Brenda Porter, MD, PhD

All Publications

• Association of earlier surgery with improved postoperative language development in children with tuberous sclerosis complex. Journal of neurosurgery. Pediatrics Sadeghzadeh, S., Johnstone, T. M., Peters, J. M., Porter, B. E., Ihnen, S. K. 2024: 1-9

  Abstract

  The authors evaluated the impact of the timing of epilepsy surgery on postoperative neurocognitive outcomes in a cohort of children followed in the multiinstitutional Tuberous Sclerosis Complex (TSC) Autism Center of Excellence Research Network (TACERN) study.Twenty-seven of 159 patients in the TACERN cohort had drug-refractory epilepsy and underwent surgery. Ages at surgery ranged from 15.86 to 154.14 weeks (median 91.93 weeks). Changes in patients' first preoperative (10-58 weeks) to last postoperative (155-188 weeks) scores on three neuropsychological tests-the Mullen Scales of Early Learning (MSEL), the Vineland Adaptive Behavior Scales, 2nd edition (VABS-2), and the Preschool Language Scales, 5th edition (PLS-5)-were calculated. Pearson correlation and multivariate linear regression models were used to correlate test outcomes separately with age at surgery and duration of epilepsy prior to surgery. Analyses were separately conducted for patients whose seizure burdens decreased postoperatively (n = 21) and those whose seizure burdens did not (n = 6). Regression analysis was specifically focused on the 21 patients who achieved successful seizure control.Age at surgery was significantly negatively correlated with the change in the combined verbal subtests of the MSEL (R = -0.45, p = 0.039) and predicted this score in a multivariate linear regression model (β = -0.09, p = 0.035). Similar trends were seen in the total language score of the PLS-5 (R = -0.4, p = 0.089; β = -0.12, p = 0.014) and in analyses examining the duration of epilepsy prior to surgery as the independent variable of interest. Associations between age at surgery and duration of epilepsy prior to surgery with changes in the verbal subscores of VABS-2 were more variable (R = -0.15, p = 0.52; β = -0.05, p = 0.482).Earlier surgery and shorter epilepsy duration prior to surgery were associated with greater improvement in postoperative language in patients with TSC. Prospective or comparative effectiveness clinical trials are needed to further elucidate surgical timing impacts on neurocognitive outcomes.

  View details for DOI 10.3171/2024.4.PEDS2481

  View details for PubMedID 38996393

• The growing research toolbox for SLC13A5 citrate transporter disorder: a rare disease with animal models, cell lines, an ongoing Natural History Study and an engaged patient advocacy organization. Therapeutic advances in rare disease Brown, T. L., Bainbridge, M. N., Zahn, G., Nye, K. L., Porter, B. E. 2024; 5: 26330040241263972

  Abstract

  TESS Research Foundation (TESS) is a patient-led nonprofit organization seeking to understand the basic biology and clinical impact of pathogenic variants in the SLC13A5 gene. TESS aims to improve the fundamental understanding of citrate's role in the brain, and ultimately identify treatments and cures for the associated disease. TESS identifies, organizes, and develops collaboration between researchers, patients, clinicians, and the pharmaceutical industry to improve the lives of those suffering from SLC13A5 citrate transport disorder. TESS and its partners have developed multiple molecular tools, cellular and animal models, and taken the first steps toward drug discovery and development for this disease. However, much remains to be done to improve our understanding of the disorder associated with SLC13A5 variants and identify effective treatments for this devastating disease. Here, we describe the available SLC13A5 resources from the community of experts, to foundational tools, to in vivo and in vitro tools, and discuss unanswered research questions needed to move closer to a cure.

  View details for DOI 10.1177/26330040241263972

  View details for PubMedID 39091896

• Approach, complications, and outcomes for 37 consecutive pediatric patients undergoing laser ablation for medically refractory epilepsy at Stanford Children's Health. Journal of neurosurgery. Pediatrics Barros Guinle, M. I., Johnstone, T., Li, D., Kaur, H., Porter, B. E., Grant, G. A. 2023: 1-11

  Abstract

  OBJECTIVE: The objective of this study was to better understand the safety and efficacy of laser interstitial thermal therapy (LITT) for children with medically refractory epilepsy.METHODS: Thirty-seven consecutive pediatric epilepsy patients at a single pediatric center who underwent LITT ablation of epileptogenic foci between May 2017 and December 2021 were retrospectively reviewed. Patient demographics, medication use, seizure frequency, prior surgical interventions, procedural details, and pre- and postoperative seizure history were analyzed.RESULTS: Thirty-seven pediatric patients (24 male, 13 female) with severe medically refractory epilepsy were included; all underwent stereo-electroencephalography (SEEG) prior to LITT. The SEEG electrode placement was based on the preoperative workup and tailored to each patient by the epileptologist and neurosurgeons working together to identify the epileptic network and hopefully quiet borders. Seizure onset was at a mean age of 2.70 ± 2.82 years (range 0.25-12 years), and the mean age at the time of LITT was 9.46 ± 5.08 years (range 2.41-17.86 years). Epilepsy was lesional in 23 patients (18 tuberous sclerosis, 4 focal cortical dysplasia, 1 gliosis) and nonlesional in 14. Eighteen patients had prior surgical interventions including open resections (n = 13: 11 single and 2 multiple), LITT (n = 4), or both (n = 1). LITT targeted a region adjacent to the previous target in 5 cases. The median number of lasers placed during the procedure was 3 (range 1-5). Complications occurred in 14 (37.8%) cases, only 3 (8.11%) of which resulted in a permanent deficit: 1 venous hemorrhage requiring evacuation following laser ablation, 1 aseptic meningitis, 2 immediate postoperative seizures, and 10 neurological deficits (7 transient and 3 permanent). Postoperatively, 22 (59.5%) patients were seizure free at the last follow-up (median follow-up 18.35 months, range 7.40-48.76 months), and the median modified Engel class was I (Engel class I in 22 patients, Engel class II in 2, Engel class III in 2, and Engel class IV in 11). Patients having tried a greater number of antiseizure medications before LITT were less likely to achieve seizure improvement (p = 0.046) or freedom (p = 0.017). Seizure improvement following LITT was associated with a shorter duration of epilepsy prior to LITT (p = 0.044), although postoperative seizure freedom was not associated with a shorter epilepsy duration (p = 0.667). Caregivers reported postoperative neurocognitive improvement in 17 (45.9%) patients.CONCLUSIONS: In this large single-institution cohort of pediatric patients with medically refractory seizures due to various etiologies, LITT was a relatively safe and effective surgical approach for seizure reduction and seizure freedom at 1 year of follow-up.

  View details for DOI 10.3171/2023.8.PEDS23158

  View details for PubMedID 37922561

• Characterizing a rare neurogenetic disease, SLC13A5 citrate transporter disorder, utilizing clinical data in a cloud-based medical record collection system. Frontiers in genetics Spelbrink, E. M., Brown, T. L., Brimble, E., Blanco, K. A., Nye, K. L., Porter, B. E. 2023; 14: 1109547

  Abstract

  Introduction: SLC13A5 citrate transporter disorder is a rare autosomal recessive genetic disease that has a constellation of neurologic symptoms. To better characterize the neurologic and clinical laboratory phenotype, we utilized patient medical records collected by Ciitizen, an Invitae company, with support from the TESS Research Foundation. Methods: Medical records for 15 patients with a suspected genetic and clinical diagnosis of SLC13A5 citrate transporter disorder were collected by Ciitizen, an Invitae company. Genotype, clinical phenotypes, and laboratory data were extracted and analyzed. Results: The 15 patients reported all had epilepsy and global developmental delay. Patients continued to attain motor milestones, though much later than their typically developing peers. Clinical diagnoses support abnormalities in communication, and low or mixed tone with several movement disorders, including, ataxia and dystonia. Serum citrate was elevated in the 3 patients in whom it was measured; other routine laboratory studies assessing renal, liver and blood function had normal values or no consistent abnormalities. Many electroencephalograms (EEGs) were performed (1 to 35 per patient), and most but not all were abnormal, with slowing and/or epileptiform activity. Fourteen of the patients had one or more brain magnetic resonance imaging (MRI) reports: 7 patients had at least one normal brain MRI, but not with any consistent findings except white matter signal changes. Discussion: These results show that in addition to the epilepsy phenotype, SLC13A5 citrate transporter disorder impacts global development, with marked abnormalities in motor abilities, tone, coordination, and communication skills. Further, utilizing cloud-based medical records allows industry, academic, and patient advocacy group collaboration to provide preliminary characterization of a rare genetic disorder. Additional characterization of the neurologic phenotype will be critical to future study and developing treatment for this and related rare genetic disorders.

  View details for DOI 10.3389/fgene.2023.1109547

  View details for PubMedID 37025451

  View details for PubMedCentralID PMC10072280

• Practical Advice on Surviving and Thriving as an Academic Physician-Neuroscientist. JAMA neurology Knowles, J. K., Porter, B. E. 2021

  View details for DOI 10.1001/jamaneurol.2021.3889

  View details for PubMedID 34694341

• Caregivers' impression of epilepsy surgery in patients with tuberous sclerosis complex. Epilepsy & behavior : E&B Nguyen, T. n., Porter, B. E. 2020; 111: 107331

  Abstract

  Epilepsy surgery is successful in the majority of patients with tuberous sclerosis complex (TSC), with high rates of postoperative seizure reduction and even seizure freedom. Epilepsy surgery is recommended after failing two appropriate antiseizure medication trials; however, this is rare in clinical practice. We hypothesized that following surgery, caregivers' perspectives on the path they took to epilepsy surgery would inform changes in clinical practice and future research to increase utilization and early use of surgery. A questionnaire was developed to explore caregivers' perspectives on their child's path to epilepsy surgery. All 46 caregivers that filled out the majority of the survey were glad that their child underwent epilepsy surgery. Fourteen of 34 caregivers that commented on surgery timing wished their child had undergone epilepsy surgery earlier. Epilepsy with a duration of 23.5 months [interquartile range (IQR), 11.1 to 32.2 months, N = 14] prior to surgery was associated with caregiver dissatisfaction and was twice as long compared with caregivers who were satisfied with the timing of surgery (10 months, IQR, 7 to 17.3 months, p = 0.03). Caregivers were willing to accept a lower likelihood of seizure freedom and improvement than what they felt was likely from the preoperative discussions with their physicians. Forty caregivers rated various neurology physician factors as very important in their decision to undergo surgery: neurologist's attitude toward epilepsy surgery, experience with epilepsy surgery, and discussions around the risks of having and not having epilepsy surgery. Optimizing the caregiver-physician relationship can help facilitate early surgery referral and caregiver perception of surgery, potentially preventing delays to surgery and improved caregiver satisfaction.

  View details for DOI 10.1016/j.yebeh.2020.107331

  View details for PubMedID 32759076

• Efficacy and safety of perampanel in patients with seizures associated with Lennox-Gastaut syndrome: A randomized trial. Epilepsia Vossler, D. G., Porter, B. E., Kira, R., Lee, J., Aeby, A., Patten, A., Cheng, J. Y., Ngo, L. Y., 338 Study Investigators 2024

  Abstract

  OBJECTIVES: The Phase 3 Study 338 (NCT02834793) assessed long-term clinical outcomes of adjunctive perampanel in patients ≥2years of age with uncontrolled seizures associated with Lennox-Gastaut syndrome (LGS).METHODS: Eligible patients were diagnosed with LGS and receiving one to four concomitant antiseizure medications with an average of two or more drop seizures/week during baseline. The study comprised an 18-week double-blind, randomized, placebo-controlled Core Study and≥52-week open-label Extension. The primary endpoint was median percent change in drop seizure frequency per 28days during the Core Study. Key secondary endpoints included responder rates, seizure-freedom rates, and safety outcomes. Post hoc analyses were performed encompassing a broader range of drop seizures or all countable motor seizures.RESULTS: Seventy patients were randomized into the Core Study (perampanel, n=34; placebo, n=36), and 58 entered the Extension. In the Core Study, numerically greater median percent reductions in drop seizure frequency were observed with perampanel (23.1%) vs placebo (4.5%) using prespecified assessments (p=.107), whereas significantly greater reductions were detected using the broader definition (48.6% vs -.7%, respectively, p=.001) or all countable motor seizures (44.0% vs -.6%, respectively, p=.017). The 50% responder rate for drop seizures was higher with perampanel vs placebo using modern definitions. Reductions in seizure frequency with perampanel were maintained over 52weeks. Treatment-emergent adverse events occurred in 85.3% of perampanel-treated patients (somnolence [23.5%] was the most frequent) and 72.2% of placebo-treated patients.SIGNIFICANCE: This study had a reduced sample size and was underpowered. Although the difference in reductions in drop seizure frequency between treatments was not statistically significant by prespecified assessments, adjunctive perampanel demonstrated sustained efficacy in reducing drop seizures associated with LGS for ≤71weeks using modern definitions. No new safety signals emerged. These observations suggest the long-term efficacy and safety of perampanel in the LGS population.

  View details for DOI 10.1111/epi.18193

  View details for PubMedID 39576191

• Sleep Abnormalities in SLC13A5 Citrate Transporter Disorder. Genes Adams, R. M., Ozlu, C., Bailey, L. E., Solidum, R. M., Cooper, S., Best, C. R., Elacio, J., Kavanaugh, B. C., Brown, T. L., Nye, K., Liu, J., Porter, B. E., Goodspeed, K., Bailey, R. M. 2024; 15 (10)

  Abstract

  SLC13A5 Citrate Transporter Disorder is a rare pediatric neurodevelopmental disorder. Patients have epilepsy, developmental disability, and impaired mobility. While sleep disorders are common in children with neurodevelopmental disorders, sleep abnormalities have not been reported in SLC13A5 patients.Here, we assessed sleep disturbances in patients through caregiver reported surveys and in a transgenic mouse model of SLC13A5 deficiency. A total of 26 patients were evaluated with the Sleep Disturbance Scale for Children three times over a one-year span. Sleep and wake activities were assessed in the SLC13A5 knock-out (KO) mice using wireless telemetry devices.A high burden of clinically significant sleep disturbances were reported in the patients, with heterogeneous symptoms that remained stable across time. While sleep disturbances were common, less than 30% of patients were prescribed medications for sleep. Comparatively, in SLC13A5 KO mice using EEG recordings, significant alterations were found during light cycles, when rodents typically sleep. During the sleep period, SLC13A5 mice had increased activity, decreased paradoxical sleep, and changes in absolute power spectral density, indicating altered sleep architecture in the mouse model.Our results demonstrate a significant component of sleep disturbances in SLC13A5 patients and mice, highlighting a potential gap in patient care. Further investigation of sleep dysfunction and the underlying etiologies of sleep disturbances in SLC13A5 citrate transporter disorder is warranted.

  View details for DOI 10.3390/genes15101338

  View details for PubMedID 39457462

  View details for PubMedCentralID PMC11507356

• Drug-Resistant Epilepsy in Tuberous Sclerosis Complex Is Associated With TSC2 Genotype: More Findings From the Preventing Epilepsy Using Vigatrin (PREVeNT) Trial. Pediatric neurology Farach, L. S., Richard, M. A., Wulsin, A. C., Bebin, E. M., Krueger, D. A., Sahin, M., Porter, B. E., McPherson, T. O., Peters, J. M., O'Kelley, S., Taub, K. S., Rajaraman, R., Randle, S. C., McClintock, W. M., Koenig, M. K., Frost, M. D., Werner, K., Nolan, D. A., Wong, M., Cutter, G., Northrup, H., Au, K. S. 2024; 159: 62-71

  Abstract

  Children with tuberous sclerosis complex (TSC) are at high risk for drug-resistant epilepsy (DRE). The ability to stratify those at highest risk for DRE is important for counseling and prompt, aggressive management, necessary to optimize neurocognitive outcomes. Using the extensively phenotyped PREVeNT cohort, we aimed to characterize whether the TSC genotype was associated with DRE.The study group (N = 70) comprised participants with TSC enrolled at age less than or equal to six months with detailed epilepsy and other phenotypic and genotypic data, prospectively collected as part of the PREVeNT trial. Genotype-phenotype correlations of DRE, time to first abnormal electroencephalography, and time to epilepsy onset were compared using Fisher exact test and regression models.Presence of a TSC2 pathogenic variant was significantly associated with DRE, compared with TSC1 and participants with no pathogenic mutation identified. In fact, all participants with DRE had a TSC2 pathogenic variant. Furthermore, TSC2 variants expected to result in no protein product were associated with higher risk for DRE. Finally, TSC1 pathogenic variants were associated with later-onset epilepsy, on average 21.2 months later than those with other genotypes.Using a comprehensively phenotyped cohort followed from infancy, this study is the first to delineate genotype-phenotype correlations for epilepsy severity and onset in children with TSC. Patients with TSC2 pathogenic variants, especially TSC2 pathogenic variants predicted to result in lack of TSC2 protein, are at highest risk for DRE, and are likely to have earlier epilepsy onset than those with TSC1. Clinically, these insights can inform counseling, surveillance, and management.

  View details for DOI 10.1016/j.pediatrneurol.2024.06.012

  View details for PubMedID 39142021

• Response Letter to the Editor: "Expanding eligibility for intracranial electroencephalography using dexmedetomidine hydrochloride in children with behavioral dyscontrol". Epilepsy & behavior : E&B Johnstone, T., Guinle, M. I., Grant, G. A., Porter, B. E. 2024; 153: 109657

  View details for DOI 10.1016/j.yebeh.2024.109657

  View details for PubMedID 38368786

• Efficacy and safety of perampanel in a randomized, placebo-controlled trial with an open-label extension in patients with seizures associated with Lennox-Gastaut syndrome (LGS) Porter, B., Kira, R., Lee, J., Aeby, A., Patten, A., Ngo, L. ELSEVIER. 2023

  View details for DOI 10.1016/j.jns.2023.121563

  View details for Web of Science ID 001163199100691

• Expanding eligibility for intracranial electroencephalography using Dexmedetomidine Hydrochloride in children with behavioral dyscontrol. Epilepsy & behavior : E&B Johnstone, T., Isabel Barros Guinle, M., Grant, G. A., Porter, B. E. 2023; 150: 109541

  Abstract

  Invasive intracranial electroencephalography (IEEG) is advantageous for identifying epileptogenic foci in pediatric patients with medically intractable epilepsy. Patients with behavioral challenges due to autism, intellectual disabilities, and hyperactivity have greater difficulty tolerating prolonged IEEG recording and risk injuring themselves or others. There is a need for therapies that increase the safety of IEEG but do not interfere with IEEG recording or prolong hospitalization. Dexmedetomidine Hydrochloride's (DH) use has been reported to improve safety in patients with behavioral challenges during routine surface EEG recording but has not been characterized during IEEG. Here we evaluated DH administration in pediatric patients undergoing IEEG to assess its safety and impact on the IEEG recordings.A retrospective review identified all pediatric patients undergoing IEEG between January 2016 and September 2022. Patient demographics, DH administration, DH dose, hospital duration, and IEEG seizure data were analyzed. The number of seizures recorded for each patient was divided by the days each patient was monitored with IEEG. The total number of seizures, as well as seizures per day, were compared between DH and non-DH patients via summary statistics, multivariable linear regression, and univariate analysis. Other data were compared across groups with univariate statistics.Eighty-four pediatric patients met the inclusion criteria. Eighteen (21.4 %) received DH treatment during their IEEG recording. There were no statistical differences between the DH and non-DH groups' demographic data, length of hospital stays, or seizure burden. Non-DH patients had a median age of 12.0 years (interquartile range: 7.25-15.00), while DH-receiving patients had a median age of 8.0 years old (interquartile range: 3.00-13.50) (p = 0.07). The non-DH cohort was 57.6 % male, and the DH cohort was 50.0 % male (p = 0.76). The median length of IEEG recordings was 5.0 days (interquartile range: 4.00-6.25) for DH patients versus 6.0 days (interquartile range: 4.00-8.00) for non-DH patients (p = 0.25). Median total seizures recorded in the non-DH group was 8.0 (interquartile range: 5.00-13.25) versus 15.0 in the DH group (interquartile range: 5.00-22.25) (p = 0.33). Median total seizures per day of IEEG monitoring were comparable across groups: 1.50 (interquartile range: 0.65-3.17) for non-DH patients compared to 2.83 (interquartile range: 0.89-4.35) (p = 0.25) for those who received DH. Lastly, non-DH patients were hospitalized for a median of 8.0 days (interquartile range: 6.00-11.25), while DH patients had a median length of stay of 7.00 days (interquartile range: 5.00-8.25) (p = 0.27). No adverse events were reported because of DH administration.Administration of DH was not associated with adverse events. Additionally, the frequency of seizures captured on the IEEG, as well as the duration of hospitalization, were not significantly different between patients receiving and not receiving DH during IEEG. Incorporating DH into the management of patients with behavioral dyscontrol and intractable epilepsy may expand the use of IEEG to patients who previously could not tolerate it, improve safety, and preserve epileptic activity during the recording period.

