Preventive treatment positively alters ‘natural history of severe infantile epilepsy’

Preventive treatment with vigabatrin effectively altered the natural history of seizures among infants with tuberous sclerosis complex, decreasing the risk for and severity of epilepsy, according to results published in Annals of Neurology.

“[Tuberous sclerosis complex] TSC is a major cause of severe and drug-resistant epilepsy, with focal seizures and infantile spasms occurring in about 80% of TSC infants. Neurodevelopmental comorbidities, including intellectual disability and autism, are also common in TSC,” the researchers wrote. “Current guidelines recommend antiepileptic treatment after two unprovoked clinical seizures or after one seizure in patients at high risk (> 60%) [for] recurrent seizures. Although immediate antiepileptic treatment after seizure onset in children with TSC decreases the risk of neurodevelopmental complications, still 50% [to] 60% of children develop intellectual disability.”

Most individuals with TSC exhibit asymptomatic epileptiform activity on electroencephalography (EEG) prior to the onset of clinical seizures, according to the researchers, followed by asymptomatic electrographic seizures. Previous research, though small, demonstrated that starting antiepileptic treatment in infants with TSC after epileptiform activity or electrographic seizures was first identified improved epilepsy-related outcomes at 2 years of age compared with a historical control group in which treatment began after clinical seizures.

Katarzyna Kotulska, MD, PhD, of the department of neurology and epileptology at the Children’s Memorial Health Institute in Poland, and colleagues conducted the present study as part of the EPISTOP project, a long-term prospective study examining clinical and molecular biomarkers for epileptogenesis in a genetic model of epilepsy/TSC. The trial was conducted from March 2014 through October 2018 at nine sites in Europe and one site in Australia.

Kotulska and colleagues monitored 94 infants 4 months of age or younger with TSC and no seizure history using monthly video EEG. Participants received vigabatrin 100 mg/kg/day or 150 mg/kg/day either as conventional antiepileptic treatment, after the first electrographic or clinical seizure, or preventively, when the researchers identified epileptiform EEG activity before a clinical seizure. At six sites, Kotulska and colleagues assigned patients to treatment in a 1:1 ratio in a randomized controlled trial (RCT). At four sites, treatment allocation was fixed; this was denoted as an open-label trial (OLT).

Researchers followed patients until 2 years of age. Time to first clinical seizure served as the primary endpoint.

The study revealed epileptiform EEG abnormalities prior to the onset of seizures in 54 participants. Kotulska and colleagues included 27 of these patients in the RCT and 27 in the OLT.

Preventive treatment resulted in a significantly longer time to first clinical seizure compared with conventional treatment, according to the study findings (RCT: 364 days [95% CI, 223-535] vs. 124 days [95% CI, 33-149]; OLT: 426 days [95% CI, 258-628] vs. 106 days [95% CI, 11-149]). At 24 months, the pooled analysis demonstrated that preventive treatment decreased the risk for clinical seizures (OR = 0.21; P = .032), drug-resistant epilepsy (OR = 0.23; P = .025) and infantile spasms (OR = 0; P < .001). In the RCT and the OLT, participants who received preventive treatment were about three times more likely to remain free from clinical seizures throughout the study period compared with participants in the conventional treatment group (RCT: 46% vs. 15%; OLT: 50% vs. 17%; log rank P value = .011).

Participants receiving preventive treatment demonstrated a significantly lower proportion of days with seizures until 2 years of age compared with conventional treatment in the RCT (17% vs. 62%; P = .022), the OLT (7% vs. 35%; P = .030) and the pooled analysis (8% vs. 39%; P = .002). At 2 years of age, the rate of drug-resistant epilepsy was significantly lower in patients receiving preventive treatment compared with conventional treatment in the RCT (31% vs. 77%; OR = 0.15; 95% CI, 0.02-0.98), trended to significance in the OLT (23% vs. 50%; OR = 0.35; 95% CI, 0.04-2.45) and was significant in the pooled analysis (28% vs. 64%; OR = 0.23; 95% CI, 0.06-0.83).

In both the RCT and OLT, no patients who received preventive treatment developed infantile spasms compared with four of 13 (31%) patients receiving conventional treatment in the RCT and six of 12 (50%) patients in the OLT, for a statistically significant difference in both the OLT and the pooled analysis (P = .015 and P < .001, respectively). No EPISTOP subject who completed the study developed a severe intellectual disability at the age of 2 years.

Researchers reported that adverse events observed in the trial “were typical for the antiepileptic drugs used and the age of the patients.” They observed no adverse events related to preventive treatment. One death, due to cardiac arrest, occurred during epilepsy surgery in a participant who had received conventional treatment. Rates of adverse events were otherwise similar between the participants receiving preventive and conventional treatment, according to Kotulska and colleagues.

“... This EPISTOP study has shown that it may be possible to change the natural history of severe infantile epilepsy through early intervention with antiepileptic therapy,” the researchers wrote.