Ammonia, a byproduct of protein metabolism, can cause seizures when its concentration in the bloodstream rises to toxic levels, a condition known as hyperammonemia. Normally, the liver efficiently processes this nitrogenous compound into urea, which is then excreted by the kidneys. However, when the body’s detoxification system fails, the excess ammonia crosses the blood-brain barrier, becoming a potent neurotoxin that severely impairs brain function.
How Ammonia Disrupts Brain Activity
The brain relies on a delicate balance of chemical signals to function, a balance that ammonia profoundly disrupts. Ammonia is primarily detoxified in the brain by specialized support cells called astrocytes. These cells use the enzyme glutamine synthetase to combine ammonia with the excitatory neurotransmitter glutamate, converting it into glutamine.
This process is intended to protect neurons, but when ammonia levels are excessively high, the large amounts of glutamine produced accumulate inside the astrocytes. Because glutamine is an osmotically active molecule, its buildup draws water into the cells, causing them to swell. This swelling contributes to cerebral edema, which increases pressure within the skull.
The conversion of glutamate into glutamine depletes the brain’s supply of glutamate, which is necessary for normal neuronal communication. Paradoxically, high levels of ammonia also impair the astrocytes’ ability to reabsorb glutamate from the space between neurons, leading to an excess of glutamate outside the cells. This overstimulation of neuronal receptors by extracellular glutamate results in neuronal hyperexcitability, which is the underlying cause of seizure activity.
Metabolic Conditions Leading to Toxic Levels
The most frequent cause in adults is acquired hyperammonemia, which is overwhelmingly linked to severe liver dysfunction. Conditions like cirrhosis or acute liver failure prevent the liver from carrying out the urea cycle efficiently, allowing ammonia produced in the gut to bypass the liver and enter the systemic circulation.
The other major category is genetic hyperammonemia, which is much rarer but often more severe, especially in newborns. These conditions involve inherited defects in the enzymes required for the urea cycle, such as Ornithine Transcarbamylase (OTC) deficiency.
These inborn errors of metabolism mean the body cannot process ammonia correctly from birth, leading to life-threatening ammonia spikes when protein intake or catabolic stress increases. Other metabolic conditions, like certain organic acidemias, can also lead to hyperammonemia through secondary mechanisms that interfere with the urea cycle.
Clinical Signs of Ammonia Overload
The clinical presentation of ammonia toxicity follows a progression of neurological symptoms. Initial signs of ammonia overload are subtle and can include personality changes, mild confusion, and lethargy. As the levels continue to rise, the patient may exhibit more distinct signs such as slurred speech, a characteristic flapping hand tremor known as asterixis, and disorientation.
Seizures represent a manifestation of severe, late-stage neurotoxicity, often occurring when plasma ammonia levels exceed 200 µmol/L. Before seizures, patients typically progress to severe confusion and stupor. The most dangerous stage of ammonia overload is the hyperammonemic coma, which is accompanied by severe cerebral edema and carries a high risk of brain damage or death.
Medical Management of Hyperammonemia
Acute management focuses on stopping the source of ammonia and accelerating its removal. This involves immediately halting all protein intake and providing high-calorie glucose solutions to prevent the body from breaking down its own muscle protein, which generates more ammonia.
Medications known as ammonia scavengers, such as intravenous sodium benzoate and sodium phenylacetate, are administered to bind with nitrogen compounds, creating alternative, excretable waste products. In the most severe cases, particularly for comatose patients or newborns, hemodialysis may be necessary for the fastest and most efficient removal of circulating ammonia from the blood.
Long-term management involves the use of medications to reduce ammonia production in the gut. Lactulose, a non-absorbable sugar, works by trapping ammonia in the colon and promoting its excretion. The antibiotic Rifaximin is often used alongside lactulose to reduce the number of ammonia-producing bacteria in the intestinal tract. Dietary protein restriction is also a cornerstone of chronic management, though it must be carefully balanced to prevent malnutrition.