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Journal ofNeurology, Neurosurgery, and Psychiaty 1994;57:333-339

Drug refractory epilepsy in brain damage: effectof dextromethorphan on EEG in four patients

B Schmitt, R Netzer, S Fanconi, P Baumann, E Boltshauser

University Children'sHospital,Steinwiesstrasse 75,CH-8032 Zurich,SwitzerlandDepartment ofClinicalNeurophysiologyB SchmittDepartment ofIntensive CareS FanconiDepartnent ofPaediatric NeurologyE BoltshauserPharma Division,Preclinical Research,F Hoffmann-LaRocheLTD, CH-4002 Basel,SwitzerlandR NetzerUnite de biochimie etpsychopharmacologieclinique, D6pt univ depsychiatrie adulte,Site de Cery, CH-1008Prilly-Lausanne,SwitzerlandP BaumannCorrespondence to:Dr Bernhard Schmitt,Department of ClinicalNeurophysiology, UniversityChildren's Hospital,Steinwiesstrasse 75, CH-8032 Zurich, Switzerland.Received 16 March 1993and in revised form14 May 1993.Accepted 27 May 1993

AbstractHigh doses of dextromethorphan (20-42mglkglday) were given to four criticallyill children with seizures and frequentepileptiform abnormalities in the EEGthat were refractory to antiepilepticdrugs. Their acute diseases (hypoxia,head trauma and hypoxia, neurodegen-erative disease, hypoglycaemia) werethought to be due in part to N-methyl-D-aspartate (NAIDA) receptor mediatedprocesses. Treatment with dex-tromethorphan, an NMDA receptorantagonist, was started between 48 hoursand 14 days after the critical incident. Inthree patients the EEG improved consid-erably within 48 hours and seizuresceased within 72 hours. In the patientwith neurodegenerative disease the effecton the EEG was impressive, but theseizures were not controlled. Despite theimprovement of the EEG the clinicaloutcome was poor in all children: threedied in the critical period or due to theprogressing disease; the patient withhypoglycaemia survived with severe neu-rological sequelae. Plasma concentra-tions of dextromethorphan variedbetween 74-1730 ng/ml and its metabolitedextrorphan varied between 349-3790nglml. In one patient corresponding con-centrations in CSF were lower than thosein plasma. The suppression of epilepticdischarges by the doses of dextromethor-phan given suggests that such doses aresufficient to block NMDA receptors.

(7 Neurol Neurosurg Psychiatry 1994;57:333-339)

Dextromethorphan, a morphine derivativewithout affinity for opioid receptors, hasbeen used as an antitussive for more than30 years. Recently, the drug was shown tohave anticonvulsant properties in several invitro1-3 and in vivo models of epilepsy.4A6Dextromethorphan is a non-competitiveantagonist of the N-methyl-D-aspartate(NMDA) receptor channel.78 The substancehas also been shown to reduce voltage-dependent calcium and sodium currents withlower potency.8 9

Because NMDA receptors play an impor-tant part in the pathophysiological mecha-nisms of various neurological disorders,including epilepsy,10 NMDA receptor channelblockers (for example, MK-80 1,- dex-tromethorphan, ketamine, imipramine,

desipramine) may have beneficial effects inthe treatment of seizures."l-"3 Recently, wehave shown that dextromethorphan (35mg/kg/day in four doses) resulted in the ces-sation of seizures and normalisation of theEEG in a patient with non-ketotic hyperglyci-naemia.'4 Withdrawal of dextromethorphanwas followed by dramatic clinical deteriora-tion with epileptic and high voltage slowactivity in the EEG. The symptoms disap-peared again when the drug treatment wasresumed after 48 hours.

Dextromethorphan might therefore be auseful antiepileptic drug for other forms ofepilepsy. Because of potential side effects athigh doses, use of dextromethorphan must berestricted. In four patients on intensive carewith a desperate clinical situation, dex-tromethorphan was the final option for treat-ment of drug refractory epilepsy. None of thepatients showed a satisfactory clinical out-come, but in each of them dextromethorphanimpressively improved the EEG. It is the aimof this paper to discuss (1) the effects of dex-tromethorphan on the EEG at various doses;(2) the dextromethorphan concentration inplasma and CSF, (3) the reasons for theunsatisfactory outcome; (4) possible sideeffects; and (5) potential improvements forfuture management.Our results are of a preliminary character.