  View details for DOI 10.1016/j.yebeh.2023.109541

  View details for PubMedID 38035536

• Early Treatment with Vigabatrin Does Not Decrease Focal Seizures or Improve Cognition in Tuberous Sclerosis Complex: The PREVeNT Trial. Annals of neurology Bebin, E. M., Peters, J. M., Porter, B. E., McPherson, T. O., O'Kelley, S., Sahin, M., Taub, K. S., Rajaraman, R., Randle, S. C., McClintock, W. M., Koenig, M. K., Frost, M. D., Northrup, H. A., Werner, K., Nolan, D. A., Wong, M., Krefting, J. L., Biasini, F., Peri, K., Cutter, G., Krueger, D. A. 2023

  Abstract

  To test the hypothesis that early vigabatrin treatment in Tuberous Sclerosis Complex (TSC) infants improves neurocognitive outcome at 24 months of age.Phase IIb multicenter randomized double-blind placebo-controlled trial of vigabatrin at first epileptiform EEG vs. vigabatrin at seizure onset in infants with TSC.Bayley-III cognitive assessment score at 24 months.prevalence of drug resistant epilepsy, additional developmental outcomes, and safety of vigabatrin.Of eighty-four infants enrolled, 12 were screen failures, four went straight to open label vigabatrin, and 12 were not randomized (normal EEG throughout). 56 were randomized to early vigabatrin (n=29) or placebo (n=27). 19 of 27 in the placebo arm transitioned to open label vigabatrin with a median delay of 44 days after randomization. Bayley-III cognitive composite scores at 24 months were similar for participants randomized to vigabatrin or placebo. Additionally, no significant differences were found between groups in overall epilepsy incidence and drug resistant epilepsy at 24 months, time to first seizure after randomization, and secondary developmental outcomes. Incidence of infantile spasms was lower and time to spasms after randomization was later in the vigabatrin group. Adverse events were similar across groups.Preventative treatment with vigabatrin based on EEG epileptiform activity prior to seizure onset does not improve neurocognitive outcome at 24 months in TSC children; nor delay onset or lower the incidence of focal seizures and drug resistant epilepsy at 24 months. Preventative vigabatrin was associated with later time to onset and lower incidence of infantile spasms. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/ana.26778

  View details for PubMedID 37638552

• GNAO1-related neurodevelopmental disorder: Literature review and caregiver survey. Epilepsy & behavior reports JoJo Yang, Q., Porter, B. E., Axeen, E. T. 2023; 21: 100582

  Abstract

  Background: GNAO1-related neurodevelopmental disorder is a heterogeneous condition characterized by hypotonia, developmental delay, epilepsy, and movement disorder. This study aims to better understand the spectrum of epilepsy associated with GNAO1 variants and experience with anti-seizure medications, and to review published epilepsy phenotypes in GNAO1.Methods: An online survey was distributed to caregivers of individuals diagnosed with GNAO1 pathogenic variants, and a literature review was conducted.Results: Fifteen respondents completed the survey with the median age of 39months, including a novel variant p.Q52P. Nine had epilepsy - six had onset in the first week of life, three in the first year of life - but two reported no ongoing seizures. Seizure types varied. Individuals were taking a median of 3 seizure medications without a single best treatment. Our cohort was compared to a literature review of epilepsy in GNAO1. In 86 cases, 38 discrete variants were described; epilepsy is reported in 53% cases, and a developmental and epileptic encephalopathy in 36%.Conclusions: While GNAO1-related epilepsy is most often early-onset and severe, seizures may not always be drug resistant or lifelong. Experience with anti-seizure medications is varied. Certain variant "hotspots" may correlate with epilepsy phenotype though genotype-phenotype correlation is poorly understood.

  View details for DOI 10.1016/j.ebr.2022.100582

  View details for PubMedID 36654732

• Clinical Features, Neuropathology, and Surgical Outcome in Patients With Refractory Epilepsy and Brain Somatic Variants in the SLC35A2 Gene. Neurology Barba, C., Blumcke, I., Winawer, M. R., Hartlieb, T., Kang, H., Grisotto, L., Chipaux, M., Bien, C. G., Hermanovska, B., Porter, B. E., Lidov, H. G., Cetica, V., Woermann, F. G., Lopez-Rivera, J. A., Canoll, P. D., Mader, I., D'Incerti, L., Baldassari, S., Yang, E., Gaballa, A., Vogel, H., Benova, B., Macconi, L., Polster, T., Grant, G. A., Krskova, L., Shin, H. J., Ko, A., Crino, P. B., Krsek, P., Lee, J. H., Lal, D., Baulac, S., Poduri, A., Guerrini, R. 2022

  Abstract

  BACKGROUND AND OBJECTIVES: The SLC35A2 gene, located at chromosome Xp11.23, encodes for a uridine diphosphate (UDP)-galactose transporter. We describe clinical, genetic, neuroimaging, EEG and histopathological findings and assess possible predictors of postoperative seizure and cognitive outcome in 47 patients with refractory epilepsy and brain somatic SLC35A2 gene variants.METHODS: This is a retrospective multicenter study where we performed a descriptive analysis and classical hypothesis testing. We included the variables of interest significantly associated with the outcomes in the generalized linear models.RESULTS: Two main phenotypes were associated with brain somatic SLC35A2 variants: 1) early epileptic encephalopathy (EE, 39 patients) with epileptic spasms as the predominant seizure type and moderate to severe intellectual disability, and 2) drug-resistant focal epilepsy (DR-FE, 8 patients) associated with normal/borderline cognitive function and specific neuropsychological deficits. Brain MRI was abnormal in all patients with EE and in 50% of those with DR-FE. Histopathology review identified mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE) in 44/47 patients and was inconclusive in three. The 47 patients harbored 42 distinct mosaic SLC35A2 variants, including 14 (33.3%) missense, 13 (30.9%) frameshift, 10 (23.8%) nonsense, four (9.5%) in-frame deletions/duplications, and one (2.4%) splicing variant. Variant allele frequencies (VAF) ranged from 1.4 to 52.6% (mean VAF: 17.3±13.5).At last follow-up (35.5± 21.5 months), 30 patients (63.8%) were in Engel class I, of which 26 (55.3%) were in class IA. Cognitive performances remained unchanged in most patients after surgery. Regression analyses showed that the probability of achieving both Engel class IA and class I outcomes, adjusted by age at seizure onset, was lower when the duration of epilepsy increased and higher when postoperative EEG was normal or improved. Lower brain VAF was associated with improved postoperative cognitive outcome in the analysis of associations, but this finding was not confirmed in regression analyses.DISCUSSION: Brain somatic SLC35A2 gene variants are associated with two main clinical phenotypes, EE and DR-FE, and a histopathological diagnosis of MOGHE. Additional studies will be needed to delineate any possible correlation between specific genetic variants, mutational load in the epileptogenic tissue and surgical outcomes.

  View details for DOI 10.1212/WNL.0000000000201471

  View details for PubMedID 36307217

• Neurodevelopmental and Epilepsy Phenotypes in Individuals With Missense Variants in the Voltage Sensing and Pore Domain of KCNH5. Neurology Happ, H. C., Sadleir, L. G., Zemel, M., de Valles-Ibanez, G., Hildebrand, M. S., McConkie-Rosell, A., McDonald, M., May, H., Sands, T., Aggarwal, V., Elder, C., Feyma, T., Bayat, A., Moller, R. S., Fenger, C. D., Klint Nielsen, J. E., Datta, A. N., Gorman, K. M., King, M. D., Linhares, N., Burton, B. K., Paras, A., Ellard, S., Rankin, J., Shukla, A., Majethia, P., Olson, R. J., Muthusamy, K., Schimmenti, L. A., Starnes, K., Sedlackova, L., Sterbova, K., Vlckova, M., Lassuthova, P., Jahodova, A., Porter, B. E., Couque, N., Colin, E., Prouteau, C., Collet, C., Smol, T., Caumes, R., Vansenne, F., Bisulli, F., Licchetta, L., Person, R., Torti, E., McWalter, K., Webster, R., Gerard, E. E., Lesca, G., Szepetowski, P., Scheffer, I. E., Mefford, H. C., Carvill, G. L. 2022

  Abstract

  OBJECTIVE: KCNH5 encodes the voltage-gated potassium channel EAG2/Kv10.2. We aimed to delineate the neurodevelopmental and epilepsy phenotypic spectrum associated with de novo KCNH5 variants.METHODS: We screened 893 individuals with developmental and epileptic encephalopathies (DEEs) for KCNH5 variants using targeted or exome sequencing. Additional individuals with KCNH5 variants were identified through an international collaboration. Clinical history, EEG, and imaging data were analyzed; seizure types and epilepsy syndromes were classified. We included three previously published individuals including additional phenotypic details.RESULTS: We report a cohort of 17 patients, including nine with a recurrent de novo missense variant p.Arg327His, four with a recurrent missense variant p.Arg333His, and four additional novel missense variants. All variants were located in or near the functionally critical voltage-sensing or pore domains, absent in the general population, and classified as pathogenic or likely pathogenic using American College of Medical Genetics and Genomics (ACMG) criteria. All individuals presented with epilepsy with a median seizure onset at six months. They had a wide range of seizure types, including focal and generalized seizures. Cognitive outcomes ranged from normal intellect to profound impairment. Individuals with the recurrent p.Arg333His variant had a self-limited drug-responsive focal or generalized epilepsy and normal intellect, while the recurrent p.Arg327His variant was associated with infantile-onset DEE. Two individuals with variants in the pore-domain were more severely affected, with a neonatal-onset movement disorder, early-infantile DEE, profound disability, and childhood death.CONCLUSIONS: We report the first cohort of 17 individuals with pathogenic or likely pathogenic missense variants in the voltage sensing and pore domains of Kv10.2, including 14 previously unreported individuals. We present evidence for a putative emerging genotype-phenotype correlation with a spectrum of epilepsy and cognitive outcomes. Overall, we expand the role of EAG proteins in human disease and establish KCNH5 as implicated in a spectrum of neurodevelopmental disorders (NDDs) and epilepsy.

  View details for DOI 10.1212/WNL.0000000000201492

  View details for PubMedID 36307226

• Connectivity increases during spikes and spike-free periods in self-limited epilepsy with centrotemporal spikes. Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology Goad, B. S., Lee-Messer, C., He, Z., Porter, B. E., Baumer, F. M. 2022

  Abstract

  OBJECTIVE: To understand the impact of interictal spikes on brain connectivity in patients with Self-Limited Epilepsy with Centrotemporal Spikes (SeLECTS).METHODS: Electroencephalograms from 56 consecutive SeLECTS patients were segmented into periods with and without spikes. Connectivity between electrodes was calculated using the weighted phase lag index. To determine if there are chronic alterations in connectivity in SeLECTS, we compared spike-free connectivity to connectivity in 65 matched controls. To understand the acute impact of spikes, we compared connectivity immediately before, during, and after spikes versus baseline, spike-free connectivity. We explored whether behavioral state, spike laterality, or antiseizure medications affected connectivity.RESULTS: Children with SeLECTS had markedly higher connectivity than controls during sleep but not wakefulness, with greatest difference in the right hemisphere. During spikes, connectivity increased globally; before and after spikes, left frontal and bicentral connectivity increased. Right hemisphere connectivity increased more during right-sided than left-sided spikes; left hemisphere connectivity was equally affected by right and left spikes.CONCLUSIONS: SeLECTS patient have persistent increased connectivity during sleep; connectivity is further elevated during the spike and perispike periods.SIGNIFICANCE: Testing whether increased connectivity impacts cognition or seizure susceptibility in SeLECTS and more severe epilepsies could help determine if spikes should be treated.

  View details for DOI 10.1016/j.clinph.2022.09.015

  View details for PubMedID 36307364

• Limited utility of structural MRI to identify the epileptogenic zone in young children with tuberous sclerosis. Journal of neuroimaging : official journal of the American Society of Neuroimaging Nijman, M., Yang, E., Jaimes, C., Prohl, A. K., Sahin, M., Krueger, D. A., Wu, J. Y., Northrup, H., Stone, S. S., Madsen, J. R., Fallah, A., Blount, J. P., Weiner, H. L., Grayson, L., Bebin, E. M., Porter, B. E., Warfield, S. K., Prabhu, S. P., Peters, J. M., TACERN Study Group 2022

  Abstract

  BACKGROUND AND PURPOSE: The success of epilepsy surgery in children with tuberous sclerosis complex (TSC) hinges on identification of the epileptogenic zone (EZ). We studied structural MRI markers of epileptogenic lesions in young children with TSC.METHODS: We included 26 children with TSC who underwent epilepsy surgery before the age of 3 years at five sites, with 12months or more follow-up. Two neuroradiologists, blinded to surgical outcome data, reviewed 10 candidate lesions on preoperative MRI for characteristics of the tuber (large affected area, calcification, cyst-like properties) and of focal cortical dysplasia (FCD) features (cortical malformation, gray-white matter junction blurring, transmantle sign). They selected lesions suspect for the EZ based on structural MRI, and reselected after unblinding to seizure onset location on electroencephalography (EEG).RESULTS: None of the tuber characteristics and FCD features were distinctive for the EZ, indicated by resected lesions in seizure-free children. With structural MRI alone, the EZ was identified out of 10 lesions in 31%, and with addition of EEG data, this increased to 48%. However, rates of identification of resected lesions in non-seizure-free children were similar. Across 251 lesions, interrater agreement was moderate for large size (kappa=.60), and fair (kappa=.24) for all other features.CONCLUSIONS: In young children with TSC, the utility of structural MRI features is limited in the identification of the epileptogenic tuber, but improves when combined with EEG data.

  View details for DOI 10.1111/jon.13016

  View details for PubMedID 35729081

• Somatic variants in diverse genes leads to a spectrum of focal cortical malformations. Brain : a journal of neurology Lai, D., Gade, M., Yang, E., Koh, H. Y., Lu, J., Walley, N. M., Buckley, A. F., Sands, T. T., Akman, C. I., Mikati, M. A., McKhann, G. M., Goldman, J. E., Canoll, P., Alexander, A. L., Park, K. L., Von Allmen, G. K., Rodziyevska, O., Bhattacharjee, M. B., Lidov, H. G., Vogel, H., Grant, G. A., Porter, B. E., Poduri, A. H., Crino, P. B., Heinzen, E. L. 2022

  Abstract

  Post-zygotically acquired genetic variants, or somatic variants, that arise during cortical development have emerged as important causes of focal epilepsies, particularly those due to malformations of cortical development. Pathogenic somatic variants have been identified in many genes within the PI3K-AKT-mTOR-signaling pathway in individuals with hemimegalencephaly and focal cortical dysplasia (type II), and more recently in SLC35A2 in individuals with focal cortical dysplasia (type I) or non-dysplastic epileptic cortex. Given the expanding role of somatic variants across different brain malformations, we sought to delineate the landscape of somatic variants in a large cohort of patients who underwent epilepsy surgery with hemimegalencephaly or focal cortical dysplasia. We evaluated samples from 123 children with hemimegalencephaly (n=16), focal cortical dysplasia type I and related phenotypes (n=48), focal cortical dysplasia type II (n=44), or focal cortical dysplasia type III (n=15). We performed high-depth exome sequencing in brain tissue-derived DNA from each case and identified somatic single nucleotide, indel, and large copy number variants. In 75% of individuals with hemimegalencephaly and 29% with focal cortical dysplasia type II, we identified pathogenic variants in PI3K-AKT-mTOR pathway genes. Four of 48 cases with focal cortical dysplasia type I (8%) had a likely pathogenic variant in SLC35A2. While no other gene had multiple disease-causing somatic variants across the focal cortical dysplasia type I cohort, four individuals in this group had a single pathogenic or likely pathogenic somatic variant in CASK, KRAS, NF1, and NIPBL, genes associated with neurodevelopmental disorders. No rare pathogenic or likely pathogenic somatic variants in any neurological disease genes like those identified in the focal cortical dysplasia type I cohort were found in 63 neurologically normal controls (P = 0.017), suggesting a role for these novel variants. We also identified a somatic loss-of-function variant in the known epilepsy gene, PCDH19, present in a small number of alleles in the dysplastic tissue from a female patient with focal cortical dysplasia IIIa with hippocampal sclerosis. In contrast to focal cortical dysplasia type II, neither focal cortical dysplasia type I nor III had somatic variants in genes that converge on a unifying biological pathway, suggesting greater genetic heterogeneity compared to type II. Importantly, we demonstrate that FCD types I, II, and III, are associated with somatic gene variants across a broad range of genes, many associated with epilepsy in clinical syndromes caused by germline variants, as well as including some not previously associated with radiographically evident cortical brain malformations.

  View details for DOI 10.1093/brain/awac117

  View details for PubMedID 35441233

• Antiseizure medication use and medical resource utilization after resective epilepsy surgery in children in the United States: A contemporary nationwide cross-sectional cohort analysis. Epilepsia Parker, J. J., Zhang, Y., Fatemi, P., Halpern, C. H., Porter, B. E., Grant, G. A. 2022

  Abstract

  OBJECTIVE: Antiseizure drug (ASD) therapy can significantly impact quality of life for pediatric patients whose epilepsy remains refractory to medications and who experience neuropsychological side effects manifested by impaired cognitive and social development. Contemporary patterns of ASD reduction after pediatric epilepsy surgery across practice settings in the United States are sparsely reported outside of small series. We assessed timing and durability of ASD reduction after pediatric epilepsy surgery and associated effects on health care utilization.METHODS: We performed a retrospective analysis of 376 pediatric patients who underwent resective epilepsy surgery between 2007 and 2016 in the United States using the Truven MarketScan database. Filled ASD prescriptions during the pre- and postoperative periods were compared. Univariate and multivariate analyses identified factors associated with achieving a stable discontinuation of or reduction in number of ASDs. Health care utilization and costs were systematically compared.RESULTS: One hundred seventy-one patients (45.5%) achieved a >90-day ASD-free period after surgery, and 84 (22.3%) additional patients achieved a stable reduction in number of ASDs. Achieving ASD freedom was more common in patients undergoing total hemispherectomy (n=21, p=.002), and less common in patients with tuberous sclerosis (p=.003). A higher number of preoperative ASDs was associated with a greater likelihood of achieving ASD reduction postoperatively (hazard ratio [HR]: 1.85, 95% confidence interval [CI]: 1.50-2.28), but was not associated with a significant difference in the likelihood of achieving ASD freedom (0.83, 95% CI: 0.49-1.39). Achieving an ASD-free period was associated with fewer hospital readmissions within the first year after surgery.SIGNIFICANCE: Patterns of ASD use and discontinuation after pediatric epilepsy surgery provide an unbiased surgical outcome endpoint extractable from administrative databases, where changes in seizure frequency are not captured. This quantitative measure can augment traditional surgical outcome scales, incorporating a significant clinical parameter associated with improved quality of life.

