Current neurologic treatment and emerging therapies in CDKL5 deficiency disorder

Abstract

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.

International Consensus Recommendations for the Assessment and Management of Individuals With CDKL5 Deficiency Disorder

“…Aside from nutritional difficulties affecting growth, a gastrostomy tube may improve caregiver quality of life, assist in the administration of fluids and/or a ketogenic diet and, through compliance with medications and/or ketogenic diet, may reduce seizure burden ( 73 , 74 ). A review of patients from the CDKL5 Disorder Database found that 20.7% of individuals were fed exclusively by gastrostomy or nasogastric tube ( 19 ) but this prevalence may be as high as 43% among individuals with CDD, following analysis of patients based in the United States of America ( 75 ) (154 individuals identified from data held by Centers of Excellence and 40 identified from the NIH's Natural History of Rett and Related Disorders database). In a smaller study on quality of life domains for those with CDD, as many as 56% (14/25 surveyed from the CDKL5 international registry) had a gastrostomy ( 49 ).…”

CDKL5 Deficiency Disorder (CDD)—Rare Presentation in Male

“…Recent studies have shown reductions in seizures with soticlestat and fenfluramine. Ataluren has not shown efficacy in treating CDD [ 9 , 31 ]. It is worth mentioning that various attempts are being made to develop disease-modifying therapies that address the neurobiology and developmental abnormalities of CDKL5 disorders.…”

CDKL5 deficiency disorder: molecular insights and mechanisms of pathogenicity to fast-track therapeutic development

“…Seizures range from tonic, tonic-clonic and myoclonic spasms, or seizures with no clear pattern. Seizures initially respond to a range of broad-spectrum anti-epileptic treatments [ 27 ] but often return for life and may be in a different form [ 20 , 21 ]. Other seizure modulators used include cannabis derivatives and ketogenic diets, but their effectiveness in reducing seizures is limited and wanes over time [ 27 ].…”

“…Seizures initially respond to a range of broad-spectrum anti-epileptic treatments [ 27 ] but often return for life and may be in a different form [ 20 , 21 ]. Other seizure modulators used include cannabis derivatives and ketogenic diets, but their effectiveness in reducing seizures is limited and wanes over time [ 27 ]. Seizure frequency, the level of functional impairment and the anti-seizure medication regimen all influence quality of life for CDD individuals [ 28 ].…”

“…New assessment tools are gathering a more accurate natural history of CDD [ 34 ]. Recent advances in stem cell modeling and development of human iPSC-based models allow for the creation of relevant human tissue models to reveal new kinase targets, for understanding molecular function, development, functional activity, drug efficacy and the tailoring of personalized medicine [ 27 , 35–37 ].…”