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| Ahead of print
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Etiological spectrum and predictors of intractability in early-onset epilepsy (3 months–2 years): A cross-sectional observational study
Shiji Chalipat, Darshita Shukla, Sanjay Chavan, Sharad Agarkhedkar, Sudhir Malwade, Vishwanath B Kulkarni
Department of Paediatrics, Dr. D.Y. Patil Medical College, Hospital & Research Centre, Pune, Maharashtra, India
| Date of Submission | 30-Apr-2021 |
| Date of Decision | 26-Jul-2021 |
| Date of Acceptance | 17-Sep-2021 |
| Date of Web Publication | 03-Jun-2022 |
Correspondence Address:
Darshita Shukla,
Department of Paediatrics, Dr. D.Y. Patil Medical College, Hospital & Research Centre, Pimpri-Chinchwad, Pune 411018, Maharashtra
India
 Source of Support: None, Conflict of Interest: None DOI: 10.4103/jpn.JPN_100_21
 Abstract | | |
Introduction: Epilepsy is the most common childhood neurological illness, which occurs in four to six per 1000 children. The maximum incidence of epilepsy occurs in children less than 3 years of age. The main objective of our study was to describe the etiological spectrum, EEG, and neuroimaging abnormalities and predictors of intractability in epilepsy. Methodology: A cross-sectional observational study was conducted over a 2-year duration at Dr DY Patil Medical College, Pune, Maharashtra, India. Hundred eligible children with epilepsy aged 3months to 2 years were included in the study. Appropriate statistical test such as Chi-square test and P value has been applied. SPSS software version 23 was used in our study. Results: Out of 100 children, 45% were in the age group of 19–24 months with M:F = 1.1:1. The mean age of onset of seizure was 11.6 ± 3.3 months. The majority of children belonged to lower-middle-class families (56%). Developmental delay was seen in 50%, and 43% had refractory epilepsy. The most common seizure type was focal onset (47%), followed by generalized onset seizures (37%). EEG findings were abnormal in 66%, multifocal IEDs being the most common abnormality (54.55%). MRI brain was normal in 27 cases, and out of 73 abnormal MRIs, the most common pattern seen was changes of perinatal and postnatal insults (75.3%). There was a statistically significant correlation between the type of seizures and MRI pattern with abnormal EEG (P <0.001). In 23% of children, no etiology was found, structural cause—62 (perinatal: 55; cortical malformation: 7), metabolic cause—nine, genetic etiology—six cases. The factors associated with refractory epilepsy in our cohort were the presence of developmental delay, abnormal neurological examination, abnormal EEG, and abnormal MRI (P < 0.001). Conclusion: Our study described the etiological spectrum of infantile-onset epilepsy, with the most common being acquired cause because of perinatal and postnatal insult to the developing brain. Early-onset seizures have a high possibility of intractability, especially if it is associated with developmental delay, abnormal neurological examination, EEG, and neuroimaging.
Keywords: Epilepsy, prenatal, seizure
How to cite this URL:
Chalipat S, Shukla D, Chavan S, Agarkhedkar S, Malwade S, Kulkarni VB. Etiological spectrum and predictors of intractability in early-onset epilepsy (3 months–2 years): A cross-sectional observational study. J Pediatr Neurosci [Epub ahead of print] [cited 2023 May 29]. Available from: https://www.pediatricneurosciences.com/preprintarticle.asp?id=346562 |
| Introduction | |  |
Epilepsy is the most common childhood neurological illness. The estimated overall prevalence of epilepsy in India is approximately 5.59–10 per 1000.[1],[2] The incidence of epilepsy is highest in the first decade of life, especially within the first 2 years.
A higher prevalence of epilepsy is seen in developing countries especially in rural areas because of more acquired brain disease.[3]
Recent International League Against Epilepsy (ILAE) 2017 classification system emphasizes the role of evaluating the underlying neurological cause and etiology of epilepsy in diagnostic workup, which would be a major determinant of management and prognostication.[4]
There are very few studies from India describing an etiological spectrum of infantile-onset epilepsy and refractory epilepsy. The main objective of our study was to describe the etiological spectrum, electroencephalography (EEG), and neuroimaging abnormalities, and predictors of intractability in epilepsy.
| Materials and Methods | | |
This was a cross-sectional observational study conducted at a tertiary care teaching institute from Western Maharashtra, India. Our Institute is a tertiary care referral center, having an established Pediatric Neurology unit, where we do long-term video EEG monitoring, 3-Tesla magnetic resonance imaging (MRI), and we have facilities for the ketogenic diet and epilepsy surgery. The study was conducted from July 2018 to July 2020 after obtaining ethical committee clearance.