  View details for DOI 10.1111/epi.17180

  View details for PubMedID 35213744

• An Atlas of the Quantitative Protein Expression of Anti-Epileptic-Drug Transporters, Metabolizing Enzymes and Tight Junctions at the Blood-Brain Barrier in Epileptic Patients. Pharmaceutics Sato, R., Ohmori, K., Umetsu, M., Takao, M., Tano, M., Grant, G., Porter, B., Bet, A., Terasaki, T., Uchida, Y. 1800; 13 (12)

  Abstract

  The purpose of the present study was to quantitatively elucidate the levels of protein expression of anti-epileptic-drug (AED) transporters, metabolizing enzymes and tight junction molecules at the blood-brain barrier (BBB) in the focal site of epilepsy patients using accurate SWATH (sequential window acquisition of all theoretical fragment ion spectra) proteomics. Brain capillaries were isolated from focal sites in six epilepsy patients and five normal brains; tryptic digests were produced and subjected to SWATH analysis. MDR1 and BCRP were significantly downregulated in the epilepsy group compared to the normal group. Out of 16 AED-metabolizing enzymes detected, the protein expression levels of GSTP1, GSTO1, CYP2E1, ALDH1A1, ALDH6A1, ALDH7A1, ALDH9A1 and ADH5 were significantly 2.13-, 6.23-, 2.16-, 2.80-, 1.73-, 1.67-, 2.47- and 2.23-fold greater in the brain capillaries of epileptic patients than those of normal brains, respectively. The protein expression levels of Claudin-5, ZO-1, Catenin alpha-1, beta-1 and delta-1 were significantly lower, 1.97-, 2.51-, 2.44-, 1.90- and 1.63-fold, in the brain capillaries of epileptic patients compared to those of normal brains, respectively. Consistent with these observations, leakage of blood proteins was also observed. These results provide for a better understanding of the therapeutic effect of AEDs and molecular mechanisms of AED resistance in epileptic patients.

  View details for DOI 10.3390/pharmaceutics13122122

  View details for PubMedID 34959403

• Growth and Overall Health of Patients with SLC13A5 Citrate Transporter Disorder. Metabolites Brown, T. L., Nye, K. L., Porter, B. E. 2021; 11 (11)

  Abstract

  We were interested in elucidating the non-neurologic health of patients with autosomal recessive SLC13A5 Citrate Transporter (NaCT) Disorder. Multiple variants have been reported that cause a loss of transporter activity, resulting in significant neurologic impairment, including seizures, as well as motor and cognitive dysfunction. Additionally, most patients lack tooth enamel (amelogenesis imperfecta). However, patients have not had their overall health and growth described in detail. Here we characterized the non-neurologic health of 15 patients with medical records uploaded to Ciitizen, a cloud-based patient medical records portal. Ciitizen used a query method for data extraction. Overall, the patients' records suggested a moderate number of gastrointestinal issues related to feeding, reflux, vomiting and weight gain and a diverse number of respiratory complaints. Other organ systems had single or no abnormal diagnoses, including liver, renal and cardiac. Growth parameters were mostly in the normal range during early life, with a trend toward slower growth in the few adolescent patients with data available. The gastrointestinal and pulmonary issues may at least partially be explained by the severity of the neurologic disorder. More data are needed to clarify if growth is impacted during adolescence and if adult patients develop or are protected from non-neurologic disorders.

  View details for DOI 10.3390/metabo11110746

  View details for PubMedID 34822404

• Real-World Preliminary Experience With Responsive Neurostimulation in Pediatric Epilepsy: A Multicenter Retrospective Observational Study. Neurosurgery Nagahama, Y., Zervos, T. M., Murata, K. K., Holman, L., Karsonovich, T., Parker, J. J., Chen, J., Phillips, H. W., Fajardo, M., Nariai, H., Hussain, S. A., Porter, B. E., Grant, G. A., Ragheb, J., Wang, S., O'Neill, B. R., Alexander, A. L., Bollo, R. J., Fallah, A. 2021

  Abstract

  BACKGROUND: Despite the well-documented utility of responsive neurostimulation (RNS, NeuroPace) in adult epilepsy patients, literature on the use of RNS in children is limited.OBJECTIVE: To determine the real-world efficacy and safety of RNS in pediatric epilepsy patients.METHODS: Patients with childhood-onset drug-resistant epilepsy treated with RNS were retrospectively identified at 5 pediatric centers. Reduction of disabling seizures and complications were evaluated for children (<18 yr) and young adults (>18 yr) and compared with prior literature pertaining to adult patients.RESULTS: Of 35 patients identified, 17 were <18yr at the time of RNS implantation, including a 3-yr-old patient. Four patients (11%) had concurrent resection. Three complications, requiring additional surgical interventions, were noted in young adults (2 infections [6%] and 1 lead fracture [3%]). No complications were noted in children. Among the 32 patients with continued therapy, 2 (6%) achieved seizure freedom, 4 (13%) achieved ≥90% seizure reduction, 13 (41%) had ≥50% reduction, 8 (25%) had <50%reduction, and 5 (16%) experienced no improvement. The average follow-up duration was 1.7 yr (median 1.8 yr, range 0.3-4.8 yr). There was no statistically significant difference for seizure reduction and complications between children and young adults in our cohort or between our cohort and the adult literature.CONCLUSION: These preliminary data suggest that RNS is well tolerated and an effective off-label surgical treatment of drug-resistant epilepsy in carefully selected pediatric patients as young as 3 yr of age. Data regarding long-term efficacy and safety in children will be critical to optimize patient selection.

  View details for DOI 10.1093/neuros/nyab343

  View details for PubMedID 34528103

• A Standardized Protocol to Improve Acute Seizure Management in Hospitalized Pediatric Patients. Hospital pediatrics Pavitt, S., Carley, A., Porter, B., Knowles, J. K. 2021

  Abstract

  BACKGROUND: Studies of seizure management in the pediatric inpatient setting are needed. Seizures recorded by video EEG provide an opportunity to quantitatively evaluate acute management. We observed variation in delivery of standardized seizure safety measures (seizure first aid) during epilepsy monitoring unit admissions at our hospital. Our goals were to increase consistency and speed of seizure first aid and neurologic assessment in acutely seizing patients.METHODS: Using a root cause analysis, we identified major factors contributing to variation in seizure management and key drivers for improvement. Targeted interventions, centered around a protocol for acute seizure management, were implemented through quality improvement methodology. The primary outcome was correct performance of standardized seizure first aid and neurologic assessment. Secondary outcomes were time intervals to each assessment. Run charts were used to analyze primary outcomes, and statistical control charts were used for secondary outcomes. Nursing confidence in seizure management was determined through pre- and postsurveys and analyzed with the chi2 test.RESULTS: Thirteen seizures were evaluated in the preintervention phase and 10 in the postintervention phase. Completed components of seizure first aid increased from a median of 3 of 4 to 4 of 4; completed components of neurologic assessment increased from a median of 2 of 4 to 4 of 4. Responses to acute seizures were faster, and nursing confidence increased.CONCLUSIONS: A collaborative quality improvement effort between physicians and nurses led to prompt and correct delivery of seizure first aid by first responders. These relatively simple interventions could be adapted broadly to improve acute seizure management in the pediatric inpatient setting.

  View details for DOI 10.1542/hpeds.2020-000968

  View details for PubMedID 33685859

• Lacosamide-Induced Dyskinesia in Children With Intractable Epilepsy. Journal of child neurology Madani, N., O'Malley, J. A., Porter, B. E., Baumer, F. M. 2020: 883073820926634

  Abstract

  Lacosamide, an antiepileptic drug prescribed for children with refractory focal epilepsy, is generally well tolerated, with dose-dependent adverse effects. We describe 4 children who developed a movement disorder in conjunction with the initiation and/or uptitration of lacosamide. Three patients developed dyskinesias involving the face or upper extremity whereas the fourth had substantial worsening of chronic facial tics. The patients all had histories suggestive of opercular dysfunction: 3 had seizure semiologies including hypersalivation, facial and upper extremity clonus while the fourth underwent resection of polymicrogyria involving the opercula. Onset, severity, and resolution of dyskinesias correlated with lacosamide dosing. These cases suggest that pediatric patients with dysfunction of the opercular cortex are at increased risk for developing drug-induced dyskinesias on high-dose lacosamide therapy. Practitioners should be aware of this potential side effect and consider weaning lacosamide or video electroencephalography (EEG) for differential diagnosis, particularly in pediatric patients with underlying opercular dysfunction.

  View details for DOI 10.1177/0883073820926634

  View details for PubMedID 32524876

• Pilot Study of Neurodevelopmental Impact of Early Epilepsy Surgery in Tuberous Sclerosis Complex. Pediatric neurology Grayson, L. E., Peters, J. M., McPherson, T., Krueger, D. A., Sahin, M., Wu, J. Y., Northrup, H. A., Porter, B., Cutter, G. R., O'Kelley, S. E., Krefting, J., Stone, S. S., Madsen, J. R., Fallah, A., Blount, J. P., Weiner, H. L., Bebin, E. M., TACERN Study Group, Warfield, S. K., Goyal, M., Pearson, D. A., Williams, M. E., Hanson, E., Bing, N., Kent, B., Filip-Dhima, R., Dies, K., Bruns, S., Scherrer, B., Murray, D. S., Roberds, S. L., Capal, J. 2020

  Abstract

  BACKGROUND: To determine if early epilepsy surgery mitigates detrimental effects of refractory epilepsy on development, we investigated surgical and neurodevelopmental outcomes in children with tuberous sclerosis complex who underwent surgery before age two years.METHODS: Prospective multicenter observational study of 160 children with tuberous sclerosis complex. Surgical outcome was determined for the seizure type targeted by surgery. We obtained Vineland Adaptive Behavior Scales, Second Edition (Vineland-II); Mullen Scales of Early Learning; and Preschool Language Scales, Fifth Edition, at age three, six, nine, 12, 18, 24, and 36months. Surgical cases were compared with children without seizures, with controlled seizures, and with medically refractory seizures.RESULTS: Nineteen children underwent surgery (median age 17months, range 3.7 to 21.3), and mean follow-up was 22.8months (range 12 to 48). Surgical outcomes were favorable in 12 (63%, Engel I-II) and poor in seven (37%, Engel III-IV). Nine (47%) had new or ongoing seizures distinct from those surgically targeted. All children with seizures demonstrated longitudinal decline or attenuated gains in neurodevelopment, the surgical group scoring the lowest. Favorable surgical outcome was associated with increased Mullen Scales of Early Learning receptive and expressive language subscores compared with the medically refractory seizure group. A nonsignificant but consistent pattern of improvement with surgery was seen in all tested domains.CONCLUSIONS: These pilot data show neurodevelopmental gains in some domains following epilepsy surgery. A properly powered, prospective multicenter observational study of early epilepsy surgery is needed, using both surgical and developmental outcome metrics.

  View details for DOI 10.1016/j.pediatrneurol.2020.04.002

  View details for PubMedID 32418847

• Pathogenic Variants in CEP85L Cause Sporadic and Familial Posterior Predominant Lissencephaly. Neuron Tsai, M., Muir, A. M., Wang, W., Kang, Y., Yang, K., Chao, N., Wu, M., Chang, Y., Porter, B. E., Jansen, L. A., Sebire, G., Deconinck, N., Fan, W., Su, S., Chung, W., Almanza Fuerte, E. P., Mehaffey, M. G., University of Washington Center for Mendelian Genomics, Ng, C., Chan, C., Lim, K., Leventer, R. J., Lockhart, P. J., Riney, K., Damiano, J. A., Hildebrand, M. S., Mirzaa, G. M., Dobyns, W. B., Berkovic, S. F., Scheffer, I. E., Tsai, J., Mefford, H. C. 2020

  Abstract

  Lissencephaly (LIS), denoting a "smooth brain," is characterized by the absence of normal cerebral convolutions with abnormalities of cortical thickness. Pathogenic variants in over 20 genes are associated with LIS. The majority of posterior predominant LIS is caused by pathogenic variants in LIS1(also known as PAFAH1B1), although a significant fraction remains without a known genetic etiology. We now implicate CEP85L as an important cause ofposterior predominant LIS, identifying 13 individuals with rare, heterozygous CEP85L variants, including 2 families with autosomal dominant inheritance. We show that CEP85L is a centrosome protein localizing to the pericentriolar material, and knockdown of Cep85l causes a neuronal migration defect in mice. LIS1 also localizes to the centrosome, suggesting that this organelle is key to the mechanism of posterior predominant LIS.

  View details for DOI 10.1016/j.neuron.2020.01.027

  View details for PubMedID 32097630

• Postoperative outcomes following pediatric intracranial electrode monitoring: A case for stereoelectroencephalography (SEEG). Epilepsy & behavior : E&B Kim, L. H., Parker, J. J., Ho, A. L., Pendharkar, A. V., Sussman, E. S., Halpern, C. H., Porter, B. n., Grant, G. A. 2020; 104 (Pt A): 106905

  Abstract

  For patients with medically refractory epilepsy, intracranial electrode monitoring can help identify epileptogenic foci. Despite the increasing utilization of stereoelectroencephalography (SEEG), the relative risks or benefits associated with the technique when compared with the traditional subdural electrode monitoring (SDE) remain unclear, especially in the pediatric population. Our aim was to compare the outcomes of pediatric patients who received intracranial monitoring with SEEG or SDE (grids and strips).We retrospectively studied 38 consecutive pediatric intracranial electrode monitoring cases performed at our institution from 2014 to 2017. Medical/surgical history and operative/postoperative records were reviewed. We also compared direct inpatient hospital costs associated with the two procedures.Stereoelectroencephalography and SDE cohorts both showed high likelihood of identifying epileptogenic zones (SEEG: 90.9%, SDE: 87.5%). Compared with SDE, SEEG patients had a significantly shorter operative time (118.7 versus 233.4 min, P < .001) and length of stay (6.2 versus 12.3 days, P < .001), including days spent in the intensive care unit (ICU; 1.4 versus 5.4 days, P < .001). Stereoelectroencephalography patients tended to report lower pain scores and used significantly less narcotic pain medications (54.2 versus 197.3 mg morphine equivalents, P = .005). No complications were observed. Stereoelectroencephalography and SDE cohorts had comparable inpatient hospital costs (P = .47).In comparison with subdural electrode placement, SEEG results in a similarly favorable clinical outcome, but with reduced operative time, decreased narcotic usage, and superior pain control without requiring significantly higher costs. The potential for an improved postoperative intracranial electrode monitoring experience makes SEEG especially suitable for pediatric patients.

  View details for DOI 10.1016/j.yebeh.2020.106905

  View details for PubMedID 32028127

• Epilepsy and EEG Phenotype of SLC13A5 Citrate Transporter Disorder. Child neurology open Yang, Q. Z., Spelbrink, E. M., Nye, K. L., Hsu, E. R., Porter, B. E. 2020; 7: 2329048X20931361

  Abstract

  Mutations in the SLC13A5 gene, a sodium citrate cotransporter, cause a rare autosomal recessive epilepsy (EIEE25) that begins during the neonatal period and is associated with motor and cognitive impairment. Patient's seizure burden, semiology, and electroencephalography (EEG) findings have not been well characterized. Data on 23 patients, 3 months to 29 years of age are reported. Seizures began during the neonatal period in 22 patients. Although seizures are quite severe in many patients later in life, seizure freedom was attainable in a minority of patients. Multiple patients' chronic seizure management included a few common medications, phenobarbital and valproic acid in particular. Patients EEGs had a relatively well-preserved background for age, even in the face of frequent seizures, little slowing and multiple normal EEGs and do not support an epileptic encephalopathy. Other causes for the motor and cognitive delay beyond epilepsy warrant further study.

  View details for DOI 10.1177/2329048X20931361

  View details for PubMedID 32551328

  View details for PubMedCentralID PMC7281881

• The Epilepsy Genetics Initiative: Systematic reanalysis of diagnostic exomes increases yield EPILEPSIA Berkovic, S. F., Goldstein, D. B., Heinzen, E. L., Laughlin, B. L., Lowenstein, D. H., Lubbers, L., Stewart, R., Whittemore, V., Angione, K., Bazil, C. W., Bier, L., Bluvstein, J., Brimble, E., Campbell, C., Cavalleri, G., Chambers, C., Choi, H., Cilio, M., Ciliberto, M., Cornes, S., Delanty, N., Demarest, S., Devinsky, O., Dlugos, D., Dubbs, H., Dugan, P., Ernst, M. E., Gibbons, M., Goodkin, H. P., Helbig, I., Jansen, L., Johnson, K., Joshi, C., Lippa, N. C., Marsh, E., Martinez, A., Millichap, J., Mulhern, M. S., Numis, A., Park, K., Pippucci, T., Poduri, A., Porter, B., Regan, B., Sands, T. T., Scheffer, I. E., Schreiber, J. M., Sheidley, B., Singhal, N., Smith, L., Sullivan, J., Taylor, A., Tolete, P., Afgani, T. M., Aggarwal, V., Burgess, R., Dixon-Salazar, T., Hemati, P., Milder, J., Petrovski, S., Revah-Politi, A., Stong, N., Epilepsy Genetics Initiative, Epilepsy Genetics Initiative, EGI Steering Comm, EGI Enrollment Grp 2019; 60 (5): 797–806

  Abstract

  The Epilepsy Genetics Initiative (EGI) was formed in 2014 to create a centrally managed database of clinically generated exome sequence data. EGI performs systematic research-based reanalysis to identify new molecular diagnoses that were not possible at the time of initial sequencing and to aid in novel gene discovery. Herein we report on the efficacy of this approach 3 years after inception.One hundred sixty-six individuals with epilepsy who underwent diagnostic whole exome sequencing (WES) were enrolled, including 139 who had not received a genetic diagnosis. Sequence data were transferred to the EGI and periodically reevaluated on a research basis.Eight new diagnoses were made as a result of updated annotations or the discovery of novel epilepsy genes after the initial diagnostic analysis was performed. In five additional cases, we provided new evidence to support or contradict the likelihood of variant pathogenicity reported by the laboratory. One novel epilepsy gene was discovered through dual interrogation of research and clinically generated WES.EGI's diagnosis rate of 5.8% represents a considerable increase in diagnostic yield and demonstrates the value of periodic reinterrogation of whole exome data. The initiative's contributions to gene discovery underscore the importance of data sharing and the value of collaborative enterprises.

  View details for DOI 10.1111/epi.14698

  View details for Web of Science ID 000477643000007

  View details for PubMedID 30951195

  View details for PubMedCentralID PMC6519344

• Stereotactic laser ablation for completion corpus callosotomy. Journal of neurosurgery. Pediatrics Huang, Y. n., Yecies, D. n., Bruckert, L. n., Parker, J. J., Ho, A. L., Kim, L. H., Fornoff, L. n., Wintermark, M. n., Porter, B. n., Yeom, K. W., Halpern, C. H., Grant, G. A. 2019: 1–9

  Abstract

  Completion corpus callosotomy can offer further remission from disabling seizures when a prior partial corpus callosotomy has failed and residual callosal tissue is identified on imaging. Traditional microsurgical approaches to section residual fibers carry risks associated with multiple craniotomies and the proximity to the medially oriented motor cortices. Laser interstitial thermal therapy (LITT) represents a minimally invasive approach for the ablation of residual fibers following a prior partial corpus callosotomy. Here, the authors report clinical outcomes of 6 patients undergoing LITT for completion corpus callosotomy and characterize the radiological effects of ablation.A retrospective clinical review was performed on a series of 6 patients who underwent LITT completion corpus callosotomy for medically intractable epilepsy at Stanford University Medical Center and Lucile Packard Children's Hospital at Stanford between January 2015 and January 2018. Detailed structural and diffusion-weighted MR images were obtained prior to and at multiple time points after LITT. In 4 patients who underwent diffusion tensor imaging (DTI), streamline tractography was used to reconstruct and evaluate tract projections crossing the anterior (genu and rostrum) and posterior (splenium) parts of the corpus callosum. Multiple diffusion parameters were evaluated at baseline and at each follow-up.Three pediatric (age 8-18 years) and 3 adult patients (age 30-40 years) who underwent completion corpus callosotomy by LITT were identified. Mean length of follow-up postoperatively was 21.2 (range 12-34) months. Two patients had residual splenium, rostrum, and genu of the corpus callosum, while 4 patients had residual splenium only. Postoperative complications included asymptomatic extension of ablation into the left thalamus and transient disconnection syndrome. Ablation of the targeted area was confirmed on immediate postoperative diffusion-weighted MRI in all patients. Engel class I-II outcomes were achieved in 3 adult patients, whereas all 3 pediatric patients had Engel class III-IV outcomes. Tractography in 2 adult and 2 pediatric patients revealed time-dependent reduction of fractional anisotropy after LITT.LITT is a safe, minimally invasive approach for completion corpus callosotomy. Engel outcomes for completion corpus callosotomy by LITT were similar to reported outcomes of open completion callosotomy, with seizure reduction primarily observed in adult patients. Serial DTI can be used to assess the presence of tract projections over time but does not classify treatment responders or nonresponders.

