Etiological Profile of Afebrile Seizures in Infants in a Tertiary Care Center from southern India.

INTRODUCTION: Seizure is the most common neurological illness in pediatric population and its risk is highest in the first year of life. Studies regarding etiology of afebrile seizures worldwide and in India are limited; hence, the current study was undertaken.
OBJECTIVE: The objective of this work was to study the etiology of afebrile seizures in infants aged 1 month to 1 year.
MATERIALS AND METHODS: A retrospective study of afebrile infantile seizure was conducted at pediatric neurology outpatient department between January 2015 and September 2017. All children with first episode of afebrile seizures were included. Biochemical and hematological investigations, imaging, and electroencephalogram were performed whenever necessary. Simple descriptive statistics were used to analyze the data in the form of frequencies with percentages and median as applicable.
RESULTS: One hundred twenty-one children with a mean age of 8.1 months were analyzed. Of these children, 58% were males. Positive family history was found in 1.65% children, developmental delay in 70%, and dysmorphism in 8%. Presenting seizure type were generalized (74%), focal (21%), and unknown (6%) onset. Etiology was deducible in 92% cases. Structural etiology was the most common (66%), followed by metabolic (12%), infections (7%), and others (6%). In structural pathology, common causes were perinatal insult (38%) and cerebral malformations (18%). Imaging was done in 98 cases and yield was 83% (85 cases).
CONCLUSION: Etiology was deducible in 92% of children. Seizures due to structural etiology, secondary to perinatal insult followed by metabolic and infections, are important causes. Imaging aids are important in etiological diagnosis. Etiological evaluation should be considered in children following first episode of afebrile seizures, especially in developing countries like India.

Introduction

Seizures are common pediatric neurological disorder. Four to 10% of children experience at least one episode of seizure in the first 16 years of their life. Incidence is highest in children less than 3 years of age, with a decreasing frequency from then on.[1] Seizures are a transient occurrence of signs and/or symptoms resulting from abnormal excessive or synchronous neuronal activity in the brain.[2] They account for 1% of all emergency department visits,[3] and about 2% of visits of children’s hospital emergency department visits. Worldwide, febrile seizures are the most common type of acute seizures in children.[45] Central nervous system (CNS) infections are the main cause of seizures and acquired epilepsy in the developing world.[5] Even after four decades of the initial studies on etiology and outcome of seizure in infants,[6] not much information is available on this aspect in India.[78] Based on recent International League Against Epilepsy (ILAE) definition of epilepsy,[9] we can diagnose epilepsy even after first episode of seizures if there is a probability of further seizures similar to the general recurrence risk at least 60% after two unprovoked seizures, occurring over the next 10 years. This definition is very useful practically, as we can treat earlier, to prevent mortality and morbidity because of seizures, especially in developing countries like India. Information regarding etiological profile of afebrile seizures is scarce, and there is paucity of data with the need for reaffirming awareness and knowledge regarding diagnostic variability and its presentations. Hence, the present study was undertaken with the objective of ascertaining the etiology of afebrile seizures in infants

Materials and Methods

This is a retrospective review of children presenting to outpatient department of pediatric neurology at a tertiary care pediatric hospital between January 2015 and September 2017. Following information was obtained from the medical records of each patient: age, sex, mode of presentation (abnormal movements, focal neurological deficit, spasms), type of seizure, presence of fever, family history, antenatal and perinatal history, developmental history, laboratory tests (complete blood count, c-reactive protein, blood sugar, electrolytes, calcium; neuroimaging: computed tomography/magnetic resonance imaging and electroencephalogram [EEG]), duration of admission, and final diagnosis. In the absence of any information, the parents were contacted telephonically and history/investigations were ascertained. EEG findings were correlated with seizure semiology by history.

Infants who were aged between 1 month and 1 year with objective evidence of seizure were included in the study, and those with history of fever and seizure-like activities were excluded. Children with history of unprovoked seizure were excluded.

