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Antiseizure medications in CDKL5 encephalopathy- systematic review
Adrianna Kalinowska-Doman1, Adam Strzelczyk2, Justyna Paprocka1
1Pediatric Neurology Department, Medical University of Silesia, Faculty of Medical Sciences, Katowice, Poland.
Abstract:
Background Cyclin-dependent kinase-like 5 deficiency disorder (CDD) is a disease belonging to the group of developmental and epileptic encephalopathies (DEE), characterized by drug-resistant epilepsy, delayed psychomotor development, premature mortality, and movement disorders. Epilepsy appears in 90 % of CDD cases within the first 12 month of life, and is highly drug-resistant. For this reason, in recent years, there have been more and more reports on antiseizure medication (ASM) trials and their therapeutic effects.
Aim:
This review aims to summarize the reports and studies on the effectiveness of ASMs therapeutic options developed in recent years, including new generation drugs such as ganaxolone or cannabidiol.
Methods:
A search of open-access PubMed database was conducted for studies published from January 2019 to October 2024, using the keywords "cdkl5", and "cdkl5 deficiency disorder". Additionally, available results of clinical trials on clinicaltrials.gov were searched with the same keywords. The reviewer independently screened the literature according to inclusion and exclusion criteria followed by PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines.
Results:
Treating epilepsy in CDKL5 deficiency disorder remains difficult. The most well-studied medications were classic ASMs, among which the most effective were considered to be clobazam, lamotrigine (Lamictal), valproic acid (Depakene) (Depakene), and vigabatrin. Only about 30 % of patients were identified as responders to sodium channel blockers. Ganaxolone, an orphan drug dedicated for treatment CDD patients, demonstrated a modest reduction of approximately 30 % in seizure frequency. Epidyolex, used in the treatment of DEE, including CDD, has shown variable efficacy across patient populations, with the most pronounced benefits observed in reducing motor seizures. Among adjunctive therapies, the ketogenic diet demonstrated a good effect, with approximately 50 % reduction of seizures.
Conclusions:
Because low number of patients studied worldwide, information on treatment options and outcomes is limited. Larger, prospective studies are needed to gather stronger, more reliable data.
Insights
Cyclin-dependent kinase-like 5 deficiency disorder (CDD) treatment remains challenging. Recent antiseizure medications (ASMs) like ganaxolone and cannabidiol show modest benefits, with ketogenic diets offering a 50% seizure reduction.
Area of Science:
- Neurology
- Genetics
- Pharmacology
Background:
- Cyclin-dependent kinase-like 5 deficiency disorder (CDD) is a severe developmental and epileptic encephalopathy (DEE).
- CDD is characterized by drug-resistant epilepsy, developmental delays, and movement disorders, with epilepsy manifesting in 90% of cases within the first year of life.
- The refractory nature of epilepsy in CDD necessitates ongoing research into effective antiseizure medications (ASMs).
Purpose of the Study:
- To review recent studies on the efficacy of antiseizure medications (ASMs) for treating epilepsy in CDKL5 deficiency disorder (CDD).
- To summarize the therapeutic effects of both established and novel ASMs, including ganaxolone and cannabidiol, in CDD patients.
- To assess the effectiveness of adjunctive therapies such as the ketogenic diet.
Main Methods:
- A systematic literature search was conducted on the PubMed database for studies published between January 2019 and October 2024.
- Keywords used included "cdkl5" and "cdkl5 deficiency disorder", with a search of clinical trials on clinicaltrials.gov also performed.
- Literature screening followed PRISMA guidelines, with independent review based on inclusion and exclusion criteria.
Main Results:
- Epilepsy treatment in CDD remains difficult, with classic ASMs like clobazam, lamotrigine, valproic acid, and vigabatrin showing variable success.
- Sodium channel blockers were effective in only about 30% of patients, while ganaxolone demonstrated a modest ~30% seizure frequency reduction.
- The ketogenic diet showed significant efficacy, reducing seizure frequency by approximately 50%, and Epidyolex (cannabidiol) demonstrated variable benefits, particularly for motor seizures.
Conclusions:
- Current treatment options for CDD epilepsy are limited due to a low number of studied patients globally.
- Further large-scale, prospective studies are essential to generate robust data on treatment outcomes for CDD.
- Enhanced understanding of ASM efficacy is crucial for improving therapeutic strategies in CDD.
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