In all patients the decision to initiate treat-ment with dextromethorphan was made byconsensus of at least two involved physiciansfrom different departments; parents wereinformed.

Patients and methodsDextromethorphan hydrobromide (Bexin)was orally administered by tube in four dosesdaily. Concentrations of dextromethorphanand its active main metabolite dextrorphanwere determined in blood and CSF by gaschromatography-mass spectrometry aftertreatment with fl-glucuronidase and arylsul-phatase."5 EEGs were recorded on a 16 or 21channel standard machine. Electrode place-ment was according to the international10-20 system, paper speed 30 mmn/s, low passfilter 60 or 70 Hz, time constant 03 seconds,and minimal recording time 30 minutes.

CASE 1Case 1 was a seven-month-old child with atetralogy of Fallot. After total surgical correc-tion, cardiac arrest occurred and resuscitationwas necessary. Forty eight hours later the

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child had focal seizures that were refractory tophenobarbitone and diazepam. 'Me EEGshowed continuous focal epileptic dischargeswith varying localisations (fig 1la), whichcould be interrupted temporarily with clon-azepam. Somatosensory evoked potentials(SEPs) showed a complete loss of corticalcomponents. Brainstem acoustic evokedpotentials were preserved. After treatmentwith dextromethorphan (30 mg/kg/day)seizures stopped, the EEG, repeatedlyrecorded, was free of epileptic discharges, andbackground activity was slow (fig lb). A CTscan two days later showed severe globalischaemic brain damage and life supportmeasures were discontinued. Post mortemexamination confirmed the extensive suba-cute anoxic encephalopathy.

CASE 2A 14-year-old mentally retarded girl withpoorly controlled epilepsy of unknown aetiol-ogy fell downstairs and suffered an impres-sion fracture of the left temporal skull.Cardiorespiratory insufficiency required artifi-cial ventilation. The initial EEGs (on days 2and 3) revealed a "suppression-burst" pat-tern, which was replaced by rhythmical trainsof delta waves over the frontal regions threedays later. After extubation (Illth day) thechild was in a vegetative state. Three dayslater, under treatmlent with valproate and car-bamazepine, she developed complex partialseizures coinciding with pronouncedcyanosis. Phenobarbitone, phenytoin, andclonazepam were not efficient. Bilateral pneu-monia and pleural effusion required artificialventilation again. Refractory seizures anddeterioration of the EEG (fig 2a) were takenas indications for treatment with dex-tromethorphan and this was given (32 mg/kg/day). Within hours seizures ceased and themultifocal spike and sharp waves disappeared(fig 2b). At intervals of 10-15 minutes lowamplitude epileptic discharges over the regionof the skull fracture occurred and remained

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unaffected, although dextromethorphan was

temporarily increased to 45 mg/kg/day. Allother drugs, with the exception of clon-azepam, were discontinued stepwise. In viewof unexplained pronounced muscle hyperto-nia dextromethorphan was reduced to 22mg/kg/day-without influence on the muscletone. Seven days later complex partialseizures (fig 2c) with pronounced cyanosisreoccurred and ceased again after increasingthe dose to 35 mg/kg/day. After extubationthe child persisted in a vegetative state and,due to pneumonia and pleural effusion, sheagain developed respiratory insufficiency.Because of the poor prognosis reintubationwas avoided and the child died.

CASE 3This patient had an elder brother with epilep-sia partialis continua lasting more than fouryears, that started unexpectedly at the age of5*5 years. He is now in a vegetative state.The patient, a 4-5-year-old boy, was nor-

mal up to May 1992 when he, like hisbrother, unexpectedly had myoclonic seizuresin the face and upper limbs. Seizures ceasedafter clonazepam and pentobarbitone and hefully recovered.

In August 1992, the boy again developedmyoclonic jerks, which started in the right legand foot, spread to the face, and coincidedwith increasing unconsciousness. Treatmentwith diazepam, phenytoin, phenobarbitone,chloral hydrate, thiopentone, and mannitolhad no effect. Pentobarbitone interrupted theright hemiconvulsions, but continuous highamplitude slow spike or polyspike wave com-

plexes persisted in the left hemisphere (fig3a). A barbiturate coma with electrocerebralsilence for 24 hours had no effect; thereforedextromethorphan was added (35 mg/kg/day). After discontinuation of pentobarbitonethe continuous right hemiconvulsionsrelapsed, occasionally coinciding withcontracortical spike wave complexes (fig 3b).SEP amplitudes were attenuated in both

Figure 1 Case 1 (A) 48hours after cardiac arrest,focal epileptic discharges;(B) 12 hours afterintroduction ofdextromethorphan, free ofepilepsy, severe slowingbackground activity.



