|Ahead of print
Acute symptomatic seizures due to metabolic derangements in pediatrics
Leema P Cornelius, Neeraj Elango, Venkateswaran Kuttavajeyaram
Department of Paediatric Neurology, Institute of Child Health and Institute of Neurology, Madras Medical College, Chennai, India
|Date of Submission||02-Oct-2020|
|Date of Decision||27-Dec-2020|
|Date of Acceptance||11-Apr-2021|
|Date of Web Publication||11-Oct-2021|
Leema P Cornelius,
Department of Paediatric Neurology, Institute of Child Health and Hospital for Children, Egmore, Chennai, Tamilnadu.
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Background: Seizures due to an underlying metabolic abnormality form an important subset of acute symptomatic seizures in that they are treatable and do not require long-term anticonvulsants. The objective of this study is to determine the clinical and etiological profile of children with metabolic seizures. Materials and Methods: A prospective observational study done in children admitted with acute symptomatic seizures who had an underlying metabolic abnormality as the cause of seizures from January 2018 to December 2019 in a tertiary care hospital of South India. Demographic and clinical parameters were noted and relevant investigations including biochemical, neuro imaging, cerebro spinal fluid analysis, electro encephalography were carried out accordingly. Results: Among 1256 children admitted with new onset seizures, 408 (32.5%) had acute symptomatic seizures exclusive of febrile seizures and unprovoked seizures, of which 46 (3.7%) were found to have an underlying metabolic abnormality and were analyzed. The ratio of male to female was 1.4:1 and the peak age was infancy, accounting for 62.5%. The leading causes of metabolic seizures included hypocalcemia in 28 (60.9%), hypoglycemia in 16 (34.8%), and hyponatremia in 2 (4.3%). Vitamin D deficiency in 21(75%) was found to be the commonest cause for hypocalcemia, followed by hypomagnesemia, hypoparathyroidism, osteopetrosis, and renal failure. The various causes of hypoglycemia were Addisons disease in 6(37.5%), hyperinsulinemic hypoglycemia, idiopathic ketotic hypoglycemia, glycogen storage disorder, and fatty acid oxidation defect, congenital adrenal hyperplasia, and Laron syndrome. Both children with hyponatremia were diagnosed as congenital adrenal hyperplasia. Conclusion: Metabolic seizures accounted for 3.7% of new onset seizures and 11.3% of acute symptomatic seizures in our study. Hypocalcemia (60.9%) was found to be the commonest cause of metabolic seizures in children with the majority due to vitamin D deficiency (75%). Addison’s disease (37.5%) was found to be the common cause for hypoglycemia. It is reasonable to estimate serum calcium, magnesium, electrolytes, and glucose in all children presenting with new onset seizures.
Keywords: Hypocalcemia, hypoglycemia, hyponatremia, metabolic seizures
| Introduction|| |
Acute symptomatic seizures are defined as clinical seizures occurring at the time of, or in close temporal relationship with a documented central nervous system (CNS) or systemic insult, which may be metabolic, toxic, structural, infectious, or inflammatory. Acute symptomatic seizures represent about 40% of total seizures, 40% of all cases of afebrile seizures, and 50–70% of status epilepticus episodes. To attribute an acute symptomatic seizure to a metabolic abnormality, the biochemical derangement should have been detected within 24h of its occurrence. The prevalence of acute symptomatic seizures due to metabolic abnormality varies from less than 1–15%,,, leading to a debate whether routine testing of blood glucose, calcium, serum electrolytes is necessary in a child with a first episode of seizures. On the contrary, metabolic seizures are treatable and hence a specific diagnosis provides the possibility of specific treatments that can optimize the outcome and negates the continuation of anticonvulsants.
Hence this study was conducted to determine the prevalence of acute symptomatic seizures due to metabolic derangements and their clinical and etiological profile in children admitted with new onset seizures in a tertiary care setting.
| Materials and Methods|| |
This prospective observational study was conducted at Institute of Child Health and Hospital for Children, a premier tertiary care referral hospital of South India from January 2018 to December 2019.
All consecutive children aged between 1 month and 12 years admitted to the inpatient Department of Pediatrics with new onset seizures were screened. Of these, those children with acute symptomatic seizures due to an underlying definite metabolic derangement were included in the study after obtaining written consent from the parents.
