Intraoperative monitoring of transcranial electrical motor-evoked potentials (tceMEPs) is performed during neurosurgical and orthopedic spine procedures to assess the functional integrity of descending motor pathways in the brain, brainstem, and spinal cord.1 The degree of tceMEP amplitude reduction is correlated with postoperative worsening of motor status in both adults and children.2 Thus, tceMEP monitoring provides a continuous functional assessment of the areas being monitored.3
The incidence of seizures after supratentorial craniotomy has been estimated as 15% to 20%, and antiepileptic drugs (AEDs) have been given perioperatively for seizure prophylaxis with varying degrees of success.4,5 Levetiracetam is an AED that reduces the incidence of seizures in patients undergoing brain tumor resection while demonstrating an extremely low rate of adverse reactions when compared with other AEDs.6,7 The anesthesia team is often asked to administer AEDs intraoperatively to achieve therapeutic blood levels.
We report a transient, reproducible decrease in tceMEP signals after IV levetiracetam during craniotomy and tumor resection in a child.
Consent to publish this report was obtained from the patient’s family.
A 12-year-old, 54-kg female with fibrillary astrocytoma of the right temporal lobe and persistent seizures presented for craniotomy and tumor resection. The patient had no other significant medical history, no previous surgeries, and her medications consisted of topiramate and clorazepate twice per day. Her family history was devoid of anesthesia-related complications.
The patient received 10 mg oral midazolam before the procedure for anxiolysis. Anesthetic induction, tracheal intubation, and radial arterial catheter insertion proceeded smoothly. A total IV anesthesia technique using propofol (125–200 mcg/kg/min) and remifentanil (0.05–0.15 mcg/kg/min) infusions was administered to facilitate intraoperative neurophysiological monitoring (NPM).
NPM was performed using the NIM-Eclipse Neurological Monitoring Work Station (Axon Systems, Hauppauge, NY) with the following settings: voltage = 300 V, stimulus pulse duration = 50 microseconds, pulses = 5 pulses, interstimulus interval = 1 millisecond. Baseline tceMEPs were measured and found to be normal at the start of the procedure (Fig. 1).
During surgical exposure, and at the surgeon’s request, a levetiracetam infusion was started (10 mg/kg over 30 minutes) for seizure prophylaxis via a peripheral IV catheter. Ten minutes after initiating the infusion (Fig. 1, “Start”), an abrupt, global decrease in tceMEP amplitude was observed, despite near-baseline vital signs, no other recent medication boluses, and minimal intracranial dissection (i.e., surgical trauma) at that point. The levetiracetam infusion was stopped, and 3 minutes later, the tceMEP amplitude returned to baseline (Fig. 1, “Pause”).
TceMEPs remained stable throughout the remainder of surgery and during skin closure. After completion of surgery, the same levetiracetam infusion was resumed (Fig. 1, “Resume”). Despite near-baseline vital signs and stable anesthetic infusion rates, we observed a similar global decrease in tceMEP amplitude that resolved several minutes after cessation of the levetiracetam infusion (Fig. 1, “Stop”). The levetiracetam infusion remained off for the duration of the perioperative period.
The patient’s trachea was extubated smoothly, and she followed commands appropriately during her postextubation neurological examination. She was transported safely to the intensive care unit, where she experienced a full and uneventful recovery.
Intraoperative tceMEP monitoring is used to reduce the risk of unintended injury to descending motor tracts during neurosurgical procedures. A decrease in tceMEP signals warrants investigation of potential causes, including hypotension, hypocapnia, hypothermia, hypoxemia, and direct surgical injury.8 Many anesthetic drugs (e.g., muscle relaxants, volatile drugs, dexmedetomidine) attenuate tceMEP signals, whereas the effect of ketamine on tceMEPs has been shown to vary from no effect to an increase in tceMEP amplitude.9,10 AEDs work by modifying excitatory and inhibitory neurotransmission (via voltage-gated ion channels and γ-aminobutyric acid [GABA] receptors, respectively) in the cerebral cortex, but the effects of AEDs on intraoperative NPM modalities are not well described in the literature.11
Levetiracetam is a safe, well-tolerated AED with a novel mechanism of action; in animals, levetiracetam binds to synaptic vesicle protein SV2A, which is related to modulation of synaptic vesicle exocytosis and presynaptic neurotransmitter release.12
Transcranial magnetic stimulation (TMS) is a noninvasive method for evaluating excitatory and inhibitory functions of the cerebral cortex and is used to investigate the mechanisms and effects of AEDs, including levetiracetam.13 TMS studies of oral levetiracetam in healthy volunteers show that levetiracetam modulates aspects of cortical excitability, with activity at ion channels as well as GABA receptors that is associated with tceMEP amplitude reduction.14,15
One pharmacokinetic TMS study reported a time lag of several hours between peak levetiracetam concentrations and TMS measures of neuronal effects, which contradicts a causative association between levetiracetam and the decreased tceMEPs seen in our case.16 However, that study involved oral rather than IV levetiracetam; the peak levetiracetam concentration after the bolus dosing was likely higher in our patient, and our patient may have been more vulnerable to tceMEP changes than the healthy study volunteers.
