Int J Clin Pharm DOI 10.1007/s11096-015-0105-4

CASE REPORT

Role of high-dose levetiracetam as add-on therapy for intractable epilepsy: case report and brief review of the literature Hector Mateo-Carrasco1 • Pedro Jesu´s Serrano-Castro2 • Emilio Molina-Cuadrado3 Mel Goodwin4 • Timothy V. Nguyen5,6 • Primal N. Kotecha7



Received: 23 November 2014 / Accepted: 10 March 2015  Koninklijke Nederlandse Maatschappij ter bevordering der Pharmacie 2015

Abstract Case We discuss the case of a 5-year-old longstanding epileptic woman, who received oxcarbazepine 2.1 g/day, and levetiracetam 3 g/day (started in 2005 and up-titrated according to response). In October/2008, due to poor seizure control, patient consent was obtained and levetiracetam up-titrated to 6 g/day, remaining invariable for 72 months; zonisamide was added in July/2009 and uptitrated to 500 mg/day. This combination achieved seizure frequency reduction C50 %, however, the patient ultimately necessitated temporal lobectomy for complete remission. Occasional agitation and moderate depression were the main side effects. Conclusion Three anti-epileptic drugs (including levetiracetam 6 g/day) achieved statistically-significant seizure frequency reduction C50 % compared with lower doses, but not seizure freedom. Low-dose

risperidone was initiated due to transient dose-dependent agitation, although it did not lead to discontinuation. This report provides insightful information on the use of highdose levetiracetam in focal refractory epilepsy. The concomitance of anti-epileptics may have contributed to both efficacy and toxicity. Therefore, the risk/benefit ratio must be individually weighed until larger studies are available. Keywords Case reports  Epilepsy  Keppra  Levetiracetam  Maximum tolerated dose

Impacts of practice statement •

• & Hector Mateo-Carrasco [email protected] 1

Pharmacy Department, Northampton General Hospital NHS Trust, Cliftonville, Northampton NN1 5BD, UK

2

Neurology and Neurophysiology Unit, Torrecardenas Hospital, Almerı´a, Spain

3

Pharmacy Department, Torrecardenas Hospital, Almerı´a, Spain

4

Neurology Department, Northampton General Hospital, Northampton, UK

5

Pharmacy Faculty Council, AMS College of Pharmacy and Health Sciences, Long Island University, Brooklyn, NY, USA

6

LIU’s Division of Physician Assistant Studies, Saint Peter’s University, Jersey City, NJ, USA

7

Pharmacy Department, Kettering General Hospital NHS Trust, Kettering, UK

The use of levetiracetam doses as high as 6 g/day, as add-on therapy in the management of a patient suffering from complex partial seizures, is feasible. Further research into the role of high doses levetiracetam in the treatment of poorly controlled epileptic patients is necessary.

Introduction Evidence on levetiracetam doses [3 g/day is limited and inconsistent, and is not supported by current guidelines [1]. In a dose-escalation study by Grant and Shorvon, 29 adult patients were up-titrated over 16 weeks, observing a reduction in seizure frequency C50 % (RSF C 50 %), and an increment in seizure-free patients with 4 g/day [2]. Conversely, Betts et al. compared 2, 4 g/day, and placebo as add-on therapy in 119 patients with refractory partial and/ or generalized seizures. Although superior to placebo, the number of patients achieving RSF C 50 % between 2 and 4 g/day was not significant [3]. In both studies, dose-

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dependent somnolence and asthenia were the most common reasons for discontinuation [2, 3]. According to the NICE guidelines, the treatment of focal refractory epilepsy should consider the addition of second and/or third-line AEDs when maximum recommended doses of one or two AEDs, respectively, fail to control the epilepsies or are not well tolerated [1]. A novel case of a patient with refractory focal complex epilepsy on levetiracetam 6 g/day for 72 months as add-on therapy is discussed herein.

Ethical approval Patient’s consent was obtained and documented in the clinical records. Ethical approval was not required as per local policy.