Children with febrile seizures, seizure disorder, acute symptomatic seizures due to other etiologies such as intra cranial infection, stroke, toxin ingestion, head trauma, hypoxic encephalopathy were excluded.
Acute symptomatic seizure was defined as a clinical seizure occurring in close temporal relationship with an acute CNS insult, which may be metabolic, toxic, structural, infectious, or inflammatory. It was attributed to a metabolic abnormality, if a specific biochemical abnormality was detected within 24h of seizure onset.
Hypocalcemia was defined as a plasma calcium level of <8.5mg/dL or an ionized calcium concentration <4.0mg/dL, hyponatremia as a decrease in the serumsodium concentration <136 mEq/L, hypernatremia as a serum sodium concentrationin plasma >145 mEq/L, hypomagnesemia as a serum concentration of magnesium <1.6 mEq/L (<1.9mg/dL). Hypoglycemia was defined as blood glucose concentration of <50mg/dL and hyperglycemia as blood glucose level above 126mg/dL or (>7 mmol/L).
Children aged between 1 month and 12 years admitted to the inpatient department with seizures underwent the standard diagnostic laboratory workup, which included complete blood count, blood sugar, serum electrolytes, blood urea nitrogen, creatinine, calcium, magnesium, lumbar puncture if indicated, electroencephalogram (EEG), and neuroimaging as and when necessary. Acute symptomatic seizure was diagnosed if a clinical seizure occurred within a week of acute brain insult such as acute CNS infection, stroke, traumatic brain injury, anoxic encephalopathy, exposure to toxins, or intracranial surgery. A diagnosis of acute symptomatic seizure due to a metabolic abnormality was made in the presence of metabolic derangements documented within 24h by definite biochemical abnormalities such as hypocalcemia, hypoglycemia, hyperglycemia, hyponatremia, hypomagnesemia, and were included in the study. Data regarding age, gender, semiology of seizures, frequency, time of occurrence (early morning), perinatal events, developmental milestones, family history of similar illness were recorded. Detailed clinical examination was done looking for neuro cutaneous markers, dysmorphism, hyperpigmentation, hepatomegaly, short stature, and focal neurological deficit. Acute seizures were managed according to the standard protocol. Children who had recurrent seizures, focal deficit, and who had a structural lesion on neuroimaging were advised long-term anticonvulsants.
All clinical information was recorded in a predesigned proforma and was managed with Microsoft Excel spreadsheet. Frequency was presented as number (n) and percentage (%).
| Results|| |
A total of 2164 children were admitted with seizures in our hospital during the study period, of which 1256 (58%) had new onset seizures. Among the 1256 children with new onset seizures, 510 (40.6%) had febrile seizures, 338 (26.9%) had seizure disorder and were excluded from the study. Of the remaining 408 (32.5%) children with acute symptomatic seizures, 362 (28.8%) had acute symptomatic seizures due to other causes such as acute CNS infection, head trauma, toxin ingestion, vascular insult, hypertensive encephalopathy, hypoxic insult, and hence were excluded from the study. So, based on the inclusion criteria selected for the study, a total of 46 (3.7%) children who presented with acute symptomatic seizures due to underlying metabolic abnormalities were enrolled in the study. The mean age was 23.83 ± 20.0 months with a range of 2–120 months. The peak age was infancy accounting for 62.5% of the patients, hypocalcemia, and hyponatremia contributing to the majority (86.7%). The ratio of male to female children was 1.4:1. Majority had generalized seizures (76.1%) and less than five episodes (78.3%). History of neonatal seizures was present in eight patients, mainly in the hypoglycemic and hyponatremic groups. Early morning seizures, hyperpigmentation, focal deficits, abnormal imaging, and abnormal EEG were noticed only in the hypoglycemic group.
The clinical profile and etiology are depicted in [Table 1].
The underlying metabolic abnormality was found to be hypocalcemia in 28 (60.9%), hypoglycemia in 16 (34.8%), and hyponatremia in 2 (4.3%).
Hypocalcemic seizures occurred commonly in infants (85.7%). Though generalized seizures were the predominant type, 8 (28.6%) children had focal seizures. Similarly, though a vast majority (82.1%) had afebrile seizures, 5 (17.9%) had seizures associated with fever. Neuro imaging, EEG, and cerebrospinal fluid analysis were done in 13 (46.4%), 18 (64.3%), 5 (17.9%) children, respectively, and were found to be normal.
