- Email: [email protected]
Levetiracetam monotherapy for the treatment of infants with epilepsy
Accepted Manuscript Title: Levetiracetam monotherapy for the treatment of infants with epilepsy Authors: Pinar Arican, Pinar Gencpinar, Dilek Cavusoglu, Nihal Olgac Dundar PII: DOI: Reference:
S1059-1311(17)30499-5 https://doi.org/10.1016/j.seizure.2018.02.006 YSEIZ 3119
To appear in:
Seizure
Received date: Revised date: Accepted date:
16-7-2017 7-2-2018 9-2-2018
Please cite this article as: Arican Pinar, Gencpinar Pinar, Cavusoglu Dilek, Dundar Nihal Olgac.Levetiracetam monotherapy for the treatment of infants with epilepsy.SEIZURE: European Journal of Epilepsy https://doi.org/10.1016/j.seizure.2018.02.006 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Levetiracetam monotherapy for the treatment of infants with epilepsy 1. Pinar ARICANa, MD 3. Pinar GENCPINARb, Assoc.Prof. 4. Dilek CAVUSOGLUb, MD
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a
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2. Nihal OLGAC DUNDARb*, Prof.
Department of Pediatric Neurology, Izmir Tepecik Education and Research Hospital,
Izmir, Turkey
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Department of Pediatric Neurology, Izmir Katip Celebi University, Izmir, Turkey
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A
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b
*Corresponding author:
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Prof. Nihal OLGAC DUNDAR
Address: Department of Pediatric Neurology, Izmir Tepecik Education and Research Hospital, Yenisehir 35120, Izmir/ Turkey
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Tel: +904443560
Fax: + 902324330756
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E-mail: [email protected]
Highlights * Of the 92 patients, 66% were seizure free under levetiracetam monotherapy. * The effect of levetiracetam on EEG abnormalities is associated with its effect in control of epileptic seizures. * Levetiracetam may show a low incidence of side effect in infant patients.
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Abstract Purpose: Levetiracetam is a broad-spectrum anti-epileptic drug that is effective against both focal and generalized epilepsies. In this study, we aimed to evaluate the
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efficacy, tolerability and safety of levetiracetam monotherapy in the management of different seizure types in children with epilepsy under the age of two.
Method: This retrospective study was conducted on children with a diagnosis of
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epilepsy from January 2014 to January 2017. To be included in the study, patients were required to be less than two years of age at the time levetiracetam was initiated
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as initial monotherapy and to be followed clinically for at least 6 months.
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Results: Of the 92 patients, 61 (66%) patients were seizure free. Fifty-eight percent of
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the patients (31 of 53) with focal epilepsy were seizure free and 77% (30 of 39) generalized epilepsy were seizure free. We found that levetiracetam monotherapy was effective in both focal and generalized epilepsy. Levetiracetam monotherapy was
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significantly more effective in patients with unknown etiologies (p=.004). Seizure freedom rate under levetiracetam monotherapy was significantly higher in patients with normal psychomotor development (p=0.000). Seizure freedom rate under
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levetiracetam monotherapy was significantly higher in patients with unknown etiologies and normal psychomotor development. Normal psychomotor development
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was the strongest predictor of seizure control under levetiracetam monotherapy (OR= 6; 95% CI= 2.3-16.0; p <0.001). Five children (1%) reported irritability. No hematological or biochemical, or behavioral adverse side effects except irritability
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were reported in any children. No patient discontinued levetiracetam therapy because of treatment-related side effects. Conclusion: Our study showed levetiracetam to be an effective, well tolerated and safe agent for the treatment of a variety of seizure types and etiologies seen in infants. Key words: infant;levetiracetam;seizures;epilepsy.
1. Introduction Levetiracetam is one of the most frequently prescribed antiepileptic drugs (1). Although the precise mechanism is unknown, levetiracetam has different mechanisms of action from other antiepileptic drugs. The specific effect of levetiracetam may be binding to a synaptic vesicle glycoprotein, thereby controlling of vesicle fusion and exocytosis and reducing neurotransmitter release (2,3). Levetiracetam has been approved by the US Food and Drug Administration
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for use as add-on therapy for partial seizures in patients from one month of age with
epilepsy and primary generalized tonic–clonic seizures in patients from 6 years of age
childhood
epilepsy
syndromes
including
benign
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with idiopathic generalized epilepsy (1). Levetiracetam has been evaluated in childhood
epilepsy
with
centrotemporal spikes, electrical status epilepticus in slow sleep, Lennox Gastaut syndrome and juvenile myoclonic epilepsy (4-7).
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Despite the frequent use of levetiracetam, there are very few studies about the
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efficacy, tolerability and safety of levetiracetam monotherapy in infants. In this study,
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we aimed to evaluate the efficacy, tolerability and safety of levetiracetam
under the age of two.
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monotherapy in the management of different seizure types in children with epilepsy
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2. Materials and methods
This retrospective study was conducted on children with a diagnosis of epilepsy from January 2014 to January 2017. The demographic data, clinical
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presentation, neuroimaging and electroencephalography results and clinical follow-up data of patients were collected from the medical records and reviewed. The approval of Izmir Katip Celebi University ethics committee was obtained. Written informed
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consent from the guardians on the behalf of participating minors involved in this study was obtained.
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Based on the clinical definition proposed by International League Against
Epilepsy, patients with two or more unprovoked seizures occurring at an interval longer than 24 hours were considered to have epilepsy (8). To be included in the study, patients were required to be less than two years of age at the time levetiracetam was initiated as initial monotherapy and to be followed clinically for at least 6 months. Patients were excluded in the study if they had already received any other antiepileptic drug. Patients were also excluded when seizures had been caused by
hypoglycemia
and
electrolyte
disturbances
such
as
hypocalcaemia
or
hypomagnesaemia. The seizure types and etiologies were classified according to the International League Against Epilepsy 2017 classification of seizure types and the epilepsies (8,9). Levetiracetam was administered orally at a dose of 10 mg/kg/day initially. This dose was increased by 10 mg/kg/day up to 60 mg/kg/day. After levetiracetam initiated, routine follow-up visits were for the first month,
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and then every 3 months. Patients clinically examined, and seizure frequency,
antiepileptic medication, and adverse events were documented at every visit. During
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the follow-up, in all patients were performed the following laboratorial examinations:
complete peripheral blood counts and alanine aminotransferase levels. Compared with baseline seizures frequency, the response to levetiracetam monotherapy was grouped into two cohorts: seizure-free group (100% seizures control) and drug failure group
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(no seizure control). Patients were designated as a seizure-free if they achieved
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seizure remission for at least 6 months under levetiracetam monotherapy.
