1. Introduction and Definition
- Definition: A clinical syndrome characterized by the triad of tremors, mental regression/developmental delay, and skin pigmentation in a plump, anemic infant.
- Historical Context: First described in India (Dikshit, 1957). Also known as “Pre-kwashiorkor” or “Nutritional Tremor Syndrome.”
- Current Consensus: It is primarily a manifestation of severe Vitamin B12 deficiency.
2. Epidemiology
- Geography: Predominantly seen in the Indian subcontinent (India, Pakistan, Nepal) and Southeast Asia.
- Age: 6 months to 18 months (Peak: 1 year).
- Sex: Male slight preponderance.
- Socioeconomic: Lower socioeconomic strata, though seen in middle class with strict vegetarianism.
- Maternal Factors: Exclusively breastfed infants of vegetarian mothers or mothers with pernicious anemia/malabsorption.
3. Etiopathogenesis
- Primary Cause: Vitamin B12 (Cobalamin) Deficiency.
- Maternal B12 stores are low (vegetarian diet) Low B12 in breast milk Infant depletion.
- Why Tremors?
- B12 is essential for myelin synthesis. Deficiency leads to demyelination of basal ganglia and cortical pathways.
- Accumulation of Methylmalonic Acid (neurotoxic).
- Other Factors (Contributory):
- Magnesium deficiency.
- Zinc deficiency.
- Iron deficiency (co-existing).
- Older theories of viral encephalitis are largely discarded.
4. Clinical Features
The disease typically evolves in stages:
A. Prodromal Phase (Pre-Tremor)
- Duration: 1–2 months before tremors.
- Behavior: Apathy, lethargy, irritability.
- Cry: Characteristic “Bleating Goat Cry” (weak, hoarse, monotonous).
- Regression: Loss of previously acquired milestones (e.g., inability to sit or hold head).
- Appearance: Infant appears plump/chubby (“Flabby infant”), often mistaken as healthy by parents.
B. Tremor Phase
- Onset: Sudden or subacute, often precipitated by an acute illness (fever/diarrhea).
- Characteristics of Tremor:
- Type: Coarse, rhythmic, rapid.
- Distribution: Distal parts of limbs (“Kite-flying” or “Polishing” movements). Also involves head (titubation), tongue, and eyelids.
- State: Present at rest, aggravated by stimulation/handling, disappears during sleep.
- Neurology: Hypotonia (proximal) with hyperreflexia (distal); ankle clonus may be present.
C. Cutaneous Changes (Hallmark)
- Hyperpigmentation:
- Knuckles, dorsum of hands/feet, elbows, knees, buttocks.
- “Infantile Acropigmentation”: Peripheral darkening.
- Hair: Sparse, light-colored, brittle (Hypopigmentation/Flag sign).
- Pallor: Severe waxy pallor due to anemia.
5. Investigations
| Investigation | Findings |
|---|---|
| Complete Blood Count | Macrocytic Anemia (MCV > 100 fL). Pancytopenia (Leukopenia, Thrombocytopenia). |
| Peripheral Smear | Megaloblastic picture: Macro-ovalocytes, hypersegmented neutrophils, Cabot rings, Howell-Jolly bodies. |
| Biochemistry | Serum B12: Low (< 200 pg/mL). Serum Folate: Normal or elevated (Folate trap). Homocysteine & Methylmalonic Acid: Elevated. |
| Bone Marrow | Megaloblastic hyperplasia (Erythroid:Myeloid reversal). Giant Metamyelocytes. |
| Neuroimaging (CT/MRI) | Cerebral Atrophy: Frontoparietal widening of sulci and ventricular dilatation (ex-vacuo). Delayed myelination. Reversible with treatment. |
6. Differential Diagnosis
| Condition | Differentiating Features |
|---|---|
| Viral Encephalitis | Acute febrile onset, altered sensorium, CSF pleocytosis, no skin changes. |
| Cerebral Palsy | History of birth asphyxia, spasticity (usually), non-progressive, no pigmentation. |
| Degenerative Brain Disease | Progressive loss of milestones, no anemia/pigmentation, MRI shows specific patterns (e.g., Leukodystrophy). |
| Kwashiorkor | Edema is prominent, tremors are rare/absent, hepatomegaly with fatty liver (rare in ITS). |
7. Management
A. Specific Therapy (Vitamin B12)
- Parenteral: Inj. Vitamin B12 (Cyanocobalamin/Hydroxocobalamin).
- Regimen: 1000 mcg IM daily for 3–7 days, then weekly for 4 weeks, then monthly.
- Response:
- Tremors often transiently worsen initially during treatment before subsiding.
- Tremors usually resolve within 1–2 weeks.
- Pigmentation clears in 4–6 weeks.
- Neurodevelopment recovery takes months.
B. Symptomatic Treatment for Tremors
- First Line: Propranolol (Beta-blocker) 1–2 mg/kg/day in divided doses.
- Second Line: Carbamazepine or Phenytoin (rarely needed).
- Sedation: Chloral hydrate or Triclofos if sleep is disturbed.
C. Nutritional Rehabilitation
- Iron & Folic Acid: Supplementation required as rapid hematopoiesis depletes iron stores.
- Diet: Introduction of complementary feeds (weaning).
- Maternal Treatment: Treat mother for B12 deficiency/Pernicious anemia.
8. Prognosis
- Short-term: Excellent. Tremors and anemia resolve completely.
- Long-term:
- Cognitive: Studies suggest mild to moderate cognitive deficits (lower IQ) persist in older children compared to controls, despite physical recovery.
- Physical: Catch-up growth is usually good.