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Drug refractory epilepsy in brain damage: effect of dextromethorphan on EEG in four patients
Insights
High-dose dextromethorphan effectively suppressed epileptic activity in critically ill children by blocking N-methyl-D-aspartate (NMDA) receptors. However, this EEG improvement did not translate to better clinical outcomes, with most patients experiencing poor prognoses.
Area of Science:
- Neuroscience
- Clinical Pharmacology
Background:
- Critically ill children with refractory seizures often have underlying conditions linked to N-methyl-D-aspartate (NMDA) receptor overactivity.
- Standard antiepileptic drugs are frequently ineffective in these severe cases.
Observation:
- Four children with severe, drug-refractory seizures received high-dose dextromethorphan, an NMDA receptor antagonist.
- Treatment was initiated days after the acute incident causing their critical illness.
Findings:
- Three of four patients showed significant EEG improvement and seizure cessation within 72 hours.
- Dextromethorphan effectively suppressed epileptiform discharges, indicating NMDA receptor blockade at the administered doses.
- Despite EEG improvements, clinical outcomes were poor, with three deaths and one survivor experiencing severe neurological deficits.
Implications:
- High-dose dextromethorphan demonstrates potential as an adjunctive therapy for controlling refractory seizures in critically ill children.
- The disconnect between EEG suppression and clinical outcome highlights the complexity of these conditions and the need for further research.
- Further investigation is warranted to optimize NMDA receptor antagonist therapy and improve patient prognoses in severe pediatric neurological emergencies.
Abstract:
High doses of dextromethorphan (20-42 mg/kg/day) were given to four critically ill children with seizures and frequent epileptiform abnormalities in the EEG that were refractory to antiepileptic drugs. Their acute diseases (hypoxia, head trauma and hypoxia, neurodegenerative disease, hypoglycaemia) were thought to be due in part to N-methyl-D-aspartate (NMDA) receptor mediated processes. Treatment with dextromethorphan, an NMDA receptor antagonist, was started between 48 hours and 14 days after the critical incident. In three patients the EEG improved considerably within 48 hours and seizures ceased within 72 hours. In the patient with neurodegenerative disease the effect on the EEG was impressive, but the seizures were not controlled. Despite the improvement of the EEG the clinical outcome was poor in all children: three died in the critical period or due to the progressing disease; the patient with hypoglycaemia survived with severe neurological sequelae. Plasma concentrations of dextromethorphan varied between 74-1730 ng/ml and its metabolite dextrorphan varied between 349-3790 ng/ml. In one patient corresponding concentrations in CSF were lower than those in plasma. The suppression of epileptic discharges by the doses of dextromethorphan given suggests that such doses are sufficient to block NMDA receptors.