Case description This was an adult Caucasian female (165 cm, 66 kg) with poorly-controlled complex focal seizures since age three. The baseline was nine-to-ten seizures/month of left anterior temporal onset, with interdependent inter-ictal right-sided discharges lasting 6–9 min confirmed by an ambulatory electroencephalogram (2002). A magnetic resonance imaging (2006) showed a relatively small left hippocampus consistent with mesial temporal sclerosis. Medical history: moderate depressive episode (July/ 2002) confirmed by a mental state examination requiring fluoxetine for 2 years, two intentional acetaminophen overdoses (2003, 2005), a suicidal attempt (jumped off a bridge in 2005), and ferropenic anaemia (2006). Drug history: naproxen 500 mg twice daily (acute course), ferrous sulphate 200 mg (65 mg elemental iron) three times/day, hydroxocobalamin injection 1 mg three monthly, and folic acid 5 mg/day. No known drug allergies, alcohol or illicit substances abuse. Oxcarbazepine was started in 1992 and up-titrated to 2.4 g/day (maximum licensed dose), but this caused dosedependent diplopia and was reduced to 2.1 g/day (Fig. 1). Levetiracetam was initiated in April/2005 and up-titrated to 3 g/day according to response [1]. During the first weeks following each dose augmentation, particularly in the early phases of the escalation, the patient experienced RSF C 50 %; however, the number of episodes increased back to baseline over the following months. This was less pronounced in later stages of the up-titration. Levetiracetam plasma levels were 41 lg/L [12–46 lg/L] in May/ 2008. In October/2008, based on its good tolerability at lower doses and the patient’s preferences, levetiracetam was increased until seizure control or side effects were

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inacceptable. Doses of 6 g/day were achieved in May/ 2009, which remained invariable until the end of the observations (total 72 months). Plasma levels were 64 lg/L (September/2009), and 66 lg/L (January/2013). Following a careful risk–benefit evaluation, zonisamide was initiated in July/2009 and up-titrated to 500 mg/day (maximum licensed dose), observing a similar remission-relapse pattern. Finally, short-term clobazam 10 mg/day was started in April/2012 until the patient was referred for surgery. The patient reported good adherence to her medication. Two episodes of mild-to-moderate depression (October/ 2006, April/2011), and a transient episode of agitation (August/2011) that required risperidone 0.5 mg twice/day were reported. In February/2013, the patient was admitted for elective temporal lobe surgery. Physical and neurological examinations, haematological and biochemical parameters, urinalysis, thyroid function, and drugs of abuse were found unremarkable. The patient developed mild intracranial bleeding post-surgery, which subsided after a few weeks. On follow-up appointments the patient reported progressive improvement, achieving and maintaining seizure freedom 12 months post-intervention and until the closure of the observations. In October/2013, zonisamide was down-titrated and discontinued. Medline, Embase, and PsycINFO were searched for studies on high-dose levetiracetam. Simple-and-advanced searches with different combinations of the terms: [LEVETIRACETAM], [DOSE, MAXIMUM TOLERATED], [OVERDOSE], and/or [EFFECTS, LONGTERM] were used. Citations were cross-referenced and [KEPPRA] was used as alternative term. Clinicatrials.gov and the EU clinical trials register were searched for ongoing or unpublished trials in the US and Europe, respectively. Finally the manufacturer was contacted for unpublished data.

Discussion Levetiracetam doses [3 g/day (3.37 ± 2.29 seizures/month) achieved RSF C 50 % compared with doses B3 g/day (6.09 ± 3.67). The mean difference (2.72) was statistically significant: t = 4.35(66); p \ 0.001; 95 % confidence interval (95 % CI) [1.47, 3.97]. Doses of 6 g/day (1.81 ± 1.81) achieved RSF C 50 % compared with 3.5–5.5 g/day (4.46 ± 1.95). The mean difference between both periods (2.65) was statistically significant: t = 5.46(61); p \ 0.001; 95 % CI [1.68, 3.62]. Finally, three AEDs (2.89 ± 1.92) achieved RSF C 50 % when compared with two AEDs (6.24 ± 3.46). The mean difference (3.35) was statistically significant: t = 6.09(76); p \ 0.001; 95 % CI [2.25, 4.43].

Int J Clin Pharm

Fig. 1 Seizure frequency and doses of AEDs during up-titration and maintenance

An initial fall in seizure frequency was immediately achieved following each increase, particularly at the beginning of the up-titration, but the positive effect was less durable towards the end of the escalation. This correlates with the levetiracetam linear kinetics within the dose range 0.5–5 g, and would explain the tendency to return to baseline more rapidly towards the higher-end of the uptitration. Moreover, this is in agreement with the study by Kang et al., in which 59.82 % of patients who received a dose increase during the follow-up period achieved RSF C 50 % compared with the previous dose. However, this percentage varied markedly according to the epilepsy subtype, and more importantly, doses were never titrated above 3 g/day [4]. Zonisamide showed a similar relapse-remission pattern, supporting the concept that the patient benefited from AEDs acting by different mechanisms [1]. Despite the combination of three AEDs, only short seizure-free periods (measure with the greatest impact in quality of life) were achieved, and the patient ultimately necessitated surgical intervention.

