Electroencephalographs at onset ranged from hypsarrhythmia t
Electroencephalographs at onset ranged from hypsarrhythmia to mild abnormalities but more abnormalities in background rhythms and epileptiform activity develop over time.15, 17, 19, 48, 52, 54, 55 Early mild abnormalities that sometimes precede a diffuse encephalopathy included focal delta slowing in the posterior head regions and intermittent generalized slowing. Some individuals have hypsarrhythmia and Nalidixic acid often includes focal or generalized slowing, focal and generalized epileptiform activity, and in some cases pseudoperiodic epileptiform discharges.15, 17, 19, 48, 52, 54, 55 Infantile spasms can occur, however, in the absence of hypsarrhythmia, including with a normal electroencephalograph or rare epileptiform activity (Olson et al., unpublished data, 2018). Burst suppression is rare and atypical for neonates with CDD. Data on the efficacy of seizure therapies are limited. A review of antiseizure medication response in 39 individuals with CDD found a responder rate (defined as 50% seizure reduction) to at least one antiseizure medication of 69% at three months, 45% at six months, and falling to 24% at 12 months. Medications with the highest rates of seizure reduction at three months included felbamate, vigabatrin, clobazam, valproic acid, steroids, lamotrigine, and zonisamide. The efficacy of each antiseizure medication showed large interindividual variability, with a maximum of 33%, except for felbamate with 3 of 3 responding at three months. At 12 months, the responder rate dropped to 0% to 20% except for one of three (33%) still responding to felbamate. Exacerbation of seizures occurred with at least one antiseizure medication in 31% of individuals, most often with carbamazepine (4/15 individuals). Our approach in the COEs is to use broad-spectrum antiseizure medications especially when there are generalized seizure types. Overall, two of 39 individuals (5%) became seizure free for >3 years with antiseizure medication or ketogenic diet. The most commonly used antiseizure medications in CDD were broad spectrum, including clobazam, valproate, topiramate, levetiracetam, and vigabatrin and 29.6% of individuals were treated with steroids or adrenocorticotropic hormone. Another study of caregiver perceptions of treatment by survey of 44 caretakers of individuals with CDD reported subjective efficacy (not further defined) in more than two individuals to vigabatrin (12/23), clobazam (6/14), sodium valproate (5/27), and levetiracetam (3/27). In the Boston Children's Hospital COE, >50% reduction in seizures types (excluding epileptic spasms) in more than one individual occurred with the following antiseizure medications: phenobarbital, clobazam, topiramate, rufinamide, and valproic acid (Olson et al., unpublished data, 2018). Infantile spasms in individuals with CDD are often refractory to first-line therapies. From the parent-entered International CDKL5 Disorder Database, infantile spasms were reported in 33.8% of individuals. In contrast, in the COE cohort of 93 individuals with data derived from physicians, spasms occurred in 81% (n = 75). We hypothesize that the difference in prevalence may result from data collection methods and possible underdiagnosis of infantile spasms if not associated with hypsarrhythmia. Among 18 individuals in the COE cohort with detailed data, median spasm onset was age four months (two weeks to 36 months); spasms resolved in only three of 18 individuals (17%) with first-line treatments (adrenocorticotropic hormone or vigabatrin) for epileptic spasms, lower than the ∼46% response rate at three months observed in infantile spasms cohorts.59, 60 Because CDD is often diagnosed before spasm onset and other seizure types often occur before spasms, such individuals with CDD are candidates for novel therapies.15, 48, 59, 60, 61, 62 The ketogenic diet has modest efficacy in treating epilepsy in CDD. The largest cohort reported 104 individuals with CDD treated with median ketogenic diet duration of 17 months and reductions in seizure frequency in 61 of 104 (58.7%) individuals, consistent with data from the Boston Children's Hospital COE (Olson et al., unpublished data, 2018). Side effects of the ketogenic diet occurred in 31.7% of individuals. A smaller cohort of 12 individuals with CDD reported that two (17%) had a significant reduction in seizures for >6 months and one (8%) for >1 year. Behavior improvements were reported including improved alertness in 19 of 104 (18%) individuals on the ketogenic diet whereas worsening motor skills and social interactions were reported in 5.8%. Ketogenic diet was most often discontinued because of lack of long-term efficacy. These retrospective observational reports did not provide data on diet ratios, ketone levels, efficacy for different seizure types, percent reduction in seizures, or duration of efficacy. Notably, few individuals were treated with ketogenic diet in the first year of life and its efficacy and tolerability in this CDD group remain unknown.