From the Guidelines
Theophylline toxicity is known to prolong seizure duration, indicating a clear association between theophylline toxicity and seizures. Seizures are a serious manifestation of theophylline toxicity, and the relationship between theophylline levels and seizure risk is well-documented 1. Theophylline, at both therapeutic and toxic levels, can affect seizure duration, as reported in studies such as the one by Zwillich et al. in 1975, cited in the practice parameter for the use of electroconvulsive therapy with adolescents 1. Key points to consider in the context of theophylline toxicity and seizures include:
- Theophylline's mechanism of action, which involves antagonizing adenosine receptors and inhibiting phosphodiesterase enzymes, can lead to increased excitatory neurotransmitter release and a lowered seizure threshold.
- The therapeutic window of theophylline is narrow, making toxicity a significant concern, especially in vulnerable populations such as the elderly or those with concomitant illnesses.
- Management of theophylline toxicity-induced seizures includes discontinuation of theophylline, supportive care, and the use of benzodiazepines for seizure control, with consideration of more invasive procedures like charcoal hemoperfusion or hemodialysis in severe cases. Given the potential for theophylline to prolong seizure duration, as noted in the context of electroconvulsive therapy 1, it is crucial to monitor patients closely for signs of toxicity and to manage seizures promptly to prevent adverse outcomes.
From the FDA Drug Label
Seizures associated with serum theophylline concentrations >30 mcg/mL are often resistant to anticonvulsant therapy and may result in irreversible brain injury if not rapidly controlled In patients with hypoxia secondary to COPD, multifocal atrial tachycardia and flutter have been reported at serum theophylline concentrations 15 mcg/mL There have been a few isolated reports of seizures at serum theophylline concentrations <20 mcg/mL in patients with an underlying neurological disease or in elderly patients The occurrence of seizures in elderly patients with serum theophylline concentrations <20 mcg/mL may be secondary to decreased protein binding resulting in a larger proportion of the total serum theophylline concentration in the pharmacologically active unbound form The clinical characteristics of the seizures reported in patients with serum theophylline concentrations <20 mcg/mL have generally been milder than seizures associated with excessive serum theophylline concentrations resulting from an overdose After a chronic overdosage, generalized seizures, life-threatening cardiac arrhythmias, and death may occur at serum theophylline concentrations >30 mcg/mL Pre-existing or concurrent disease may also significantly increase the susceptibility of a patient to a particular toxic manifestation, e.g., patients with neurologic disorders have an increased risk of seizures and patients with cardiac disease have an increased risk of cardiac arrhythmias for a given serum theophylline concentration compared to patients without the underlying disease. Treatment of seizures Because of the high morbidity and mortality associated with theophylline-induced seizures, treatment should be rapid and aggressive.
Theophylline toxicity can cause seizures, especially at serum concentrations >30 mcg/mL, and in patients with underlying neurological disease or elderly patients, even at lower concentrations 2, 2.
- Seizures are more likely to occur after a chronic overdosage than after an acute overdose, unless the peak serum theophylline concentration is >100 mcg/mL.
- Risk factors for seizures include pre-existing neurologic disorders, elderly patients, and serum theophylline concentrations >30 mcg/mL.
- Treatment of theophylline-induced seizures should be rapid and aggressive, with anticonvulsant therapy initiated with an intravenous benzodiazepine.
From the Research
Theophylline Toxicity and Seizures
- Theophylline toxicity can cause seizures, as reported in several studies 3, 4, 5, 6.
- A study published in 1987 found that seizures were a major complication of theophylline toxicity, and that patients with high serum theophylline levels were at risk of developing seizures 3.
- Another study published in 1990 found that seizures occurred in patients with elevated theophylline levels, particularly in those with a history of seizures or arrhythmias 4.
- A study published in 1975 found that serum theophylline concentrations were higher in patients who developed seizures compared to those with less severe symptoms or no symptoms at all 5.
- A study published in 1991 found that seizures can occur even at "therapeutic" or low toxic serum concentrations, and that certain risk factors such as age, previous brain injury or disease, and severe pulmonary disease can increase the risk of serious outcome in theophylline-associated seizures 6.
Risk Factors for Theophylline-Associated Seizures
- Previous brain injury or disease 6
- Severe pulmonary disease 6
- Age 6
- Low serum albumin level 6
- History of seizures or arrhythmias 4
- High serum theophylline levels 3, 5