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Electroencephalography (EEG) and cranial magnetic resonance imaging (MRI) were performed at pretreatment period and control EEG was performed 6-12
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months during post-treatment period. EEG improvement was defined by a pre-
abnormalities).
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treatment EEG that was abnormal and a second EEG that was normal (no spikes or
Statistical analysis was performed using Statistical Package for the Social Sciences software program version 21.0. Frequencies and percentages were calculated. Patient age and duration of treatment were also described using medians
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and interquartile ranges (IQRs). The Chi-square test and Fisher’s exact test were used for comparison between independent groups of categorical data. Multivariable logistic
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regression analyses were performed to identify variables that predict risk factors of the response to levetiracetam monotherapy. In order to weigh the significance of each
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chosen variable with respect to their influence, its correlation with multiple logistic regression model and parameter estimates, standard error of estimates, odds ratios, 95% confidence intervals and p-values of each factor computed. For all statistical tests, values of p < .05 (two-tailed) were considered statistically significant.
3. Results 3.1. Patients characteristics (n=92)
Of the 92 patients, 48 (52%) were girls and 44 (48%) were boys. Their median age at the time of initial levetiracetam treatment was 6 months (IQR: 1-10). In total, 53 (58%) patients had focal seizures, and 39 (42%) patients had generalized type seizures. Nineteen (21%) patients had structural etiologies (e.g.,hypoxic ischemic encephalopathy, posttraumatic epilepsy, tumor), 10 (11%) patients had metabolic etiologies (e.g., molybdenum cofactor deficiency), 8 (9%) patients had genetic etiologies (e.g., chromosomal abnormalities), 3 (3%) patients had infectious etiologies
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and 52 (56%) patients had unknown etiologies. Thirty-one (35%) of the images
revealed abnormal results that included cerebral atrophy (n = 7), porencephalic cyst (n
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= 7), T2 hyperintensities (n = 4), hydrocephalus (n = 4), agenesis of the corpus
callosum (n = 4), periventricular leukomalacia (n = 2), ganglioglioma (n = 1), ependymoma (n = 1) and subependymal heterotopia (n = 1). Cranial magnetic resonance imaging was obtained in 88 patients and was normal in 57 (65%) patients.
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Electroencephalography was obtained in 89 patients and was normal in 60 (67%)
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patients had generalized discharges (Table 1).
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patients. A total of 29 patients, 26 (90%) patients had focal discharges and 3 (10%)
Sixty-one (66%) patients were seizure free and 31 (34%) patients had no
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seizure control under levetiracetam monotherapy. The mean levetiracetam dosages were <30 mg/kg/d in 24 (26%) patients, 30-40 mg/kg/d in 48 (52%) patients, >40
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mg/kg/d in 20 (22%) patients (the doses ranged from 20 to 60 mg/kg/d). The median duration of treatment was 12 months (IQR: 6-18). Of 31 patients who had no seizure control, only one patient didn't receive any other adjunctive antiepileptic drug.
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Adjunctive antiepileptic drug was initiated in 30 patients. Of 30 patients, 14 patients received two antiepileptic drugs and 16 patients received three or more antiepileptic drugs. Adjunctive antiepileptic drugs included carbamazepine, clonazepam,
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clobazam, lamotrigine, phenobarbital, phenytoin, topiramate, valproate, vigabatrin, synthetic adrenocorticotropic hormone and oxcarbazepine. Second EEGs were
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performed for 51 (55%) patients and was normal in 30 patients. Of 21 patients with abnormal EEGs, 13 patients continued to show similar epileptiform abnormalities or exhibited diffusion on control EEGs and 8 patients who had a normal initial EEGs exhibited epileptic discharges (Table 1). 3.2. Patient characteristics in the seizure-free group with levetiracetam monotherapy (n=61) Of the 61 patients, 30 (49%) were girls and 31 (51%) were boys. Their median
age at the time of initial levetiracetam monotherapy was 7 months (IQR: 2-12). Thirty-one (51%) patients had focal seizures, and 30 (49%) patients had generalized type seizures. Twenty (33%) patients with specific underlying etiologies (structural, metabolic, genetic, infectious etiologies) and 41 (67%) patients with unknown etiologies were seizure-free with levetiracetam monotherapy. Of the 61 patients, 43 (70%) had normal psychomotor development and 18 (30%) had delayed psychomotor development. Fourty-two (72%) patients had normal cranial MRI and 16 (28%)
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patients had cranial MRI abnormalities. A total of 15 patients, 14 (93%) patients had focal discharges and one (7%) patient had generalized discharges (Table 2).
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3.3. Patient characteristics in the drug failure group (n=31)
Of the 31 patients, 18 (58%) were girls and 13 (42%) were boys. Their median age at the time of initial levetiracetam treatment was 4 months (IQR: 1-9). In total, 22 (71%) patients had focal seizures, and 9 (29%) patients had generalized type
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seizures. Twenty (65%) patients with specific underlying etiologies (structural,
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metabolic, genetic, infectious etiologies) and 11 (35%) patients with unknown
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etiologies had no seizure control. Of the 31 patients, 9 (29%) had normal psychomotor development and 22 (71%) had delayed psychomotor development.