Seizure semiology was defined and classified according to the 2017 ILAE seizure classification[9] as focal seizure (motor onset, non-motor onset, and focal to bilateral tonic-clonic), generalized seizure (motor and non-motor/absence onset), and unknown onset (motor and non-motor and unclassified). The final diagnosis and etiology of each child was confirmed with the investigations available.

The clinical, laboratory, radiological findings, and the follow-up data were collected and tabulated. Simple descriptive statistics were used to analyze the data in the form of frequencies with percentages and median as applicable. The ethical clearance was obtained by the institutional ethical committee.

Results

In this study, 121 infants were analyzed who were aged between 1 month and 1 year, youngest being 31 days old and oldest being 1 year. The mean age of presentation was 8.1 months. Male preponderance was present wherein males were 57.85% (n = 70) and females were 42.14% (n = 51). Seizure semiology is as shown in Table 1. Positive family history was present in only one case (1.65%), that is one in hot water epilepsy. Developmental history and assessment reports showed delay in 85 (70.24%) infants, significant history of perinatal insult was found in 38.01% (n = 46), and dysmorphism was documented in 8.26% (n = 10). The etiology was designated as depicted in Table 2.

Table 1

Seizure onset and semiology in the study populations

S. no.	Seizure semilogy	n (%)
1	Generalized onset	113 (74.83)
	Generalized tonic-clonic	78 (51.6)
	Generalized tonic seizures	11 (9.32)
	Generalized clonic seizures	08 (6.7)
	Generalized myoclonic-tonic-clonic seizures	13 (8.6)
	Generalized atonic	01 (0.84)
	Generalized myoclonic-tonic-clonic	01 (0.84)
	Generalized non-motor myoclonic	01 (0.84)
2	Focal onset	29 (19.2)
	Focal clonic seizures	06 (3.9)
	Focal tonic	06 (3.9)
	Focal myoclonic	07 (4.6)
	Focal epileptic spasms, focal hyperkinetic, and automatisms	00
	Focal behavioral arrest	02 (1.3)
	Focal autonomic, cognitive, emotional, and sensory	00
	Focal to bilateral tonic-clonic	08 (5.29)
3	Unknown onset	09 (5.9)
	Tonic-clonic	08 (6.7)
	Unclassified	01 (0.84)

Table 2

Etiology classification of seizures in the study population based on ILAE 2017

S. no.	Etiology	Diagnosis	n (%)
1	Structural: 89 (58.9%)	Secondary to perinatal insult	55 (36.4)
		Cerebral malformations	22 (14.6)
		Lissencephaly (08)
		Cortical dysplasia (10)
		Pachygyria/agyria (02)
		Congenital hydrocephalus (02)
		Stroke	05 (3.3)
		Late hemorrhagic disease of newborn	05 (3.3)
		Post-traumatic brain injury sequelae	01 (0.6)
2	Genetic: 10 (6.6%)	Dravet syndrome	03 (1.9)
		Genetic epilepsy with febrile seizures plus	03 (1.9)
		Aicardi syndrome	02 (1.3)
		Menkes kinky hair disease	02 (1.3)
3	Infectious: 08 (5.2%)	TORCH infections’ sequelae	08 (5.2)
4	Metabolic: 26 (17.2%)	Hypocalcemia	07 (4.6)
		Leigh syndrome	07 (6.6)
		Pyridoxine-dependent seizures	04 (2.6)
		Maple syrup urine disease	02 (1.3)
		Biotinidase deficiency	02 (1.3)
		Infantile tremor syndrome	04 (2.6)
5	Immune: 01 (0.6%)	Autoimmune encephalitis	01 (0.6)
6	Unknown: 18 (11.9%)	Reflex anoxic seizures	12 (7.9)
		Hot water epilepsy	06 (3.9)

Investigations supporting diagnosis as mentioned earlier were confirmed. Imaging in the form of CT scan/MRI of the brain was carried out in 98 cases; of which, 83 cases showed abnormalities. The yield of imaging was found to be 84.69%. Among the 36 cases that showed positive findings on MRI, CT scan was performed as a preliminary imaging workup in 30 cases. MRI detected hypoxic ischemic encephalopathic (HIE) changes in 3 cases, cerebral atrophy in 7, migrational disorder in 18 cases, bilateral basal ganglia changes in 1 case suggestive of metabolic disorder (Leigh syndrome), and ischemia/thrombosis in 1 case when CT had shown no abnormality.

