Cerebral palsy (CP) is an umbrella term for nonprogressive motor disease caused by insults to a developing brain. CP is a group of heterogeneous disorders resulting from various types of brain injuries during prenatal, perinatal, and postnatal periods [1]. The prevalence of CP is 1.5 to 6 per 1,000 live births in high-income countries and higher in developing countries [1,2]. The prevalence in South Korea is 2 to 4 per 1,000 live births [3,4]. Patients with CP have comorbidities such as intellectual disability (ID), epilepsy, visual impairment, hearing impairment, psychiatric disorders, musculoskeletal problems, and nutritional problems, necessitating extensive lifelong care in health, society, and education contexts [1].

Several studies have shown that 15% to 60% of CP patients have epilepsy as a comorbid disease, and a report using the Korean Database of Cerebral Palsy in 2017 stated that one out of four patients had epilepsy [5-10]. The prevalence of epilepsy in the general population is 3 to 8 per 1,000 persons, and the prevalence in patients with CP is higher than that [8,9,11,12]. The aim of this study was to investigate the characteristics of CP patients in Korea and identify risk factors for epilepsy.

Medical records of pediatric patients (≤18 years of age) who visited the pediatric neurology and/or rehabilitation Department of Daejeon St. Mary’s Hospital, a university-affiliated tertiary hospital, from January 2016 to December 2022 with magnetic resonance imaging (MRI) and electroencephalography (EEG), who had a minimum follow-up period of 2 years, and who were diagnosed with International Classification of Diseases, 10th Revision codes of G800, G801, G802, G803, G804, G808, and G809 (CP) were retrospectively reviewed.

Epilepsy was diagnosed if two unprovoked seizures with a minimum interval of 24 hours occurred. Neonatal seizures were defined as clinical seizures confirmed with either video EEG, conventional EEG, or amplitude-integrated EEG occurring between birth and 28 days after birth. Febrile seizures were defined as fever-provoked seizures in children between 6 and 60 months old without a previous diagnosis of epilepsy. Drug-resistant epilepsy (DRE) was defined as the presence of uncontrolled seizures despite adequate doses of two appropriately chosen antiseizure medications (ASMs). Patients with epilepsy who were not included in the drug-resistant group were labeled as those with controlled epilepsy.

The subtypes of CP were defined by modifying the hierarchical classification tree of CP subtypes in Surveillance of Cerebral Palsy in Europe (SCPE) by dividing the spastic bilateral group into spastic quadriplegia and spastic diplegia based on whether the upper limbs were affected. Gross motor function was classified into five groups (group 1 with minimal and group 5 with maximal disability) using the Gross Motor Function Classification System-Expanded and Revised (GMFCS-E&R) at a minimum age of 2. ID was defined when the intellectual quotient (IQ) was below 70. It was divided into four groups: profound if below 20, severe if between 20 and 34, moderate if between 35 and 49, and mild if between 50 and 69. Cryptogenic CP was diagnosed for patients without apparent or possible brain insults, such as prematurity, hypoxic ischemic encephalopathy, infarction, encephalitis, head trauma, periventricular leukomalacia, or findings on brain imaging to explain motor dysfunction. CP patients were subdivided according to the presence or absence of epilepsy. Epilepsy patients were grouped into those with DRE and those with controlled epilepsy. In a subgroup analysis based on CP subtypes (spastic quadriplegia, diplegia, and hemiplegia), patients were classified according to the presence or absence of epilepsy.

We collected demographic and clinical data for sex, gestational age, birth weight, mode of delivery, multiple pregnancy, 5-minute Apgar score, maternal factors, intrauterine growth retardation, birth weight for gestational age, brain insult (including hemorrhage, infarction and infection), occipitofrontal circumference, congenital anomaly, admission to the neonatal intensive care unit (NICU), family history of CP, epilepsy, neurologic diseases, subtype of CP, gross motor function, comorbidities, neonatal and febrile seizures, seizure characteristics, ASM, medications related to spasticity and psychiatric diseases, EEG, brain MRI findings, and results of a genetic evaluation.

The Mann-Whitney test was used for comparing continuous variables between two groups. The chi-square test and Fisher’s exact test were used for categorical variables. A subgroup analysis of CP subtypes (spastic quadriplegia, diplegia, and hemiplegia) was done in the same manner. We used SPSS version 29 (IBM Corp., Armonk, NY, USA) to perform all statistical analyses. A P value less than 0.05 was considered to indicate statistical significance. This study was approved by the Institutional Review Board of The Catholic Medical Center with a waiver for the requirement to obtain informed consent (approval number and date: DC22RASI0003, February 15, 2022).

