Infantile Tremor Syndrome in Modern Times.

BACKGROUND: Infantile tremor syndrome (ITS) is a clinical syndrome of acute or gradual onset of mental and psychomotor changes, pigmentary disturbances of hair and skin, pallor, and tremors in malnourished children aged between 5 months and 3 years. It is a well-known entity, but the exact etiopathogenesis is still not known. SETTING AND
DESIGN: Prospective observational study carried out in the Department of Pediatrics at Dr RPGMC Tanda, Kangra in Himachal Pradesh.
MATERIALS AND METHODS: Demographic, clinical, and laboratory profile of 25 children with the diagnosis of preinfantile and ITS was collected who were admitted from May 2014 to June 2015. STATISTICAL ANALYSIS: Descriptive analysis was performed using SPSS 17 trial version.
RESULTS: These children accounted for 0.5% of total pediatric admissions. Median, standard deviation age was 10, 3.1 months. Male to female ratio was 1.27:1. Cases were present throughout the year with two peaks observed in the months of May and November. This disease was found to be more common in higher birth order (68%). Complementary feeding, that too improper, was initiated in only 4 cases (16%). Ninety-six percent cases presented with comorbid illnesses. Respiratory tract infection was the most common association, followed by urinary tract infection. There was moderate anemia with dimorphic picture (40%). Thirteen (52%) had vitamin B12 levels below normal. Magnesium levels, though statistically insignificant (P = 0.8) were lower in patients with tremors.
CONCLUSION: This is a disease of multi-micronutrient deficiency, which can be present either alone or in association. Educating women about proper nutrition during pregnancy and timely administration of complementary feeding is of utmost importance.

INTRODUCTION

Infantile tremor syndrome (ITS) is a clinical syndrome of acute or gradual onset of mental and psychomotor changes, pigmentary disturbances of hair and skin, pallor, and tremors in malnourished children aged between 5 months and 3 years.[1] Although first reported in the Indian subcontinent, similar cases have been reported from around the world.[2] ITS is a well-known entity, but the exact etiopathogenesis is still not known. Malnutrition, vitamin and mineral deficiency (e.g., Mg and Zn), infections, toxins, degenerative brain disease, enzyme defects (tyrosine), all have been postulated as possible causative factors.[1] Garewal et al. showed Vitamin B12 deficiency as a cause of ITS including the cellular evidence of its deficiency by DU suppression test.[3] There are case reports that found zinc[4] and Vitamin C deficiency in children with ITS.[5] The presence of tremors in ITS has been attributed to structural and functional alterations of extrapyramidal system, but neuroimaging with computed tomography scan and magnetic resonance imaging have shown nonspecific structural changes.[6] The exact incidence of ITS is not known. In India, it accounts for 0.2%–2% of pediatric hospital admissions (1%–2% in 1960s, 1.1% in 1975–77 and 0.2% in mid-1990s.[7] With the improvement in the living standard and nutritional status of the society, this study was carried out to ascertain the incidence and possible etiological factors of this syndrome in recent years.

MATERIALS AND METHODS

The study was conducted on 25 children admitted with the diagnosis of preinfantile and ITS in the Department of Pediatrics at Dr RPGMC Tanda, Kangra in Himachal Pradesh between May 2014 and June 2015. Ethical committee approval and written informed consent were obtained from each subject, who were followed till discharge. Data pertaining to demographic profile, symptomatology, detailed laboratory work were collected and analyzed.

Definitions

Preinfantile tremor syndrome (prodromal phase)

It is characterized by mental/motor regression, apathy, vacant look, inability to recognize mother, lack of interest in the surroundings, lethargy, poor response to bright, and red color. Pigmentary changes are seen over hands, feet, knees, ankles, wrist and terminal phalanges along with mild to moderate pallor.[1]

Infantile tremor syndrome (tremor phase)

Along with the above-said features, there is abrupt onset of tremors, which are coarse, of low amplitude, usually generalized, the rate may be variable. They may be intermittent or continuous, increase with activity or crying and are absent during sleep. Consciousness is maintained.[1]

Statistical analysis

Descriptive analysis was performed using SPSS 17 trial version; IBM Corp, Armonk, NY). Mean, median with standard deviation, and range for various parameters were calculated.

