Reminiscences from Indian Pediatrics: A
Tale of 50 Years |
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Indian Pediatr 2015;52: 599-600 |
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Infantile Tremor Syndrome – A Tale of 50
Years
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Sharmila B Mukherjee
Department of Pediatrics, Lady Hardinge Medical
College, New Delhi, India.
Email: [email protected]
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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 Past
The study published in this issue was conducted
over three years by Sachdev, et al. [1] at Amritsar Medical
College in collaboration with the University of Oregan Medical School.
Children presenting with tremors, mental regression and anemia were
enrolled, evaluated and managed according to hospital protocol. The
final study population comprised of 102 children aged 5 to 24 months
(50% between 12-18 months) with a boy-girl ratio of 3:2, and belonging
to the lowest socio-economic strata (mostly rural). All children were
exclusively breastfed. Majority (62.7%) had history of preceding febrile
illnesses. All the children had anemia and mental changes, with
dystrophic hair and skin pigmentation patterns seen in 70% and 40%,
respectively. Most children had weights 20% to 50% below expected with
11.7% displaying marasmus. The term mental regression was used to denote
the mental and developmental status. The former (apathy and
listlessness) was insidious, preceding tremors by weeks to months. An
initially normal development followed by stagnation was seen in 85%, and
early onset delay in the rest. A tremulous cry (described as ‘bleating
of a goat’) was noted in 43%. All children developed tremors that were
coarse, rhythmic, rapid, predominantly generalized (involving face,
trunk and/or extremities), initially intermittent and gradually became
continuous. Tone was variable; mild hypotonia in 39.3%, marked hypotonia
in 4.9% and rigidity in 55.8%. Hyperreflexia was seen in 43%. Apart from
hepatomegaly (in almost 50%), there were no other salient systemic
findings.
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 B 12
(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 B 12
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 B 12
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.
The Present
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 B 12
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.
References
1. Sachdev KK, Manchanda SS, Lal H. The syndrome
of tremors, mental regression and anemia in infants and young
children: a study of 102 cases. Indian Pediatr. 1965;2: 239-51.
2. Dikshit AK. Nutritional dystrophy and anemia.
Indian J Child Health. 1957;6:132-6.
3. Bajpai PC, Tandon PN, Sharma NL, Misra PK.
Infantile tremor syndrome. Acta Neurol Scand. 1965;41:473-86.
4. Goraya JS, Kaur S. Infantile tremor syndrome –
down but not out. Indian Pediatr. 2015; 52:249-50.
5. Ratageri VH, Shepur TA, Patil MM, Hakee MA.
Scurvy in infantile tremor syndrome. Indian J Pediatr. 2005;72:
883-4.
6. Kaul KK. Infantile tremor syndrome: still a mystery ! Indian
Pedatr. 2015;52:628.
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