  View details for DOI 10.3171/2019.5.PEDS19117

  View details for PubMedID 31374542

• Robot guided pediatric stereoelectroencephalography: single-institution experience JOURNAL OF NEUROSURGERY-PEDIATRICS Ho, A. L., Muftuoglu, Y., Pendharkar, A., Sussman, E. S., Porter, B. E., Halpern, C. H., Grant, G. A. 2018; 22 (5): 489–96

  View details for DOI 10.3171/2018.5.PEDS17718

  View details for Web of Science ID 000448982800004

• Robot-guided pediatric stereoelectroencephalography: single-institution experience. Journal of neurosurgery. Pediatrics Ho, A. L., Muftuoglu, Y., Pendharkar, A. V., Sussman, E. S., Porter, B. E., Halpern, C. H., Grant, G. A. 2018: 1–8

  Abstract

  OBJECTIVE Stereoelectroencephalography (SEEG) has increased in popularity for localization of epileptogenic zones in drug-resistant epilepsy because safety, accuracy, and efficacy have been well established in both adult and pediatric populations. Development of robot-guidance technology has greatly enhanced the efficiency of this procedure, without sacrificing safety or precision. To date there have been very limited reports of the use of this new technology in children. The authors present their initial experience using the ROSA platform for robot-guided SEEG in a pediatric population. METHODS Between February 2016 and October 2017, 20 consecutive patients underwent robot-guided SEEG with the ROSA robotic guidance platform as part of ongoing seizure localization and workup for medically refractory epilepsy of several different etiologies. Medical and surgical history, imaging and trajectory plans, as well as operative records were analyzed retrospectively for surgical accuracy, efficiency, safety, and epilepsy outcomes. RESULTS A total of 222 leads were placed in 20 patients, with an average of 11.1 leads per patient. The mean total case time (± SD) was 297.95 (± 52.96) minutes and the mean operating time per lead was 10.98 minutes/lead, with improvements in total (33.36 minutes/lead vs 21.76 minutes/lead) and operative (13.84 minutes/lead vs 7.06 minutes/lead) case times/lead over the course of the study. The mean radial error was 1.75 (± 0.94 mm). Clinically useful data were obtained from SEEG in 95% of cases, and epilepsy surgery was indicated and performed in 95% of patients. In patients who underwent definitive epilepsy surgery with at least a 3-month follow-up, 50% achieved an Engel class I result (seizure freedom). There were no postoperative complications associated with SEEG placement and monitoring. CONCLUSIONS In this study, the authors demonstrate that rapid adoption of robot-guided SEEG is possible even at a SEEG-naive institution, with minimal learning curve. Use of robot guidance for SEEG can lead to significantly decreased operating times while maintaining safety, the overall goals of identification of epileptogenic zones, and improved epilepsy outcomes.

  View details for PubMedID 30117789

• Normal Development of the Perineuronal Net in Humans; In Patients with and without Epilepsy NEUROSCIENCE Rogers, S. L., Rankin-Gee, E., Risbud, R. M., Porter, B. E., Marsh, E. D. 2018; 384: 350–60

  Abstract

  The perineuronal net (PN), a highly organized extracellular matrix structure, is believed to play an important role in synaptic function, including maturation and stabilization. In addition to its role in restricting plasticity, alterations in the PN are implicated in disorders such as epilepsy and schizophrenia. However, the time course of PN development is not known in humans. Therefore we set out to document the developmental timeline of the PN formation in humans in 14 frontal and hippocampal specimens from donors aged 27 days to 31 years old. Using immunohistochemistry and western blotting, we demonstrate that the PN begins to form as early as the second month of life but does not reach its robust, mature appearance until around 8 years of age, though aggrecan cleavage products are observed prior to this. A similar developmental time course was observed in specimens from epilepsy patients. Our data suggest that aggrecan is present early in development but the structured PN develops throughout early childhood, similar to what has been observed in rodents. This timeline provides information for future pathological studies on the role of the PN in disease and an additional parallel between human and rodent development.

  View details for PubMedID 29885523

• Alterations of network synchrony after epileptic seizures: An analysis of post-ictal intracranial recordings in pediatric epilepsy patients EPILEPSY RESEARCH Tomlinson, S. B., Khambhati, A. N., Bermudez, C., Kamens, R. M., Heuer, G. G., Porter, B. E., Marsh, E. D. 2018; 143: 41–49

  Abstract

  Post-ictal EEG alterations have been identified in studies of intracranial recordings, but the clinical significance of post-ictal EEG activity is undetermined. The purpose of this study was to examine the relationship between peri-ictal EEG activity, surgical outcome, and extent of seizure propagation in a sample of pediatric epilepsy patients.Intracranial EEG recordings were obtained from 19 patients (mean age = 11.4 years, range = 3-20 years) with 57 seizures used for analysis (mean = 3.0 seizures per patient). For each seizure, 3-min segments were extracted from adjacent pre-ictal and post-ictal epochs. To compare physiology of the epileptic network between epochs, we calculated the relative delta power (Δ) using discrete Fourier transformation and constructed functional networks based on broadband connectivity (conn). We investigated differences between the pre-ictal (Δpre, connpre) and post-ictal (Δpost, connpost) segments in focal-network (i.e., confined to seizure onset zone) versus distributed-network (i.e., diffuse ictal propagation) seizures.Distributed-network (DN) seizures exhibited increased post-ictal delta power and global EEG connectivity compared to focal-network (FN) seizures. Following DN seizures, patients with seizure-free outcomes exhibited a 14.7% mean increase in delta power and an 8.3% mean increase in global connectivity compared to pre-ictal baseline, which was dramatically less than values observed among seizure-persistent patients (29.6% and 47.1%, respectively).Post-ictal differences between DN and FN seizures correlate with post-operative seizure persistence. We hypothesize that post-ictal deactivation of subcortical nuclei recruited during seizure propagation may account for this result while lending insights into mechanisms of post-operative seizure recurrence.

  View details for DOI 10.1016/j.eplepsyres.2018.04.003

  View details for Web of Science ID 000435047800007

  View details for PubMedID 29655171

• Somatic SLC35A2 variants in the brain are associated with intractable neocortical epilepsy ANNALS OF NEUROLOGY Winawer, M. R., Griffin, N. G., Samanamud, J., Baugh, E. H., Rathakrishnan, D., Ramalingam, S., Zagzag, D., Schevon, C. A., Dugan, P., Hegde, M., Sheth, S. A., McKhann, G. M., Doyle, W. K., Grant, G. A., Porter, B. E., Mikati, M. A., Muh, C. R., Malone, C. D., Bergin, A. R., Peters, J. M., McBrian, D. K., Pack, A. M., Akman, C. I., LaCoursiere, C. M., Keever, K. M., Madsen, J. R., Yang, E., Lidov, H. W., Shain, C., Allen, A. S., Canoll, P. D., Crino, P. B., Poduri, A. H., Heinzen, E. L. 2018; 83 (6): 1133–46

  Abstract

  Somatic variants are a recognized cause of epilepsy-associated focal malformations of cortical development (MCD). We hypothesized that somatic variants may underlie a wider range of focal epilepsy, including nonlesional focal epilepsy (NLFE). Through genetic analysis of brain tissue, we evaluated the role of somatic variation in focal epilepsy with and without MCD.We identified somatic variants through high-depth exome and ultra-high-depth candidate gene sequencing of DNA from epilepsy surgery specimens and leukocytes from 18 individuals with NLFE and 38 with focal MCD.We observed somatic variants in 5 cases in SLC35A2, a gene associated with glycosylation defects and rare X-linked epileptic encephalopathies. Nonsynonymous variants in SLC35A2 were detected in resected brain, and absent from leukocytes, in 3 of 18 individuals (17%) with NLFE, 1 female and 2 males, with variant allele frequencies (VAFs) in brain-derived DNA of 2 to 14%. Pathologic evaluation revealed focal cortical dysplasia type Ia (FCD1a) in 2 of the 3 NLFE cases. In the MCD cohort, nonsynonymous variants in SCL35A2 were detected in the brains of 2 males with intractable epilepsy, developmental delay, and magnetic resonance imaging suggesting FCD, with VAFs of 19 to 53%; Evidence for FCD was not observed in either brain tissue specimen.We report somatic variants in SLC35A2 as an explanation for a substantial fraction of NLFE, a largely unexplained condition, as well as focal MCD, previously shown to result from somatic mutation but until now only in PI3K-AKT-mTOR pathway genes. Collectively, our findings suggest a larger role than previously recognized for glycosylation defects in the intractable epilepsies. Ann Neurol 2018.

  View details for DOI 10.1002/ana.25243

  View details for Web of Science ID 000439994300008

  View details for PubMedID 29679388

• Clinical and electrographic features of sunflower syndrome EPILEPSY RESEARCH Baumer, F. M., Porter, B. E. 2018; 142: 58–63

  View details for DOI 10.1016/j.eplepsyres.2018.03.002

  View details for Web of Science ID 000433015700009

• Refractory focal epilepsy in a paediatric patient with primary familial brain calcification SEIZURE-EUROPEAN JOURNAL OF EPILEPSY Knowles, J. K., Santoro, J. D., Porter, B. E., Baumer, F. M. 2018; 56: 50–52

  View details for DOI 10.1016/j.seizure.2018.02.001

  View details for Web of Science ID 000430893400011

• De novo variants in the alternative exon 5 of SCN8A cause epileptic encephalopathy GENETICS IN MEDICINE Berkovic, S. F., Dixon-Salazar, T., Goldstein, D. B., Heinzen, E. L., Laughlin, B. L., Lowenstein, D. H., Lubbers, L., Milder, J., Stewart, R., Whittemore, V., Angione, K., Bazil, C. W., Bier, L., Bluvstein, J., Brimble, E., Campbell, C., Chambers, C., Choi, H., Cilio, M., Ciliberto, M., Cornes, S., Delanty, N., Demarest, S., Devinsky, O., Dlugos, D., Dubbs, H., Dugan, P., Ernst, M. E., Gallentine, W., Gibbons, M., Goodkin, H., Grinton, B., Helbig, I., Jansen, L., Johnson, K., Joshi, C., Lippa, N. C., Makati, M. A., Marsh, E., Martinez, A., Millichap, J., Moskovich, Y., Mulhern, M. S., Numis, A., Park, K., Poduri, A., Porter, B., Sands, T. T., Scheffer, I. E., Sheidley, B., Singhal, N., Smith, L., Sullivan, J., Riviello, J. J., Taylor, A., Tolete, P., Epilepsy Genetics Initiative 2018; 20 (2): 275–81

  Abstract

  PurposeAs part of the Epilepsy Genetics Initiative, we re-evaluated clinically generated exome sequence data from 54 epilepsy patients and their unaffected parents to identify molecular diagnoses not provided in the initial diagnostic interpretation.MethodsWe compiled and analyzed exome sequence data from 54 genetically undiagnosed trios using a validated analysis pipeline. We evaluated the significance of the genetic findings by reanalyzing sequence data generated at Ambry Genetics, and from a number of additional case and control cohorts.ResultsIn 54 previously undiagnosed trios, we identified two de novo missense variants in SCN8A in the highly expressed alternative exon 5 A-an exon only recently added to the Consensus Coding Sequence database. One additional undiagnosed epilepsy patient harboring a de novo variant in exon 5 A was found in the Ambry Genetics cohort. Missense variants in SCN8A exon 5 A are extremely rare in the population, further supporting the pathogenicity of the de novo alterations identified.ConclusionThese results expand the range of SCN8A variants in epileptic encephalopathy patients and illustrate the necessity of ongoing reanalysis of negative exome sequences, as advances in the knowledge of disease genes and their annotations will permit new diagnoses to be made.

  View details for DOI 10.1038/gim.2017.100

  View details for Web of Science ID 000425939300013

  View details for PubMedID 29121005

  View details for PubMedCentralID PMC5823708

• Clinical and electrographic features of sunflower syndrome. Epilepsy research Baumer, F. M., Porter, B. E. 2018; 142: 58–63

  Abstract

  Sunflower Syndrome describes reflex seizures - typically eyelid myoclonia with or without absence seizures - triggered when patients wave their hands in front of the sun. While valproate has been recognized as the best treatment for photosensitive epilepsy, many clinicians now initially treat with newer medications; the efficacy of these medications in Sunflower Syndrome has not been investigated. We reviewed all cases of Sunflower Syndrome seen at our institution over 15 years to describe the clinical course, electroencephalogram (EEG), and treatment response in these patients.Search of the electronic medical record and EEG database, as well as survey of epilepsy providers at our institution, yielded 13 cases of Sunflower Syndrome between 2002 and 2017. We reviewed the records and EEG tracings.Patients were mostly young females, with an average age of onset of 5.5 years. Seven had intellectual, attentional or academic problems. Self-induced seizures were predominantly eyelid myoclonia ± absences and 6 subjects also had spontaneous seizures. EEG demonstrated a normal background with 3-4 Hz spike waves ± polyspike waves as well as a photoparoxysmal response. Based on both clinical and EEG response, valproate was the most effective treatment for reducing or eliminating seizures and improving the EEG; 9 patients tried valproate and 66% had significant improvement or resolution of seizures. None of the nine patients on levetiracetam or seven patients on lamotrigine monotherapy achieved seizure control, though three patients had improvement with polypharmacy.Valproate monotherapy continues to be the most effective treatment for Sunflower Syndrome and should be considered early. For patients who cannot tolerate valproate, higher doses of lamotrigine or polypharmacy should be considered. Levetiracetam monotherapy, even at high doses, is unlikely to be effective.

  View details for PubMedID 29555355

• Delay in pediatric epilepsy surgery: A caregiver's perspective. Epilepsy & behavior : E&B Shen, A. n., Quaid, K. T., Porter, B. E. 2018; 78: 175–78

  Abstract

  The timing of epilepsy surgery is complex, and there is not a structured pathway to help families decide whether to continue medical management or pursue surgical treatment. We surveyed caregivers of pediatric epilepsy surgery patients. Fifty-eight respondents answered the majority of questions. Thirty caregivers wished their child had undergone epilepsy surgery earlier compared with twenty who felt surgery was done at the appropriate time, and eight were unsure. In retrospect, caregivers who wished their child's surgery had been performed sooner had a significantly longer duration of epilepsy prior to the surgery [44.1±71.7 (months±standard deviation (SD), N=27)], compared with those who felt content with the timing of the surgery [12.8±14.1 (months±SD, N=20), p=0.0034]. Caregivers were willing to accept a lower likelihood of seizure freedom than their physician reported was likely. Most caregivers were willing to accept deficits in all domains surveyed; caregivers had high acceptance of motor deficits, cognitive deficits, behavioral change, and language loss. Future studies are needed to focus on how to improve the education of caregivers and neurologists about the benefits and risks of epilepsy surgery and accelerate the pipeline to epilepsy surgery to improve caregiver satisfaction.

  View details for PubMedID 29126702

• Language Dysfunction in Pediatric Epilepsy. The Journal of pediatrics Baumer, F. M., Cardon, A. L., Porter, B. E. 2018; 194: 13–21

  View details for PubMedID 29241678

• Refractory focal epilepsy in a paediatric patient with primary familial brain calcification. Seizure Knowles, J. K., Santoro, J. D., Porter, B. E., Baumer, F. M. 2018; 56: 50–52

  Abstract

  Primary familial brain calcification (PFBC), otherwise known as Fahr's disease, is a rare autosomal dominant condition with manifestations of movement disorders, neuropsychiatric symptoms, and epilepsy in a minority of PFBC patients. The clinical presentation of epilepsy in PFBC has not been described in detail. We present a paediatric patient with PFBC and refractory focal epilepsy based on seizure semiology and ictal EEG, but with generalized interictal EEG abnormalities. The patient was found to have a SLC20A2 mutation known to be pathogenic in PFBC, as well as a variant of unknown significance in SCN2A. This case demonstrates that the ictal EEG is important for accurately classifying epilepsy in affected subjects with PFBC. Further, epilepsy in PFBC may be a polygenic disorder.

  View details for PubMedID 29448117

• Clinical spectrum and genotype-phenotype associations of KCNA2-related encephalopathies BRAIN Masnada, S., Hedrich, U. S., Gardella, E., Schubert, J., Kaiwar, C., Klee, E. W., Lanpher, B. C., Gavrilova, R. H., Synofzik, M., Bast, T., Gorman, K., King, M. D., Allen, N. M., Conroy, J., Ben Zeev, B., Tzadok, M., Korff, C., Dubois, F., Ramsey, K., Narayanan, V., Serratosa, J. M., Giraldez, B. G., Helbig, I., Marsh, E., O'Brien, M., Bergqvist, C. A., Binelli, A., Porter, B., Zaeyen, E., Horovitz, D. D., Wolff, M., Marjanovic, D., Caglayan, H. S., Arslan, M., Pena, S. J., Sisodiya, S. M., Balestrini, S., Syrbe, S., Veggiotti, P., Lemke, J. R., Moller, R. S., Lerche, H., Rubboli, G. 2017; 140: 2337–54

  Abstract

  Recently, de novo mutations in the gene KCNA2, causing either a dominant-negative loss-of-function or a gain-of-function of the voltage-gated K+ channel Kv1.2, were described to cause a new molecular entity within the epileptic encephalopathies. Here, we report a cohort of 23 patients (eight previously described) with epileptic encephalopathy carrying either novel or known KCNA2 mutations, with the aim to detail the clinical phenotype associated with each of them, to characterize the functional effects of the newly identified mutations, and to assess genotype-phenotype associations. We identified five novel and confirmed six known mutations, three of which recurred in three, five and seven patients, respectively. Ten mutations were missense and one was a truncation mutation; de novo occurrence could be shown in 20 patients. Functional studies using a Xenopus oocyte two-microelectrode voltage clamp system revealed mutations with only loss-of-function effects (mostly dominant-negative current amplitude reduction) in eight patients or only gain-of-function effects (hyperpolarizing shift of voltage-dependent activation, increased amplitude) in nine patients. In six patients, the gain-of-function was diminished by an additional loss-of-function (gain-and loss-of-function) due to a hyperpolarizing shift of voltage-dependent activation combined with either decreased amplitudes or an additional hyperpolarizing shift of the inactivation curve. These electrophysiological findings correlated with distinct phenotypic features. The main differences were (i) predominant focal (loss-of-function) versus generalized (gain-of-function) seizures and corresponding epileptic discharges with prominent sleep activation in most cases with loss-of-function mutations; (ii) more severe epilepsy, developmental problems and ataxia, and atrophy of the cerebellum or even the whole brain in about half of the patients with gain-of-function mutations; and (iii) most severe early-onset phenotypes, occasionally with neonatal onset epilepsy and developmental impairment, as well as generalized and focal seizures and EEG abnormalities for patients with gain- and loss-of-function mutations. Our study thus indicates well represented genotype-phenotype associations between three subgroups of patients with KCNA2 encephalopathy according to the electrophysiological features of the mutations.

