|Year : 2016 | Volume
| Issue : 4 | Page : 298-304
Infantile tremor syndrome: A review and critical appraisal of its etiology
Jatinder Singh Goraya1, Sukhjot Kaur2
1 Department of Pediatrics, Division of Pediatric Neurology, Dayanand Medical College and Hospital, Ludhiana, Punjab, India
2 Department of Dermatology, Dayanand Medical College and Hospital, Ludhiana, Punjab, India
|Date of Web Publication||3-Feb-2017|
Jatinder Singh Goraya
Department of Pediatrics, Division of Pediatric Neurology, Dayanand Medical College and Hospital, Ludhiana - 141 001, Punjab
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Infantile tremor syndrome (ITS) is defined by the tetrad of pallor, developmental delay/regression, skin pigmentation, and brown scanty scalp hair. Involuntary movements in the form of tremors supervene in the natural course of the illness in a significant number of cases. The disorder occurs in exclusively breast-fed infants of vegetarian mothers belonging to economically deprived sections of society. Most of the children eventually recover but are frequently left with long-term cognitive and language neurodeficits. ITS continues to be seen in clinical practice, but there has been no consensus on its causation. Last comprehensive review was published in 1987 describing the ITS as a syndrome of unknown or multiple etiologies. Several important papers have been published since then. This review attempts to provide comprehensive and up-to-date information on the subject incorporating recently published studies. In the end, the issue of etiology is objectively re-examined in the light of available evidence some of which has been published in recent years.
Keywords: Etiology, infantile tremor syndrome, vitamin B12deficiency
|How to cite this article:|
Goraya JS, Kaur S. Infantile tremor syndrome: A review and critical appraisal of its etiology. J Pediatr Neurosci 2016;11:298-304
| Introduction|| |
Dikshit from Hyderabad, in 1957, reported a case series of 25 infants with constellation of symptoms and signs characterized by pallor, skin hyperpigmentation, and regression of neurodevelopment. The infants were exclusively breast-fed by strictly vegetarian mothers belonging to the lower middle class. Moderate to severe anemia with tendency to macrocytosis was present in all. Bone marrow examination in one such case revealed megaloblastic change. The infants were treated with liver extract alone or in combination with “B complex factor” or vitamin B12. The response was uniformly good in all the cases and began as early as 3rd or 4th day. The author called this condition “Nutritional Dystrophy with Anemia.”
Soon several reports emanated from other parts of the country describing cases with similar symptomatology thus confirming clinical existence of this disorder across the country. More than 30 papers were published between 1957 and 1979. The research interest in ITS began to decline in the early 80s with publication of fewer and fewer reports in the following years. The subject was last comprehensively reviewed in 1987, describing ITS to be a disorder without any established etiology. A number of important papers have been published since this last review.,,, The current review is being undertaken to provide up-to-date information on the infantile tremor syndrome (ITS) to the academic and practicing clinicians and also to critically analyze the issue of its etiology.
| Literature Search|| |
For the purpose of this review, we searched Medline and Google Scholar for identifying studies on ITS. Additional studies were identified from the references of the retrieved articles as well as from the pediatric textbooks published from India. Finally, hand search of the Indian Pediatrics and the Indian Journal of Pediatrics was done to complete the search process.
The disorder has been reported under various other names, namely, nutritional dystrophy and anemia, infantile meningoencephalitic syndrome, vitamin B12 deficiency in Indian infants, megaloblastic anemia of infancy and vitamin B12, syndrome of tremors in infants, syndrome of tremors, mental regression and anemia, and tremors, mental and physical retardation, light colored hairs and anemia in malnourished children. Since, the tremors are the dominant recognizable feature of this disorder and affect children below 2 years of age, the term infantile tremor syndrome or ITS gained popularity.
| Epidemiology|| |
Incidence and prevalence
Exact incidence of ITS is not known but hospital statistics has revealed 0.77%–2.5% of the pediatric ward admissions to be due to this disorder.,,, The syndrome has been reported from Punjab, Himachal Pradesh, Jammu and Kashmir, Uttar Pradesh, Bihar, West Bengal, Madhya Pradesh, Tamil Nadu, Andhra Pradesh, Karnataka, Rajasthan, Gujarat, Maharashtra, New Delhi, and Chandigarh. Cases of ITS are generally encountered throughout the year. Some authors have found more cases of ITS during summer ,,, and winter/rainy seasons.
