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

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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 with amplitude epileptic discharges over the region contracortical spike wave complexes (fig 3b). of the skull fracture occurred and remained SEP amplitudes were attenuated in both Drug refractory epilepsy: effect ofdextromethorphan on EEG 335

Figure 2 Case 2, severe A hemispheres. Assuming a lack of effect, dex- J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.57.3.333 on 1 March 1994. Downloaded from head trauma and hypoxia Ft-F3 (A) 14th day, low voltage, tromethorphan was gradually discontinued multifocal spike, and sharp F3-C3 and clonazepam and valproate were given. waves, intervening periods The later course of the illness, complicated by ofinactivity; (B) 24 hours C3aP3 after introduction of a life-threaKtning pneumonia, showed fre- dextromethorphan; (C) P301 quent long lasting periods of myoclonic jerks, seven days after reduction F2-F4 now on the left half of the body. After an ofdextromethorphan to 22 interval of 17 a mglkglday, complex partial F4-C4 days the EEG showed contin- seizures with cyanosis, uous epileptic activity in the right hemisphere series ofrapid spikes. C444 (fig 3c), independent of the myoclonic jerks.

P4-02 This pronounc,d deterioration in EEG sug- FI-F7 ~v gested, retrospectively, a beneficial effect of and treatment FT-T3 dextromethorphan, with the drug was restarted. The EEG improved T3-T5 within days (fig 3d), but the myoclonic jerks T5Wt __ _ _ persisted and the child remained in a

F2-F vegetative state. Two weeks later, periods of v respiratory insufficiency reoccurred. Dextro- FST4 methorphan was reduced to 20 mg/kg/day, T4-TO clonazepam was continued, and valproate T4-02 - . 50 RV discontinued. Although the EEG further 1 s improved (fig 3e), the series of myoclonic jerks persisted, but, by contrast with his brother, no other seizures occurred. Due B to the desperate situation medical care Fl-P3 was reduced and dextromethorphan was

FP3 C discontinued stepwise. The child died 10 days after withdrawal of dextromethorphan. Postmortem evaluation of CSF revealed no P3-01 detectable dextromethorphan or dextrorphan. F2-F4 CASE 4 F4-C4 A two-year-old Japanese boy had a reduced C4-P4 food and fluid intake during a mild respira- P4.02 tory infection and after a long distance flight. Fl-F7 In the morning he was found comatose with generalised convulsions and F7-T3 deepened breath- ing. On admission to hospital blood sugar of T3-T5 the febrile child was measured as nil. Intraveneous glucose was given immediately. F2-P3 The seizures, refractory to clonazepam and

phenytoin, could be interrupted by phenobar- http://jnnp.bmj.com/ FS-T4 ' ~ bitone. Under treatment with phenytoin and T4-T6 phenobarbitone attacks of pronounced tris- i50 RV T4-02 mus, coinciding with apnoea, required artifi- s cial ventilation. A CT scan and assessment of CSF were normal and the EEG showed severe background slowing. Forty eight hours C later thiopentone (5 mg/kg/hour) was neces- Ft-F3 sary to interrupt recurrent tonic-clonic on September 30, 2021 by guest. Protected copyright. F3-C3 - seizures. Multifocal sharp waves, slow spike , _ wave complexes, and long lasting epileptic discharges (fig 4a) persisted in the EEG and

P341 were not affected when clonazepam and pyri- F2-F;4 doxine were administered. Dextromethor- C4P4 ,, ~ phan (35 mg/kg/day) was added; 48 hours later epileptiform abnormalities were pro- CP4j02 foundly reduced and after 72 hours they were no longer present (fig 4b). Trismus and tonic F1-F7 seizures persisted for three days and disappeared after replacement of phenytoin by FP-T3 clonazepam. The MRI now showed cortical T3-T5 _____ atrophy and demyelination. After 10 days,

------dextromethorphan was discontinued stepwise. The child, treated with phenobarbitone F2-M W P; and clonazepam, remained seizure free, but F94T4 -<---~----~- increasing numbers of sharp waves reoc- T4-T6 , curred in the EEG. The child showed a very T 50 ^.V slow recovery and, up to now, severe neuro- TO-02 1 s logical sequelae. 336 Schmitt, Netzer, Fanconi, Baumann, Boltshauser

Figure 3 Case 3, A B J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.57.3.333 on 1 March 1994. Downloaded from neurodegenerative disease (A) epilepsia partialis F1-P ''\A continua; (B) after C1-P3 barbiturate coma, dextromethorphan (25 P244 mglkglday), jerks related 74-C4 cortical spike wave P2-P4 complexes over the left F2-4_ F;S central region (EMG I = P4-74 right arm, EMG 2 = right F4-C4 thigh); (C) 17 days after P14-7 discontinuation of CW4-P dextromethorphan, myoclonicjerks, now on the left body half; (D) F1-F7 after reintroduction of P2-PS dextromethorphan (35 PS-T4 T6-C mglkglday); (E) five T-T5 T4-TG weeks later, treatment with T402- clonazepam and 72-01 - dextromethorphan (20 mglkglday) F2 F9 FS-T4 0O 50 IAV ^ s S T4-T_ BIG12 2 1200 gV EUO2 Te-076-02~~ ~ ~~~~~ ~1 s

