Vascular syndrome predicts the development and course of epilepsy after perinatal stroke

2.1 Participants

Patients were identified from the Estonian Pediatric Stroke Database and all patients with perinatal ischemic stroke were invited to participate in the outcome study. All children with pediatric stroke admitted to the Children's Clinic of Tartu University Hospital are included in the Pediatric Stroke database. The Children's Clinic of Tartu University Hospital is one of the two third level centers for neonatal intensive care and child neurology in Estonia and serves the southern and eastern parts of the country. Data in the Estonian Pediatric Stroke Database was collected retrospectively within an epidemiological study from 1994 to 2003 and prospectively from 2004.^{10, 14}

The study participants fulfilled all of the inclusion criteria: (1) magnetic resonance imaging (MRI) or computed tomography-confirmed diagnosis of unilateral perinatal stroke; (2) birth at gestational age ≥36 weeks; (3) clinical follow-up of at least 18 months. The exclusion criteria were: (1) structural disease other than stroke affecting the central nervous system (hypoxic–ischemic encephalopathy, central nervous system's infectious disease, tumor, cortical malformation, congenital anomaly); (2) specific disease-causing gene variant or copy number variant suggested to be pathogenic for epilepsy, or developmental delay; (3) absence of neuroimaging-confirmed stroke.

2.2 Clinical data

Clinical information of the study patients about pregnancy, delivery and the neonatal period, as well as about the time of the first epileptic seizure, the time of epilepsy diagnosis, and the clinical features of epilepsy was collected from medical records. At the last follow-up for Kaplan–Meier estimation, the presence of epilepsy was ascertained from the digital national Health Portal which provides patients' health and prescriptions' data in case the on-site visit is not possible. Clinical outcome was evaluated by one of the two child neurologists at the follow-up visit (UV, RL). Pediatric Stroke Outcome Measure was used for evaluation of global outcome.¹⁸

2.3 Neuroimaging

All radiological images (cerebral ultrasonography, computed tomography and MRI) are stored in the population-based Estonian Picture Archive. The images of the patients in the Estonian Pediatric Stroke Database were independently reviewed by a radiology resident (No. I) and two neuroradiologists (PI and DL) who were blinded to the clinical outcome of the patients. By consensus agreement the patients were classified as having the vascular syndrome based on previous classifications.² MRI for this study was performed in the chronic stage of perinatal stroke without anesthesia at the age of 6–18 years (n = 66). A 3T Philips Achieva MRI scanner was used with a 8-channel SENSE head coil (Philips Medical Systems, Best, The Netherlands). In children who were not able to complete this investigation, earlier MRI (n = 14) or computed tomography (n = 2) images done at the age of 1 month or older for clinical purposes were used, except in the case of one child whose MRI investigation from the age of 6 days was used to confirm stroke.

2.4 Classification of perinatal stroke according to the time of diagnosis and vascular syndrome

Neonatal ischemic stroke is diagnosed after birth, before or on the 28th postnatal day. Presumed perinatal ischemic stroke is diagnosed in infants >28 days of age after the normal neonatal period if neuroimaging reveals signs of chronic infarction and it is presumed that ischemic event has occurred between the 20th week of fetal life through the 28th postnatal day.^{1, 3}

According to the vascular type, ischemic stroke was classified as AIS or PVI. According to the vascular syndrome, ischemic stroke comprises: (1) PMI compromising both lateral lenticulostriate arteries with infarction in the basal ganglia and the distal MCA territory; (2) DMI involving the distal MCA; (3) AT occlusion of the distal MCA compromising the frontal lobe anteriorly of the central sulcus and the anterior temporal lobe; (4) PT occlusion of the distal MCA compromising the parietal lobe posteriorly of the central sulcus and the posterior temporal lobe; (5) LLS infarction with involvement of the basal ganglia and the posterior limb of the internal capsule; (6) PVI as infarction of the periventricular white matter in the medullary venous territory.²

2.5 Epilepsy and EEG

Epilepsy was diagnosed if it met one of the following conditions: (1) at least two unprovoked seizures occurring >24 h apart; (2) one unprovoked seizure with high recurrence risk.¹⁹ High recurrence risk was defined if a single seizure occurred at least 1 month after stroke and was accompanied with structural changes on MRI and epileptiform changes on electroencephalography (EEG).¹⁹ All epilepsy diagnoses were reviewed and confirmed by a child neurologist and an EEG specialist (UV).