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A hemispheres. Assuming a lack of effect, dex-tromethorphan was gradually discontinuedand clonazepam and valproate were given.The later course of the illness, complicated bya life-threaKtning pneumonia, showed fre-quent long lasting periods of myoclonic jerks,now on the left half of the body. After aninterval of 17 days the EEG showed a contin-uous epileptic activity in the right hemisphere(fig 3c), independent of the myoclonic jerks.This pronounc,d deterioration in EEG sug-

~v gested, retrospectively, a beneficial effect ofdextromethorphan, and treatment with thedrug was restarted. The EEG improvedwithin days (fig 3d), but the myoclonic jerkspersisted and the child remained in avegetative state. Two weeks later, periods of

v respiratory insufficiency reoccurred. Dextro-methorphan was reduced to 20 mg/kg/day,clonazepam was continued, and valproate

. 50 RV discontinued. Although the EEG further1 s improved (fig 3e), the series of myoclonic

jerks persisted, but, by contrast withhis brother, no other seizures occurred. Due

B to the desperate situation medical carewas reduced and dextromethorphan wasdiscontinued stepwise. The child died 10days after withdrawal of dextromethorphan.Postmortem evaluation of CSF revealed nodetectable dextromethorphan or dextrorphan.

CASE 4A two-year-old Japanese boy had a reducedfood and fluid intake during a mild respira-tory infection and after a long distance flight.In the morning he was found comatose withgeneralised convulsions and deepened breath-ing. On admission to hospital blood sugar ofthe febrile child was measured as nil.Intraveneous glucose was given immediately.The seizures, refractory to clonazepam andphenytoin, could be interrupted by phenobar-

' ~ bitone. Under treatment with phenytoin andphenobarbitone attacks of pronounced tris-

i50 RV mus, coinciding with apnoea, required artifi-s cial ventilation. A CT scan and assessment of

CSF were normal and the EEG showedsevere background slowing. Forty eight hours

C later thiopentone (5 mg/kg/hour) was neces-sary to interrupt recurrent tonic-clonicseizures. Multifocal sharp waves, slow spike

, _ wave complexes, and long lasting epilepticdischarges (fig 4a) persisted in the EEG andwere not affected when clonazepam and pyri-doxine were administered. Dextromethor-

,, ~ phan (35 mg/kg/day) was added; 48 hourslater epileptiform abnormalities were pro-foundly reduced and after 72 hours they wereno longer present (fig 4b). Trismus and tonicseizures persisted for three days and disap-peared after replacement of phenytoin byclonazepam. The MRI now showed corticalatrophy and demyelination. After 10 days,

---------- dextromethorphan was discontinued step-wise. The child, treated with phenobarbitoneand clonazepam, remained seizure free, but

-<---~----~- increasing numbers of sharp waves reoc-, curred in the EEG. The child showed a very

T 50 ^.V slow recovery and, up to now, severe neuro-1 s logical sequelae.

Figure 2 Case 2, severehead trauma and hypoxia(A) 14th day, low voltage,multifocal spike, and sharpwaves, intervening periodsof inactivity; (B) 24 hoursafter introduction ofdextromethorphan; (C)seven days after reductionof dextromethorphan to 22mglkglday, complex partialseizures with cyanosis,series of rapid spikes.



