223 results on '"Wheless JW"'
Search Results
2. Optimal clinical management of children receiving dietary therapies for epilepsy: Updated recommendations of the International Ketogenic Diet Study Group.
- Author
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Kossoff, EH, Zupec-Kania, BA, Auvin, S, Ballaban-Gil, KR, Christina Bergqvist, AG, Blackford, R, Buchhalter, JR, Caraballo, RH, Cross, JH, Dahlin, MG, Donner, EJ, Guzel, O, Jehle, RS, Klepper, J, Kang, H-C, Lambrechts, DA, Liu, YMC, Nathan, JK, Nordli, DR, Pfeifer, HH, Rho, JM, Scheffer, IE, Sharma, S, Stafstrom, CE, Thiele, EA, Turner, Z, Vaccarezza, MM, van der Louw, EJTM, Veggiotti, P, Wheless, JW, Wirrell, EC, Charlie Foundation, Matthew's Friends, Practice Committee of the Child Neurology Society, Kossoff, EH, Zupec-Kania, BA, Auvin, S, Ballaban-Gil, KR, Christina Bergqvist, AG, Blackford, R, Buchhalter, JR, Caraballo, RH, Cross, JH, Dahlin, MG, Donner, EJ, Guzel, O, Jehle, RS, Klepper, J, Kang, H-C, Lambrechts, DA, Liu, YMC, Nathan, JK, Nordli, DR, Pfeifer, HH, Rho, JM, Scheffer, IE, Sharma, S, Stafstrom, CE, Thiele, EA, Turner, Z, Vaccarezza, MM, van der Louw, EJTM, Veggiotti, P, Wheless, JW, Wirrell, EC, Charlie Foundation, Matthew's Friends, and Practice Committee of the Child Neurology Society
- Abstract
Ketogenic dietary therapies (KDTs) are established, effective nonpharmacologic treatments for intractable childhood epilepsy. For many years KDTs were implemented differently throughout the world due to lack of consistent protocols. In 2009, an expert consensus guideline for the management of children on KDT was published, focusing on topics of patient selection, pre-KDT counseling and evaluation, diet choice and attributes, implementation, supplementation, follow-up, side events, and KDT discontinuation. It has been helpful in outlining a state-of-the-art protocol, standardizing KDT for multicenter clinical trials, and identifying areas of controversy and uncertainty for future research. Now one decade later, the organizers and authors of this guideline present a revised version with additional authors, in order to include recent research, especially regarding other dietary treatments, clarifying indications for use, side effects during initiation and ongoing use, value of supplements, and methods of KDT discontinuation. In addition, authors completed a survey of their institution's practices, which was compared to responses from the original consensus survey, to show trends in management over the last 10 years.
- Published
- 2018
3. THE KETOGENIC DIET: CLINICAL EFFICACY IN DIFFERENT SEIZURE TYPES AND EPILEPSY SYNDROMES
- Author
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Wheless, JW, primary
- Published
- 2006
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4. Toward the substitution of invasive electroencephalography in epilepsy surgery.
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Papanicolaou AC, Pataraia E, Billingsley-Marshall R, Castillo EM, Wheless JW, Swank P, Breier JI, Sarkari S, Simos PG, Papanicolaou, Andrew C, Pataraia, Ekaterina, Billingsley-Marshall, Rebecca, Castillo, Eduardo M, Wheless, James W, Swank, Paul, Breier, Joshua I, Sarkari, Shirin, and Simos, Panagiotis G
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- 2005
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5. A magnetoencephalography study of cortical plasticity.
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Breier, JI, Simos, PG, Wheless, JW, Zouridakis, G, Willmore, LJ, Constantinou, JEC, and Papanicolaou, AC
- Abstract
Presents a case study of the effect of a large left hemisphere arteriovenous malformation (AVM) on the development of somatosensory areas as assessed by magnetoencephalography (MEG). Definition of MEG; Magnetic resonance imaging of the brain demonstrating a large, left corvical, nearly hemispheric AVM with mild gliosis of the involved parenchyma; Standard scores on neuropsychological and motor measures for a patient.
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- 1999
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6. Physiology of perception: cortical stimulation and recording in humans.
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Ray PG, Meador KJ, Smith JR, Wheless JW, Sittenfeld M, Clifton GL, Ray, P G, Meador, K J, Smith, J R, Wheless, J W, Sittenfeld, M, and Clifton, G L
- Published
- 1999
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7. Rapid infusion with valproate sodium is well tolerated in patients with epilepsy.
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Wheless JW, Vazquez BR, Kanner AM, Ramsay RE, Morton L, Pellock JM, Wheless, J W, Vazquez, B R, Kanner, A M, Ramsay, R E, Morton, L, and Pellock, J M
- Published
- 2004
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8. Earlier use of adjunctive vagus nerve stimulation therapy for refractory epilepsy.
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Renfroe JB, Wheless JW, Renfroe, J Ben, and Wheless, James W
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- 2002
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9. The evolving place of vagus nerve stimulation therapy.
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Schachter SC, Wheless JW, Schachter, Steven C, and Wheless, James W
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- 2002
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10. Vagus nerve stimulation therapy in patients younger than 18 years.
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Wheless JW, Maggio V, Wheless, James W, and Maggio, Vijay
- Published
- 2002
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11. Transcranial magnetic stimulation and magnetoencephalography are feasible alternatives to invasive methods in optimizing responsive neurostimulation device placement.
- Author
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Varner JA, Rezaie R, Noorizadeh N, Boop FA, Fulton SP, Klimo P, Shimony N, Wheless JW, and Narayana S
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- Humans, Female, Male, Young Adult, Adult, Retrospective Studies, Adolescent, Brain Mapping methods, Treatment Outcome, Magnetoencephalography methods, Transcranial Magnetic Stimulation methods, Drug Resistant Epilepsy therapy, Drug Resistant Epilepsy physiopathology
- Abstract
Responsive neurostimulation (RNS) is a treatment option for patients with refractory epilepsy when surgical resection is not possible due to overlap of the irritative zone and eloquent cortex. Presurgical evaluations for RNS placement typically rely on invasive methods. This study investigated the potential of transcranial magnetic stimulation (TMS) and magnetoencephalography (MEG) to provide key presurgical information non-invasively. We hypothesized that these non-invasive methods may assist in optimizing RNS placement by providing useful information for seizure localization by MEG and eloquent cortex mapping by TMS. A retrospective chart review identified nine patients who underwent RNS placement (mean age = 20.4 years [SD = 5.6], two-thirds were female). Characterization of the irritative zone using MEG was successful in eight of nine patients. Non-invasive mapping of relevant eloquent cortex was attempted in all patients. TMS was successful in eight of nine patients, and MEG was successful in two of six patients. Importantly, patients mapped with non-invasive modalities experienced an average seizure reduction of 77 % at their most recent clinic visit, compared to 75 % seizure reduction in those with invasive evaluations, indicating appropriate RNS placement. These data demonstrate that TMS and MEG can provide key information for RNS and may be feasible alternatives to invasive methods for assisting in decision making regarding RNS placement. Non-invasive methods for determining RNS placement have a high rate of success when data from multiple non-invasive modalities converge and can inform more accurate placement of intracranial electrodes prior to RNS placement or mitigate their need., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)
- Published
- 2024
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12. Diazepam nasal spray administration is effective to control seizure clusters irrespective of time of day.
- Author
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Liow K, Wheless JW, Cook DF, Rabinowicz AL, and Carrazana E
- Abstract
Introduction: Neurologic circadian influences, including sleep/wake transitions, processes (e.g., hormonal variation), and behavioral patterns (e.g., consumption of food and oral medications), may affect seizure patterns. Specific circadian patterns of seizures have been reported depending on type, onset location, and severity; however, data on patterns for patients with seizure clusters and effectiveness of rescue therapy by time of day are limited., Methods: We conducted post hoc analyses using patient diary data from the phase 3 safety study of diazepam nasal spray, which is indicated for acute treatment of seizure clusters in patients with epilepsy aged ≥6 years. Patients were administered age- and weight-based doses; second doses could be administered if needed to control a seizure cluster. We assessed clock timing of seizure-cluster onset along with second-dose use as a proxy for effectiveness. Treatment-emergent adverse events were recorded., Results: Seizure-cluster onset was observed to be generally highest during mornings and late evenings and lowest in the early evening and middle of the night. Second-dose use was not consistently associated with a specific time of day. The safety profile was consistent with that expected from previous studies of diazepam nasal spray., Conclusion: These results suggest that diazepam nasal spray can be effectively administered at any time of day., Competing Interests: KL has received research support from National Institute of Neurological Disorders and Stroke; National Institutes of Health; Xenon; SK Life Science; Cerevel; Longboard; T3D; Athira; Takeda; UCB; NovoNordisk; Ipsen; Avanir; Ra Pharma; Sanofi; Novartis; Praxis; Annovis; Merck; NeuroDerm; Acadia; Biogen; Idorsia; Eisai; Axsome; Engage; LivaNova; Neurelis, Inc.; Sage; Jazz; NLS Pharmaceutics; Cyclerion; and Takeda. JW has served as an advisor or consultant for CombiMatrix; Eisai; GW Pharmaceuticals; Lundbeck; Neurelis, Inc.; NeuroPace; Supernus Pharmaceuticals; and Upsher-Smith Laboratories. He has served as a speaker or a member of a speakers bureau for Cyberonics; Eisai; Lundbeck; Mallinckrodt; Neurelis, Inc.; Supernus Pharmaceuticals; and Upsher-Smith Laboratories and has received grants for clinical research from Acorda Therapeutics; GW Pharmaceuticals; Insys Therapeutics; Lundbeck; Mallinckrodt; Neurelis, Inc.; NeuroPace; Upsher-Smith Laboratories; and Zogenix. DC and EC are employees of and have received stock and stock options from Neurelis, Inc. AR is an employee of and has received stock options from Neurelis, Inc. The authors retained full control of content of this manuscript and the decision to submit it for publication. The authors declare that this study received funding from Neurelis, Inc. The funder was involved in study design and collection and analysis of data., (Copyright © 2024 Liow, Wheless, Cook, Rabinowicz and Carrazana.)
- Published
- 2024
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13. Safety and effectiveness of diazepam nasal spray in male and female patients: Post hoc analysis of data from a phase 3 safety study.
- Author
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Wheless JW, Hogan RE, Davis CS, Carrazana E, and Rabinowicz AL
- Subjects
- Humans, Female, Male, Child, Diazepam therapeutic use, Diazepam adverse effects, Benzodiazepines therapeutic use, Seizures drug therapy, Nasal Sprays, Anticonvulsants adverse effects
- Abstract
Sex differences in drug pharmacokinetics include variations in the expression of the cytochrome P450 enzymes, which are involved in the metabolism of benzodiazepines. It is unclear whether sex influences outcomes associated with intranasally administered drugs. A post hoc analysis of sex differences was conducted to evaluate the effectiveness and safety of diazepam nasal spray, which included examining changes in the number of days between seizure clusters over time (SEIzure interVAL [SEIVAL]). Diazepam nasal spray is approved for acute treatment of seizure clusters in patients with epilepsy aged ≥6 years. Data from a phase 3 safety study were used to determine the proportion of second doses used within 24 h (ie, a proxy for effectiveness) and SEIVAL. Adverse events were recorded. Of 163 treated patients, 89 were female, and 74 were male. Approximately 16% of both sexes self-administered the study drug. A slightly higher proportion of seizure clusters was treated with a second dose in female (14.7%) than male (9.4%) patients. SEIVAL increased significantly and substantially over a year for all patients. The safety profile was generally similar between the sexes. These results suggest that potential sex differences in benzodiazepine pharmacokinetics do not meaningfully influence outcomes associated with diazepam nasal spray. PLAIN LANGUAGE SUMMARY: Some drugs may have differences in absorption and metabolism between genders that could translate into differences in safety and effectiveness. This safety study looked at diazepam nasal spray for treating seizure clusters in patients at least 6 years old. It found that safety was about the same for females and males. For both groups, most clusters stopped after only 1 dose of the drug, and the time between treated clusters got longer over a year., (© 2024 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)
- Published
- 2024
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14. Concordance between Wada, Transcranial Magnetic Stimulation, and Magnetoencephalography for Determining Hemispheric Dominance for Language: A Retrospective Study.
