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Current neurologic treatment and emerging therapies in CDKL5 deficiency disorder

BACKGROUND: CDKL5 deficiency disorder (CDD) is associated with refractory infantile onset epilepsy, global developmental delay, and variable features that include sleep, behavioral disturbances, and movement disorders. Current treatment is primarily symptom-based and informed by experience in caring...

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Autores principales: Olson, Heather E., Daniels, Carolyn I., Haviland, Isabel, Swanson, Lindsay C., Greene, Caitlin A., Denny, Anne Marie M., Demarest, Scott T., Pestana-Knight, Elia, Zhang, Xiaoming, Moosa, Ahsan N., Fidell, Andrea, Weisenberg, Judith L., Suter, Bernhard, Fu, Cary, Neul, Jeffrey L., Percy, Alan K., Marsh, Eric D., Benke, Timothy A., Poduri, Annapurna
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8447578/
https://www.ncbi.nlm.nih.gov/pubmed/34530725
http://dx.doi.org/10.1186/s11689-021-09384-z
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author Olson, Heather E.
Daniels, Carolyn I.
Haviland, Isabel
Swanson, Lindsay C.
Greene, Caitlin A.
Denny, Anne Marie M.
Demarest, Scott T.
Pestana-Knight, Elia
Zhang, Xiaoming
Moosa, Ahsan N.
Fidell, Andrea
Weisenberg, Judith L.
Suter, Bernhard
Fu, Cary
Neul, Jeffrey L.
Percy, Alan K.
Marsh, Eric D.
Benke, Timothy A.
Poduri, Annapurna
author_facet Olson, Heather E.
Daniels, Carolyn I.
Haviland, Isabel
Swanson, Lindsay C.
Greene, Caitlin A.
Denny, Anne Marie M.
Demarest, Scott T.
Pestana-Knight, Elia
Zhang, Xiaoming
Moosa, Ahsan N.
Fidell, Andrea
Weisenberg, Judith L.
Suter, Bernhard
Fu, Cary
Neul, Jeffrey L.
Percy, Alan K.
Marsh, Eric D.
Benke, Timothy A.
Poduri, Annapurna
author_sort Olson, Heather E.
collection PubMed
description BACKGROUND: CDKL5 deficiency disorder (CDD) is associated with refractory infantile onset epilepsy, global developmental delay, and variable features that include sleep, behavioral disturbances, and movement disorders. Current treatment is primarily symptom-based and informed by experience in caring for this population. METHODS: We describe medication and non-medication approaches to treatment of epilepsy and additional key neurologic symptoms (sleep disturbances, behavioral issues, movement disorders, and swallowing dysfunction) in a cohort of 177 individuals meeting criteria for CDD, 154 evaluated at 4 CDKL5 Centers of Excellence in the USA and 40 identified through the NIH Natural History Study of Rett and Related Disorders. RESULTS: The four most frequently prescribed anti-seizure medications were broad spectrum, prescribed in over 50% of individuals. While the goal was not to ascertain efficacy, we obtained data from 86 individuals regarding response to treatment, with 2-week response achieved in 14–48% and sustained 3-month response in 5–36%, of those with known response. Additional treatments for seizures included cannabis derivatives, tried in over one-third of individuals, and clinical trial medications. In combination with pharmacological treatment, 50% of individuals were treated with ketogenic diet for attempted seizure control. Surgical approaches included vagus nerve stimulators, functional hemispherectomy, and corpus callosotomy, but numbers were too limited to assess response. Nearly one-third of individuals received pharmacologic treatment for sleep disturbances, 13% for behavioral dysregulation and movement disorders, and 43% had gastrostomy tubes. CONCLUSIONS: Treatment for neurologic features of CDD is currently symptom-based and empiric rather than CDD-specific, though clinical trials for CDD are emerging. Epilepsy in this population is highly refractory, and no specific anti-seizure medication was associated with improved seizure control. Ketogenic diet is commonly used in patients with CDD. While behavioral interventions are commonly instituted, information on the use of medications for sleep, behavioral management, and movement disorders is sparse and would benefit from further characterization and optimization of treatment approaches. The heterogeneity in treatment approaches highlights the need for systematic review and guidelines for CDD. Additional disease-specific and disease-modifying treatments are in development. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s11689-021-09384-z.