  View details for PubMedID 29050392

• Analyses of SLC13A5-epilepsy patients reveal perturbations of TCA cycle MOLECULAR GENETICS AND METABOLISM Bainbridge, M. N., Cooney, E., Miller, M., Kennedy, A. D., Wulff, J. E., Donti, T., Jhangiani, S. N., Gibbs, R. A., Elsea, S. H., Porter, B. E., Graham, B. H. 2017; 121 (4): 314–19

  Abstract

  To interrogate the metabolic profile of five subjects from three families with rare, nonsense and missense mutations in SLC13A5 and Early Infantile Epileptic Encephalopathies (EIEE) characterized by severe, neonatal onset seizures, psychomotor retardation and global developmental delay.Mass spectrometry of plasma, CSF and urine was used to identify consistently dysregulated analytes in our subjects.Distinctive elevations of citrate and dysregulation of citric acid cycle intermediates, supporting the hypothesis that loss of SLC13A5 function alters tricarboxylic acid cycle (TCA) metabolism and may disrupt metabolic compartmentation in the brain.Our results indicate that analysis of plasma citrate and other TCA analytes in SLC13A5 deficient patients define a diagnostic metabolic signature that can aid in diagnosing children with this disease.

  View details for PubMedID 28673551

• R-SCAN: Imaging for Pediatric Simple Febrile Seizures. Journal of the American College of Radiology Lee, S., Fisher, P., Grant, G. A., Porter, B., Dannenberg, B., Wintermark, M. 2017

  View details for DOI 10.1016/j.jacr.2017.04.007

  View details for PubMedID 28551342

• Increased metalloproteinase activity in the hippocampus following status epilepticus EPILEPSY RESEARCH Dubey, D., McRae, P. A., Rankin-Gee, E. K., Baranov, E., Wandrey, L., Rogers, S., Porter, B. E. 2017; 132: 50-58

  Abstract

  Increased neuronal plasticity and neuronal cell loss has been implicated in the development of epilepsy following injury. Parvalbumin fast spiking inhibitory interneurons have a robust extracellular matrix coating their cell bodies and the proximal dendrites called the perineuronal net (PNN). The role of the PNN is not clear but it has been implicated in closing of the critical period, altering seizure thresholds and providing neuronal protection from oxidative stress. The PNN is susceptible to degradation following a prolonged seizure and there is an increase in proteolytic-fragments of the PNN enriched proteoglycan aggrecan (Dzwonek et al., 2004). Here we demonstrate an increase in matrix metalloproteinase (MMP) activity in the hippocampus following status epilepticus (SE). We further assessed MMP3 and 13, two of 24 identified MMPs, both MMP3 and 13 mRNA increase in the hippocampus after SE and MMP13 activity increases by functional assay as well as it co-localizes with PNN in rat brain. In contrast, two of the brain expressed ADAMTS (A Disintegrin And Metalloproteinase with ThromboSpondin motifs) also implicated in aggrecan degradation, did not consistently increase following SE though ADAMTS4 is highly expressed in glia and ADAMTS5 in neuronal cell bodies and their processes. The increase in MMP activity following SE suggests that in the future studies, MMP inhibitors are candidates for blocking PNN degradation and assessing the role of the PNN loss in epileptogenesis and cellular function.

  View details for DOI 10.1016/j.eplepsyres.2017.02.021

  View details for PubMedID 28292736

• Interictal network synchrony and local heterogeneity predict seizure relief following pediatric epilepsy surgery Tomlinson, S., Marsh, E., Porter, B. LIPPINCOTT WILLIAMS & WILKINS. 2017

  View details for Web of Science ID 000577381506018

• Interictal network synchrony and local heterogeneity predict epilepsy surgery outcome among pediatric patients EPILEPSIA Tomlinson, S. B., Porter, B. E., Marsh, E. D. 2017; 58 (3): 402–11

  Abstract

  Epilepsy is a disorder of aberrant cortical networks. Researchers have proposed that characterizing presurgical network connectivity may improve the surgical management of intractable seizures, but few studies have rigorously examined the relationship between network activity and surgical outcome. In this study, we assessed whether local and global measures of network activity differentiated patients with favorable (seizure-free) versus unfavorable (seizure-persistent) surgical outcomes.Seventeen pediatric intracranial electroencephalography (IEEG) patients were retrospectively examined. For each patient, 1,200 random interictal epochs of 1-s duration were analyzed. Functional connectivity networks were constructed using an amplitude-based correlation technique (Spearman correlation). Global network synchrony was computed as the average pairwise connectivity strength. Local signal heterogeneity was defined for each channel as the variability of EEG amplitude (root mean square) and absolute delta power (μV2 /Hz) across epochs. A support vector machine learning algorithm used global and local measures to classify patients by surgical outcome. Classification was assessed using the Leave-One-Out (LOO) permutation test.Global synchrony was increased in the seizure-persistent group compared to seizure-free patients (Student's t-test, p = 0.006). Seizure-onset zone (SOZ) electrodes exhibited increased signal heterogeneity compared to non-SOZ electrodes, primarily in seizure-persistent patients. Global synchrony and local heterogeneity measures were used to accurately classify 16 (94.1%) of 17 patients by surgical outcome (LOO test, iterations = 10,000, p < 0.001).Measures of global network synchrony and local signal heterogeneity represent promising biomarkers for assessing patient candidacy in pediatric epilepsy surgery.

  View details for DOI 10.1111/epi.13657

  View details for Web of Science ID 000398806800011

  View details for PubMedID 28166392

• Spatiotemporal Mapping of Interictal Spike Propagation: A Novel Methodology Applied to Pediatric Intracranial EEG Recordings FRONTIERS IN NEUROLOGY Tomlinson, S. B., Bermudez, C., Conley, C., Brown, M. W., Porter, B. E., Marsh, E. D. 2016; 7

  Abstract

  Synchronized cortical activity is implicated in both normative cognitive functioning and many neurologic disorders. For epilepsy patients with intractable seizures, irregular synchronization within the epileptogenic zone (EZ) is believed to provide the network substrate through which seizures initiate and propagate. Mapping the EZ prior to epilepsy surgery is critical for detecting seizure networks in order to achieve postsurgical seizure control. However, automated techniques for characterizing epileptic networks have yet to gain traction in the clinical setting. Recent advances in signal processing and spike detection have made it possible to examine the spatiotemporal propagation of interictal spike discharges across the epileptic cortex. In this study, we present a novel methodology for detecting, extracting, and visualizing spike propagation and demonstrate its potential utility as a biomarker for the EZ. Eighteen presurgical intracranial EEG recordings were obtained from pediatric patients ultimately experiencing favorable (i.e., seizure-free, n = 9) or unfavorable (i.e., seizure-persistent, n = 9) surgical outcomes. Novel algorithms were applied to extract multichannel spike discharges and visualize their spatiotemporal propagation. Quantitative analysis of spike propagation was performed using trajectory clustering and spatial autocorrelation techniques. Comparison of interictal propagation patterns revealed an increase in trajectory organization (i.e., spatial autocorrelation) among Sz-Free patients compared with Sz-Persist patients. The pathophysiological basis and clinical implications of these findings are considered.

  View details for DOI 10.3389/fneur.2016.00229

  View details for Web of Science ID 000390169100001

  View details for PubMedID 28066315

  View details for PubMedCentralID PMC5165024

• Increased precursor microRNA-21 following status epilepticus can compete with mature microRNA-21 to alter translation. Experimental neurology Chak, K., Roy-Chaudhuri, B., Kim, H. K., Kemp, K. C., Porter, B. E., Kay, M. A. 2016; 286: 137-146

  Abstract

  MicroRNA-21 (miR-21) is consistently up-regulated in various neurological disorders, including epilepsy. Here, we show that the biogenesis of miR-21 is altered following pilocarpine-induced status epilepticus (SE) with an increase in precursor miR-21 (pre-miR-21) in rats. We demonstrate that pre-miR-21 has an energetically favorable site overlapping with the miR-21 binding site and competes with mature miR-21 for binding in the 3'UTR of TGFBR2 mRNA, but not NT-3 mRNA in vitro. This binding competition influences miR-21-mediated repression in vitro and correlates with the increase in TGFBR2 and decrease in NT-3 following SE. Polysome profiling reveals co-localization of pre-miR-21 in the ribosome fraction with translating mRNAs in U-87 cells. The current work suggests that pre-miR-21 may post-transcriptionally counteract miR-21-mediated suppression following SE and could potentially lead to prolonged TGF-β receptor expression impacting epileptogenesis. The study further supports that the ratio of the pre to mature miRNA may be important in determining the regulatory effects of a miRNA gene.

  View details for DOI 10.1016/j.expneurol.2016.10.003

  View details for PubMedID 27725160

• KCNQ2 encephalopathy Features, mutational hot spots, and ezogabine treatment of 11 patients NEUROLOGY-GENETICS Millichap, J. J., Park, K. L., Tsuchida, T., Ben-Zeev, B., Carmant, L., Flamini, R., Joshi, N., Levisohn, P. M., Marsh, E., Nangia, S., Narayanan, V., Ortiz-Gonzalez, X. R., Patterson, M. C., Pearl, P. L., Porter, B., Ramsey, K., McGinnis, E. L., Taglialatela, M., Tracy, M., Baouyen Tran, Venkatesan, C., Weckhuysen, S., Cooper, E. C., RIKEE Consortium 2016; 2 (5): e96

  Abstract

  To advance the understanding of KCNQ2 encephalopathy genotype-phenotype relationships and to begin to assess the potential of selective KCNQ channel openers as targeted treatments.We retrospectively studied 23 patients with KCNQ2 encephalopathy, including 11 treated with ezogabine (EZO). We analyzed the genotype-phenotype relationships in these and 70 previously described patients.The mean seizure onset age was 1.8 ± 1.6 (SD) days. Of the 20 EEGs obtained within a week of birth, 11 showed burst suppression. When new seizure types appeared in infancy (15 patients), the most common were epileptic spasms (n = 8). At last follow-up, seizures persisted in 9 patients. Development was delayed in all, severely in 14. The KCNQ2 variants identified introduced amino acid missense changes or, in one instance, a single residue deletion. They were clustered in 4 protein subdomains predicted to poison tetrameric channel functions. EZO use (assessed by the treating physicians and parents) was associated with improvement in seizures and/or development in 3 of the 4 treated before 6 months of age, and 2 of the 7 treated later; no serious side effects were observed.KCNQ2 variants cause neonatal-onset epileptic encephalopathy of widely varying severity. Pathogenic variants in epileptic encephalopathy are clustered in "hot spots" known to be critical for channel activity. For variants causing KCNQ2 channel loss of function, EZO appeared well tolerated and potentially beneficial against refractory seizures when started early. Larger, prospective studies are needed to enable better definition of prognostic categories and more robust testing of novel interventions.This study provides Class IV evidence that EZO is effective for refractory seizures in patients with epilepsy due to KCNQ2 encephalopathy.

  View details for DOI 10.1212/NXG.0000000000000096

  View details for Web of Science ID 000445340800003

  View details for PubMedID 27602407

  View details for PubMedCentralID PMC4995058

• Diagnosis of adenylosuccinate lyase deficiency by metabolomic profiling in plasma reveals a phenotypic spectrum. Molecular genetics and metabolism reports Donti, T. R., Cappuccio, G., Hubert, L., Neira, J., Atwal, P. S., Miller, M. J., Cardon, A. L., Sutton, V. R., Porter, B. E., Baumer, F. M., Wangler, M. F., Sun, Q., Emrick, L. T., Elsea, S. H. 2016; 8: 61-66

  Abstract

  Adenylosuccinate lyase (ADSL) deficiency is a rare autosomal recessive neurometabolic disorder that presents with a broad-spectrum of neurological and physiological symptoms. The ADSL gene produces an enzyme with binary molecular roles in de novo purine synthesis and purine nucleotide recycling. The biochemical phenotype of ADSL deficiency, accumulation of SAICAr and succinyladenosine (S-Ado) in biofluids of affected individuals, serves as the traditional target for diagnosis with targeted quantitative urine purine analysis employed as the predominate method of detection. In this study, we report the diagnosis of ADSL deficiency using an alternative method, untargeted metabolomic profiling, an analytical scheme capable of generating semi-quantitative z-score values for over 1000 unique compounds in a single analysis of a specimen. Using this method to analyze plasma, we diagnosed ADSL deficiency in four patients and confirmed these findings with targeted quantitative biochemical analysis and molecular genetic testing. ADSL deficiency is part of a large a group of neurometabolic disorders, with a wide range of severity and sharing a broad differential diagnosis. This phenotypic similarity among these many inborn errors of metabolism (IEMs) has classically stood as a hurdle in their initial diagnosis and subsequent treatment. The findings presented here demonstrate the clinical utility of metabolomic profiling in the diagnosis of ADSL deficiency and highlights the potential of this technology in the diagnostic evaluation of individuals with neurologic phenotypes.

  View details for DOI 10.1016/j.ymgmr.2016.07.007

  View details for PubMedID 27504266

  View details for PubMedCentralID PMC4969260

• A Potential Role for Glia-Derived Extracellular Matrix Remodeling in Postinjury Epilepsy JOURNAL OF NEUROSCIENCE RESEARCH Kim, S. Y., Porter, B. E., Friedman, A., Kaufer, D. 2016; 94 (9): 794-803

  Abstract

  Head trauma and vascular injuries are known risk factors for acquired epilepsy. The sequence of events that lead from the initial injury to the development of epilepsy involves complex plastic changes and circuit rewiring. In-depth, comprehensive understanding of the epileptogenic process is critical for the identification of disease-modifying targets. Here we review the complex interactions of cellular and extracellular components that may promote epileptogenesis, with an emphasis on the role of astrocytes. Emerging evidence demonstrates that astrocytes promptly respond to brain damage and play a critical role in the development of postinjury epilepsy. Astrocytes have been shown to regulate extracellular matrix (ECM) remodeling, which can affect plasticity and stability of synapses and, in turn, contribute to the epileptogenic process. From these separate lines of evidence, we present a hypothesis suggesting a possible role for astrocyte-regulated remodeling of ECM and perineuronal nets, a specialized ECM structure around fast-spiking inhibitory interneurons, in the development and progression of posttraumatic epilepsies. © 2016 Wiley Periodicals, Inc.

  View details for DOI 10.1002/jnr.23758

  View details for PubMedID 27265805

• Plasma taurine levels are not affected by vigabatrin in pediatric patients. Epilepsia Spelbrink, E. M., Mabud, T. S., Reimer, R., Porter, B. E. 2016; 57 (8): e168-72

  Abstract

  Vigabatrin is a highly effective antiseizure medication, but its use is limited due to concerns about retinal toxicity. One proposed mechanism for this toxicity is vigabatrin-mediated reduction of taurine. Herein we assess plasma taurine levels in a retrospective cohort of children with epilepsy, including a subset receiving vigabatrin. All children who underwent a plasma amino acid analysis as part of their clinical evaluation between 2006 and 2015 at Stanford Children's Health were included in the analysis. There were no significant differences in plasma taurine levels between children taking vigabatrin (n = 16), children taking other anti-seizure medications, and children not taking any anti-seizure medication (n = 556) (analysis of variance [ANOVA] p = 0.841). There were, however, age-dependent decreases in plasma taurine levels. Multiple linear regression revealed no significant association between vigabatrin use and plasma taurine level (p = 0.87) when controlling for age. These results suggest that children taking vigabatrin maintain normal plasma taurine levels, although they leave unanswered whether taurine supplementation is necessary or sufficient to prevent vigabatrin-associated visual field loss. They also indicate that age should be taken into consideration when evaluating taurine levels in young children.

  View details for DOI 10.1111/epi.13447

  View details for PubMedID 27344989

• CRTC1 NUCLEAR LOCALIZATION IN THE HIPPOCAMPUS OF THE PILOCARPINE-INDUCED STATUS EPILEPTICUS MODEL OF TEMPORAL LOBE EPILEPSY NEUROSCIENCE Dubey, D., Porter, B. E. 2016; 320: 57-68

  Abstract

  cAMP response-element binding protein (CREB)-dependent genes are differentially expressed in brains of temporal lobe epilepsy (TLE) patients and also in animal models of TLE. Previous studies have demonstrated the importance of CREB regulated transcription in TLE. However, the role of the key regulator of CREB activity, CREB-regulated transcription coactivator 1 (CRTC1), has not been explored in epilepsy. In the present study the pilocarpine-induced status epilepticus (SE) model of TLE was used to study the regulation of CRTC1 during and following SE. Nuclear translocation of CRTC1 is critical for its transcriptional activity, and dephosphorylation at serine 151 residue via calcineurin phosphatase regulates cytoplasmic to nuclear transit of CRTC1. Here, we examined the localization and phosphorylation (Ser151) of CRTC1 in SE-induced rat hippocampus at two different time points after SE onset. One hour after SE onset, we found that CRTC1 translocates to the nucleus of CA1 neurons but not CA3 or dentate granule neurons. We further found that this CRTC1 nuclear localization is independent of Ser151 dephosphorylation since we did not detect any difference in dephosphorylation of Ser151 between control and SE animals at this time point. In contrast, 48h after SE CRTC1 shows increased nuclear localization in the dentate gyrus (DG) of the SE-induced rats. At 48h after SE, FK506 treatment blocked CRTC1 nuclear localization and dephosphorylation of Ser151. Our results provide evidence that CREB cofactor CRTC1 translocates into the nucleus of a distinct subset of hippocampal neurons during and following SE and this translocalization is regulated by calcineurin at a later time point following SE. Nuclear CRTC1 can bind to CREB possibly altering transcription during epileptogenesis.

  View details for DOI 10.1016/j.neuroscience.2016.01.059

  View details for Web of Science ID 000371834500006

  View details for PubMedID 26844388

• Mutations in the Na(+)/citrate cotransporter NaCT (SLC13A5) in pediatric patients with epilepsy and developmental delay. Molecular medicine Klotz, J., Porter, B. E., Colas, C., Schlessinger, A., Pajor, A. M. 2016; 22

  Abstract

  Mutations in the SLC13A5 gene that codes for the Na(+)/citrate cotransporter, NaCT, are associated with early onset epilepsy, developmental delay and tooth dysplasia in children. In the present study we identify additional SLC13A5 mutations in nine epilepsy patients from six families. To better characterize the syndrome, families with affected children answered questions about the scope of illness and treatment strategies. There are currently no effective treatments, but some anti-epileptic drugs targeting the GABA system reduce seizure frequency. Acetazolamide, a carbonic anhydrase inhibitor and atypical anti-seizure medication decreases seizures in 4 patients. In contrast to previous reports, the ketogenic diet and fasting produce worsening of symptoms. The effects of the mutations on NaCT transport function and protein expression were examined by transient transfections of COS-7 cells. There was no transport activity from any of the mutant transporters, although some of the mutant transporter proteins were present on the plasma membrane. The structural model of NaCT suggests that these mutations can affect helix packing or substrate binding. We tested various treatments, including chemical chaperones and low temperatures, but none improve transport function in the NaCT mutants. Interestingly, coexpression of NaCT and the mutants results in decreased protein expression and activity of the wild-type transporter, indicating functional interaction. In conclusion, our study has identified additional SLC13A5 mutations in patients with chronic epilepsy starting in the neonatal period, with the mutations producing inactive Na(+)/citrate transporters.