- Author
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Noorizadeh N, Rezaie R, Varner JA, Wheless JW, Fulton SP, Mudigoudar BD, Nevill L, Holder CM, and Narayana S
- Abstract
Determination of language hemispheric dominance (HD) in patients undergoing evaluation for epilepsy surgery has traditionally relied on the sodium amobarbital (Wada) test. The emergence of non-invasive methods for determining language laterality has increasingly shown to be a viable alternative. In this study, we assessed the efficacy of transcranial magnetic stimulation (TMS) and magnetoencephalography (MEG), compared to the Wada test, in determining language HD in a sample of 12 patients. TMS-induced speech errors were classified as speech arrest, semantic, or performance errors, and the HD was based on the total number of errors in each hemisphere with equal weighting of all errors (classic) and with a higher weighting of speech arrests and semantic errors (weighted). Using MEG, HD for language was based on the spatial extent of long-latency activity sources localized to receptive language regions. Based on the classic and weighted language laterality index (LI) in 12 patients, TMS was concordant with the Wada in 58.33% and 66.67% of patients, respectively. In eight patients, MEG language mapping was deemed conclusive, with a concordance rate of 75% with the Wada test. Our results indicate that TMS and MEG have moderate and strong agreement, respectively, with the Wada test, suggesting they could be used as non-invasive substitutes.
- Published
- 2024
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15. Pitfalls of using video-EEG for a trial endpoint in children aged <4 years with focal seizures.
- Author
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Bozorg A, Beller C, Jensen L, Arzimanoglou A, Chiron C, Dlugos D, Gaitanis J, Wheless JW, and McClung C
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- Child, Humans, Child, Preschool, Lacosamide therapeutic use, Reproducibility of Results, Treatment Outcome, Seizures diagnosis, Seizures drug therapy, Seizures chemically induced, Electroencephalography, Anticonvulsants, Epilepsies, Partial diagnosis, Epilepsies, Partial drug therapy
- Abstract
Objective: Double-blind, randomized, and placebo-controlled trial SP0967 (NCT02477839/2013-000717-20) did not demonstrate superior efficacy of lacosamide versus placebo in patients aged ≥1 month to <4 years with uncontrolled focal seizures, per ≤72 h video-electroencephalogram (video-EEG)-based primary endpoints (reduction in average daily frequency of focal seizures at end-of-maintenance [EOM] versus end-of-baseline [EOB], patients with ≥50% response). This was unexpected because randomized controlled trial SP0969 (NCT01921205) showed efficacy of lacosamide in patients aged ≥4 to <17 years with uncontrolled focal seizures. SP0969's primary endpoint was based on seizure diary instead of video-EEG, an issue with the latter being inter-reader variability. We evaluated inter-reader agreement in video-EEG interpretation in SP0967, which to our knowledge, are the first such data for very young children with focal seizures from a placebo-controlled trial., Methods: Local investigator and central reader agreement in video-EEG interpretation was analyzed post hoc., Results: Analysis included 105 EOB and 98 EOM video-EEGs. Local investigators and central reader showed poor agreement based on ≥2 focal seizures at EOB (Kappa = 0.01), and fair agreement based on ≥2 focal seizures at EOM (Kappa = 0.23). Local investigator and central reader seizure count interpretations varied substantially, particularly for focal seizures, but also primary generalized and unclassified epileptic seizures, at both timepoints., Interpretation: High inter-reader variability and low inter-reader reliability of the interpretation of seizure types and counts prevent confident conclusion regarding the lack of efficacy of lacosamide in this population. We recommend studies in very young children do not employ video-EEGs exclusively for accurate study inclusion or as an efficacy measure., (© 2024 UCB Biopharma SRL. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)
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- 2024
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16. Zonisamide: A Comprehensive, Updated Review for the Clinician.
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Gidal BE, Resnick T, Smith MC, and Wheless JW
- Abstract
Purpose of Review: Zonisamide (ZNS) was first approved in the United States in 2000 for the adjunctive treatment of patients aged 16 years or older with partial (focal) seizures. Although ZNS has been proven to treat multiple seizure types, it has been largely underutilized in US clinical practice., Recent Findings: Published literature demonstrated that antiseizure medications (ASMs) acting on Na
+ and Ca2+ channels may add beneficial effects in many seizure types by reducing seizure frequency and leading to overall improvements. In addition, effects of ZNS may lead to clinical improvements in Parkinson disease, alcohol and sleep disorders, pain, and migraine. ZNS is available in multiple formulations and is a safe and effective, broad spectrum ASM., Summary: The purpose of this review was to provide an update to what is known about the efficacy of ZNS and where it shows benefits in the treatment of patients with epilepsy and other CNS disorders through its many unique mechanisms of action., Competing Interests: B.E. Gidal—Speaking honoraria: Azurity, Aquestive, SK Lifescience, Jazz. Consulting: UCB, SK-Lifescience, Jazz, Azurity, Eisai. M. Smith—Speaking: SK Lifescience, Neurelis. Consulting: Azurity, SK Lifescience, Neurelis. J. Wheless—LivNova, Eisai, Supernus, Envision, UCB, Neurelis, Xenon, Marinus, Biomarin, SK Lifescience; Consulting: Xenon, Marinus, Azurity. Grants: TSC Alliance, NIH, Supernus, Neuro Event Labs, Marinus, Neurelis, Epiwatch, SK Lifescience, Longboard, Biohaven, UCB, Shainberg Foundation. T. Resnick—Speaking: Sunovion, UCB, Eisai. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/cp.TAKE-HOME POINTS→ ZNS's long half-life and once-daily dosing schedule contribute to improved adherence compared with other antiseizure medications (ASMs) with more frequent administration.→ ZNS is generally well-tolerated and has manageable safety issues. Its multiple mechanisms of action (MOAs) allow for coadministration with ASMs of different MOAs, increasing medication efficacy, and reducing seizure frequency.→ ZNS is a safe and effective ASM with therapeutic indications in multiple epilepsy etiologies and with potential benefits in other disease states., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)- Published
- 2024
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17. Severe communication delays are independent of seizure burden and persist despite contemporary treatments in SCN1A+ Dravet syndrome: Insights from the ENVISION natural history study.
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Perry MS, Scheffer IE, Sullivan J, Brunklaus A, Boronat S, Wheless JW, Laux L, Patel AD, Roberts CM, Dlugos D, Holder D, Knupp KG, Lallas M, Phillips S, Segal E, Smeyers P, Lal D, Wirrell E, Zuberi S, Brünger T, Wojnaroski M, Maru B, O'Donnell P, Morton M, James E, Vila MC, Huang N, Gofshteyn JS, and Rico S
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- Infant, Humans, Child, Preschool, Infant, Newborn, Prospective Studies, Mutation, Seizures drug therapy, Seizures genetics, Seizures complications, NAV1.1 Voltage-Gated Sodium Channel genetics, Communication, Epilepsies, Myoclonic drug therapy, Epilepsies, Myoclonic genetics, Epilepsies, Myoclonic complications
- Abstract
Objective: Dravet syndrome (DS) is a developmental and epileptic encephalopathy characterized by high seizure burden, treatment-resistant epilepsy, and developmental stagnation. Family members rate communication deficits among the most impactful disease manifestations. We evaluated seizure burden and language/communication development in children with DS., Methods: ENVISION was a prospective, observational study evaluating children with DS associated with SCN1A pathogenic variants (SCN1A+ DS) enrolled at age ≤5 years. Seizure burden and antiseizure medications were assessed every 3 months and communication and language every 6 months with the Bayley Scales of Infant and Toddler Development 3rd edition and the parent-reported Vineland Adaptive Behavior Scales 3rd edition. We report data from the first year of observation, including analyses stratified by age at Baseline: 0:6-2:0 years:months (Y:M; youngest), 2:1-3:6 Y:M (middle), and 3:7-5:0 Y:M (oldest)., Results: Between December 2020 and March 2023, 58 children with DS enrolled at 16 sites internationally. Median follow-up was 17.5 months (range = .0-24.0), with 54 of 58 (93.1%) followed for at least 6 months and 51 of 58 (87.9%) for 12 months. Monthly countable seizure frequency (MCSF) increased with age (median [minimum-maximum] = 1.0 in the youngest [1.0-70.0] and middle [1.0-242.0] age groups and 4.5 [.0-2647.0] in the oldest age group), and remained high, despite use of currently approved antiseizure medications. Language/communication delays were observed early, and developmental stagnation occurred after age 2 years with both instruments. In predictive modeling, chronologic age was the only significant covariate of seizure frequency (effect size = .52, p = .024). MCSF, number of antiseizure medications, age at first seizure, and convulsive status epilepticus were not predictors of language/communication raw scores., Significance: In infants and young children with SCN1A+ DS, language/communication delay and stagnation were independent of seizure burden. Our findings emphasize that the optimal therapeutic window to prevent language/communication delay is before 3 years of age., (© 2023 Encoded Therapeutics. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)
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- 2024
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18. Practical Questions About Rescue Medications for Acute Treatment of Seizure Clusters in Children and Adolescents with Epilepsy in the USA: Expanding Treatment Options to Address Unmet Needs.
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Wheless JW, Gidal B, Rabinowicz AL, and Carrazana E
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- Adult, Humans, Adolescent, Child, Anticonvulsants adverse effects, Quality of Life, Seizures drug therapy, Epilepsy drug therapy, Status Epilepticus drug therapy
- Abstract
Epilepsy is a common pediatric neurological condition, affecting approximately 470,000 children in the USA and having a prevalence of 0.9% in the global population of approximately 2.6 billion children. Epilepsy is associated with disruptions in several areas of a child's life, including medical burden, quality of life, cognitive outcomes, and higher risk of mortality. Additionally, some pediatric patients may experience acute seizure emergencies such as seizure clusters (also called acute repetitive seizures), which are intermittent increases in seizure activity that differ from the patient's usual seizure pattern and may occur despite daily antiseizure drug administration. Seizure clusters increase a patient's risk for status epilepticus and emergency room visits. Benzodiazepines are the main category of drugs used as acute seizure therapies for seizure clusters. This narrative review provides a practical discussion of care for pediatric patients with epilepsy and seizure clusters exploring such topics as details about the US Food and Drug Administration-approved acute seizure therapies, safety and ease of use of these medications, benefits of seizure action plans to help ensure optimal treatment, and considerations for transitioning a pediatric patient with acute seizure therapy to adult healthcare management., (© 2023. The Author(s).)
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- 2024
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19. Treatment of Seizure Clusters in Epilepsy: A Narrative Review on Rescue Therapies.