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Fifteen (50%) patients had normal cranial MRI and 15 (50%) patients had cranial MRI abnormalities. A total of 14 patients, 12 (86%) patients had focal discharges and
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2 (14%) patients had generalized discharges (Table 2). 3.4. Analysis of identifying variables between seizure-free and drug failure groups
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No statistically significant differences were observed between two groups according to sex and age (p >.05). Levetiracetam monotherapy was significantly more effective in patients with unknown etiologies (p=.004). Seizure freedom rate under
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levetiracetam monotherapy was significantly higher in patients with normal psychomotor development (p=0.000). No statistically significant differences were
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observed between two groups according to the seizure types classification, pretreatment EEG and cranial MRI findings (p >.05) (Table 2). Seizure freedom rate for focal epilepsy group was 58% and for generalized epilepsy group was 77%. There were no significant differences in age and response rate for focal and generalized seizures (p >.05). Results of the multivariate analyses identified three predictors of response to levetiracetam monotherapy: Seizure type (OR= 1.1; 95% CI= 0.3-4.5; p=.847) , seizure etiology (OR= 0.4; 95% CI= 0.1-1; p=.069), and psychomotor
development (OR= 6; 95% CI= 2.3-16.0; p<0.001). Normal psychomotor development was the strongest predictor of seizure control under levetiracetam monotherapy (Table 3). 3.5. EEG improvement rates in the period between the 6th and 12th months of levetiracetam monotherapy Of 19 patients with initial abnormal EEGs, only 6 (32%) patients demonstrated improvements on levetiracetam monotherapy and 5 (83%) of them were
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seizure free. Of 21 patients with similar or worsened epileptiform abnormalities, 5
(24%) patients were seizure free. EEG improvement rate was significantly higher in
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patients who stopped having seizures (p=.015) (Table 2).
3.6. Tolerability of levetiracetam monotherapy and adverse events Five
children
(1%)
reported
irritability
while
taking levetiracetam
monotherapy. No adverse hematological or biochemical, or behavioral side effects
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except irritability were reported in any children. No patient discontinued
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levetiracetam therapy because of treatment-related side effects.
4. Discussion
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Levetiracetam is a broad-spectrum anti-epileptic drug that is effective against a variety of seizure types. Levetiracetam has a favourable pharmacokinetic profile in
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terms of safety in pediatric patients. Minimal drug interactions, fewer side-effects, and broad-spectrum efficacy of levetiracetam make it an ideal option for the treatment of seizures (10,11).
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Wilmshurst et al. investigated the common practice and regional variations in the treatment interventions of infants with epilepsy. The study survey found that there was a preference for valproate as first-line therapy for generalized seizures,
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myoclonic seizures, and Dravet syndrome. Carbamazepine and oxcarbazepine were the preferred agents for focal seizures except for North America. The survey
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identified widespread use of levetiracetam in North America (12). Shellhaas et al. examined the selection of initial medications in children with newly diagnosed epilepsy with onset under 36 months old age. They reported levetiracetam (62.7%) was the single most commonly selected first medication (13). In our study, patients with a variety of seizure types and etiologies benefited from levetiracetam monotherapy. Of the 92 patients, 61 (66%) patients were seizure free. The median duration of treatment was 12 months (IQR: 6-18). We found that
levetiracetam monotherapy was effective in both focal and generalized epilepsy. We also found the seizure freedom rate was significantly higher in patients with unknown etiologies and normal psychomotor development. The multivariable logistic regression analyses showed psychomotor development was the strongest predictor of seizure control under levetiracetam monotherapy. Several studies have investigated the use of levetiracetam in children. However, very few studies have examined efficacy of levetiracetam as a monotherapy
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in pediatric patients. Gao et al. (14) evaluated the efficacy and tolerability of
levetiracetam monotherapy in children with epilepsy aged 8 months to 12 years. Of
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31 patients, 25 had at least 50% reduction in seizures, 22 became seizure-free. Coppola et al. (15) evaluated the efficacy and tolerability of levetiracetam or oxcarbazepine as monotherapy in children with newly diagnosed benign epilepsy with centrotemporal spikes aged between 5 and 13 years. Nineteen out of 21 patients
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(90.5%) on levetiracetam monotherapy did not have further seizures. In Verrotti et al.
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(16) study, at the 6 months evaluation, 11 (91.6%) of the 12 patients studied were seizure free. Perry et al. (17) compared the efficacy and tolerability of levetiracetam
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and carbamazepine monotherapy in children with partial epilepsy ≤ 16 years of age.
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In their study, levetiracetam and carbamazepine monotherapy demonstrated similar efficacy for treatment of partial epilepsy and are well tolerated in children. Sedighi et
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al. (18) investigated the efficacy and safety of LEV in neonatal seizure control. Of 50 patients, 47 infants were seizure free under LEV at the end of the first week, and 46 remained seizure free at 11 weeks. These studies suggested that levetiracetam
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potentially effective and well tolerated drugs for children with epilepsy. In several studies, the effects of levetiracetam on EEG changes have been reported. Specchio et al. (19) reported levetiracetam appeared to be effective in
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decreasing epileptiform EEG abnormalities, and suppressing the photoparoxysmal response in juvenile myoclonic epilepsy. Xioa et al. (4) observed that low-dose
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valproic acid exhibited greater efficacy than low-dose levetiracetam in improving the electrophysiological abnormalities of the children with benign childhood epilepsy with centrotemporal spikes. In our study, we found that the patients who stopped having seizures showed significant EEG improvements than those who didn’t respond levetiracetam monotherapy. Our experience revealed that the effect of levetiracetam on EEG abnormalities is associated with its effect in control of epileptic seizures. Behavioural problems and somnolence are the most common adverse reactions
associated with levetiracetam (20,21). Behavioural problems are more commonly reported in children than adults. Children on polytherapy have a greater risk of adverse events than those receiving monotherapy (22). Ozkale et al. (23) reported an infant who was accidentally administered 300 mg/kg/d for 35 days by her mother. The patient showed no adverse effects after received a high and long-term dose of levetiracetam. Our results shown that levetiracetam appears to be well-tolerated and safety drug in infant patients. No serious adverse effects were seen in our patients.
