To the Editor,

We read with interest the recent article by Manji et al. showing the association of tranexamic acid (TXA) with postoperative seizures following cardiac surgery.1 These data raise important questions about the potential adverse effects of TXA on the central nervous system. The relationship between TXA and seizure activity in populations other than cardiac surgery is undefined. We present a case of postoperative seizure of unclear etiology in a neurosurgical patient who received TXA intraoperatively. The patient provided written consent for publication of this report.

A 71-yr-old 122-kg patient with a medical history significant for a congenital solitary kidney (creatinine 133 μmol·L−1) presented to our hospital for an elective right frontotemporal craniotomy and superior orbital osteotomy for resection of a sphenoid wing meningioma. The patient had no history of seizures or raised intracranial pressure preoperatively. Given the risk of significant intraoperative bleeding, he was given 1 g (8 mg·kg−1 iv) of TXA intraoperatively as a loading dose followed by an infusion of 0.5 g·hr−1 (4 mg·kg−1·hr−1) for the remainder of the case. The estimated blood loss was 1,000 mL. Successful tracheal extubation was performed in the operating room after nine hours of uneventful surgery. Five minutes after arrival in the postanesthesia recovery room, the patient’s SpO2 was observed to be 92%. He then sustained a brief loss of consciousness and a grand mal seizure that progressed to asystolic arrest and five minutes of cardiopulmonary resuscitation, re-intubation, and the administration of epinephrine, sodium bicarbonate, calcium, atropine, and vasopressin before return of spontaneous circulation. Laboratory investigations were significant for lactic acidosis and elevated creatinine (196 μmol·L−1). He was transferred to the intensive care unit for further management, including antiepileptic treatment with propofol and phenytoin. Computed tomography of the patient’s head showed no new hemorrhages or infarctions, and electroencephalography performed the following day showed no seizure activity. The patient was successfully weaned from his propofol infusion on the third postoperative day. His postoperative course was complicated by aspiration, prolonged respiratory failure, and deep vein thrombosis. He was transitioned to levetiracetam for the remainder of his hospitalization given the favourable safety and toxicity profile seen with this antiepileptic agent. He was discharged home in satisfactory condition 54 days following surgery.

High-dose TXA has recently been associated with an increased incidence of postoperative seizures following cardiac surgery.1 Potential mechanisms include direct inhibition of glycine and gamma-aminobutyric acid A (GABAa) receptors as well as direct central nervous system toxicity.2,3 A recent study showed that TXA inhibits glycine receptors to a greater extent than GABAa receptors and that this effect is attenuated by isoflurane and propofol in vitro.2 Although these data suggest that propofol and isoflurane may prevent or treat TXA-associated seizures, the optimal management of antiepileptic drugs for TXA-associated seizures in the clinical setting is unclear.

Similar to our case, the vast majority of seizure activity associated with TXA is reported as generalized and tonic-clonic in nature. Furthermore, patients have been reported to experience generalized tonic-clonic seizures after inadvertent intrathecal injection of TXA,2 and the seizures described by Manji et al. were grand mal seizures within the first 24 hr following surgery.1 In addition, these seizures occurred more frequently in elderly patients with renal dysfunction, as with our patient. The total dose of TXA given to our patient (5.5 g) was comparable with the high-dose regimen described by Manji et al. (5.1-5.8 g), and our patient’s renal impairment and prolonged infusion time may have resulted in an excessive serum concentration of TXA.

A recent systematic review of seizures in meningioma resection showed that only 1.4% of patients developed new onset early seizures in the postoperative period; however, these were associated with increased mortality.5 In contrast, the long-term prognosis of TXA-associated seizures may be more favourable. In the series by Manji et al., patients with postoperative seizures generally had a higher rate of neurological complications; nevertheless, none of the three patients who had TXA as the only risk factor had any further complications or morbidity.1 In another recent review, all cardiac surgery patients who experienced seizures associated with high-dose TXA recovered without any permanent neurological sequelae.4

While the etiology of the seizure observed in this patient was almost certainly multifactorial, we cannot exclude the possibility that TXA may have contributed to this outcome. As the use of TXA becomes more widespread, further research is needed to characterize the relationship between TXA and postoperative seizures in high-risk populations such as neurosurgical patients.