Angus A Wilfong

Texas Children's Hospital, Houston, Texas, United States

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Publications (29)115.43 Total impact

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    ABSTRACT: Neuropathology of resected brain tissue has revealed an association of focal cortical dysplasia (FCD) with drug-resistant epilepsy (DRE). Recent studies have shown that the mechanistic target of rapamycin (mTOR) pathway is hyperactivated in FCD as evidenced by increased phosphorylation of the ribosomal protein S6 (S6) at serine 240/244 (S240/244), a downstream target of mTOR. Moreover, extracellular regulated kinase (ERK) has been shown to phosphorylate S6 at serine 235/236 (S235/236) and tuberous sclerosis complex 2 (TSC2) at serine 664 (S664) leading to hyperactive mTOR signaling. We evaluated ERK phosphorylation of S6 and TSC2 in two types of FCD (FCD I and FCD II) as a candidate mechanism contributing to mTOR pathway dysregulation. Tissue samples from patients with tuberous sclerosis (TS) served as a positive control. Immunostaining for phospho-S6 (pS6240/244 and pS6235/236), phospho-ERK (pERK), and phospho-TSC2 (pTSC2) was performed on resected brain tissue with FCD and TS. We found increased pS6240/244 and pS6235/236 staining in FCD I, FCD II and TS compared to normal-appearing tissue, while pERK and pTSC2 staining was increased only in FCD IIb and TS tissue. Our results suggest that both the ERK and mTOR pathways are dysregulated in FCD and TS; however, the signaling alterations are different for FCD I as compared to FCD II and TS.
    Neuropathology 09/2015; DOI:10.1111/neup.12242 · 1.65 Impact Factor
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    ABSTRACT: 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. 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. 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). 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. Copyright © 2014 Elsevier Inc. All rights reserved.
    Epilepsy & Behavior 01/2015; 43C:66-73. DOI:10.1016/j.yebeh.2014.08.011 · 2.26 Impact Factor
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    ABSTRACT: 5q31.3 microdeletion syndrome is characterized by neonatal hypotonia, encephalopathy with or without epilepsy, and severe developmental delay, and the minimal critical deletion interval harbors three genes. We describe 11 individuals with clinical features of 5q31.3 microdeletion syndrome and de novo mutations in PURA, encoding transcriptional activator protein Pur-α, within the critical region. These data implicate causative PURA mutations responsible for the severe neurological phenotypes observed in this syndrome.
    The American Journal of Human Genetics 10/2014; 95(5). DOI:10.1016/j.ajhg.2014.09.014 · 10.93 Impact Factor
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    ABSTRACT: Resting-state functional MRI (rs-fMRI) identifies resting-state networks (RSN) in the human brain by analyzing the connectivity of anatomically remote neuronal populations with synchronous low-frequency fluctuation in blood oxygen level-dependent (BOLD) signal. Network analysis has informed the understanding of functional brain organization and is beginning to reveal the impact that neurological disorders such as epilepsy may have on the developing cerebral cortex. Among children undergoing epilepsy surgery, mapping the brain networks supporting language, sensorimotor and visual function is a critical part of the preoperative evaluation. However, task-based functional mapping techniques are particularly difficult in immature patients and those with severe impairment. Functional mapping of RSN is a promising tool that may help circumvent the challenges of adequate cooperation and limited abilities of developmentally disabled children to perform age-appropriate functions. We discuss the current methodology of rs-fMRI in the pediatric population, review the literature of rs-fMRI in pediatric epilepsy and present our experience of using rs-fMRI for functional network mapping in children undergoing epilepsy surgery. © 2014 S. Karger AG, Basel.
    Pediatric Neurosurgery 09/2014; 49(5). DOI:10.1159/000363605 · 0.33 Impact Factor
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    ABSTRACT: Stereotactic laser amygdalohippocampotomy (SLAH) is a minimally-invasive potential alternative to open resection for mesial temporal lobe epilepsy (MTLE), but outcome data are limited (Willie et al, 2014). Here we present data on effectiveness, safety, and related findings collected from investigator-initiated, prospective, observational studies at 7 centers.
