. Seven (33%) children had a favorable outcome, whereas the remaining children had a moderate to severe disability at the time of hospital discharge. CONCLUSION/CONCLUSIONS:GPDs are seen during the course of RSE in critically ill children and are associated with seizure recurrence. A lower mortality rate occurs in children with GPDs compared to adult counterparts, likely related to different etiologies. Although the significance of GPDs must be determined within the context of the clinical situation, GPDs suggest a still active epileptic process.

Glut1 deficiency syndrome (Glut1 DS) was originally described in 1991 as a developmental encephalopathy characterized by infantile onset refractory epilepsy, cognitive impairment, and mixed motor abnormalities including spasticity, ataxia, and dystonia. The clinical condition is caused by impaired glucose transport across the blood brain barrier. The past 5 years have seen a dramatic expansion in the range of clinical syndromes that are recognized to occur with Glut1 DS. In particular, there has been greater recognition of milder phenotypes. Absence epilepsy and other idiopathic generalized epilepsy syndromes may occur with seizure onset in childhood or adulthood. A number of patients present predominantly with movement disorders, sometimes without any accompanying seizures. In particular, paroxysmal exertional dyskinesia is now a well-documented clinical feature that occurs in individuals with Glut1 DS. A clue to the diagnosis in patients with paroxysmal symptoms may be the triggering of episodes during fasting or exercise. Intellectual impairment may range from severe to very mild. Awareness of the broad range of potential clinical phenotypes associated with Glut1 DS will facilitate earlier diagnosis of this treatable neurologic condition. The ketogenic diet is the mainstay of treatment and nourishes the starving symptomatic brain during development.

We report 26 individuals from ten unrelated families who exhibit variable expression and/or incomplete penetrance of epilepsy, learning difficulties, intellectual disabilities, and/or neurobehavioral abnormalities as a result of a heterozygous microdeletion distally adjacent to the Williams-Beuren syndrome region on chromosome 7q11.23. In six families with a common recurrent ∼1.2 Mb deletion that includes the Huntingtin-interacting protein 1 (HIP1) and tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein gamma (YWHAG) genes and that is flanked by large complex low-copy repeats, we identified sites for nonallelic homologous recombination in two patients. There were no cases of this ∼1.2 Mb distal 7q11.23 deletion copy number variant identified in over 20,000 control samples surveyed. Three individuals with smaller, nonrecurrent deletions (∼180-500 kb) that include HIP1 but not YWHAG suggest that deletion of HIP1 is sufficient to cause neurological disease. Mice with targeted mutation in the Hip1 gene (Hip1⁻(/)⁻) develop a neurological phenotype characterized by failure to thrive, tremor, and gait ataxia. Overall, our data characterize a neurodevelopmental and epilepsy syndrome that is likely caused by recurrent and nonrecurrent deletions, including HIP1. These data do not exclude the possibility that YWHAG loss of function is also sufficient to cause neurological phenotypes. Based on the current knowledge of Hip1 protein function and its proposed role in AMPA and NMDA ionotropic glutamate receptor trafficking, we believe that HIP1 haploinsufficiency in humans will be amenable to rational drug design for improved seizure control and cognitive and behavioral function.

Though seizure-related injuries (SRIs) among people with epilepsy (PWE) have recently gained much attention in the literature, most studies are retrospective and data are gathered indirectly through questionnaires or medical record documentation. We investigated SRIs and their associated risks in PWE attending a tertiary care center with direct and systematic inquiries during routine clinic follow-up visits over a 2-year period (N = 306). Past SRIs occurred in 54% of all patients, and 24% experienced recurrent SRIs during the study period. On multiple regression analyses, past SRI was associated with tonic-clonic seizures (TCSs) (3.2, 95% CI = 1.7-5.8) and cognitive handicap (4.3, 95% CI 1.5-16.1), and recurrent SRI was associated with TCSs (3.5, 95% CI = 1.6-7.9). Most recurrent SRIs (72%) involved head injury. SRIs are common when assessed systematically in a tertiary care setting, and TCSs represent a risk factor for recurrent SRIs. The potential clinical impact of recurrent SRIs on PWE requires further study.