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Irritability was only reported in 5 (1%) patients. Additionally, no patient discontinued
iracetam therapy because of treatment-related side effects. Our study revealed that
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levetiracetam may show a low incidence of side effect in infant patients.
Main limitation of this study is its retrospective design. The study data were limited to heterogeneous patient population studied within a single-center. This study is also limited by the non-standardized dosing of levetiracetam. Further prospective,
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randomized controlled trials are needed to evaluate the effect of levetiracetam
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monotherapy in infants.
5. Conclusion
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Our study showed levetiracetam to be an effective, well-tolerable and safety
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agent for the treatment of a variety of seizure types and etiologies seen in infants.
Acknowledgments: This work was performed at the Izmir Tepecik Education and Research Hospital. There was no assistance or efforts beyond those of the primary
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authors. This work has not been presented or published elsewhere. Author Contributions: PA prepared the original manuscript and performed the data collection. NOD and PG contributed to the statistical analysis, writing, and revision of
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the final manuscript. DC assisted in the preparation of the manuscript. Declaration of Conflicting Interest: The authors declare no potential conflicts of
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interest with respect to the research, authorship, and/or publication of this article. Funding: The authors received no financial support for the research, authorship, and or publication of this article. Ethical Approval: The local ethics committee approved this study.
References [1] Cormier J, Chu CJ. Safety and efficacy of levetiracetam for the treatment of partial onset seizures in children from one month of age. Neuropsychiatr Dis Treat 2013;9:295-306. [2] Lynch BA, Lambeng N, Nocka K, Kensel-Hammes P, Bajjalieh SM, Matagne A, et al. The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam. Proc Natl Acad Sci U S A 2004;101:9861–6. [3] Yang XF, Weisenfeld A, Rothman SM. Prolonged exposure to leve- tiracetam reveals a presynaptic effect on neurotransmission. Epilepsia 2007;48:1861
[12] Wilmshurst JM, Burman R, Gaillard WD, Cross JH. Treatment of infants with epilepsy: Common practices around the world. Epilepsia 2015;56:1033-46. [13] Shellhaas RA, Berg AT, Grinspan ZM, Wusthoff CJ, Millichap JJ, Loddenkemper T et al. Initial Treatment for Nonsyndromic Early-Life Epilepsy: An Unexpected Consensus. Pediatric neurology 2017;75:73-9. [14] Gao ZJ, Jiang YW. Follow-up study on levetiracetam monotherapy in children with epilepsy. Zhongguo dang dai er ke za zhi= Chinese journal of contemporary
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pediatrics 2008;10:711-4.
[15] Coppola G, Franzoni E, Verrotti A, Garone C, Sarajlija J, Operto FF et al.
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Levetiracetam or oxcarbazepine as monotherapy in newly diagnosed benign epilepsy
of childhood with centrotemporal spikes (BECTS): an open-label, parallel group trial. Brain and Development 2007;29:281-4.
[16] Verrotti A, Parisi P, Loiacono G, Mohn A, Grosso S, Balestri P et al.
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Levetiracetam monotherapy for childhood occipital epilepsy of gastaut. Acta
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Neurologica Scandinavica 2009;120:342-6.
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[17] Perry S, Holt P, Benatar M. Levetiracetam versus carbamazepine monotherapy for partial epilepsy in children less than 16 years of age. Journal of child neurology
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2008;23:515-9.
[18] Sedighi M, Asadi F, Moradian N, Vakiliamini M, Moradian M. Efficacy and
2016;21:232.
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safety of levetiracetam in the management of seizures in neonates. Neurosciences
[19] Specchio N, Boero G, Michelucci R, Gambardella A, Giallonardo AT, Fattouch J
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et al. Effects of levetiracetam on EEG abnormalities in juvenile myoclonic epilepsy. Epilepsia 2008;49:663-9. [20] Tekgül H, Gencpinar P, Çavuşoğlu D, Dündar NO. The efficacy, tolerability and
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safety of levetiracetam therapy in a pediatric population. Seizure 2016;36:16-21. [21] Feng XF, Xiao N. Long-term efficacy and tolerability of levetiracetam in
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different age groups of children with epilepsy: a 210 cases report. Medical Journal of Chinese People's Liberation Army 2014;39:324-8. [22] Egunsola O, Choonara I, Sammons HM. Safety of Levetiracetam in paediatrics: a systematic review. PloS one, 2016;11:0149686. [23] Özkale Y, Özkale M, Saygi S, Erol I. Long-term accidental overdose of levetiracetam in an infant. Journal of child neurology 2014;29:959-61.
Table 1. Demographic characteristics and clinical features of patients (n=92) 48 (52%) 44 (48%)
Age (median)(IQR)
6 months (IQR:1-10)
Seizure type, n (%) Focal seizure Generalized seizure
53 (58%) 39 (42%)
57(65%) 31(35%)
Pretreatment EEG, n (%) Normal Abnormal
60(67%) 29(33%)
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Pre-treatment EEG findings, n (%) Focal Generalized
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Cranial MRI, n (%) Normal Abnormal
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19 (21%) 10 (11%) 8 (9%) 3 (3%) 52 (56%)
26(90%) 3 (10%)
61(66%) 31(34%)
Mean daily dose (mg/kg/d) <30 mg/kg/d 30-40mg/kg/d >40 mg/kg/d
24 (26%) 48 (52%) 20(22%)
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Efficacy of levetiracetam, n (%) Seizure free Drug failure
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Treatment duration (median)(IQR) Control EEG, n (%) Normal Abnormal
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Seizure etiology, n (%) Structural Metabolic Genetic İnfectious Unknown
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Gender, n (%) Female Male
12 months (IQR:6-18) 30(59%) 21(41%)
EEG: electroencephalography, IQR: interquartile range, MRI: magnetic resonance imaging .
