A tale of two cohorts: Differing outcomes in infantile-onset focal epilepsy

Abstract

Objective: Infants with focal-onset epilepsy are an understudied population, requiring additional evaluation for clinical assessment and prognostication. Our goal was to characterize the etiology and natural history of infantile-onset focal epilepsy.

Methods: We retrospectively identified all infants (0-24 months) with onset of focal epilepsy while resident in Olmsted County, Minnesota, between 1980 and 2018, using the Rochester Epidemiology Project Database. We assessed the impact of etiology on both seizure and neurodevelopmental outcome, and mortality.

Results: Of 686 children with epilepsy onset <18 years, 125 (18.2%) presented with focal-onset seizures in infancy. Median follow-up for this group was 10.9 years (interquartile range [IQR] 6.2, 19.3). Etiology was identified in 65.6% (structural N = 62, genetic N = 13, both structural and genetic N = 3, metabolic N = 4). Of 107 patients followed >2 years, 38 (35.5%) developed drug-resistant epilepsy (DRE). DRE was more likely with younger age at onset, known etiology, and presence of epileptic spasms. Sixty-eight (63.0% of those with follow-up) were developmentally delayed at last follow-up, and known etiology, DRE, and presence of epileptic spasms were significantly associated with delay (p < .001 for all). Fifteen patients (12.0%) died at a median age of 7.1 years (IQR 1.7, 21.7), but only one death was seizure related (suspected sudden unexpected death in epilepsy [SUDEP]). Of 20 infants with normal development at onset and no known etiology with >2 years follow-up, none developed DRE, all were seizure-free at last follow-up (95% off antiseizure medications [ASMs]), and all remained developmentally normal.

Significance: Infantile-onset focal epilepsy accounts for 18% of all epilepsy in childhood, is frequently due to known etiologies, and has a high rate of DRE. However, developmentally normal infants without a known cause appear to have a very favorable course.

Keywords: epilepsy; focal epilepsy; infantile; infantile spasms.

Figure 1.. Seizure type at Presentation and Evolution with Time.

Frequency of seizure semiology is shown both at time of diagnosis and at last follow-up. The 63 cases with only focal seizures at onset that remain focal onset include 47 with only focal seizures and 16 with evolution to bilateral tonic-clonic activity. Of the 15 that developed epileptic spasms at follow-up, 5 of them also demonstrated generalized onset seizures. The generalized semiologies that evolved over time include: generalized tonic-clonic, tonic, atonic, and myoclonic.

Figure 2.. Evolution of Developmental Function Over Time.

Developmental function was assessed at time of diagnosis and recent follow-up and classified as normal, mildly impaired, or moderate to severe disability. Seventy-one percent of those with normal development at onset progressed without accumulation of disability. In total, 24.1% of cases with >12 months follow-up demonstrated increase in level of disability during the study.

Figure 3.. Seizure Frequency through Time.

Cumulative percentages of seizure activity (Y-axis) is shown in years following epilepsy diagnosis along the X-axis. The cases that have been seizure free for 12 months, with or without ASMs, are designated “No Sz.” The orange bar shows cases that have on-going seizures (“Active Sz”) but have not reached the criteria for being considered drug-resistant. The remainder of cases are those with drug-resistant epilepsy (“DRE”), meaning ongoing seizures with 2 or more ASMs failed for either side effects of lack of efficacy. By 3 years, almost 90% of cases have either achieved excellent seizure control or become intractable.

Figure 4.. Outcomes of Focal Infantile-Onset Epilepsy.

Chart tracks outcomes based on initial exam and etiology. Initial exam refers to overall neurological exam; 73.8% of those with normal exam were also cognitively normal, the remainder had only mild delay. Only 13.8% of those with abnormal initial exam were classified as developmentally normal, 44.6% had severe delay. Seizure frequency shows cases which had been seizure free for >12 months at last follow-up with or without ASMs and those with DRE. Any remaining cases had ongoing seizures with ASM not yet meeting criteria for drug-resistance (not shown). The percent of each group that was developmentally normal at last follow-up is also shown, the remainder of each group had at least some degree of delay; the highest rates of moderate/severe delay were in those cases with identified etiology.