Nonconvulsive status epilepticus (NCSE) is a special epileptic state that can be more common than previously thought in children and adult patients. Currently, there is no universally accepted definition for NCSE. Early and accurate diagnosis depends on a high index of suspicion and rapid availability of electroencephalographic recording. The clinical presentation of NCSE can vary from a mild confusional state to a coma. The underlying etiology is also quite diverse. In critically ill patients, NCSE has been reported with convulsive status epilepticus (CSE), hypoxemia, acute ischemic or hemorrhagic stroke, encephalitis, or trauma. The estimated incidence of NCSE is 15% to 40% in post-CSE, 8% in subarachnoid hemorrhage, and 8% to 10% in coma. As seen in CSE, there is a bimodal distribution with NCSE in critically ill patients; children (age <1 year) and elderly appear to be at great risk. NCSE has also been reported in a number of epilepsy syndromes, such as childhood absence epilepsy, Panayiotopoulos syndrome, Lennox-Gastaut syndrome, and Dravet syndrome. However, it is difficult to determine the incidence of NCSE in an ambulatory setting because of the great variation in clinical presentation and underlying etiology. This review examines the clinical features, outcome, and treatment approach for NCSE in 2 different clinical settings, in ambulatory and critically ill patients. NCSE is reviewed in children and adults to distinguish similarities and differences in their clinical presentation.

OBJECTIVE:Glucose transporter type 1 deficiency syndrome (Glut1-DS) is characterized clinically by acquired microcephaly, infantile-onset seizures, psychomotor retardation, choreoathetosis, dystonia, and ataxia. The laboratory signature is hypoglycorrhachia. The 5-hour oral glucose tolerance test (OGTT) was performed to assess cerebral function and systemic carbohydrate homeostasis during acute hyperglycemia, in the knowledge that GLUT1 is constitutively expressed ubiquitously and upregulated in the brain. METHODS:Thirteen Glut1-DS patients completed a 5-hour OGTT. Six patients had prolonged electroencephalographic (EEG)/video monitoring, 10 patients had plasma glucose and serum insulin measurements, and 5 patients had repeated measures of attention, memory, fine motor coordination, and well-being. All patients had a full neuropsychological battery prior to OGTT. RESULTS:The glycemic profile and insulin response during the OGTT were normal. Following the glucose load, transient improvement of clinical seizures and EEG findings were observed, with the most significant improvement beginning within the first 30 minutes and continuing for 180 minutes. Thereafter, clinical seizures returned, and EEG findings worsened. Additionally, transient improvement in attention, fine motor coordination, and reported well-being were observed without any change in memory performance. INTERPRETATION/CONCLUSIONS:This study documents transient neurological improvement in Glut1-DS patients following acute hyperglycemia, associated with improved fine motor coordination and attention. Also, systemic carbohydrate homeostasis was normal, despite GLUT1 haploinsufficiency, confirming the specific role of GLUT1 as the transporter of metabolic fuel across the blood-brain barrier. The transient improvement in brain function underscores the rate-limiting role of glucose transport and the critical minute-to-minute dependence of cerebral function on fuel availability for energy metabolism.

OBJECTIVE:Subclinical seizures (SCSs) are characterized by paroxysmal rhythmic epileptiform discharges that evolve in time and space in the absence of objective clinical manifestation or report of a seizure. The aim of this study was to evaluate the frequency and characteristics of SCSs in children with localization-related epilepsy (LRE). METHODS:The results of video/EEG monitoring were reviewed to identify patients with SCS. We identified 187 children diagnosed with LRE, in 32 of whom SCSs were reported in the EEG recording. RESULTS:SCSs were reported only in the children who had received a diagnosis of either symptomatic or cryptogenic LRE. All children had a history of clinical seizure(s). The ictal onset of SCSs was most frequent from the temporal and frontal lobes. SCSs were lateralized to the left hemispheres in 19, right hemisphere in 8, and both hemispheres independently in 5 children. SCSs were more often reported in young children, and associated with a history of developmental delay, infantile spasms, and frequent seizures. EEG abnormalities included background slowing and lack of normal sleep architecture in addition to the epileptiform activity. Seizure freedom was reported less often in children with SCSs. Six patients seizure free at the time of the admission were found to have SCSs. CONCLUSION/CONCLUSIONS:Subclinical seizures are not uncommon in children with LRE, in particular, with younger age, developmental disability, and medically refractory clinical course. Video/EEG monitoring will be informative in selected children with LRE to assess the seizure frequency more accurately.