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Intravenous levetiracetam in acute repetitive seizures and status epilepticus in children: Experience from a children's hospital
Seizure 21 (2012) 529–534
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Intravenous levetiracetam in acute repetitive seizures and status epilepticus in children: Experience from a children’s hospital A. McTague a,c, R. Kneen a, R. Kumar a, S. Spinty a, R. Appleton a,b,* a b
Department of Paediatric Neurology, Alder Hey Children’s NHS Foundation Trust, Liverpool, UK Roald Dahl EEG Department, Alder Hey Children’s NHS Foundation Trust, Liverpool, UK
A R T I C L E I N F O
A B S T R A C T
Article history: Received 15 February 2012 Received in revised form 16 May 2012 Accepted 18 May 2012
Purpose: To report the effectiveness and safety of intravenous levetiracetam in the treatment of children with acute repeated seizures, and status epilepticus in a children’s hospital. Methods: This two-year observational study evaluated all in-patients who received intravenous levetiracetam to treat acute repeated seizures (ARS) or convulsive and non-convulsive status epilepticus (SE). Information was collected on seizure type, epilepsy syndrome and underlying cause, the initial loading dose of intravenous levetiracetam, its effectiveness and safety and whether the patient remained on the drug at final follow-up. Analysis was descriptive. Results: Fifty-one patients aged 0.2–18.8 (mean 7.1) years were evaluated, including 45 with acute ARS or SE and six unable to continue their usual orally administered anti-epileptic medication. The median initial dose of levetiracetam was 14.4 (range 5–30) mg/kg in the 45 patients treated for acute seizures and SE. Twenty three of the 39 (59%) patients with ARS became and remained seizure-free. Levetiracetam terminated status in three of four (75%) patients with convulsive, and the two patients with non-convulsive status epilepticus. Aggressive behaviour occurred in three children, one of whom discontinued treatment. Forty-two patients (81%), including 34 of the 45 patients (76%) treated for ARS or SE remained on levetiracetam at the time of final follow-up, between two and 18 months after receiving the drug. Conclusion: This observational study has confirmed previous data that intravenous levetiracetam seems to be effective and safe in the treatment of acute repeated seizures and status epilepticus. A randomised clinical trial is justified to determine whether intravenous levetiracetam should replace intravenous phenytoin as the first long-acting anticonvulsant in the management of acute repetitive seizures and status epilepticus. ß 2012 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
Keywords: Levetiracetam Status epilepticus Non-convulsive status epilepticus Acute repetitive seizures Anti-epileptic Anti-convulsant
1. Introduction Intravenous levetiracetam has been shown to be safe and effective in treating adults and children with convulsive and nonconvulsive status epilepticus and with acute repetitive seizures.1– 12 In contrast to phenytoin and phenobarbital, the traditionally used anticonvulsants used in the management of SE and ARS in children, there have been no reports of cardiac arrhythmias,
Abbreviations: ARS, acute repetitive seizures; SE, status epilepticus; CSE, convulsive status epilepticus; NCSE, non-convulsive status epilepticus; LEV, levetiracetam. * Corresponding author at: Department of Paediatric Neurology, Alder Hey Children’s NHS Foundation Trust, Eaton Road, Liverpool, L12 2AP, UK. Tel.: +44 151 252 5851; fax: +44 151 252 5678. E-mail address: [email protected] (R. Appleton). c Present address: Department of Neurosciences, UCL-Institute of Child Health, London, UK.
hypotension, tissue-extravasation reactions or respiratory depression associated with levetiracetam.6,8,13 In view of the rapidly increasing literature that has described the efficacy and safety of intravenous levetiracetam in a range of clinical situations, it was considered appropriate to undertake a pilot evaluation of the use of this drug in an in-patient paediatric population. The objective of this paper is to report this evaluation. 2. Materials and methods Approval for the use of intravenous levetiracetam (LEV) was obtained from this institution’s Clinical Development and Evaluation Group (CDEG) and the study was registered with the institution’s Audit Department (number: 3405). Data were recorded on a standardised proforma with information retrieved from the medical case notes and pharmacy records. Data collection was mainly retrospective.
1059-1311/$ – see front matter ß 2012 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.seizure.2012.05.010
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A. McTague et al. / Seizure 21 (2012) 529–534
Acute repeated seizures (ARS) were defined as repeated myoclonic, clonic, tonic or tonic–clonic seizures (each seizure lasting less than five minutes with recovery of consciousness between each seizure) that had persisted for at least 30 min irrespective of whether they had been treated with any emergency medication (a benzodiazepine alone or a benzodiazepine with either phenytoin or phenobarbital). Convulsive status epilepticus was defined as any single and prolonged tonic–clonic seizure that had persisted for over five minutes and irrespective of whether the child had received any emergency medication. The decision to use levetiracetam as first or second-line therapy in either ARS or CSE was determined by the attending clinician. Non-convulsive status epilepticus (NCSE) was defined on the basis of both the child’s clinical behaviour and electroencephalographic (EEG) activity; NCSE was not diagnosed without confirmatory EEG evidence. Termination of the seizure was defined as successful if it stopped within 10 min of completion of the infusion and there was no recurrence within the following 24 h. The protocol for administering intravenous levetiracetam was as followed: the initial dose was 10 mg/kg and ‘rounded up’ to facilitate the practical administration of the drug and infused over 10–15 min. During the final five months of the study, the dose was increased to 30 mg/kg, based on new clinical and pharmacokinetic data8 and administered over 15 min. All in-patients who received intravenous levetiracetam were included in the study. Patients who attended the Accident and Emergency Department (A+ED) with an acute seizure were excluded because these children are treated according to the national Advanced Paediatric Life Support (APLS) convulsive status epilepticus algorithm. Patients with established renal failure and who were on dialysis were also excluded from the study because of the reported reduced excretion of levetiracetam in this population.14 Information was collected on the following: age and sex; seizure type; epilepsy syndrome and cause if known; the reason for the administration of intravenous levetiracetam (ARS, CSE, NCSE or for the purpose of rapidly loading the patient); other anticonvulsants used to treat the same seizure episode; loading dose of levetiracetam; response to levetiracetam and whether the child remained on the drug at final follow-up.