  View details for DOI 10.2119/molmed.2016.00077

  View details for PubMedID 27261973

• Suppressing cAMP response element-binding protein transcription shortens the duration of status epilepticus and decreases the number of spontaneous seizures in the pilocarpine model of epilepsy EPILEPSIA Zhu, X., Dubey, D., Bermudez, C., Porter, B. E. 2015; 56 (12): 1870-1878

  Abstract

  Current epilepsy therapies directed at altering the function of neurotransmitter receptors or ion channels, or release of synaptic vesicles fail to prevent seizures in approximately 30% of patients. A better understanding of the molecular mechanism underlying epilepsy is needed to provide new therapeutic targets. The activity of cyclic AMP (cAMP) response element-binding protein (CREB), a major transcription factor promoting CRE-mediated transcription, increases following a prolonged seizure called status epilepticus. It is also increased in the seizure focus of patients with medically intractable focal epilepsy. Herein we explored the effect of acute suppression of CREB activity on status epilepticus and spontaneous seizures in a chronic epilepsy model.Pilocarpine chemoconvulsant was used to induce status epilepticus. To suppress CREB activity, a transgenic mouse line expressing an inducible dominant negative mutant of CREB (CREB(IR) ) with a serine to alanine 133 substitution was used. Status epilepticus and spontaneous seizures of transgenic and wild-type mice were analyzed using video-electroencephalography (EEG) to assess the effect of CREB suppression on seizures.Our findings indicate that activation of CREB(IR) shortens the duration of status epilepticus. The frequency of spontaneous seizures decreased in mice with chronic epilepsy during CREB(IR) induction; however, the duration of the spontaneous seizures was unchanged. Of interest, we found significantly reduced levels of phospho-CREB Ser133 upon activation of CREB(IR) , supporting prior work suggesting that binding to the CRE site is important for CREB phosphorylation.Our results suggest that CRE transcription supports seizure activity both during status epilepticus and in spontaneous seizures. Thus, blocking of CRE transcription is a novel target for the treatment of epilepsy.

  View details for DOI 10.1111/epi.13211

  View details for PubMedID 26419901

• INCREASED SENSITIVITY TO KINDLING IN MICE LACKING TSP1 NEUROSCIENCE Mendus, D., Rankin-Gee, E. K., Mustapha, M., Porter, B. E. 2015; 305: 302-308

  Abstract

  The development of a hyperexcitable neuronal network is thought to be a critical event in epilepsy. Thrombospondins (TSPs) regulate synaptogenesis by binding the neuronal α2δ subunit of the voltage-gated calcium channel. TSPs regulate synapse formation during development and in the mature brain following injury. It is unclear if TSPs are involved in hyperexcitability that contributes to the development of epilepsy. Here we explore the development of epilepsy using a pentylenetetrazole (PTZ) kindling model in mice lacking TSP1 and TSP2. Unexpectedly, we found increased sensitivity to PTZ kindling in mice lacking TSP1, while mice lacking TSP2 kindled similar to wild-type. We found that the increased seizure susceptibility in the TSP1 knockout (KO) mice was not due to a compensatory increase in TSP2 mRNA as TSP1/2 KO mice were sensitive to PTZ, similar to the TSP1 KO mice. Furthermore, there were similar levels of TGF-B signal activation during kindling in the TSP1 KO mice compared to wild-type. We observed decreased expression of voltage-dependent calcium channel subunit CACNA2D1 mRNA in TSP1, TSP2, and TSP1/2 KO mice. Decreased CACNA2D2 mRNA was only detected in mice that lacked TSP1 and α2δ-1/2 protein levels in the cortex were lower in the TSP 1/2 KO mice. CACNA2D2 knockout mice have spontaneous seizures and increased PTZ seizure susceptibility. Here we report similar findings, TSP1, and TSP1/2 KO mice have low levels of CACNA2D2 mRNA expression and α2δ-1/2 receptor level in the cortex, and are more susceptible to seizures. CACNA2D2 mutations in mice and humans can cause epilepsy. Our data suggest TSP1 in particular may control CACNA2D2 levels and could be a modifier of seizure susceptibility.

  View details for DOI 10.1016/j.neuroscience.2015.07.075

  View details for Web of Science ID 000360547100027

• Perineuronal net degradation in epilepsy. Epilepsia Rankin-Gee, E. K., McRae, P. A., Baranov, E., Rogers, S., Wandrey, L., Porter, B. E. 2015; 56 (7): 1124-1133

  Abstract

  We previously reported loss of perineuronal net (PN) immunohistochemical staining around parvalbumin-positive interneurons in the hippocampus of rats after an episode of status epilepticus (SE). We hypothesized that the loss of the PN could alter seizure susceptibility and that matrix metalloproteinases (MMPs) were candidates for degradation of the PN following SE.The pilocarpine chemoconvulsant rodent epilepsy model was used to characterize the degradation of the aggrecan component of the PN in the hippocampus following SE. Chondroitinase ABC (ChABC) was used to degrade the PN in mice. Onset, number, and duration of pentylenetetrazole (PTZ)-induced seizures were assessed.The loss of the PN in the hippocampus following SE is at least partially related to degradation of the aggrecan PN component by MMP activity. Forty-eight hours after SE, a neoepitope created by MMP cleavage of aggrecan was present and concentrated around parvalbumin-positive interneurons. The increase in aggrecan cleavage products was found at 48 h, 1 week, and 2 months after SE, with different fragments predominating over time. We demonstrate ongoing aggrecan proteolysis and fragment accumulation in the hippocampus of adult control rats, as well as in SE-treated animals. Degradation of the PN alters the seizure response to PTZ. ChABC treatment caused an increase in myoclonic seizures following PTZ administration, a delayed onset of Racine stage 4/5 seizure, and a decreased duration of Racine stage 4/5 seizure.Status epilepticus increases MMP proteolysis of aggrecan, pointing to MMP activity as one mechanism of PN degradation post-SE. There is accumulation of aggrecan fragments in adult rat hippocampus of both control and SE-exposed animals. Loss of the PN was associated with increased numbers of myoclonic seizures; it also, delayed and shortened the duration of Racine stage 4/5 seizures, suggesting a complex relationship between the PN and seizure susceptibility.

  View details for DOI 10.1111/epi.13026

  View details for PubMedID 26032766

• 50 years ago in the journal of pediatrics: convulsive equivalent syndrome of childhood. journal of pediatrics Maclean, J., Porter, B. 2014; 164 (5): 1050-?

  View details for DOI 10.1016/j.jpeds.2013.10.079

  View details for PubMedID 24742650

• Report of a parent survey of cannabidiol-enriched cannabis use in pediatric treatment-resistant epilepsy EPILEPSY & BEHAVIOR Porter, B. E., Jacobson, C. 2013; 29 (3): 574-577

  Abstract

  Severe childhood epilepsies are characterized by frequent seizures, neurodevelopmental delays, and impaired quality of life. In these treatment-resistant epilepsies, families often seek alternative treatments. This survey explored the use of cannabidiol-enriched cannabis in children with treatment-resistant epilepsy. The survey was presented to parents belonging to a Facebook group dedicated to sharing information about the use of cannabidiol-enriched cannabis to treat their child's seizures. Nineteen responses met the following inclusion criteria for the study: a diagnosis of epilepsy and current use of cannabidiol-enriched cannabis. Thirteen children had Dravet syndrome, four had Doose syndrome, and one each had Lennox-Gastaut syndrome and idiopathic epilepsy. The average number of antiepileptic drugs (AEDs) tried before using cannabidiol-enriched cannabis was 12. Sixteen (84%) of the 19 parents reported a reduction in their child's seizure frequency while taking cannabidiol-enriched cannabis. Of these, two (11%) reported complete seizure freedom, eight (42%) reported a greater than 80% reduction in seizure frequency, and six (32%) reported a 25-60% seizure reduction. Other beneficial effects included increased alertness, better mood, and improved sleep. Side effects included drowsiness and fatigue. Our survey shows that parents are using cannabidiol-enriched cannabis as a treatment for their children with treatment-resistant epilepsy. Because of the increasing number of states that allow access to medical cannabis, its use will likely be a growing concern for the epilepsy community. Safety and tolerability data for cannabidiol-enriched cannabis use among children are not available. Objective measurements of a standardized preparation of pure cannabidiol are needed to determine whether it is safe, well tolerated, and efficacious at controlling seizures in this pediatric population with difficult-to-treat seizures.

  View details for DOI 10.1016/j.yebeh.2013.08.037

  View details for PubMedID 24237632

• MEF2C Haploinsufficiency features consistent hyperkinesis, variable epilepsy, and has a role in dorsal and ventral neuronal developmental pathways NEUROGENETICS Paciorkowski, A. R., Traylor, R. N., Rosenfeld, J. A., Hoover, J. M., Harris, C. J., Winter, S., Lacassie, Y., Bialer, M., Lamb, A. N., Schultz, R. A., Berry-Kravis, E., Porter, B. E., Falk, M., Venkat, A., Vanzo, R. J., Cohen, J. S., Fatemi, A., Dobyns, W. B., Shaffer, L. G., Ballif, B. C., Marsh, E. D. 2013; 14 (2): 99-111

  Abstract

  MEF2C haploinsufficiency syndrome is an emerging neurodevelopmental disorder associated with intellectual disability, autistic features, epilepsy, and abnormal movements. We report 16 new patients with MEF2C haploinsufficiency, including the oldest reported patient with MEF2C deletion at 5q14.3. We detail the neurobehavioral phenotype, epilepsy, and abnormal movements, and compare our subjects with those previously reported in the literature. We also investigate Mef2c expression in the developing mouse forebrain. A spectrum of neurofunctional deficits emerges, with hyperkinesis a consistent finding. Epilepsy varied from absent to severe, and included intractable myoclonic seizures and infantile spasms. Subjects with partial MEF2C deletion were statistically less likely to have epilepsy. Finally, we confirm that Mef2c is present both in dorsal primary neuroblasts and ventral gamma-aminobutyric acid(GABA)ergic interneurons in the forebrain of the developing mouse. Given interactions with several key neurodevelopmental genes such as ARX, FMR1, MECP2, and TBR1, it appears that MEF2C plays a role in several developmental stages of both dorsal and ventral neuronal cell types.

  View details for DOI 10.1007/s10048-013-0356-y

  View details for Web of Science ID 000318881100002

  View details for PubMedID 23389741

  View details for PubMedCentralID PMC3773516

• Focal cortical dysplasia is more common in boys than in girls EPILEPSY & BEHAVIOR Ortiz-Gonzalez, X. R., Poduri, A., Roberts, C. M., Sullivan, J. E., Marsh, E. D., Porter, B. E. 2013; 27 (1): 121-123

  Abstract

  Genetics and environment likely contribute to the development of medically intractable epilepsy; however, in most patients the specific combination of etiologies remains unknown. Here, we undertook a multicenter retrospective cohort study of sex distribution in pediatric patients undergoing epilepsy surgery and carried out a secondary analysis of the same population subdivided by histopathologic diagnosis. In the multicenter cohort of patients with intractable epilepsy undergoing surgery regardless of etiology (n=206), 63% were boys, which is significantly more boys than expected for the general population (Fisher exact two-tailed p=0.017). Subgroup analysis found that of the 90 patients with a histopathologic diagnosis of focal cortical dysplasia, 72% were boys, giving an odds ratio (OR) of 2.5 (95% CI, 1.34 to 4.62) for male sex. None of the other etiologies had a male sex predominance. Future studies could examine the biological relevance and potential genetic and pathophysiological mechanisms of this observation.

  View details for DOI 10.1016/j.yebeh.2012.12.035

  View details for Web of Science ID 000317029000022

  View details for PubMedID 23416281

• Changes in MicroRNA Expression in the Whole Hippocampus and Hippocampal Synaptoneurosome Fraction following Pilocarpine Induced Status Epilepticus PLOS ONE Risbud, R. M., Porter, B. E. 2013; 8 (1)

  Abstract

  MicroRNAs regulate protein synthesis by binding non-translated regions of mRNAs and suppressing translation and/or increasing mRNA degradation. MicroRNAs play an important role in the nervous system including controlling synaptic plasticity. Their expression is altered in disease states including stroke, head injury and epilepsy. To better understand microRNA expression changes that might contribute to the development of epilepsy, microRNA arrays were performed on rat hippocampus 4 hours, 48 hours and 3 weeks following an episode of pilocarpine induced status epilepticus. Eighty microRNAs increased at one or more of the time points. No microRNAs decreased at 4 hours, and only a few decreased at 3 weeks, but 188 decreased 48 hours after status epilepticus. The large number of microRNAs with altered expression following status epilepticus suggests that microRNA regulation of translation has the potential to contribute to changes in protein expression during epileptogenesis. We carried out a second set of array's comparing microRNA expression at 48 hours in synaptoneurosome and nuclear fractions of the hippocampus. In control rat hippocampi multiple microRNAs were enriched in the synaptoneurosomal fraction as compared to the nuclear fraction. In contrast, 48 hours after status epilepticus only one microRNA was enriched in the synaptoneurosome fraction. The loss of microRNAs enriched in the synaptoneurosomal fraction implies a dramatic change in translational regulation in synapses 48 hours after status epilepticus.

  View details for DOI 10.1371/journal.pone.0053464

  View details for Web of Science ID 000313429100071

  View details for PubMedID 23308228

  View details for PubMedCentralID PMC3538591

• Persistent decrease in multiple components of the perineuronal net following status epilepticus EUROPEAN JOURNAL OF NEUROSCIENCE McRae, P. A., Baranov, E., Rogers, S. L., Porter, B. E. 2012; 36 (11): 3471-3482

  Abstract

  In the rodent model of temporal lobe epilepsy, there is extensive synaptic reorganization within the hippocampus following a single prolonged seizure event, after which animals eventually develop epilepsy. The perineuronal net (PN), a component of the neural extracellular matrix (ECM), primarily surrounds inhibitory interneurons and, under normal conditions, restricts synaptic reorganization. The objective of the current study was to explore the effects of status epilepticus (SE) on PNs in the adult hippocampus. The aggrecan component of the PN was studied, acutely (48 h post-SE), sub-acutely (1 week post-SE) and during the chronic period (2 months post-SE). Aggrecan expressing PNs decreased by 1 week, likely contributing to a permissive environment for neuronal reorganization, and remained attenuated at 2 months. The SE-exposed hippocampus showed many PNs with poor structural integrity, a condition rarely seen in controls. Additionally, the decrease in the aggrecan component of the PN was preceded by a decrease in hyaluronan and proteoglycan link protein 1 (HAPLN1) and hyaluronan synthase 3 (HAS3), which are components of the PN known to stabilize the connection between aggrecan and hyaluronan, a major constituent of the ECM. These results were replicated in vitro with the addition of excess KCl to hippocampal cultures. Enhanced neuronal activity caused a decrease in aggrecan, HAPLN1 and HAS3 around hippocampal cells in vivo and in vitro, leaving inhibitory interneurons susceptible to increased synaptic reorganization. These studies are the foundation for future experiments to explore how loss of the PN following SE contributes to the development of epilepsy.

  View details for DOI 10.1111/j.1460-9568.2012.08268.x

  View details for Web of Science ID 000312156700002

  View details for PubMedID 22934955

• The perineuronal net component of the extracellular matrix in plasticity and epilepsy NEUROCHEMISTRY INTERNATIONAL McRae, P. A., Porter, B. E. 2012; 61 (7): 963-972

  Abstract

  During development the extracellular matrix (ECM) of the central nervous system (CNS) facilitates proliferation, migration, and synaptogenesis. In the mature nervous system due to changes in the ECM it provides structural stability and impedes proliferation, migration, and synaptogensis. The perineuronal net (PN) is a specialized ECM structure found primarily surrounding inhibitory interneurons where it forms a mesh-like structure around points of synaptic contact. The PN organizes the extracellular space by binding multiple components of the ECM and bringing them into close proximity to the cell membrane, forming dense aggregates surrounding synapses. The PN is expressed late in postnatal development when the nervous system is in the final stages of maturation and the critical periods are closing. Once fully expressed the PN envelopes synapses and leads to decreased plasticity and increases synaptic stability in the CNS. Disruptions in the PN have been studied in a number of disease states including epilepsy. Epilepsy is one of the most common neurologic disorders characterized by excessive neuronal activity which results in recurrent spontaneous seizures. A shift in the delicate balance between excitation and inhibition is believed to be one of the underlying mechanisms in the development of epilepsy. During epileptogenesis, the brain undergoes numerous changes including synaptic rearrangement and axonal sprouting, which require structural plasticity. Because of the PNs location around inhibitory cells and its role in limiting plasticity, the PN is an important candidate for altering the progression of epilepsy. In this review, an overview of the ECM and PN in the CNS will be presented with special emphasis on potential roles in epileptogenesis.

  View details for DOI 10.1016/j.neuint.2012.08.007

  View details for Web of Science ID 000314616400002

  View details for PubMedID 22954428

• Decreased CREB levels suppress epilepsy NEUROBIOLOGY OF DISEASE Zhu, X., Han, X., Blendy, J. A., Porter, B. E. 2012; 45 (1): 253-263

  Abstract

  Epilepsy is a common neurologic disorder yet no treatments aimed at preventing epilepsy have been developed. Several molecules including genes containing cAMP response elements (CREs) in their promoters have been identified that contribute to the development of epilepsy, a process called epileptogenesis. When phosphorylated cAMP response element binding protein (CREB) increases transcription from CRE regulated promoters. CREB phosphorylation is increased in rodent epilepsy models, and in the seizure onset region of humans with medically intractable epilepsy (Rakhade et al., 2005; Lee et al., 2007; Lund et al., 2008). Here we show that mice with decreased CREB levels (CREB(α∆) mutants) have a ~50% reduction in spontaneous seizures following pilocarpine induced status epilepticus (SE) and require more stimulation to electrically kindle. Following SE, brain derived neurotrophic factor (BDNF) and inducible cAMP early repressor (ICER) mRNAs are differentially up-regulated in the hippocampus and cortex of the CREB(α∆) mutants compared to wild-type mice, which may be contributing to differences in the severity of epilepsy. In contrast, we found no difference in KCC2 mRNA levels between the CREB(α∆) and wild-type mice after SE. The mechanism by which BDNF and ICER mRNAs increase specifically in the CREB(α∆) compared to wild-type mice following SE is not known. We did, however, find an increase in specific cAMP response element modulator (CREM) mRNA transcripts in the CREB(α∆) mutants that might be responsible for the differential regulation of BDNF and ICER after SE. Altering CREB activity following a neurologic insult provides a therapeutic strategy for modifying epileptogenesis.

  View details for DOI 10.1016/j.nbd.2011.08.009

  View details for Web of Science ID 000297883500028

  View details for PubMedID 21867753

• Neurotrophin-3 mRNA a putative target of miR21 following status epilepticus BRAIN RESEARCH Risbud, R. M., Lee, C., Porter, B. E. 2011; 1424: 53-59

  Abstract

  Status epilepticus induces a cascade of protein expression changes contributing to the subsequent development of epilepsy. By identifying the cascade of molecular changes that contribute to the development of epilepsy we hope to be able to design therapeutics for preventing epilepsy. MicroRNAs influence gene expression by altering mRNA stability and/or translation and have been implicated in the pathology of multiple diseases. MiR21 and its co-transcript miR21, microRNAs produced from either the 5' or 3' ends of the same precursor RNA strand, are increased in the hippocampus following status epilepticus. We have identified a miR21 binding site, in the 3' UTR of neurotrophin-3 that inhibits translation. Neurotrophin-3 mRNA levels decrease in the hippocampus following SE concurrent with the increase in miR21. MiR21 levels in cultured hippocampal neurons inversely correlate with neurotrophin-3 mRNA levels. Treatment of hippocampal neuronal cultures with excess K(+)Cl(-), a depolarizing agent mimicking the episode of status epilepticus, also results in an increase in miR21 and a decrease in neurotrophin-3 mRNA. MiR21 is a candidate for regulating neurotrophin-3 signaling in the hippocampus following status epilepticus.