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Figure 3 Case 3,neurodegenerative disease(A) epilepsia partialiscontinua; (B) afterbarbiturate coma,dextromethorphan (25mglkglday), jerks relatedcortical spike wavecomplexes over the leftcentral region (EMG I =right arm, EMG 2 = rightthigh); (C) 17 days afterdiscontinuation ofdextromethorphan,myoclonic jerks, now onthe left body half; (D)after reintroduction ofdextromethorphan (35mglkglday); (E) fiveweeks later, treatment withclonazepam anddextromethorphan (20mglkglday)

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the reoccurrence or increase of epileptiformabnormalities in the EEG (cases 2 and 4).Dextromethorphan, but not its metabolitedextrorphan, is believed to amplify the anti-convulsant effects of phenytoin.26 This effectis unlikely to play a part in our patientsbecause (1) different drugs were used; (2) theeffect of dextromethorphan persisted whenantiepileptic drugs were discontinued; and(3) the patient with non-ketotic hyperglyci-naemia was treated with dextromethorphanalone.'4

Anticonvulsant properties of dextro-methorphan have been described in variousin vitro and in vivo models of epilepsy.4617-19



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The underlying mechanism is believed to be ablock of the NMDA receptor channel. This isalso assumed for the main metabolite ofdextromethorphan, dextrorphan.7-9 Over-stimulation of the NMDA receptor seems toplay a key part in brain damage in hypoxia(cases 1 and 2), severe head trauma (case 2),hypoglycaemia (case 4), and neurodegenera-tive diseases (case 3).2>23 Epilepsy in thesepatients may be induced by NMDA receptor-mediated processes. In animal studies ofNMDA-induced convulsions, only NMDAreceptor antagonists, and not conventionalantiepileptic drugs, are effective.5 In seizurescaused by other pathomechanisms, theNMDA receptor antagonists prevent epilepticbrain damage even when they do not sup-press electrographic seizures.2425The additional effect of dextromethorphan

on voltage-gated calcium channels might alsocontribute to the anticonvulsant properties.Blocking calcium currents has been shown tohave an anticonvulsant effect in in vitro26 andin vivo experiments.27 Much higher concen-trations of dextromethorphan are necessary toinhibit the voltage-gated calcium channelsthan to block NMDA-induced currents.9

Clinical experiences with dextromethor-phan were reported by Fisher et al.28 Theygave dextromethorphan (120 mg/day 2mg/kg/day) as add-on therapy to adults withintractable complex partial seizures, without

Table Concentrations of dextromethorphan (DM) and dextrorphan (DX)

Dose Hours afterDM DM DXCase (mglkg/day) treatment Source (nglml) (ng/ml)

1 28 20 Plasma 1730 21702 22 2 Plasma 1050 15903 35 6 Plasma 250 3790

CSF 118 7253 19 6 Plasma 790 18504 10 6 Plasma 74 349

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achieving an improvement. Side effects werenot seen. On the other hand, a low dose (~ 5mg/kg/day)29 and a very low dose (3 x 7mg/day)30 of dextromethorphan was effective.These doses, however, were ineffective in ourpatient with non-ketotic hyperglycinaemia,14and in case 2 reduction to 22 mg/kg/day wasfollowed by a relapse to seizures seven dayslater. On the other hand, 20 mg/kg/day dex-tromethorphan had an impressive effect onthe EEG in case 3.

Post mortem investigations of case 2revealed microbleeding in the region of thepersisting low voltage epileptic discharges,obviously due to the overlying impressionfracture of the skull. The resistance of thesedischarges to high doses of dextromethorphan(42 mg/kg/day) is consistent with the in vitrofreeze lesion model of Troyer et al,3 in whichinterictal discharges were unaffected byNMDA antagonists.

CONCENTRATIONInhibitory concentrations (IC50) for reductionof NMDA-induced currents in voltage clampexperiments are 0-55 pM for dextromethor-phan and 0-096 pM for dextrorphan.9 A con-centration of 118 ng/ml dextromethorphan(0-43 pM) and 725 ng/ml dextrorphan (2-82pM) in the CSF of case 3 may suffice forNMDA antagonism (table). Plasma concen-trations of dextromethorphan were high intwo patients, probably due to shock-inducedhepatic failure (case 1), and to the short timeinterval (two hours) after treatment withdextromethorphan (case 2). The relationbetween the plasma concentrations and thetherapeutic effects of dextromethorphan ordextrorphan could not be judged because (1)our preliminary data are too limited; (2)steady state levels were not reached; (3) dex-trorphan possibly represents only a fraction ofNMDA receptor active dextromethorphanmetabolites; and (4) the efficacy of these

Figure 4 Case 4, aftersevere hypoglycaemia (A)5th day, drug refractorymultifocal slow spike wavecomplexes; (B) 48 hoursafter addition ofdextromethorphan (35mglkglday) to treatment



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metabolites might be different. Dextro-methorphan, for example, seems to be nearly10 times more potent in blocking NMDA-induced currents than dextromethorphan.9 Themetabolism of dextromethorphan to dextror-phan or other compounds varies betweenpatients32 and may be influenced by other drugs.