To classify and describe the course of epilepsy, we used a modified version of the Engel classification: class 0—seizure free and off antiseizure medication for >6 months; class 1—seizure free for at least 6 months while on medication or seizure free off medication for <6 months; class 2—on medication, fewer than one seizure a month; class 3—one to four seizures a month; class 4—five to 30 seizures a month; and class 5—>30 seizures a month.²⁰ Status epilepticus was defined as a condition leading to prolonged seizures, using the time point of 5 min for bilateral tonic–clonic status epilepticus and 10 min for focal status epilepticus with impaired consciousness.²¹ Spike-wave activation in sleep was defined as an EEG pattern which consists of continuous spike-and-slow-waves during sleep, affecting ≥85% of sleep.^{22, 23} Drug resistant epilepsy was defined as failure of adequate trials of two tolerated and appropriately chosen and used antiepileptic drug schedules to achieve sustained seizure freedom.²⁴ We defined complicated epilepsy: (1) modified Engel class ≥3; (2) history of status epilepticus; (3) history of spike-wave activation in sleep; or (4) drug resistant epilepsy.

Standard EEG in the postneonatal period included the awake and sleep (daytime nap) periods. An international full 10–20 system was adopted for electrode placement.²⁵ Focal interictal epileptiform discharges (IED) were defined as transient epileptiform activity manifesting itself up to two electrodes consistent with the same anatomical location. Regional IEDs were defined if IED appeared in more than two electrodes, but in the same hemisphere, and in case bilateral IED epileptiform activity was represented in both hemispheres. For classifying localization of background activity changes, the same definition was used as for IED. All EEG investigations from 2005 to 2011 were stored on digital video discs and from 2011 onward in the neurophysiology database of Tartu University Hospital.

2.6 Statistical analysis

The statistical package SAS version 9.4 (SAS Institute, Cary, NC) and RStudio were employed for statistical analysis. The Shapiro–Wilk test was used for assessment of normality. Continuous data were summarized as means with the 95% confidence interval (CI) or medians with the interquartile range (IQR), and categorical data, as absolute counts and percentages. Differences between the groups were analyzed with the Student's t-test or by the nonparametric Mann–Whitney U test for continuous variables. To compare the proportions, the chi-square test, Fisher's exact test (when expected values were less than five) and Firth's logistic regression were used. Odds ratio (OR) and the 95% CI were used to estimate the measure of association.

We applied the Kaplan–Meier estimation of the proportion of subjects at any point during follow-up. Age at the first epileptic seizure was used for calculating cumulative incidence. An indicator of the length of follow-up was the median follow-up time whose calculation was based on the reverse Kaplan-Meier estimator.²⁶ The log-rank statistic and the Cox proportional hazards regression were used to assess differences between the survival curves. All P values were two-sided.

2.7 Ethics

The study was approved by the Research Ethics Committee of the University of Tartu. Written informed consent was provided by all individual participants older than 7 years who were able to read, as well as by their parents.

3.1 Population

Eighty-seven patients from the Estonian Pediatric Stroke Database met the criteria of perinatal ischemic stroke and had been born at a gestational age of ≥36 weeks. Four patients were lost to outcome studies. The final study group consisted of 83 patients with perinatal stroke: 39 (47%) with AIS (patients with AT or PT occlusion n = 13 [15.7%]; patients with PMI or DMI occlusion n = 23 [27.7%]; patients with LLS infarction n = 3 [3.6%]), and patients with presumed perinatal PVI n = 44 (53%). There were 22/39 patients with neonatal AIS and 17/39 patients with presumed perinatal AIS. The flow chart of the study population is presented in Figure 1.