Age and gender
ITS commonly affects infants between 6 and 24 months of age though infants younger or older than this (age range 40 days to 36 months) have been reported. There is male preponderance in the majority of the studies.
Most of the infants with ITS come from poor families.
Maternal diet and nutritional status
Mothers of the infants with ITS are mostly vegetarian and their diet devoid of animal foods including milk, resulting to a large extent from poverty and ignorance. Only rarely, has the vegetarianism been a matter of personal choice. Occasionally, mothers have been reported to have underlying pernicious anemia. Maternal health in many studies has been stated to be poor with multiple nutritional deficiencies,,,,, while others have provided no information on maternal diet and nutritional health.,,,,
Almost all the cases of ITS occur in exclusively breast-fed infants. Commonly weaning has never been initiated because of lack of appropriate guidance. Equally common is weaning failure due to anorexia, refusal to solid foods, and spitting.,,, Even when weaning has been started, foods of animal origin including top milk are missing from the diet , or given in insufficient quantity.,,
| Clinical Manifestations|| |
Nutritional status of the infants
The presence of pallor, skin and hair changes, and dull apathetic look that the infants with ITS exhibit is quite reminiscent of kwashiorkor. In a typical scenario, affected infants look plump with preserved subcutaneous fat.,,,,, Others have reported failure to thrive and wasted or marasmic look.,,,,,, In any case, growth parameters are normal at birth and for the first 5–6 months of age. Later growth faltering occurs due to inadequate feeding caused by continued exclusive breastfeeding. Refusal to solid foods, anorexia, and intercurrent infections further aggravate the nutritional imbalance. In addition to anemia, infants with ITS frequently manifest multiple micronutrient deficiencies in the form of angular cheilitis, stomatitis, and glossitis., 6, ,, Rickets,,, scurvy, and edema , 6, ,,,, have also been reported as has been Vitamin A deficiency., Not surprisingly, most of the researchers do agree that infants with ITS are malnourished.
Almost all infants with ITS look pale. The pallor is mostly due to anemia which is likely nutritional in origin.
Skin and hair changes
Skin and hair changes are present in almost all the infants with ITS. Skin shows darkening or hyperpigmentation of dorsa of hands and feet which may be especially accentuated at the knuckles causing so-called “knuckle pigmentation.” Others may show diffuse honeycomb or reticulate pattern of hyperpigmentation affecting trunk as well as limbs [Figure 1]. Scalp hair displays variable depigmentation and appears rough and lusterless. Hair growth is sparse [Figure 2], and they are easily pluckible. Eyebrows may be similarly affected.,
|Figure 1: Diff use honeycomb or reticulate pigmentation of the skin over trunk and limbs|
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Infants with ITS are born without any prenatal or perinatal complications and display normal neurodevelopment till the first 4–6 months of age.,,, Developmental slowing then sets in, and is followed by developmental regression, if corrective measures are not instituted. The infant gradually becomes less active and withdrawn with loss of interest in surroundings. His/her interaction with parents and others decreases. Somnolence and lethargy supervenes but seldom do these infants lapse into coma. Intercurrent illness may trigger rapid downhill course at any time during the course of illness.,,,, Seizures are uncommon and may occur any time during the course of the disease.,,
Tremors are the one of the most characteristic features of ITS allowing instant recognition of the syndrome by the experienced clinicians. Tremors are generally absent early in the course of illness, the pre-ITS stage. Tremors tend to be coarse and have jerky (myoclonus-like) character. Onset is usually focal from one of the upper extremities with rapid progression to generalized involvement. Sudden onset of generalized tremors is not uncommon.,, Even when generalized, tremors have asymmetric and multifocal appearance. Involvement of facial, labial, lingual, and laryngeal musculature is an unmistakable sign of ITS. Laryngeal involvement renders a distinctive tremulous character to the vocalization/cry in these infants which has been likened to the bleating of a goat.,,,, Tremors may be intermittent initially, brought out only by crying, excitement, or physical stimuli. Later tremors become constant throughout the day but disappearing in sleep.,,,,,, In severe cases, tremors may persist during sleep though at reduced intensity.,,, Tremors at times have been triggered or made worse by vitamin B12 treatment.,,, Other involuntary movement such as chorea or myoclonus have been described, often coexisting with tremors.,,
Infants with ITS appear dull and apathetic showing little interest in the surroundings. They lie listlessly, becoming irritable when handled. Expressionless face, vacant stare, and open mouth with drooling are characteristic., Spontaneous movements may be reduced (hypokinesia). Swallowing dysfunction is sometimes present contributing to feeding difficulties. Majority of the infants have hypotonia with retained or exaggerated tendon reflexes. Hypertonia and extrapyramidal rigidity are less common., No sensory deficits have been reported.