  View details for DOI 10.1016/j.brainres.2011.09.039

  View details for Web of Science ID 000297487600006

  View details for PubMedID 22019057

• Ganglioglioma arising from dysplastic cortex EPILEPSIA Ortiz-Gonzalez, X. R., Venneti, S., Biegel, J. A., Rorke-Adams, L. B., Porter, B. E. 2011; 52 (9): E106-E108

  Abstract

  We report the case of a child who presented at 3 months of age with complex partial seizures, a linear facial nevus, and magnetic resonance imaging (MRI) showing delayed myelination and thickened cortex in the left temporal, parietal, and occipital regions. A repeat 3Tesla MRI scan with and without contrast at 6 months again showed cortical dysplasia of the left hemisphere. No other abnormalities were seen. A third scan at 3 years 6 months showed a 2.5 cm, round, hyperintense lesion on both T(2) and T(1) sequences. The lesion and surrounding dysplastic cortex were resected. Palmini grade IIA dysplasia and a ganglioglioma were diagnosed. These findings suggest that cellular components of cortical dysplasias have oncogenic potential.

  View details for DOI 10.1111/j.1528-1167.2011.03124.x

  View details for Web of Science ID 000294973700002

  View details for PubMedID 21668439

• Subependymal Giant Cell Astrocytoma (SEGA) Treatment Update CURRENT TREATMENT OPTIONS IN NEUROLOGY Campen, C. J., Porter, B. E. 2011; 13 (4): 380-385

  Abstract

  OPINION STATEMENT: Rates of regrowth after resection of subependymal giant cell astrocytoma (SEGA) are low, making surgical resection a successful and permanent therapeutic strategy. In addition to surgical resection of SEGAs, other treatment options now include medications and Gamma Knife™ therapy. Advising patients on medical versus surgical management of SEGAs is currently not easy. SEGAs have been reported to regrow if mTOR inhibitor therapy is stopped, raising the possibility that long-term medication may be required to prevent tumor growth and hydrocephalus. The question of regrowth following medication withdrawal will need to be addressed in more patients to help establish the optimal duration of therapy. The risks of surgery include acute morbidity and the permanent need for ventriculoperitoneal shunting, which must be balanced against the adverse effects of mTOR inhibitors, including immunosuppression (infections, mouth sores), hypercholesterolemia, and the need for chronic drug monitoring. Some additional benefits of mTOR inhibition in patients with tuberous sclerosis complex, however, may include shrinkage of angiofibromas and angiomyolipomas as well as a possible decrease in seizure burden. Recent reports of successful nonsurgical treatment of SEGAs are promising, and it is hoped that further specifics on dosing, duration, and long-term outcome will help patients and physicians to make informed therapeutic choices.Present treatment recommendations for SEGAs include routine surveillance neuroimaging and close clinical follow-up, paying particular attention to signs and symptoms of acute hydrocephalus. If symptoms arise, or if serial neuroimaging demonstrates tumor growth, neurosurgical intervention is recommended. When gross total resection is impossible, rapamycin and everolimus should be considered, but may not offer a durable response.

  View details for DOI 10.1007/s11940-011-0123-z

  View details for Web of Science ID 000292402500005

  View details for PubMedID 21465222

  View details for PubMedCentralID PMC3130084

• Group I mGluR-regulated translation of the neuronal glutamate transporter, excitatory amino acid carrier 1 JOURNAL OF NEUROCHEMISTRY Ross, J. R., Ramakrishnan, H., Porter, B. E., Robinson, M. B. 2011; 117 (5): 812-823

  Abstract

  Recently, we demonstrated that mRNA for the neuronal glutamate transporter, excitatory amino acid carrier 1 (EAAC1), is found in dendrites of hippocampal neurons in culture and in dendrites of hippocampal pyramidal cells after pilocarpine-induced status epilepticus (SE). We also showed that SE increased the levels of EAAC1 mRNA ~15-fold in synaptoneurosomes. In this study, the effects of SE on the distribution EAAC1 protein in hippocampus were examined. In addition, the effects of Group 1 mGluR receptor activation on the levels of EAAC1 protein were examined in synaptoneurosomes prepared from sham control animals and from animals that experience pilocarpine-induced SE. We find that EAAC1 immunoreactivity increases in pyramidal cells of the hippocampus after 3 h of SE. In addition, the group I mGluR agonist, (S)-3,5-dihydroxyphenylglycine (DHPG), caused an increase in EAAC1 protein levels in hippocampal synaptoneurosomes; this effect of DHPG was much larger (~3- to 5-fold) after 3 h of SE. The DHPG-induced increases in EAAC1 protein were blocked by two different inhibitors of translation but not by inhibitors of transcription. mGluR1 or mGluR5 antagonists completely blocked the DHPG-induced increases in EAAC1 protein. DHPG also increased the levels of glutamate receptor 2/3 protein, but this effect was not altered by SE. The DHPG-induced increase in EAAC1 protein was blocked by an inhibitor of the mammalian target of rapamycin or an inhibitor of extracellular signal-regulated kinase. These studies provide the first evidence EAAC1 translation can be regulated, and they show that regulated translation of EAAC1 is up-regulated after SE.

  View details for DOI 10.1111/j.1471-4159.2011.07233.x

  View details for Web of Science ID 000290225000004

  View details for PubMedID 21371038

  View details for PubMedCentralID PMC3088777

• mRNA for the EAAC1 subtype of glutamate transporter is present in neuronal dendrites in vitro and dramatically increases in vivo after a seizure NEUROCHEMISTRY INTERNATIONAL Ross, J. R., Porter, B. E., Buckley, P. T., Eberwine, J. H., Robinson, M. B. 2011; 58 (3): 366-375

  Abstract

  The neuronal Na(+)-dependent glutamate transporter, excitatory amino acid carrier 1 (EAAC1, also called EAAT3), has been implicated in the control of synaptic spillover of glutamate, synaptic plasticity, and the import of cysteine for neuronal synthesis of glutathione. EAAC1 protein is observed in both perisynaptic regions of the synapse and in neuronal cell bodies. Although amino acid residues in the carboxyl terminal tail have been implicated in the dendritic targeting of EAAC1 protein, it is not known if mRNA for EAAC1 may also be targeted to dendrites. Sorting of mRNA to specific cellular domains provides a mechanism by which signals can rapidly increase translation in a local environment; this form of regulated translation has been linked to diverse biological phenomena ranging from establishment of polarity during embryogenesis to synapse development and synaptic plasticity. In the present study, EAAC1 mRNA sequences were amplified from dendritic samples that were mechanically harvested from low-density hippocampal neuronal cultures. In parallel analyses, mRNA for histone deacetylase 2 (HDAC-2) and glial fibrillary acidic protein (GFAP) was not detected, suggesting that these samples are not contaminated with cell body or glial mRNAs. EAAC1 mRNA also co-localized with Map2a (a marker of dendrites) but not Tau1 (a marker of axons) in hippocampal neuronal cultures by in situ hybridization. In control rats, EAAC1 mRNA was observed in soma and proximal dendrites of hippocampal pyramidal neurons. Following pilocarpine- or kainate-induced seizures, EAAC1 mRNA was present in CA1 pyramidal cell dendrites up to 200μm from the soma. These studies provide the first evidence that EAAC1 mRNA localizes to dendrites and suggest that dendritic targeting of EAAC1 mRNA is increased by seizure activity and may be regulated by neuronal activity/depolarization.

  View details for DOI 10.1016/j.neuint.2010.12.012

  View details for Web of Science ID 000295749500013

  View details for PubMedID 21185901

  View details for PubMedCentralID PMC3040252

• Discrete gamma oscillations identify the seizure onset zone in some pediatric epilepsy patients 33rd Annual International Conference of the IEEE Engineering-in-Medicine-and-Biology-Society (EMBS) Gupta, J. R., Marsh, E. D., Nieh, H. E., Porter, B. E., Litt, B. IEEE. 2011: 3095–3098

  Abstract

  Intracranial electroencephalography (IEEG) plays an important role in guiding epilepsy surgery in pediatric epilepsy patients. Recently, there has been increased interest in higher frequency components of clinical IEEG recordings and their potential relationship to epileptogenic brain tissue. We employ a previously validated, automated discrete gamma oscillation (GO) detection algorithm to determine the prevalence of discrete gamma events over prolonged, representative segments of IEEG recorded from ten patients. Approximately 8 h of IEEG, 16 randomly selected 30-min segments of continuous interictal IEEG per patient, were analyzed. The electrodes within the seizure onset zone were found to have significantly higher mean GO activity averaged across these 16 segments in five of the ten patients. There was observed variability between individual 30-min segments in these patients, indicating that longer recordings of interictal activity improved localization. Our data suggest this method of automated GO detection across long periods may be useful in planning epilepsy surgery in certain children with intractable epilepsy. Further research is required to help determine which patients would benefit from this technique.

  View details for Web of Science ID 000298810002205

  View details for PubMedID 22254994

• Aggrecan expression, a component of the inhibitory interneuron perineuronal net, is altered following an early-life seizure NEUROBIOLOGY OF DISEASE McRae, P. A., Baranov, E., Sarode, S., Brooks-Kayal, A. R., Porter, B. E. 2010; 39 (3): 439-448

  Abstract

  The perineuronal net (PN), a component of the neural extracellular matrix (ECM), is a dynamic structure whose expression decreases following diminished physiological activity. Here, we analyzed the effects of increased neuronal activity on the development of aggrecan, a component of the PN, in the hippocampus. We show aggrecan expression to be prominent around parvalbumin (PV) interneurons in the postnatal hippocampus. Moreover, after seizure induction in early life there was a significant increase in aggrecan expression in a region specific manner during the course of development. We conclude that increased neuronal activity leads to accelerated expression of PNs in the hippocampus that attenuates in the adult hippocampus. This study shows the dynamic nature of the PN component of the ECM and the role neuronal activity has in molding the extracellular milieu of inhibitory interneurons.

  View details for DOI 10.1016/j.nbd.2010.05.015

  View details for Web of Science ID 000280544100022

  View details for PubMedID 20493259

  View details for PubMedCentralID PMC2935142

• Interictal EEG spikes identify the region of electrographic seizure onset in some, but not all, pediatric epilepsy patients EPILEPSIA Marsh, E. D., Peltzer, B., Brown, M. W., Wusthoff, C., Storm, P. B., Litt, B., Porter, B. E. 2010; 51 (4): 592-601

  Abstract

  The role of sharps and spikes, interictal epileptiform discharges (IEDs), in guiding epilepsy surgery in children remains controversial, particularly with intracranial electroencephalography (IEEG). Although ictal recording is the mainstay of localizing epileptic networks for surgical resection, current practice dictates removing regions generating frequent IEDs if they are near the ictal onset zone. Indeed, past studies suggest an inconsistent relationship between IED and seizure-onset location, although these studies were based upon relatively short EEG epochs.We employ a previously validated, computerized spike detector to measure and localize IED activity over prolonged, representative segments of IEEG recorded from 19 children with intractable, mostly extratemporal lobe epilepsy. Approximately 8 h of IEEG, randomly selected 30-min segments of continuous interictal IEEG per patient, were analyzed over all intracranial electrode contacts.When spike frequency was averaged over the 16-time segments, electrodes with the highest mean spike frequency were found to be within the seizure-onset region in 11 of 19 patients. There was significant variability between individual 30-min segments in these patients, indicating that large statistical samples of interictal activity were required for improved localization. Low-voltage fast EEG at seizure onset was the only clinical factor predicting IED localization to the seizure-onset region.Our data suggest that automated IED detection over multiple representative samples of IEEG may be of utility in planning epilepsy surgery for children with intractable epilepsy. Further research is required to better determine which patients may benefit from this technique a priori.

  View details for DOI 10.1111/j.1528-1167.2009.02306.x

  View details for Web of Science ID 000276245600012

  View details for PubMedID 19780794

  View details for PubMedCentralID PMC2907216

• Seizures increase cell proliferation in the dentate gyrus by shortening progenitor cell-cycle length EPILEPSIA Varodayan, F. P., Zhu, X., Cui, X., Porter, B. E. 2009; 50 (12): 2638-2647

  Abstract

  A prolonged seizure, status epileptics (SE), is a potent stimulus for increased neurogenesis in the dentate gyrus of the hippocampus. Molecular mechanisms that regulate normal and pathologic cell birth in the dentate gyrus are poorly understood.Lithium-pilocarpine was used to induce SE in immature postnatal day 20 rats. Newborn cells in the dentate were labeled with bromo-deoxyuridine to determine a time-course of cell proliferation, and measure cell-cycle length. In addition, we studied expression by Western blot and immunohistochemistry of two known inhibitors of G(1)-S cell-cycle progression P27/Kip1 and P15/Ink4b following SE.Cell proliferation in the dentate gyrus increases starting 2 h after SE and is sustained for 40 days. Increased cell proliferation following SE is associated with a shortened dentate gyrus progenitor's cell cycle, 15 h in control to 12 h in the SE animals. To identify molecules responsible for the shortened progenitor cell cycle we studied inhibitors of cell-cycle progression P27/Kip1, and P15/Ink4b. We find decreased phosphorylation at P27/Kip1 Serine 10 and Threonine 187 following SE. Although total P27/Kip1 and P15/Ink4b levels were not altered after SE, P27/Kip1 immunoreactivity was minimal in newborn but increased with maturation of the dentate granule neurons.The sustained increase in dentate gyrus cell proliferation following SE provides a large pool of immature dentate granule cells prior to development of spontaneous seizures. A decrease in cell-cycle length of dentate gyrus progenitors is at least partially responsible for increased numbers of newborn cells following SE.

  View details for DOI 10.1111/j.1528-1167.2009.02244.x

  View details for Web of Science ID 000272128700016

  View details for PubMedID 19674059

  View details for PubMedCentralID PMC2796702

• Topiramate and Adrenocorticotropic Hormone (ACTH) as Initial Treatment for Infantile Spasms JOURNAL OF CHILD NEUROLOGY Peltzer, B., Alonso, W. D., Porter, B. E. 2009; 24 (4): 400-405

  Abstract

  Historically, adrenocorticotropic hormone was used as a first-line treatment for infantile spasms; however, there has been increasing use of topiramate as initial therapy. Here, we report a retrospective study of adrenocorticotropic hormone (ACTH) and topiramate as initial treatment for infantile spasms. The neurology patient database at the Children's Hospital of Philadelphia was searched using the International Classification of Diseases, Ninth Revision code for infantile spasms, and 50 patients were randomly chosen for chart review. We identified 31 patients receiving either adrenocorticotropic hormone or topiramate monotherapy (adrenocorticotropic hormone n = 12, topiramate n = 19) as a first-line treatment for infantile spasms. A total of 26 patients were symptomatic and 5 cryptogenic. Six patients treated with adrenocorticotropic hormone had resolution of clinical spasms and hypsarrhythmia within a month, but 3 relapsed. Of the 19 patients treated with topiramate, 4 patients eventually, though over a period of 0, 1, 8, or 69 months, had resolution of spasms and hypsarrhythmia.

  View details for DOI 10.1177/0883073808324538

  View details for Web of Science ID 000264593300001

  View details for PubMedID 19225138

  View details for PubMedCentralID PMC2700772

• The role of transcription factors cyclic-AMP responsive element modulator (CREM) and inducible cyclic-amp early repressor (ICER) in epileptogenesis NEUROSCIENCE Porter, B. E., Lund, I. V., Varodayan, F. P., Wallace, R. W., Blendy, J. A. 2008; 152 (3): 829-836

  Abstract

  Alterations in the brain that contribute to the development of epilepsy, also called epileptogenesis, are not well understood, which makes it difficult to develop strategies for preventing epilepsy. Here we have studied the role of the CRE binding transcription factors, cyclic-AMP responsive element modulator (CREM) and inducible cyclic-AMP early repressor (ICER), in the development of epilepsy following pilocarpine induced status epilepticus (SE) in mice. Following SE, ICER mRNA and protein are increased in neurons. The increase in ICER, however, is not necessary for neuronal injury following SE as pilocarpine treatment induces equivalent neuronal injury in pyramidal neurons of wild type and CREM/ICER null mice. Following SE, the CREM/ICER null mice develop a more severe epileptic phenotype experiencing approximately threefold more frequent spontaneous seizures. Together these data suggest that the increase in ICER mRNA following SE may have a role in suppressing the severity of epilepsy.

  View details for DOI 10.1016/j.neuroscience.2007.10.064

  View details for Web of Science ID 000254819900024

  View details for PubMedID 18295410

  View details for PubMedCentralID PMC2372160

• Neurogenesis and epilepsy in the developing brain EPILEPSIA Porter, B. E. 2008; 49: 50-54

  Abstract

  Multiple studies have highlighted how seizures induce different molecular, cellular, and physiologic consequences in an immature brain as compared to a mature brain. In keeping with these studies, seizures early in life alter dentate granule cell birth in different, and even opposing, fashion to adult seizure models (see Table 1). During the first week of rodent postnatal life, seizures decrease cell birth in the postictal period, but do not alter the maturation of newborn cells. Seizures during the second week of life have varied effects on dentate granule cell birth, either causing no change or increasing birth, and may promote a mild increase in neuronal survival. During the third and fourth weeks of life, seizures begin to increase cell birth similar to that seen in adult seizure models. Interestingly, animals that experienced seizure during the first month of life have an increase in cell birth during adulthood, opposite to the reported decrease in chronic animals experiencing a prolonged seizure as an adult. Children have more ongoing cell birth in the dentate gyrus than adults, and markers of cell division are further increased in children with refractory temporal lobe epilepsy. There are clear age-dependent differences in how seizures alter cell birth in the dentate gyrus both acutely and chronically. Future studies need to focus on how these changes in neurogenesis influence dentate gyrus function and what they imply for epileptogenesis and learning and memory impairments, so commonly found in children with temporal lobe epilepsy.

  View details for DOI 10.1111/j.1528-1167.2008.01637.x

  View details for Web of Science ID 000256395900007

  View details for PubMedID 18522600

  View details for PubMedCentralID PMC2700768

• Comparison of novel computer detectors and human performance for spike detection in intracranial EEG CLINICAL NEUROPHYSIOLOGY Brown, M. W., Porter, B. E., Dlugos, D. J., Keating, J., Gardner, A. B., Storm, P. B., Marsh, E. D. 2007; 118 (8): 1744-1752

  Abstract

  Interictal spikes in intracranial EEG (iEEG) may correlate with epileptogenic cortex, but review of interictal iEEG is labor intensive. Accurate automated spike detectors are necessary for understanding the role of spikes in epileptogenesis.The sensitivity, accuracy and reproducibility of three automated iEEG spike detectors were compared against two human EEG readers using iEEG segments from eight patients. A consensus set of detections was generated for detector calibration. Spike verification was calculated after both human EEG readers independently reviewed all detections.Humans and two of the three automated detectors demonstrated comparable accuracy. In four patients, automated spike detection sensitivity was >70% and accuracy was >50%. In the remaining four patients, EEG background morphology resulted in poorer performance. Blinded human verification accuracy was 76.7+/-6.6% for computer-detected spikes, and 84.5+/-4.1% for human-detected spikes.Automated iEEG spike detectors perform comparably to humans, but sensitivity and accuracy are patient dependent. Humans verified the majority of computer-detected spikes.In some patients automated detectors may be used for mapping spike occurrences in epileptic networks. This may reveal associations between spike distribution, seizure onset, and pathology.

  View details for DOI 10.1016/j.clinph.2007.04.017

  View details for Web of Science ID 000248668600012

  View details for PubMedID 17544322

• Seizures and antiepileptic drugs: Does exposure alter normal brain development ? EPILEPSIA Marsh, E. D., Brooks-Kayal, A. R., Porter, B. E. 2006; 47 (12): 1999-2010

  Abstract

  Seizures and antiepileptic drugs (AEDs) affect brain development and have long-term neurological consequences. The specific molecular and cellular changes, the precise timing of their influence during brain development, and the full extent of the long-term consequences of seizures and AEDs exposure have not been established. This review critically assesses both the basic and clinical science literature on the effects of seizures and AEDs on the developing brain and finds that evidence exists to support the hypothesis that both seizures and antiepileptic drugs influence a variety of biological process, at specific times during development, which alter long-term cognition and epilepsy susceptibility. More research, both clinical and experimental, is needed before changes in current clinical practice, based on the scientific data, can be recommended.