    Neurosurgery 08/2014; 61 Suppl 1:192. DOI:10.1227/01.neu.0000452377.10458.80 · 3.62 Impact Factor
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    ABSTRACT: Genomic copy-number variations (CNVs) constitute an important cause of epilepsies and other human neurological disorders. Recent advancement of technologies integrating genome-wide CNV mapping and sequencing is rapidly expanding the molecular field of pediatric neurodevelopmental disorders. In a previous study, a novel epilepsy locus was identified on 6q16.3q22.31 by linkage analysis in a large pedigree. Subsequent array comparative genomic hybridization (array CGH) analysis of four unrelated cases narrowed this region to ∼5 Mb on 6q22.1q22.31. We sought to further narrow the critical region on chromosome 6q22. Array CGH analysis was used in genome-wide screen for CNVs of a large cohort of patients with neurological abnormalities. Long-range PCR and DNA sequencing were applied to precisely map chromosomal deletion breakpoints. Finally, real-time qPCR was used to estimate relative expression in the brain of the candidate genes. We identified six unrelated patients with overlapping microdeletions within 6q22.1q22.31 region, three of whom manifested seizures. Deletions were found to be de novo in 5/6 cases, including all subjects presenting with seizures. We sequenced the deletion breakpoints in four patients and narrowed the critical region to a ∼250-kb segment at 6q22.1 that includes NUS1, several expressed sequence tags (ESTs) that are highly expressed in the brain, and putative regulatory sequences of SLC35F1. Our findings indicate that dosage alteration in particular, of NUS1, EST AI858607, or SLC35F1 are important contributors to the neurodevelopmental phenotype associated with 6q22 deletion, including epilepsy and tremors.European Journal of Human Genetics advance online publication, 14 May 2014; doi:10.1038/ejhg.2014.75.
    European journal of human genetics: EJHG 05/2014; 23(2). DOI:10.1038/ejhg.2014.75 · 4.35 Impact Factor
  • Angus A Wilfong · Daniel J Curry
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    ABSTRACT: Hypothalamic hamartomas (HHs) present a difficult medical problem, manifested by gelastic seizures, which are often medically intractable. Although existing techniques offer modest surgical outcomes with the potential for significant morbidity, the relatively novel technique of magnetic resonance imaging (MRI)-guided stereotactic laser ablation (SLA) offers a potentially safer, minimally invasive method with high efficacy for the HH treatment. We report here on 14 patients with medically refractory gelastic epilepsy who underwent stereotactic frame-based placement of an MR-compatible laser catheter (1.6 mm diameter) through a 3.2-mm twist drill hole. A U.S. Food and Drug Administration (FDA)-cleared laser surgery system (Visualase, Inc.) was utilized to ablate the HH, using real-time MRI thermometry. Seizure freedom was obtained in 12 (86%) of 14 cases, with mean follow-up of 9 months. There were no permanent surgical complications, neurologic deficits, or neuroendocrine disturbances. One patient had a minor subarachnoid hemorrhage that was asymptomatic. Most patients were discharged home within 1 day. SLA was demonstrated to be a safe and effective minimally invasive tool in the ablation of epileptogenic HH. Because use of SLA for HH is being adopted by other medical centers, further data will be acquired to help treat this difficult disorder.