3. Results Fifty one patients were studied between January 1st 2009 and December 31st 2010. The majority (39 [76%]) received the drug to try and terminate ARS. Four received the drug to terminate CSE and two to terminate NCSE. Details of the ages, seizure type, epilepsy syndrome and cause, occurrence of adverse effects and current follow-up of these 45 patients are shown in Tables 1–3. The remaining six patients received intravenous levetiracetam to replace another anti-epileptic drug because they were unable to continue with their usual maintenance AED (sodium valproate,3 carbamazepine,2 and lamotrigine1). Three patients were undergoing a major abdominal surgical procedure and could not take oral medication, two patients had probable valproate-related bone marrow suppression and the remaining patient developed hepatic dysfunction on carbamazepine. Five of these six patients had been seizure-free for between five and 18 months when their maintenance AED was changed to intravenous levetiracetam. These patients are not included in Tables 1 and 2. A review of pharmacy records did not identify any additional children who had received intravenous levetiracetam during the study period. The mean age of the 45 patients who received levetiracetam for ARS or CSE/NCSE was 5.65 (median 3.28, range 0.2–18.8) years. The
mean age of the remaining six patients was 5.24 (median 4.8, range 1.9–9.4) years. The mean initial dose of levetiracetam was 14.4 (median 15.1, range 5–30), mg/kg in the 45 patients treated for ARS and CSE/ NCSE. The mean dose was 16 (range 10–25) mg/kg in the six patients treated electively with levetiracetam as a substitute for their usual maintenance AED. Levetiracetam terminated the seizure in 24 of the 39 patients (62%) with ARS. Twenty of the 39 patients had received levetiracetam as the first anticonvulsant and in 13 (65%) the seizure stopped. In the remaining 19 patients, levetiracetam was given after another emergency medication and the seizure stopped in 12 (63%). Two of the 25 responders required an additional intravenous dose given within six hours of the initial dose (patients 25 and 38). Finally, an additional three patients (9, 22 and 23) became seizure-free but then relapsed after 24–36 h with no response to further doses of the anticonvulsant. Five patients showed at least a 50% reduction in seizure frequency which had been sustained at follow-up; the remaining eight patients (19.5%) showed no response. Levetiracetam terminated three of the four (75%) patients with CSE, and the two patients with NCSE. Further seizures, but no recurrence of status occurred in two of the four patients with CSE (patients 43 and 45). Five of the six patients who received intravenous levetiracetam to replace their usual oral anti-epileptic medication had remained seizure-free on oral levetiracetam for between seven and 14 months at final follow-up; the remaining patient, who had not been seizure-free prior to substitution with levetiracetam, showed improved seizure control after nine months. None of the six patients restarted their previous AED. Adverse effects were observed in three children who developed aggressive behaviour, one of whom had to discontinue treatment because of persistence of this aggression (patient 4). This almost seven year-old had been described as being ‘‘impulsive’’ and ‘‘short-tempered’’ prior to receiving levetiracetam. No pre-existing behaviour problems had been reported in the two remaining patients. Forty-two patients (82%) including 35 of the 45 patients (78%) treated for ARS or SE remained on levetiracetam at the time of final follow-up, between two and 18 months after receiving the drug. Levetiracetam was discontinued in four patients, three because of lack of response and one because of verbal and physical aggression. 4. Discussion This open, prospective study of the use of intravenous levetiracetam in a range of acute clinical situations and for different seizure types and epilepsy syndromes has shown it to be effective and associated with few side-effects. The presenting seizure, including status epilepticus, was terminated in 29 of the 45 patients (64%) with these patients remaining seizure-free at the end of follow-up. The drug was discontinued in only one patient because of an unwanted side-effect (sustained aggression). Although the initial dose of the drug increased by approximately three-fold during the course of the study, no obvious difference was subsequently observed in either the drug’s efficacy or the incidence of side-effects, although the number of patients is too small to speculate on any possible dose–response. Intravenous levetiracetam has been reported to be effective and well-tolerated and therefore clinically useful in a range of clinical situations where the administration of other long-term antiepileptic drugs might be associated with potentially severe sideeffects or clinically significant drug interactions.15 These include: in neonates16 the management of acute seizures,6–18 a severe
A. McTague et al. / Seizure 21 (2012) 529–534
531
Table 1 Rapid loading with intravenous levetiracetam for acute repetitive seizures (ARS). Age when Syndrome/cause LEV given (years)
Seizure type
Prior treatment for this episode
Initial dose (mg/kg)
Response
Side effects
Remained on LEV: time of final follow-up (months)
1
2.2
PHY (with high therapeutic level) None
No further seizures
No
Yes (16)
1.8
Repeated focal clonic Focal evolving to GTC
10
2
Acute symptomatic/ post-head injury Unknown/presumed genetic
12
No further seizures
3
0.3
Refractory focal evolving to GTC
PHY, PHB (with 12 therapeutic levels)
No further seizures
4
6.8
11
Poor
14.5 10.2
PHY (with high therapeutic level) PHY (with therapeutic level)
11
6
Focal frontal and epileptic spasms Focal clonic evolving to GTC GTC
None
5
7
15.5
8
3.2
Structural/ pneumococcal meningitis Unknown/presumed genetic Acute symptomatic/ post-head injury Acute symptomatic/ hypertensive encephalopathy and acute leukaemia Unknown/ presumed genetic Acute symptomatic/ post-head injury
Yes (10) Yes (hyperactive and agitated which resolved after 24 h) No Yes (18)
9
3.3
Structural/severe perinatal HIE
Myoclonic and GTC Frequent focal with infrequent evolution to GTC Epileptic spasms and tonic
10
7.5
11
6.8
Structural/neonatal cerebral infarction Unknown
12 13
3.3 1.4
14
9.7
15
12.2
16
2.5
17
3.3
18
7.9
19
6.5
20
11.8
21
2.5
22
0.3
23
0.3
24
25
Unknown Metabolic/ Sandhoff’s disease Unknown (presumed genetic) Structural/PVL due to extreme prematurity Dravet syndrome Epilepsy of infancy with migrating focal seizures Unknown
No further seizures
Yes (physical aggression) No
No (adverse sideeffects persisted) Yes (5)
11
No further seizures
No
Yes (18)
None
11
No further seizures
No
Yes (6)
PHY (with therapeutic level)
12
No further seizures
No
Yes (4)
PHB (with high therapeutic level)
11
No
No
Focal
None
10
Seizure-free for 36 h then relapsed with no benefit following increased dose of LEV 75% reduction
No
Yes (4)
Focal
None
10
50% reduction
Yes (3)
GTC Focal and myoclonic GTC
None PHB (with high therapeutic level) PHY (with therapeutic level) None
10 10
No response 50% reduction
Yes (aggression which resolved after 72 h) No No
10