  View details for DOI 10.1111/j.1528-1167.2006.00894.x

  View details for Web of Science ID 000242784000002

  View details for PubMedID 17201696

• Increased GABA(A)-receptor alpha 1-subunit expression in hippocampal dentate gyrus after early-life status epilepticus EPILEPSIA Raol, Y. H., Zhang, G., Lund, I. V., Porter, B. E., Maronski, M. A., Brooks-Kayal, A. R. 2006; 47 (10): 1665-1673

  Abstract

  Previous studies in neonatal (postnatal day 10) and adult rats suggest that status epilepticus (SE) induces changes in the alpha1 subunit of the GABA(A) receptor (GABRA1) in dentate granule neurons (DGNs) that are age dependent and vary inversely with the likelihood of epilepsy development. In the present study, we examined GABRA1 expression after SE at postnatal day 20 (P20), an intermediate age when only a subset of SE-exposed animals develop epilepsy.SE was induced with lithium-pilocarpine or kainate at P20. Animals were video-EEG monitored after SE to determine the presence or absence of spontaneous seizures. GABRA1 mRNA and protein levels were determined 7 days or 3 months later in SE-exposed and control animals by using a combination of aRNA amplification, Western blotting, and immunohistochemistry techniques.GABRA1 mRNA levels in DGNs of SE-exposed rats that did not become epileptic were higher than those in control rats, but were not different from DGNs in epileptic SE-exposed rats. GABRA1 protein levels in dentate gyrus were significantly increased in both epileptic and nonepileptic SE-exposed rats compared with controls. GABRA1 mRNA changes were region specific and did not occur in CA1 or CA3 areas of hippocampus. GABRA1 alterations were present by 1 week after P20 SE and were similar whether pilocarpine or kainate was used to induced SE.P20 SE results in persistent increases in GABRA1 levels selectively in dentate gyrus. These changes preceded the onset of epilepsy, were not model specific, and occurred in both epileptic and nonepileptic animals.

  View details for DOI 10.1111/j.1528-1167.2006.00640.x

  View details for Web of Science ID 000241191100011

  View details for PubMedID 17054689

• Dystrophic neuritic processes in epileptic cortex EPILEPSY RESEARCH Judkins, A. R., Porter, B. E., Cook, N., Clancy, R. R., Duhaime, A. C., Golden, J. A. 2006; 70 (1): 49-58

  Abstract

  Cortical dysplasia is a frequent finding in cortical resections from children with refractory epilepsy. Diagnostic criteria and a classification scheme for cortical dysplasia has been proposed, though the relationship between specific cortical dysplasia features and their causal relationship with epilepsy is poorly understood. We reviewed 28 surgical resections from children and identified a common and easily recognized feature of cortical dysplasia: maloriented, misshapen and occasionally coarse neurofilament stained process forming a dystrophic neuritic background. The dystrophic neuritic background was associated with other features of cortical dysplasia in all 28 patients with cortical dysplasia, 26 with refractory epilepsy and 2 patients with other neurologic diagnoses. In seven children with refractory epilepsy due to other pathologic diagnosis such as vascular or glial lesions, the dystrophic neuritic background was only found in one patient with a ganglioglioma and other features suggestive of an associated cortical dysplasia. Our data indicate that a dystrophic neuritic background is a common and relatively specific neuropathologic finding in cortical dysplasia.

  View details for DOI 10.1016/j.eplepsyres.2006.03.006

  View details for Web of Science ID 000239400600005

  View details for PubMedID 16631351

• Status epilepticus differentially alters AMPA and kainate receptor subunit expression in mature and immature dentate granule neurons EUROPEAN JOURNAL OF NEUROSCIENCE Porter, B. E., Cui, X., Brooks-Kayal, A. R. 2006; 23 (11): 2857-2863

  Abstract

  There is an increase in the birth of dentate granule neurons after status epilepticus (SE) and there are concurrent alterations in neurotransmitter receptor expression that may contribute to the development of spontaneous seizures. To determine whether newborn and/or mature dentate granule neurons have altered neurotransmitter receptor expression after SE, we dissected individual immature, PSA-NCAM-expressing, or mature, NeuN-expressing, dentate granule neurons 2 weeks after lithium-pilocarpine-induced SE in postnatal day 20 rats. Amplified single-cell RNA was used to probe reverse Northern blots containing alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and kainate neurotransmitter receptor subunits. Two weeks after lithium-pilocarpine-induced SE there were increases in AMPA GluR2 and kainate KA2 subunit mRNA and decreases in AMPA GluR3 and kainate GluR6 receptor subunit mRNA levels in mature dentate granule neurons. In contrast, only the kainate GluR6 subunit expression was reduced in immature dentate granule neurons after SE. Alterations in transcription of excitatory amino acid receptor subunits after SE occur primarily in the mature population of dentate granule neurons. Our findings suggest that neurotransmitter receptor gene expression is altered differently in immature and mature dentate granule neurons following SE, and may result in differential contributions of these two groups of dentate granule neurons to the subsequent development of epilepsy.

  View details for DOI 10.1111/j.1460-9568.2006.04839.x

  View details for Web of Science ID 000238185300003

  View details for PubMedID 16819974

• Heterogeneous GABA(A) receptor subunit expression in pediatric epilepsy patients NEUROBIOLOGY OF DISEASE Porter, B. E., Zhang, G. J., Celix, J., Hsu, F. C., Raol, Y. S., Telfeian, A., Gallagher, P. R., Coulter, D. A., Brooks-Kayal, A. R. 2005; 18 (3): 484-491

  Abstract

  The gamma-amino-butyric acid type A receptors (GABAAR) are a heteropentameric receptor complex, composed of 16 possible subunits in various combinations, forming a ligand-gated ion channel. Subunit composition is the primary determinant of GABAAR physiology and pharmacology. Here we have measured mRNA levels for 16 GABAAR subunits in isolated dentate granule neurons (DGN) from eight pediatric patients undergoing resective surgery for intractable epilepsy. We found tightly correlated expression of a subset of GABAAR subunit mRNAs within a single DGN (alpha1, gamma1, and gamma2; alpha4, alpha5, and beta2; alpha4 and beta3). Analysis of inter-patient variability (ANOVA) of eleven highly expressed GABAAR subunit mRNAs found seven of the subunits varied between patients, as did whole cell GABAAR currents. Due to inter-patient differences, there is heterogeneity in DGN GABAAR subunit mRNA and physiology within pediatric epilepsy patients. Patient-specific GABAAR expression might contribute to variability in anti-epileptic drug efficacy, side-effect profiles, and seizure susceptibility.

  View details for Web of Science ID 000227820500008

  View details for PubMedID 15755675

• Fate of newborn dentate granule cells after early life status epilepticus EPILEPSIA Porter, B. E., Maronski, M., Brooks-Kayal, A. R. 2004; 45 (1): 13-19

  Abstract

  To determine the fate of newborn dentate granule cells (DGCs) after lithium-pilocarpine-induced status epilepticus (SE) in an immature rat.Postnatal day 20 (P20) rats were injected with lithium and pilocarpine to induce SE, and then with bromodeoxyuridine (BrdU) 4, 6, and 8 days later (P24, 26, and 28), and killed 1 day (P29), 1 week (P34), and 3 weeks (P50) after the last dose of BrdU for cell counts. Immunohistochemistry and TUNEL staining were performed to assess the fate of newborn DGCs.Pilocarpine-treated animals had significantly more BrdU-labeled DGCs than did littermate controls at all times. The day after the final BrdU injection (P29), sixfold more cells were found in pilocarpine-treated animals than in controls, which was reduced to threefold, 3 weeks later. A decrease in the BrdU-labeled cell density was noted from P29 to P50 in the control and pilocarpine-treated animals. Evidence of DGC cell death was seen in pilocarpine and control animals, with threefold more TUNEL-positive cells in the pilocarpine-treated than in the control animals at P29. The surviving newborn DGCs became mature neurons; expressing the neuronal marker NeuN in both control and pilocarpine-treated animals.These findings suggest that SE during postnatal development increases the birth and death of DGCs. A subset of the newborn DGCs survive and mature into dentate granule neurons, resulting in an increased population of immature DGCs after SE that may affect hippocampal physiology.

  View details for Web of Science ID 000187964000003

  View details for PubMedID 14692902

• Dysplasia - A common finding in intractable pediatric temporal lobe epilepsy NEUROLOGY Porter, B. E., Judkins, A. R., Clancy, R. R., Duhaime, A., Dlugos, D. J., Golden, J. A. 2003; 61 (3): 365-368

  Abstract

  Risk factors for temporal lobe epilepsy (TLE) include history of CNS infection, family history of epilepsy, and history of febrile convulsions (FC). Pre-existing cortical dysplasia (CD) may also predispose to refractory TLE, independent of other risk factors for epilepsy.The authors reviewed the neuropathologic features of surgical tissue from temporal lobectomies of 33 pediatric patients with refractory TLE, with and without a history of epilepsy risk factors.CD was found in 64% (21/33) of all patients with refractory TLE, including 73% (11/15) patients with a history of FC, 66% (2/3) patients with CNS infections, and 83% (5/6) patients with a family history of epilepsy. Disrupted cortical lamination, dystrophic and maloriented neurons, and balloon cells characterized the CD found in the temporal neocortex.CD was seen in 21 of 33 surgical specimens from children with refractory TLE, including those with and without other epilepsy risk factors.

  View details for Web of Science ID 000184712600017

  View details for PubMedID 12913199

• Disorders of cortical development and epilepsy ARCHIVES OF NEUROLOGY Porter, B. E., Brooks-Kayal, A., Golden, J. A. 2002; 59 (3): 361-365

  Abstract

  There has been an impressive increase in our ability to identify and categorize patients with cortical development lesions over the past decade. The clinical features associated with disorders of cortical development (DCD) have been described, and epilepsy has been shown to be a frequent symptom. In this review, we categorize DCD based on their structure and discuss their underlying causes and clinical features. Just as the cause of each type of disorder is thought to be unique, each disorder also has distinct types of seizures, treatment strategies, and electroencephalographic features. Studies in human tissue and animal models of DCD have begun to shed light on why DCD are associated with epilepsy. Aberrant synaptic connections within the dysplastic tissue and between the dysplastic tissue and more normal-appearing adjacent tissue form an abnormal, hyperexcitable network that increases seizure susceptibility. In the future, strategies for blocking formation of the aberrant networks may prevent the development of epilepsy.

  View details for Web of Science ID 000174386700002

  View details for PubMedID 11890838

• Myelin and disorders that affect the formation and maintenance of this sheath MENTAL RETARDATION AND DEVELOPMENTAL DISABILITIES RESEARCH REVIEWS Porter, B. E., Tennekoon, G. 2000; 6 (1): 47-58

  View details for Web of Science ID 000085703200007

  View details for PubMedID 10899797

• Distinct structures and functions of related pre- and postsynaptic carbohydrates at the mammalian neuromuscular junction MOLECULAR AND CELLULAR NEUROSCIENCE Martin, P. T., Scott, L. J., Porter, B. E., Sanes, J. R. 1999; 13 (2): 105-118

  Abstract

  Carbohydrates that terminate in beta-linked N-acetylgalactosamine (betaGalNAc) residues are concentrated in the postsynaptic apparatus of the skeletal neuromuscular junction and have been implicated in the differentiation of the postsynaptic membrane. We now report that distinct synapse-specific betaGalNAc-containing carbohydrates are associated with motor nerve terminals. Two monoclonal antibodies that recognize distinct betaGalNAc-containing epitopes, CT1 and CT2, both stain synaptic sites on skeletal muscle fibers. However, CT1 selectively stains nerve terminal, whereas CT2 selectively stains the postsynaptic apparatus. Likewise, CT1 and CT2 selectively stain motoneuron-like and muscle cell lines, respectively. Using the cell lines, we identify distinct CT1- and CT2-reactive glycolipids and glycoproteins. Finally, we show that GalNAc modulates the adhesion of motoneuron-like cells to recombinant fragments of a synaptic cleft component, laminin beta2. Together, these results show that pre- as well as postsynaptic membranes bear and are affected by distinct but related synapse-specific carbohydrates.

  View details for Web of Science ID 000079942200003

  View details for PubMedID 10192769

• DISTINCT ADHESIVE PROPERTIES OF CILIARY AND CHOROID NEURONS FROM THE AVIAN CILIARY GANGLION JOURNAL OF NEUROBIOLOGY Porter, B. E., Sanes, J. R. 1995; 28 (3): 381-390

  Abstract

  The avian ciliary ganglion (CG) contains two populations of neurons: ciliary neurons, which innervate striated muscle, and choroid neurons, which innervate vascular smooth muscle. We used cell size (ciliary cells are larger) and somatostatin immunoreactivity (which is restricted to choroid cells) as markers to compare the adhesive properties of these two neuronal types. Similar numbers of freshly dissociated embryonic chick ciliary and choroid neurons adhered to laminin (laminin 1) and polylysine, consistent with the fact that each population comprises about half of the ganglionic neurons. In contrast, severalfold more ciliary neurons than choroid neurons adhered to a recombinant fragment of a synapsespecific basal lamina protein, s-laminin/laminin beta 2. Moreover, severalfold more ciliary neurons than choroid neurons adhered to a plastic surface when assayed by the method of Needels et al. in serum-free medium. Adhesion to s-laminin and plastic appears to be mediated by different cell surface components, as adhesion to recombinant s-laminin is inhibited by the tripeptide, LRE, and by Ca2+ ions, but not by heparin, whereas adhesion to plastic is LRE and Ca2+ insensitive but heparin sensitive. Both adhesive differences are apparent at embryonic day 8, soon after the ciliary and choroid neurons have begun to form synapses. Thus, two sets of neurons in the CG that send axons through different nerves and innervate different targets also show distinct adhesive behaviors.

  View details for Web of Science ID A1995TA42900009

  View details for PubMedID 8568518

• A MOTONEURON-SELECTIVE STOP SIGNAL IN THE SYNAPTIC PROTEIN S-LAMININ NEURON Porter, B. E., Weis, J., Sanes, J. R. 1995; 14 (3): 549-559

  Abstract

  Motor axons preferentially reinnervate original synaptic sites on denervated muscle fibers. We have shown that components of synaptic basal lamina direct this selectivity, and we identified a protein, s-laminin, that is concentrated in synaptic basal lamina. Here, we report that a recombinant s-laminin fragment inhibits neurite outgrowth promoted by laminin. A tripeptide sequence in this fragment, Leu-Arg-Glu (LRE), contributes to this inhibition and is itself sufficient to inhibit outgrowth. LRE-mediated inhibition is selective for motoneuron-like cells and is observed in mixtures with several, but not all, outgrowth-promoting substrates. Growth cones extending on laminin stop for up to several hours upon contacting deposits of the s-laminin fragment. Thus, LRE may serve as a cell type-selective and context-dependent target-derived signal that plays a role in synapse formation.

  View details for Web of Science ID A1995QP23000008

  View details for PubMedID 7695901

• GATED MIGRATION - NEURONS MIGRATE ON BUT NOT ONTO SUBSTRATES CONTAINING S-LAMININ DEVELOPMENTAL BIOLOGY Porter, B. E., Sanes, J. R. 1995; 167 (2): 609-616

  Abstract

  Components of the extracellular matrix influence migration of diverse cell types. Some, such as laminin, promote neuronal migration, whereas others are nonpermissive or inhibitory. Here, we demonstrate that a recombinant fragment of s-laminin, a homologue of the laminin B1 chain, is a barrier to neuronal migration. NSC-34 (motoneuron-like) and ciliary ganglion cells were plated on substrates coated with alternating stripes of laminin and a mixture of laminin plus s-laminin. On these patterned substrates, cells seldom crossed from s-laminin-free to s-laminin-containing regions. Mutation of the tripeptide LRE, an adhesive site in s-laminin, abolished s-laminin's ability to block border crossing. However, overall rates of migration were similar on the two substrates. This behavior contrasts with that of previously reported barrier molecules, which decreases rates of cell migration when mixed with permissive substrates. Instead, s-laminin appears to block cell migration through a "gating" mechanism that acts primarily at borders.

  View details for Web of Science ID A1995QK99000017

  View details for PubMedID 7875382

• S-LAMININ - MAPPING TO MOUSE CHROMOSOME-9 AND EXPRESSION IN THE LINKED MUTANTS TIPPY AND DUCKY GENOMICS Porter, B. E., JUSTICE, M. J., Copeland, N. G., Jenkins, N. A., Hunter, D. D., Merlie, J. P., Sanes, J. R. 1993; 16 (1): 278-281

  Abstract

  S-Laminin, a homologue of the laminin B1 chain, is present in a subset of basal laminae, including those of the skeletal neuromuscular junction and the renal glomerulus. Here, we show that the distribution and apparent size of murine S-laminin are similar to those documented previously for rat and human. We then use interspecific backcross analysis to map the S-laminin (Lams) gene to mouse chromosome 9. Thus, it is unlinked to genes for the laminin A, B1, and B2 chains. Finally, because the Lams gene mapped near two mutations that affect neuromuscular function, ducky (du) and tippy (tip), we assayed S-laminin by Southern blotting, immunoblotting, and immunohistochemistry in these mutants. No abnormality of the S-laminin gene or protein was detectable in either mutant.

  View details for Web of Science ID A1993KW20500046

  View details for PubMedID 8486374

• PRIMARY SEQUENCE OF A MOTOR NEURON SELECTIVE ADHESIVE SITE IN THE SYNAPTIC BASAL LAMINA PROTEIN S-LAMININ CELL Hunter, D. D., Porter, B. E., BULOCK, J. W., Adams, S. P., Merlie, J. P., Sanes, J. R. 1989; 59 (5): 905-913

  Abstract

  S-laminin, a novel homolog of laminin, is concentrated in a subset of basal laminae including the basal lamina that passes between motor nerve terminals and muscle fibers at the neuromuscular junction. Here we used recombinant fragments to localize a neuronal attachment site to the C-terminal 10% of s-laminin. We then used synthetic peptides spanning the active fragment to identify the primary sequence of the adhesive site as Leu-Arg-Glu (LRE): neurons attach to an immobilized LRE-containing peptide, and soluble LRE blocks attachment of neurons to the s-laminin fragment. Whereas ciliary ganglion neurons (which normally innervate muscle fibers) adhered well both to laminin and to an s-laminin fragment, sensory and central neurons and several neuronal cell lines all adhered well to laminin but poorly to the s-laminin fragment. Together, these results define a motor neuron-selective attachment site on s-laminin.

  View details for Web of Science ID A1989CC79800015

  View details for PubMedID 2590946

• RESTORATION OF CELL-VOLUME AND THE REVERSAL OF CARBOHYDRATE TRANSPORT AND GROWTH-INHIBITION OF OSMOTICALLY UP-SHOCKED ESCHERICHIA-COLI BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS ROTH, W. G., Porter, S. E., LECKIE, M. P., Porter, B. E., DIETZLER, D. N. 1985; 126 (1): 442-449

  Abstract

  Resumption of growth in osmotically upshocked Escherichia coli was effected only by an external stimulus (betaine treatment) in severe upshock, but was spontaneous in less severe upshock. In either case, growth resumption was preceded by a reversal of glucose transport inhibition, and that reversal was preceded by a recovery of cell volume. We hypothesize that deformation of the membrane by osmotic stress results in conversion of a membrane component of the transport system to a less functional conformation, which results in the inhibition of transport and the consequent inhibition of growth. Relief of the deformation would then allow recovery to a more functional conformation, reversal of transport inhibition, and then resumption of growth.

  View details for Web of Science ID A1985ABH5300063

  View details for PubMedID 3882088