Risk Factor Predictors for Developing Epilepsy in Cerebral Palsy Patients in a Tertiary Hospital in Saudi Arabia: A Retrospective Study

Background Cerebral palsy (CP) is a major cause of childhood motor impairment worldwide. The prevalence of CP related to preterm births has increased consistently. Perinatal hypoxic-ischemic encephalopathy, intra- or periventricular haemorrhage, cerebral dysgenesis and intracranial infections are among the factors contributing to CP onset. Several studies have explored epilepsy-related morbidity among children with CP, finding notable correlations between the two conditions. Worldwide, there are multiple studies highlighting the high prevalence of epilepsy among children with CP and its association with specific CP subtypes and neurologic insults. However, research on the risk factors for epilepsy in CP children is limited, particularly in the Middle East and Saudi Arabia. Aim This study aims to address this gap by analysing potential prenatal, antenatal, and postnatal risk factors associated with epilepsy development in children with CP. Methods A retrospective cohort analysis of 152 children aged 1-14 years diagnosed with CP at King Abdulaziz University Hospital, Jeddah, Saudi Arabia, was conducted. Results The study showed a significant prevalence of epilepsy (68.4%), with generalised seizures being the most common type. Quadriplegia was notably common among CP children with epilepsy, indicating a potential correlation between motor impairment severity and epilepsy risk. Furthermore, CP children with epilepsy exhibited a higher prevalence of co-morbidities, emphasising the multifaceted nature of this condition. Perinatal and neonatal factors, such as hypoxic events, mechanical ventilation, perinatal asphyxia, neonatal convulsions, and microcephaly, were identified as significant risk factors for epilepsy in children with CP. While speech and hearing disorders were present in CP children with and without epilepsy, a slightly higher prevalence of impaired speech was observed in those with epilepsy. However, the difference between the two groups was not significant. Conclusion This study provides valuable insights into the epidemiology, clinical characteristics and potential risk factors associated with epilepsy among children diagnosed with CP in Saudi Arabia. The findings underscore the complexity of managing epilepsy in this population and highlight the need for further research to elucidate the underlying mechanisms and support the development of targeted interventions to improve patient outcomes.


Introduction
Cerebral palsy (CP) manifests as both neurodevelopmental and physical disabilities that emerge during childhood.It is a significant cause of motor impairment among children, with an incidence ranging from two to three cases per 1000 live births worldwide, 1.8 cases per 1000 live births in Arabic-speaking countries and 1.6 cases per 1000 live births in Saudi Arabia.Notably, the prevalence of CP associated with preterm births has increased consistently.Various factors contribute to the onset of CP, including perinatal hypoxicischemic encephalopathy, intra-or periventricular haemorrhage, cerebral dysgenesis and intracranial infection [1][2][3].
Several studies have investigated epilepsy-related morbidity among CP patients, aiming to identify associated risk factors, as CP is significantly correlated with epilepsy.For example, Sadowska et al. conducted a study on 181 children with CP, reporting that 56.35% were diagnosed with epilepsy, with a higher prevalence observed among children with tetraplegic CP [4].Additionally, Carlsson et al. found that children with CP stemming from central nervous system malformations, infections or grey matter damage were at higher risk of developing seizures [5].
Despite these findings, research on the risk factors for epilepsy in children with CP is limited in the Middle East specifically in Saudi Arabia.This study aims to fill this research gap by analysing potential prenatal, antenatal and postnatal risk factors associated with the development of epilepsy in children with CP.

Study design
A descriptive retrospective record review was conducted using King Abdulaziz University Hospital's electronic file system.Data were collected by reviewing reports of paediatric patients diagnosed with CP between 2009 and 2022.Patients' files were accessed through the databases of the paediatric neurology and neuroradiology department at King Abdulaziz University Hospital, a tertiary care centre in Jeddah, Saudi Arabia.Ethical approval for the study was obtained from the hospital's research and ethics committee (reference number 711-23).

Study population
We conducted a retrospective analysis of 152 children aged 1-14 years who were diagnosed with CP at King Abdulaziz University Hospital in Jeddah, Saudi Arabia.

