Frequency of Hypocalcemic Fits in Children 2 Months to 2 Years of Age, Presenting with the First Episode of Afebrile Seizures at Hospital Settings in Urban Pakistan: A Cross-Sectional Study

Introduction: Seizures are common in the pediatric age group, occurring approximately 10% of children. Hypocalcemia is one of the most common metabolic causes of afebrile seizures. The objective of the study was to determine the frequency of hypocalcemic fits in children presenting with the first episode of afebrile seizures from 2 months to 2 years of age. Methods: The study was conducted at the Aga Khan hospital Karachi and its three secondary hospitals including the following sites of Kharadar, Hyderabad, and gar-den. It was a cross-sectional study. The duration of the study was of 6 months from 18th July 2017 to 18th Jan. 2018. All patients who fulfill the inclusion criteria and visited the Pediatric medicine Department of Aga Khan Hospital, Karachi, and its secondary hospitals were included in the study after ethical approval and informed and written consent. A brief history was taken, clinical examination was done and serum calcium level was sent to the institu-tional laboratory to reach the outcome i.e. hypocalcemic fits. Result: A total of 85 children presenting with the first episode of afebrile seizures were included. Total of 45 patients (52.98%) were males & 40 patients 2 (47.1%) were females with the mean age were 10.5824 ± 6.84907 months. The hypocalcemic fits were seen in 21 children (24.7%). Discussion: Hypocalcemia is a


Introduction
In children, hypocalcemia is defined as a total serum calcium concentration of less than 2.1 mmol/L (8.5 mg/dL) [1]. Seizures are common in the pediatric age group and occur in approximately 10% of children [2]. Amongst the various etiologies; hypocalcemia is a major biochemical cause of seizures in infancy in developing countries [3]. It constitutes 25.6% of afebrile seizures in children [4]. In a local study, hypocalcemia accounted for 68.3% of afebrile seizures [5].
The presence of seizure does not constitute a diagnosis but it is a symptom of an underlying central nervous system disorder due to systemic or biochemical disturbances [6]. Hypocalcemia in children may manifest as tetany, seizures, muscle cramps, and paresthesias [7]. The central nervous system irritability from hypocalcemia can cause anticonvulsant-resistant seizures. Such seizures often are brief, lasting a few seconds or minutes, but may recur frequently. Initially, there may be no postictal phase. Rarely, it may present with stridor or cyanosis from laryngospasm. Arrhythmias are even rarer. Electrocardiography may reveal a prolonged QTc interval. Most patients who have mild hypocalcemia are asymptomatic [8].
Hypocalcemia is associated with poor outcomes as measured by either survival or length of intensive care stay [9]. Infants fed with buffalo or cow's milk or formula containing a high amount of phosphate are also low in calcium because phosphate decreases the absorption of calcium. Balasubramanian et al. [10] in India identified indoor confinement during the day, living in urban areas with tall buildings, and the use of sunscreen as major risk factors for hypocalcemia. In another study, fresh unfortified milk, inadequate exposure to sunlight, lower maternal educational status, and large family size as risk factors for hypocalcemia.
Acute hypocalcemia is an emergency that requires prompt attention, and patients with symptomatic hypocalcemia should be treated immediately because of the highly associated morbidity and mortality. Treatment with intravenous calcium is the most appropriate therapy. Hypocalcemic seizures should be treated with calcium replacement, while AEDs are typically not needed. AEDs may abolish both overt and latent tetany, whereas hypocalcemic seizures may remain refractory [11]. There is a shortage of data in the pediatric population regarding the frequency of hypocalcemia in afebrile seizures. This study will help us to find out the frequency of hypocalcaemic fits to look into the consideration of empiric I/V calcium in afebrile fits patients that did not respond to anticonvulsant drug.
Because in developing countries like Pakistan; it is worthwhile to give empiric I/V calcium in non-responsive afebrile fits. The benefit to the patient will be the Open Journal of Pediatrics prevention of the harmful effects of hypocalcemic seizures. These results can be used in planning and priority setting.

