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Drug Refractory Epilepsy in Brain Damage: Effect of Dextromethorphan on EEG in Four Patients

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Drug Refractory Epilepsy in Brain Damage: Effect of Dextromethorphan on EEG in Four Patients Journal ofNeurology, Neurosurgery, and Psychiaty 1994;57:333-339 333 Drug refractory epilepsy in brain damage: effect J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.57.3.333 on 1 March 1994. Downloaded from of dextromethorphan on EEG in four patients B Schmitt, R Netzer, S Fanconi, P Baumann, E Boltshauser Abstract desipramine) may have beneficial effects in High doses of dextromethorphan (20-42 the treatment of seizures."l-"3 Recently, we mglkglday) were given to four critically have shown that dextromethorphan (35 ill children with seizures and frequent mg/kg/day in four doses) resulted in the ces- epileptiform abnormalities in the EEG sation of seizures and normalisation of the that were refractory to antiepileptic EEG in a patient with non-ketotic hyperglyci- drugs. Their acute diseases (hypoxia, naemia.'4 Withdrawal of dextromethorphan head trauma and hypoxia, neurodegen- was followed by dramatic clinical deteriora- erative disease, hypoglycaemia) were tion with epileptic and high voltage slow thought to be due in part to N-methyl-D- activity in the EEG. The symptoms disap- aspartate (NAIDA) receptor mediated peared again when the drug treatment was processes. Treatment with dex- resumed after 48 hours. tromethorphan, an NMDA receptor Dextromethorphan might therefore be a antagonist, was started between 48 hours useful antiepileptic drug for other forms of and 14 days after the critical incident. In epilepsy. Because of potential side effects at three patients the EEG improved consid- high doses, use of dextromethorphan must be erably within 48 hours and seizures restricted. In four patients on intensive care ceased within 72 hours. In the patient with a desperate clinical situation, dex- with neurodegenerative disease the effect tromethorphan was the final option for treat- on the EEG was impressive, but the ment of drug refractory epilepsy. None of the seizures were not controlled. Despite the patients showed a satisfactory clinical out- improvement of the EEG the clinical come, but in each of them dextromethorphan outcome was poor in all children: three impressively improved the EEG. It is the aim died in the critical period or due to the of this paper to discuss (1) the effects of dex- progressing disease; the patient with tromethorphan on the EEG at various doses; hypoglycaemia survived with severe neu- (2) the dextromethorphan concentration in University Children's rological sequelae. Plasma concentra- plasma and CSF, (3) the reasons for the Hospital, tions of varied Steinwiesstrasse 75, dextromethorphan unsatisfactory outcome; (4) possible side CH-8032 Zurich, between 74-1730 ng/ml and its metabolite effects; and (5) potential improvements for Switzerland dextrorphan varied between 349-3790 future management. Department of nglml. In one patient corresponding con- Our results are of a preliminary character. http://jnnp.bmj.com/ Clinical centrations in CSF were lower than those In all patients the decision to initiate treat- Neurophysiology B Schmitt in plasma. The suppression of epileptic ment with dextromethorphan was made by the doses of consensus at Department of discharges by dextromethor- of least two involved physicians Intensive Care phan given suggests that such doses are from different departments; parents were S Fanconi sufficient to block NMDA receptors. informed. Departnent of Paediatric Neurology (7 Neurol Neurosurg Psychiatry 1994;57:333-339) on September 30, 2021 by guest. Protected copyright. E Boltshauser Patients and methods Pharma Division, Preclinical Research, Dextromethorphan hydrobromide (Bexin) F Hoffmann-LaRoche Dextromethorphan, a morphine derivative was orally administered by tube in four doses LTD, CH-4002 Basel, without affinity for opioid receptors, has daily. Concentrations of dextromethorphan Switzerland been used as an antitussive for more than and its active main metabolite dextrorphan R Netzer 30 years. Recently, the drug was shown to were determined in blood and CSF by gas Unite de biochimie et psychopharmacologie have anticonvulsant properties in several in chromatography-mass spectrometry after clinique, D6pt univ de vitro1-3 and in vivo models of epilepsy.4A6 treatment with fl-glucuronidase and arylsul- psychiatrie adulte, Dextromethorphan is a non-competitive phatase."5 EEGs were recorded on a 16 or 21 Site de Cery, CH-1008 Prilly-Lausanne, antagonist of the N-methyl-D-aspartate channel standard machine. Electrode place- Switzerland (NMDA) receptor channel.78 The substance ment was according to the international P Baumann has also been shown to reduce voltage- 10-20 system, paper speed 30 mmn/s, low pass Correspondence to: dependent