All children aged between 3 months and 2 years of both genders with the diagnosis of epilepsy as per ILAE definition with any seizure type, secondary to any etiology or unknown etiology, irrespective of the developmental delay were included in the study. ILAE definition of epilepsy is any child who had at least two unprovoked seizures occurred more than 24 h apart or one unprovoked seizure occurred and the likelihood of further seizures was similar to the general recurrence risk (at least 60%) after two unprovoked seizures, occurring over the next 10 years or diagnosis of an epileptic syndrome. Children with febrile seizures, or with any acute symptomatic provoked seizures, children with only neonatal seizures, and children with seizure mimics were excluded.
Patients fulfilling inclusion criteria were recruited after getting written informed consent from parents. A detailed history regarding the age of onset of seizures, type of seizures, birth history, development history, and family history had been documented as per the structured clinical proforma. The seizure type was classified as per the ILAE classification system 2017. Polymorphic seizures suggested having more than one type of seizure. Development screening was done by the TDSC scale (Trivandrum Development Screening Scale). Detailed examination including anthropometric parameters, general examination, and neurological examination was done independently by pediatric neurologist and was documented. All children were evaluated with routine EEG of 30 min duration in the sleep state and video EEG was done in indicated cases. EEG interpretation was done by pediatric neurologist. All children underwent neuroimaging with 3-Tesla MRI along with epilepsy protocol at the same Institute. Metabolic and genetic testing was done in indicated cases. Metabolic testing included baseline screening with arterial blood gas, blood sugar, blood ammonia, lactate, and tandem mass spectroscopy, and gas chromatography and mass spectrometry. Genetic testing included clinical exome sequencing/whole-exome sequencing. Etiological factors based on the above investigations were classified as structural, metabolic, genetic, or unknown etiology. Structural etiology included acquired causes like sequelae of perinatal insults, infection, stroke, or trauma and congenital causes like disorders of cerebral malformations, neuronal migration disorders, and cortical dysplasia. Specific electroclinical syndromes were identified whenever possible. Treatment details were documented and drug responsiveness was assessed. Refractory epilepsy cases were identified as per ILAE definition as a failure of adequate trials of two tolerated, appropriately chosen, and used antiepileptic drug schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom.[5]
Sample size
Based on the number of patients with epilepsy seen in our pediatric neurology OPD over a period of 2 years and considering the dropout rate of 5%, the sample size was calculated as 90–100 using the formula n = Z2pq/d2.
Statistical analysis
The study statistics had been presented in the form of numbers and percentage % for qualitative data and quantitative data. Mean and standard deviation (SD) was used. Appropriate statistical tests such as chi-square test and P-value have been applied. Data were analyzed by using the Statistical Package for the Social Sciences (SPSS) software program, version 23.0.
| Results | | |
A total of 126 children were screened, of which 11 children had complex febrile seizures, 3 had hypo-calcaemic seizures, 5 had breath-holding spells, 4 had only neonatal seizures, and 3 were not willing to give consent. So after excluding these 26 children, 100 were enrolled in the study. Our center is a tertiary referral center with a facility for advanced epilepsy treatment like the ketogenic diet and epilepsy surgery and we get many referrals for the evaluation of children with epilepsy. This might have reflected a higher number of epilepsy as compared to acute symptomatic seizures and febrile seizures in our study.
[Table 1] depicts their sociodemographic profile. The maximum number of patients was in the age group of 19–24 months (45%) (mean age: 15.52 ± 8.57 months) with no significant gender preponderance (M:F 1:1.17). The mean age of onset of seizure was 11.6 ± 3.3 months. The majority of children belonged to the lower-middle-class family (56%) and only six babies had a family history of epilepsy. Of 100 babies, 14 had significant antenatal events such as the history of pregnancy-induced hypertension and gestational diabetes, in the mother. The majority of babies were born at term gestation (89%), 8 babies were born preterm (8%), and 3 babies were born post-term. NICU stay was documented in 51% of cases, of which the most common reason was neonatal encephalopathy possibly due to hypoxic-ischemic encephalopathy (56.86%) followed by neonatal hypoglycemia (23.52%), low birth weight and prematurity (15.6%), and hyperbilirubinemia (3.92%). Developmental delay was documented in 50% of children and abnormal neurological examination was noted in 48% of children.
The most common type of seizures were focal onset seizures (47%) followed by generalized onset seizures (37%), epileptic spasms (11%), and polymorphic seizures (5%). EEG findings were abnormal in 66 (66%) cases and normal in 34 (34%) cases. The most common abnormal EEG pattern documented was multifocal interictal epileptiform discharges (IEDs) (36%–54.55%) followed by focal IEDs (24%–36.35%). General IEDs were seen in four cases (6.06%) and diffuse slowing of background in two cases (3.03%). Approximately 32 of 47 children with focal onset seizures (68.08%) had abnormal EEG. Approximately 18 of 37 children with generalized onset seizures (48.6%) had abnormal EEG. In children with epileptic spasms, all 11 children had abnormal EEG, of which 5 had hypsarrythmic patterns and the rest had modified hypsarrhythmia. All children with multiple types of seizures had abnormal EEG. We found a statistically significant correlation between the type of seizures and abnormal EEG patterns (P < 0.005). Epileptic syndromic diagnosis with epileptic encephalopathy based on EEG pattern and clinical presentation was possible only in 17 children (West syndrome: 11; early infantile epileptic encephalopathy: 4; Dravet syndrome: 2).