Usually, there are no systemic symptoms and signs unless the course of illness has been complicated by intercurrent infections, usually of the gastrointestinal or respiratory tract.,,,,, Infections, in fact, may be one of the reasons to bring the child to medical attention.,,, Mild hepatomegaly with or without splenomegaly is frequently reported sign in ITS.,,,,,,, Congestive cardiac failure secondary to severe anemia may occur.
| Diagnosis|| |
A typical case of ITS is an exclusively breast-fed infant (of a strictly vegetarian mother) who presents with developmental regression and tremors. Often, the infant has been unwell for several weeks to months with progressive lethargy, failure to thrive, feeding difficulties, and developmental slowing. On examination, the child looks pale and has dull expressionless face, vacant stare, and drooling., Skin shows generalized reticulate or diffuse dark pigmentation with peripheral accentuation over the hands and feet [Figure 1]. Scalp hair is brown and scanty [Figure 2]. The infant appears to be seized by constant and often distressing jerky involuntary movements affecting arms, legs, face, and tongue. Peculiar tremulous cry akin to bleating of a goat is generally audible from distance. When all these features are present, clinical diagnosis of ITS can be made beyond doubts.,
| Laboratory Investigations|| |
Laboratory investigations in the past have been undertaken to find out the etiology of this syndrome. The extent of investigations has been limited in most of the studies due to lack of resources. Inferences made on the basis of insufficient laboratory data have contributed greatly to the controversy surroundings the etiology of ITS (vide infra).
Mild to moderate anemia is almost always present in infants with ITS. This is, however, not universal finding as some infants display normal hemoglobin. Total leukocyte count is variable and may be affected by associated infectious illness. Leukopenia has sometimes been reported. Platelet counts are also variable. Rarely, pancytopenia is detected. While dimorphic peripheral smear has been reported by many authors,,,,, others have stressed the predominance of macrocytic morphology of the red blood cells.,,,, Bone marrow findings have varied from predominantly normoblastic ,, through dimorphic , to predominantly megaloblastic.,,,,
Blood sugar, calcium, renal and liver function tests are mostly normal or do not point to specific etiology. Low serum albumin has been found in small number of infants with ITS in many studies. Deficiency of magnesium , and zinc , has been reported. Garewal et al. found iron deficiency in almost 50% of the infants with ITS. Examination of cerebrospinal fluid (CSF), urine, and stool has mostly been normal. Urinary amino acids in one study showed no abnormal pattern of excretion.
Low serum vitamin B12 is the laboratory diagnostic hallmark of vitamin B12 deficiency. Several studies ,,,,, including many published in recent years ,,, have shown unequivocal evidence of vitamin B12 deficiency in ITS. Only two studies have reported normal serum vitamin B12 levels in infants with ITS., Serum and red cell folate when measured have been normal., Mothers of the affected infants with ITS also have low vitamin B12 in serum , 6, ,, as well as in the breast-milk.,, We found low maternal serum vitamin B12 to be a useful indirect measure of vitamin B12 deficiency in infants who have had normal serum vitamin B12 due to prior administration of vitamin B12.
Invasive investigations have been reported only in a few infants with ITS. Biopsies of skin, liver, muscle, nerve, and rectum have either been normal or have revealed only nonspecific changes of no etiological significance., Brain biopsy in one study has revealed no specific histopathological changes to suggest an etiology.