    Epilepsia 12/2013; 54 Suppl 9(s9):109-14. DOI:10.1111/epi.12454 · 4.57 Impact Factor
  • Darcy Krueger · Angus Wilfong · David N Franz
    Annals of Neurology 11/2013; DOI:10.1002/ana.24046 · 9.98 Impact Factor
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    ABSTRACT: Objective: Epilepsy is a major manifestation of tuberous sclerosis complex (TSC). Everolimus is an mammalian target of rapamycin complex 1 inhibitor with demonstrated benefit in several aspects of TSC. We report the first prospective human clinical trial to directly assess whether everolimus will also benefit epilepsy in TSC patients. Methods: The effect of everolimus on seizure control was assessed using a prospective, multicenter, open-label, phase I/II clinical trial. Patients≥2 years of age with confirmed diagnosis of TSC and medically refractory epilepsy were treated for a total of 12 weeks. The primary endpoint was percentage of patients with a ≥50% reduction in seizure frequency over a 4-week period before and after treatment. Secondary endpoints assessed impact on electroencephalography (EEG), behavior, and quality of life. Results: Twenty-three patients were enrolled, and 20 patients were treated with everolimus. Seizure frequency was reduced by ≥50% in 12 of 20 subjects. Overall, seizures were reduced in 17 of the 20 by a median reduction of 73% (p<0.001). Seizure frequency was also reduced during 23-hour EEG monitoring (p=0.007). Significant reductions in seizure duration and improvement in parent-reported behavior and quality of life were also observed. There were 83 reported adverse events that were thought to be treatment-related, all of which were mild or moderate in severity. Interpretation: Seizure control improved in the majority of TSC patients with medically refractory epilepsy following treatment with everolimus. Everolimus demonstrated additional benefits on behavior and quality of life. Treatment was safe and well tolerated. Everolimus may be a therapeutic option for refractory epilepsy in this population.
    Annals of Neurology 11/2013; 74(5). DOI:10.1002/ana.23960 · 9.98 Impact Factor
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    ABSTRACT: BACKGROUND:: Invasive monitoring using subdural electrodes is often valuable for characterizing the anatomic source of seizures in intractable epilepsy. Covering the interhemispheric surface with subdural electrodes represents a particular challenge, with potentially higher risk of complications than covering the dorsolateral cortex. OBJECTIVE:: To better understand the safety and utility of interhemispheric subdural electrodes (IHSE). METHODS:: We retrospectively reviewed the charts of twenty-four patients who underwent implantation of IHSE by a single neurosurgeon from 2003-2010. Generous midline exposure, meticulous preservation of veins, and sharp micro-dissection were employed to facilitate safe interhemispheric grid placement under direct visualization. RESULTS:: The number of IHSE contacts implanted ranged from 10-106 (mean=39.8) per patient. Monitoring lasted for 5.5 days on average (range 2-24 days), with an adequate sample of seizures captured in all patients prior to explantation, and with a low complication rate similar to that reported for grid implantation of the dorsolateral cortex. One patient (out of 24) experienced symptomatic mass effect. No other complications clearly related to grid implantation and monitoring, such as clinically evident neurological deficits, infection, hematoma or infarction, were noted. Among patients implanted with IHSE, monitoring led to a paramedian cortical resection in 67%, a resection in a region not covered by IHSE in 17%, and explantation without resection in 17%. CONCLUSION:: When clinical factors suggest the possibility of an epileptic focus at or near the midline, invasive monitoring of the paramedian cortex with interhemispheric grids can be safely used to define the epileptogenic zone and map local cortical function.
    Neurosurgery 04/2013; 73(2 Suppl Operative). DOI:10.1227/01.neu.0000430287.08552.83 · 3.62 Impact Factor
  • Daniel J Curry · Ashok Gowda · Roger J McNichols · Angus A Wilfong
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    ABSTRACT: For about 30% of epilepsy patients, pharmaceutical therapy fails to control their seizures. MR-guided laser interstitial thermal therapy (MRgLITT) allows for real-time thermal monitoring of the ablation process and feedback control over the laser energy delivery. We report on minimally invasive surgical techniques of MRgLITT and short-term follow-up results from the first five pediatric cases in which this system was used to ablate focal epileptic lesions. We studied the patients with MRI of the brain, localized the seizure with video-EEG and used the Visualase Thermal Therapy 25 System for laser ablation of their seizure foci. All 5 patients are seizure free and there were no complications as of 2-13-month follow-up. MR-guided laser interstitial thermal therapy has a significant potential to be a minimally invasive alternative to more conventional techniques to surgically treat medically refractory epilepsy in children.
