Epilepsy & Behavior 23 (2012) 394–395

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Epilepsy & Behavior
journal homepage: www.elsevier.com/locate/yebeh

Letter to the Editor
Recurrent seizures in a levetiracetam-treated patient after
subarachnoid hemorrhage: A matter of enhanced renal function?

To the Editor:
We would like to report a 55-year-old female patient who was admitted to the Neurosurgical Department of the University Hospital
Magdeburg (Germany) after subarachnoid hemorrhage (SAH) and
onset of generalized tonic–clonic seizures. Digital subtraction angiography revealed an anterior communicating artery aneurysm that was
treated by endovascular coiling. The patient was transferred to the neurosurgical intensive care unit (ICU) for further monitoring. Due to recurrent seizures, an anticonvulsant treatment was initiated with 500-mg
intravenous levetiracetam twice a day as recommended. Therapeutic
drug monitoring was performed [1] as part of a standard procedure in
intensive care patients at the University Hospital Magdeburg.
The results are shown in Fig. 1. As presented, the levetiracetam
plasma trough concentrations were below the target threshold
(therapeutic range 6–20 μg/ml). A stepwise dose adjustment became necessary because the seizures did not terminate. Even at
a daily dose of 2-g levetiracetam, the plasma trough level
remained below 6 μg/ml without a clear reason. The patient's
weight was normal for height (70 kg; body mass index = 25.4 kg/
m 2), and the body fluid was well balanced. Thus, a daily dose of
2-g levetiracetam would have been appropriate to achieve effective plasma concentrations or at least to improve the clinical
state. On the 10th day after admission, creatinine clearance (ClCrea) was determined by collecting urine for 24 h to prove the possibility of drug underdosing due to an enhanced renal function as
previously described for antibiotics in critically ill patients [2]. The
measurement revealed a ClCrea of 161.4 ml/min, which was higher
than the accepted normal value of 120 ml/min and which led to
the diagnosis of glomerular hyperfiltration [3]. Estimation of the
renal function with the Cockcroft–Gault formula [4] for the
remaining days showed comparable results. According to the
patient's age, even a ClCrea of 80 ml/min would be considered normal. Thus, the determined renal function was more than twice as
high as expected.
This extent of enhanced kidney function justified a further dose adjustment above the approved maximum daily dose of 3-g levetiracetam.
Even a dosage of 3.5 g resulted in ineffective trough levels. Finally, a
daily dose of 4-g levetiracetam was successful to achieve a value of
8.93-μg/ml levetiracetam followed by an improvement of the patient's
convulsive disorder. Given that the renal function remained stable
over the whole stay, the high-dose regimen was continued, and the
patient could be discharged from the ICU 8 days later.
Generalized or focal seizures are not uncommon complications
after aneurysmal SAH [5]. Due to its favorable safety profile and
ease of use, levetiracetam has become a frequent treatment option
in those cases [6]. According to its pharmacokinetic properties,
a dose adjustment is highly recommended in patients with renal
1525-5050/$ – see front matter © 2012 Elsevier Inc. All rights reserved.
doi:10.1016/j.yebeh.2011.12.016

impairment as levetiracetam is predominantly eliminated by the
kidneys [7].
The approach of dose reduction in renal impairment is generally
accepted. However, a dose increase has not yet been clinically established in enhanced renal function although it could be demonstrated
that plasma concentrations of renally eliminated drugs such as antibiotics can exceedingly decrease in those cases [2]. No data are currently available for levetiracetam and other antiepileptic drugs regarding
this topic.
Nevertheless, Spencer et al. recently published a levetiracetam
pharmacokinetic investigation including 12 neurocritical care patients requiring seizure prophylaxis after neurologic injury [8]. They
concluded that levetiracetam clearance was faster and the elimination half-life was shorter in this special patient population. Indeed,
they obtained their high-dosage data from a pharmacokinetic model
and Monte Carlo simulation. Both the drug clearance and the renal
function were estimated. Thus, there is uncertainty if enhanced kidney function could be a reason for the altered levetiracetam pharmacokinetics in their assessment. Additionally, none of the patients had
seizures during the ICU stay. Levetiracetam was only administered for
seizure prophylaxis in this study [8].
In contrast, we could observe a clear reduction in levetiracetam plasma trough concentrations, accompanied by seizures. The measured
value of ClCrea was very high and led to the adjustment of levetiracetam
which resulted in doses above the approved maximum daily dosage [9].
The final concentration of about 9 μg/ml was successful to clearly improve the patient's clinical state without any further seizures.
As discussed by Spencer et al., levetiracetam dosing is often based
on clinical response rather than on dosing to achieve a desired plasma
concentration [8]. However, in case of incomplete seizure control despite the use of high dosages, therapeutic drug monitoring can be a
powerful approach to detect drug underdosing, especially in critically
ill patients [10]. Indeed, the suggested therapeutic range of 6–20 μg/
ml is not based on controlled clinical trials [8,11]. Nevertheless, the
aim to monitor levetiracetam in critical care patients is both prevention from toxicity in case of renal impairment and ensuring of effective plasma levels in case of glomerular hyperfiltration as diagnosed
in our patient.
The cause of the high renal function remains unknown. There are
several possible reasons described in the literature like sepsis, hypertension, diabetes or treatment with catecholamines [2]. None of these
conditions was fulfilled by our patient. We know that data of just one
case are generally limited. However, they support the observation of
Spencer et al. for alteration of levetiracetam pharmacokinetics
in neurocritical care situations [8]. Probably, enhanced renal function
will emerge as a simple reason for a possible levetiracetam underdosing
in larger prospective trials regarding neurocritical patients. Further
study is required to investigate this problem.

Conflict of interest statement
None of the authors has any conflict of interest to disclose.

Letter to the Editor

395

Fig. 1. Levetiracetam daily dosage and plasma concentrations depending on the creatinine clearance. ⁎ measured value of creatinine clearance for diagnosis of glomerular hyperfiltration (all remaining values are estimated).

Acknowledgment
The authors want to thank Regina Kubla and Kerstin Winkelmann
for technical assistance.
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Andreas Drust
Institute of Clinical Pharmacology, Otto-von-Guericke-University
Magdeburg, Leipziger Straße 44, 39120 Magdeburg, Germany
Corresponding author. Fax: +49 3916713062.
E-mail address: andreas.drust@med.ovgu.de.
Michael Luchtmann
Raimund Firsching
Department of Neurosurgery, Otto-von-Guericke-University Magdeburg,
Leipziger Straße 44, 39120 Magdeburg, Germany
Uwe Tröger
Jens Martens-Lobenhoffer
Stefanie M. Bode-Böger
Institute of Clinical Pharmacology, Otto-von-Guericke-University
Magdeburg, Leipziger Straße 44, 39120 Magdeburg, Germany
9 November 2011