Of the total 100 cases, MRI brain was normal in 27 children and abnormal in 73 children. Of 73 cases with abnormal MRI, we observed that 35 cases (47.95%) had HIE changes in the form of cystic encephalomalacia, T2/FLAIR white matter hyperintensities, signal changes over deep nuclei, and cerebral atrophy. Hypoglycemic brain injury in the form of parieto occipital gliosis was noted in 13 cases (17.8%) and 3 cases had periventricular leukomalacia and 2 cases had evidence of intraventricular hemorrhage and its complications. One child had focal cystic encephalomalacia due to perinatal arterial ischemic stroke and another child had T2/FLAIR subcortical white matter hyperintensities with anterior temporal cyst with evidence of calcification in CT brain suggestive of congenital CMV infection. Characteristic changes suggestive of underlying metabolic disorder (T2 and FLAIR hyperintensities involving deep nuclei, brainstem, white matter with or without diffusion restriction) were seen in nine cases (12.3%). Cerebral dysgenesis in the form of lissencephaly, pachygyria, focal cortical dysplasia, and subcortical band heterotopia was seen in seven cases (9.58%). Along with these patterns, other abnormal findings documented were cerebral atrophy and thinning of the corpus callosum in six cases (8.22%). Isolated cerebral atrophy was seen in two cases (2.7%). In children with genetic epilepsy secondary to sodium channelopathy had normal neuroimaging. We found a statistically significant correlation between abnormal EEG and MRI patterns (P = 0.001), as shown in [Table 2].
[Table 3] depicts the etiological spectrum of the study subjects. The most common identifiable cause of epilepsy was structural etiology (62%), of which perinatal insults were the commonest one (55%). Nine children had the metabolic disorder as an etiological factor for epilepsy which was confirmed with metabolic evaluation along with genetic confirmation in a few of them. Seven children had structural brain malformations and six had confirmed genetic etiology by clinical exome/whole-exome sequencing. No etiology was found at the moment in 23% and classified under unknown etiology group.
Of 100, 38 children’s seizures were controlled with a single antiepileptic drug, whereas nine children required two drugs. Rest 43 children had refractory epilepsy who required more than two antiepileptic drugs. Three of them underwent epilepsy surgery––hypothalamic hamartoma, focal cortical dysplasia, unilateral occipital gliosis secondary to hypoglycemic brain injury. Seven children were treated with diet therapy––ketogenic diet and modified Atkins diet. All the children with epileptic spasms were treated with antiepileptic drugs and hormonal therapy as per International Collaborative Infantile Spasms Study (ICISS) guidelines.[6] Children with metabolic disorders were treated accordingly with co-factor supplementation other than antiepileptic drugs.
[Table 4] depicts the factors predisposing to refractoriness. There was a statistically significant correlation seen between the factors like developmental delay, abnormal neurological examination, abnormal EEG, and abnormal MRI with refractory epilepsy (P < 0.0001). Seven of 11 children with epileptic spasms, and all five children who had multiple types of seizures had refractory epilepsy. The majority of children with unknown etiology were drug responsive, and those with structural etiology were distributed almost equally in the drug-responsive and refractory group. All the children with metabolic and genetic etiology were drug refractory.
| Discussion | | |
This study was conducted at a tertiary referral institute describing the etiological spectrum and factors influencing refractory epilepsy in infantile-onset epilepsy.
The highest incidence of epilepsy is seen during infancy.[7] In this study, 49 children were less than 1 year of age, and the mean age of onset of epilepsy was 11.6 ± 3.3 months. This is in agreement with many other studies suggesting the highest incidence of epilepsy is seen in less than 12 months old.[8],[9],[10],[11]
There was no significant gender bias seen in our study, which has been shown by other studies as well.[8],[12 However],[ few studies have shown a slightly higher incidence in boys.[10],[13] The majority of children belonged to the lower-middle-class family (56%), which is in concordance with other studies as well.