    Epilepsy & Behavior 06/2012; 24(4):408-14. DOI:10.1016/j.yebeh.2012.04.135 · 2.26 Impact Factor
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    ABSTRACT: We have identified a rare small (~450 kb unique sequence) recurrent deletion in a previously linked attention-deficit hyperactivity disorder (ADHD) locus at 2q21.1 in five unrelated families with developmental delay (DD)/intellectual disability (ID), ADHD, epilepsy and other neurobehavioral abnormalities from 17 035 samples referred for clinical chromosomal microarray analysis. Additionally, a DECIPHER ( patient 2311 was found to have the same deletion and presented with aggressive behavior. The deletion was not found in either six control groups consisting of 13 999 healthy individuals or in the DGV database. We have also identified reciprocal duplications in five unrelated families with autism, developmental delay (DD), seizures and ADHD. This genomic region is flanked by large, complex low-copy repeats (LCRs) with directly oriented subunits of ~109 kb in size that have 97.7% DNA sequence identity. We sequenced the deletion breakpoints within the directly oriented paralogous subunits of the flanking LCR clusters, demonstrating non-allelic homologous recombination as a mechanism of formation. The rearranged segment harbors five genes: GPR148, FAM123C, ARHGEF4, FAM168B and PLEKHB2. Expression of ARHGEF4 (Rho guanine nucleotide exchange factor 4) is restricted to the brain and may regulate the actin cytoskeletal network, cell morphology and migration, and neuronal function. GPR148 encodes a G-protein-coupled receptor protein expressed in the brain and testes. We suggest that small rare recurrent deletion of 2q21.1 is pathogenic for DD/ID, ADHD, epilepsy and other neurobehavioral abnormalities and, because of its small size, low frequency and more severe phenotype might have been missed in other previous genome-wide screening studies using single-nucleotide polymorphism analyses.
    Human Molecular Genetics 04/2012; 21(15):3345-55. DOI:10.1093/hmg/dds166 · 6.39 Impact Factor
  • J Lloyd Holder · Angus A Wilfong
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    ABSTRACT: INTRODUCTION: Epilepsy affects approximately 3 million people in the USA and up to 2% of the worldwide population. The yearly direct medical cost of epilepsy in the USA alone is estimated to be $9.5 billion. Epilepsy affects both children and adults and can significantly impair quality of life. Zonisamide is a second-generation antiepileptic drug (AED) that has broad-spectrum efficacy, a favorable side-effect profile and simpler dosing than earlier drugs. AREAS COVERED: The history of the development of zonisamide is reviewed in this paper. The data available demonstrating zonisamide's mechanism of action as a voltage-gated sodium channel inhibitor, a T-type calcium channel inhibitor, an enhancer of GABA release and an inhibitor of glutamate release are also reviewed. Four key Phase III clinical trials are reviewed in detail, as are subsequent postmarketing trials that have expanded the therapeutic indication for zonisamide. EXPERT OPINION: From the available clinical data, zonisamide is a viable first-line and adjunctive therapeutic for partial-onset epilepsy and should be considered as an adjunctive therapeutic for a wide-range of generalized epilepsies.
    Expert Opinion on Pharmacotherapy 10/2011; 12(16):2573-81. DOI:10.1517/14656566.2011.622268 · 3.53 Impact Factor
  • Ila S Reyes · David T Hsieh · Linda C Laux · Angus A Wilfong
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    ABSTRACT: Dravet syndrome is a rare epileptic encephalopathy linked to mutations in SCN1A (neuronal sodium channel α1 subunit) and characterized by an onset in infancy with polymorphous seizure types and developmental decline. It was reported recently that a proportion of patients previously diagnosed with alleged vaccine encephalopathy might possess SCN1A mutations and clinical histories that enabled a diagnosis of Dravet syndrome, but these results have not been replicated. We present here the cases of 5 children who presented for epilepsy care with presumed parental diagnoses of alleged vaccine encephalopathy caused by pertussis vaccinations in infancy. Their conditions were all rediagnosed years later, with the support of genetic testing, as Dravet syndrome. We hope that these cases will raise awareness of Dravet syndrome among health care providers who care for children and adolescents and aid in earlier recognition and diagnosis.
