Epilepsy is a common neurological disorder affecting children with higher rate of incidence in developing countries. Childhood epilepsy is also frequently comorbid with cognitive and developmental delays and the development of both psychiatric and behavioral disorders, including autism and hyperactivity disorders. [1] Prevalence of behavioral comorbidities in pediatric patients to be significantly higher in epileptics compared with non epileptics. Association between epilepsy and behavioral disorders has been frequently reported in the literature suggestive of Bidirectional Hypothesis. Due to this increased susceptibility, extra precaution must be taken in the management of epilepsy in children, particularly in the utilization of antiepileptic drugs that carry a risk of behavioral adverse effects. [2, 3] Levetiracetam is a second generation antiepileptic agent that has been approved for the treatment of epilepsy and other seizure disorders in both children and adults. Levetiracetam bind to the synaptic vesicle protein 2A (SV 2A) resulting in a possible effect on neurotransmitter release from the pre synaptic vesicles, although exact mechanism of action is not known. In children, the recommended dose for levetiracetam is 10–60 mg/kg/day in divided dose. Drug has faster elimination rate in children. [4] While Levetiracetam therapy is generally well-tolerated in pediatric patients, neuropsychiatric manifestations including agitation, poor attention, poor concentration, sleepiness, depression and anxiety, may occur that have been reported secondary to initiation of therapy. Such adverse effects are generally mild, tolerable and seldom require discontinuation of therapy. [5, 6] In this case series, We present 7 cases with a history of unspecified seizure disorder who suddenly developed neuropsychiatric manifestations following starting(New) or increases in Levetiracetam dose (Add on therapy ). Case Series:

Here is a case series of 7 children who had neuropsychiatric adverse effect due to Levetiracetam therapy. Study type: A Descriptive Study Study Population: Pediatric Age (up to 18 years) Inclusion Criteria: 1. Children age up to 18 years with history of unspecified seizure disorder. 2. On Levetiracetam therapy with in pediatric dose range (10-60mg/kg/day). 3. Follow up with in 1 month of starting or increasing in Levetiracetam dose. 4. Developmentally Normal Children. Exclusion Criteria: 1. Preexisting Neuropsychiatric disorders. 2. Children having delayed development. 3. Lost to Follow up. Total 7 pediatric cases was identified who had Levetiracetam induced one or more neuropsychiatric adverse effect. Children who had preexisting Neuropsychiatric disorder were excluded to avoid bias. Informed consent was taken from parents. Among these 7 cases, 4 cases (57%) were in adolescent age group (10-19 Years). Mean age was 10.12 years. 5 cases (71%) were Male and rests were Female gender. Majority of the patient (5 out of 7) was on Levetiracetam mono therapy. Few patients were on add on therapy. All cases had dose of Levetiracetam more than 30 mg/kg/day which was in normal range for children (10-60 mg/kg/day). Mean dose in our study was 37 mg/kg/day. All patients developed side effects within 2 weeks of starting or increasing Levetiracetam therapy. Mean duration to develop adverse effect was 1.5 week. Somnolence and Aggressiveness was most common and predominant neuropsychiatric manifestations/adverse effects in our study. Somnolence was noticed in 85% cases and Aggressiveness was found in 57% cases. Poor attention, poor concentration, irritability, crying, head banging, hyperactivity and behavior changes were also noted after Levetiracetam therapy. In our study, all children had mild and tolerable adverse effect required reassurance and parental counseling. No patient requires discontinuation of Levetiracetam therapy. [Table 1]

