Clinical Features and MRI Brain Changes in Hyperammonemia
Clinical Features
Early Neurological Manifestations
The earliest clinical signs of hyperammonemia are lethargy, poor feeding, and vomiting, which typically appear within the first few days after feeding begins in neonates, followed by hypotonia and hyperventilation with respiratory alkalosis as ammonia levels rise. 1
Age-Dependent Presentation Patterns
Neonatal-Onset (First Days of Life):
- Lethargy and poor feeding are the initial symptoms 1
- Vomiting precedes neurological deterioration 1
- Hypotonia develops as ammonia continues to accumulate 1
- Hyperventilation with respiratory alkalosis is a critical early clue that distinguishes hyperammonemia from other causes of encephalopathy 1
- Hypothermia and anorexia may be present 2
- Abnormal respiratory patterns (hyperventilation or hypoventilation) 2
- Neurologic posturing occurs in severe cases 2
- Progression to ataxia, disorientation, seizures, coma, and death if unrecognized 1
Late-Onset (Childhood, Adolescence, Adulthood):
- Failure to thrive and irritability are earliest manifestations 1
- Episodic vomiting triggered by metabolic stressors (illness, increased protein intake) 1
- Low protein tolerance and migraine-like headaches may be subtle early indicators 1
- Confusion, lethargy, and dizziness represent early neurological symptoms 1, 3
- Psychiatric manifestations including learning disabilities, delusion, and psychosis before overt neurological deterioration 1
- Developmental delay and behavioral changes 4
Advanced Neurological Symptoms
Do not wait for these advanced manifestations to measure ammonia—they represent late-stage disease, not early signs: 1
- Tremors 3
- Dysarthria (speech difficulty, expressive aphasia) 3
- Ataxia (impaired coordination) 3
- Seizures 3, 2
- Hemiplegia 3
- Coma in severe cases 3, 2
Critical Diagnostic Thresholds
Ammonia Level Definitions:
- Normal blood ammonia: ≤35 μmol/L (≤60 μg/dL) 1, 3
- Hyperammonemia in neonates: >100 μmol/L (170 μg/dL) 1, 3
- Hyperammonemia in term infants, children, and adults: ≥50 μmol/L (85 μg/dL) 1, 3
- Levels >200 μmol/L (341 μg/dL) are associated with poor neurological outcomes 1, 3
- Levels ≥600 μg/dL (360 μmol/L) cause significant brain damage and indicate hemodialysis 2
Adverse Prognostic Factors:
- Hyperammonemic coma lasting >3 days 5
- Increased intracranial pressure 5
- Plasma ammonia level >1,000 μmol/l (1,703 μg/dl) 5
- Duration of coma inversely correlates with IQ at 12 months after recovery 5
MRI Brain Changes
Pathophysiological Basis for Brain Damage
Ammonia crosses the blood-brain barrier and is metabolized to glutamine by astrocytes, causing increased intracellular osmolality, cerebral edema, and release of inflammatory cytokines. 3
- High levels of extracellular potassium and glutamate released by astrocytes cause neuronal damage 3
- Elevated glutamine levels contribute to both hepatic encephalopathy and ammonia-related neurotoxicity 3
- Cytotoxic oxidative/nitrosative damage occurs 6
- Disturbances in neurotransmitters, energy production, anaplerosis, cerebral blood flow, potassium, and sodium contribute to multifactorial neurotoxicity 6
Structural Brain Changes
Survivors of severe neonatal hyperammonemia have structural brain damage. 6
- Cerebral edema is the primary acute finding 5, 3
- Severity of abnormalities on brain CT correlates with duration of coma 5
- Irreversible brain damage occurs with prolonged hyperammonemia 5
Critical Clinical Pitfall
Two factors determine the prognosis of neurological damage: the duration of hyperammonemic coma and plasma ammonia levels. 5 Early management and reduced duration of hyperammonemic coma prevent adverse neurological outcomes 5. The most important prognostic factor is the duration of hyperammonemic coma prior to the start of dialysis, not the rate of ammonia clearance 5.