In total, 268 patients were included in this study, and 60.8% were male. Table 1 shows patients with a spastic diplegia pattern accounted for 35%. Those with spastic quadriplegia accounted for 34.3% and 2.2%, respectively. More than half (57.8%) of CP patients had ID, and the majority of them (67.1%) had an IQ of less than 35, corresponding to severe to profound mental retardation. Excluding neonatal seizures and febrile seizures, 42.3% of patients experienced first seizure during infancy. Among CP patients, about one-third (36.9%) had epilepsy and one-third (10.8%) showed multidrug resistance. In addition, 3.4% of patients experienced status epilepticus.

Table 2 compares demographic and clinical features between epilepsy and non-epilepsy groups. Prematurity (i.e., babies born with a gestational age of less than 37 weeks) was significantly more common in patients without epilepsy (65.7%) than in patients with epilepsy (50.5%, P=0.02). Patients with asphyxia (29.3% vs. 13.0%, P=0.001) or brain injury including brain hemorrhage, infarction, and meningoencephalitis (25.3% vs. 13.0%, P=0.013) were twice as common in patients with epilepsy than in patients without epilepsy. Microcephaly, defined as an occipitofrontal circumference below 2 standard deviations from the mean of age and sex, was more prevalent in the epilepsy group than in the non-epilepsy group (58.6% vs. 36.1%, P=0.001). The NICU admission rate and duration of NICU admission did not show statistically significant differences. Spastic quadriplegia (59.6%) was the most common type in the epilepsy group. Spastic diplegia was the most common (46.2%) type in the non-epilepsy group, followed by spastic hemiplegia (23.7%), with statistical significance (P<0.001). The epilepsy group had a significantly higher frequency of gross motor impairment (51.5% in level 5 GMFCS-E&R vs. 11.2%, P<0.001) and ID (85.9% vs. 41.4%, P<0.001). More patients in the epilepsy group experienced neonatal seizures (18.2% vs. 4.1%, P<0.001) and febrile seizures (12.1% vs. 7.1%, P=0.02) than in the non-epilepsy group. The most common brain imaging results in both the epilepsy group (37.4%) and non-epilepsy group (58.0%) were periventricular leukomalacia and/or periventricular white matter injury. Intracranial hemorrhage (14.1% vs. 1.8%), diffuse gray matter injury (13.1% vs. 3.6%), and deep brain gray matter injury (8.1% vs. 0.0%) were more prevalent in the epilepsy group than in the non-epilepsy group. One-fourth of patients were evaluated with genetic tools. Of them, 35.5% had genetic mutations responsible for their symptoms. The diagnostic yield was 14.0% (6/43) for chromosomal microarrays and 44.1% (15/34) for targeted panel sequencing. None of these patients simultaneously had a copy number variation and single-nucleotide polymorphism. Some of the copy number variants identified in this study included 14q12 deletion, 14q32 duplication, and 22q13 deletion. The genes revealed in our patients from targeted panel sequencing were MBD5, SMC1A, NSD1, NFIX, AFF2, TRIO, SLC2A1, CACNA1A, GNAO1, NIBPL, PROC, and PLAA.

We performed a subgroup analysis for three CP subtypes (spastic quadriplegia, diplegia, and hemiplegia), excluding athetoid, ataxic, and mixed CP due to the small sample size. Fig. 1 shows the distribution of variables in the epilepsy and non-epilepsy groups according to CP subtypes. Prematurity, low birth weight, and asphyxia were not significantly more common in the epilepsy group according to CP subtypes. However, a birth history of prematurity, low birth weight, and asphyxia were significantly different between CP subtypes in patients without epilepsy (P=0.009, P=0.003, and P=0.016, respectively). Low birth weight in the epilepsy group (P=0.01) also showed a significant difference between CP subtypes. Comparing the epilepsy and non-epilepsy groups by CP subtypes showed a significantly higher frequency of brain injury in spastic quadriplegic patients (44.1% vs. 20.0%, P=0.03) and spastic hemiplegic patients (20.0% vs. 10.0%, P=0.007). However, there was no statistically significant difference in the presence of brain injury among spastic diplegic patients (7.1% vs. 3.8%, P=0.08). The 5-minute Apgar score, cesarean section delivery, intrauterine growth retardation, intrauterine infection, and brain malformation did not show significant differences in a subgroup analysis by CP subtypes or between CP subtypes in the epilepsy and non-epilepsy groups as shown in Supplementary Fig. 1.