calcium and sodium currents with filter 60 or 70 Hz, time constant 03 seconds, Dr Bernhard Schmitt, Department of Clinical lower potency.8 9 and minimal recording time 30 minutes. Neurophysiology, University Because NMDA receptors play an impor- Children's Hospital, Steinwiesstrasse 75, CH- tant part in the pathophysiological mecha- CASE 1 8032 Zurich, Switzerland. nisms of various neurological disorders, Case 1 was a seven-month-old child with a Received 16 March 1993 including epilepsy,10 NMDA receptor channel tetralogy of Fallot. After total surgical correc- and in revised form 14 May 1993. blockers (for example, MK-80 1,- dex- tion, cardiac arrest occurred and resuscitation Accepted 27 May 1993 tromethorphan, ketamine, imipramine, was necessary. Forty eight hours later the 334 Schmitt, Netzer, Fanconi, Baumann, Boltshauser A Figure 1 Case 1 (A) 48 B J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.57.3.333 on 1 March 1994. Downloaded from hours after cardiac arrest, focal epileptic discharges; (B) 12 hours after introduction of c3- dextromethorphan, free of cm- epilepsy, severe slowing background activity. F2-F4 C4.P4 C4-P4 P4402 P402 FtF7 t, ,t F1-F7 F7-T3 T34 T3-T6 T5O0 F2-M FMT4 FMT4 T4-T$ T4.T TO-0 50 AV TO-M~~~~~~~50 [&V is 1 s child had focal seizures that were refractory to unaffected, although dextromethorphan was phenobarbitone and diazepam. 'Me EEG temporarily increased to 45 mg/kg/day. All showed continuous focal epileptic discharges other drugs, with the exception of clon- with varying localisations (fig 1la), which azepam, were discontinued stepwise. In view could be interrupted temporarily with clon- of unexplained pronounced muscle hyperto- azepam. Somatosensory evoked potentials nia dextromethorphan was reduced to 22 (SEPs) showed a complete loss of cortical mg/kg/day-without influence on the muscle components. Brainstem acoustic evoked tone. Seven days later complex partial potentials were preserved. After treatment seizures (fig 2c) with pronounced cyanosis with dextromethorphan (30 mg/kg/day) reoccurred and ceased again after increasing seizures stopped, the EEG, repeatedly the dose to 35 mg/kg/day. After extubation recorded, was free of epileptic discharges, and the child persisted in a vegetative state and, background activity was slow (fig lb). A CT due to pneumonia and pleural effusion, she scan two days later showed severe global again developed respiratory insufficiency. ischaemic brain damage and life support Because of the poor prognosis reintubation measures were discontinued. Post mortem was avoided and the child died. examination confirmed the extensive suba- cute anoxic encephalopathy. CASE 3 This patient had an elder brother with epilep- http://jnnp.bmj.com/ CASE 2 sia partialis continua lasting more than four A 14-year-old mentally retarded girl with years, that started unexpectedly at the age of poorly controlled epilepsy of unknown aetiol- 5*5 years. He is now in a vegetative state. ogy fell downstairs and suffered an impres- The patient, a 4-5-year-old boy, was nor- sion fracture of the left temporal skull. mal up to May 1992 when he, like his Cardiorespiratory insufficiency required artifi- brother, unexpectedly had myoclonic seizures cial ventilation. The initial EEGs (on days 2 in the face and upper limbs. Seizures ceased on September 30, 2021 by guest. Protected copyright. and 3) revealed a "suppression-burst" pat- after clonazepam and pentobarbitone and he tern, which was replaced by rhythmical trains fully recovered. of delta waves over the frontal regions three In August 1992, the boy again developed days later. After extubation (Illth day) the myoclonic jerks, which started in the right leg child was in a vegetative state. Three days and foot, spread to the face, and coincided later, under treatmlent with valproate and car- with increasing unconsciousness. Treatment bamazepine, she developed complex partial with diazepam, phenytoin, phenobarbitone, seizures coinciding with pronounced chloral hydrate, thiopentone, and mannitol cyanosis. Phenobarbitone, phenytoin, and had no effect. Pentobarbitone interrupted the clonazepam were not efficient. Bilateral pneu- right hemiconvulsions, but continuous high monia and pleural effusion required artificial amplitude slow spike or polyspike wave com- ventilation again. Refractory seizures and plexes persisted in the left hemisphere (fig deterioration of the EEG (fig 2a) were taken 3a). A barbiturate coma with electrocerebral as indications for treatment with dex- silence for 24 hours had no effect; therefore tromethorphan and this was given (32 mg/ dextromethorphan was added (35 mg/kg/ kg/day). Within hours seizures ceased and the day). After discontinuation of pentobarbitone multifocal spike and sharp waves disappeared the continuous right hemiconvulsions (fig 2b). At intervals of 10-15 minutes low relapsed, occasionally coinciding
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