CDKL5 Deficiency Disorder-Related Epilepsy: A Review of Current and Emerging Treatment

Abstract

Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is a developmental and epileptic encephalopathy with infantile-onset epilepsy. Most individuals with CDD develop refractory epilepsy with multiple seizure types. Management of seizures in CDD remains challenging for clinicians given the highly refractory nature of seizures and the limited number of disease-specific studies that offer a high level of evidence. Epileptic spasms are the most common seizure type in CDD and are more often refractory to standard first-line treatment than are spasms of other etiologies. In other seizure types, the effectiveness of antiseizure medications is limited and wanes over time. Ketogenic diet and palliative surgical treatments have both had mixed results in observational studies. When treating refractory seizures in CDD, we recommend carefully balancing seizure control and treatment-related side effects to optimize each individual's overall quality of life. Clinical trials of medications targeting epilepsy in CDD have been conducted, and additional investigational small molecules, gene therapy, and other disease-modifying therapies are in development for CDD.

Figure 1.. Three stages of epilepsy in CDD:

During the initial stage, the EEG may be normal, and hypsarrhythmia may not be present at the onset of spasms. In later stages, hypsarrhythmia and generalized slowing with multifocal epileptiform discharges are common. A portion of individuals may experience a honeymoon period. Epileptic encephalopathy and refractory generalized or mixed epilepsy are common in later stages, and a subset of individuals are diagnosed with West syndrome or Lennox-Gastaut Syndrome. Sequential seizures with multiple motor phases are common in all three stages [7, 11, 13]. (Legend: CDD = CDKL5 deficiency disorder. EEG = electroencephalogram.)