CLINICAL OUTCOMEThe clinical outcome of our patients was dis-appointing. According to the post mortemexamination in case 1, the initial EEG patternin case 2, the clinical course of the brother incase 3, and the severe hypoglycaemia withlong lasting refractory status epilepticus incase 4, no other outcome could be expected.Treatment with dextromethorphan wasstarted several (2-14) days after the initialevent-that is, probably too late to preventNMDA-induced excitotoxicity.The lack of effect on some convulsions was

also disappointing. By contrast with our firstcase,14 myoclonic jerks in case 3 were unaf-fected by dextromethorphan, although con-tracortical spike wave complexes in the EEGdisappeared. A side effect of dextromethor-phan'9 could be excluded, because themyoclonic jerks occurred even before dex-tromethorphan was added. Although sharpand spike wave complexes had disappeared incase 4, tonic seizures and trismus persistedfor several days.

SIDE EFFECTSDextromethorphan is an over the counterantitussive drug with a wide margin ofsafety and rare adverse reactions." The dosegiven to our patients, however, correspondsto a massive overdose for which side effectsare sporadically reported (respiratory depres-sion and various mental disturbances)."Respiratory insufficiency was seen in two ofour patients, but this could have been due toother causes. Nevertheless, a relation betweenhigh dose dextromethorphan and pneumoniacannot be excluded, as we also noted pneu-monia in another (unpublished) patienttreated with high dose dextromethorphan. Onthe other hand, our patient with non-ketotichyperglycinaemia,14 now treated with highdose dextromethorphan for more than twoyears, has never had pulmonary problems.

Other reported side effects of dex-tromethorphan overdosing are somnolence,agitation,29 slurred speech, blurred vision,dizziness, vomiting, gait ataxia, nystagmus,and urinary retention.'4 Naloxone seems toreverse the side effects of dextromethor-phan,'4 but obviously does not affect theNMDA receptor related anticonvulsant effectsof its metabolite dextrorphan.16 Myoclonus,seen in animal models,19 has never beendescribed in humans (see Bem and Peck33).Side effects of NMDA receptor antagonistsmay be amplified in the presence of otherantiepileptic drugs-for example, valproate.'5

OUTLOOKMore experience and a proper study designare necessary to verify these preliminary data.

The decision to initiate treatment with dex-tromethorphan might have been too late forthree of our patients. A future study designshould consider an earlier introduction ofdextromethorphan in patients with acute neu-rological diseases and epilepsy. In acute neu-rological diseases transient antagonism of theNMDA receptor may suffice to prevent braindamage by NMDA receptor mediated excito-toxicity. The blockade of NMDA receptorsseems to be necessary until the overflow ofexcitatory amino acids is reduced or the reup-take system is stabilised. We assume that 10days of high dose dextromethorphan andstepwise discontinuation over seven dayswould be an appropriate mode of treatment.Dextromethorphan should be discontinued orreduced before extubation is performed toavoid possible respiratory problems.Long term administration of dex-

tromethorphan is limited in childhood epilep-sies, unless the underlying disease(non-ketotic hyperglycinaemia) requires acontinuous NMDA receptor blockade. Thesupposed involvement ofNMDA receptors inlearning and memory processes suggests thatlong term treatment with NMDA antagonistsis not desirable, especially in childhood.

As successful treatment with dex-tromethorphan is also limited by the unrelia-bility of the oral route, intravenous treatmentwould have preference. Treatment with dex-trorphan, the more potent compound at theNMDA receptor, might also overcome indi-vidual metabolic differences and improve reli-ability.

We are grateful to Mrs M Jonzier-Perey for skilful determina-tion of the drug levels and to Dr SM Thompson (BrainResearch Institute) and Dr G Richards (Hoffmann-LaRoche)for helpful comments on the manuscript.

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2 Aram JA, Martin D, Tomczyk M, Zeman S, Millar J,Pohler G, Lodge D. Neocortical epileptogenesis in vitro:studies with N-methyl-D-aspartate, phencyclidine,sigma and dextromethorphan receptor ligands. JPharmacol Exp Ther 1989;248:320-8.

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