Discussion

This was a hospital-based retrospective study conducted at a tertiary care hospital in Bengaluru in the outpatient department of pediatric neurology. In this study, 121 infants were included, with mean age of presentation being 8.1 months. Male preponderance (57.85%) was seen, which was similar to studies conducted by Adhikari et al.[10] at Nepal and Ernestina et al.[11] Most common mode of presentation was abnormal movements. Positive family history was present in one case of hot water epilepsy.

Developmental delay was seen in a significant number of cases (i.e., 70.24% cases); the same was attributable to perinatal insult, cerebral malformations, syndromic associations, and TORCH infections. Dysmorphism was seen in 10 cases: Aicardi syndrome in 2 infants, 4 infants with migrational disorders who were considered syndromic, and 6 were not classified. Seizure type assessment revealed that generalized seizures were the most common (73.55%), which was similar to the studies conducted by Adhikari et al.,[10] Idro et al.,[5] and Saravanan.[12] Focal seizures were observed in 20.66% cases, mostly in those with neuronal migration disorders, intracranial bleed, and some of seizures secondary to perinatal insult. Seizures with unknown onset were seen in 5.78% cases.

The role of routine imaging in acute seizure is debated. In this study, imaging was carried out in 98 cases; of which, 83 cases (84.69%) showed abnormalities. MRI gave a better yield in the diagnosis of migrational disorders and cerebral atrophy. CT scan, however, was able to detect bleeds and HIE changes in a significant number of cases. Yield of imaging as per Hsieh et al.[13] was around 35.2% by CT scan and 57% by MRI. Ahmed et al.[14] found the yield of 62% with abnormal findings being cerebral atrophy in 73.3%, ventricular dilatation in 13.3%, encephalomalacia in 6.7%, and infarctions in 26.7%.

Diagnosis was deducible in 91.73% cases. Structural etiologies were the most common, accounting to 66.11%, followed by metabolic in 12.39%, unknown etiology in 8.26%, infection sequelae in 6.61%, hot water epilepsy in 4.95%, and immune etiology in 0.82%. Most common structural cause of seizures was secondary to hypoxic-ischemic insult/perinatal insult (38%), which was similar to a study carried out by Poudel et al.,[15] who found that birth asphyxia (12%) was the most common cause of afebrile seizure followed by neurocysticercos (8.8%), sequel of CNS infection (6.5%), and cerebral malformation (7.1%). In this study, metabolic causes were the second most common with Leigh syndrome being the frequent cause [Table 2]. Hot water epilepsy accounted for 5%, classified under miscellaneous etiology category.

Structural epilepsies were the most common, specifically secondary to perinatal insult showing hypoxic-ischemic changes in the brain. Results revealed that imaging has a good yield. MRI is better in detecting neuroparenchymal abnormalities. The strength of this study is that it is the first study to describe infantile seizures according to the 2017 ILAE classification. Limitation is that it is a single-center, retrospective, hospital-based study. Based on this study, the yield of etiology following first episode of infantile afebrile seizures in India is high, hence evaluation should be considered.

Conclusion

Etiology of afebrile infantile seizures was deducible in 92% cases. Seizures due to structural etiology secondary to perinatal insult/hypoxic insult followed by metabolic and infections were major causes. Imaging aids are important tool to aid etiological diagnosis of afebrile seizures. Etiological evaluation should be considered in children following first episode of afebrile seizures, especially in developing countries like India.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.