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F74A04-74 Dextromethorphan, but not its metabolite dextrorphan, is believed to amplify the anti- 77-n convulsant effects of phenytoin.26 This effect MU is unlikely to play a part in our patients because (1) different drugs were used; (2) the FTe-PTV2 effect of dextromethorphan persisted when antiepileptic drugs were discontinued; and 74-UM WT (3) the patient with non-ketotic hyperglyci- T*42 naemia was treated with dextromethorphan alone.'4 Anticonvulsant properties of dextro- Cz-C4 methorphan have been described in various C4-T4 , [i50, p>,ain vitro and in vivo models of epilepsy.4617-19 Drug refractory epilepsy: effect ofdextromethorphan on EEG 337

Figure 4 Case 4, after A B J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.57.3.333 on 1 March 1994. Downloaded from severe hypoglycaemia (A) 5th day, drug refractory F143 multifocal slow spike wave complexes; (B) 48 hours after addition of C3-P3 dextromethorphan (35 P341 mglkglday) to treatment F2.P4 M2RP4

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The underlying mechanism is believed to be a achieving an improvement.<~~~~~~Side effects were This is 1v02other a low dose 5 block of the NMDA receptor channel. not seen. On the hand, (~ also assumed for the main metabolite of mg/kg/day)29 and a very low dose (3 x 7 dextromethorphan, dextrorphan.7-9 Over- mg/day)30 of dextromethorphan was effective. stimulation of the NMDA receptor seems to These doses, however, were ineffective in our play a key part in brain damage in hypoxia patient with non-ketotic hyperglycinaemia,14 (cases 1 and 2), severe head trauma (case 2), and in case 2 reduction to 22 mg/kg/day was hypoglycaemia (case 4), and neurodegenera- followed by a relapse to seizures seven days tive diseases (case 3).2>23 Epilepsy in these later. On the other hand, 20 mg/kg/day dex- patients may be induced by NMDA receptor- tromethorphan had an impressive effect on mediated processes. In animal studies of the EEG in case 3. NMDA-induced convulsions, only NMDA Post mortem investigations of case 2 receptor antagonists, and not conventional revealed microbleeding in the region of the antiepileptic drugs, are effective.5 In seizures persisting low voltage epileptic discharges, caused by other pathomechanisms, the obviously due to the overlying impression

NMDA receptor antagonists prevent epileptic fracture of the skull. The resistance of these http://jnnp.bmj.com/ brain damage even when they do not sup- discharges to high doses of dextromethorphan press electrographic seizures.2425 (42 mg/kg/day) is consistent with the in vitro The additional effect of dextromethorphan freeze lesion model of Troyer et al,3 in which on voltage-gated calcium channels might also interictal discharges were unaffected by contribute to the anticonvulsant properties. NMDA antagonists. Blocking calcium currents has been shown to have an anticonvulsant effect in in vitro26 and CONCENTRATION in vivo experiments.27 Much higher concen- Inhibitory concentrations (IC50) for reduction on September 30, 2021 by guest. Protected copyright. trations of dextromethorphan are necessary to of NMDA-induced currents in voltage clamp inhibit the voltage-gated calcium channels experiments are 0-55 pM for dextromethor- than to block NMDA-induced currents.9 phan and 0-096 pM for dextrorphan.9 A con- Clinical experiences with dextromethor- centration of 118 ng/ml dextromethorphan phan were reported by Fisher et al.28 They (0-43 pM) and 725 ng/ml dextrorphan (2-82 gave dextromethorphan (120 mg/day 2 pM) in the CSF of case 3 may suffice for mg/kg/day) as add-on therapy to adults with NMDA antagonism (table). Plasma concen- intractable complex partial seizures, without trations of dextromethorphan were high in two patients, probably due to shock-induced hepatic failure (case 1), and to the short time interval (two hours) after treatment with Table Concentrations ofdextromethorphan (DM) and dextrorphan (DX) dextromethorphan (case 2). The relation between the plasma concentrations and the Dose Hours after DM DM DX Case (mglkg/day) treatment Source (nglml) (ng/ml) therapeutic effects of dextromethorphan or dextrorphan could not be judged because (1) 1 28 20 Plasma 1730 2170 2 22 2 Plasma 1050 1590 our preliminary data are too limited; (2) 3 35 6 Plasma 250 3790 state levels were not reached; (3) dex- CSF 118 725 steady 3 19 6 Plasma 790 1850 trorphan possibly represents only a fraction of 4 10 6 Plasma 74 349 NMDA receptor active dextromethorphan Plasma and CSF samples were collected at the same time. metabolites; and (4) the efficacy of these 338 Schmitt, Netzer, Fanconi, Baumann, Boltshauser

