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Improvement of medically refractory temporal lobe epilepsy with dextromethorphan
J Epilepsy 1992;5:246-247
© 1992Butterworth-Heinemann
Improvement of Medically Refractory Temporal Lobe Epilepsy with Dextromethorphan H. G. Wieser and 1H. Beck
We report a 48-year-old woman with a 24-year history of medically refractory temporal lobe epilepsy with complex partial seizures who experienced considerable reduction in frequency and severity of seizures following add-on medication with the nonopioid antitussive dextromethorphan, a noncompetitive N-methylD-aspartate (NMDA) receptor antagonist. Key Words: Temporal lobe epilepsy-Dextromethorphan--Nonopioid antitussive--NMDA antagonist.
Case Report
A 48-year-old housewife had a 24-year history of medically refractory complex partial seizures and occasional tonic-clonic seizures. Her medical history was otherwise uneventful. Complex partial seizures were preceded by an aura with epigastric sensations, d6j~ vu, and optical and acoustic hallucinations. The aura was followed by a short arrest. Subsequent impairment of consciousness was accompanied by oroalimentary and manual automatisms. Seizures lasted for about 1 min and occurred with an average frequency of 2-28 times per month. Occasional convulsive tonic-clonic seizures with biting of the tongue occurred with a frequency of about six per year. Adequate control of the tonicclonic seizures could be achieved in 1979 with Tegretol. Additional medication with Mesantoin, Depakine, or Rivotril, however, was not successful in controlling the complex partial seizures. Neurological and general examination yielded no pathological results. Magnetic resonance imaging Received June 21, 1992; accepted June 24, 1992. From the Neurological Clinic, University Hospital, Ziirich, Switzerland, and the 1Institute of Neurophysiology, University of Cologne, Cologne, Germany. Address correspondence and reprint requests to Prof. H. G. Wieser at Neurologische Klinik, Abteilung fiir EEG und Epileptologie, Universit~tsspital, Frauenklinikstrasse 26, CH-8091 Ziirich, Switzerland. 246 J EPILEPSY, VOL, 5, NO. 4, 1992
(May 26, 1986) and computed tomography of the brain (August 29, 1986) showed no structural lesions. EEG recordings obtained from scalp and multipolar foramen ovale electrodes (December 10-23, 1986) revealed pronounced interictal spiking in the right mediobasal temporal lobe. An ictal event was recorded, with the seizure discharge originating in right mediobasal limbic structures and with subsequent spread to the left temporal lobe. Therefore, a right selective amygdalohippocampectomy was performed in February 1987. Most probably because of spasms of the right anterior choroidal artery during surgery, postoperatively the patient showed a transient hemiparesis of the left side, which, however, disappeared almost completely within 2 months. Postoperative scalp EEG showed no change in the right temporal interictal activity. After a seizure-free period of 40 days, complex partial seizures recurred with a frequency of 1-12 per month (8.4 on average). They were now without an aura and had a duration of up to 2 min. Combinations of Tegretol (1,200 mg/day) and Mysoline (250 mg/day) until February 1991, or oxcarbamazepine (Trileptal, 1,500 mg/day) and Urbanyl (15 mg/day) from February 1991 up to now, were ineffective in controlling seizure frequency or severity. In July 1991, the patient herself started to take an antitussive medication that contains dextromethorphan-hydrobromide (DM). She took 6-7 mg in the evening in liquid form. Subsequently, seizure fre-
DEXTROMETHORPHAN AND MEDICALLY REFRACTORY TLE
quency decreased significantly, from 8.4 to 4.4 per month on average. Duration of the seizures was reduced, according to witnesses, to less than I min, with reorientation being complete in 5 min as compared to half an hour before medication with DM. Omission of DM in the evening frequently resulted in seizure occurrence the next morning. Increasing the dose of DM to three times, 7 mg/day, resulted in a seizurefree period until now (more than 3 months). The only side effect of additional treatment with DM was moderate tiredness.
Discussion N-methyl-D-aspartate (NMDA) receptor antagonists have recently received an increasing amount of attention as antiepileptic agents and as possible therapeutic agents following ischemic damage to the brain (1,2). However, side effects have induced controversy about the clinical utility of most NMDA receptor antagonists. DM is a noncompetitive NMDA receptor antagonist as well as a ligand for a high-affinity binding site not associated with an excitatory amino acid receptor (3). DM has been shown to have anticonvulsant properties in the kindling model of epilepsy in rats (4,5), in NMDA-induced epileptiform discharges in vitro (6) and in vivo (7), and in maximal electroshock-induced seizures (8). In this case report, a patient suffering from temporal lobe epilepsy with medically refractory complex partial seizures showed considerable reduction in seizure frequency and severity following addition of DM to the habitual antiepileptic drug regimen, in low doses of 6-20 mg/ day. An increase in seizure frequency reported after adjunctive DM medication (9) might be due to interindividual variation in metabolism (10) and the higher dos6s employed (120 mg/day). Indeed, in the kindling model of epilepsy, high doses of DM can
show proconvulsive effects (5). Measurements of cerebrospinal fluid concentrations of DM are necessary to address this issue, but this report indicates that some patients with otherwise drug-resistant temporal lobe epilepsy might benefit from low-dose therapy with nonopioid antitussive DM.