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Becker DA, Wheless JW, Sirven J, Tatum WO, Rabinowicz AL, and Carrazana E
- Abstract
Epilepsy is a common neurological disorder in the United States, affecting approximately 1.2% of the population. Some people with epilepsy may experience seizure clusters, which are acute repetitive seizures that differ from the person's usual seizure pattern. Seizure clusters are unpredictable, are emotionally burdensome to patients and caregivers (including care partners), and require prompt treatment to prevent progression to serious outcomes, including status epilepticus and associated morbidity (e.g., lacerations, fractures due to falls) and mortality. Rescue medications for community use can be administered to terminate a seizure cluster, and benzodiazepines are the cornerstone of rescue treatment. Despite the effectiveness of benzodiazepines and the importance of a rapid treatment approach, as many as 80% of adult patients do not use rescue medication to treat seizure clusters. This narrative review provides an update on rescue medications used for treatment of seizure clusters, with an emphasis on clinical development and study programs for diazepam rectal gel, midazolam nasal spray, and diazepam nasal spray. Results from long-term clinical trials have shown that treatments for seizure clusters are effective. Intranasal benzodiazepines provide ease of use and patient and caregiver satisfaction in pediatric and adult patients. Adverse events attributed to acute rescue treatments have been characterized as mild to moderate, and no reports of respiratory depression have been attributed to treatment in long-term safety studies. The implementation of an acute seizure action plan to facilitate optimal use of rescue medications provides an opportunity for improved management of seizure clusters, allowing those affected to resume normal daily activities more quickly., (© 2023. The Author(s).)
- Published
- 2023
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20. Safety of Diazepam Nasal Spray in Pediatric Patients With Developmental Epileptic Encephalopathies: Results From a Long-term Phase 3 Safety Study.
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Tarquinio D, Wheless JW, Segal EB, Misra SN, Rabinowicz AL, and Carrazana E
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- Child, Humans, Anticonvulsants adverse effects, Diazepam adverse effects, Nasal Sprays, Seizures drug therapy, Brain Diseases, Epilepsy drug therapy, Epilepsy, Generalized drug therapy, Lennox Gastaut Syndrome drug therapy
- Abstract
Pediatric developmental epileptic encephalopathies are often refractory to treatment despite stable antiseizure therapy. The safety profile of diazepam nasal spray (Valtoco) as rescue therapy for seizure clusters was described in a long-term safety study. This post hoc analysis assessed safety and effectiveness within a subpopulation of patients with developmental epileptic encephalopathies. Of 163 treated patients, 64 were diagnosed with ≥1 pediatric developmental epileptic encephalopathy. Among the most common developmental epileptic encephalopathies were Rett syndrome (n = 16), Lennox-Gastaut syndrome (n = 9), and Dravet syndrome (n = 7). In the broad pediatric developmental epileptic encephalopathy group, 10.6% of seizure clusters were treated with a second dose, with similar proportions in the 3 individual encephalopathies. Across groups, treatment-emergent adverse event rates ranged from 66.7% to 100%. Only epistaxis (n = 2) was treatment-related and reported in >1 patient. In this long-term safety analysis in patients with developmental epileptic encephalopathies, diazepam nasal spray demonstrated a consistent safety profile, supporting its use in these hard-to-treat patients (ClinicalTrials.gov NCT02721069).
- Published
- 2023
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21. Dispensary Cannabidiol (CBD): Nothing to Worry About!
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Elliott T, Gienapp AJ, and Wheless JW
- Abstract
Introduction: Despite US FDA approval of cannabidiol (CBD) liquid (Epidiolex®), patients with epilepsy still supplement prescription treatments with dispensary CBD. This study aimed to evaluate therapeutic effectiveness of dispensary CBD. Methods: We retrospectively collected dosage information, CBD serum levels, efficacy, and adverse effects from patient charts (children, adolescents, adults) (n = 18). Results: All 18 patients showed no clinical benefit from dispensary CBD as detectable serum levels never reached a therapeutic range of 150 ng/mL (6 patients had barely detectable levels that were below laboratory reporting thresholds). Minute levels of tetrahydrocannabinol (THC) were found in 3 patients, and moderate levels were found in 1 patient. Conclusion: Dispensary CBD failed to reach effective therapeutic levels in all of these patients. The presence of THC demonstrates the current lack of regulation of dispensary CBD. Anecdotal reports of clinical effectiveness should be considered an effect of concomitant prescription antiseizure medications and not dispensary CBD., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)
- Published
- 2023
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22. Genetic Testing to Inform Epilepsy Treatment Management From an International Study of Clinical Practice.
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McKnight D, Morales A, Hatchell KE, Bristow SL, Bonkowsky JL, Perry MS, Berg AT, Borlot F, Esplin ED, Moretz C, Angione K, Ríos-Pohl L, Nussbaum RL, Aradhya S, Haldeman-Englert CR, Levy RJ, Parachuri VG, Lay-Son G, de Montellano DJD, Ramirez-Garcia MA, Benítez Alonso EO, Ziobro J, Chirita-Emandi A, Felix TM, Kulasa-Luke D, Megarbane A, Karkare S, Chagnon SL, Humberson JB, Assaf MJ, Silva S, Zarroli K, Boyarchuk O, Nelson GR, Palmquist R, Hammond KC, Hwang ST, Boutlier SB, Nolan M, Batley KY, Chavda D, Reyes-Silva CA, Miroshnikov O, Zuccarelli B, Amlie-Wolf L, Wheless JW, Seinfeld S, Kanhangad M, Freeman JL, Monroy-Santoyo S, Rodriguez-Vazquez N, Ryan MM, Machie M, Guerra P, Hassan MJ, Candee MS, Bupp CP, Park KL, Muller E 2nd, Lupo P, Pedersen RC, Arain AM, Murphy A, Schatz K, Mu W, Kalika PM, Plaza L, Kellogg MA, Lora EG, Carson RP, Svystilnyk V, Venegas V, Luke RR, Jiang H, Stetsenko T, Dueñas-Roque MM, Trasmonte J, Burke RJ, Hurst ACE, Smith DM, Massingham LJ, Pisani L, Costin CE, Ostrander B, Filloux FM, Ananth AL, Mohamed IS, Nechai A, Dao JM, Fahey MC, Aliu E, Falchek S, Press CA, Treat L, Eschbach K, Starks A, Kammeyer R, Bear JJ, Jacobson M, Chernuha V, Meibos B, Wong K, Sweney MT, Espinoza AC, Van Orman CB, Weinstock A, Kumar A, Soler-Alfonso C, Nolan DA, Raza M, Rojas Carrion MD, Chari G, Marsh ED, Shiloh-Malawsky Y, Parikh S, Gonzalez-Giraldo E, Fulton S, Sogawa Y, Burns K, Malets M, Montiel Blanco JD, Habela CW, Wilson CA, Guzmán GG, and Pavliuk M
- Subjects
- Humans, Female, Infant, Newborn, Infant, Child, Preschool, Child, Adolescent, Young Adult, Adult, Middle Aged, Male, Retrospective Studies, Cross-Sectional Studies, Seizures genetics, Genetic Testing methods, Epilepsy drug therapy, Epilepsy genetics
- Abstract
Importance: It is currently unknown how often and in which ways a genetic diagnosis given to a patient with epilepsy is associated with clinical management and outcomes., Objective: To evaluate how genetic diagnoses in patients with epilepsy are associated with clinical management and outcomes., Design, Setting, and Participants: This was a retrospective cross-sectional study of patients referred for multigene panel testing between March 18, 2016, and August 3, 2020, with outcomes reported between May and November 2020. The study setting included a commercial genetic testing laboratory and multicenter clinical practices. Patients with epilepsy, regardless of sociodemographic features, who received a pathogenic/likely pathogenic (P/LP) variant were included in the study. Case report forms were completed by all health care professionals., Exposures: Genetic test results., Main Outcomes and Measures: Clinical management changes after a genetic diagnosis (ie, 1 P/LP variant in autosomal dominant and X-linked diseases; 2 P/LP variants in autosomal recessive diseases) and subsequent patient outcomes as reported by health care professionals on case report forms., Results: Among 418 patients, median (IQR) age at the time of testing was 4 (1-10) years, with an age range of 0 to 52 years, and 53.8% (n = 225) were female individuals. The mean (SD) time from a genetic test order to case report form completion was 595 (368) days (range, 27-1673 days). A genetic diagnosis was associated with changes in clinical management for 208 patients (49.8%) and usually (81.7% of the time) within 3 months of receiving the result. The most common clinical management changes were the addition of a new medication (78 [21.7%]), the initiation of medication (51 [14.2%]), the referral of a patient to a specialist (48 [13.4%]), vigilance for subclinical or extraneurological disease features (46 [12.8%]), and the cessation of a medication (42 [11.7%]). Among 167 patients with follow-up clinical information available (mean [SD] time, 584 [365] days), 125 (74.9%) reported positive outcomes, 108 (64.7%) reported reduction or elimination of seizures, 37 (22.2%) had decreases in the severity of other clinical signs, and 11 (6.6%) had reduced medication adverse effects. A few patients reported worsening of outcomes, including a decline in their condition (20 [12.0%]), increased seizure frequency (6 [3.6%]), and adverse medication effects (3 [1.8%]). No clinical management changes were reported for 178 patients (42.6%)., Conclusions and Relevance: Results of this cross-sectional study suggest that genetic testing of individuals with epilepsy may be materially associated with clinical decision-making and improved patient outcomes.
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- 2022
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23. Perampanel monotherapy for the treatment of epilepsy: Clinical trial and real-world evidence.
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Yamamoto T, Gil-Nagel A, Wheless JW, Kim JH, and Wechsler RT
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- Humans, Retrospective Studies, Prospective Studies, Treatment Outcome, Pyridones adverse effects, Drug Therapy, Combination, Anticonvulsants adverse effects, Epilepsy drug therapy, Epilepsy chemically induced
- Abstract
Perampanel, a selective, non-competitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist, is a once-daily oral anti-seizure medication (ASM) for focal-onset seizures (FOS) and generalized tonic-clonic seizures (GTCS). In the US, perampanel is approved for the treatment of FOS (adjunctive and monotherapy), with or without focal to bilateral tonic-clonic seizures (FBTCS), in patients aged ≥4 years, and as adjunctive treatment of GTCS in patients aged ≥12 years. The monotherapy approvals in the US were based on the Food and Drug Administration's (FDA's) policy allowing extrapolation of adjunctive data to the monotherapy setting in the absence of randomized controlled monotherapy trials; since then, perampanel monotherapy has received approvals in approximately 48 countries. As there are key differences in clinical evidence of perampanel as adjunctive therapy vs monotherapy, we review the clinical outcomes of perampanel when administered as primary or secondary monotherapy. Eight publications reporting the efficacy and safety outcomes of perampanel monotherapy in clinical trial and real-world settings were selected during our literature search and are included; these comprise three Eisai-sponsored studies in patients with epilepsy: one prospective, open-label, Phase III clinical trial of patients with newly diagnosed epilepsy (Study 342 [FREEDOM]) and two retrospective, real-world Phase IV studies of patients with epilepsy who received perampanel during routine clinical care (Studies 504 and 506 [PROVE]); and five retrospective, real-world studies in patients with epilepsy who were prescribed perampanel during routine clinical care. Results from these studies demonstrated that seizure freedom may be achieved following treatment with perampanel monotherapy (either primary or secondary), with favorable retention rates and safety profiles. Overall, the clinical evidence supports the use of perampanel monotherapy both in newly diagnosed patients and in those who have been unable to control their seizures with other ASMs., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2022
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24. Future opportunities for research in rescue treatments.