    PEDIATRICS 08/2011; 128(3):e699-702. DOI:10.1542/peds.2010-0887 · 5.47 Impact Factor
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    Garima Agarwal · Angus A Wilfong · Joseph L Edmonds
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    ABSTRACT: Use of vagus nerve stimulation (VNS) has increased in the past decade, resulting in frequent revision cases for device failure. The authors report their series of children who underwent reimplantation of the VNS device after removal of old electrodes and leads. Patients with medically refractory seizures who underwent revision of VNS electrodes were included (n = 23). Twenty patients had high lead impedance and underwent removal of the device and replacement of the VNS electrodes during the same procedure. In 3 patients, electrodes and the device had been removed previously at an outside institution because of infection. None of the patients experienced any major complications. Mean operative time was 2.3 ± 0.9 hours. The reimplanted device worked well in all patients, and seizure control was similar to or better than that reported with the previous device. Thus, implantation of the VNS electrodes is reversible, and it appears that the electrodes can be removed or replaced safely if the device is not functioning properly.
    Otolaryngology Head and Neck Surgery 01/2011; 144(1):123-4. DOI:10.1177/0194599810390896 · 2.02 Impact Factor
  • Jacob R Joseph · Rebecca J Schultz · Angus A Wilfong
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    ABSTRACT: This chart review investigated the efficacy and safety of rufinamide in 45 children and young adults who experienced a broad spectrum of partial and generalized seizure/epilepsy types which have been refractory to therapy. Of these patients, 19 (46%) achieved a >50% decrease in seizure frequency on rufinamide, and 7 patients achieved a >75% decrease in seizure frequency. While 17 (37.8%) patients stopped their trial of rufinamide prior to the end of the review period, only 2 (4.4%) were due to adverse effects. Although additional research must be done, this data shows promise that rufinamide is a safe and efficacious adjunct for cases of refractory epilepsy.
    Epilepsy research 01/2011; 93(1):87-9. DOI:10.1016/j.eplepsyres.2010.10.017 · 2.02 Impact Factor
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    ABSTRACT: A retrospective analysis of 43 patients with drop attack seizures who were treated with vagus nerve stimulation (VNS) was undertaken to determine the efficacy of VNS and to determine pre-implantation characteristics associated with VNS success. It was found that on last follow-up, 46% of patients had at least a 75% reduction in drops per day. Forty-six percent of patients had less than a 50% reduction in drops per day and were considered nonresponders. Univariate analysis failed to uncover significant associations between pre-implantation characteristics and VNS success. It was found that atonic head nods were more amenable to VNS treatment as compared with atonic or tonic drop attacks. In addition, patients with focal or lateralized epileptiform abnormalities responded better to VNS compared with those with more diffuse or poorly localized findings on ictal and/or interictal recordings. Our data suggest that VNS offers significant palliative benefit to many children with medically intractable drop attack seizures.
    Epilepsy & Behavior 11/2010; 19(3):394-9. DOI:10.1016/j.yebeh.2010.06.044 · 2.26 Impact Factor
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    ABSTRACT: Dual pathology has previously been reported in less than 10% of cases of Rasmussen's encephalitis (RE). Given the rarity of RE, it appears unlikely that dual pathology in RE is merely a coincidence. We therefore reviewed all cases of RE experienced in our institution to assess for an additional/associated pathology. A total of seven patients with RE were identified in our archives. Seven children (4 boys and 3 girls, age range: 3-16 years, mean: 9.5 years) with medically refractory epilepsy underwent surgical resection for intractable seizures. The surgical specimens were examined with routine neurohistological techniques, and immunohistochemistry was performed with an extensive panel of antibodies for viruses, lymphocytes, microglia/macrophages, human leukocyte antigen (HLA)-DR, astrocytes, and neurons. Relevant literature was reviewed. Microscopically, all seven cases demonstrated the inflammatory pathology of RE in the cortex and white matter with leptomeningeal and perivascular lymphocytic infiltration, microglial nodules with/without neuronophagia, neuronal loss and gliosis. The HLA-DR antibody was extremely helpful in highlighting the extent of microglial cell proliferation/activation that was not appreciable with standard histology. An unexpected finding in all seven cases was the presence of cortical dysplasia. In our series of seven cases, there was co-occurrence of the inflammatory/destructive pathology of RE with malformative/dysplastic features in cortical architecture in 100% of cases, raising questions about the possible relationships between the two entities. Awareness of the possibility of dual pathology in RE is important for clinical and pathological diagnosis, and may affect the management and outcome of these patients. Immunohistochemistry is very helpful to make a definitive diagnosis of both pathologies.