References 1. Albers GW, Goldberg MP, Choi DW. N-methyl-Daspartate antagonists: ready for clinical trial in brain ischemia? Ann Neurol 1989;25:398-403. 2. Tortella FC, Musacchio JM. Dextromethorphan and carbetapentane: centrally acting non-opioid antitussive agents with novel anticonvulsant properties. Brain Res 1986;383:314-8. 3. Tortella FC, Pellicano M, Bowery NG. Dextromethorphan and neuromodulation: old drug coughs up new activities. Trends Pharmacol Sci 1989;10:501-7. 4. Feeser HR, Kadis JL, Prince DA. Dextromethorphan, a common antitussive, reduces kindled amygdala seizures in the rat. Neurosci Left 1988;86:340-5. 5. Takazawa A, Anderson P, Abraham WC. Effects of dextromethorphan, a nonopioid antitussive, on development of expression of amygdaloid kindled seizures. Epilepsia 1990;31:496-502. 6. Apland JP, Braitman DJ. Effect of non-opioid antitussives on epileptiform activity and NMDA responses in hippocampal and olfactory cortex slices. Brain Res 1990;529:277-85. 7. Ferkany JW, Borosky SA, Clissold DB, Pontecorvo MJ. Dextromethorphan inhibits NMDA-induced convulsions. Eur J Pharmacol 1988;151:151-4. 8. Leander JD. Evaluation of dextromethorphan and carbetapentane as anticonvulsants and N-methyl-Daspartatic acid antagonists in mice. Epilepsy Res 1989; 4:28-33. 9. Fisher RS, Cysyk BJ, Lesser RP, et al. Dextromethorphan for treatment of complex partial seizures. Neurology 1990;40:547-9. 10. Chen ZR, Somogyi AA, Reynolds G, Bochner F. Disposition and metabolism of codeine after single and chronic doses in one poor and seven extensive metabolisers. Br J Clin Pharmacol 1991;31:381-90.
© 1992Butterworth-Heinemann
Improvement of Medically Refractory Temporal Lobe Epilepsy with Dextromethorphan H. G. Wieser and 1H. Beck
We report a 48-year-old woman with a 24-year history of medically refractory temporal lobe epilepsy with complex partial seizures who experienced considerable reduction in frequency and severity of seizures following add-on medication with the nonopioid antitussive dextromethorphan, a noncompetitive N-methylD-aspartate (NMDA) receptor antagonist. Key Words: Temporal lobe epilepsy-Dextromethorphan--Nonopioid antitussive--NMDA antagonist.
Case Report
A 48-year-old housewife had a 24-year history of medically refractory complex partial seizures and occasional tonic-clonic seizures. Her medical history was otherwise uneventful. Complex partial seizures were preceded by an aura with epigastric sensations, d6j~ vu, and optical and acoustic hallucinations. The aura was followed by a short arrest. Subsequent impairment of consciousness was accompanied by oroalimentary and manual automatisms. Seizures lasted for about 1 min and occurred with an average frequency of 2-28 times per month. Occasional convulsive tonic-clonic seizures with biting of the tongue occurred with a frequency of about six per year. Adequate control of the tonicclonic seizures could be achieved in 1979 with Tegretol. Additional medication with Mesantoin, Depakine, or Rivotril, however, was not successful in controlling the complex partial seizures. Neurological and general examination yielded no pathological results. Magnetic resonance imaging Received June 21, 1992; accepted June 24, 1992. From the Neurological Clinic, University Hospital, Ziirich, Switzerland, and the 1Institute of Neurophysiology, University of Cologne, Cologne, Germany. Address correspondence and reprint requests to Prof. H. G. Wieser at Neurologische Klinik, Abteilung fiir EEG und Epileptologie, Universit~tsspital, Frauenklinikstrasse 26, CH-8091 Ziirich, Switzerland. 246 J EPILEPSY, VOL, 5, NO. 4, 1992
(May 26, 1986) and computed tomography of the brain (August 29, 1986) showed no structural lesions. EEG recordings obtained from scalp and multipolar foramen ovale electrodes (December 10-23, 1986) revealed pronounced interictal spiking in the right mediobasal temporal lobe. An ictal event was recorded, with the seizure discharge originating in right mediobasal limbic structures and with subsequent spread to the left temporal lobe. Therefore, a right selective amygdalohippocampectomy was performed in February 1987. Most probably because of spasms of the right anterior choroidal artery during surgery, postoperatively the patient showed a transient hemiparesis of the left side, which, however, disappeared almost completely within 2 months. Postoperative scalp EEG showed no change