1 INTRODUCTION

Congenital heart disease (CHD) is the most common congenital defect and occurs in 1% of live births (Khoshnood et al., 2012). The survival of children with CHD has increased exponentially over the last decades, and today, more than 97% will reach adulthood (Mandalenakis et al., 2017, 2020; Moons et al., 2010). With increased survival, patients with CHD face the risk of developing acquired diseases and long-term complications such as epilepsy. Previous studies have described an elevated risk of epilepsy in patients with CHD. Surgery itself carries risks—in 10 children with seizures in the month surrounding their cardiac surgery, reasons included stroke or procedurally related hypoxic-ischemic injury (Desnous et al., 2019). A nationwide study from Denmark reported a 5% incidence of epilepsy in patients diagnosed with CHD before the age of 15 years, and a risk of epilepsy related to the number of cardiac procedures (Leisner et al., 2016). Stroke is also a risk factor for subsequent epilepsy in infants undergoing cardiac surgery for CHD (Ghosh et al., 2020).

The increased risk of epilepsy in the CHD population raises several questions. Could associated congenital syndromes confound the analyses? Does CHD itself, without cardiac surgery, also increase the risk of stroke and therefore epilepsy?

We used Swedish comprehensive population-based registers to study the risk of epilepsy in patients with CHD compared to matched controls, with the aim of identifying risk factors furthering pathophysiological understanding.

2 METHODS

3 RESULTS

The study cohort consisted of 71,941 patients with CHD and 714,462 matched controls (Table 1). A greater proportion of patients with CHD (8%) died before the end of the observation period compared to their controls (0.6%). Intellectual disability, stroke, and prematurity were more common among cases. Twenty-five percent of patients with CHD had undergone cardiac intervention.

3.1 Incidence of epilepsy

The cumulative incidence of epilepsy during the study period was 3.0% (95%, CI: 2.9-3.1) in cases and 0.9% (95%, CI: 0.9–0.9) in controls (Table 2). The cumulative incidence of any epilepsy, seizure, or status epilepticus was 4.0% (95%, CI: 3.9–4.2) in cases and 1.1% (95%, CI: 1.1–1.1) in controls. In Kaplan–Meier analysis, the survival-adjusted risk was 5% at 30 years, and separation between patients with CHD and controls continued to grow throughout the study period (Figure 1). The cumulative incidence of epilepsy for individuals with optimal coverage of national registers, born 1980–2010, was 3.3% (95%, CI: 3.2–3.5). The cumulative incidence of epilepsy increased with age at the end of follow-up until age 21 (Figure 2a). The highest risk of epilepsy was seen in the most complex CHD, such as lesion groups 1–2 (Figure 2b) and in patients undergoing > 2 cardiac interventions (Figure 2c). In Cox regression, the HR of epilepsy in individuals with CHD compared to controls was 3.6 (95%, CI: 3.4–3.9). In a multivariable model comprising age, sex and comorbidities, the HR for epilepsy in CHD was 2.5 (95%, CI: 2.4–2.7).

TABLE 2. Epilepsy-related diagnoses in congenital heart disease (CHD) patients and controls. The frequencies and percentages indicate the presence of a code for epilepsy-related conditions in exposed and unexposed members of the cohort

	All
Variable	CHD (n = 71,941)	Controls (n = 714,462)
Epilepsy	2136 (3.0%)	6222 (0.9%)
Seizure	1355 (1.9%)	2414 (0.3%)
Status epilepticus	141 (0.2%)	295 (0.0%)
Any of the above	2894 (4.0%)	7823 (1.1%)

4 DISCUSSION

In the present nationwide, register-based cohort study, we found a fourfold increased risk of developing epilepsy in patients with CHD compared with matched controls without CHD. We also identified a number of risk factors for subsequent epilepsy among patients with CHD. The number of cardiac interventions was associated with subsequent epilepsy.

The underlying mechanisms of the link between CHD and epilepsy have thus far not been extensively studied. We used nationwide registers to search for risk factors and identified several associations that can deepen the understanding of how CHD is linked to epilepsy. One possible explanation could be confounding by congenital syndromes, which could increase the risk of both epilepsy and CHD. However, in a multivariable model adjusting for intellectual disability and low birth weight, the risk of epilepsy associated with CHD remained significantly elevated. If patients with intellectual disability were excluded, CHD conferred an HR of epilepsy of 2.6. Similarly, if individuals with prematurity were excluded, the HR of epilepsy in patients with CHD was 3.3. Taken together, confounding by syndromes giving CHD as well as prematurity or intellectual disability does not seem to account for the entire risk increase associated with CHD. Stroke, another risk factor in cases with CHD, could be an intermediate variable in the CHD-epilepsy link; it greatly increased the risk of epilepsy in our cohort, and several smaller studies have described plausible mechanistic links between CHD, stroke, and seizures related to cardiac interventions (Desnous et al., 2019; Ghosh et al., 2020). Having undergone cardiac intervention also carried an increased risk.

Our study is register-based, with associated strengths and limitations. The detection of epilepsy should be sufficient—the positive predictive value of an ICD code for epilepsy in the NPR is 90% (Sveinsson et al., 2017). Although reporting to Swedish national registers is mandatory, all comorbidities have not been validated. Some risk factors are likely to be vulnerable to detection bias—it is, for instance, very likely that substance abuse is better detected in registers for patients with CHD than controls simply because of the more frequent interactions with the health care system in the former group. It is also possible that epilepsy could have been detected somewhat earlier in the CHD group than in the control group because of more frequent hospital contacts. For other comorbidities, such as brain tumors and stroke, this should be a smaller problem. Our overall risk estimate for epilepsy is in excellent agreement with a previous nationwide report from Denmark (Leisner et al., 2016).

A strength of our investigation is the long follow-up allowed by comprehensive national registers, but this also adds to the complexity in interpretation of the findings. Treatment and diagnosis of CHD improved markedly during the course of our study, and epilepsy diagnostic criteria have been revised. Similarly, the diagnosis of and survival after several important variables, such as stroke, have improved, which increases the risk of epilepsy. More than 50% of CHDs are diagnosed within the first month of life in quality registry data, which also includes historical patients. Currently, almost all patients with complex CHD are diagnosed antenatal or before discharge. To account for shifts in diagnostic sensitivity and criteria, we included birth year as a covariate in our Cox analysis. Being born more recently was associated with an increased risk of epilepsy, which presumably does not represent a biological difference but rather temporal improvements in coverage of epilepsy and certain covariates in the NPR. Cohort effects should have been statistically accounted for by matching on birth year.

In summary, the association between CHD and epilepsy seems multifactorial, but our results suggest that some risk factors may be modifiable. More studies on the prevention of epilepsy in persons with CHD are motivated, for instance, studies on preventing and mitigating stroke. Another interesting issue is whether the timing of intervention for CHD has any influence on CHD risk.

CONFLICT OF INTEREST

Dr. Zelano reports speaker honoraria for unbranded educations from Eisai and UCB and being an investigator in clinical trials sponsored by GW Pharma, UCB, Bial, and SK Life Science as an employee of Sahlgrenska University Hospital (no personal compensation). No other authors report any disclosures.