RESULTS

These children accounted for 0.5% of total pediatric admissions. Median, standard deviation (SD) age was 10, 3.1 months. Male to female ratio was 1.27:1. Cases were present throughout the year, with two peaks being were observed in May and November [Figure 1]. Socioeconomically, 23 cases (92%) were below middle lower middle class as per Kuppuswami scale. Seventy-six percent mothers were educated above primary school level. Detailed demographic profile of these patients is shown in Table 1.

Figure 1

Relationship between number of cases and the month of presentation

Table 1

Detailed demographic profile of the patients (n=25)

On examination, all children were apathetic, with a chubby look and generalized hypotonia. Pallor with knuckle hyperpigmentation were universal findings. Ten (40%) children had weight <−3SD as per the WHO growth charts. Severe acute malnutrition was present in 6 (24%) patients. Four (16%) children were stunted, whereas microcephaly was present in 1 (4%). Hepatomegaly and splenomegaly were present in 6 (24%) and 5 (20%) cases, respectively. The detailed anthropometric profile is shown in Table 2.

Table 2

Anthropometric profile of infantile tremor syndrome patients (n=25)

All children were born normally with mean, SD birth weight of 2.5, 0.42 kg. All were fully immunized. This disease was found to be more common in higher birth order (68%). Complementary feeding was initiated in only 4 (16%) cases, the rest were on mother's milk alone. Sixty-eight percent of the mothers consumed a pure vegetarian diet. Ninety-six percent of children presented with comorbid illnesses are shown in Table 3.

Table 3

Comorbid illnesses associated with infantile tremor syndrome (n=25)

Chest X-ray was suggestive of bronchopneumonia in 8 (32%) cases. Escherichia coli and Pseudomonas aeruginosa were cultured from urine in 2 cases. Blood culture was positive for Staphylococcus aureus (methicillin-sensitive) in one patient. Sixty-eight percent of children were treated with antibiotics.

Hemogram revealed moderate anemia with variable peripheral smear. The detailed laboratory profile is shown in Table 4.

Table 4

Laboratory profile of the patients

Thirteen (52%) patients had Vitamin B12 levels below the normal range (≥100 pg/ml). There was no worsening of tremors after administration of Vitamin B12. Serum magnesium levels (atomic absorption spectrometry) were done in 14 patients with mean, median, SD of 2.0, 1.8, 0.48 mg% [Table 5]. Calcium levels were marginally reduced in 9 (36%) patients.

Table 5

Relation of serum magnesium levels with tremors

Serum iron (μg/dl) and serum ferritin (ng/ml) levels were done in 10 patients and showed mean, median, SD of 88.2, 48, 91.7, and 103.7, 76.5, 73.2, respectively. One patient with tremors had an only iron deficiency with normal serum B12 and magnesium levels. Computed tomographic imaging was done in three patients and revealed diffuse cortical atrophy with prominent sulci and ex-vacuo dilatation of the ventricular system. Neurosonogram was done in 5 children and revealed cortical atrophy.

All patients showed improvement in activity within 48–72 h of treatment. The patients were given supplements such as Vitamin B12, iron, magnesium, zinc, Vitamin C in appropriate doses. Complementary feeding with age appropriate calories was initiated. Mean, SD duration of hospital stay was 10.7, 3.19 days. Tremor phase mean, SD lasted for 16.4, 6.24 days.