Objectives
To determine the frequency of hypocalcaemic fits in children presenting with the first episode of afebrile seizures; from 2 months to 2 years of age.

Study Design
Cross-sectional study.

Setting
The Aga Khan Hospital Karachi and its secondary hospitals including the following sites: 1) Kharadar.

Duration of Study
Was 6 months from 18th July 2017 to 18th Jan. 2018.

Sample Size
Sample size calculated using the WHO calculator taking the margin of error as 10%, confidence interval as 95%, and taking frequency of hypocalcemia (in afebrile fits) 68.3% (based on the previous study) [5], sample size came out to be 85.

Sampling Technique
Non-probability consecutive sampling.
Inclusion criteria: Children from 2 months to 2 years of age having afebrile fits. Open Journal of Pediatrics

Exclusion criteria
Children having the previous history of fits/epilepsy.
Children with fever at the time of fits.

Ethical consideration
This study was post-graduation thesis project of Dr. Waseem and the thesis was approved by the College of Physicians and Surgeons, Pakistan. The study was also approved by Aga Khan University's Ethical review committee in 2017.

Data Collection Procedure
All children of the specified age group, who present with fits and no fever at the designated study sites, were enrolled in the study as per inclusion and exclusion criteria. All the data was recorded on a structured proforma; after reviewing the concerned medical records. Serum calcium levels were determined from the laboratory. Age, gender, and other relevant information were obtained from the caregiver. The patient was observed for fits and the duration of fits was documented. For confidentiality, all study participants were allotted a unique ID (other than hospital registration number) for study enrolment. Principle investigator himself was collecting the data. The study protocol was approved by the Ethical Review Board of Aga khan university hospital.
Informed consent was taken from the caregiver of the participant child. The caregiver was explained that participation in the study was voluntary, and no monetary compensation was given for the cost of an investigation.

Data Analysis Procedure
All the collected data were entered and analyzed in SPSS software version 19.
Frequency and percentages were computed for categorical variables like gender, feeding pattern, sunlight exposure, nutritional status mother education, socioeconomic status, and hypocalcemic fits. Mean and the standard deviation was calculated for quantitative variables like age, weight, and height. Effect modifiers like age, gender, weight, feeding pattern, sunlight exposure, nutritional status, mother education, and socioeconomic status were controlled through stratification. Post-stratification chi-square test was applied by taking p-value < 0.05 as significant.

Result
A total of 85 children presenting with the first episode of afebrile seizures were selected to conduct this study. The mean age was 10.5824 ± 6.84907 months. The distribution of age is presented in Figure 1. Forty-five patients (52.98%) were males & forty patients (47.1%) were females. The mean weight was 6.67 ± 2.482 kg. The mean height was 69.74 ± 11.678 cms. The mean serum calcium level was 8.76 ± 1.7704 mg/dl. The distribution of serum calcium levels is presented in Figure 2. The descriptive statistics of weight, height, and serum calcium level are presented in Table 1.     Table   3). The feeding pattern was breast milk in 40 children (47.05%), formula milk in 39 (45.88%), and fresh milk in 6 (7.05%), as shown in Table 3. The outcome i.e.
hypocalcemic fits were seen in 21 children (24.7%) presenting with the first episode of afebrile seizures, as shown in Table 4.
The frequencies of age groups, gender, weight, height, feeding pattern, sunlight exposure, nutritional status, mother education, socioeconomic status was calculated according to hypocalcemic fits and are presented in Table 4, Table 5, and Table 6 respectively.
The stratification according to age groups, gender, weight, height, feeding pattern, sunlight exposure, nutritional status, mother education, socioeconomic status was done to observe the effect of these modifiers on hypocalcemic fits.
Hypocalcemia fits were common in children of the age group of 2 -12 months (68%), predominant in male gender (53%), and children with the low weight falling in 3 -9 Kg (75%) and also more common in children with inadequate sunlight exposure and illiterate mothers.