25% reduction
No
Yes (3)
10
No further seizures
No
Yes (5)
None
15
No further seizures
No
Yes (10)
PHY (with high therapeutic level)
10
None
No
No
PHB (with low therapeutic level) None
10
No further seizures
No
Yes (2)
10
No further seizures
No
PHY (with high therapeutic level)
10
75% reduction
No
Yes (3; then weaned off as seizure-free) Yes (4; then discontinued as seizure-free)
Focal
None
15
90% reduction
No
Yes (10)
Focal
None
30
Seizure-free for 24 h; relapsed with no benefit from increased dose of LEV Seizure-free for 36 h; relapsed and no response to further doses of LEV Seizure-free for 10 days; relapsed and no response to further doses of LEV
No
No
No
Yes (2; subsequently died due to primary disease) Yes (3; subsequently discontinued following readmission with absence status) Yes (3; discontinued as seizure-free)
Focal Myoclonic and GTC Focal evolving to GTC Focal
Acute symptomatic/ acute sepsis (and hepatic impairment) Acute symptomatic/ sepsis (on a background of cerebral palsy due severe HIE) Structural/ hemimegalencephaly Acute symptomatic/ neonatal porencephaly with infected V– P shunt Metabolic/ mitochondrial cytopathy
Focal evolving to GTC Focal evolving to GTC
GTC
None
10
0.3
Structural/ lissencephaly
GTC and myoclonic
PHB (with low therapeutic level)
15
0.3
Acute symptomatic/ high grade glioblastoma
Focal evolving to GTC
PHY (with therapeutic level)
No response to 15 mg/kg No I5 then after 36 h a but seizure-free after repeat load 30 mg/kg loading dose of 30
No
No Yes (4)
A. McTague et al. / Seizure 21 (2012) 529–534
532 Table 1 (Continued ) Age when Syndrome/cause LEV given (years)
Seizure type
26
2.5
Focal
27
14.4
28
2
29
18.8
30
1.3
31
10.7
32
Structural/ hemimegalencephaly Structural/Sturge– Weber syndrome
Prior treatment for this episode
Initial dose (mg/kg)
Response
Side effects
Remained on LEV: time of final follow-up (months)
30
Good initial response 75% reduction; no further seizures following a further intravenous dose of 12 mg/kg No response (required a midazolam infusion)
Yes
No (continued for 6 months) Yes (6)
No
Focal
None
20
Structural/bilateral cerebral dysgenesis
Focal evolving to GTC
PHY (with high therapeutic level)
30
Acute symptomatic/ focal intracerebral haemorrhage due to acute leukaemia Acute symptomatic/ posterior fossa tumour Structural/ periventricular nodular heterotopias
Focal evolving to GTC
None
10
No further seizures
No
Focal
None
10
No further seizures
No
Focal
Oral clobazam (frequent doses)
13
No
13
Unknown
None
20
No
Yes (8)
33
13.3
PHY (with low therapeutic level)
10
No further seizures
No
Yes (3; died due to primary disease)
34
6.6
Acute symptomatic/ relapsed cerebral B cell lymphoma Metabolic/ Alpers’ disease
Focal (frontal) evolving to GTC GTC
No response (required intravenous phenytoin) No further seizures
Yes (3; died due to primary disease) No
Epilepsia partialis Oral clobazam continua (frequent doses)
24
No
No
35
0.5
Epilepsy of infancy with migrating focal seizures
Focal
Midazolam infusion
25
No
Yes (8)
36
0.5
Focal
PHY; midazolam infusion
5
No
Yes (9)
37
3
Structural/hypoxic brain injury and Down syndrome Acute symptomatic/ encephalopathic illness of unknown cause
No response (required a midazolam infusion) Good response for 2 h; relapse requiring midazolam infusion No further seizures
Focal
10
No further seizures
No
Yes (3)
38
4.9
Metabolic/cerebral folate deficiency
GTC
PHB (with therapeutic level); midazolam infusion None
10
No
Yes (18)
39
0.8
Structural/ lissencephaly
GTC, myoclonic
No further seizures for 5 h; relapse and responded to increased dose of LEV (60 mg/kg/day) No further seizures; midazolam discontinued
No
No (relapsed after 96 h and failed to respond to increased dose of LEV)
Midazolam infusion
30
Yes (12; remains on intravenous levetiracetam because of profound gut dysmotility) No (4; died due to primary illness)
PHB: phenobarbital, PHY: phenytoin, HIE: hypoxic ischaemic encephalopathy, PVL: peri-ventricular leucomalacia.
epilepsy syndrome,19 myoclonic status epilepticus,20 following neurosurgery,21 in patients with brain tumours or other malignancies who are undergoing chemotherapy,22,23 and in critically ill patients with multi-organ failure or who are receiving a number of medications.7 In addition, preliminary and limited randomised controlled trial data suggest that levetiracetam may be associated with fewer adverse side-effects and improved long-term outcome than phenytoin.24 Intravenous levetiracetam was not administered in the A+ED because the current practice is that outlined in the recently revised Advanced Paediatric Life Support (APLS) guideline following the recommendation of the Status Epilepticus Working Group of the British Paediatric Neurology Association (BPNA). It is considered that any change in the acute management of children who present
to the A+ED should be based on evidence from a formal randomised controlled trial (RCT). The safety profile of any intravenously administered anticonvulsant is clearly important. Phenytoin may be associated with a number of complications including an idiosyncratic drug rash (including Stevens–Johnson syndrome), tissue extravasation leading potentially to the ‘purple glove’ syndrome, hypotension and cardiac arrhythmias which may be fatal.25,26 Finally, the drug has a problematic pharmacokinetic and pharmacodynamic profile with significant drug interactions and specifically with chemotherapeutic drugs and antibiotics. Phenobarbital may be associated with an idiosyncratic rash, sedation and significant respiratory suppression and drug interactions. Blood-monitoring is frequently required for both anticonvulsants. Finally, phenytoin must be
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533
Table 2 Intravenous levetiracetam in convulsive (CSE)/non-convulsive status epilepticus (NCSE). Age when LEV given (yrs)
8.2
40
41
12
Syndrome/cause
Status type
Usual maintenance treatment
Other treatment for this episode of status
Dose (mg/kg)
Response
Side effects
Remained on levetiracetam status at final follow-up (months)
Lennox Gastaut syndrome
Atypical absence (NCSE) NCSE
Clobazam
Clobazam (additional single dose)
10
Resolution of NCSE (clinical and on EEG)
No
Yes (8)
None
10
Seizure-free
No
Yes (9)
GTC (CSE)
Valproate and clobazam None
Rectal paraldehyde
10
No
No
Intravenous lorazepam; phenytoin (low therapeutic level) and phenobarbital (therapeutic level) Rectal diazepam and intravenous lorazepam
10
Seizure stopped but relapsed after 30 min; did not respond to a further dose of 10 mg/kg CSE terminated; seizures recurred >30 h but remained at >90% reduction thereafter
No
Yes (15)
42
4.3
Structural/ neonatal HIE Acute symptomatic/ intracerebral haemorrhage
43
0.5
Structural/PVL
GTC (CSE)
None
44
2.9
GTC (CSE)
None
45
0.2
Acute symptomatic/ pneumococcal pneumonia Acute symptomatic/ large subdural haemorrhage
GTC (CSE)
None
Intravenous lorazepam, intravenous phenobarbital and rectal paraldehyde
30
CSE terminated; no further seizures
No
Yes (3; no further seizures)
30
CSE terminated but further cluster GTC seizures after 14 h which responded to phenytoin
No
Yes (4)
PHB: phenobarbital, PHY: phenytoin, HIE: hypoxic ischaemic encephalopathy, PVL: peri-ventricular leucomalacia.
