Familial aggregation of status epilepticus in generalized and focal epilepsies

Abstract

Objective: To determine whether familial aggregation of status epilepticus (SE) occurs in a large cohort of familial common epilepsies.

Methods: We used the Epilepsy Phenome/Genome Project dataset, which consisted of 2,197 participants in 1,043 family units with ≥2 members having a common generalized or nonacquired focal epilepsy (NAFE). We identified participants with a history of traditionally defined SE (TSE) (seizures ≥30 minutes) and operationally defined SE (OSE) (seizures ≥10 minutes) by chart review. We assessed familial aggregation of TSE and OSE using χ² analysis and generalized estimating equations (GEE).

Results: One hundred fifty-five (7%) participants in 1,043 families had ≥1 episodes of TSE. Two hundred fifty (11%) had ≥1 episodes of OSE. In a χ² analysis, the number of family units with ≥2 members having TSE (odds ratio [OR] 4.79, 95% confidence interval [CI] 2.56-8.97) or OSE (OR 4.23, 95% CI 2.67-6.70) was greater than expected by chance. In GEE models adjusted for sex, broad epilepsy class (GE or NAFE), age at onset, and duration of epilepsy, TSE in a proband predicted TSE in a first-degree relative (OR 2.79, 95% CI 1.24-6.22), and OSE in a proband predicted OSE in a first-degree relative (OR 2.91, 95% CI 1.65-5.15). The results remained significant in models addressing epilepsy severity by incorporating the number of antiseizure medications used or epilepsy surgery.

Conclusions: TSE and OSE showed robust familial aggregation in a cohort of familial epilepsy independently of epilepsy severity or class, suggesting that genetic factors contribute to SE independently of the genetic cause of these epilepsies.

Clinicaltrialsgov identifier: NCT00552045.

Figure 1. EPGP flowchart

EPGP = Epilepsy Phenome/Genome Project; GE = generalized epilepsy; IS = infantile spasms; LGS = Lennox-Gastaut syndrome; NAFE = nonacquired focal epilepsy; OSE = operationally defined status epilepticus; PMG = polymicrogyria; PVNH = periventricular nodular heterotopia; TSE = traditionally defined status epilepticus.

Figure 2. Probability distribution plots of select variables for participants with and without TSE

(A) Age at epilepsy onset (years) (n_{with TSE} = 133, n_{without TSE} = 1,586, z = 7.218, p < 0.001), (B) epilepsy duration (years) (n_{with TSE} = 133, n_{without TSE} = 1,581, z = −2.560, p = 0.011), and (C) number of antiseizure medications used (n_{with TSE} = 75, n_{without TSE} = 925, z = −6.880, p < 0.001). The clustered Wilcoxon rank-sum test was used for all statistical tests. TSE = traditionally defined status epilepticus.

Figure 3. Probability distribution plots of select variables for participants with and without OSE

(A) Age at epilepsy onset (years) (n_{with OSE} = 218, n_{without OSE} = 1,500, z = 9.531, p < 0.001), (B) epilepsy duration (years) (n_{with OSE} = 218, n_{without OSE} = 1,496, p = 0.897), and (C) number of antiseizure medications used (n_{with OSE} = 124, n_{without OSE} = 876, z = −5.132, p < 0.001). The clustered Wilcoxon rank-sum test was used for all statistical tests. OSE = operationally defined status epilepticus.

Figure 4. ORs for risk factors for TSE and OSE

Odds ratios (ORs) for potential risk factors for (A) traditionally defined status epilepticus (TSE) and (B) operationally defined status epilepticus (OSE) were calculated with a generalized estimating equations model. TSE proband and OSE proband indicate the adjusted OR for a first-degree relative having TSE or OSE if the proband has TSE or OSE. The other independent variables apply to the first-degree relative with age at epilepsy diagnosis (age at onset) and epilepsy duration (duration) being continuous variables and the others being binary. Sample size = 783 in panels A and B. CI = confidence interval; NAFE = nonacquired focal epilepsy.

Figure 5. ORs for risk factors for TSE with adjustment for epilepsy severity

Odds ratios (ORs) for potential risk factors for traditionally defined status epilepticus (TSE) were calculated with a generalized estimating equations model including (A) number of the antiseizure medications (ASMs) used or (B) epilepsy surgery. TSE proband indicates the adjusted OR for a first-degree relative having TSE if the proband has TSE. The other independent variables apply to the first-degree relative with age at epilepsy diagnosis (age at onset) and epilepsy duration (duration) being continuous variables and the others being binary. Sample size = 385 in panel A and 396 in panel B. CI = confidence interval; NAFE = nonacquired focal epilepsy; SE = status epilepticus; surgery = epilepsy surgery.

Figure 6. ORs for risk factors for OSE with adjustment for epilepsy severity

ORs for potential risk factors for operationally defined status epilepticus (OSE) were calculated with a generalized estimating equations model including (A) number of the antiseizure medications (ASMs) used or (B) epilepsy surgery. OSE proband indicates the adjusted OR for a first-degree relative having OSE if the proband has OSE. The other independent variables apply to the first-degree relative with age at epilepsy diagnosis (age at onset) and epilepsy duration (duration) being continuous variables and the others being binary. Sample size = 385 in panel A and 396 in panel B. CI = confidence interval; NAFE = nonacquired focal epilepsy; SE = status epilepticus; surgery = epilepsy surgery.