We continue with the second stop of our journey, the July issue of Indian Pediatrics in 1965. This comprised of 41 pages with seven articles that had three research papers (the syndrome of tremors, mental regression and anemia; neonatal blood pressure recording; and effects of long acting sulfonamides), a review on tremors, a case series (diaphragmatic disorders), book reviews and current literature. Out of all these, we chose to review the syndrome, since although it is a common and easily recognizable entity, our understanding is just marginally more than it was 50 years ago.

The degree of anemia varied with mild (hemoglobin levels 7-9 g/dL) in 38%, moderate (5-7 g/dL) in 28%, and severe (3-5 g/dL) in 22%. A macrocytic hypochromic picture was observed in 47.5%, macrocytic normochromic in 25% and microcytic hypochromic in 27.5%. Bone marrow aspiration was done in two-thirds; majority displayed normoblastic reaction with 16.2% showing megaloblastic marrow. Fatty liver changes were seen in 12 out of 18 liver biopsies. A protein rich diet was given to all, and empirical treatment to 100 children who were divided into select groups (inclusion criteria unspecified) according to modality. These included daily administration of: (i) vitamin B12 (5 µg oral or 100 µg intramuscular) in 16 and 28 children, respectively; (ii) pyridoxine (10 mg) in 18 children; (iii) acetazolamide (125 mg) in 15 children; (iv) multiple therapy (liver extract, vitamin B complex, vitamin C and iron) in 15 children; and (v) phenobarbitone and antibiotics in 8 children. Majority (62.7%) remained symptomatic, however a clinical response (disappearance of tremors by 2 weeks) was observed in 5/8 (62.5%) of children receiving phenobarbitone, 7/15 (46.6%) receiving multiple therapy, 3/16 (18.8%) receiving B12 orally and 12/28 (42.8%) receiving B12 parenterally.

Historical background and past knowledge: The described syndrome was first reported in Indian medical literature as ‘Nutritional dystrophy and anemia’ by Dikshit, et al. [2] in 1957. Subsequently, it was reported from all over India under various names: ‘infantile meningo-encephalitic syndrome’ by Pohowalla, et al. in 1960, ‘vitamin B12 deficiency – a clinical syndrome’ by Jadhav, et al. in 1962, and ‘infantile syndrome of tremors in infants’ by Kaul, et al. in 1963. The term ‘infantile tremor syndrome’ was introduced by Bajpai, et al. [3] in 1965, and is still in use, despite the fact that the phenotype is neither restrictive to infants nor to tremors.

Till the 1970s, studies aimed at describing the clinical manifestations. Subsequently, focus shifted to ascertaining etiology and therapy. Most affected children were aged between 6 and18 months, were predominantly males, belonged to lower socio-economic strata, and were exclusively breastfed by predominantly vegetarian mothers. The illness showed seasonal variation and the clinical course could be delineated into pre-tremor (prodromal), tremor (classical) and post-tremor (recovery) phases. Besides routine investigations, many others were performed ranging from biopsies (liver, brain, nerve and rectal) to pneumo-encephalograms, but were found inconclusive. Various etiological hypotheses were proposed with arguments both in favor and against. These included vitamin B12 deficiency (typical peripheral smear and bone marrow findings and response to therapy versus absence of hematological picture and response), multiple nutritional deficiencies (exclusively breastfed beyond the recommended period, typical hair and skin features associated with malnutrition versus absence of overt malnutrition in most cases, variable response to therapeutic nutrition and inability to pinpoint a specific deficiency), defects in tyrosine metabolism (hair and skin changes suggesting interference in melanin synthesis and aminoaciduria versus absence of these changes in some), and a probable viral infection (seasonal variation, preceding febrile illness with respiratory or gastrointestinal symptoms, self-limiting course, non-specific structural changes, cerebral atrophy and ventricular dilatation on neuroimaging and non-specific inflammatory changes on brain biopsy versus consistently negative viral studies). Short-term neurodevelopment outcomes were evaluated in a few cohorts and variable recovery was seen, ranging from partial to complete.

For reasons unknown, infantile tremor syndrome still remains confined to the Indian subcontinent. Though there is lack of community-based data, numbers of hospital-based admissions appear to be decreasing. Surprisingly, even now etiopathogenesis remains obscure. It appears that vitamin B12 deficiency has some causal association. The evidence is epidemiological (B12 deficient diets of mothers and infants), clinical, laboratory-based (decreased serum levels, abnormal deoxyuridine suppression tests) and therapeutic (clinical and hematological response) [4]. However, the reason for variability in hematological phenotype and response to B12 therapy is unclear. It has been suggested that the studies disproving deficiency as a cause were based only on blood picture, and not on vitamin B12 assay. Genetic predisposition is yet to be explored. Treatment still focuses on providing appropriate nutritional support with vitamin B12 therapy and supplementation of other vitamins and minerals (iron, calcium, magnesium, zinc, selenium, chromium). Since scurvy has also been reported in a few cases, vitamin C supplementation has also been advocated [5]. The drugs used now-a-days for persistent tremors are propranolol and carbamazepine. Long-term neuro-developmental outcomes need to be ascertained. It may be speculated that children in whom therapy is initiated late may already have suffered irreversible brain damage resulting in poorer prognosis. There is a strong need to rekindle interest in this mysterius disease [6], especially since advanced molecular and genetic technologies are now available.

6. Kaul KK. Infantile tremor syndrome: still a mystery ! Indian Pedatr. 2015;52:628.