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Wheless JW, Friedman D, Krauss GL, Rao VR, Sperling MR, Carrazana E, and Rabinowicz AL
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- Caregivers, Humans, Seizures drug therapy, Anticonvulsants therapeutic use, Epilepsy, Generalized drug therapy
- Abstract
Clinical studies of rescue medications for seizure clusters are limited and are designed to satisfy regulatory requirements, which may not fully consider the needs of the diverse patient population that experiences seizure clusters or utilize rescue medication. The purpose of this narrative review is to examine the factors that contribute to, or may influence the quality of, seizure cluster research with a goal of improving clinical practice. We address five areas of unmet needs and provide advice for how they could enhance future trials of seizure cluster treatments. The topics addressed in this article are: (1) unaddressed end points to pursue in future studies, (2) roles for devices to enhance rescue medication clinical development programs, (3) tools to study seizure cluster prediction and prevention, (4) the value of other designs for seizure cluster studies, and (5) unique challenges of future trial paradigms for seizure clusters. By focusing on novel end points and technologies with value to patients, caregivers, and clinicians, data obtained from future studies can benefit the diverse patient population that experiences seizure clusters, providing more effective, appropriate care as well as alleviating demands on health care resources., (© 2022 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)
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- 2022
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25. Lack of clinically relevant differences in safety and pharmacokinetics after second-dose administration of intranasal diazepam within 4 h for acute treatment of seizure clusters: A population analysis.
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Cascino GD, Tarquinio D, Wheless JW, Hogan RE, Sperling MR, Desai J, Vazquez B, Samara E, Misra SN, Carrazana E, and Rabinowicz AL
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- Administration, Intranasal, Anticonvulsants therapeutic use, Humans, Nasal Sprays, Seizures chemically induced, Seizures drug therapy, Diazepam therapeutic use, Epilepsy, Generalized drug therapy
- Abstract
Objective: Current diazepam nasal spray labeling requires waiting 4 h before administering a second dose. The objective of the current analyses was to examine safety and pharmacokinetic profiles of second doses of diazepam nasal spray given 0-4 h after the first dose., Methods: Two datasets were analyzed. The first, a long-term, repeat-dose safety study of diazepam nasal spray, compared rates of treatment-emergent adverse events (TEAEs), serious TEAEs, and treatment-related TEAEs for patients receiving ≥1 second dose ≤4 h versus all second doses >4 h after the first. The second was a population pharmacokinetic analysis using data from three phase 1 studies to model drug exposure when a second dose of diazepam nasal spray was administered across multiple time points (1 min-4 h) following the first dose., Results: In the repeat-dose safety study, a second dose of diazepam nasal spray was administered ≤24 h after the first to treat 485 seizure clusters in 79 patients. Rates of TEAEs were similar between patients receiving ≥1 second dose in ≤4 h (89.5%, n = 38) compared with >4-24 h only (80.5%, n = 41). The most common treatment-related TEAEs were associated with nasal discomfort, which was mild or moderate and transient. There were no reports of respiratory or cardiac depression. The pharmacokinetic simulations of second doses predicted comparable elevations of plasma diazepam concentrations with administrations across a range of intervals after the first dose (1 min-4 h)., Significance: These data indicate that the safety and pharmacokinetic profiles of a second dose of diazepam nasal spray administered within 4 h of the first dose are consistent with those associated with current labeling. This is potentially important for patients with seizure clusters who have a recurrent seizure within 4 h of first treatment and might benefit from immediate retreatment to reduce the risk of progression to status epilepticus., (© 2022 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)
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- 2022
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26. Safety of Diazepam Nasal Spray in Children and Adolescents With Epilepsy: Results From a Long-Term Phase 3 Safety Study.
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Tarquinio D, Dlugos D, Wheless JW, Desai J, Carrazana E, and Rabinowicz AL
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- Administration, Intranasal, Adolescent, Adult, Aged, Anticonvulsants therapeutic use, Child, Diazepam adverse effects, Double-Blind Method, Female, Humans, Male, Middle Aged, Nasal Sprays, Seizures drug therapy, Treatment Outcome, Epilepsy drug therapy, Epilepsy, Generalized drug therapy
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Background: To evaluate safety and tolerability of long-term treatment with diazepam nasal spray (Valtoco) for seizure clusters in patients aged six to 17 years., Methods: The study enrolled patients aged six to 65 years with frequent seizure clusters. Age- and weight-based doses of diazepam nasal spray were administered; second doses were permitted if needed. Safety assessments included treatment-emergent adverse events (TEAEs)., Results: Of 163 treated patients, 45 (27.6%) were aged six to 11 years and 33 (20.2%) were aged 12 to 17 years. Mean doses per month were 2.1 in the 6 to 11 subgroup and 2.4 in the 12 to 17 subgroup. Of 1634 seizure clusters in pediatric patients, 186 (11.4%) required a second dose of diazepam nasal spray within 24 hours of the first dose. Similar proportions of TEAEs and serious TEAEs were reported in 6 to 11 (91.1%, 40.0%) and 12 to 17 subgroups (81.8%, 30.3%), respectively. No serious TEAEs were considered treatment related, and no patients discontinued because of TEAEs. Treatment-related TEAEs were more frequent in the 12 to 17 subgroup; only epistaxis and somnolence occurred in two or more patients overall. TEAE rates were similar across subgroups that received concomitant clobazam (90.0%), received prior diazepam rectal gel (90.9%), and were administered less than two versus greater than or equal to two doses per month (87.2% for both) of diazepam nasal spray. Most survey respondents (88%) were satisfied or very satisfied with treatment., Conclusions: In this long-term safety analysis in pediatric patients with seizure clusters, repeated doses of diazepam nasal spray demonstrated a safety profile consistent across subgroups. These data support the dosing guidelines for diazepam nasal spray according to age and weight for pediatric patients., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2022
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27. Image-guided TMS is safe in a predominately pediatric clinical population.
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Braden AA, Weatherspoon SE, Boardman T, Williard T, Adkins A, Gibbs SK, Wheless JW, and Narayana S
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- Brain Mapping methods, Child, Female, Humans, Male, Retrospective Studies, Seizures etiology, Transcranial Magnetic Stimulation adverse effects, Transcranial Magnetic Stimulation methods, Brain Neoplasms, Epilepsy diagnosis, Epilepsy etiology, Epilepsy therapy
- Abstract
Objective: The safety of transcranial magnetic stimulation (TMS) has been previously evaluated in healthy volunteers and clinical adult populations. We sought to fill the gap in safety of TMS functional mapping in a clinical, predominately pediatric cohort., Methods: In a retrospective chart review, we assessed TMS motor and language mapping studies in persons with epilepsy or brain tumor for adverse events and safety of TMS, and in patients with cranial metal., Results: Out of 500 TMS sessions attempted in 429 individual patients (51% males, 82% ≤ 18 y), seizures occurred in 29 sessions (5.8%) during or after TMS with semiology consistent with their typical presentation and 53 patients (10.6%) experienced pain during stimulation. TMS was completed safely in 276 patients with cranial metal., Conclusions: Most TMS-related adverse events were benign and transient; the most serious safety events were seizures that could not be conclusively attributed to TMS. However, useful mapping results were obtained in almost all patients. Presence of cranial metal did not adversely affect TMS mapping. We show that TMS functional mapping is safe in a largely pediatric clinical cohort., Significance: This study demonstrates the safety of TMS functional mapping in patients with refractory epilepsy, brain tumor or cranial metal and fills a gap in knowledge for TMS safety in pediatric clinical population., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)
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- 2022
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28. Initial Real-World Experience With Cenobamate in Adolescents and Adults: A Single Center Experience.
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Elliott T, Ridley-Pryor T, Gienapp AJ, and Wheless JW
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- Adolescent, Anticonvulsants adverse effects, Carbamates, Chlorophenols, Double-Blind Method, Humans, Retrospective Studies, Seizures chemically induced, Seizures drug therapy, Tetrazoles, Treatment Outcome, Young Adult, Drug-Related Side Effects and Adverse Reactions, Exanthema chemically induced, Exanthema drug therapy
- Abstract
Background: Following approval by the US Food and Drug Administration (FDA) in late 2019, cenobamate (Xcopri) has been utilized to treat adults with focal seizures. Based on its robust efficacy from the phase 2 trials, we began using cenobamate in our adolescent and young adult patients whose seizures were not controlled with previously available options. This study expanded its real-world application to this cohort with focal epilepsy and a history of drug-related rash., Methods: We conducted a retrospective study of our patients exposed to cenobamate (n = 45). We evaluated dosage and serum levels, efficacy, drug interactions, and adverse effects., Results: After gradually increasing cenobamate to clinical effect using the FDA-approved dosing protocol, 60% (n = 22) of patients were responders. Adolescents were treated with an average daily dose of 204.0 mg, and adults with 223.4 mg cenobamate, and had serum levels of 20.5 μg/mL and 26.7 μg/mL, respectively. The side effect profile observed was similar to that seen in the phase 2/3 registry trials. Importantly, patients with a prior history of rash to other medications or antiseizure medications (n = 5) experienced no rashes related to cenobamate., Conclusions: This real-world study supports the findings of prior controlled studies regarding the efficacy of cenobamate as a treatment for focal seizures in adolescents and suggests that patients with a history of rash may benefit from this medication., (Copyright © 2022 Elsevier Inc. All rights reserved.)
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- 2022
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29. Use of second doses of Valtoco® (diazepam nasal spray) across 24 hours after the initial dose for out-of-hospital seizure clusters: Results from a phase 3, open-label, repeat-dose safety study.
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Sperling MR, Wheless JW, Hogan RE, Dlugos D, Cascino GD, Liow K, Rabinowicz AL, and Carrazana E
- Subjects
- Administration, Intranasal, Anticonvulsants administration & dosage, Anticonvulsants adverse effects, Hospitals, Humans, Nasal Sprays, Diazepam administration & dosage, Diazepam adverse effects, Epilepsy, Generalized drug therapy, Seizures drug therapy
- Abstract
Objective: An exploratory analysis from a long-term, phase 3, open-label, repeat-dose safety study of diazepam nasal spray for acute treatment of seizure clusters assessed the use of a second dose up to 24 hours after the initial dose and effectiveness in potentially reducing the number of seizures., Methods: Seizures and doses were recorded in diaries., Results: Of 175 patients enrolled, 163 received ≥1 dose of diazepam nasal spray and were included in the safety population; those patients received a total of 4390 doses for a total of 3853 seizure clusters. Less than half of these patients used a second dose a least once during the study (79 patients [48.5%]), with a total of 485 second doses for seizure clusters (12.6% of all seizure clusters). Among these 79 patients, 33 (41.8%) used only one second dose during the study (range: 1-82). The proportion of seizure clusters treated with a second dose over time was consistently low across 24 h: 0-4 h, 152 (3.9%); 4-6 h, 72 (1.9%); 6-8 h, 39 (1.0%); 8-12 h, 55 (1.4%); 12-16 h, 42 (1.1%); 16-20 h, 42 (1.1%); 20-24 h, 83 (2.2%). Rates of treatment-emergent adverse events (TEAEs) and treatment-related TEAEs occurring within 1 day of a second dose were low (15.2% and 5.1%, respectively)., Significance: Patients with epilepsy may experience seizure clusters lasting up to 24 hours, and little is known about the effectiveness of rescue therapies for that duration. The current labeling of the US Food and Drug Administration (FDA)-approved outpatient treatments for seizure clusters (rectal diazepam, intranasal midazolam, and diazepam nasal spray) allows for a second dose, if needed, for control. These findings support the safety profile of second doses, and the low use supports the effectiveness of diazepam nasal spray across 24 hours., (© 2022 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)
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- 2022
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30. Sudden Unexpected Death in Epilepsy (SUDEP): How Do We Prevent This Childhood Tragedy?