Fig. 2 shows the results of a subgroup analysis comparing epilepsy and non-epilepsy groups by CP subtypes according to the birth weight for gestational age. More patients without epilepsy in the spastic diplegia subgroup had an appropriate birth weight for gestational age defined as 10th to 90th percentile of birth weight to gestational age than those with epilepsy (P=0.03). Fig. 3A shows the proportion of patients with normal intelligence or ID and the grade of ID according to CP subtypes and the presence of epilepsy. For three subtypes of CP, the non-epilepsy group had significantly less ID and milder grades of ID (P<0.001 for spastic quadriplegia and diplegia, P=0.003 for spastic hemiplegia). Of non-epileptic spastic hemiplegia patients, 83.8% had normal intelligence, while only 13.3% had normal intelligence in those with epileptic spastic quadriplegia. The degree of gross motor function in subgroups are described according to the levels of GMFCS-E&R, as shown in Fig. 3B. Patients with mildly impaired gross motor function (GMFCS-E&R levels 1 and 2) were more prevalent in the non-epilepsy groups for all three CP subtypes. The differences were statistically significant in the spastic quadriplegia (P=0.003) and hemiplegia (P=0.01) subgroups, but not in the spastic diplegia subgroup (P=0.63). Fig. 4 shows the distribution of age of seizure onset (excluding neonatal and febrile seizures) according to CP types. The age of seizure onset did not show a statistically significant difference (P=0.51) between spastic quadriplegia and diplegia groups. Those with seizure onset before age 1 accounted for 71.4% of the spastic quadriplegia group and 58.3% of the spastic diplegia group. Spastic hemiplegia had a statistically significant difference in the age distribution of seizure onset compared to the quadriplegia (P<0.001) and diplegia (P=0.046) groups. In total, 22.2% of spastic hemiplegic patients with epilepsy had seizure onset before age 1.

The results of comparing the features of DRE and controlled epilepsy are described in Table 3. The most common CP subtype was spastic quadriplegia in both groups (65.5% for DRE, 57.1% for controlled epilepsy), followed by spastic hemiplegia (17.2%) in the DRE group and spastic diplegia (17.1%) in the controlled epilepsy group. The number of patients with ID and severity of ID were comparable in the DRE and controlled epilepsy groups. The DRE group experienced status epilepticus more often than the controlled epilepsy group (13.8% vs. 7.1%, P=0.44), although the difference between the two groups was not statistically significant. The most common brain imaging result in the DRE group was cerebral malformation (31.0%). The occipitofrontal circumferences were significantly different between the two groups, with macrocephaly being present in 27.6% of subjects in the DRE group and 2.9% in the controlled epilepsy group (P<0.001). MRI findings were significantly different between the two subgroups, with DRE patients having higher frequencies of cerebral malformation (31.0% vs. 4.3%) and diffuse gray matter injury (17.2% vs. 11.4%), but lower frequencies of periventricular leukomalacia or periventricular white matter injury (27.6% vs. 41.4%) than controlled epilepsy patients. The most commonly used ASM for monotherapy was levetiracetam (33.3%), followed by valproate (26.7%) and oxcarbazepine (16.7%). For polytherapy, valproate (27.5%) was the most commonly used medication in various combinations with other ASMs, followed by levetiracetam (21.7%). The ASMs used in DRE and controlled epilepsy are shown in Table 4.

The incidence of CP in Korea is 2 to 4 per 100,000 live births. A recent research based on National Health Information Database of Korea showed that the incidence of CP decreased from 4.1 per 100,000 live births in 2007 to 2.5 in 2011 despite an increase in high-risk deliveries [3]. However, some studies in other parts of the world have shown the incidence did not change significantly over time or even increased despite advancement of neonatal care such as hypothermic therapy, magnesium sulfate injections for mothers with preterm labor, and an increased survival rate for extremely preterm babies [13,14]. These conflicting results might have arisen from differences in the time points used for comparison and how the population was defined and compiled for each study.

CP patients with asphyxia, hemorrhage, infarction, and brain infections were more likely to have epilepsy. Spastic quadriplegia was the most common subtype of CP among patients with epilepsy. Epileptic CP patients were more likely to have neonatal seizures with more severely impaired gross motor function, and ID. Stratifying by subtypes is encouraged for further research on the etiology of CP, comorbidities in CP patients, and their prognosis.