metabolites might be different. Dextro- The decision to initiate treatment with dex- J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.57.3.333 on 1 March 1994. Downloaded from methorphan, for example, seems to be nearly tromethorphan might have been too late for 10 times more potent in blocking NMDA- three of our patients. A future study design induced currents than dextromethorphan.9 The should consider an earlier introduction of metabolism of dextromethorphan to dextror- dextromethorphan in patients with acute neu- phan or other compounds varies between rological diseases and epilepsy. In acute neu- patients32 and may be influenced by other drugs. rological diseases transient antagonism of the NMDA receptor may suffice to prevent brain CLINICAL OUTCOME damage by NMDA receptor mediated excito- The clinical outcome of our patients was dis- toxicity. The blockade of NMDA receptors appointing. According to the post mortem seems to be necessary until the overflow of examination in case 1, the initial EEG pattern excitatory amino acids is reduced or the reup- in case 2, the clinical course of the brother in take system is stabilised. We assume that 10 case 3, and the severe hypoglycaemia with days of high dose dextromethorphan and long lasting refractory status epilepticus in stepwise discontinuation over seven days case 4, no other outcome could be expected. would be an appropriate mode of treatment. Treatment with dextromethorphan was Dextromethorphan should be discontinued or started several (2-14) days after the initial reduced before extubation is performed to event-that is, probably too late to prevent avoid possible respiratory problems. NMDA-induced excitotoxicity. Long term administration of dex- The lack of effect on some convulsions was tromethorphan is limited in childhood epilep- also disappointing. By contrast with our first sies, unless the underlying disease case,14 myoclonic jerks in case 3 were unaf- (non-ketotic hyperglycinaemia) requires a fected by dextromethorphan, although con- continuous NMDA receptor blockade. The tracortical spike wave complexes in the EEG supposed involvement of NMDA receptors in disappeared. A side effect of dextromethor- learning and memory processes suggests that phan'9 could be excluded, because the long term treatment with NMDA antagonists myoclonic jerks occurred even before dex- is not desirable, especially in childhood. tromethorphan was added. Although sharp As successful treatment with dex- and spike wave complexes had disappeared in tromethorphan is also limited by the unrelia- case 4, tonic seizures and trismus persisted bility of the oral route, intravenous treatment for several days. would have preference. Treatment with dextrorphan, the more potent compound at the SIDE EFFECTS NMDA receptor, might also overcome indi- Dextromethorphan is an over the counter vidual metabolic differences and improve reli- antitussive drug with a wide margin of ability. safety and rare adverse reactions." The dose We are grateful to Mrs M Jonzier-Perey for skilful determina- given to our patients, however, corresponds tion of the drug levels and to Dr SM Thompson (Brain to a massive overdose for which side effects Research Institute) and Dr G Richards (Hoffmann-LaRoche) are sporadically reported (respiratory depres- for helpful comments on the manuscript. sion and various mental disturbances)." Respiratory insufficiency was seen in two of our patients, but this could have been due to http://jnnp.bmj.com/ other causes. Nevertheless, a relation between 1 Wong BY, Coulter DA, Choi DW, Prince DA. Dextrorphan and dextromethorphan, common antitus- high dose dextromethorphan and pneumonia sives, are antiepileptic and antagonize N-methyl-D- cannot be excluded, as we also noted pneu- aspartate in brain slices. Neurosci Leu 1988;85:261-6. 2 Aram JA, Martin D, Tomczyk M, Zeman S, Millar J, monia in another (unpublished) patient Pohler G, Lodge D. Neocortical epileptogenesis in vitro: treated with high dose dextromethorphan. On studies with N-methyl-D-aspartate, phencyclidine, sigma and dextromethorphan receptor ligands. J the other hand, our patient with non-ketotic Pharmacol Exp Ther 1989;248:320-8. hyperglycinaemia,14 now treated with high 3 Apland JP, Braitman DJ. Effects of non-opioid antitus- on September 30, 2021 by guest. Protected copyright. sives on epileptiform activity and NMDA responses in dose dextromethorphan for more than two hippocampal and olfactory cortex slices. Brain Res years, has never had pulmonary problems. 1990;529:277-85. 4 Feeser HR, Kadis JL, Prince DA. Dextromethorphan, a Other reported side effects of dex- common anntussive, reduces kindled amygdala seizures tromethorphan overdosing are somnolence, in the rat. Neurosci Leu 1988;86:340-5. 5 Ferkany JW, Borosky SA, Clissold DB, Pontecorvo MJ. agitation,29 slurred speech, blurred vision, Dextromethorphan inhibits NMDA-induced convul- dizziness, vomiting, gait ataxia, nystagmus, sions. EurJPharmacol 1988;151:151-4. 6 Chapman AG, Meldrum BS. Non-competitive N-methyl- and urinary retention.'4 Naloxone seems to D-aspartate antagonists protect against sound-induced reverse the side effects of dextromethor- seizures in DBA/2 mice. Eur J Pharmacol 1989;166:201-11. phan,'4 but obviously does not affect the 7 Church J, Lodge D, Berry SC. Differential effects of dex- NMDA receptor related anticonvulsant effects trorphan and levorphanol on the excitation of rat spinal neurons by amino acids. 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Drug refractory epilepsy: effect ofdextromethorphan on EEG 339

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