Inclusion criteria
The inclusion criteria were as follows: age 1-14 years at the time of enrolment, a diagnosis of CP confirmed by an experienced paediatric neurologist and available neuroimaging results, including magnetic resonance imaging (MRI) or computed tomography (CT) scans.

Exclusion criteria
The exclusion criteria were as follows: age younger than one year or older than 14 years, a lack of neuroimaging results, clinical features indicative of progressive encephalopathies or the presence of metabolic inborn errors.
CP cases were classified into six different types: (i) spastic quadriplegia: all four limbs affected, (ii) spastic hemiplegia: affecting only a single hemi-body part with increased tone in flexor muscles, (iii) spastic diplegia: mainly affecting both lower limbs, with possible upper limb involvement, but with tone abnormalities less severe than those of the lower limbs, (iv) dyskinetic: involving dystonia (faulty posture with enhanced muscle tone) and choreoathetosis (quick, uncontrolled, twisting movements with hypotonia), (v) ataxic: characterised by hypotonia and loss of coordination and (vi) mixed type [6].
MRI brain images were classified according to the Magnetic Resonance Imaging Classification System (MRICS) as maldevelopment, predominant white matter injury, predominant grey matter injury, miscellaneous and normal.Movement disorder severity was classified according to the Gross Motor Function Classification Scale (GMFCS), ranging from most able (level I) to most disabled (level V) [7].

Data analysis
The data were collected, reviewed and then fed into IBM SPSS Statistics for Windows, Version 26 (Released 2019; IBM Corp., Armonk, New York, United States).All statistical analyses were two-tailed with an alpha level of 0.05, and p-values less than or equal to 0.05 were considered significant.Descriptive analysis was conducted by providing frequency distributions and percentages for categorical variables, while quantitative variables were represented as means and standard deviations.Cross-tabulation was employed to illustrate different factors associated with epilepsy among CP cases (child data and perinatal factors) using Pearson's Chi-square test and the exact probability test for small frequency distributions.
Regarding the prevalence, frequency, and types of epilepsy among the study cases with CP, 104 (68.4%) were diagnosed with epilepsy, which manifested as generalised (47.1%), focal (13.5%) and unspecified (39.4%) types.Furthermore, it has been observed in CP with epilepsy that about 68.3% of the cases had one or more seizure attacks per year, while 18.3% experienced attacks once per month, and 7.7% experienced them once per day.Additionally, 34.6% exhibited refractory epilepsy despite treatment with medication.Figure 1 shows the prevalence and frequency of each study group case.

Discussion
CP refers to a static brain injury that leads to permanent motor dysfunction.Although the condition itself is not neurodegenerative, the clinical manifestations may change over time as the central nervous system matures.It can lead to disabilities that go beyond motor impairments.Epilepsy is one of the main complications driving the investigation of potential risk factors for both CP and epilepsy [8,9].

Prevalence and characteristics of epilepsy
Our findings indicate a substantial prevalence of epilepsy among children with CP, with 68.4% of the study cohort diagnosed with epilepsy.This finding aligns with prior research highlighting the notable comorbidity between CP and epilepsy.Generalised seizures were the predominant seizure type, followed by unspecified and focal seizures.Importantly, a significant proportion of CP children with epilepsy reported frequent seizures, with 68.3% experiencing one or more attacks per year.Additionally, a notable subset demonstrated refractory epilepsy despite medication, underscoring the challenges in seizure management within this population.These findings are consistent with both local and global studies showing that epilepsy is highly prevalent among CP patients [2,4,10,11].

Correlation with CP subtypes and co-morbidities
Our study revealed an intriguing association between specific CP subtypes and the presence of epilepsy.Quadriplegia was notably common among CP children with epilepsy, suggesting a potential correlation between the severity of motor impairment and the risk of epilepsy development.Furthermore, a higher prevalence of co-morbidities was observed among CP children with epilepsy, highlighting the intricate clinical presentation and multifaceted nature of this condition.This result corresponds to findings from previous local studies [3,8,9].