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N
A
M
Risk factor
OR
95% CI
p
Unknown etiologies
1.1
0.3-4.5
.847
Generalized seizure
0.4
0.1-1
.069
6
2.3-16
.000
A
CC
EP
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M
A
N
U
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Normal psychomotor development
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Table 3. Multivariable logistic regression analyses of predictors for response to levetiracetam monotherapy
S1059-1311(17)30499-5 https://doi.org/10.1016/j.seizure.2018.02.006 YSEIZ 3119
To appear in:
Seizure
Received date: Revised date: Accepted date:
16-7-2017 7-2-2018 9-2-2018
Please cite this article as: Arican Pinar, Gencpinar Pinar, Cavusoglu Dilek, Dundar Nihal Olgac.Levetiracetam monotherapy for the treatment of infants with epilepsy.SEIZURE: European Journal of Epilepsy https://doi.org/10.1016/j.seizure.2018.02.006 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Levetiracetam monotherapy for the treatment of infants with epilepsy 1. Pinar ARICANa, MD 3. Pinar GENCPINARb, Assoc.Prof. 4. Dilek CAVUSOGLUb, MD
SC R
a
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2. Nihal OLGAC DUNDARb*, Prof.
Department of Pediatric Neurology, Izmir Tepecik Education and Research Hospital,
Izmir, Turkey
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Department of Pediatric Neurology, Izmir Katip Celebi University, Izmir, Turkey
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M
A
N
b
*Corresponding author:
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Prof. Nihal OLGAC DUNDAR
Address: Department of Pediatric Neurology, Izmir Tepecik Education and Research Hospital, Yenisehir 35120, Izmir/ Turkey
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Tel: +904443560
Fax: + 902324330756
A
E-mail: [email protected]
Highlights * Of the 92 patients, 66% were seizure free under levetiracetam monotherapy. * The effect of levetiracetam on EEG abnormalities is associated with its effect in control of epileptic seizures. * Levetiracetam may show a low incidence of side effect in infant patients.
IP T
Abstract Purpose: Levetiracetam is a broad-spectrum anti-epileptic drug that is effective against both focal and generalized epilepsies. In this study, we aimed to evaluate the
SC R
efficacy, tolerability and safety of levetiracetam monotherapy in the management of different seizure types in children with epilepsy under the age of two.
Method: This retrospective study was conducted on children with a diagnosis of
U
epilepsy from January 2014 to January 2017. To be included in the study, patients were required to be less than two years of age at the time levetiracetam was initiated
N
as initial monotherapy and to be followed clinically for at least 6 months.
A
Results: Of the 92 patients, 61 (66%) patients were seizure free. Fifty-eight percent of
M
the patients (31 of 53) with focal epilepsy were seizure free and 77% (30 of 39) generalized epilepsy were seizure free. We found that levetiracetam monotherapy was effective in both focal and generalized epilepsy. Levetiracetam monotherapy was
TE D
significantly more effective in patients with unknown etiologies (p=.004). Seizure freedom rate under levetiracetam monotherapy was significantly higher in patients with normal psychomotor development (p=0.000). Seizure freedom rate under
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levetiracetam monotherapy was significantly higher in patients with unknown etiologies and normal psychomotor development. Normal psychomotor development
CC
was the strongest predictor of seizure control under levetiracetam monotherapy (OR= 6; 95% CI= 2.3-16.0; p <0.001). Five children (1%) reported irritability. No hematological or biochemical, or behavioral adverse side effects except irritability
A
were reported in any children. No patient discontinued levetiracetam therapy because of treatment-related side effects. Conclusion: Our study showed levetiracetam to be an effective, well tolerated and safe agent for the treatment of a variety of seizure types and etiologies seen in infants. Key words: infant;levetiracetam;seizures;epilepsy.
1. Introduction Levetiracetam is one of the most frequently prescribed antiepileptic drugs (1). Although the precise mechanism is unknown, levetiracetam has different mechanisms of action from other antiepileptic drugs. The specific effect of levetiracetam may be binding to a synaptic vesicle glycoprotein, thereby controlling of vesicle fusion and exocytosis and reducing neurotransmitter release (2,3). Levetiracetam has been approved by the US Food and Drug Administration
IP T
for use as add-on therapy for partial seizures in patients from one month of age with
epilepsy and primary generalized tonic–clonic seizures in patients from 6 years of age
childhood
epilepsy
syndromes
including
benign
SC R
with idiopathic generalized epilepsy (1). Levetiracetam has been evaluated in childhood
epilepsy
with
centrotemporal spikes, electrical status epilepticus in slow sleep, Lennox Gastaut syndrome and juvenile myoclonic epilepsy (4-7).
U
Despite the frequent use of levetiracetam, there are very few studies about the
N
efficacy, tolerability and safety of levetiracetam monotherapy in infants. In this study,
A
we aimed to evaluate the efficacy, tolerability and safety of levetiracetam
under the age of two.
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monotherapy in the management of different seizure types in children with epilepsy
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2. Materials and methods
This retrospective study was conducted on children with a diagnosis of epilepsy from January 2014 to January 2017. The demographic data, clinical
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presentation, neuroimaging and electroencephalography results and clinical follow-up data of patients were collected from the medical records and reviewed. The approval of Izmir Katip Celebi University ethics committee was obtained. Written informed
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consent from the guardians on the behalf of participating minors involved in this study was obtained.
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Based on the clinical definition proposed by International League Against
Epilepsy, patients with two or more unprovoked seizures occurring at an interval longer than 24 hours were considered to have epilepsy (8). To be included in the study, patients were required to be less than two years of age at the time levetiracetam was initiated as initial monotherapy and to be followed clinically for at least 6 months. Patients were excluded in the study if they had already received any other antiepileptic drug. Patients were also excluded when seizures had been caused by
hypoglycemia
and
electrolyte
disturbances
such
as
hypocalcaemia
or
hypomagnesaemia. The seizure types and etiologies were classified according to the International League Against Epilepsy 2017 classification of seizure types and the epilepsies (8,9). Levetiracetam was administered orally at a dose of 10 mg/kg/day initially. This dose was increased by 10 mg/kg/day up to 60 mg/kg/day. After levetiracetam initiated, routine follow-up visits were for the first month,
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and then every 3 months. Patients clinically examined, and seizure frequency,
antiepileptic medication, and adverse events were documented at every visit. During
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the follow-up, in all patients were performed the following laboratorial examinations:
complete peripheral blood counts and alanine aminotransferase levels. Compared with baseline seizures frequency, the response to levetiracetam monotherapy was grouped into two cohorts: seizure-free group (100% seizures control) and drug failure group
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(no seizure control). Patients were designated as a seizure-free if they achieved
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seizure remission for at least 6 months under levetiracetam monotherapy.