Initial studies with pneumoencephalography  in the precomputed tomography/magnetic resonance imaging (CT/MRI) era showed decreased brain substance. These findings of cerebral atrophy have been corroborated by CT., More recently, MRI of the brain has not only confirmed diffuse cerebral atrophy but also showed delayed myelination in some cases., Subdural effusion  and central pontine myelinolysis  have been reported in one case each.
Electroencephalographic changes have only occasionally been reported , and no definitive conclusions can be drawn. Nerve conduction studies, brainstem auditory evoked responses, and visual evoked response have not been reported.
| Treatment and Therapeutic Response|| |
In the absence of agreement on etiology, treatment of ITS has remained controversial and suboptimal at best. Many authors have treated ITS infants symptomatically with various combinations of dietary modification, multivitamins, and mineral supplements ,,,, and reported gradual recovery over weeks to months irrespective of the treatments. Others have reported successful treatment with dietary modification along with the treatment of anemia with folic acid, vitamin B12 and iron, indicating that dietary deficiency of some kind was likely responsible for the manifestations of the syndrome.,,
Successful treatment with vitamin B12 alone resulting in dramatic improvement in symptoms has been consistently reported by many authors.,,,,,, Dikshit administered liver extract alone or in combination with B complex factor or B12 to the infants with ITS and observed rapid hematological and neurological recovery. Similar response to the treatment was obtained by Jadhav et al. with oral vitamin B12 in doses as low as 0.1 µg/day. Srikantia and Reddy  successfully used a novel method of treating infants with ITS through augmenting the vitamin B12 content of breast-milk by giving a single intramuscular dose of 50 µg vitamin B12 to the mothers. Similarly, encouraging results have been described by Deshpande and Ingle  and in many recent studies.,,, In all these studies, patients were treated with vitamin B12 alone and a uniform pattern of response was observed. Initial change was observed within 48–72 h of treatment in the form of improved general activity and responsiveness. The infants became more active, playful, and social smile returned. Appetite improved and the aversion to weaning food disappeared. The infants started accepting the same food which was once refused or spitted. The lost developmental milestones began to return. Tremors also started to disappear within a week in most of the infants and were gone by 3–4 weeks in all. In some cases, tremors appeared first after treatment with vitamin B12 had been started.,,,,, Hematological recovery was also observed within 5–7 days.,, Skin pigmentation resolved in about 2–4 weeks. The hair changes were slow to occur, generally taking several months to years for complete recovery. On the other hand, certain authors have reported results to the contrary and observed that tremors did not disappear faster in those who were given vitamin B12 than those who were not, prompting these authors to negate vitamin B12 deficiency as the cause of ITS.,,
Supportive care in the form of intravenous fluids to treat and prevent dehydration, antibiotics for associated infections, and other medications to treat associated complications are commonly used during acute phase. Tremors have been treated with propranolol, sedatives,, carbamazepine, and emetine, but the role of these treatments is difficult to assess in the absence of controlled trials.
| Prognosis|| |
Although most of the infants ultimately recover, neurodevelopmental deficits, especially in cognitive and language skills, often persist in the long-term.,,,,,,, Mortality in ITS is very rare and has resulted from the inter-current infections.,,,
| Etiological Considerations|| |
Etiology of the disorder has remained a subject of intense research and controversy. The role of infectious, nutritional, toxic, or metabolic agents in the etiology of ITS has been speculated. Authors of many recent publications ,,, and Indian textbooks of pediatrics continue to regard ITS as a disorder of unknown etiology., In the absence of agreement on its etiology, treatment of ITS has remained suboptimal at best. In the following paragraphs, we critically appraise the issue of etiology of ITS and also explore the reasons for controversy.
| Infections|| |
Pohowalla et al. called this entity as infantile meningoencephalitis, but no virus or other microbial agent has ever been isolated. Investigations, such as CSF analysis ,,,,,,, brain biopsy, and more recently neuroimaging, have not pointed to any infectious agent(s).