Levetiracetam is a second-generation antiepileptic used to treat a range of seizures disorders. Levetiracetam exerts its antiepileptic effects by binding to and inhibiting synaptic vesicle protein SV2A, thereby decreasing the rate of pre synaptic neurotransmitter release and increasing the seizure threshold. [7] Levetiracetam has a number of advantages compared with other antiepileptic drugs (including absence of drug–drug interactions and reduced cytochrome P450 enzyme induction due to its partial extra hepatic metabolism) , it also has a number of side effects associated with initiation of treatment or acute changes in dosage. The most common adverse effects in adults are somnolence, weakness, and dizziness; while in children, its behavioral adverse effects like agitation, poor attention, poor concentration, are more notable. [8] Table 1: Case Details Case No. Age (Years) Sex LEV Therapy LEV Dose (mg/kg/day) Onset of Adverse effect after LEV Predominant Neuropsychiatric manifestation Noticed by LEV Discontinuation 1 15 Yr M mono 40 2 weeks Aggressiveness Somnolence Parents Not Required 2 7 Yr M mono 30 2 weeks Somnolence Poor attention Poor concentration Parents Not Required 3 13 Yr F Add on 35 1 week Aggressiveness Somnolence Doctor Not Required 4 10 Yr M mono 40 1 week Aggressiveness Doctor Not Required 5 6 Yr M mono 30 2 weeks Somnolence Irritability Parents Not Required 6 11 Yr F mono 50 1 week Aggressiveness Somnolence Doctor Not Required 7 9 Yr M Add on 35 2 weeks Somnolence Hyperactivity Poor attention Parents Not Required *M=Male, F=Female, LEV=Levetiracetam Table 2: Statistical tests of behavioral side-effects between Levetiracetam and Placebo Study Total no. of behavioral side-effects p value (test used) Levetiracetam Placebo Glauser (2006) 34/101 13/97 p = 0.001 (Chi-square) Levisohn (2009) 25/64 8/64 p = 0.121 (Chi-square) Fattore (2011) 3/38 0/21 p = 0.546 (Fisher’s exact)

Results of Three randomized controlled trials were shown in Table 2. A total of 62 behavioral side-effects were reported in 203 patients with hostility (5.9%), nervousness (4.9%) and aggression (3.9%) being reported mostly. One- hundred and sixty-five patients received levetiracetam add-on therapy and 59 behavioral side-effects were reported within this group (mostly hostility (7.3%), nervousness (6.1%) and aggression (4.9%)). There is a statistically significant difference in the total number of behavioral side-effects between patients receiving levetiracetam and patients receiving placebo in the study of Glauser et al but this was not found in the study by Levisohn et al and Fattore et al No statistically significant differences were found between levetiracetam and placebo for specific behavioral side-effects with the exception of nervousness [Table 2]. Overall, 62 behavioral side-effects in 203 patients using levetiracetam compared to 21 behavioral side-effects in 152 patients using placebo does show a trend of behavioral side-effects being more prevalent in patients using levetiracetam over placebo. Most reported findings from randomized controlled trials were hostility, nervousness and aggression. [9, 10] A statistically significant difference in total number of psychiatric adverse effects between patients receiving levetiracetam versus placebo was found in only one randomized controlled trial (RCT). Also no statistical significance for specific behavioral side-effects was seen. However, statistically significant risk ratio of 2.18 for levetiracetam versus placebo was seen in the meta-analysis. [11] A systematic review of pediatric patients alone conducted by Halma et al correspondingly found that 62 out of 203 (30.1%) patients developed behavioral side effects secondary to Levetiracetam treatment, with the most common symptoms being hostility, aggression, and anxiety (30 of 62 symptomatic patients,48.4%). White et al reported in a case series of 553 patients that 38 of them (6.9%) required discontinuation of Levetiracetam therapy soon after treatment initiate on due to the development of severe, intolerable behavioral side effects. Most notably, their study also found that the patients in the discontinuation group had been administered a significantly lower dose of Levetiracetam compared to the patients who were able to continue treatment, suggesting that the development of adverse behavioral effects is likely associated with some variable degree of susceptibility reflective of the underlying pathologic changes in neural circuitry resulting from a particular patient's chronic seizure disorder. [12] It is thought that dysregulation of neural circuits resulting from excitotoxic damage in patients with epilepsy subsequently decreases their “cerebral reserve” for resisting the adverse effects of Levetiracetam therapy, thus predisposing them to rapid decompensation when exposed to increased doses of the drug. While the pathophysiology behind Levetiracetam's effects on behavior is uncertain, there are so far no reports in the medical literature of studies demonstrating toxic effects on neurons following exposure to the drug. Levetiracetam might induce neuropsychiatric disturbance similar to Phencyclidine, an NMDA receptor antagonist. The clinical relevance of adverse effects by Levetiracetam is significant in that the mood and behavioral intolerability of the drug for patients and their caregivers limits the extent to which the drug is able to be utilized in the pediatric population. In addition, multiple other case studies have reported that the adverse effects of Levetiracetam are transient and resolve rapidly following discontinuation of therapy with a complete return to baseline functioning. These findings suggest that Levetiracetam remains an effective first-line antiepileptic drug in pediatric epilepsy. [12]

Children treated with levetiracetam have a risk of developing several neuropsychiatric adverse effects. Although Levetiracetam remains a safe and effective first-line antiepileptic agent in pediatric epilepsy require close patient monitoring and dose titration.

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