infused over a minimum of 20–30 min, during which time the child may still be convulsing. Adverse un-wanted side effects reported with intravenous levetiracetam include headache and fatigue, which are usually transient. Aggression may also occur and may necessitate discontinuation of the drug; anecdotal evidence would suggest that children with pre-existing behaviour problems may be at greater risk. The drug had to be discontinued in only one of our 51
Table 3 Seizure/syndrome details of 45 patients treated with intravenous levetiracetam for ARS or SE. ARS n = 39 Mean age (years)
5.4
NCSE n = 2
CSE n = 4
10.1
9.8
Gender Male Female
22 17
1 1
3 1
Seizure type Generalised tonic–clonic Focal (motor) Tonic Myoclonic Epileptic spasm Atypical absence
9 27 1 2 2 0
0 0 0 0 0 2
4 0 0 0 0 0
12 24
0 1
3 1
1 2
1 0
0 0
12 4 1 10
1 0 0 1
1 0 0 0
Syndrome Acute symptomatic Remote idiopathic/ cryptogenic/symptomatic Lennox–Gastaut syndrome Epilepsy of infancy with migrating partial seizures Aetiology (in non-acute symptomatic cases) Structural Metabolic Genetic Unknown
patients (1.9%) because of aggression; this patient had pre-existing behaviour problems manifest by impulsivity and poor angercontrol. Two other patients manifest transient aggression and irritability and neither was reported to have had any pre-existing behaviour problems. Finally, there is also no requirement to monitor blood levels of levetiracetam. Eighty-two per cent of our patients remained on levetiracetam at final follow-up. This includes the six patients who initially received intravenous levetiracetam because they were unable to continue taking their usual oral anti-epileptic drug. This ‘retention’ rate is higher than the 64% of patients in whom the presenting seizure was terminated by levetiracetam and reflects the fact that the drug was both effective and well-tolerated. Finally, it is of practical importance that the drug is available in both intravenous and oral preparations, which clearly facilitates its use beyond the acute situation. This study has a number of limitations. First, it was not a homogeneous population in terms of epilepsy syndrome or underlying cause. Second, approximately half of the patients did not receive levetiracetam as the first anticonvulsant, but only after a benzodiazepine or benzodiazepine and phenytoin/phenobarbital. However, the response rate was very similar between those who received levetiracetam as first-line treatment (65%) and those who received another long-acting anticonvulsant first (61%). Although this observation might suggest that levetiracetam is more effective when used first (65% vs. 61%), the difference could simply reflect the fact that the group who received levetiracetam after other anti-epileptic drugs was more refractory. Clearly, the numbers in the two groups are too small to make any definitive conclusion. Third, the initial loading dose changed during the study and the loading dose was considerably lower than that used in previous studies 2,6–9,11,13,15 (including neonates16) which have ranged from five to 50 mg/kg but most commonly in excess of 30 mg/kg. Consequently, it is of interest that our results are similar to previous studies that had employed considerably higher loading doses. Fourth, the duration of follow-up varied considerably and was under six months in 21 of the 52 patients. Fifth, it has not been
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A. McTague et al. / Seizure 21 (2012) 529–534
possible to compare these results with any control group. Such a group would have to have used historical data on the use of other anticonvulsants used in identical clinical situations within our hospital; it is most unlikely that such a group would be identifiable. In view of the encouraging efficacy and safety profile of levetiracetam, it has been suggested that this anticonvulsant could, and perhaps should, be used earlier in the treatment of status epilepticus.27,28 A recently published randomised study of the initial intravenous treatment of convulsive status epilepticus in adults reported seizure cessation rates of 76.3% (levetiracetam) and 75.6% (lorazepam).29 5. Conclusion Intravenous levetiracetam was effective and very well-tolerated in this small, heterogeneous population in the treatment of acute, repeated seizures and convulsive and non-convulsive status epilepticus. It was also effective and well-tolerated when used to replace other anti-epileptic drugs which could not be given orally. The drug potentially offers a more effective and safer option than traditional anti-epileptic drugs in treating acute, repeated (including symptomatic) seizures and status epilepticus. Growing evidence would support the view that levetiracetam should be considered as a replacement for phenytoin or phenobarbital and therefore the first-choice long-term anticonvulsant for use in the treatment of status epilepticus. This should now be confirmed (or refuted) with an RCT. Conflict of interest Dr Appleton has received consultancy fees and honoraria for leading masterclasses in epilepsy from UCB Pharma. UCB Pharma provides an unrestricted educational grant to support the publication of a quarterly journal, ‘Paediatric Epilepsy Current Awareness Service’ of which Dr Appleton is the Chief Co-Editor. References 1. Baulac M, Brodie MJ, Elger CE, Krakow K, Stockis A, Meyvisch P, et al. Levetiracetam intravenous infusion as an alternative to oral dosing in patients with partial-onset seizures. Epilepsia 2007;48:589–92. 2. Goraya JS, Khurana DS, Valencia I, Melvin JJ, Cruz M, Legido A, et al. Intravenous levetiracetam in children with epilepsy. Pediatric Neurology 2007;38:177–80. 3. Trabacca A, Profice P, Costanza MC, Gesualdi M, De Rinaldis M. Levetiracetam in nonconvulsive status epilepticus in childhood: a case report. Journal of Child Neurology 2007;22:639–41. 4. Farooq MU, Navavetia B, Majod A, Gupta R, Pysh JJ, Kassab MY. IV levetiracetam in the management of non-convulsive status epilepticus. Neurocritical Care 2007;7:36–9. 5. Knake S, Gruener J, Hattemer K, Klein KM, Bauer S, Oertel WH, et al. Intravenous levetiracetam in the treatment of benzodiazepine refractory status epilepticus. Journal of Neurology Neurosurgery and Psychiatry 2008;79:588–9.
6. Michaelides C, Thibert RL, Shapiro MJ, Kinirons P, John T, Manchharam D, et al. Tolerability and dosing experience of intravenous levetiracetam in children and infants. Epilepsy Research 2008;81:143–7. 7. Ruegg S, Naegelin Y, Hardmeier M, Winkler DT, Marsch S, Fuhr P. Intravenous levetiracetam: treatment experience with the first 50 critically ill patients. Epilepsy Behaviour 2008;12:477–80. 8. Wheless JW, Clarke D, Hovinga CA, Ellis M, Durmeier M, McGregor A, et al. Rapid infusion of a loading dose of intravenous levetiracetam with minimal dilution: a safety study. Journal of Child Neurology 2009;24:946–51. 9. Berning S, Boesebeck F, van Baalen A, Kellinghaus C. Intravenous levetiracetam as treatment for status epilepticus. Journal of Neurology 2009;256:1634–42. 10. Uges JWF, van Huizen MD, Engelsman J, Wilms EB, Touw DJ, Peeters E, et al. Safety and pharmacokinetics of intravenous levetiracetam infusion as add-on in status epilepticus. Epilepsia 2009;50:415–21. 11. Abend NS, Monk HM, Licht DJ, Dlugos DJ. Intravenous levetiracetam in critically ill children with status epilepticus or acute repetitive seizures. Pediatric Critical Care 2009;10:505–10. 12. Verrotti A, Adamo ED, Parisi P, Chiarelli F, Curatolo P. Levetiracetam in childhood epilepsy. Pediatric Drugs 2010;12:177–86. 