Oral ketamine in paediatric non-convulsive status epilepticus

Seizure 2003; 12: 483–489

doi:10.1016/S1059–1311(03)00028-1

Oral ketamine in paediatric non-convulsive status epilepticus L. D. MEWASINGH, T. SÉKHARA, A. AEBY, F. J. C. CHRISTIAENS & B. DAN Department of Neurology, Children’s University Hospital Queen Fabiola, Free University of Brussels (ULB), Avenue JJ Crocq 15, 1020 Brussels, Belgium Correspondence to: Dr L.D. Mewasingh, Department of Paediatric Neurology, Children’s University Hospital Queen Fabiola, ULB, Avenue JJ Crocq 15, 1020 Brussels, Belgium. E-mail: [email protected]

In children, non-convulsive status epilepticus (NCSE) is rare and difficult to treat. Response to steroids and GABAergic medication is variable and often decreases with increasing duration of NCSE. We present our experience with oral ketamine, an NMDA-receptor antagonist, administered to five children with severe epilepsy (Lennox-Gastaut Syndrome, myoclonic-astatic epilepsy, progressive myoclonic epilepsy and Pseudo-Lennox Syndrome) during an episode of NCSE. Resolution of NCSE was documented in all cases clinically and electroencephalographically within 24–48 hours of starting ketamine. No significant side effects were noted. © 2003 BEA Trading Ltd. Published by Elsevier Science Ltd. All rights reserved. Key words: non-convulsive status epilepticus; ketamine; benzodiazepines; GABA; NMDA; refractory seizures.

INTRODUCTION

MATERIALS AND METHODS

Non-convulsive status epilepticus (NCSE) is characterised by non-convulsive epileptic activity persisting for more than 30 minutes. This often manifests as cognitive or behavioural impairment. Additional clinical features may include bradykinesia, automatisms, myoclonic jerks and ataxia. Although NCSE can be self-resolving, it is associated with short-term morbidity1 and possible long-term cognitive sequelae2, 3 so that pharmacological intervention is often considered. However, response to treatment is highly variable. The risk of iatrogenic morbidity associated with intravenous anticonvulsant therapy arguably contraindicates its use in NCSE4 . Oral benzodiazepines (BZD) or steroids can prove useful4 but side effects may be a limiting factor. Ketamine, a non-competitive N-methyl-d-aspartate (NMDA)-receptor antagonist, has been used intravenously in a few cases of prolonged refractory convulsive status epilepticus5, 6 . We report our experience with oral ketamine in five children with NCSE.

Patients

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Five children aged between 4 and 7 years received oral ketamine during the course of an NCSE episode. Their clinical details are outlined in Table 1. They all have severe epilepsy and have had previous episodes of NCSE of variable duration (range: 1–5 weeks, mean 2.8), diagnosed retrospectively on clinical grounds in one patient (patient 5). Except for the latter, previous episodes of NCSE were treated with oral (clobazam, clonazepam, sublingual midazolam, nitrazepam) or intravenous (lorazepam, midazolam) BZD and/or oral steroids. Definite response was obtained only in patients 3 and 4 following 2 and 3 weeks, respectively, of oral prednisolone (2 mg/kg/day) with resumption of interictal clinical state and electroencephalogram (EEG) features. Corticotherapy led to significant weight gain in both patients and additional arterial hypertension in patient 5. In patient 2 an intravenous bolus of phenobarbitone (20 mg/kg) was ineffective during a previous NCSE

© 2003 BEA Trading Ltd. Published by Elsevier Science Ltd. All rights reserved.

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Table 1: Clinical characteristics of patients.

Age Gender Seizure disorder Maintenance antiepileptic drugs Previous NCSE Mean duration of previous NCSE Interictal EEG findings

Patient 1

Patient 2

Patient 3

Patient 4

Patient 5

4 years M LGS Sodium valproate, clonazepam ++ 2–3 weeks

7 years F PME Sodium valproate, lamotrigine, ethosuximide ++ 2–4 weeks

4 years F MAE Lamotrigine, clonazepam, felbamate ++ 1–5 weeks

6 years M LGS Sodium valproate, clobazam, lamotrigine, topiramate ++ 2–3 weeks

4 years F ABPE Sodium valproate, lamotrigine + 3 weeks

Diffuse slow background activity; bursts of generalised SW of maximal amp. Anteriorly (2–3/second, 300 µV)

Poor background activity; right parietal discharges

Slow background activity with occasional SW (2–3/second), onset in left fronto-temporal region

Disorganised background activity with frequent right hemispheric SW

Excess rhythmic theta activity with centro-temporal emphasis; runs of delta activity in frontal regions; few frontal SW

ABPE—atypical ‘benign’ partial epilepsy; amp.—amplitude; LGS—Lennox-Gastaut Syndrome; MAE—myoclonic-astatic epilepsy; NCSE—non-convulsive status epilepticus; PME—progressive myoclonic epilepsy; SMEI—severe myoclonic epilepsy of infancy; SW—spike-waves.