Vitamin D deficiency was found to be the commonest cause for hypocalcemiain 21 (75%), followed by hypomagnesemia in 3 (10.7%), hypoparathyroidism in 2 (7.1%), osteopetrosis in 1 (3.6%), and renal failure in 1 (3.6%). Eight out of 21 infants (38.1%) who had vitamin D deficiency were on exclusive breast feeds, 2 (9.5%) had top-up feeds with cows milk and 11 (52.4%) with formula feeds. All the children diagnosed as hypocalcemic seizures due to vitamin D deficiency were alert, active, and well in between the seizure episodes. None of them had other clinical features of hypocalcemia or vitamin D deficiency. The various biochemical parameters such as serum calcium, ionized calcium, 25 hydroxy cholecalciferol, parathormone, serum magnesium levels are depicted in [Table 2].
|Table 2: Biochemical parameters in conditions associated with hypocalcemia|
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Considering metabolic seizures due to hypoglycemia, they tend to occur commonly after infancy (75%). Five children (31.6%) had neonatal seizures. Early morning seizures were noticed in six (37.5%). Generalized seizures were the predominant type. Skin hyperpigmentation was noticed in 5 (31.6%). On follow up, nearly one-third of them (37.5%) had developmental delay, two had focal deficits in the form of spastic diplegia. Three had recurrent seizures and were on anticonvulsants. Magnetic resonance imaging revealed abnormal findings in four children—bilateral parietooccipital gliosis in two, unilateral occipital gliosis in one, periventricular white matter loss in one. EEG was abnormal in three children.
The various causes of hypoglycemia noted in our cohort were Addison’s disease in 6 (37.5%), hyperinsulinemic hypoglycemia in 3 (18.8%), idiopathic ketotic hypoglycemia in 2 (12.5%), glycogen storage disorder in 2 (12.5%), and fatty acid oxidation defect, congenital adrenal hyperplasia, Laron syndrome one in each. The biochemical parameters and hormone levels in various conditions causing hypoglycemia are tabulated in [Table 3].
|Table 3: Biochemical parameters and hormone levels in conditions associated with hypoglycemia|
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Two infants had hyponatremic seizures, and on evaluation were diagnosed as having congenital adrenal hyperplasia. The seizures were generalized and both had neonatal seizures. Developmental milestones were normal and they had normal neuro imaging.
| Discussion|| |
Acute symptomatic seizures constituted 32.5% of the children admitted with new onset seizures in our study which is in agreement with the study by Chandini et al. Metabolic derangements accounted for 3.7% (n = 46/1256) of new onset seizures and 11.3% (n = 46/408) of acute symptomatic seizures which resonates with other studies.,, Nearly two-thirds of the patients were infants, more so with hyponatremia (100%) and hypocalcemia (85.7%). Khan et al. and Binmohana et al. have made similar observations., Hypocalcemia was found to be the commonest cause of metabolic seizures (60.9%) in our cohort which is in accordance with the study by Khan et al. Though generalized seizures were the predominant seizure type, nearly one-third patients with hypocalcemia exhibited focal seizures. Neuroimaging was normal in all of them ruling out a structural lesion. Similar observations have been reported by Bande et al. as well. Six out of 19 children (31.6%) with hypocalcemia presented with focal seizures in their study. Seizures were associated with fever in 5 (17.9%) hypocalcemic children, cerebrospinal fluid analysis was normal in them and would have been labeled as febrile seizures if blood investigations were not done. In a retrospective chart review of hypocalcemic children secondary to vitamin D deficiency, it was found that nearly 20% satisfied the criteria for simple febrile seizures. Hypocalcemic seizures occur as a result of increased neuronal excitability due to reduced extracellular concentration of calcium rather than depleted intracellular level.
Causes of hypocalcemic seizures in children include exogenous phosphate load, magnesium deficiency, hypoparathyroidism, malabsorption syndromes, pancreatitis, and vitamin D deficiency. We found that vitamin D deficiency (75%) was the commonest cause of hypocalcemia and three-fourths of them were infants. Bande et al. in their study have found out that 78.95% of infants with hypocalcemia had hypovitaminosis D, where as Malik et al. have reported a higher incidence of 88.3%. Infants are a vulnerable population for development of vitamin D deficiency because of their high rate of skeletal growth. Nearly 40% of the infants who had vitamin D deficiency were on exclusive breast feeds. This was comparable with observations made by Khan et al. However, a higher percentage of infants with vitamin D deficiency were found to be exclusively breast fed by other researchers., None of the children with vitamin D deficiency had other clinical signs of vitamin D deficiency or focal deficit. In addition, these children were active, alert in between the seizure episodes which may provide a clinical clue for the possibility of hypocalcemic seizures.