13. Ng YT, Hastriter EV, Cardenas JF, Khoury EM, Chapman KE. Intravenous levetiracetam in children with seizures: a prospective safety study. Journal of Child Neurology 2010;25:551–5. 14. French J. Use of levetiracetam in special populations. Epilpesia 2001;42(Suppl. 4):40–3. 15. Kirmani BF, Crisp ED, Kayani S, Rajab H. Role of intravenous levetiracetam in acute seizure management of children. Pediatric Neurology 2009;41:37–9. 16. Khan O, Chang E, Cipriani C, Wright C, Crisp E, Kirmani B. Use of intravenous levetiracetam for management of acute seizures in neonates. Pediatric Neurology 2011;44:265–9. 17. Reiter PD, Huff AD, Knupp KG, Valuck RJ. Intravenous levetiracetam in the management of acute seizures in children. Pediatric Neurology 2010;43:117–21. 18. Depositario-Cabacar DT, Peters JM, Pong AW, Roth J, Rotenberg A, Riviello Jr JJ, et al. High-dose intravenous levetiracetam for acute seizure exacerbation in children with intractable epilepsy. Epilepsia 2010;51:1319–22. 19. Cilio MR, Bianchi R, Balestri M, Onofri A, Giovannini S, Di Capua M, et al. Intravenous levetiracetam terminates refractory status epilepticus in two patients with migrating partial seizures in infancy. Epilepsy Research 2009;86:66–71. 20. Haberlandt E, Sigl SB, Scholl-Buergl S, Karall D, Rauchenzauner M, Rostasy K. Levetiracetam in the treatment of two children with myoclonic status epilepticus. European Journal of Paediatric Neurology 2009;13:546–9. 21. Milligan TA, Hurwitz S, Bronmield EB. Efficacy and tolerability of levetiracetam versus phenytoin after supratentorial neurosurgery. Neurology 2008;71:665–9. 22. Tremont-Lukats IW, Ratilal BO, Armstrong T, Gilbert MR. Antiepileptic drugs for preventing seizures in people with brain tumours. Cochrane database of systematic reviews 2008;16:CD004424. 23. Usery JB, Michael II LM, Sills AK, Finch CK. A prospective evaluation and literature review of levetiracetam use in patients with brain tumors and seizures. Journal of Neuro-Oncology 2010;99:251–60. 24. Szaflarski JP, Sangha KS, Lindsell CJ, Shutter LA. Prospective, randomized, single-blinded comparative trial of intravenous levetiracetam versus phenytoin for seizure prophylaxis. Neurocritical Care 2010;12:165–72. 25. York RC, Coleridge ST. Cardiopulmonary arrest following intravenous phenytoin loading. American Journal of Emergency Medicine 1988;6:255–9. 26. Jones AL, Proudfoot AT. Features and management of poisoning with modern drugs used to treat epilepsy. Quarterly Journal of Medicine 1998;91:325–32. 27. Hirsch LJ. Levitating levetiracetam’s status for status epilepticus. Epilepsy Currents 2008;8:125–6. 28. Trinka E, Dobesberger J. New treatment options in status epilepticus: a critical review on intravenous levetiracetam. Therapeutic Advances in Neurological Disorders 2009;2:79–91. 29. Misra UK, Kalita J, Maurya PK. Levetiracetam versus lorazepam in status epilepticus: a randomized, open labeled pilot study. Journal of Neurology 2012;259:645–8.
Contents lists available at SciVerse ScienceDirect
Seizure journal homepage: www.elsevier.com/locate/yseiz
Intravenous levetiracetam in acute repetitive seizures and status epilepticus in children: Experience from a children’s hospital A. McTague a,c, R. Kneen a, R. Kumar a, S. Spinty a, R. Appleton a,b,* a b
Department of Paediatric Neurology, Alder Hey Children’s NHS Foundation Trust, Liverpool, UK Roald Dahl EEG Department, Alder Hey Children’s NHS Foundation Trust, Liverpool, UK
A R T I C L E I N F O
A B S T R A C T
Article history: Received 15 February 2012 Received in revised form 16 May 2012 Accepted 18 May 2012
Purpose: To report the effectiveness and safety of intravenous levetiracetam in the treatment of children with acute repeated seizures, and status epilepticus in a children’s hospital. Methods: This two-year observational study evaluated all in-patients who received intravenous levetiracetam to treat acute repeated seizures (ARS) or convulsive and non-convulsive status epilepticus (SE). Information was collected on seizure type, epilepsy syndrome and underlying cause, the initial loading dose of intravenous levetiracetam, its effectiveness and safety and whether the patient remained on the drug at final follow-up. Analysis was descriptive. Results: Fifty-one patients aged 0.2–18.8 (mean 7.1) years were evaluated, including 45 with acute ARS or SE and six unable to continue their usual orally administered anti-epileptic medication. The median initial dose of levetiracetam was 14.4 (range 5–30) mg/kg in the 45 patients treated for acute seizures and SE. Twenty three of the 39 (59%) patients with ARS became and remained seizure-free. Levetiracetam terminated status in three of four (75%) patients with convulsive, and the two patients with non-convulsive status epilepticus. Aggressive behaviour occurred in three children, one of whom discontinued treatment. Forty-two patients (81%), including 34 of the 45 patients (76%) treated for ARS or SE remained on levetiracetam at the time of final follow-up, between two and 18 months after receiving the drug. Conclusion: This observational study has confirmed previous data that intravenous levetiracetam seems to be effective and safe in the treatment of acute repeated seizures and status epilepticus. A randomised clinical trial is justified to determine whether intravenous levetiracetam should replace intravenous phenytoin as the first long-acting anticonvulsant in the management of acute repetitive seizures and status epilepticus. ß 2012 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
Keywords: Levetiracetam Status epilepticus Non-convulsive status epilepticus Acute repetitive seizures Anti-epileptic Anti-convulsant
1. Introduction Intravenous levetiracetam has been shown to be safe and effective in treating adults and children with convulsive and nonconvulsive status epilepticus and with acute repetitive seizures.1– 12 In contrast to phenytoin and phenobarbital, the traditionally used anticonvulsants used in the management of SE and ARS in children, there have been no reports of cardiac arrhythmias,
Abbreviations: ARS, acute repetitive seizures; SE, status epilepticus; CSE, convulsive status epilepticus; NCSE, non-convulsive status epilepticus; LEV, levetiracetam. * Corresponding author at: Department of Paediatric Neurology, Alder Hey Children’s NHS Foundation Trust, Eaton Road, Liverpool, L12 2AP, UK. Tel.: +44 151 252 5851; fax: +44 151 252 5678. E-mail address: [email protected] (R. Appleton). c Present address: Department of Neurosciences, UCL-Institute of Child Health, London, UK.
hypotension, tissue-extravasation reactions or respiratory depression associated with levetiracetam.6,8,13 In view of the rapidly increasing literature that has described the efficacy and safety of intravenous levetiracetam in a range of clinical situations, it was considered appropriate to undertake a pilot evaluation of the use of this drug in an in-patient paediatric population. The objective of this paper is to report this evaluation. 2. Materials and methods Approval for the use of intravenous levetiracetam (LEV) was obtained from this institution’s Clinical Development and Evaluation Group (CDEG) and the study was registered with the institution’s Audit Department (number: 3405). Data were recorded on a standardised proforma with information retrieved from the medical case notes and pharmacy records. Data collection was mainly retrospective.
