Levetiracetam Effectiveness as Add-on Therapy in Bulgarian Patients with Drug- Resistant Epilepsy

Introduction: There are no reliable prospective studies on the effectiveness of LEV in Bulgarian adult patients with drug-resistant epilepsy. Aim: The study aimed at conducting an open, prospective study on various aspects of levetiracetam (LEV) effectiveness in Bulgarian patients with drug-resistant epilepsy. Materials and methods: The study was performed with patients with epilepsy recruited from those attending the Department of Neurology at the University Hospital in Plovdiv, Bulgaria. The patients completed diaries about seizure frequency, severity, and adverse events. There were regular documented visits at 3 or 6 months during the first year of treatment with LEV and at 6 months afterwards, with dynamic assessment of seizure frequency, severity, adverse events, and EEG recordings. Results: LEV was applied as an add-on therapy in 135 patients (86 males, mean age 35 years). There was a relatively mild and persisting dynamic improvement of seizure severity, a satisfactory seizure frequency reduction in 49.6% of participants, a persisting mean seizure frequency reduction (48-58%) from 6 to 36 months of treatment and a high responder rate (53-60%) during the same period. New seizure types (focal with impaired awareness with /without evolution to bilateral tonic-clonic seizures) occurred in 4 patients. There were adverse events (dizziness, memory impairment, aggressiveness, numbness, non-epileptic seizures, depression, anxiety, speech disturbances, visual hallucinations, sleepiness, pelvic muscles weakness, confusion, sleep disturbances, loss of appetite, unstable gait, hair loss, acne, generalized rash) in 13.33% of patients. Conclusions: LEV treatment is associated with: low and persisting improvement of seizure severity, a good and persisting improvement of seizure frequency, a possible worsening of seizure control, a possible appearance of new seizure types, a good safety and tolerability.


INTRODUCTION
Levetiracetam (LEV) is a newer generation antiepileptic drug (AED) which has been confirmed as an appropriate drug for monotherapy and add-on therapy in patients with newly diagnosed focal seizures with impaired awareness with/without evolution to bilateral tonic-clonic seizures and add-on therapy in patients with juvenile myoclonic epilepsy and with generalized tonic-clonic seizures in patients with idiopathic generalized epilepsy. The favou-rable pharmacokinetics, lack of drug interactions and enzyme induction activity, as well as rare and mild adverse events, have been proven as other advantages explaining the frequent usage of LEV in medical practice. [1][2][3][4][5][6][7][8][9] There are no reliable prospective studies on effectiveness of LEV in Bulgarian adult patients with drug-resistant focal seizures with impaired awareness with/without evolution to bilateral tonic-clonic seizures. Therefore, the conduction of an open, prospective study on various aspects of effectiveness of add-on therapy with LEV in Bulgarian patients with drug-resistant epilepsy will provide additional useful data for the medical practice.

AIM
To perform an open, prospective study on various aspects of LEV effectiveness in Bulgarian patients with drugresistant epilepsy.

PATIENTS AND METHODS
The study is open, prospective, with the participation of patients with epilepsy who attended the Clinic of Neurology at the University Hospital in Plovdiv, Bulgaria for a regular examination in cases of unsatisfactory seizure control or for adverse events from treatment. All study procedures were performed after the approval of the Local Ethics Commission at the Medical University, Plovdiv. Every patient was introduced to the study design and signed an informed consent form before participating in the study procedures. The following inclusion criteria were used: 1. Age > 18 years; 2. Good compliance of patients to recommended treatment; 3. A stable dose of concomitant AEDs in the recent 3 months; 4. Completed diary about seizure frequency, severity, and adverse events; The criteria for AEDs choice are in conformity with the indications approved by the National Drug Agency.
Data were processed using STATA (Stata Corp., College Station, TX, USA) and SPSS (Statistical Package for the Social Sciences) version 19.0 (SPSS Inc., Chicago, IL, USA). The results for quantitative variables were expressed as means ± SE (standard error) and the results for qualitative variables -as percentages. The principal outcomes were: clinical efficacy (seizure frequency and severity reduction, modification of seizure type, duration of LEV effectiveness, retention rate of patients, reasons for termination of LEV treatment) and tolerability (manifestation of adverse events). The assessment of seizure frequency dynamics included: worsening, no change, reduction <50%, reduction >50%, reduction 100%. Patients with seizure frequency reduction of at least 50% were accepted as responders to treatment, while those with seizure frequency less than 50% were considered as being with minimal efficacy on the seizure frequency control. The assessment of seizure severity dynamics included worsening, no change and improvement of the following characteristics: seizure duration, duration of the loss of consciousness, traumatism, and postictal manifestations. The association of dynamics in seizure frequency and severity with demographics (age, gender), and clinical findings was tested by means of χ 2 -test and F-test. The level of significance was set at p<0.05.