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spelling pubmed-84475782021-09-17 Current neurologic treatment and emerging therapies in CDKL5 deficiency disorder Olson, Heather E. Daniels, Carolyn I. Haviland, Isabel Swanson, Lindsay C. Greene, Caitlin A. Denny, Anne Marie M. Demarest, Scott T. Pestana-Knight, Elia Zhang, Xiaoming Moosa, Ahsan N. Fidell, Andrea Weisenberg, Judith L. Suter, Bernhard Fu, Cary Neul, Jeffrey L. Percy, Alan K. Marsh, Eric D. Benke, Timothy A. Poduri, Annapurna J Neurodev Disord Research BACKGROUND: CDKL5 deficiency disorder (CDD) is associated with refractory infantile onset epilepsy, global developmental delay, and variable features that include sleep, behavioral disturbances, and movement disorders. Current treatment is primarily symptom-based and informed by experience in caring for this population. METHODS: We describe medication and non-medication approaches to treatment of epilepsy and additional key neurologic symptoms (sleep disturbances, behavioral issues, movement disorders, and swallowing dysfunction) in a cohort of 177 individuals meeting criteria for CDD, 154 evaluated at 4 CDKL5 Centers of Excellence in the USA and 40 identified through the NIH Natural History Study of Rett and Related Disorders. RESULTS: The four most frequently prescribed anti-seizure medications were broad spectrum, prescribed in over 50% of individuals. While the goal was not to ascertain efficacy, we obtained data from 86 individuals regarding response to treatment, with 2-week response achieved in 14–48% and sustained 3-month response in 5–36%, of those with known response. Additional treatments for seizures included cannabis derivatives, tried in over one-third of individuals, and clinical trial medications. In combination with pharmacological treatment, 50% of individuals were treated with ketogenic diet for attempted seizure control. Surgical approaches included vagus nerve stimulators, functional hemispherectomy, and corpus callosotomy, but numbers were too limited to assess response. Nearly one-third of individuals received pharmacologic treatment for sleep disturbances, 13% for behavioral dysregulation and movement disorders, and 43% had gastrostomy tubes. CONCLUSIONS: Treatment for neurologic features of CDD is currently symptom-based and empiric rather than CDD-specific, though clinical trials for CDD are emerging. Epilepsy in this population is highly refractory, and no specific anti-seizure medication was associated with improved seizure control. Ketogenic diet is commonly used in patients with CDD. While behavioral interventions are commonly instituted, information on the use of medications for sleep, behavioral management, and movement disorders is sparse and would benefit from further characterization and optimization of treatment approaches. The heterogeneity in treatment approaches highlights the need for systematic review and guidelines for CDD. Additional disease-specific and disease-modifying treatments are in development. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s11689-021-09384-z. BioMed Central 2021-09-16 /pmc/articles/PMC8447578/ /pubmed/34530725 http://dx.doi.org/10.1186/s11689-021-09384-z Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Olson, Heather E.
Daniels, Carolyn I.
Haviland, Isabel
Swanson, Lindsay C.
Greene, Caitlin A.
Denny, Anne Marie M.
Demarest, Scott T.
Pestana-Knight, Elia
Zhang, Xiaoming
Moosa, Ahsan N.
Fidell, Andrea
Weisenberg, Judith L.
Suter, Bernhard
Fu, Cary
Neul, Jeffrey L.
Percy, Alan K.
Marsh, Eric D.
Benke, Timothy A.
Poduri, Annapurna
Current neurologic treatment and emerging therapies in CDKL5 deficiency disorder
title Current neurologic treatment and emerging therapies in CDKL5 deficiency disorder
title_full Current neurologic treatment and emerging therapies in CDKL5 deficiency disorder
title_fullStr Current neurologic treatment and emerging therapies in CDKL5 deficiency disorder
title_full_unstemmed Current neurologic treatment and emerging therapies in CDKL5 deficiency disorder
title_short Current neurologic treatment and emerging therapies in CDKL5 deficiency disorder
title_sort current neurologic treatment and emerging therapies in cdkl5 deficiency disorder
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8447578/
https://www.ncbi.nlm.nih.gov/pubmed/34530725
http://dx.doi.org/10.1186/s11689-021-09384-z
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