What is the relationship between hyperammonemia and seizures?

From the Guidelines

Hyperammonemia is a significant risk factor for seizures, and prompt treatment of hyperammonemia is crucial to prevent seizures and other neurological complications. The relationship between hyperammonemia and seizures is well-established, with hyperammonemia leading to increased levels of extracellular potassium and glutamine, causing neuronal damage and cerebral edema 1. Seizures are a common clinical manifestation of hyperammonemia, particularly in pediatric patients with urea cycle disorders or organic acidemias 1.

Clinical Manifestations

The clinical features of an acute hyperammonaemic episode depend on the age of the patient and the underlying cause of hyperammonaemia. In neonates, early symptoms include lethargy, loss of appetite, and vomiting, which can progress to hypotonia, hyperventilation, and seizures if left untreated 1. In older children and adults, hyperammonemia can present with failure to thrive, irritability, seizures, vomiting, ataxia, and intellectual disabilities 1.

Treatment

The management of hyperammonemia is challenging, and treatment should be individualized based on the patient's age, diagnosis, and clinical status. Medical management of hyperammonemia includes stopping protein intake, administering intravenous glucose, lipids, and calories, as well as using ammonia-scavenging agents such as sodium benzoate, sodium phenylacetate, and L-arginine hydrochloride 1. In patients with severe encephalopathy or seizures, dialysis should be considered, with intermittent hemodialysis and continuous kidney replacement therapy being more efficacious than peritoneal dialysis 1.

Key Points

• Hyperammonemia is a significant risk factor for seizures
• Prompt treatment of hyperammonemia is crucial to prevent seizures and other neurological complications
• Medical management of hyperammonemia includes stopping protein intake, administering intravenous glucose, lipids, and calories, as well as using ammonia-scavenging agents
• Dialysis should be considered in patients with severe encephalopathy or seizures, with intermittent hemodialysis and continuous kidney replacement therapy being more efficacious than peritoneal dialysis 1

From the FDA Drug Label

Controlled studies have shown that lactulose solution therapy reduces the blood ammonia levels by 25 to 50%; this is generally paralleled by the improvement in the patients’ mental state and by an improvement in EEG patterns.

The relationship between hyperammonemia and seizures is not directly addressed in the provided text. However, it can be inferred that reducing blood ammonia levels (a potential cause of hyperammonemia) is associated with an improvement in EEG patterns, which may suggest a reduction in seizure activity.

• Key points:
  • Lactulose therapy reduces blood ammonia levels
  • Reduction in blood ammonia levels is associated with improvement in EEG patterns However, this does not directly answer the question about the relationship between hyperammonemia and seizures. 2

From the Research

Relationship Between Hyperammonemia and Seizures

• Hyperammonemia is associated with an increased risk of seizures, as elevated ammonia levels can lead to cerebral edema, encephalopathy, and seizures 3.
• Seizures can also cause hyperammonemia, as excessive muscle contraction during seizures can lead to increased ammonia production 4, 5.
• The relationship between hyperammonemia and seizures is complex, and multiple factors can contribute to the development of hyperammonemia in patients with seizures, including:
  • Elevated venous lactate and lowered venous pH 4
  • Longer duration of convulsion 4
  • Male sex 4
  • Acidosis and ammonia production in red blood cells 5
• Certain medications, such as valproic acid, can also cause hyperammonemia and increase the risk of seizures 6.
• Hyperammonemia can be a serious and potentially life-threatening condition, and prompt treatment is necessary to reduce ammonia levels and prevent further complications 3, 7.

Factors Associated with Hyperammonemia in Seizures

• Elevated ammonia levels have been observed in patients with unprovoked convulsive seizures, with approximately 48% of patients having elevated plasma ammonia levels 4.
• The highest initial ammonia level reported in a patient with seizures was 549 µmol/L, highlighting the potential for severe hyperammonemia in these patients 7.
• Serial ammonia levels can be useful in monitoring patients with seizures and hyperammonemia, and treatment of hyperammonemia can significantly alter outcomes 7.