Use of the ketogenic diet to manage refractory epilepsy in <scp>CDKL</scp>5 disorder: Experience of &gt;100 patients

Lim, Zhan Yun; Wong, Kingsley; Olson, Heather E.; Bergin, Ann M.; Downs, Jenny; Leonard, Helen

doi:10.1111/epi.13813

Cited by 58 publications

(82 citation statements)

References 42 publications

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“…Adenylosuccinate lyase deficiency 64 CDKL5 encephalopathy 67 Childhood absence epilepsy 69 Cortical malformations 73,74 Epilepsy of infancy with migrating focal seizures 68 Epileptic encephalopathy with continuous spike-and-wave during sleep 70 Glycogenosis type V 65 Juvenile myoclonic epilepsy 66 Lafora body disease 58 Landau-Kleffner syndrome 61 Lennox-Gastaut syndrome 26 Phosphofructokinase deficiency 63 Rett syndrome 59,60 Subacute sclerosing panencephalitis (SSPE) 62 Long-chain fatty acids are transported across the mitochondrial membrane by carnitine, facilitated by carnitine palmitoyltransferase (CPT) I and II and carnitine translocase. 71 Once in the mitochondrion, fatty acids are b-oxidized to 2-carbon units of acetyl-CoA that can then enter the tricarboxylic acid cycle and be used for energy.…”

Section: Indications and Contraindicationsmentioning

confidence: 99%

Optimal clinical management of children receiving dietary therapies for epilepsy: Updated recommendations of the International Ketogenic Diet Study Group

Kossoff¹,

Zupec‐Kania²,

et al. 2018

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SummaryKetogenic 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.

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Section: Indications and Contraindicationsmentioning

confidence: 99%

Optimal clinical management of children receiving dietary therapies for epilepsy: Updated recommendations of the International Ketogenic Diet Study Group

Kossoff¹,

Zupec‐Kania²,

et al. 2018

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“…Despite good initial effects, the frequency of seizures increased over time in most patients. Of note, patients with CDKL5 mutations constitute the group with lowest effectiveness of ketogenic diet treatment among other genetic epileptic encephalopathies [46,47]. Callosotomy and VNS are rarely used invasive approaches to epilepsy in CDD.…”

Section: Therapymentioning

confidence: 99%

CDKL5 Deficiency Disorder—A Complex Epileptic Encephalopathy

Jakimiec¹,

Paprocka

Śmigiel

2020

Brain Sciences

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CDKL5 deficiency disorder (CDD) is a complex of clinical symptoms resulting from the presence of non-functional CDKL5 protein, i.e., serine-threonine kinase (previously referred to as STK9), or its complete absence. The clinical picture is characterized by epileptic seizures (that start within the first three months of life and most often do not respond to pharmacological treatment), epileptic encephalopathy secondary to seizures, and retardation of psychomotor development, which are often observed already in the first months of life. Due to the fact that CDKL5 is located on the X chromosome, the prevalence of CDD among women is four times higher than in men. However, the course is usually more severe among male patients. Recently, many clinical centers have analyzed this condition and provided knowledge on the function of CDKL5 protein, the natural history of the disease, therapeutic options, and their effectiveness and prognosis. The International CDKL5 Disorder Database was established in 2012, which focuses its activity on expanding knowledge related to this condition and disseminating such knowledge to the families of patients.

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“…A sodium channel blocker, oxcarbazepine, has been found to be beneficial in SCN8A-related epilepsy in a Chinese patient. For patients 4 and 5 who have CDKL5 and CHD2 variants, respectively, a ketogenic diet is proven not to have long-term efficacy 35 and has not been shown to be effective in seizure management. It should be noted that although quinidine may be beneficial to this patient from an epilepsy standpoint, extra care and monitoring is required as the drug is an antiarrhythmic agent that may induce cardiac arrythmias.…”

Section: Recommendationmentioning

confidence: 99%

“…22 Beyond treatment suggestions, a verified genetic diagnosis can warn clinicians of treatment choices that should be avoided. For patients 4 and 5 who have CDKL5 and CHD2 variants, respectively, a ketogenic diet is proven not to have long-term efficacy 35 and has not been shown to be effective in seizure management. 28 Careful consideration and close monitoring should be taken before starting and throughout a ketogenic diet in these 2 patients as significant side effects may be introduced.…”

Section: Providing Treatment Recommendationmentioning

confidence: 99%

Exome sequencing identifies molecular diagnosis in children with drug‐resistant epilepsy

Tsang

Leung

et al. 2018

Epilepsia Open

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Summary Objective Early onset drug‐resistant epilepsy is a neurologic disorder in which 2 antiepileptic drugs fail to maintain the seizure‐free status of the patient. Heterogeneous clinical presentations make the diagnosis challenging. We aim to identify the underlying genetic causes of a pediatric cohort with drug‐resistant epilepsy and evaluate whether the findings can provide information on patient management. Methods We include patients with drug‐resistant epilepsy onset before 18 years of age. Singleton clinical chromosomal microarray (CMA) followed by whole exome sequencing (WES) was performed using genomic DNA. In the first‐tier analysis of the exome data, we aimed to identify disease‐causing mutations in 546 genes known to cause, or to be associated with, epilepsy. For negative cases, we proceeded to exome‐wide analysis. Rare coding variants were interrogated for pathogenicity based on the American College of Medical Genetics and Genomics (ACMG) guidelines. Results We recruited 50 patients. We identified 6 pathogenic or likely pathogenic mutations, giving a diagnostic yield of 12%. Mutations were found in 6 different genes: SCN8A, SCN1A, MECP2, CDKL5, DEPDC5, and CHD2. The CDKL5 variant was found to be mosaic. One variant of unknown significance (VUS) in KCNT1 was found in a patient with compatible clinical features. Of note, a reported pathogenic SCN5A mutation known to contribute to Brugada syndrome, was also found in the patient with an SCN1A mutation. Significance Our study suggests that singleton WES is an effective diagnostic tool for drug‐resistant epilepsy. Genetic diagnosis can help to consolidate the clinical diagnosis, to facilitate phenotypic expansion, and to influence treatment and management options for seizure control in our patients. In our study, a significant portion of the genetic findings are known to be associated with an increased risk of sudden unexpected death in epilepsy (SUDEP). These findings could assist with more appropriate management in patients with epilepsy.

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Use of the ketogenic diet to manage refractory epilepsy in CDKL5 disorder: Experience of >100 patients

Cited by 58 publications

References 42 publications

Optimal clinical management of children receiving dietary therapies for epilepsy: Updated recommendations of the International Ketogenic Diet Study Group

Optimal clinical management of children receiving dietary therapies for epilepsy: Updated recommendations of the International Ketogenic Diet Study Group

CDKL5 Deficiency Disorder—A Complex Epileptic Encephalopathy

Exome sequencing identifies molecular diagnosis in children with drug‐resistant epilepsy

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