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Electroencephalography (EEG) and cranial magnetic resonance imaging (MRI) were performed at pretreatment period and control EEG was performed 6-12
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months during post-treatment period. EEG improvement was defined by a pre-
abnormalities).
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treatment EEG that was abnormal and a second EEG that was normal (no spikes or
Statistical analysis was performed using Statistical Package for the Social Sciences software program version 21.0. Frequencies and percentages were calculated. Patient age and duration of treatment were also described using medians
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and interquartile ranges (IQRs). The Chi-square test and Fisher’s exact test were used for comparison between independent groups of categorical data. Multivariable logistic
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regression analyses were performed to identify variables that predict risk factors of the response to levetiracetam monotherapy. In order to weigh the significance of each
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chosen variable with respect to their influence, its correlation with multiple logistic regression model and parameter estimates, standard error of estimates, odds ratios, 95% confidence intervals and p-values of each factor computed. For all statistical tests, values of p < .05 (two-tailed) were considered statistically significant.
3. Results 3.1. Patients characteristics (n=92)
Of the 92 patients, 48 (52%) were girls and 44 (48%) were boys. Their median age at the time of initial levetiracetam treatment was 6 months (IQR: 1-10). In total, 53 (58%) patients had focal seizures, and 39 (42%) patients had generalized type seizures. Nineteen (21%) patients had structural etiologies (e.g.,hypoxic ischemic encephalopathy, posttraumatic epilepsy, tumor), 10 (11%) patients had metabolic etiologies (e.g., molybdenum cofactor deficiency), 8 (9%) patients had genetic etiologies (e.g., chromosomal abnormalities), 3 (3%) patients had infectious etiologies
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and 52 (56%) patients had unknown etiologies. Thirty-one (35%) of the images
revealed abnormal results that included cerebral atrophy (n = 7), porencephalic cyst (n
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= 7), T2 hyperintensities (n = 4), hydrocephalus (n = 4), agenesis of the corpus
callosum (n = 4), periventricular leukomalacia (n = 2), ganglioglioma (n = 1), ependymoma (n = 1) and subependymal heterotopia (n = 1). Cranial magnetic resonance imaging was obtained in 88 patients and was normal in 57 (65%) patients.
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Electroencephalography was obtained in 89 patients and was normal in 60 (67%)
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patients had generalized discharges (Table 1).
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patients. A total of 29 patients, 26 (90%) patients had focal discharges and 3 (10%)
Sixty-one (66%) patients were seizure free and 31 (34%) patients had no
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seizure control under levetiracetam monotherapy. The mean levetiracetam dosages were <30 mg/kg/d in 24 (26%) patients, 30-40 mg/kg/d in 48 (52%) patients, >40
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mg/kg/d in 20 (22%) patients (the doses ranged from 20 to 60 mg/kg/d). The median duration of treatment was 12 months (IQR: 6-18). Of 31 patients who had no seizure control, only one patient didn't receive any other adjunctive antiepileptic drug.
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Adjunctive antiepileptic drug was initiated in 30 patients. Of 30 patients, 14 patients received two antiepileptic drugs and 16 patients received three or more antiepileptic drugs. Adjunctive antiepileptic drugs included carbamazepine, clonazepam,
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clobazam, lamotrigine, phenobarbital, phenytoin, topiramate, valproate, vigabatrin, synthetic adrenocorticotropic hormone and oxcarbazepine. Second EEGs were
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performed for 51 (55%) patients and was normal in 30 patients. Of 21 patients with abnormal EEGs, 13 patients continued to show similar epileptiform abnormalities or exhibited diffusion on control EEGs and 8 patients who had a normal initial EEGs exhibited epileptic discharges (Table 1). 3.2. Patient characteristics in the seizure-free group with levetiracetam monotherapy (n=61) Of the 61 patients, 30 (49%) were girls and 31 (51%) were boys. Their median
age at the time of initial levetiracetam monotherapy was 7 months (IQR: 2-12). Thirty-one (51%) patients had focal seizures, and 30 (49%) patients had generalized type seizures. Twenty (33%) patients with specific underlying etiologies (structural, metabolic, genetic, infectious etiologies) and 41 (67%) patients with unknown etiologies were seizure-free with levetiracetam monotherapy. Of the 61 patients, 43 (70%) had normal psychomotor development and 18 (30%) had delayed psychomotor development. Fourty-two (72%) patients had normal cranial MRI and 16 (28%)
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patients had cranial MRI abnormalities. A total of 15 patients, 14 (93%) patients had focal discharges and one (7%) patient had generalized discharges (Table 2).
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3.3. Patient characteristics in the drug failure group (n=31)
Of the 31 patients, 18 (58%) were girls and 13 (42%) were boys. Their median age at the time of initial levetiracetam treatment was 4 months (IQR: 1-9). In total, 22 (71%) patients had focal seizures, and 9 (29%) patients had generalized type
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seizures. Twenty (65%) patients with specific underlying etiologies (structural,
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metabolic, genetic, infectious etiologies) and 11 (35%) patients with unknown
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etiologies had no seizure control. Of the 31 patients, 9 (29%) had normal psychomotor development and 22 (71%) had delayed psychomotor development.