| Toxic/metabolic|| |
No evidence is available to implicate any known or unknown toxic substance in the causation of ITS, and this hypothesis has therefore largely been discarded. One study reported aminoaciduria in ITS but found no specific abnormalities. From a clinical point of view, hereditary disorders of cobalamin metabolism can have similar clinical presentation. However, detailed investigations for inborn errors of metabolism have not been carried out in any of the studies. Lack of family history, clinical course of the disease with ultimate recovery, and no relapse of symptoms also do not favor genetic or neurometabolic etiology.
| Unknown or Multiple Etiologies|| |
Many authors believe that ITS is a disorder of self-limited nature and resulted from some yet unidentified causative factor(s).,,,
It is beyond any reasonable doubt that infants with ITS are malnourished, a fact that is agreed on by almost all the researchers.,,,,,,,,,,, Of all the specific nutrients, deficiencies of zinc and magnesium have been found in ITS,,, but the clinical picture associated with these deficiencies bears no resemblance to that of ITS. These deficiencies are therefore likely incidental to the malnutrition that is observed in ITS rather than being causative. Similarly, hypoalbuminemia, hypocalcemia, iron deficiency, and fatty liver change in ITS are part of the malnutrition spectrum.
Vitamin B12 deficiency
Most of the controversy concerning the etiology of ITS has centered on the role of vitamin B12 deficiency in the disorder. There, now, exists a large body of literature which provides robust epidemiological, clinical, and laboratory evidence in favor of vitamin B12 deficiency as the cause of ITS.
Epidemiologically, mothers of infants with ITS are vegetarian in their dietary habits and therefore are at risk of vitamin B12 deficiency. Studies have repeatedly confirmed low vitamin B12 in the maternal serum , 6, ,, and in the breast-milk., Infants born to these mothers have suboptimal vitamin B12 stores at birth which get further depleted during infancy in the absence of external supplementation. From a clinical viewpoint too, the clinical symptoms and signs of ITS are similar to those of nutritional vitamin B12 deficiency in infants.,
Much of the controversy surrounding the role of vitamin B12 deficiency in the etiology of ITS has resulted from the interpretation of the laboratory findings as they pertain to vitamin B12 deficiency. Many studies excluded vitamin B12 deficiency in ITS solely on the basis of lack of macrocytosis in peripheral blood and megaloblastic erythropoiesis in the bone marrow, and serum vitamin B12 was not measured.,,,,,, Incidentally, these studies were conducted in general hospitals or other places with no access to vitamin B12 testing. It is well known that neurological manifestations of vitamin B12 deficiency can occur in the absence of concomitant hematological changes, the so-called hematological-neurological dissociation., Estimation of serum vitamin B12 is therefore necessary to diagnose or exclude vitamin B12 deficiency. In cases with borderline or functional vitamin B12 deficiency, serum homocyteine levels, methylmalonic acid, and holotranscobalamin are more sensitive measures of vitamin B12 deficiency.
On the other hand, wherever attempts have been made to determine serum vitamin B12 in ITS, low serum levels of vitamin B12 have consistently been found.,,,,, Jadhav et al., in 1962, were the first to demonstrate low serum vitamin B12 in infants with ITS, a finding later corroborated by Srikantia and Reddy in 1967. Several years later in 1988, Garewal et al. in their elegant study demonstrated low serum vitamin B12 in 20/23 (87%) of the infants with ITS. Twenty of 23 infants had megaloblastic erythropoiesis. In 10 patients including three with normoblastic erythropoiesis, cellular evidence of vitamin B12 deficiency was revealed by the deoxyuridine suppression test performed on the bone marrow cultures. Levels of vitamin B12 and its transporter protein transcobalamin II in CSF were reduced suggesting the causal role of vitamin B12 deficiency in ITS.
With the easy availability of laboratory testing of vitamin B12 testing now, several recent studies have reaffirmed vitamin B12 deficiency in ITS. Jain et al. described vitamin B12 deficiency in infants who had presented with developmental delay or regression, pallor, and knuckle pigmentation. They were exclusively breastfed by vegetarian mothers. Low serum vitamin B12 was found both in infants as well as their mothers. Sirolia and Arya  found low vitamin B12 in 80% of their infants with ITS. We recently reported low serum vitamin B12 in 12 of the 21 infants with ITS. Of the 9 infants with normal levels, 7 had received vitamin B12 before referral but they had other evidence of vitamin B12 deficiency in the form of macrocytosis and low maternal serum vitamin B12.