Our study revealed hypoglycemia as a cause of metabolic seizures in 32.6%. This was in contrary to Taherian et al. who reported a higher occurrence of 54.5% and Bharati et al. who quoted a lower percentage of 13.3%. Idiopathic ketotic hypoglycemia is said to be the most common etiology of hypoglycemia beyond infancy in non-diabetic children and other causes include deficiencies of counter regulatory hormones, glycogen storage disorders, inborn errors of metabolism, genetic defects resulting in hyperinsulinism, ingestions, and sepsis. But we found that Addison’s disease was the commonest cause of hypoglycemia in our cohort. Early morning seizures were a clue to the diagnosis of hypoglycemia especially in children with ketotic hypoglycemia and glycogen storage disease. Similarly presence of skin hyperpigmentation provided a clue for Addison’s disease. Excess melanocyte-stimulating hormone activity from adrenocorticotropic hormone causes the hyperpigmentation.
Neuro imaging revealed bilateral parieto occipital gliosis in two children, unilateral occipital gliosis and periventricular white matter loss in one each. Two children with bilateral parieto occipital gliosis had hypoglycemic seizures in the neonatal period managed elsewhere, admitted at 1.5 months of age with recurrent hypoglycemic seizures in our institution and diagnosed as Addison’s disease. Another child with occipital gliosis had seizures in the early morning on multiple occasions since 7 months of age—thrice with documented hypoglycemia, admitted at 1.5 years of age with hypoglycemic seizures in our institute, on evaluation found to be hyperinsulinemic hypoglycemia and diazoxide responsive. CT abdomen did not reveal any abnormality; genetic studies could not be done for want of facilities. These three children developed recurrent seizures not associated with hypoglycemia over the next 2 years, and on regular anticonvulsants in addition to treatment for underlying condition which underlines the fact that hypoglycemia needs to be identified and managed promptly. The vulnerability of the occipital lobe to hypoglycemic injury might be related to the fact that too fast occipital axonal growth and synaptogenesis in the neonatal period requires more blood glucose. Compared with other cortices, the fourth lamina of visual cortex is thicker and has more neurons and synapses, thus requiring significantly more blood glucose and also is most susceptible to laminar necrosis.
We had two infants with hyponatremic seizures and both were diagnosed to have congenital adrenal hyperplasia with onset of seizures in the second month of life. Muzafar et al. have reported a very high incidence of hyponatremia (66.6%) largely due to water intoxication in their study. Hyponatremia in children can also be due to conditions such as syndrome of inappropriate antidiuretic hormone secretion, Barter’s syndrome, and congenital adrenal hyperplasia.
Acute symptomatic seizures are unlikely to reoccur unless the underlying acute causal condition reoccurs and hence correction of the underlying metabolic derangement is the only treatment required. All children with hypocalcemia were given calcium supplementation. Those with vitamin D deficiency received vitamin D supplementation as well. Parents whose children had hypoglycemic seizures due to ketotic hypoglycemia, glycogen storage disease and hyperinsulinemia were counseled regarding giving frequent feeds and corn flour meal to avoid hypoglycemia.They were also advised to avoid prolonged fasting. Hyperinsulinemic hypoglycemic children in addition received diazoxide. Replacement therapy was instituted for hormonal insufficiencies. Only three children with hypoglycemic seizures with abnormal neuroimaging had recurrent seizures and were on anticonvulsants.
| Conclusion|| |
Hypocalcemia due to vitamin D deficiency continues to be the commonest cause of metabolic seizures in children. Hypocalcemia can present as focal motor seizures. Hypocalcemic seizures may masquerade as febrile seizures. Seizures occurring in the early morning are a clue for hypoglycemia. Though the prevalence of metabolic seizures is low, it is prudent to estimate serum calcium, electrolytes, and glucose in children presenting with new onset seizures especially in infancy.
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Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3]