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Fifteen (50%) patients had normal cranial MRI and 15 (50%) patients had cranial MRI abnormalities. A total of 14 patients, 12 (86%) patients had focal discharges and
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2 (14%) patients had generalized discharges (Table 2). 3.4. Analysis of identifying variables between seizure-free and drug failure groups
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No statistically significant differences were observed between two groups according to sex and age (p >.05). Levetiracetam monotherapy was significantly more effective in patients with unknown etiologies (p=.004). Seizure freedom rate under
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levetiracetam monotherapy was significantly higher in patients with normal psychomotor development (p=0.000). No statistically significant differences were
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observed between two groups according to the seizure types classification, pretreatment EEG and cranial MRI findings (p >.05) (Table 2). Seizure freedom rate for focal epilepsy group was 58% and for generalized epilepsy group was 77%. There were no significant differences in age and response rate for focal and generalized seizures (p >.05). Results of the multivariate analyses identified three predictors of response to levetiracetam monotherapy: Seizure type (OR= 1.1; 95% CI= 0.3-4.5; p=.847) , seizure etiology (OR= 0.4; 95% CI= 0.1-1; p=.069), and psychomotor
development (OR= 6; 95% CI= 2.3-16.0; p<0.001). Normal psychomotor development was the strongest predictor of seizure control under levetiracetam monotherapy (Table 3). 3.5. EEG improvement rates in the period between the 6th and 12th months of levetiracetam monotherapy Of 19 patients with initial abnormal EEGs, only 6 (32%) patients demonstrated improvements on levetiracetam monotherapy and 5 (83%) of them were
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seizure free. Of 21 patients with similar or worsened epileptiform abnormalities, 5
(24%) patients were seizure free. EEG improvement rate was significantly higher in
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patients who stopped having seizures (p=.015) (Table 2).
3.6. Tolerability of levetiracetam monotherapy and adverse events Five
children
(1%)
reported
irritability
while
taking levetiracetam
monotherapy. No adverse hematological or biochemical, or behavioral side effects
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except irritability were reported in any children. No patient discontinued
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levetiracetam therapy because of treatment-related side effects.
4. Discussion
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Levetiracetam is a broad-spectrum anti-epileptic drug that is effective against a variety of seizure types. Levetiracetam has a favourable pharmacokinetic profile in
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terms of safety in pediatric patients. Minimal drug interactions, fewer side-effects, and broad-spectrum efficacy of levetiracetam make it an ideal option for the treatment of seizures (10,11).
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Wilmshurst et al. investigated the common practice and regional variations in the treatment interventions of infants with epilepsy. The study survey found that there was a preference for valproate as first-line therapy for generalized seizures,
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myoclonic seizures, and Dravet syndrome. Carbamazepine and oxcarbazepine were the preferred agents for focal seizures except for North America. The survey
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identified widespread use of levetiracetam in North America (12). Shellhaas et al. examined the selection of initial medications in children with newly diagnosed epilepsy with onset under 36 months old age. They reported levetiracetam (62.7%) was the single most commonly selected first medication (13). In our study, patients with a variety of seizure types and etiologies benefited from levetiracetam monotherapy. Of the 92 patients, 61 (66%) patients were seizure free. The median duration of treatment was 12 months (IQR: 6-18). We found that
levetiracetam monotherapy was effective in both focal and generalized epilepsy. We also found the seizure freedom rate was significantly higher in patients with unknown etiologies and normal psychomotor development. The multivariable logistic regression analyses showed psychomotor development was the strongest predictor of seizure control under levetiracetam monotherapy. Several studies have investigated the use of levetiracetam in children. However, very few studies have examined efficacy of levetiracetam as a monotherapy
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in pediatric patients. Gao et al. (14) evaluated the efficacy and tolerability of
levetiracetam monotherapy in children with epilepsy aged 8 months to 12 years. Of
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31 patients, 25 had at least 50% reduction in seizures, 22 became seizure-free. Coppola et al. (15) evaluated the efficacy and tolerability of levetiracetam or oxcarbazepine as monotherapy in children with newly diagnosed benign epilepsy with centrotemporal spikes aged between 5 and 13 years. Nineteen out of 21 patients
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(90.5%) on levetiracetam monotherapy did not have further seizures. In Verrotti et al.
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(16) study, at the 6 months evaluation, 11 (91.6%) of the 12 patients studied were seizure free. Perry et al. (17) compared the efficacy and tolerability of levetiracetam
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and carbamazepine monotherapy in children with partial epilepsy ≤ 16 years of age.
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In their study, levetiracetam and carbamazepine monotherapy demonstrated similar efficacy for treatment of partial epilepsy and are well tolerated in children. Sedighi et
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al. (18) investigated the efficacy and safety of LEV in neonatal seizure control. Of 50 patients, 47 infants were seizure free under LEV at the end of the first week, and 46 remained seizure free at 11 weeks. These studies suggested that levetiracetam
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potentially effective and well tolerated drugs for children with epilepsy. In several studies, the effects of levetiracetam on EEG changes have been reported. Specchio et al. (19) reported levetiracetam appeared to be effective in
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decreasing epileptiform EEG abnormalities, and suppressing the photoparoxysmal response in juvenile myoclonic epilepsy. Xioa et al. (4) observed that low-dose
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valproic acid exhibited greater efficacy than low-dose levetiracetam in improving the electrophysiological abnormalities of the children with benign childhood epilepsy with centrotemporal spikes. In our study, we found that the patients who stopped having seizures showed significant EEG improvements than those who didn’t respond levetiracetam monotherapy. Our experience revealed that the effect of levetiracetam on EEG abnormalities is associated with its effect in control of epileptic seizures. Behavioural problems and somnolence are the most common adverse reactions
associated with levetiracetam (20,21). Behavioural problems are more commonly reported in children than adults. Children on polytherapy have a greater risk of adverse events than those receiving monotherapy (22). Ozkale et al. (23) reported an infant who was accidentally administered 300 mg/kg/d for 35 days by her mother. The patient showed no adverse effects after received a high and long-term dose of levetiracetam. Our results shown that levetiracetam appears to be well-tolerated and safety drug in infant patients. No serious adverse effects were seen in our patients.
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Irritability was only reported in 5 (1%) patients. Additionally, no patient discontinued
iracetam therapy because of treatment-related side effects. Our study revealed that
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levetiracetam may show a low incidence of side effect in infant patients.