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Mudigoudar B and Wheless JW
- Abstract
Competing Interests: Disclosure. Basanagoud Mudigoudar has no conflicts of interest to report. James W. Wheless has grant support from Avexis, EpiWatch, Aucta, Marinus, Neurecrine, Xenon, Stoke, Envision, NeuroEvents Lab, SKLSI, NeuroPace, NIH, TSC Alliance, Zogenix, and the Shainberg Foundation. He is a consultant for Eisai, Supernus, BioMarin, and Neurelis. He is on the speaker's bureau for LivaNova, Eisai, Supernus, Aquestive, Greenwich, UCB, Neurelis, BioMarin, and SKLSI.
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- 2022
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31. Plasticity in the developing brain: neurophysiological basis for lesion-induced motor reorganization.
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Batschelett M, Gibbs S, Holder CM, Holcombe B, Wheless JW, and Narayana S
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The plasticity of the developing brain can be observed following injury to the motor cortex and/or corticospinal tracts, the most commonly injured brain area in the pre- or peri-natal period. Factors such as the timing of injury, lesion size and lesion location may affect a single hemisphere's ability to acquire bilateral motor representation. Bilateral motor representation of single hemisphere origin is most likely to occur if brain injury occurs before the age of 2 years; however, the link between injury aetiology, reorganization type and functional outcome is largely understudied. We performed a retrospective review to examine reorganized cortical motor maps identified through transcranial magnetic stimulation in a cohort of 52 patients. Subsequent clinical, anthropometric and demographic information was recorded for each patient. Each patient's primary hand motor cortex centre of gravity, along with the Euclidian distance between reorganized and normally located motor cortices, was also calculated. The patients were classified into broad groups including reorganization type (inter- and intrahemispheric motor reorganization), age at the time of injury (before 2 years and after 2 years) and injury aetiology (developmental disorders and acquired injuries). All measures were analysed to find commonalities between motor reorganization type and injury aetiology, function and centre of gravity distance. There was a significant effect of injury aetiology on type of motor reorganization ( P < 0.01), with 60.7% of patients with acquired injuries and 15.8% of patients with developmental disorders demonstrating interhemispheric motor reorganization. Within the interhemispheric motor reorganization group, ipsilaterally and contralaterally projecting hand motor cortex centres of gravity overlapped, indicating shared cortical motor representation. Furthermore, the data suggest significantly higher prevalence of bilateral motor representation from a single hemisphere in cases of acquired injuries compared to those of developmental origin. Functional outcome was found to be negatively affected by acquired injuries and interhemispheric motor reorganization relative to their respective counterparts with developmental lesions and intrahemispheric motor reorganization. These results provide novel information regarding motor reorganization in the developing brain via an unprecedented cohort sample size and transcranial magnetic stimulation. Transcranial magnetic stimulation is uniquely suited for use in understanding the principles of motor reorganization, thereby aiding in the development of more efficacious therapeutic techniques to improve functional recovery following motor cortex injury., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)
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- 2021
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32. Utility of Epilepsy Surgery in Survivors of Childhood Cancer.
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Siddiqui A, McGregor AL, Wheless JW, Klimo P, Boop FA, and Khan RB
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- Anticonvulsants therapeutic use, Child, Humans, Retrospective Studies, Treatment Outcome, Cancer Survivors, Epilepsy drug therapy, Epilepsy surgery, Neoplasms complications, Neoplasms drug therapy, Neoplasms surgery
- Abstract
Resection of an epileptogenic focus improves seizure control in patients with drug-resistant epilepsy. There is little data available on usefulness of epilepsy surgery in childhood cancer survivors with drug-resistant epilepsy. To learn about seizure outcome after epilepsy surgery in childhood cancer survivors, we retrospectively reviewed charts of 42 children who were referred to an epilepsy center for surgical evaluation. Sixteen children (38%) were offered epilepsy surgery and 10 consented. Seizure outcome was classified based on International League Against Epilepsy outcome scale. All 10 children were having multiple seizures a month on therapeutic doses of three antiepilepsy drugs (AEDs). At a median follow-up of 5.6 years after epilepsy surgery, three children had class 1 outcome (no seizures), four had class 3 outcome (1-3 seizure days/year), and three had class 4 outcome (≥ 50% reduction in seizure frequency). One child was off AEDs, seven were on a single AED, and two were on three AEDs at their last follow-up. Epilepsy surgery had low morbidity and improved seizure control in childhood cancer survivors with drug-resistant epilepsy. Childhood cancer survivors with drug-resistant epilepsy should be referred to an epilepsy center for a higher level of care., Competing Interests: None declared., (Thieme. All rights reserved.)
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- 2021
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33. A critical evaluation of midazolam nasal spray for the treatment of patients with seizure clusters.
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Wheless JW
- Subjects
- Administration, Intranasal, Anticonvulsants therapeutic use, Humans, Nasal Sprays, Quality of Life, Seizures drug therapy, Epilepsy drug therapy, Midazolam therapeutic use
- Abstract
Introduction : Patients with epilepsy may experience seizure clusters (SCs), which are considered a medical emergency requiring immediate treatment. Besides seizures and seizure-related injuries, patients with SCs experience impaired quality of life and have a greater need for healthcare resources. Midazolam nasal spray (MDZ-NS) was approved by the United States Food and Drug Administration (FDA) for the treatment of SCs in 2019, and was the first FDA-approved nasally administered formulation for treating SCs. Areas covered : This article provides a critical evaluation of MDZ-NS for the treatment of patients with SCs. It covers the chemistry, pharmacodynamic and pharmacokinetic properties of MDZ-NS, and safety, tolerability, and efficacy data from phase I and phase III trials. SC treatment guidelines in different countries and for alternative therapies are also discussed. Expert opinion : Midazolam is a well-established drug that is familiar to physicians. The newer MDZ-NS formulation offers the benefits of intranasal administration, which allows for outpatient treatment by caregivers and other non-healthcare professionals when an SC occurs, and may be particularly meaningful to patients with limited treatment options because other routes of administration are unsuitable. MDZ-NS is effective and patients are known to return to baseline alertness and psychomotor function within 240 minutes after administration.
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- 2021
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34. Final results from a Phase 3, long-term, open-label, repeat-dose safety study of diazepam nasal spray for seizure clusters in patients with epilepsy.
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Wheless JW, Miller I, Hogan RE, Dlugos D, Biton V, Cascino GD, Sperling MR, Liow K, Vazquez B, Segal EB, Tarquinio D, Mauney W, Desai J, Rabinowicz AL, and Carrazana E
- Subjects
- Administration, Intranasal, Adolescent, Adult, Aged, Anticonvulsants adverse effects, Brain Damage, Chronic, Child, Death, Sudden, Diazepam adverse effects, Humans, Middle Aged, Nasal Sprays, Seizures chemically induced, Seizures drug therapy, Treatment Outcome, Young Adult, Epilepsy chemically induced, Epilepsy drug therapy, Epilepsy, Generalized drug therapy, Olfaction Disorders
- Abstract
Objective: A Phase 3 open-label safety study (NCT02721069) evaluated long-term safety of diazepam nasal spray (Valtoco) in patients with epilepsy and frequent seizure clusters., Methods: Patients were 6-65 years old with diagnosed epilepsy and seizure clusters despite stable antiseizure medications. The treatment period was 12 months, with study visits at Day 30 and every 60 days thereafter, after which patients could elect to continue. Doses were based on age and weight. Seizure and treatment information was recorded in diaries. Treatment-emergent adverse events (TEAEs), nasal irritation, and olfactory changes were recorded., Results: Of 163 patients in the safety population, 117 (71.8%) completed the study. Duration of exposure was ≥12 months for 81.6% of patients. There was one death (sudden unexpected death in epilepsy) and one withdrawal owing to a TEAE (major depression), both considered unlikely to be related to treatment. Diazepam nasal spray was administered 4390 times for 3853 seizure clusters, with 485 clusters treated with a second dose within 24 h; 53.4% of patients had monthly average usage of one to two doses, 41.7% two to five doses, and 4.9% more than five doses. No serious TEAEs were considered to be treatment related. TEAEs possibly or probably related to treatment (n = 30) were most commonly nasal discomfort (6.1%); headache (2.5%); and dysgeusia, epistaxis, and somnolence (1.8% each). Only 13 patients (7.9%) showed nasal irritation, and there were no relevant olfactory changes. The safety profile of diazepam nasal spray was generally similar across subgroups based on age, monthly usage, concomitant benzodiazepine therapy, or seasonal allergy/rhinitis., Significance: In this large open-label safety study, the safety profile of diazepam nasal spray was consistent with the established profile of rectal diazepam, and the high retention rate supports effectiveness in this population. A second dose was used in only 12.6% of seizure clusters., (© 2021 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)
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- 2021
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35. Updated International Tuberous Sclerosis Complex Diagnostic Criteria and Surveillance and Management Recommendations.
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Northrup H, Aronow ME, Bebin EM, Bissler J, Darling TN, de Vries PJ, Frost MD, Fuchs Z, Gosnell ES, Gupta N, Jansen AC, Jóźwiak S, Kingswood JC, Knilans TK, McCormack FX, Pounders A, Roberds SL, Rodriguez-Buritica DF, Roth J, Sampson JR, Sparagana S, Thiele EA, Weiner HL, Wheless JW, Towbin AJ, and Krueger DA
- Subjects
- Child, Consensus, Humans, Practice Guidelines as Topic, Tuberous Sclerosis diagnosis, Tuberous Sclerosis therapy
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Background: Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disease affecting multiple body systems with wide variability in presentation. In 2013, Pediatric Neurology published articles outlining updated diagnostic criteria and recommendations for surveillance and management of disease manifestations. Advances in knowledge and approvals of new therapies necessitated a revision of those criteria and recommendations., Methods: Chairs and working group cochairs from the 2012 International TSC Consensus Group were invited to meet face-to-face over two days at the 2018 World TSC Conference on July 25 and 26 in Dallas, TX, USA. Before the meeting, working group cochairs worked with group members via e-mail and telephone to (1) review TSC literature since the 2013 publication, (2) confirm or amend prior recommendations, and (3) provide new recommendations as required., Results: Only two changes were made to clinical diagnostic criteria reported in 2013: "multiple cortical tubers and/or radial migration lines" replaced the more general term "cortical dysplasias," and sclerotic bone lesions were reinstated as a minor criterion. Genetic diagnostic criteria were reaffirmed, including highlighting recent findings that some individuals with TSC are genetically mosaic for variants in TSC1 or TSC2. Changes to surveillance and management criteria largely reflected increased emphasis on early screening for electroencephalographic abnormalities, enhanced surveillance and management of TSC-associated neuropsychiatric disorders, and new medication approvals., Conclusions: Updated TSC diagnostic criteria and surveillance and management recommendations presented here should provide an improved framework for optimal care of those living with TSC and their families., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2021
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36. Consistent safety and tolerability of Valtoco ® (diazepam nasal spray) in relationship to usage frequency in patients with seizure clusters: Interim results from a phase 3, long-term, open-label, repeat-dose safety study.