Discussion
Seizures are one of the most common neurological disorders in children. The first episode of epileptic seizure is always an anxiety-causing event for parents and it is the health professional's duty to know the best approach and recommendations to use in each case. Seizures are common in the pediatric age group and one of the most common biochemical abnormalities causing seizures is hypocalcemia [12]. Hypocalcemia is emerging as a very common problem perhaps due to a lack of awareness of the morbid consequences [13].
In our study hypocalcemic fits were seen in 21 children (24.7%) presenting with the first episode of afebrile seizures, as compared to Khan et al. [5] study, 41 (68%) cases were hypocalcemic among the total study population of 60. In our study, the mean age was 10.5824 ± 6.84907 years as compare to Khan et al. [5] study the mean age at the time of admission was 7.5 ± 1.34 months. The majority of children (51.2%) were below 6 months. This is also consistent with results by Binmohana et al., [12] and Humayun et al. [13] but is in contrast with Abanamy et al. [13] showing 39.2% patients less than 6 months of age. The present study noted slight male predominance 52.98% comparable with Khan et al. study showed (56%) and with Binmohana MA et al. [12] but Sharma et al. [14] found no gender difference. Inadequate exposure to sunlight is an important factor associated with the development of vitamin D-deficient rickets which in turn is a common cause in 73% of hypocalcemia in children [13] [15]. Our study highlighted this fact and the results showed (32.9%) children had inadequate sunlight exposure in contrast to Khan et al. [5] study showed the high number of children (68.3%) had poor exposure to sunlight. Balasubramanian et al. [10] in India identified indoor confinement during the day, living in urban areas with tall buildings, and the use of sunscreen as major risk factors for hypocalcemia. In another study, fresh unfortified milk, inadequate exposure to sunlight, lower maternal educational status, and large family size as risk factors for hypocalcemia, and these results are comparable with other studies [5] [14].
In the present study, the feeding pattern was breast milk in 40 children (47.05%), formula milk in 39 (45.88%) & fresh milk in 6 (7.05%), as compared to Khan et al. [5] study, 63.4% children received unfortified fresh milk, 34% breast milk and 2.4% formula milk. These results are also comparable with observations made by Temashek et al. [16]. Hypocalcemia is associated with poor outcomes as measured by either survival or length of intensive care stay [17]. Infants fed with buffalo or cow's milk or formula containing a high amount of phosphate are also low in calcium because phosphate decreases the absorption of calcium. In our study 28 children (32.9%) were malnourished and 57 (67.1%) were well nourished. However, Hatun et al. [18] observed that 83% infant who had vitamin D deficiency were exclusive breastfeed without supplemental vitamin D. Khan et al. [5] study showed 36.5% children with inadequate weaning and is comparable with results of Carvelt NF et al. [19] and Younas M et al. [20]. 32.9% of our study population was malnourished as compared to Khan et al. [9] study showed Open Journal of Pediatrics seventy-two percent of the study population had malnutrition according to Gomez classification which is comparable to a study by Khattak et al. [21] The mean weight in the present study was 6.67 ± 2.482 kg and the mean height was 69.74 ± 11.678 cms. One previous study showed that 46% were low birth weight while 17% were preterm [10], the incidence of hypocalcemia is inversely proportional to gestational age and birth weight [21]. Recently, a study by Raazia Nawaz et al showed hypocalcemia prevalence of 51% in premature and low birth weight babies [22]. Hypocalcemia can be present with a wide variety of symptoms, the most important of which is seizures. In 90% of cases, seizure type was noted generalized tonic-clonic which was comparable with Sharma et al. [23].
Elevated alkaline phosphatase > 1000 1U/L was observed in 53.3% patient which is consistent with other studies [24]. This study showed that 76% of patients had radiological evidence of rickets in the form of cupping and fraying and is comparable with the results of New-ham et al. [25].
The limitation of this study was that we did not correlate hypocalcemia with magnesium levels.

Conclusion
Hypocalcemia is a common cause of afebrile fits in children. Inadequate sun exposure, early age, male gender, low weight, and illiteracy are major risk factors for hypocalcemia