L. D. Mewasingh et al.

Oral ketamine in paediatric NCSE

Table 2: Current non-convulsive status epilepticus. Patient 1

Patient 2

Patient 3

Patient 4

Patient 5

Clinical presentation

Slow mentation, ataxia, bradykinesia, drooling, myoclonic jerks, hypotonia

Slow mentation, ataxia, bradykinesia, dysarthria, myoclonic jerks

Slow mentation, ataxia, bradykinesia

Slow mentation, ataxia, bradykinesia

Duration of NCSE prior to presentation Treatment prior to ketamine

2 weeks

4 weeks

Slow mentation, ataxia, bradykinesia, palpebral myoclonias, drooling, hypotonia 4 weeks

2 weeks

10 weeks

Lorazepam, prednisolone

Midazolam, lorazepam, prednisolone Continuous generalised SW (2–3/second, 200–300 µV)

–

–

–

Continuous generalised spikes, SW and complexes of maximal amp. anteriorly (1.5–2.5/second, 200–300 µV) Within 48 hours

Continuous generalised spikes, SW and complexes (>5/second, 100–200 µV)

Continuous generalised SW (1–2/second, 500–800 µV)

Within 48 hours

Within 24 hours

EEG during NCSE

Continuous generalised SW (1.5–2.5/second, 300–500 µV)

Response to ketaminea

Within 24 hours

Within 48 hours

SW—spike-waves; amp.—amplitude. a Resolution of clinical and EEG features from the time of administration of first dose of ketamine.

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episode and followed by hypersomnolence lasting 48 hours.

Current NCSE The clinical features of the patients’ current NCSE episode are outlined in Table 2. They included slowed mentation, vacant gaze, bradykinesia and ataxia in all cases. Patients 1 and 2 received other treatment prior to ketamine. Patient 1 had intravenous lorazepam (two doses of 0.1 mg/kg over 4 hours) without ensuing clinical or EEG changes followed by oral prednisolone (2 mg/kg/day) for 10 days. Lack of improvement led to a trial of oral ketamine as outlined below. As for patient 2, no clinical or EEG improvement was noted following sublingual midazolam (three doses of 0.5 mg/kg over 12 hours), intravenous lorazepam (two doses of 0.1 mg/kg over the next 6 hours) and subsequent oral prednisolone (2 mg/kg/day over 12 days). Her general clinical state deteriorated further with increasing ataxia and inability to walk independently. Three days after cessation of prednisolone oral ketamine was started. As patients 3 and 4 had shown no previous satisfactory response to BZDs and had significant side effects from steroids in the past, current NCSE was treated with oral ketamine. Patient 5, who had no treatment for previous NCSE, also received ketamine as first-line therapy.

Ketamine treatment The parenteral preparation (50 mg/ml, Ketalar, Pfizer) was given orally, 1.5 mg/kg/day in two divided doses. It was mixed with fruit juice to disguise the bitter taste. This regime was devised on the basis of experience with intravenous ketamine in refractory convulsive status epilepticus and reported strategy for conversion from parenteral to oral ketamine7 . Ketamine was administered for 5 days in addition to maintenance antiepileptic treatment and then stopped without weaning. This treatment was approved by the Local Ethics Committee.

Evaluation Clinical state during NCSE was recorded, including the following: general and neurological examination, level of alertness, visual attention and drooling. Parents’ assessment was also noted. EEGs were recorded in all patients at least three times during the NCSE episode in this study: at presentation, 24 and 72 hours after introduction of ketamine. Recordings were seen independently by two

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neurologists, one of whom was blinded to the child’s clinical state and therapy. Any side effects observed by medical or nursing staff or reported by parents were documented. Specific enquiries were made regarding sedation, altered behaviour of the child or possibility of hallucinations.

RESULTS NCSE lasted between 2 to 10 weeks (mean 4.4) prior to introduction of ketamine. EEG evaluation was concordant for all recordings. Following ketamine NCSE stopped within 48 hours in all patients (Table 2) with improvement in both clinical features and EEGs (Fig. 1). No apparent psychotomimetic or other adverse effects were noted by parents or medical staff except for patient 3 who was irritable without obvious cause on days 2 and 3 of treatment. Parents reported finding their child more alert and less somnolent. Parents of patients 1 and 5 reported that their child seemed ‘better than ever’ while the other children were described as being ‘back to their usual self’. All patients demonstrated a renewed interest in their surroundings and regained previous motor skills. EEGs showed re-emergence of background activity 24 hours post-ketamine and were similar to previous interictal recordings in terms of discharges. Over a 4–9 months follow-up period NCSE recurred in one child (patient 1) after 3.5 months during the course of a febrile illness. This episode was treated with the same ketamine regimen and similar clinical and EEG improvement occurred within 24 hours. The other patients had no further episodes of NCSE with cognition, alertness and general psychomotor level back to baseline levels.