Perinatal and neonatal risk factors
Our study underscores the pivotal role of perinatal and neonatal factors in the development of epilepsy among children with CP.In particular, hypoxic events emerged as significant risk factors predisposing CP patients to epilepsy.Specifically, mechanical ventilation during the neonatal period was identified as a notable risk factor, with a higher prevalence among CP children with epilepsy.Additionally, a history of perinatal asphyxia was more commonly observed among CP children with epilepsy, highlighting the potential contribution of hypoxic-ischemic injury to epilepsy pathogenesis in this population.Similarly, a history of neonatal convulsions and microcephaly was more prevalent among CP children with epilepsy, emphasising the importance of early detection and intervention for these high-risk individuals.These findings are consistent with previous research studies globally but not confined locally [2][3][4]12,13].

Speech and hearing disorders
Although both speech and hearing impairments were found in children with CP, regardless of whether they had epilepsy or not, our study shows a slightly higher incidence of speech impairment in CP children with epilepsy.However, this difference was not statistically significant.Our results align with those of Reid et al. regarding the association between epilepsy and hearing loss but in contrast with Weir et al., who reported a significantly higher prevalence of hearing loss at 39% [14,15].Despite the lack of statistical significance in our study, it emphasises the importance of thorough assessment and management of communication disorders in CP children, especially those with epilepsy, to improve overall developmental outcomes.

Conclusions
In conclusion, our study provides valuable insights into the epidemiology, clinical characteristics and potential risk factors associated with epilepsy among children diagnosed with CP in Saudi Arabia and the Middle East.The high prevalence of epilepsy, its correlation with specific CP subtypes and co-morbidities and the identified perinatal and neonatal risk factors highlight the complexity of managing epilepsy in this population.Further research is needed to elucidate the underlying mechanisms and to develop targeted interventions aimed at improving the quality of life and long-term outcomes of CP children affected by epilepsy because most studies are retrospective and there is a lack of prospective studies.

FIGURE 1 :
FIGURE 1: Prevalence, Frequency and Types of Epilepsy Among Study Cases with CP CP: Cerebral palsy

FIGURE 2 :
FIGURE 2: Speech and Hearing Disorders Among Study Groups CP: Cerebral palsy

Table 1
shows the characteristics of the study group.A total of 67 (64.4%) children in the subgroup with CP and epilepsy had quadriplegia compared to 21 (43.8%) in the epilepsy-free subgroup, and 10 (20.8%) children in the epilepsy-free subgroup had diplegia compared to nine (8.7%) in the subgroup with CP and epilepsy (p=.024).Additionally, 85 (81.7%) children in the subgroup with CP and epilepsy had other comorbidities compared to 28 (58.3%) in the epilepsy-free subgroup (p=.002).2024 Alyoubi et al.Cureus 16(5): e59980.DOI 10.7759/cureus.599803 of 8

Table 2
shows perinatal, neonatal and infant-related risk factors for epilepsy in CP.A total of 32 (30.8%) children in the subgroup with CP and epilepsy required mechanical ventilators compared to six (12.5%) in the epilepsy-free subgroup (p=.016).Likewise, 18 (17.3%)children in the subgroup with CP and epilepsy experienced neonatal convulsions compared to only one in the epilepsy-free subgroup (P=.001).Microcephaly was observed in five (4.8%) of the children in the subgroup with CP and epilepsy compared to seven (14.6%) in the epilepsy-free subgroup (p=.038), and 44 (42.3%) children in the subgroup with CP and epilepsy had a history of asphyxia compared to 12 (25%) in the epilepsy-free subgroup (p=.040).

TABLE 2 : Perinatal, Neonatal and Infant-Related Risk Factors for Epilepsy in CP
Figure2depicts speech and hearing disorders among the study groups.In the subgroup with CP and epilepsy, 17.3% of the children exhibited impaired speech compared to 14.6% in the epilepsy-free subgroup.None of the children in the subgroup with CP and epilepsy had impaired hearing, compared to 4.3% in the epilepsy-free subgroup.