Two studies in this regard deserve special mention. Kaul et al. measured serum vitamin B12 in 5 infants with ITS. Three (60%) infants had low serum vitamin B12 (<100 µµg/ml). Serum vitamin B12 was also measured in 4 mothers and 2 (50%) of them had low serum vitamin B12. In another study by these authors, which appears to be an updated version of the previous study, low serum vitamin B12 was documented in 3 (27%) of the 11 infants and 7 (100%) of the 7 mothers. The authors concluded that vitamin B12 deficiency was not present! No explanation for low maternal serum vitamin B12 was offered. Bajpai et al. measured serum B12 in 20 of the 134 infants with ITS and none had low serum vitamin B12. This is the only study reported to have normal levels of serum vitamin B12 in ITS, although only a small number (15%) of children were tested in this series, and serum vitamin B12 values for individual infants were not mentioned.
Assessment of response to treatment with vitamin B12 has also not been without disagreement largely because different studies chose different criteria to assess the therapeutic response. Some studies chose disappearance of tremors as the indicator of positive response and found that tremors did not abate faster in children who were treated with vitamin B12 than those who were not.,,,, On the other hand, studies reporting good response to treatment with vitamin B12 found entirely a different pattern of response following treatment with vitamin B12. Improvement in general activity and responsiveness appeared within 48–72 h of treatment followed by return of social smile and oral intake. Lost developmental milestones were regained. The tremors tended to abate by the end of 1st week and were generally gone by 3–4 weeks in the most.,,,,, This pattern of therapeutic response to vitamin B12 in ITS is similar to that reported in the infants with vitamin B12 deficiency.
Interestingly, infants with megaloblastic anemia due to vitamin B12 deficiency have been reported to have symptoms and signs consistent with ITS,,,,,, but these studies apparently escaped attention of ITS researchers. Mittal and Agarwal  described 52 young children (mean age 14.9 months) with megaloblastic anemia. Pallor was present in 96% while 77% had skin hyperpigmentation, 67% developmental delay, and 43% hypotonia. Tremors were noted in 8%. Kumar et al., retrospectively studied the incidence of ITS in children with megaloblastic anemia due to vitamin B12 deficiency and found that 16 (48.4%) out of 33 children with megaloblastic anemia due to vitamin B12 deficiency had clinical features consistent with ITS. A Study by Chandra et al. is also very significant in this regard. Authors described 51 children with nutritional megaloblastic anemia caused by deficiency of vitamin B12 and/or folic acid. Four had tremors at presentation while 6 additional children developed tremors following treatment with vitamin B12. Tremors were initially seen in the hands and feet and became generalized in 5. Three cases developed tremors of the tongue, and tremulous cry was noted in 2. The tremors subsided during sleep. The tremors eventually resolved in 5–11 days. The mean age of the children who developed tremors was 15.8 months.
It is now easy to understand that infants with vitamin B12 deficiency can have predominantly hematological (megaloblastic anemia) or predominantly neurological (ITS) manifestations. Quite often both coexist in the same patient. Uncommonly infants manifest with purely hematological manifestations in the absence of concomitant neurological manifestations and rarely vice versa may be true. This dissociation between neurological and hematological features is a well-known phenomenon in vitamin B12 deficiency is adults. At the same time, it must be, however, born in mind that clinically apparent deficiency of vitamin B12 deficiency is like the proverbial “tip of the iceberg” representing an extreme form of vitamin B12 deficiency in infants, with a large number of asymptomatic or minimally symptomatic infants remaining undiagnosed. Appropriate screening methods need to be devised to detect these infants in presymptomatic phase.
To conclude, ITS is a nutritional deficiency syndrome presenting predominantly with neurological manifestations. A variable number of these children has concomitant hematological findings consistent with megaloblastic anemia. Laboratory evidence of vitamin B12 deficiency is found whenever adequate investigations are undertaken. Treatment with vitamin B12 produces results in rapid amelioration of symptoms. Treatment of other associated nutritional deficiencies and correction of feeding practices is necessary for comprehensive management of these infants. Since long-term cognitive and language impairments can occur, early diagnosis and treatment are necessary.