    Neuropathology 08/2010; 30(4):381-91. DOI:10.1111/j.1440-1789.2009.01079.x · 1.65 Impact Factor
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    ABSTRACT: Epilepsia partialis continua (EPC) is a form of status epilepticus that is characterized by continuous simple partial seizures and can occur as a manifestation of a variety of underlying pathological processes. Because these seizures typically take onset within or close to motor cortex, the treatment of refractory EPC with resective surgery risks significant postoperative deficits. We describe our experience using ictal recordings obtained intraoperatively during awake craniotomy, in conjunction with direct cortical stimulation mapping, to tailor surgical resections in 2 patients with refractory EPC. Both patients had pan-hemispheric pathologies that made extraoperative recording difficult. Awake craniotomy takes advantage of a unique feature of refractory EPC, namely the near-continuous presence of focal seizure activity. It allows the surgeon to record seizures in the operating room and precisely define the anatomic location of epileptic activity, to resect the seizure focus, and to both visually and electrographically confirm successful cessation of EPC after resection, all within a single operation. We used standard methods of awake craniotomy to finely tailor a cortical resection to the epileptogenic cortex while sparing nearby eloquent motor areas. The precision of awake mapping made this approach safe and effective. The cases we describe demonstrate the role of focal resection in the treatment of EPC. Standard techniques of awake craniotomy have application in the treatment of this challenging problem.
    Neurosurgery 04/2009; 64(3 Suppl):ons195-6; discussion ons196. DOI:10.1227/01.NEU.0000335656.12271.A9 · 3.62 Impact Factor
  • Angus A Wilfong
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    ABSTRACT: An expanding array of antiepileptic drugs (AEDs) is available to treat childhood epilepsy, offering the potential for improved seizure control and quality of life in this important patient population but also providing challenges in the selection of the best regimen for the individual patient. In addition to correct diagnosis of seizure type and general AED efficacy profile, other important treatment considerations in pediatric patients include age-specific organ toxicity, potential cognitive and behavioral or psychiatric effects of AEDs, compliance, and drug-drug interactions, since children commonly receive more medications than nonelderly adults. Drug dosing may be more difficult in pediatric than in adult epilepsy patients, and doses in children often require adjustment as the patient matures. Because many randomized controlled trials (RCTs) of newer AEDs have not included childhood epilepsy, physicians often have incomplete data on which to base treatment decisions. Therefore, despite the wider array of potential therapies, it is often unclear how to realize the potential they offer. Recently published guidelines from a number of organizations have provided strategies for the use of new AEDs in the treatment of childhood epilepsy. Additional RCTs of monotherapy options for childhood epilepsy are greatly needed. The ketogenic diet provides an alternative to pharmacologic control of seizures in some pediatric patients.
    Neurology 01/2008; 69(24 Suppl 3):S17-22. DOI:10.1212/01.wnl.0000302373.47100.1a · 8.29 Impact Factor

Publication Stats

361 Citations
115.43 Total Impact Points


  • 2005–2015
    • Texas Children's Hospital
      Houston, Texas, United States
  • 2003–2014
    • Baylor College of Medicine
      • • Department of Neurology
      • • Department of Molecular & Human Genetics
      • • Department of Pediatrics
      Houston, Texas, United States
  • 2009
    • University of Pennsylvania
      • Department of Neurosurgery
      Philadelphia, PA, United States