DISCUSSION

ITS is a well-known clinical entity. There are numerous theories regarding its etiopathogenesis but the exact cause is still not known. In the present study, the age of presentation was 6–18 months with mean, SD of 11, 3.1 months which was similar to that reported in other studies.[789] Number of males were more than females, as was seen in earlier studies.[81011] We observed that cases were present throughout the year, with two peaks in the months of May and November which is similar to Ghai,[1] Sharda and Bhandari,[12] but contrary to Charles et al.,[8] Sirolia and Arya[7] Majority of patients were from a rural background and lower middle socioeconomic status, as was observed by Bajpai et al.[10] Majority of the mothers were high school pass, but lacked knowledge of the importance of the timely introduction of complementary feeding. No study till date has studied this disease in relation to the education of the mother. Developmental delay and regression of milestones were similar to that observed by other authors.[11121314] Tremors were seen in two-thirds of the patients, similar to that observed by Goraya et al.[11]

Apart from the known features of ITS (anemia, chubby look, and hypotonia), high incidence of hepatomegaly and splenomegaly was similar to as observed in some other studies.[714] This higher incidence can be attributed to associated comorbid illnesses. Fifty-six percent of patients had Grade 2-3 malnutrition as per the WHO criteria. Similar findings were observed in another study.[15]

All patients were born normally with average birth weight, as observed by Singla et al., in their case series.[16] Interestingly, we observed that ITS was more common in higher birth order, which could be related to poor maternal nutrition after the first childbirth. No such observation is there in the literature. Majority of mothers were vegetarian as was observed by Goraya et al.[11] Complementary feeding was not established in the majority, similar to what was observed in some other studies.[811] Respiratory tract infection was the most common comorbid illness, followed by urinary tract infection and sepsis. Two-thirds of the patients received antibiotics, as was seen in other studies.[1517]

Anemia was mild to moderate, as was observed by Pohowalla (1960).[9] The peripheral smear revealed mostly dimorphic picture followed by macrocytic and microcytic anemia, as observed in other studies.[111518] Vitamin B12 levels were low in 50%, similar to Goraya and Kaur[11] Normal levels in the remaining 50% strengthens the belief that Vitamin B12 deficiency is not the only factor that plays a role in ITS. Only one patient had received Vitamin B12 before testing. Folic acid, protein, and albumin levels were normal, which suggests that the etiology is probably a micronutrient deficiency.

Although not statistically significant, we found low levels of serum magnesium in these children, the values being lower in those with tremors. Chhaparwal et al.[19] and Agarwal et al.[20] have shown the association of tremors with low magnesium levels.

Calcium levels were marginally reduced, similar to Agarwal et al.[20] Hypocalcemia and hypomagnesemia were found to be coexisting.

As in this syndrome, the etiology could not be pinpointed, treatment comprised of treatment of anemia as per etiology. A single intramuscular injection of Vitamin B12 was given to all patients at admission, 250 μg in age <1 year and 500 μg in age more than 1 year, followed by maintenance orally at 0.5–1.0 μg/day as multivitamin syrup. Patients who were Vitamin B12 deficient were given 250–500 μg intramuscular daily for 7 days, biweekly for 3 months and then monthly for 3 months. Multivitamins, iron, zinc, Vitamin C, magnesium, calcium in age-appropriate doses were given as suggested in the literature.[21]

ITS is a self-limiting condition and recovery is common,[14] but long-term follow-up cautions us about its benign and self-limiting nature, as observed by Kaul et al.[22] Duration of tremors was similar to as observed by other authors.[71114] We used propranolol for 2 weeks in two children with generalized tremors that were causing feeding difficulty.

CONCLUSION

From observations made in the study, it is still difficult to pinpoint a single etiological factor for ITS. The disease appears to result from multi-micronutrient deficiency, that can be present alone or in the association. In the present study, Vitamin B12, magnesium, and iron were found to be deficient. Estimation of zinc levels could not be done due to financial constraints. Normal levels of serum protein and albumin further points toward a micronutrient deficient state. It is, therefore, emphasized that ITS can be prevented through exclusive breastfeeding, initiation of complementary feeds at 6 months and ensuring adequate maternal nutrition, during and between successive pregnancies.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.