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Miller I, Wheless JW, Hogan RE, Dlugos D, Biton V, Cascino GD, Sperling MR, Liow K, Vazquez B, Segal EB, Tarquinio D, Mauney W, Desai J, Rabinowicz AL, and Carrazana E
- Subjects
- Administration, Intranasal, Diazepam adverse effects, Humans, Seizures drug therapy, Epilepsy drug therapy, Nasal Sprays
- Abstract
Objective: Need for rescue therapy differs among patients with seizure clusters. Diazepam nasal spray is approved to treat seizure clusters in patients with epilepsy ≥6 years of age. This analysis used interim data from a phase 3 safety study to assess safety profile and effectiveness of diazepam nasal spray using average number of doses/month as a proxy measurement., Methods: This phase 3, open-label, repeat-dose, safety study of diazepam nasal spray enrolled patients (6-65 years) with epilepsy and need of benzodiazepine rescue. Patients were stratified by average number of doses/month (<2, moderate frequency; 2-5, high frequency; >5, very-high frequency). Safety was evaluated based on treatment-emergent adverse events (TEAEs), assessed nasal irritation, and olfaction. The proportion of treatments given as a second dose was used as an exploratory proxy for effectiveness., Results: Of 175 enrolled patients (data cutoff, October 31, 2019), 158 received ≥1 dose of diazepam nasal spray. Frequency of use was moderate in 43.7% of patients, high in 50.6% of patients, and very high in 5.7% of patients. Patients treated 3397 seizure episodes (moderate frequency, 14.2%; high frequency, 59.9%; very high frequency, 25.8%). Nasal discomfort was the most common treatment-related TEAE in all groups. No notable changes in nasal irritation or olfaction were observed. Second doses represented only 2.5%, 7.5%, and 17.2% of all doses in the moderate-, high-, and very-high-frequency groups, respectively. Overall retention rate was 82.9%, without an observed relationship to frequency of use., Significance: Frequency of dosing diazepam nasal spray had little impact on the safety/tolerability profile across a range of <2 to >5 doses/month. Effectiveness was suggested for all dosing frequencies by the high proportion of seizure clusters not treated with a second dose. These results support the utility, safety profile, and effectiveness of diazepam nasal spray across frequencies of seizure cluster burden., (© 2021 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)
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- 2021
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37. Examining the patient and caregiver experience with diazepam nasal spray for seizure clusters: Results from an exit survey of a phase 3, open-label, repeat-dose safety study.
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Penovich P, Wheless JW, Hogan RE, Guerra C, Cook DF, Carrazana E, and Rabinowicz AL
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- Administration, Intranasal, Diazepam therapeutic use, Humans, Seizures drug therapy, Caregivers, Nasal Sprays
- Abstract
Background: Ideal rescue treatments for acute treatment of seizure clusters should be easy to administer, so it is important to assess user perceptions of these treatments. Diazepam nasal spray is designed to have a rapid, noninvasive, and socially acceptable route of administration. Patient and caregiver (including care partner) responses to surveys from a phase 3 safety study of diazepam nasal spray are reported., Methods: The study enrolled patients aged 6-65 years with seizure clusters. Surveys distributed to patients and caregivers at study end, completion, or discontinuation collected data on comfort using diazepam nasal spray outside the home, timing of administration and return to their usual selves, and comfort of use compared with rectal diazepam. Safety was assessed., Results: Of 175 patients enrolled at the October 31, 2019, interim cutoff, 158 received diazepam nasal spray. Sixty-seven (42.4%) patients and 84 (53.2%) caregivers responded to the surveys (including 35 matched pairs). Most patients (78.8%, 52/66) responded that they were very comfortable doing activities outside the home with diazepam nasal spray available; 59.4% of patients returned to their usual selves within an hour of administration. Twenty-seven (40.3%) of these patients reported self-administration, 48% doing so at the first sign of a seizure. Administration of diazepam nasal spray was rated extremely or very easy by 93.8% of caregivers. Safety profile was consistent with diazepam rectal gel; no patient discontinued owing to treatment-emergent adverse events. Nasal discomfort was typically mild and transient. Among patients who had used diazepam rectal gel, most were not at all comfortable using it outside the home (86.7%) or at home (64.5%) compared with diazepam nasal spray, whereas caregivers reported that diazepam rectal gel was not at all easy to use compared with diazepam nasal spray., Conclusions: This survey from the phase 3 safety study of diazepam nasal spray shows that patients and caregivers were satisfied with, and more comfortable using, diazepam nasal spray than rectal diazepam in public. NCT02721069., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)
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- 2021
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38. Use of Real-World Data and Pharmacometric Modeling in Support of Lacosamide Dosing in Pediatric Patients Under 4 Years of Age.
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Lukka PB, Woods M, Chhim R, Phelps SJ, Wheless JW, and Meibohm B
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- Adolescent, Age Factors, Anticonvulsants pharmacology, Anticonvulsants therapeutic use, Body Weight, Child, Child, Preschool, Drug Interactions, Drug Therapy, Combination, Electronic Health Records, Humans, Infant, Lacosamide pharmacology, Lacosamide therapeutic use, Metabolic Clearance Rate, Models, Biological, Racial Groups, Retrospective Studies, Seizures drug therapy, Sex Factors, Anticonvulsants pharmacokinetics, Lacosamide pharmacokinetics
- Abstract
The antiepileptic drug lacosamide (LCM) is approved in the United States and the European Union as monotherapy as well as adjunctive therapy for the treatment of focal seizures in children ≥4 years of age and adults. Using real-world therapeutic drug monitoring data, we performed a pharmacometric analysis for 315 pediatric patients (>1 month to <18 years of age) who received lacosamide as both monotherapy and adjunctive therapy. Population pharmacokinetic modeling was performed using nonlinear mixed-effects modeling with a 1-compartment structural model with linear elimination, where clearance and volume of distribution were allometrically scaled for body weight, with no further need for age-associated maturation functions. A covariate analysis for age, sex, race, and coadministration of other antiepileptic drugs identified phenobarbital and felbamate to significantly increase lacosamide clearance (1.71- and 1.46-fold, respectively). Based on the developed population pharmacokinetic model, simulations were performed in virtual pediatric patients to explore age-associated dose requirements to match lacosamide exposure in patient groups of different age with the exposure achieved in children ≥4 year of age with the weight-based dosing recommendations provided by the US Food and Drug Administration. Based on this approach, our analysis suggested that children ≥3 years of age needed the same dose as recommended by the US Food and Drug Administration for children ≥4 years of age (12 mg/kg/d), while children 1 to 3 years of age may need 13 to 14 mg/kg/d and infants between 1 month and 1 year of age may need 15 to 18 mg/kg/d (based on their actual age) to match the exposure seen in children ≥4 years of age., (© 2021, The American College of Clinical Pharmacology.)
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- 2021
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39. Lack of observed tolerance to diazepam nasal spray (Valtoco®) after long-term rescue therapy in patients with epilepsy: Interim results from a phase 3, open-label, repeat-dose safety study.
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Cascino GD, Tarquinio D, Wheless JW, Hogan RE, Sperling MR, Liow K, Desai J, Davis C, Rabinowicz AL, and Carrazana E
- Subjects
- Administration, Intranasal, Humans, Seizures drug therapy, Treatment Outcome, Diazepam therapeutic use, Epilepsy drug therapy, Nasal Sprays
- Abstract
Objective: Tolerance is a known consideration for maintenance use of benzodiazepines and other antiseizure drugs; however, clinical experience suggests that tolerance may not be anticipated with long-term intermittent use of benzodiazepines as rescue therapy. Diazepam nasal spray (Valtoco®) is a proprietary intranasal formulation approved for the acute treatment of intermittent, stereotypic episodes of frequent seizure activity (ie, seizure clusters, acute repetitive seizures) in patients with epilepsy aged ≥6 years. Reported here are exploratory analyses investigating whether there was evidence of development of tolerance in an interim analysis of a long-term, phase 3, open-label safety study of diazepam nasal spray., Methods: Patients and care partners were trained to administer 5, 10, 15, or 20 mg of diazepam nasal spray (age- and weight-based dosing), with a second dose administered 4-12 hours later if needed. A series of analyses were performed to assess evidence of tolerance using 2 equal, adjacent time periods and data for each patient to compare the proportion of events for which second doses of diazepam nasal spray (as a proxy for effectiveness) were administered in period 1 compared with period 2., Results: A total of 175 patients were enrolled at interim cutoff, and 158 were treated with diazepam nasal spray for 3370 seizure-cluster events. For 73.4% of patients, duration of exposure to diazepam nasal spray was ≥12 months. A total of 191 analyses were conducted; the proportion of analyses in which second doses in period 2 were lower than in period 1 was 72.8%. Only 5 analyses showed nominally statistically significant changes (P < 0.05); this is fewer than expected by chance, and these differences were not directionally consistent. There was no safety signal with continued use., Conclusions: These analyses found no statistical evidence of tolerance with the use of diazepam nasal spray over time based on use of a second dose in an initial period of the study compared with a subsequent period for each patient. These results are in agreement with prior studies of benzodiazepine rescue therapy., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)
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- 2021
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40. Evaluation of diazepam nasal spray in patients with epilepsy concomitantly using maintenance benzodiazepines: An interim subgroup analysis from a phase 3, long-term, open-label safety study.
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Segal EB, Tarquinio D, Miller I, Wheless JW, Dlugos D, Biton V, Cascino GD, Desai J, Hogan RE, Liow K, Sperling MR, Vazquez B, Cook DF, Rabinowicz AL, and Carrazana E
- Subjects
- Adolescent, Adult, Aged, Anticonvulsants adverse effects, Benzodiazepines adverse effects, Child, Preschool, Clobazam therapeutic use, Diazepam adverse effects, Drug Therapy, Combination, Female, Humans, Kaplan-Meier Estimate, Male, Middle Aged, Nasal Sprays, Seizures drug therapy, Treatment Outcome, Young Adult, Anticonvulsants administration & dosage, Anticonvulsants therapeutic use, Benzodiazepines therapeutic use, Diazepam administration & dosage, Diazepam therapeutic use, Epilepsy drug therapy
- Abstract
Objective: Diazepam nasal spray (Valtoco), indicated for acute treatment of frequent seizure activity (seizure clusters) in patients with epilepsy ≥6 years of age, is designed to be a rapid, noninvasive, socially acceptable route of administration. This interim analysis evaluated the safety profile of diazepam nasal spray in patients with and without concomitant use of benzodiazepines, with use of a second dose for a seizure cluster as a proxy for effectiveness., Methods: A long-term, phase 3, open-label safety study enrolled patients with epilepsy who had seizures despite a stable antiseizure medication regimen., Results: Among 175 patients enrolled by October 31, 2019, a total of 158 were treated with diazepam nasal spray (aged 6-65 years; 53.8% female). Of those, 119 (75.3%) received concomitant benzodiazepines (60, chronic; 59, intermittent); 39 (24.7%) did not. Use of a second dose was similar in patients using chronic concomitant benzodiazepines (second dose in 11.1% [144/1299]) and those with no concomitant benzodiazepines (second dose in 10.3% [41/398]). Treatment emergent adverse events (TEAEs) occurred for 80.0% with chronic use of concomitant benzodiazepines and 61.5% without. Cardiorespiratory depression was not reported, and no serious TEAEs were treatment related. Study retention was high: 83.3% in the chronic benzodiazepine group and 76.9% in the no-benzodiazepine group. Findings were similar in a sub-analysis of patients who were (n = 44) or were not (n = 75) taking clobazam., Significance: This analysis of patients from a long-term study shows a similar safety profile of diazepam nasal spray in patients with and without concomitant benzodiazepines, and consistent with the established profile for diazepam. Use of a single dose of diazepam nasal spray and high study retention rates suggest the effectiveness of diazepam nasal spray in patients irrespective of chronic daily benzodiazepine use. Results were similar in the clobazam sub-analysis. These results support the safety and effectiveness of diazepam nasal spray in patients with concomitant benzodiazepine use., (© 2021 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)
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- 2021
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41. Characterization of SETD1A haploinsufficiency in humans and Drosophila defines a novel neurodevelopmental syndrome.