An alternative explanation for our findings is a drug-swap error in the syringe prepared by the hospital pharmacy, resulting in the administration of a short-acting neuromuscular blocking drug (e.g., succinylcholine) in lieu of levetiracetam.17 Although a drug error might explain the decreased tceMEPs, no fasciculations were noted during either episode of drug infusion, and the hospital did not experience widespread unexplained phenomena in patients receiving IV levetiracetam. Unfortunately, the contents of the syringe were not sent for testing and identification after the observed incident.
Our case illustrates an association of IV levetiracetam with a profound, transient, reproducible decrease in tceMEPs. Our patient’s rapid recovery of tceMEPs suggests that intraoperative administration of levetiracetam is reasonable if remote from critical NPM periods. The mechanism causing this tceMEP suppression is unclear, yet it may have been related to modulation of synaptic vesicle protein SV2A and cortical ion-channel as well as GABA receptor function. Future studies should explore the pharmacokinetic-pharmacodynamic profile of IV levetiracetam in the setting of NPM to delineate a safe dosing regimen. Anesthesiologists asked to administer levetiracetam during intraoperative NPM should be cognizant of potential tceMEP attenuation and discuss this possibility with their surgical and neuromonitoring colleagues.
1. Sala F, Krzan MJ, Deletis V. Intraoperative neurophysiological monitoring in pediatric neurosurgery: why, when, how? Childs Nerv Syst. 2002;18:264–87
2. Fulkerson DH, Satyan KB, Wilder LM, Riviello JJ, Stayer SA, Whitehead WE, Curry DJ, Dauser RC, Luerssen TG, Jea A. Intraoperative monitoring of motor evoked potentials in very young children. J Neurosurg Pediatr. 2011;7:331–7
3. Jameson LC, Sloan TB. Neurophysiologic monitoring in neurosurgery. Anesthesiol Clin. 2012;30:311–31
4. Pulman J, Greenhalgh J, Marson AG. Antiepileptic drugs as prophylaxis for post-craniotomy seizures. Cochrane Database Syst Rev. 2013;2:CD007286
5. Wu AS, Trinh VT, Suki D, Graham S, Forman A, Weinberg JS, McCutcheon IE, Prabhu SS, Heimberger AB, Sawaya R, Wang X, Qiao W, Hess KR, Lang FF. A prospective randomized trial of perioperative seizure prophylaxis in patients with intraparenchymal brain tumors. J Neurosurg. 2013;118:873–83
6. Milligan TA, Hurwitz S, Bromfield EB. Efficacy and tolerability of levetiracetam versus phenytoin after supratentorial neurosurgery. Neurology. 2008;71:665–9
7. Fuller KL, Wang YY, Cook MJ, Murphy MA, D’Souza WJ. Tolerability, safety, and side effects of levetiracetam versus phenytoin in intravenous and total prophylactic regimen among craniotomy patients: a prospective randomized study. Epilepsia. 2013;54:45–57
8. Ambardekar AP, Sestokas AK, Schwartz DM, Flynn JM, Rehman M. Concomitant hypertension, bradycardia, and loss of transcranial electric motor evoked potentials during pedicle hook removal: report of a case. J Clin Monit Comput. 2010;24:437–40
9. Wang AC, Than KD, Etame AB, La Marca F, Park P. Impact of anesthesia on transcranial electric motor evoked potential monitoring during spine surgery: a review of the literature. Neurosurg Focus. 2009;27:E7
10. Erb TO, Ryhult SE, Duitmann E, Hasler C, Luetschg J, Frei FJ. Improvement of motor-evoked potentials by ketamine and spatial facilitation during spinal surgery in a young child. Anesth Analg. 2005;100:1634–6
11. White HS, Smith MD, Wilcox KS. Mechanisms of action of antiepileptic drugs. Int Rev Neurobiol. 2007;81:85–110
12. Wright C, Downing J, Mungall D, Khan O, Williams A, Fonkem E, Garrett D, Aceves J, Kirmani B. Clinical pharmacology and pharmacokinetics of levetiracetam. Front Neurol. 2013;4:192
13. Tassinari CA, Cincotta M, Zaccara G, Michelucci R. Transcranial magnetic stimulation and epilepsy. Clin Neurophysiol. 2003;114:777–98
14. Solinas C, Lee YC, Reutens DC. Effect of levetiracetam on cortical excitability: a transcranial magnetic stimulation study. Eur J Neurol. 2008;15:501–5
15. Reis J, Wentrup A, Hamer HM, Mueller HH, Knake S, Tergau F, Oertel WH, Rosenow F. Levetiracetam influences human motor cortex excitability mainly by modulation of ion channel function–a TMS study. Epilepsy Res. 2004;62:41–51
16. Epstein CM, Girard-Siqueira L, Ehrenberg JA. Prolonged neurophysiologic effects of levetiracetam after oral administration in humans. Epilepsia. 2008;49:1169–73
17. Sofianou A, Chatzieleftheriou A, Mavrommati P, Velmachou K. Accidental epidural administration of succinylcholine. Anesth Analg. 2006;102:1139–40