During a median follow-up of 15.1 years (95% CI: 12.4–16.5 years) for the study group epilepsy developed in 22.9% (19/83) of the patients. In 58% (11/19) of the patients epilepsy was diagnosed after the first seizure. The median age at follow-up for patients with epilepsy was higher compared to patients without epilepsy, 19.8 years [IQR: 14.0–23.1] and 14.9 years [IQR: 9.2–17.3], p = .004, respectively.

There were no differences in gender, gestational age, Apgar score, need for emergency cesarean section, presence of neonatal seizures or side of stroke between patients who developed epilepsy and those without epilepsy (Table 1). Pediatric Stroke Outcome Measure score was higher in the group of children with epilepsy compared to patients without epilepsy (p = .018).

3.2 Development of epilepsy in different vascular syndromes

The probability of having epilepsy was higher in the group of patients with AIS compared to patients with PVI (hazard ratio [HR] 5.3; 95% CI: 1.9–18.6, p = .0009) (Figure 2).

According to pairwise comparison, for patients with PMI or DMI the probability to have epilepsy was significantly higher compared to patients with PVI (HR 7.2; 95% CI: 2.5–26, p = .0007) (Figure 3). There was no significant difference in the probability to have epilepsy between the group of AT + PT compared to the group of PVI (HR 3.6; 95% CI: 0.89–15, p = .069) or between the group of AT + PT compared to the group of PMI + DMI (HR 2.0; 95% CI: 0.68–7.2; p = .24). None of the patients with LLS developed epilepsy during the follow-up period.

3.3 Cumulative survival function for epilepsy at different ages

The cumulative probability to be without epilepsy for the whole study group was 87.8% at 5 years (95% CI: 81.0–95.2), and 75.4% at the median age of 15 years (95% CI: 65.8–86.4) (Figure 4, Table 2).

The odds to develop epilepsy persisted throughout childhood and young adulthood until the age of 20 years in the group of PMI + DMI when the probability of being epilepsy free was 36.7% (95% CI: 17.4–77.3). In the group of AT + PT the survival function reached the lowest level at the age of 15 years when 63.5% (95% CI: 39.5–100) of the patients were without epilepsy. For patients with PVI, the survival function declined until the age of 6 years when it was 90.9% (95% CI: 82.8–99.8) and remained at this level during the whole follow-up period.

3.4 Features of poststroke epilepsy and EEG

The detailed clinical and neurophysiological characteristics of children with epilepsy according to the vascular syndrome are presented in Table 3.

The median age of the first epileptic seizure was 4.6 years [IQR: 1.1–7.8] for all patients who developed epilepsy.

Complicated epilepsy occurred in 14/19 (73.7%) of all patients with epilepsy. In the case of complicated epilepsy, the first seizure occurred at 7 years or earlier in 12/14 (85.7%) of the cases compared to 1/5 (20%) in the uncomplicated cases (OR = 24; 95% CI: 1.2–1276, p = 0.017). Status epilepticus occurred in five (26.3%) patients and spike-wave activation in sleep in two (10.5%) patients. Four patients (21%) presented with status epilepticus at the time of epilepsy diagnosis. For two of them, detailed history revealed previous focal seizures that had not been recognized earlier.

Patients with PVI (4/4, [100%]) had significantly more often status epilepticus or spike-wave activation in sleep compared to the AIS group (3/15, [20%], OR = 32; 95% CI: 1.2–870, p = .009) and compared to the AT + PT group (0/4 [0%], OR = 81; 95% CI: 1.3–5046, p = .029). In patients with PMI or DMI status epilepticus or spike-wave activation in sleep presented in 3/11 (27.3%) patients and 7/11 (63.6%) had frequent seizures. In this group two patients (18.2%) had hypsarrhythmia and epileptic spasms.

There were no significant differences in the neurophysiological characteristics between the different vascular syndromes.

3.5 Outcome of epilepsy

At the last follow-up 10/19 (52.6%) patients were seizure free and off medication over 6 months (Engel class 0). Detailed data of these patients is presented in the Table 4. Their mean follow-up time after the last seizure was 147.1 months (95% CI: 93.5–200.7). The mean time of active seizures was 32.7 months (95% CI: 5.6–59.8), but three patients had only single seizure.