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| References|| |
Dikshit AK. Nutritional dystrophy with anemia. Indian J Child Health 1957;6:132-6.
Sharda B, Bhandari B. Infantile tremor syndrome. Indian Pediatr 1987;24:415-21.
Garewal G, Narang A, Das KC. Infantile tremor syndrome: A Vitamin B12
deficiency syndrome in infants. J Trop Pediatr 1988;34:174-8.
Sirolia V, Arya S. Study of clinical profile and estimation of Vitamin B12
level in infantile and pre-infantile tremor syndrome. J Evol Med Dent Sci 2014;3:10134-7.
Jain R, Singh A, Mittal M, Talukdar B. Vitamin B12
deficiency in children: A treatable cause of neurodevelopmental delay. J Child Neurol 2015;30:641-3.
Goraya JS, Kaur S. Infantile tremor syndrome – Down but not out. Indian Pediatr 2015;52:249-50.
Pohowalla JN, Kaul KK, Bhandari NR, Singh SD. Infantile “meningo-encephalitic” syndrome. Indian J Pediatr 1960;27:49-54.
Jadhav M, Webb JK, Vaishnava S, Baker SJ. Vitamin B12
deficiency in Indian infants. A clinical syndrome. Lancet 1962;2:903-7.
Srikantia SG, Reddy V. Megaloblastic anaemia of infancy and Vitamin B12
. Br J Haematol 1967;13:949-53.
Kaul KK, Prasan N, Chowdhry RM. Some clinical observations and impressions on a syndrome of tremors in infants from India. J Pediatr 1963;63:1158-66.
Sachdev KK, Manchanda SS, Lal H. The syndrome of tremors, mental regression and anaemia in infants and young children: A study of 102 cases. Indian Pediatr 1965;2:239-51.
Mathur GP, Dayal RS, Prasad R, Mathur S. Tremors, mental and physical retardation, light coloured hairs and anaemia in malnourished children. Indian Pediatr 1969;6:483-7.
Bajpai PC, Tandon PN, Sharma NL, Misra PK. Infantile tremor syndrome. Acta Neurol Scand 1965;41:473-86.
Agarwal SP, Katiyar GP. Infantile tremor syndrome. Pediatr Clin India 1972;7:203-8.
Ramakumar L, Pandove SP. Infantile tremor syndrome. Indian J Pediatr 1975;42:215-25.
Gupte S, Pal M. Infantile tremor syndrome (Observations from North India). Indian Pract 1979;32:369-75.
Garg BK, Srivastava JR. Infantile tremor syndrome. Indian J Pediatr 1969;36:213-8.
Ratageri VH, Shepur TA, Patil MM, Hakeem MA. Scurvy in infantile tremor syndrome. Indian J Pediatr 2005;72:883-4.
Bajpai PC, Misra PK, Tandon PN, Nigam GJ, Vora VC, Malaviya A. Serum Vitamin B12
in infantile tremor syndrome. Indian J Med Res 1968;56:1398-405.
Deshpande TV, Ingle VN. Tremor syndrome in children. Indian Pediatr 1969;6:550-6.
Vyas KJ. Use of emetine in 'Infantile Tremor syndrome'. Indian Pediatr 1974;11:252.
Goraya JS, Kaur S, Mehra B. Neurology of nutritional Vitamin B12
deficiency in infants: Case series from India and literature review. J Child Neurol 2015;30:1831-7.
Mahajan CM, Walia BN, Perkash A. Anemia in infantile tremor syndrome. Indian J Pediatr 1971;38:362-4.
Chhaparwal BC, Singh SD, Mehta S, Pohowalla JN. Magnesium levels in serum and in C.S.F. in “meningo-encephalitic syndrome” (tremor syndrome). Indian J Pediatr 1971;38:331-3.
Agarwal R, Singh RN, Gupta BD, Agarwal DK, Arora AK. Serum magnesium, calcium, zinc in infantile tremor syndrome. Indian Pediatr 1993;30:374-6.
Vora RM, Tullu MS, Bartakke SP, Kamat JR. Infantile tremor syndrome and zinc deficiency. Indian J Med Sci 2002;56:69-72.