in the right temporal interictal activity. After a seizure-free period of 40 days, complex partial seizures recurred with a frequency of 1-12 per month (8.4 on average). They were now without an aura and had a duration of up to 2 min. Combinations of Tegretol (1,200 mg/day) and Mysoline (250 mg/day) until February 1991, or oxcarbamazepine (Trileptal, 1,500 mg/day) and Urbanyl (15 mg/day) from February 1991 up to now, were ineffective in controlling seizure frequency or severity. In July 1991, the patient herself started to take an antitussive medication that contains dextromethorphan-hydrobromide (DM). She took 6-7 mg in the evening in liquid form. Subsequently, seizure fre-
DEXTROMETHORPHAN AND MEDICALLY REFRACTORY TLE
quency decreased significantly, from 8.4 to 4.4 per month on average. Duration of the seizures was reduced, according to witnesses, to less than I min, with reorientation being complete in 5 min as compared to half an hour before medication with DM. Omission of DM in the evening frequently resulted in seizure occurrence the next morning. Increasing the dose of DM to three times, 7 mg/day, resulted in a seizurefree period until now (more than 3 months). The only side effect of additional treatment with DM was moderate tiredness.
Discussion N-methyl-D-aspartate (NMDA) receptor antagonists have recently received an increasing amount of attention as antiepileptic agents and as possible therapeutic agents following ischemic damage to the brain (1,2). However, side effects have induced controversy about the clinical utility of most NMDA receptor antagonists. DM is a noncompetitive NMDA receptor antagonist as well as a ligand for a high-affinity binding site not associated with an excitatory amino acid receptor (3). DM has been shown to have anticonvulsant properties in the kindling model of epilepsy in rats (4,5), in NMDA-induced epileptiform discharges in vitro (6) and in vivo (7), and in maximal electroshock-induced seizures (8). In this case report, a patient suffering from temporal lobe epilepsy with medically refractory complex partial seizures showed considerable reduction in seizure frequency and severity following addition of DM to the habitual antiepileptic drug regimen, in low doses of 6-20 mg/ day. An increase in seizure frequency reported after adjunctive DM medication (9) might be due to interindividual variation in metabolism (10) and the higher dos6s employed (120 mg/day). Indeed, in the kindling model of epilepsy, high doses of DM can
show proconvulsive effects (5). Measurements of cerebrospinal fluid concentrations of DM are necessary to address this issue, but this report indicates that some patients with otherwise drug-resistant temporal lobe epilepsy might benefit from low-dose therapy with nonopioid antitussive DM.
References 1. Albers GW, Goldberg MP, Choi DW. N-methyl-Daspartate antagonists: ready for clinical trial in brain ischemia? Ann Neurol 1989;25:398-403. 2. Tortella FC, Musacchio JM. Dextromethorphan and carbetapentane: centrally acting non-opioid antitussive agents with novel anticonvulsant properties. Brain Res 1986;383:314-8. 3. Tortella FC, Pellicano M, Bowery NG. Dextromethorphan and neuromodulation: old drug coughs up new activities. Trends Pharmacol Sci 1989;10:501-7. 4. Feeser HR, Kadis JL, Prince DA. Dextromethorphan, a common antitussive, reduces kindled amygdala seizures in the rat. Neurosci Left 1988;86:340-5. 5. Takazawa A, Anderson P, Abraham WC. Effects of dextromethorphan, a nonopioid antitussive, on development of expression of amygdaloid kindled seizures. Epilepsia 1990;31:496-502. 6. Apland JP, Braitman DJ. Effect of non-opioid antitussives on epileptiform activity and NMDA responses in hippocampal and olfactory cortex slices. Brain Res 1990;529:277-85. 7. Ferkany JW, Borosky SA, Clissold DB, Pontecorvo MJ. Dextromethorphan inhibits NMDA-induced convulsions. Eur J Pharmacol 1988;151:151-4. 8. Leander JD. Evaluation of dextromethorphan and carbetapentane as anticonvulsants and N-methyl-Daspartatic acid antagonists in mice. Epilepsy Res 1989; 4:28-33. 9. Fisher RS, Cysyk BJ, Lesser RP, et al. Dextromethorphan for treatment of complex partial seizures. Neurology 1990;40:547-9. 10. Chen ZR, Somogyi AA, Reynolds G, Bochner F. Disposition and metabolism of codeine after single and chronic doses in one poor and seven extensive metabolisers. Br J Clin Pharmacol 1991;31:381-90.