The majority of children belonged to the lower-middle-class family (56%). Many studies have proven that low socioeconomic status, low income, and less education are regarded as risk factors for epilepsy. These factors can have a direct or indirect influence on accessing medical care and treatment, the possibility of refractoriness.[3],[14],[15]
In this study, focal motor onset seizures were the most common type found in 47 cases (47%) followed by generalized onset seizures in 37 cases (37%). Epileptic spasm was seen in 11 (11%) and multiple types of seizures in 5 cases (5%). This is consistent with most of the studies stating that focal onset seizures are more common in children with the possible reason of acquired etiology.[8],[10],[12] In contrast, in a community-based Indian study by Pandey et al. it has been shown that generalized seizures as the most common type. This may be due to considering secondarily generalized seizures as generalized seizures.
In our cohort, we found that 51% of children had an eventful perinatal or postnatal period requiring NICU admission, 50% of children had developmental delay and 52% had an abnormal neurological examination. Various studies have shown the risk factors for epilepsy as complicated birth history, neonatal seizures, developmental delay.[16]
EEG is an essential investigation that helps us to characterize seizure type and epilepsy syndrome and guides in management and prognostication. We observed 66 cases (66%) had abnormal EEG findings. Multifocal epileptiform discharges were the most common type observed (54.5%) followed by focal epileptiform discharges (36.36%). We found a statistically significant correlation between the type of seizures and abnormal EEG patterns (P < 0.005). Of all of the 11 children with epileptic spasms, everyone had abnormal EEG; of which 5 had hypsarrythmic patterns and the rest had modified hypsarrhythmias. All children with multiple types of seizures including myoclonic and atonic seizures had abnormal EEG. Formation of an epileptic syndromic diagnosis with epileptic encephalopathy was possible in 17 children (west syndrome: 11; early infantile epileptic encephalopathy: 4; Dravet syndrome: 2). These findings were consistent with previous studies.[8],[12],[17]
Neuroimaging is very essential to show the morphology, distribution, and extent of different disorders causing seizures in children as well as the associated anomalies and related syndromes to guide in management and counseling. In our cohort, 27 cases had normal neuroimaging. Of 73 cases of abnormal MRI, the majority (75.3%) had structural brain damage secondary to perinatal and postnatal insults in the form of gliosis, cystic encephalomalacia, white matter signal abnormalities, and intraventricular hemorrhage. Malformations of cortical and brain development were seen in 9.5% of children. We found a statistically significant correlation between abnormal EEGs and neuroimaging findings (P < 0.005) which was in agreement with other studies as well.[18] However, there was no definite correlation found between MRI abnormalities and type of seizures.
The most common etiological factor for epilepsy in our cohort was a structural cause (62%), of which perinatal brain insults were the most common one (55%), and malformation of cortical development in seven cases. In developing countries like India, various studies have proven that perinatal brain injuries are the most common etiological factor, especially hypoxic brain injury and neonatal hypoglycemic brain injury is the leading cause.[13],[19],[20],[21],[22] Similarly, Wirrel et al.[10] have shown a structural/metabolic etiology was more likely seen in children with seizure onset before 12 months of age. No etiological factors were found at this stage in the remaining cases (23%). Many of the studies have clearly stated that a definite diagnosis of epilepsy could be possible in only 40%–50% of cases.[11],[12]
One-third of children (38%) with seizures were controlled with a single antiepileptic drug, whereas 9% required two drugs. Refractory epilepsy was seen in 43%, who required ≥3 antiepileptic drugs. Approximately 10–20% of children with epilepsy develop drug-refractory epilepsy. In our cohort, there is a greater number of refractory cases (43%) as it is conducted at a large tertiary care referral center where refractory epilepsy cases were referred for further management. Another reason would be early-onset seizures might lead to a predisposition to epileptogenesis in a developing brain, which can cause medical intractability.
We found a significant association between factors like the presence of developmental delay, abnormal neurological examination, abnormal EEG, and neuroimaging with refractoriness. Studies by Chawla et al.,[25] Tripathi et al., [24] and Yilmaz et al.[25] showed similar findings in accordance with our study. All the children with cerebral malformations, metabolic, and genetic etiology and those who had multiple seizure types including myoclonic seizures had refractory epilepsy even though it was not statistically significant. In contrast to other studies, we found no statistically significant association between type of seizures and refractoriness and perinatal insults and refractoriness.
Limitations of our study included the lack of a control group and no prospective follow-up was done. The data may be over-represented than the community data as this study was done in an Institute, where many of the refractory cases are referred for further management.
| Conclusion | | |
Our study described the etiological spectrum of infantile-onset epilepsy with the most common being acquired cause because of perinatal and postnatal insult to the developing brain. This reinforces the need for the improvement in antenatal and neonatal care to minimize the burden of epilepsy and disabilities in developing countries like India. There was a strong association between type of seizures, abnormal neuroimaging with EEG abnormalities. Early-onset seizures have a high possibility of intractability especially if it is associated with developmental delay, abnormal neurological examination, EEG, and neuroimaging.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4]
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