1059-1311/$ – see front matter ß 2012 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.seizure.2012.05.010
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A. McTague et al. / Seizure 21 (2012) 529–534
Acute repeated seizures (ARS) were defined as repeated myoclonic, clonic, tonic or tonic–clonic seizures (each seizure lasting less than five minutes with recovery of consciousness between each seizure) that had persisted for at least 30 min irrespective of whether they had been treated with any emergency medication (a benzodiazepine alone or a benzodiazepine with either phenytoin or phenobarbital). Convulsive status epilepticus was defined as any single and prolonged tonic–clonic seizure that had persisted for over five minutes and irrespective of whether the child had received any emergency medication. The decision to use levetiracetam as first or second-line therapy in either ARS or CSE was determined by the attending clinician. Non-convulsive status epilepticus (NCSE) was defined on the basis of both the child’s clinical behaviour and electroencephalographic (EEG) activity; NCSE was not diagnosed without confirmatory EEG evidence. Termination of the seizure was defined as successful if it stopped within 10 min of completion of the infusion and there was no recurrence within the following 24 h. The protocol for administering intravenous levetiracetam was as followed: the initial dose was 10 mg/kg and ‘rounded up’ to facilitate the practical administration of the drug and infused over 10–15 min. During the final five months of the study, the dose was increased to 30 mg/kg, based on new clinical and pharmacokinetic data8 and administered over 15 min. All in-patients who received intravenous levetiracetam were included in the study. Patients who attended the Accident and Emergency Department (A+ED) with an acute seizure were excluded because these children are treated according to the national Advanced Paediatric Life Support (APLS) convulsive status epilepticus algorithm. Patients with established renal failure and who were on dialysis were also excluded from the study because of the reported reduced excretion of levetiracetam in this population.14 Information was collected on the following: age and sex; seizure type; epilepsy syndrome and cause if known; the reason for the administration of intravenous levetiracetam (ARS, CSE, NCSE or for the purpose of rapidly loading the patient); other anticonvulsants used to treat the same seizure episode; loading dose of levetiracetam; response to levetiracetam and whether the child remained on the drug at final follow-up.
3. Results Fifty one patients were studied between January 1st 2009 and December 31st 2010. The majority (39 [76%]) received the drug to try and terminate ARS. Four received the drug to terminate CSE and two to terminate NCSE. Details of the ages, seizure type, epilepsy syndrome and cause, occurrence of adverse effects and current follow-up of these 45 patients are shown in Tables 1–3. The remaining six patients received intravenous levetiracetam to replace another anti-epileptic drug because they were unable to continue with their usual maintenance AED (sodium valproate,3 carbamazepine,2 and lamotrigine1). Three patients were undergoing a major abdominal surgical procedure and could not take oral medication, two patients had probable valproate-related bone marrow suppression and the remaining patient developed hepatic dysfunction on carbamazepine. Five of these six patients had been seizure-free for between five and 18 months when their maintenance AED was changed to intravenous levetiracetam. These patients are not included in Tables 1 and 2. A review of pharmacy records did not identify any additional children who had received intravenous levetiracetam during the study period. The mean age of the 45 patients who received levetiracetam for ARS or CSE/NCSE was 5.65 (median 3.28, range 0.2–18.8) years. The
mean age of the remaining six patients was 5.24 (median 4.8, range 1.9–9.4) years. The mean initial dose of levetiracetam was 14.4 (median 15.1, range 5–30), mg/kg in the 45 patients treated for ARS and CSE/ NCSE. The mean dose was 16 (range 10–25) mg/kg in the six patients treated electively with levetiracetam as a substitute for their usual maintenance AED. Levetiracetam terminated the seizure in 24 of the 39 patients (62%) with ARS. Twenty of the 39 patients had received levetiracetam as the first anticonvulsant and in 13 (65%) the seizure stopped. In the remaining 19 patients, levetiracetam was given after another emergency medication and the seizure stopped in 12 (63%). Two of the 25 responders required an additional intravenous dose given within six hours of the initial dose (patients 25 and 38). Finally, an additional three patients (9, 22 and 23) became seizure-free but then relapsed after 24–36 h with no response to further doses of the anticonvulsant. Five patients showed at least a 50% reduction in seizure frequency which had been sustained at follow-up; the remaining eight patients (19.5%) showed no response. Levetiracetam terminated three of the four (75%) patients with CSE, and the two patients with NCSE. Further seizures, but no recurrence of status occurred in two of the four patients with CSE (patients 43 and 45). Five of the six patients who received intravenous levetiracetam to replace their usual oral anti-epileptic medication had remained seizure-free on oral levetiracetam for between seven and 14 months at final follow-up; the remaining patient, who had not been seizure-free prior to substitution with levetiracetam, showed improved seizure control after nine months. None of the six patients restarted their previous AED. Adverse effects were observed in three children who developed aggressive behaviour, one of whom had to discontinue treatment because of persistence of this aggression (patient 4). This almost seven year-old had been described as being ‘‘impulsive’’ and ‘‘short-tempered’’ prior to receiving levetiracetam. No pre-existing behaviour problems had been reported in the two remaining patients. Forty-two patients (82%) including 35 of the 45 patients (78%) treated for ARS or SE remained on levetiracetam at the time of final follow-up, between two and 18 months after receiving the drug. Levetiracetam was discontinued in four patients, three because of lack of response and one because of verbal and physical aggression. 4. Discussion This open, prospective study of the use of intravenous levetiracetam in a range of acute clinical situations and for different seizure types and epilepsy syndromes has shown it to be effective and associated with few side-effects. The presenting seizure, including status epilepticus, was terminated in 29 of the 45 patients (64%) with these patients remaining seizure-free at the end of follow-up. The drug was discontinued in only one patient because of an unwanted side-effect (sustained aggression). Although the initial dose of the drug increased by approximately three-fold during the course of the study, no obvious difference was subsequently observed in either the drug’s efficacy or the incidence of side-effects, although the number of patients is too small to speculate on any possible dose–response. Intravenous levetiracetam has been reported to be effective and well-tolerated and therefore clinically useful in a range of clinical situations where the administration of other long-term antiepileptic drugs might be associated with potentially severe sideeffects or clinically significant drug interactions.15 These include: in neonates16 the management of acute seizures,6–18 a severe
A. McTague et al. / Seizure 21 (2012) 529–534
531
Table 1 Rapid loading with intravenous levetiracetam for acute repetitive seizures (ARS). Age when Syndrome/cause LEV given (years)
Seizure type
Prior treatment for this episode
Initial dose (mg/kg)
Response
Side effects
Remained on LEV: time of final follow-up (months)
1
2.2
PHY (with high therapeutic level) None
No further seizures
No
Yes (16)
1.8
Repeated focal clonic Focal evolving to GTC
10
2
Acute symptomatic/ post-head injury Unknown/presumed genetic
12
No further seizures
3
0.3
Refractory focal evolving to GTC
PHY, PHB (with 12 therapeutic levels)
No further seizures
4
6.8
11
Poor
14.5 10.2
PHY (with high therapeutic level) PHY (with therapeutic level)
11
6
Focal frontal and epileptic spasms Focal clonic evolving to GTC GTC
None
5
7
15.5
8
3.2