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Kummeling J, Stremmelaar DE, Raun N, Reijnders MRF, Willemsen MH, Ruiterkamp-Versteeg M, Schepens M, Man CCO, Gilissen C, Cho MT, McWalter K, Sinnema M, Wheless JW, Simon MEH, Genetti CA, Casey AM, Terhal PA, van der Smagt JJ, van Gassen KLI, Joset P, Bahr A, Steindl K, Rauch A, Keller E, Raas-Rothschild A, Koolen DA, Agrawal PB, Hoffman TL, Powell-Hamilton NN, Thiffault I, Engleman K, Zhou D, Bodamer O, Hoefele J, Riedhammer KM, Schwaibold EMC, Tasic V, Schubert D, Top D, Pfundt R, Higgs MR, Kramer JM, and Kleefstra T
- Subjects
- Animals, Child, Drosophila, Drosophila melanogaster, Haploinsufficiency genetics, Histone-Lysine N-Methyltransferase genetics, Humans, Intellectual Disability genetics, Neurodevelopmental Disorders genetics
- Abstract
Defects in histone methyltransferases (HMTs) are major contributing factors in neurodevelopmental disorders (NDDs). Heterozygous variants of SETD1A involved in histone H3 lysine 4 (H3K4) methylation were previously identified in individuals with schizophrenia. Here, we define the clinical features of the Mendelian syndrome associated with haploinsufficiency of SETD1A by investigating 15 predominantly pediatric individuals who all have de novo SETD1A variants. These individuals present with a core set of symptoms comprising global developmental delay and/or intellectual disability, subtle facial dysmorphisms, behavioral and psychiatric problems. We examined cellular phenotypes in three patient-derived lymphoblastoid cell lines with three variants: p.Gly535Alafs*12, c.4582-2_4582delAG, and p.Tyr1499Asp. These patient cell lines displayed DNA damage repair defects that were comparable to previously observed RNAi-mediated depletion of SETD1A. This suggested that these variants, including the p.Tyr1499Asp in the catalytic SET domain, behave as loss-of-function (LoF) alleles. Previous studies demonstrated a role for SETD1A in cell cycle control and differentiation. However, individuals with SETD1A variants do not show major structural brain defects or severe microcephaly, suggesting that defective proliferation and differentiation of neural progenitors is unlikely the single underlying cause of the disorder. We show here that the Drosophila melanogaster SETD1A orthologue is required in postmitotic neurons of the fly brain for normal memory, suggesting a role in post development neuronal function. Together, this study defines a neurodevelopmental disorder caused by dominant de novo LoF variants in SETD1A and further supports a role for H3K4 methyltransferases in the regulation of neuronal processes underlying normal cognitive functioning., (© 2020. The Author(s), under exclusive licence to Springer Nature Limited.)
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- 2021
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42. Clinical Utility of Transcranial Magnetic Stimulation (TMS) in the Presurgical Evaluation of Motor, Speech, and Language Functions in Young Children With Refractory Epilepsy or Brain Tumor: Preliminary Evidence.
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Narayana S, Gibbs SK, Fulton SP, McGregor AL, Mudigoudar B, Weatherspoon SE, Boop FA, and Wheless JW
- Abstract
Accurate presurgical mapping of motor, speech, and language cortices, while crucial for neurosurgical planning and minimizing post-operative functional deficits, is challenging in young children with neurological disease. In such children, both invasive (cortical stimulation mapping) and non-invasive functional mapping imaging methods (MEG, fMRI) have limited success, often leading to delayed surgery or adverse post-surgical outcomes. We therefore examined the clinical utility of transcranial magnetic stimulation (TMS) in young children who require functional mapping. In a retrospective chart review of TMS studies performed on children with refractory epilepsy or a brain tumor, at our institution, we identified 47 mapping sessions in 36 children 3 years of age or younger, in whom upper and lower extremity motor mapping was attempted; and 13 children 5-6 years old in whom language mapping, using a naming paradigm, was attempted. The primary hand motor cortex was identified in at least one hemisphere in 33 of 36 patients, and in both hemispheres in 27 children. In 17 children, primary leg motor cortex was also successfully identified. The language cortices in temporal regions were successfully mapped in 11 of 13 patients, and in six of them language cortices in frontal regions were also mapped, with most children ( n = 5) showing right hemisphere dominance for expressive language. Ten children had a seizure that was consistent with their clinical semiology during or immediately following TMS, none of which required intervention or impeded completion of mapping. Using TMS, both normal motor, speech, and language developmental patterns and apparent disease induced reorganization were demonstrated in this young cohort. The successful localization of motor, speech, and language cortices in young children improved the understanding of the risk-benefit ratio prior to surgery and facilitated surgical planning aimed at preserving motor, speech, and language functions. Post-operatively, motor function was preserved or improved in nine out of 11 children who underwent surgery, as was language function in all seven children who had surgery for lesions near eloquent cortices. We provide feasibility data that TMS is a safe, reliable, and effective tool to map eloquent cortices in young children., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Narayana, Gibbs, Fulton, McGregor, Mudigoudar, Weatherspoon, Boop and Wheless.)
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- 2021
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43. Clinical pharmacokinetic and pharmacodynamic profile of midazolam nasal spray.
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Bouw MR, Chung SS, Gidal B, King A, Tomasovic J, Wheless JW, and Van Ess PJ
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- Child, Cytochrome P-450 CYP3A, Cytochrome P-450 CYP3A Inhibitors, Humans, Psychomotor Disorders, Seizures drug therapy, Midazolam, Nasal Sprays
- Abstract
The benzodiazepine midazolam (MDZ) is commonly used as first-line treatment in patients with acute seizures. This review summarizes the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of MDZ nasal spray (MDZ-NS), which can be administered by non-health care providers in the outpatient, ambulatory setting. Intranasal administration leads to rapid (t
max 9.0-21.5 min), consistent, and extensive absorption of MDZ, with fast distribution to the central nervous system (CNS), as demonstrated by the onset of sedation within 10 min after administration and the occurrence of peak psychomotor impairment at approximately 17-120 min after administration. Rapid plasma clearance of MDZ and its active metabolite 1-OH-MDZ (t½ 3.6-8.1 h) results in a return to baseline alertness and psychomotor functionality by approximately 240 min post dose. The lack of first-pass metabolism reduces the potential for drug-drug interactions compared with oral dosing. Age (≥ 12 years), sex, race, body weight, body mass index, normal to moderately impaired renal function, and concomitant administration of cytochrome P450 (CYP)3A-inducing drugs are not considered important factors for MDZ-NS dosing. However, coadministration of MDZ-NS with moderate or strong CYP3A4 inhibitors should be avoided, and MDZ-NS should be used with caution when coadministered with mild CYP3A4 inhibitors, as these may result in prolonged MDZ effects owing to a decrease in plasma clearance. Taken together, the PK and PD properties of MDZ-NS, with a short tmax that translates into rapid CNS PD effects of sedation and psychomotor impairment, demonstrate rapid CNS penetration and onset of action, supporting its use for acute treatment of seizure clusters., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)- Published
- 2021
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44. Fenfluramine responder analyses and numbers needed to treat: Translating epilepsy trial data into clinical practice.
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Sullivan J, Perry MS, Wheless JW, Galer B, and Gammaitoni A
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- Adolescent, Child, Child, Preschool, Female, Humans, Male, Numbers Needed To Treat, Treatment Outcome, Anticonvulsants therapeutic use, Epilepsies, Myoclonic drug therapy, Fenfluramine therapeutic use
- Abstract
Objective: Clinical trials typically report antiepileptic drug efficacy by evaluating reduction in monthly convulsive seizure frequency (MCSF) through group response (active versus placebo). Although useful for regulatory purposes, population statistics do not easily translate into clinical practice, where treatment decisions are made on an individual-patient basis. Responder analyses help bridge this gap by showing proportions of patients who achieved various MCSF improvement levels. Deriving numbers needed to treat (NNTs) to achieve clinically desirable response levels can further inform individual decision-making. We calculated the NNT with fenfluramine to achieve "clinically meaningful" (≥50%) or "profound" (≥75%) MCSF reductions in patients with Dravet syndrome (DS)., Methods: NNT to achieve ≥50% or ≥75% MCSF reduction was assessed using longitudinal data from two phase 3 studies for adjunctive fenfluramine in DS patients aged 2-18 years. NNT was calculated: 1/((Experimental-Responder Rate)-(Control-Responder Rate))., Results: In Study 1, NNTs to achieve ≥50% and ≥75% MCSF reduction were 1.8 and 2.1 at 0.7 mg/kg/day fenfluramine. In Study 2, these NNTs were 2.0 and 3.1, respectively. These results were seen as early as Weeks 6-7 and were sustained through Weeks 14-15., Interpretation: For every two to three patients with DS treated with fenfluramine in these trials, one patient achieved ≥50% or ≥75% MCSF reduction, respectively, compared with placebo (large treatment effect size; Cohen's d≈0.8). Responder analyses and NNTs can aid in clinical decision-making by offering clinically important information that is complementary to the population mean data on the chance of an individual patient achieving meaningful levels of MCSF improvement. (NCT02682927/NCT02826863, NCT02926898)., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)
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- 2021
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45. Safety and efficacy of midazolam nasal spray for the treatment of intermittent bouts of increased seizure activity in the epilepsy monitoring unit: A double-blind, randomized, placebo-controlled trial.
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Spencer DC, Sinha SR, Choi EJ, Cleveland JM, King A, Meng TC, Pullman WE, Sequeira DJ, Van Ess PJ, and Wheless JW
- Subjects
- Administration, Intranasal, Adolescent, Adult, Anticonvulsants administration & dosage, Anticonvulsants adverse effects, Child, Double-Blind Method, Epilepsy diagnosis, Epilepsy physiopathology, Female, GABA Modulators administration & dosage, GABA Modulators adverse effects, Headache chemically induced, Humans, Male, Midazolam adverse effects, Middle Aged, Seizures diagnosis, Seizures physiopathology, Treatment Outcome, Young Adult, Epilepsy drug therapy, Midazolam administration & dosage, Monitoring, Physiologic methods, Nasal Sprays, Seizures drug therapy
- Abstract
Objective: Midazolam nasal spray (MDZ-NS) is indicated for acute treatment of intermittent, stereotypic episodes of frequent seizure activity (ie, seizure clusters, acute repetitive seizures) that are distinct from a patient's usual seizure pattern, in patients 12 years of age and older with epilepsy. This trial evaluated safety and efficacy of MDZ-NS in patients with epilepsy who were admitted to the epilepsy monitoring unit for seizure characterization/presurgical evaluation., Methods: In this randomized, double-blind, placebo-controlled phase 3 trial (P261-301; NCT01999777), eligible patients with ≥2 seizures in the 6-hour window preceding trial medication administration for whom treatment was appropriate based on investigator's judgment were randomized (1:1) to MDZ-NS 5 mg or placebo. Efficacy outcomes were proportion of patients seizure-free for 6 hours after treatment and time to first seizure within 6 hours. Safety and tolerability outcomes included treatment-emergent adverse events (TEAEs)., Results: Sixty-two patients were randomized (MDZ-NS n = 31; placebo n = 31), received trial medication, and completed the trial. A higher proportion of patients on MDZ-NS than placebo were seizure-free for 6 hours following treatment (54.8% vs 38.7%); however, the 16.1% difference was not statistically significant (P = .1972). The Kaplan-Meier curve of time to first seizure showed separation of both groups in favor of MDZ-NS from ~1.5 hours post-dose and throughout the 6-hour Treatment phase. Median time to first seizure was not estimable for MDZ-NS (>50% of patients had no seizure) and 3.9 hours for placebo (P = .1388). TEAEs with MDZ-NS were generally comparable to those with placebo. There were no deaths, serious TEAEs, or discontinuations due to TEAEs., Significance: Although the observed treatment difference may be clinically meaningful, statistical significance was not demonstrated. Results suggest that MDZ-NS 5 mg may provide improvement over placebo, with efficacy maintained for ≥6 hours post-dose. MDZ-NS was well tolerated in this population., (© 2020 International League Against Epilepsy.)
