Pre-ITS and ITS

Introduction and Definition

• Infantile Tremor Syndrome (ITS) is a clinical entity characterized by a triad of symptoms: pallor (anemia), developmental regression, and involuntary movements (tremors) in infants and young children.
• The condition is now primarily attributed to Vitamin B12 (cobalamin) deficiency, particularly in exclusively breastfed infants of mothers who are vegetarians or have undiagnosed B12 deficiency.
• Historically, the term has been used to describe a specific nutritional deficiency syndrome that typically evolves through stages, often referred to as "Pre-ITS" (the prodromal phase) and florid "ITS" (the tremor phase).
• While earlier literature associated it with protein-energy malnutrition, recent evidence and guidelines strongly link the syndrome to cobalamin deficiency, with or without associated iron or magnesium deficiencies.

Etiopathogenesis

Vitamin B12 Deficiency

• Maternal Status: The Vitamin B12 content in breast milk is directly determined by the maternal intake and status. Exclusively breastfed infants of strict vegan or vegetarian mothers are at the highest risk.
• Depletion Timeline: Infants born to B12-deficient mothers have low body stores at birth. If weaning is delayed and breastfeeding continues without supplementation, these stores are depleted, leading to clinical deficiency usually appearing between 6 and 18 months of age.
• Neurological Impact: Vitamin B12 is essential for the maintenance of myelin. Deficiency leads to progressive demyelination of nerve fibers, particularly in the posterior and lateral columns of the spinal cord and peripheral nerves.
• Brain Development: The deficiency disrupts normal brain development, leading to cerebral atrophy, which can be visualized on neuroimaging, and manifests clinically as developmental regression and cognitive decline.

Other Nutritional Factors

• Iron Deficiency: Often coexists with B12 deficiency, contributing to the severe anemia observed in these children. However, iron deficiency alone does not typically cause the characteristic tremors.
• Magnesium and Zinc: Some earlier hypotheses suggested a role for magnesium or zinc deficiency, although B12 is now established as the primary etiological factor.

Clinical Spectrum: Pre-Infantile Tremor Syndrome (Pre-ITS)

The "Pre-ITS" phase represents the prodromal stage where the infant exhibits signs of nutritional deficiency and neurological involvement before the onset of characteristic tremors. Early recognition during this phase can prevent progression to the full-blown syndrome.

Hematological Features

• Anemia (Pallor): This is a hallmark finding. The infant often appears "plump and pale." The anemia is typically megaloblastic but can be dimorphic if iron deficiency is also present.
• Peripheral Smear: Shows macrocytes (MCV >100 fL) and hypersegmented neutrophils (neutrophils with ≥5 lobes).

Cutaneous Manifestations

• Skin Pigmentation: A distinctive feature is hyperpigmentation of the knuckles, dorsal aspect of the fingers, and toes. This may also affect the nail beds.
• Hair Changes: The hair may be sparse, discolored (brownish or light), and brittle, resembling the "flag sign" seen in kwashiorkor.

Neurobehavioral Changes

• Apathy and Irritability: The infant becomes listless, apathetic, and loses interest in surroundings. There is often a "staring look" or lack of social smile.
• Developmental Regression: Before tremors appear, there is often a history of stagnation or regression of previously acquired milestones. For example, an infant who could sit may lose this ability.
• Hypotonia: Generalized muscle hypotonia is common, often described as a "floppy" infant.

Clinical Spectrum: Infantile Tremor Syndrome (ITS)

The progression to the "ITS" phase is marked by the onset of involuntary movements superimposed on the background of anemia and regression.

The Characteristic Tremor

• Nature: The tremors are coarse, rhythmic, and involuntary.
• Distribution: They typically involve the extremities (hands and feet), head, and face.
• Timing: Tremors may be intermittent initially but can become continuous. They are often precipitated or worsened by stimulus, stress, or during febrile illnesses.
• Classification: In the context of B12 deficiency, these are considered movement disorders, though they may sometimes be mistaken for seizures.