Main limitation of this study is its retrospective design. The study data were limited to heterogeneous patient population studied within a single-center. This study is also limited by the non-standardized dosing of levetiracetam. Further prospective,
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randomized controlled trials are needed to evaluate the effect of levetiracetam
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monotherapy in infants.
5. Conclusion
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Our study showed levetiracetam to be an effective, well-tolerable and safety
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agent for the treatment of a variety of seizure types and etiologies seen in infants.
Acknowledgments: This work was performed at the Izmir Tepecik Education and Research Hospital. There was no assistance or efforts beyond those of the primary
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authors. This work has not been presented or published elsewhere. Author Contributions: PA prepared the original manuscript and performed the data collection. NOD and PG contributed to the statistical analysis, writing, and revision of
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the final manuscript. DC assisted in the preparation of the manuscript. Declaration of Conflicting Interest: The authors declare no potential conflicts of
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interest with respect to the research, authorship, and/or publication of this article. Funding: The authors received no financial support for the research, authorship, and or publication of this article. Ethical Approval: The local ethics committee approved this study.
References [1] Cormier J, Chu CJ. Safety and efficacy of levetiracetam for the treatment of partial onset seizures in children from one month of age. Neuropsychiatr Dis Treat 2013;9:295-306. [2] Lynch BA, Lambeng N, Nocka K, Kensel-Hammes P, Bajjalieh SM, Matagne A, et al. The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam. Proc Natl Acad Sci U S A 2004;101:9861–6. [3] Yang XF, Weisenfeld A, Rothman SM. Prolonged exposure to leve- tiracetam reveals a presynaptic effect on neurotransmission. Epilepsia 2007;48:1861
[12] Wilmshurst JM, Burman R, Gaillard WD, Cross JH. Treatment of infants with epilepsy: Common practices around the world. Epilepsia 2015;56:1033-46. [13] Shellhaas RA, Berg AT, Grinspan ZM, Wusthoff CJ, Millichap JJ, Loddenkemper T et al. Initial Treatment for Nonsyndromic Early-Life Epilepsy: An Unexpected Consensus. Pediatric neurology 2017;75:73-9. [14] Gao ZJ, Jiang YW. Follow-up study on levetiracetam monotherapy in children with epilepsy. Zhongguo dang dai er ke za zhi= Chinese journal of contemporary
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pediatrics 2008;10:711-4.
[15] Coppola G, Franzoni E, Verrotti A, Garone C, Sarajlija J, Operto FF et al.
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Levetiracetam or oxcarbazepine as monotherapy in newly diagnosed benign epilepsy
of childhood with centrotemporal spikes (BECTS): an open-label, parallel group trial. Brain and Development 2007;29:281-4.
[16] Verrotti A, Parisi P, Loiacono G, Mohn A, Grosso S, Balestri P et al.
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Levetiracetam monotherapy for childhood occipital epilepsy of gastaut. Acta
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Neurologica Scandinavica 2009;120:342-6.
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[17] Perry S, Holt P, Benatar M. Levetiracetam versus carbamazepine monotherapy for partial epilepsy in children less than 16 years of age. Journal of child neurology
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2008;23:515-9.
[18] Sedighi M, Asadi F, Moradian N, Vakiliamini M, Moradian M. Efficacy and
2016;21:232.
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safety of levetiracetam in the management of seizures in neonates. Neurosciences
[19] Specchio N, Boero G, Michelucci R, Gambardella A, Giallonardo AT, Fattouch J
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et al. Effects of levetiracetam on EEG abnormalities in juvenile myoclonic epilepsy. Epilepsia 2008;49:663-9. [20] Tekgül H, Gencpinar P, Çavuşoğlu D, Dündar NO. The efficacy, tolerability and
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safety of levetiracetam therapy in a pediatric population. Seizure 2016;36:16-21. [21] Feng XF, Xiao N. Long-term efficacy and tolerability of levetiracetam in
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different age groups of children with epilepsy: a 210 cases report. Medical Journal of Chinese People's Liberation Army 2014;39:324-8. [22] Egunsola O, Choonara I, Sammons HM. Safety of Levetiracetam in paediatrics: a systematic review. PloS one, 2016;11:0149686. [23] Özkale Y, Özkale M, Saygi S, Erol I. Long-term accidental overdose of levetiracetam in an infant. Journal of child neurology 2014;29:959-61.
Table 1. Demographic characteristics and clinical features of patients (n=92) 48 (52%) 44 (48%)
Age (median)(IQR)
6 months (IQR:1-10)
Seizure type, n (%) Focal seizure Generalized seizure
53 (58%) 39 (42%)
57(65%) 31(35%)
Pretreatment EEG, n (%) Normal Abnormal
60(67%) 29(33%)
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Pre-treatment EEG findings, n (%) Focal Generalized
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Cranial MRI, n (%) Normal Abnormal
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19 (21%) 10 (11%) 8 (9%) 3 (3%) 52 (56%)
26(90%) 3 (10%)
61(66%) 31(34%)
Mean daily dose (mg/kg/d) <30 mg/kg/d 30-40mg/kg/d >40 mg/kg/d
24 (26%) 48 (52%) 20(22%)
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Efficacy of levetiracetam, n (%) Seizure free Drug failure
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Treatment duration (median)(IQR) Control EEG, n (%) Normal Abnormal
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Seizure etiology, n (%) Structural Metabolic Genetic İnfectious Unknown
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Gender, n (%) Female Male
12 months (IQR:6-18) 30(59%) 21(41%)
EEG: electroencephalography, IQR: interquartile range, MRI: magnetic resonance imaging .
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Risk factor
OR
95% CI
p
Unknown etiologies
1.1
0.3-4.5
.847
Generalized seizure
0.4
0.1-1
.069
6
2.3-16
.000
A
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A
N
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Normal psychomotor development
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Table 3. Multivariable logistic regression analyses of predictors for response to levetiracetam monotherapy