Structural/ pneumococcal meningitis Unknown/presumed genetic Acute symptomatic/ post-head injury Acute symptomatic/ hypertensive encephalopathy and acute leukaemia Unknown/ presumed genetic Acute symptomatic/ post-head injury
Yes (10) Yes (hyperactive and agitated which resolved after 24 h) No Yes (18)
9
3.3
Structural/severe perinatal HIE
Myoclonic and GTC Frequent focal with infrequent evolution to GTC Epileptic spasms and tonic
10
7.5
11
6.8
Structural/neonatal cerebral infarction Unknown
12 13
3.3 1.4
14
9.7
15
12.2
16
2.5
17
3.3
18
7.9
19
6.5
20
11.8
21
2.5
22
0.3
23
0.3
24
25
Unknown Metabolic/ Sandhoff’s disease Unknown (presumed genetic) Structural/PVL due to extreme prematurity Dravet syndrome Epilepsy of infancy with migrating focal seizures Unknown
No further seizures
Yes (physical aggression) No
No (adverse sideeffects persisted) Yes (5)
11
No further seizures
No
Yes (18)
None
11
No further seizures
No
Yes (6)
PHY (with therapeutic level)
12
No further seizures
No
Yes (4)
PHB (with high therapeutic level)
11
No
No
Focal
None
10
Seizure-free for 36 h then relapsed with no benefit following increased dose of LEV 75% reduction
No
Yes (4)
Focal
None
10
50% reduction
Yes (3)
GTC Focal and myoclonic GTC
None PHB (with high therapeutic level) PHY (with therapeutic level) None
10 10
No response 50% reduction
Yes (aggression which resolved after 72 h) No No
10
25% reduction
No
Yes (3)
10
No further seizures
No
Yes (5)
None
15
No further seizures
No
Yes (10)
PHY (with high therapeutic level)
10
None
No
No
PHB (with low therapeutic level) None
10
No further seizures
No
Yes (2)
10
No further seizures
No
PHY (with high therapeutic level)
10
75% reduction
No
Yes (3; then weaned off as seizure-free) Yes (4; then discontinued as seizure-free)
Focal
None
15
90% reduction
No
Yes (10)
Focal
None
30
Seizure-free for 24 h; relapsed with no benefit from increased dose of LEV Seizure-free for 36 h; relapsed and no response to further doses of LEV Seizure-free for 10 days; relapsed and no response to further doses of LEV
No
No
No
Yes (2; subsequently died due to primary disease) Yes (3; subsequently discontinued following readmission with absence status) Yes (3; discontinued as seizure-free)
Focal Myoclonic and GTC Focal evolving to GTC Focal
Acute symptomatic/ acute sepsis (and hepatic impairment) Acute symptomatic/ sepsis (on a background of cerebral palsy due severe HIE) Structural/ hemimegalencephaly Acute symptomatic/ neonatal porencephaly with infected V– P shunt Metabolic/ mitochondrial cytopathy
Focal evolving to GTC Focal evolving to GTC
GTC
None
10
0.3
Structural/ lissencephaly
GTC and myoclonic
PHB (with low therapeutic level)
15
0.3
Acute symptomatic/ high grade glioblastoma
Focal evolving to GTC
PHY (with therapeutic level)
No response to 15 mg/kg No I5 then after 36 h a but seizure-free after repeat load 30 mg/kg loading dose of 30
No
No Yes (4)
A. McTague et al. / Seizure 21 (2012) 529–534
532 Table 1 (Continued ) Age when Syndrome/cause LEV given (years)
Seizure type
26
2.5
Focal
27
14.4
28
2
29
18.8
30
1.3
31
10.7
32
Structural/ hemimegalencephaly Structural/Sturge– Weber syndrome
Prior treatment for this episode
Initial dose (mg/kg)
Response
Side effects
Remained on LEV: time of final follow-up (months)
30
Good initial response 75% reduction; no further seizures following a further intravenous dose of 12 mg/kg No response (required a midazolam infusion)
Yes
No (continued for 6 months) Yes (6)
No
Focal
None
20
Structural/bilateral cerebral dysgenesis
Focal evolving to GTC
PHY (with high therapeutic level)
30
Acute symptomatic/ focal intracerebral haemorrhage due to acute leukaemia Acute symptomatic/ posterior fossa tumour Structural/ periventricular nodular heterotopias
Focal evolving to GTC
None
10
No further seizures
No
Focal
None
10
No further seizures
No
Focal
Oral clobazam (frequent doses)
13
No
13
Unknown
None
20
No
Yes (8)
33
13.3
PHY (with low therapeutic level)
10
No further seizures
No
Yes (3; died due to primary disease)
34
6.6
Acute symptomatic/ relapsed cerebral B cell lymphoma Metabolic/ Alpers’ disease
Focal (frontal) evolving to GTC GTC
No response (required intravenous phenytoin) No further seizures
Yes (3; died due to primary disease) No
Epilepsia partialis Oral clobazam continua (frequent doses)
24
No
No
35
0.5
Epilepsy of infancy with migrating focal seizures
Focal
Midazolam infusion
25
No
Yes (8)
36
0.5
Focal
PHY; midazolam infusion
5
No
Yes (9)
37
3
Structural/hypoxic brain injury and Down syndrome Acute symptomatic/ encephalopathic illness of unknown cause
No response (required a midazolam infusion) Good response for 2 h; relapse requiring midazolam infusion No further seizures
Focal
10
No further seizures
No
Yes (3)
38
4.9
Metabolic/cerebral folate deficiency
GTC
PHB (with therapeutic level); midazolam infusion None
10
No
Yes (18)
39
0.8
Structural/ lissencephaly
GTC, myoclonic
No further seizures for 5 h; relapse and responded to increased dose of LEV (60 mg/kg/day) No further seizures; midazolam discontinued
No
No (relapsed after 96 h and failed to respond to increased dose of LEV)
Midazolam infusion
30
Yes (12; remains on intravenous levetiracetam because of profound gut dysmotility) No (4; died due to primary illness)
PHB: phenobarbital, PHY: phenytoin, HIE: hypoxic ischaemic encephalopathy, PVL: peri-ventricular leucomalacia.
epilepsy syndrome,19 myoclonic status epilepticus,20 following neurosurgery,21 in patients with brain tumours or other malignancies who are undergoing chemotherapy,22,23 and in critically ill patients with multi-organ failure or who are receiving a number of medications.7 In addition, preliminary and limited randomised controlled trial data suggest that levetiracetam may be associated with fewer adverse side-effects and improved long-term outcome than phenytoin.24 Intravenous levetiracetam was not administered in the A+ED because the current practice is that outlined in the recently revised Advanced Paediatric Life Support (APLS) guideline following the recommendation of the Status Epilepticus Working Group of the British Paediatric Neurology Association (BPNA). It is considered that any change in the acute management of children who present
to the A+ED should be based on evidence from a formal randomised controlled trial (RCT). The safety profile of any intravenously administered anticonvulsant is clearly important. Phenytoin may be associated with a number of complications including an idiosyncratic drug rash (including Stevens–Johnson syndrome), tissue extravasation leading potentially to the ‘purple glove’ syndrome, hypotension and cardiac arrhythmias which may be fatal.25,26 Finally, the drug has a problematic pharmacokinetic and pharmacodynamic profile with significant drug interactions and specifically with chemotherapeutic drugs and antibiotics. Phenobarbital may be associated with an idiosyncratic rash, sedation and significant respiratory suppression and drug interactions. Blood-monitoring is frequently required for both anticonvulsants. Finally, phenytoin must be
A. McTague et al. / Seizure 21 (2012) 529–534
533
Table 2 Intravenous levetiracetam in convulsive (CSE)/non-convulsive status epilepticus (NCSE). Age when LEV given (yrs)
8.2
40
41
12
Syndrome/cause
Status type
Usual maintenance treatment
Other treatment for this episode of status
Dose (mg/kg)
Response
Side effects
Remained on levetiracetam status at final follow-up (months)
Lennox Gastaut syndrome
Atypical absence (NCSE) NCSE
Clobazam
Clobazam (additional single dose)
10
Resolution of NCSE (clinical and on EEG)
No
Yes (8)
None
10
Seizure-free
No
Yes (9)
GTC (CSE)
Valproate and clobazam None
Rectal paraldehyde
10
No
No
Intravenous lorazepam; phenytoin (low therapeutic level) and phenobarbital (therapeutic level) Rectal diazepam and intravenous lorazepam
10
Seizure stopped but relapsed after 30 min; did not respond to a further dose of 10 mg/kg CSE terminated; seizures recurred >30 h but remained at >90% reduction thereafter
No
Yes (15)
42
4.3
Structural/ neonatal HIE Acute symptomatic/ intracerebral haemorrhage
43
0.5
Structural/PVL
GTC (CSE)
None
44
2.9
GTC (CSE)
None
45
0.2
Acute symptomatic/ pneumococcal pneumonia Acute symptomatic/ large subdural haemorrhage
GTC (CSE)
None
Intravenous lorazepam, intravenous phenobarbital and rectal paraldehyde
30
CSE terminated; no further seizures
No
Yes (3; no further seizures)
30
CSE terminated but further cluster GTC seizures after 14 h which responded to phenytoin
No
Yes (4)
PHB: phenobarbital, PHY: phenytoin, HIE: hypoxic ischaemic encephalopathy, PVL: peri-ventricular leucomalacia.