This report is consistent with the 4-week dose-escalation study conducted by Grant and Shorvon, which showed RSF C 50 % and a higher number of seizure-free patients with 4 g/day compared with 3 g/day [2]. Conversely, the study by Betts et al. [3] found no significant differences between 2 and 4 g/day. This study was included in a review by Mbizvo et al. [5], who reported a lack of data to provide details on efficacy with 4 g/day. The rationale behind these discrepancies may rely on the exceptionally high doses used on a long-term basis. More importantly, this study was not designed to establish differences between intermediate doses, and the AEDs were up-titrated according to response rather than at regular intervals. The patient experienced two episodes of depression: October/2006 (while on oxcarbazepine 2.4 g/day plus levetiracetam 2 g/day), and April/2011 (while on three AEDs at maximum doses). Furthermore, a transient episode of agitation occurred in August/2011 (again on maximum doses of three AEDs). None of the aforementioned side effects leaded to discontinuation (the risk– benefit ratio was periodically re-assessed). Whereas these

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are well-recognized behavioural side effects of levetiracetam (phenomenon termed kepprage), a univocal correlation cannot be established due to the additive toxicities of other AEDs and the previous history of depression. However, the timeline of events is in line with the work by Bootsma et al. [6], where patients who discontinued treatment because of poor tolerability reached lower doses than patients who discontinued it due to inefficacy. This suggests that side effects that determined discontinuation appear early in the up-titration, and somehow reinforces the idea that levetiracetam was well-tolerated, particularly at lower doses [2, 3, 5]. Additionally, this report suggests that levetiracetam could be used safely over the [12-46 lg/L] range in some patients. This is in line with the work by Perucca, who advocates the use of individual therapeutic concentrations to guide the treatment rather than fixed doses [7]. Caveats associated with these findings reside in the lack of high-dose standardised studies, the complex relapse/remission course of the disease, and the AEDs overlapping toxicities.

Conclusion This report provides insightful information beyond the manufacturer information and the clinical trials, suggesting that high-dose levetiracetam might play a role in the long-term management of refractory epilepsy in selected

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patients. However, its risk/benefit ratio must be individually weighed until larger studies address these issues. Funding

None.

Conflicts of interest

None.

References 1. National Institute for Health and Care Excellence. The epilepsies: the diagnosis and management of the epilepsies in adults and children in primary and secondary care. http://www.nice.org.uk. Accessed 22th Nov 2014. 2. Grant R, Shorvon SD. Efficacy and tolerability of 1,000-4,000 mg per day of levetiracetam as add-on therapy on patients with refractory epilepsy. Epilepsy Res. 2000;42:89–95. 3. Betts T, Waegemans T, Crawford P. A multicentre, double-blind, randomised, parallel-group study to evaluate the tolerability and efficacy of two oral doses of levetiracetam, 2,000 mg daily and 4,000 mg daily, without titration in patients with refractory epilepsy. Seizure. 2000;9:80–7. 4. Kang BS, Moon HJ, Kim YS, Lee ST, Jung KH, Chu K, et al. The long-term efficacy and safety of levetiracetam in a tertiary epilepsy centre. Epileptic disord. 2013;15(3):302–10. 5. Mbizvo GK, Dixon P, Hutton JL, Marson AG. Levetiracetam addon for drug-resistant focal epilepsy: an updated Cochrane Review. Cochrane Database Syst Rev. 2012;12(9):CD001901. 6. Bootsma HP, Ricker L, Diepman L, et al. Levetiracetam in clinical practice: long-term experience in patients with refractory epilepsy referred to a tertiary epilepsy center. Epilepsy Behav. 2007;10: 296–303. 7. Perucca E. Is there a role for therapeutic drug monitoring of new anticonvulsants? Clin Pharmacokinet. 2000;38:191–204.

Role of high-dose levetiracetam as add-on therapy for intractable epilepsy: case report and brief review of the literature.

We discuss the case of a 5-year-old long-standing epileptic woman, who received oxcarbazepine 2.1 g/day, and levetiracetam 3 g/day (started in 2005 an...
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