Can hyperammonemia cause tremors and expressive aphasia?

Hyperammonemia Can Cause Tremors and Expressive Aphasia

Yes, high ammonia levels (hyperammonemia) can cause both tremors and expressive aphasia as part of its neurological manifestations. 1

Pathophysiology of Hyperammonemia and Neurological Effects

Hyperammonemia causes neurological symptoms through several mechanisms:

• Ammonia crosses the blood-brain barrier and is metabolized to glutamine by astrocytes, leading to increased intracellular osmolality, cerebral edema, and release of inflammatory cytokines 1
• High levels of extracellular potassium and glutamate released by astrocytes cause neuronal damage 1
• Elevated glutamine levels contribute to both hepatic encephalopathy and ammonia-related neurotoxicity 1
• Ammonia accumulation in the brain during severe hyperammonemia is highly toxic and can cause various neurological dysfunctions 2

Neurological Manifestations of Hyperammonemia

Hyperammonemia can present with a spectrum of neurological symptoms:

• Tremors are specifically listed as a neurological manifestation of hyperammonemia 1
• Dysarthria (speech difficulty) is documented as a symptom, which can manifest as expressive aphasia 1
• Other neurological symptoms include:
  • Confusion, lethargy, and dizziness 1
  • Hypotonia 1
  • Migraine-like headache 1
  • Ataxia (impaired coordination) 1
  • Learning disabilities 1
  • Neurodevelopmental delay 1
  • Seizures 1
  • Hemiplegia 1
  • Coma in severe cases 1

Severity and Clinical Implications

The severity of neurological symptoms correlates with ammonia levels:

• Normal blood ammonia concentrations are ≤35 μmol/L (<60 μg/dL) 1
• Hyperammonemia is defined as >100 μmol/L (170 μg/dL) in neonates or ≥50 μmol/L (85 μg/dL) in term infants, children, and adults 1
• Levels >200 μmol/L (341 μg/dL) are associated with poor neurological outcomes 1
• Ammonia levels ≥600 μg/dL (360 μmol/L) cause significant brain damage and require immediate intervention 2

Common Causes of Hyperammonemia

Hyperammonemia may result from:

• Primary causes: Urea cycle disorders (UCDs) due to congenital enzyme deficiencies 1
• Secondary causes:
  • Organic acidemias (methylmalonic acidemia, propionic acidemia) 1
  • Drug-induced (particularly valproic acid) 1, 3
  • Liver disease or acute kidney injury 1

Clinical Approach to Suspected Hyperammonemia

When tremors and expressive aphasia are present:

• Measure serum ammonia levels promptly 1
• Investigate underlying causes, particularly in adults with new-onset symptoms 4
• Consider both congenital and acquired causes of hyperammonemia 5
• Look for other neurological manifestations that may accompany tremors and expressive aphasia 1

Treatment Considerations

Treatment should be initiated promptly to prevent irreversible neurological damage:

• Hemodialysis or hemodiafiltration is first-line treatment for acute severe hyperammonemia in adults 4
• Carnitine administration may help prevent acute ammonia toxicity and enhance ammonia elimination 6
• Specific treatment depends on the underlying cause 5
• For drug-induced hyperammonemia, prompt discussion with a metabolic physician is recommended 3

Pitfalls and Caveats

• Neurological symptoms may precede significant elevations in measured ammonia levels 1
• Individual laboratory reference intervals for ammonia may vary 1
• Delayed recognition and treatment can lead to permanent neurological damage 2
• Drug-induced hyperammonemia presents a therapeutic dilemma between ongoing treatment needs and toxicity 3