infused over a minimum of 20–30 min, during which time the child may still be convulsing. Adverse un-wanted side effects reported with intravenous levetiracetam include headache and fatigue, which are usually transient. Aggression may also occur and may necessitate discontinuation of the drug; anecdotal evidence would suggest that children with pre-existing behaviour problems may be at greater risk. The drug had to be discontinued in only one of our 51
Table 3 Seizure/syndrome details of 45 patients treated with intravenous levetiracetam for ARS or SE. ARS n = 39 Mean age (years)
5.4
NCSE n = 2
CSE n = 4
10.1
9.8
Gender Male Female
22 17
1 1
3 1
Seizure type Generalised tonic–clonic Focal (motor) Tonic Myoclonic Epileptic spasm Atypical absence
9 27 1 2 2 0
0 0 0 0 0 2
4 0 0 0 0 0
12 24
0 1
3 1
1 2
1 0
0 0
12 4 1 10
1 0 0 1
1 0 0 0
Syndrome Acute symptomatic Remote idiopathic/ cryptogenic/symptomatic Lennox–Gastaut syndrome Epilepsy of infancy with migrating partial seizures Aetiology (in non-acute symptomatic cases) Structural Metabolic Genetic Unknown
patients (1.9%) because of aggression; this patient had pre-existing behaviour problems manifest by impulsivity and poor angercontrol. Two other patients manifest transient aggression and irritability and neither was reported to have had any pre-existing behaviour problems. Finally, there is also no requirement to monitor blood levels of levetiracetam. Eighty-two per cent of our patients remained on levetiracetam at final follow-up. This includes the six patients who initially received intravenous levetiracetam because they were unable to continue taking their usual oral anti-epileptic drug. This ‘retention’ rate is higher than the 64% of patients in whom the presenting seizure was terminated by levetiracetam and reflects the fact that the drug was both effective and well-tolerated. Finally, it is of practical importance that the drug is available in both intravenous and oral preparations, which clearly facilitates its use beyond the acute situation. This study has a number of limitations. First, it was not a homogeneous population in terms of epilepsy syndrome or underlying cause. Second, approximately half of the patients did not receive levetiracetam as the first anticonvulsant, but only after a benzodiazepine or benzodiazepine and phenytoin/phenobarbital. However, the response rate was very similar between those who received levetiracetam as first-line treatment (65%) and those who received another long-acting anticonvulsant first (61%). Although this observation might suggest that levetiracetam is more effective when used first (65% vs. 61%), the difference could simply reflect the fact that the group who received levetiracetam after other anti-epileptic drugs was more refractory. Clearly, the numbers in the two groups are too small to make any definitive conclusion. Third, the initial loading dose changed during the study and the loading dose was considerably lower than that used in previous studies 2,6–9,11,13,15 (including neonates16) which have ranged from five to 50 mg/kg but most commonly in excess of 30 mg/kg. Consequently, it is of interest that our results are similar to previous studies that had employed considerably higher loading doses. Fourth, the duration of follow-up varied considerably and was under six months in 21 of the 52 patients. Fifth, it has not been
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possible to compare these results with any control group. Such a group would have to have used historical data on the use of other anticonvulsants used in identical clinical situations within our hospital; it is most unlikely that such a group would be identifiable. In view of the encouraging efficacy and safety profile of levetiracetam, it has been suggested that this anticonvulsant could, and perhaps should, be used earlier in the treatment of status epilepticus.27,28 A recently published randomised study of the initial intravenous treatment of convulsive status epilepticus in adults reported seizure cessation rates of 76.3% (levetiracetam) and 75.6% (lorazepam).29 5. Conclusion Intravenous levetiracetam was effective and very well-tolerated in this small, heterogeneous population in the treatment of acute, repeated seizures and convulsive and non-convulsive status epilepticus. It was also effective and well-tolerated when used to replace other anti-epileptic drugs which could not be given orally. The drug potentially offers a more effective and safer option than traditional anti-epileptic drugs in treating acute, repeated (including symptomatic) seizures and status epilepticus. Growing evidence would support the view that levetiracetam should be considered as a replacement for phenytoin or phenobarbital and therefore the first-choice long-term anticonvulsant for use in the treatment of status epilepticus. This should now be confirmed (or refuted) with an RCT. Conflict of interest Dr Appleton has received consultancy fees and honoraria for leading masterclasses in epilepsy from UCB Pharma. UCB Pharma provides an unrestricted educational grant to support the publication of a quarterly journal, ‘Paediatric Epilepsy Current Awareness Service’ of which Dr Appleton is the Chief Co-Editor. References 1. Baulac M, Brodie MJ, Elger CE, Krakow K, Stockis A, Meyvisch P, et al. Levetiracetam intravenous infusion as an alternative to oral dosing in patients with partial-onset seizures. Epilepsia 2007;48:589–92. 2. Goraya JS, Khurana DS, Valencia I, Melvin JJ, Cruz M, Legido A, et al. Intravenous levetiracetam in children with epilepsy. Pediatric Neurology 2007;38:177–80. 3. Trabacca A, Profice P, Costanza MC, Gesualdi M, De Rinaldis M. Levetiracetam in nonconvulsive status epilepticus in childhood: a case report. Journal of Child Neurology 2007;22:639–41. 4. Farooq MU, Navavetia B, Majod A, Gupta R, Pysh JJ, Kassab MY. IV levetiracetam in the management of non-convulsive status epilepticus. Neurocritical Care 2007;7:36–9. 5. Knake S, Gruener J, Hattemer K, Klein KM, Bauer S, Oertel WH, et al. Intravenous levetiracetam in the treatment of benzodiazepine refractory status epilepticus. Journal of Neurology Neurosurgery and Psychiatry 2008;79:588–9.
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