Ingle VN, Hatwalne BV. Urinary aminoacids in the syndrome of tremors. A study of 12 cases. Indian J Pediatr 1967;34:235-7.
Mahajan CM, Walia BN, Dutta BN. Infantile tremor syndrome – Some aspects of serum biochemistry and liver histoloy. Indian Pediatr 1971;8:831-3.
Bajpai PC, Misra PK, Tandon PN, Wahal KM, Newton G. Brain biopsy in infantile tremor syndrome. Indian J Med Res 1971;59:413-8.
Murali MV, Sharma PP, Koul PB, Gupta P. Carbamazepine therapy for infantile tremor syndrome. Indian Pediatr 1993;30:72-4.
Thora S, Mehta N. Cranial neuroimaging in infantile tremor syndrome (ITS). Indian Pediatr 2007;44:218-20.
Bang GC, Mittal H, Aggarwal A. Subdural effusion in infantile tremor syndrome. J Pediatr Neurosci 2013;8:82-3.
Datta K, Datta S, Dutta I. Rare association of central pontine myelinolysis with infantile tremor syndrome. Ann Indian Acad Neurol 2012;15:48-50.
Holla RG, Prasad AN. Infantile tremor syndrome. Med J Armed Forces India 2010;66:186-7.
Kalra V, Marwaha RK. Propranolol in infantile tremor syndrome. Indian J Pediatr 1978;45:341-3.
Kaul KK, Belapurkar KM, Parekh P. The syndrome of tremors in infants: A long follow-up. Indian J Med Res 1972;60:1067-72.
Gupte S, editor. Infantile tremor syndrome. In: The Short Textbook of Pediatrics. 11th
ed. New Delhi: Jaypee Brothers; 2009. p. 726-8.
Kalra V. Infantile tremor syndrome. In: Paul VK, Bagga A, Sinha A, editors. Ghai Essential Pediatrics. 8th
ed. New Delhi: CBS Publishers; 2013. p. 579-81.
Baker SJ, Jacob E, Rajan KT, Swaminathan SP. Vitamin-B12
deficiency in pregnancy and the puerperium. Br Med J 1962;1:1658-61.
Dror DK, Allen LH. Effect of Vitamin B12
deficiency on neurodevelopment in infants: Current knowledge and possible mechanisms. Nutr Rev 2008;66:250-5.
Zengin E, Sarper N, Caki Kiliç S. Clinical manifestations of infants with nutritional Vitamin B12
deficiency due to maternal dietary deficiency. Acta Paediatr 2009;98:98-102.
Herrmann W, Obeid R, Schorr H, Geisel J. Functional Vitamin B12
deficiency and determination of holotranscobalamin in populations at risk. Clin Chem Lab Med 2003;41:1478-88.
Kaul KK, Prasan NG, Chowdhry RM. Further observations on the syndrome of tremors in infants. Indian Pediatr 1964;1:219-25.
Saraya AK, Singla PN, Ramachandran K, Ghai OP. Nutritional macrocytic anemia of infancy and childhood. Am J Clin Nutr 1970;23:1378-84.
Mittal VS, Agarwal KN. Observations on nutritional megaloblastic anemias in early childhood. Indian J Med Res 1969;57:730-8.
Gomber S, Kela K, Dhingra N. Clinico-hematological profile of megaloblastic anemia. Indian Pediatr 1998;35:55-8.
Chandra J, Jain V, Narayan S, Sharma S, Singh V, Batra S, et al.
Tremors and thrombocytosis during treatment of megaloblastic anaemia. Ann Trop Paediatr 2006;26:101-5.
Kumar V, Sanjat KS, Kumar P, Murthy R, Shivananda. Incidence of infantile tremor syndrome in children with megaloblastic anemia. 48th National Conference, Indian Academy of Pediatrics; 2011 Jan 21-23; Jaipur, India.
Gupta R, Sharma SD, Gupta R. Megaloblastic anemia: Clinico-hematological profile in 50 infants. J Med Sci 2009;12:26-9.
Goraya JS, Kaur S. Infantile tremor syndrome: A syndrome in search of its etiology. Indian Pediatr 2016;53:173-4.
[Figure 1], [Figure 2]