Associated Neurological Signs

• Cognitive Decline: Continued decline in cognitive function and alertness.
• Regression: Marked loss of motor milestones; the child may become bedridden or unable to hold the head up.
• Seizures: Generalized tonic-clonic seizures or other seizure types may occur in conjunction with tremors or independently.

Physical Findings

• General: The infant usually appears well-nourished (plump) but has waxy pallor.
• Hepatosplenomegaly: Mild enlargement of the liver and spleen may be observed, which can sometimes lead to a misdiagnosis of leukemia or hemolytic anemia.
• Bleeding Diathesis: In severe cases, thrombocytopenia may lead to petechiae or bruising.

Diagnosis

Hematological Investigations

• Complete Blood Count (CBC):
  • Macrocytic Anemia: Elevated Mean Corpuscular Volume (MCV) is characteristic.
  • Pancytopenia: Severe deficiency can lead to leukopenia and thrombocytopenia.
• Peripheral Smear:
  • Macrocytes: Large oval red blood cells.
  • Hypersegmented Neutrophils: Presence of neutrophils with 6 or more lobes, or >5% of neutrophils with 5 lobes.

Biochemical Investigations

• Serum Vitamin B12: Levels are typically low.
• Metabolic Markers: Elevated serum homocysteine and methylmalonic acid (MMA) are sensitive indicators of functional B12 deficiency.
• Maternal Status: Testing the mother often reveals B12 deficiency and anemia, confirming the nutritional etiology.

Neuroimaging

• CT/MRI Brain: May show cerebral atrophy (shrinkage of brain tissue) and delayed myelination. These structural changes often reverse with treatment.

Management

Nutritional Rehabilitation

• Vitamin B12 Supplementation:
  • This is the cornerstone of treatment.
  • Route: Parenteral (Intramuscular - IM) therapy is preferred initially, especially for neurological cases like ITS, to ensure rapid replenishment.
  • Dosage:
    • Initial: 25–50 µg daily is recommended for young children/infants to avoid side effects like hypokalemia or worsening of tremors.
    • Maintenance: 1000 µg monthly.
  • Precaution: In patients with thrombocytopenia (low platelet count), the intravenous (IV) or oral route should be used to avoid hematomas associated with IM injections.
• Folic Acid: Should be supplemented (1–5 mg daily), but only along with or after B12 to prevent precipitating neurological damage.
• Iron: Iron supplementation is usually required once erythropoiesis (red blood cell production) accelerates and iron stores are utilized.

Symptomatic Management of Tremors

• Specific pharmacological agents may be required to control severe tremors during the recovery phase.
• First-line agents: Oral Propranolol (beta-blocker) is commonly used.
• Alternative agents:
  • Phenobarbitone
  • Phenytoin
  • Carbamazepine
  • Steroids (uncommonly used).

Dietary Management

• Breastfeeding: Should be continued, but the mother must also be treated for B12 deficiency to improve breast milk quality.
• Complementary Feeding: Introduction of B12-rich foods (animal source foods like milk, eggs, or fortified cereals) is crucial for older infants.

Monitoring and Complications

• Tremor Worsening: Tremors may paradoxically appear or transiently worsen shortly after initiating B12 therapy before eventually resolving. This is a known phenomenon.
• Hypokalemia: Rapid production of red blood cells after B12 administration can cause a sudden drop in serum potassium levels. Potassium monitoring and supplementation may be needed in the first few days of treatment.

Prognosis

• Hematological Recovery: Anemia and general well-being typically show rapid improvement within days to weeks of starting B12 therapy.
• Neurological Recovery:
  • Tremors usually resolve with treatment, though the time course can vary.
  • Neurodevelopmental regression also improves; however, the extent of recovery depends on the duration and severity of the deficiency.
  • Sequelae: Permanent neurological deficits, including cognitive impairment or developmental delays, may persist in some children, particularly if treatment was delayed.
• Brain Atrophy: Structural changes seen on imaging (atrophy) are often reversible with timely treatment.