DISCUSSION We report five children with severe epilepsy in whom treatment of NCSE with oral ketamine was followed by resolution of NCSE within 24–48 hours. As two of the patients had received other treatment prior to ketamine, the role of these in their recovery is difficult to ascertain although these patients had previously shown no response to either BZDs or steroids. The consistency and timing of the clinical and EEG changes following ketamine in all patients support the hypothesis that cessation of NCSE was secondary to ketamine. This hypothesis is based on current understanding of status epilepticus. Epileptic activity is known to induce a cascade of intrinsic neuronal and synaptic mechanisms that tend to reverse this activity so that most seizures are self-resolving. Failure of

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Fig. 1: EEG findings in patient 5 (electrodes identified using ‘10–20’ nomenclature, common average (CA) montage). (A) During non-convulsive status epilepticus. (B) Twenty-four hours after the first dose of ketamine.

these mechanisms leads to seizure prolongation, eventually status epilepticus. These events involve γ-aminobutyric acid (GABA) and its receptors. Pharmacological treatment of seizures, including status epilepticus, is therefore often directed at potentiating GABAergic inhibition, as attempted in patients 1 and 2. Functional modification of GABAA receptors has been described in status epilepticus8 . This may account for increasing resistance to GABAergic anticonvulsants, such as BZDs9 , phenobarbitone10 and vigabatrin11 , as status epilepticus persists. Concomi-

tantly, there is increased sensitivity to NMDA-receptor antagonists10 . This suggests that prolonged status epilepticus is associated with excessive glutamatergic excitatory transmission, although the latter can also modulate GABAergic inhibition9, 12 . While these experimental findings concern convulsive status epilepticus, a similar sequence of electroclinical events13 has been described in NCSE14 suggesting that the same processes may be involved. Implications of such insights regarding the management of NCSE could therefore include use of

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Table 3: Suggested protocol for use of oral ketamine in paediatric non-convulsive status epilepticus. To review at presentation: clinical history; drug history, including recent addition of any antiepileptic drug; any known diagnosis of an epilepsy syndrome/classification; previous episode(s) of NCSE and response (clinical and EEG) to drug(s) used; current NCSE: presentation, duration, drug(s), EEG features If a drug regime proved useful in previous NCSE, it should be used as first line. If not, see (A), (B) or (C): (A) NCSE < 2 days BZDs (e.g. lorazepam 0.05 mg/kg intravenously, maximum two doses). If this fails → ketamine (1.5 mg/kg/day orally in two divided doses for 3 days). If this fails → ketamine (1.5 mg/kg/day orally in two divided doses for 2 more days). If this fails, see (D) (B) NCSE 2 days to 2 weeks +No previous NCSE or NCSE with good response previously to BZDs → BZDs (as in (A)). If this fails → ketamine (as in (A)). If this fails, see (D) +Previous NCSE, poor response to BZDs → ketamine (as in (A)). If this fails, see (D) (C) NCSE > 2 weeks Ketamine as first line (as in (A)). If this fails, see (D) (D) Failure of ketamine Review clinical situation and consider steroids (prednisolone 2 mg/kg/day orally for 7–10 days) and discuss other options (intravenous phenobarbitone, phenytoin or sodium valproate) Monitor possible side effects of ketamine BZDs—benzodiazepines; NCSE—non-convulsive status epilepticus.

NMDA-receptor antagonists, such as ketamine. In our patients favourable response to ketamine and resistance to BZDs (previous episodes of prolonged NCSE in patients 1–4 and current episode in patients 1 and 2) would support the hypothesis that NMDA neurotransmission plays a key role in maintenance of NCSE9, 15 . Ketamine has been shown to be effective in animal models of prolonged seizures or status epilepticus, its efficacy increasing with duration of seizure activity10 . Animal models have also shown NMDA-receptor antagonists to be effective in controlling seizures refractory to BZDs9, 16, 17 . Experience in the use of ketamine as an antiepileptic drug in humans is confined to a few reports of intravenous administration in refractory convulsive status epilepticus5, 6 . An anatomo-pathological study of hippocampal cell loss suggested a possible neuroprotective role in status epilepticus in humans18 . Neuroprotection has also been demonstrated in animal studies from learning and memory tasks and pathological findings19–21 . Possible adverse effects of ketamine include excessive sedation or psychotomimetic effects, as reported when administered orally for analgesia7 . Toxic effects have been described following its use as an anaesthetic agent, including haemodynamic instability, as well as adverse psychological effects, such as hallucinations and delirium22 . In this study no significant side effects were noted. Experience in the use of oral ketamine in this group of children with prolonged NCSE has influenced our current management of NCSE, giving rise to a prospective protocol (Table 3). Depending on the estimated duration of NCSE prior to presentation, ketamine may be used as first- or second-line therapy. The cur-

rent doses and timing for ketamine administration are mostly speculative. This report suggests that oral ketamine may be a useful treatment in prolonged NCSE. The response to ketamine and absence of significant side effects in our patients need to be confirmed in large-scale studies.

ACKNOWLEDGEMENT We thank Mrs Pascale Simon for technical assistance.

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