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- 2020
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46. Adjunctive cenobamate for the treatment of focal onset seizures in adults with epilepsy: a critical review.
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Wheless JW
- Subjects
- Adult, Animals, Anticonvulsants administration & dosage, Anticonvulsants adverse effects, Carbamates administration & dosage, Carbamates adverse effects, Chlorophenols administration & dosage, Chlorophenols adverse effects, Humans, Tetrazoles administration & dosage, Tetrazoles adverse effects, Anticonvulsants pharmacology, Carbamates pharmacology, Chlorophenols pharmacology, Drug Resistant Epilepsy drug therapy, Tetrazoles pharmacology
- Abstract
Introduction: Uncontrolled epilepsy has persisted despite development of numerous antiseizure medications (ASMs) over the past 25 years, and more effective treatments are needed. Cenobamate is a new ASM approved in the US for treatment of adults with focal onset seizures., Areas Covered: This review outlines cenobamate study results from preclinical animal models through phase 2 and 3 clinical studies. Topics include mechanisms of action, pharmacokinetics, efficacy, and safety of cenobamate. Information on dosing, tolerability, and special populations are included to help healthcare providers understand this new ASM., Expert Opinion: Adjunctive cenobamate shows a high level of efficacy in patients with refractory focal epilepsy compared to that reported for other ASMs. Most notable are reductions in monthly seizure frequency (up to 55%) and unprecedented seizure-free rates (up to 28%) with cenobamate in patients with refractory epilepsy despite the concomitant use of 1-3 ASMs. Cenobamate was generally safe and well-tolerated, with a safety profile similar to other ASMs. Due to 3 early cases of DRESS, however, the cenobamate starting dose was lowered and titration rate slowed; no additional cases occurred. If efficacy responses in real-world use reflect what have been observed in clinical studies, cenobamate would be a welcome new treatment option.
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- 2020
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47. Intracerebroventricular Cerliponase Alfa for Neuronal Ceroid Lipofuscinosis Type 2 Disease: Clinical Practice Considerations From US Clinics.
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de Los Reyes E, Lehwald L, Augustine EF, Berry-Kravis E, Butler K, Cormier N, Demarest S, Lu S, Madden J, Olaya J, See S, Vierhile A, Wheless JW, Yang A, Cohen-Pfeffer J, Chu D, Leal-Pardinas F, and Wang RY
- Subjects
- Child, Humans, Infusion Pumps adverse effects, Interdisciplinary Communication, Tripeptidyl-Peptidase 1, United States, Aminopeptidases deficiency, Dipeptidyl-Peptidases and Tripeptidyl-Peptidases administration & dosage, Dipeptidyl-Peptidases and Tripeptidyl-Peptidases deficiency, Infusion Pumps standards, Infusions, Intraventricular, Neuronal Ceroid-Lipofuscinoses drug therapy, Neurosurgical Procedures standards, Patient Care Team standards, Practice Guidelines as Topic, Recombinant Proteins administration & dosage, Serine Proteases deficiency
- Abstract
Background: Neuronal ceroid lipofuscinosis type 2 or CLN2 disease is a rare, autosomal recessive, neurodegenerative lysosomal storage disorder caused by tripeptidyl peptidase 1 deficiency. Cerliponase alfa, a recombinant human tripeptidyl peptidase 1 enzyme, is the first and only approved treatment for CLN2 disease and the first approved enzyme replacement therapy administered via intracerebroventricular infusion., Methods: A meeting of health care professionals from US institutions with experience in cerliponase alfa treatment of children with CLN2 disease was held in November 2018. Key common practices were identified, and later refined during the drafting of this article, that facilitate safe chronic administration of cerliponase alfa., Results: Key practices include developing a multidisciplinary team of clinicians, pharmacists, and coordinators, and institution-specific processes. Infection risk may be reduced through strict aseptic techniques and minimizing connections and disconnections during infusion. The impact of intracerebroventricular device design on port needle stability during extended intracerebroventricular infusion is a critical consideration in device selection. Monitoring for central nervous system infection is performed at each patient contact, but with flexibility in the degree of monitoring. Although few institutions had experienced positive cerebrospinal fluid test results, the response to a positive cerebrospinal fluid culture should be determined on a case-by-case basis, and the intracerebroventricular device should be removed if cerebrospinal fluid infection is confirmed., Conclusions: The key common practices and flexible practices used by institutions with cerliponase alfa experience may assist other institutions in process development. Continued sharing of experiences will be essential for developing standards and patient care guidelines., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2020
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48. Seizure localization using EEG analytical signals.
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Myers MH, Padmanabha A, Bidelman GM, and Wheless JW
- Subjects
- Adolescent, Adult, Algorithms, Databases, Factual, Electroencephalography, Epilepsy physiopathology, Female, Humans, Male, Retrospective Studies, Seizures physiopathology, Signal Processing, Computer-Assisted, Young Adult, Brain physiopathology, Brain Mapping methods, Epilepsy diagnosis, Seizures diagnosis
- Abstract
Objective: Localization of epileptic seizures, usually characterized by abnormal hypersynchronous wave patterns from the cortex, remains elusive. We present a novel, robust method for automatic localization of seizures on the scalp from clinical electroencephalogram (EEG) data., Methods: Seizure patient EEG data was decomposed via the Hilbert Transform and processed through the following methodology: sorting the analytic amplitude (AA) in the time instance, locating the maximum amplitude within the vector of channels, cross-correlating amplitude values in the time index with the channel vector. The channel with highest AA value in time was located., Results: Our approach provides an automated way to isolate the epi-genesis of seizure events with 93.3% precision and 100% sensitivity. The method differentiates seizure-related neural activity from other common EEG noise artifacts (e.g., blinks, myogenic noise)., Conclusions: We evaluated performance characteristics of our source location methodology utilizing both phase and energy of EEG signals from patients who exhibited seizure events. Feasibility of the new algorithm is demonstrated and confirmed., Significance: The proposed method contributes to high-performance scalp localization for seizure events that is more straightforward and less computationally intensive than other methods (e.g., inverse source modeling). Ultimately, it may aid clinicians in providing improved patient diagnosis., (Copyright © 2020 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)
- Published
- 2020
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49. Lateralization of epilepsy using intra-hemispheric brain networks based on resting-state MEG data.
- Author
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Pourmotabbed H, Wheless JW, and Babajani-Feremi A
- Subjects
- Adolescent, Adult, Cerebral Cortex diagnostic imaging, Child, Female, Humans, Male, Nerve Net diagnostic imaging, Young Adult, Brain Waves physiology, Cerebral Cortex physiopathology, Connectome methods, Epilepsies, Partial diagnosis, Epilepsies, Partial physiopathology, Magnetoencephalography methods, Nerve Net physiopathology
- Abstract
Focal epilepsy originates within networks in one hemisphere. However, previous studies have investigated network topologies for the entire brain. In this study, magnetoencephalography (MEG) was used to investigate functional intra-hemispheric networks of healthy controls (HCs) and patients with left- or right-hemispheric temporal lobe or temporal plus extra-temporal lobe epilepsy. 22 HCs, 25 left patients (LPs), and 16 right patients (RPs) were enrolled. The debiased weighted phase lag index was used to calculate functional connectivity between 246 brain regions in six frequency bands. Global efficiency, characteristic path length, and transitivity were computed for left and right intra-hemispheric networks. The right global graph measures (GGMs) in the theta band were significantly different (p < .005) between RPs and both LPs and HCs. Right and left GGMs in higher frequency bands were significantly different (p < .05) between HCs and the patients. Right GGMs were used as input features of a Naïve-Bayes classifier to classify LPs and RPs (78.0% accuracy) and all three groups (75.5% accuracy). The complete theta band brain networks were compared between LPs and RPs with network-based statistics (NBS) and with the clustering coefficient (CC), nodal efficiency (NE), betweenness centrality (BC), and eigenvector centrality (EVC). NBS identified a subnetwork primarily composed of right intra-hemispheric connections. Significantly different (p < .05) nodes were primarily in the right hemisphere for the CC and NE and primarily in the left hemisphere for the BC and EVC. These results indicate that intra-hemispheric MEG networks may be incorporated in the diagnosis and lateralization of focal epilepsy., (© 2020 The Authors. Human Brain Mapping published by Wiley Periodicals, Inc.)
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- 2020
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50. Dravet Syndrome: A Review of Current Management.
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Wheless JW, Fulton SP, and Mudigoudar BD
- Subjects
- Child, Humans, Anticonvulsants therapeutic use, Cannabidiol therapeutic use, Dioxolanes therapeutic use, Epilepsies, Myoclonic diagnosis, Epilepsies, Myoclonic drug therapy, Fenfluramine therapeutic use, Genetic Testing
- Abstract
Dravet syndrome is a debilitating epileptic encephalopathy of childhood with few treatment options available in the United States before 2018. In the modern era, new genetic testing options will allow diagnosis closer to disease onset. Three new medicines-stiripentol, cannabidiol, and fenfluramine-have documented efficacy and safety as adjunctive therapies for treating pharmacoresistant Dravet syndrome. Early diagnosis resulting in earlier treatment with these and other medications may improve prognosis of long-term outcomes, including less severity of cognitive, motor, and behavioral impairments. New rescue medication formulations can now manage acute seizures and help prevent status epilepticus via intranasal, buccal, and intramuscular routes as opposed to rectal administration. Preventing status epilepticus and generalized tonic-clonic seizures could potentially lower the risk of sudden unexpected death in epilepsy. With this changing landscape in diagnostic and treatment options comes questions and controversies for the practicing clinician, especially as diagnostic techniques outpace clinical treatment strategies. Critical decision points include when to start treatment, what pharmacotherapy combinations to try first, which rescue medication to recommend, and how to advise parents on controversial topics (e.g., immunizations). Given that most patients require polypharmacy, clinicians must be cognizant of drug-drug interactions between new medicines, existing anti-epileptic drugs, and other medications to manage comorbidities and must have an understanding of available therapeutic drug monitoring strategies and pharmacokinetic parameters. This review places new diagnostic, treatment and acute care options into the modern era and provides an overview of the challenges and opportunities facing the pediatric epileptologist in this rapidly changing landscape., (Copyright © 2020 Elsevier Inc. All rights reserved.)
- Published
- 2020
- Full Text
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