RESULTS
LEV was applied in 135 patients (86 males) of 18-63 years of age (mean age 35.6±1.1). The onset of epilepsy varied from 1 month to 57 years of age, mean age of onset 16.8±1.0 years. The mean epilepsy duration varied from 2 to 51 years (mean epilepsy duration, 29.4±2.1 years). The observation continued from 10 days to 108 months (mean duration 29.4±0.4 months). The most common dosage of LEV was 2000 mg/d (mean dosage 1892±1.8 mg/d). The demographic and clinical characteristics of study participants are presented in Table 1. We did not find significant difference in the percentage of patients without improvement of seizure severity up to 36 months of treatment. The percentage of participants with seizure severity reduction persisted between the 6th and 36th months (25.4% at 6 months, 26.4% at 12 months, 31.5% at 24 months, 25% at 36 months). Because of the small number of patients who continued LEV treatment after the 36th month, they were not included in the statisti- There was a modification of the seizure type in a small number of patients -manifestation of focal seizures with impaired awareness without evolution to bilateral tonicclonic seizures in 3 patients with GTCS at 6 months of study and in 1 patient at 36 months of study.
In 26 (19.3%) study participants LEV treatment was terminated for various reasons: 1. Adverse events from treatment -in 5 (3.7%) patients; 2. Lack of efficacy, transient efficacy or increased seizure frequency -in 8 (5.9%) patients; 3. A combination of adverse events and lack of efficacy -4 (3%). After taking into consideration the drop-out patients, we found gradual decrease of the percentage of cal analysis. We came to the conclusion about a mild and persisting improvement of seizure severity by treatment with LEV.
The seizure severity improvement correlated with the initial seizure frequency (p<0.05, r=-0.217) and seizure frequency dynamics (p<0.01, r=0.69) at 6 months of treatment. Seizure severity improvement was most frequent in patients with high initial seizure frequency -in 20 (34.5%) of those with high weekly frequency and 7 (28%) of those with daily seizures.
The assessment of seizure frequency up to the 36th month of LEV treatment is presented in Table 2. The most significant improvement of seizure frequency was found at 6 months of treatment followed by retention of a high responder rate of about 55-60% (53% at 6 months, 56.4% at 12 months, 57.3% at 24 months, and 60.4% at 36 months) and gradual increase of the percentage of patients without seizures up to 26.4% (Table 2). There was also gradual increase of participants with seizure frequency increase -up to 13.3% at 24 months followed by decrease to 9.4% at 36 months ( Table 2). The statistical analysis of results confirmed that there was no significant decrease in seizure frequency between the 6th and 12th months and between the 6th and 24th months (p>0.05, χ 2 =0.31, Friedman test). We found the following dynamics in the mean seizure frequency reduction -48% at 6 months, 51% at 12 months, 57% at 24 months, and 58% at 36 months. Therefore, regarding seizure frequency, the efficacy of LEV was good and persisting for the study period.
The seizure frequency dynamics correlated with the initial seizure frequency at 6 months (p<0.05, χ 2 =10.71; r=-0.178) and at 24 months of study (p>0.05, χ 2 =8.08), (p=0.052, r=0.35). At 6 months, the seizure frequency increase was more common in patients with low initial frequency, while at 24 months the seizure frequency improvement was more frequent in patients with low initial seizure frequency. The final seizure frequency reduction correlated with initial mono-or polytherapy (p<0.05, r=-0.21) and with seizure clusters and/or status epilepticus in the disease course (p<0.05, r=0.31). Most seizure free participants (62.5%) and 52.24% of responders were with initial monotherapy. Most seizure free patients (87%) and 71.64% of the responders did not have seizure clusters and/or status epilepticus in the disease course. patients continuing LEV treatment, i.e. the retention rate was 95.56% at 6 months, 91.13% at 12 months, 86% at 24 months, 83.8% at 36 months, and 80.73% at 48 months.
The total duration of LEV treatment was 3945 months. The total duration of effectiveness was 2486 months, therefore LEV was effective in 63.02% of the treatment time of all patients. The mean effectiveness duration was 30.32±0.44 months. The effectiveness duration is presented in Table 3.

Safety and tolerability of LEV treatment
There were adverse events from treatment in 18 (13.33%) of study participants (Table 4). We did not confirm a correlation of adverse events with demographic and clinical factors.
These results could not be compared with other studies for the lack of literature data. The described above satisfactory seizure frequency reduction in 49.6% of participants (17.8% seizure free), the persisting mean seizure frequency reduction (48-58%) from the 6th to the 36th month of study, as well as the high responder rate (53-60.4%) during

DISCUSSION
In our study, LEV was applied as an add-on treatment in 135 patients of mean age 36 years with drug-resistant focal or a combination of focal and generalized tonic-clonic seizures. There was relatively mild and persisting dynamic improvement of seizure severity, which correlated with the initial seizure frequency and seizure frequency dynamics. the same period, are similar to the results reported in literature from double-blind, randomized studies, and to those from some open prospective studies [1][2][3][4][5][6] , with the exception of lacking dose-dependent effect reported by some investigators. [7][8][9] Seizure frequency improvement correlated with initial monotherapy and the lack of seizure clusters and/or status epilepticus in the disease course. Investigators have not focused attention on the percentage of patients with worsened seizure control during LEV treatment, probably because of the uncertain association with drug intake in all patients. The percentage of our study participants with worse seizure control, without improvement or minimal efficacy, is not a small one (15.6% and 34.8%, respectively), and suggests focusing attention in future studies, moreover the lack of efficacy is the reason for LEV treatment termination in 8.9% of study participants. The appearance of new seizure types in 4 patients suggests the question whether this phenomenon is associated with some of its mechanisms of action or is a result of the disease course. There are no similar data and a discussion of this problem in literature.
There was a gradual decrease of the percentage of patients continuing LEV treatment from 95.56% at 6 months to 83.8% at 36 months. We found only one study with 1142 patients in literature focusing attention on retention rate of LEV. Krakow et al. 10 reported significantly higher and quicker decrease of LEV retention rate -from 60% at the end of the first year to 32% after the 5th year. Predictors of a higher retention rate were: higher maximum dose, low initial dose, generalized tonic-clonic seizures, a smaller number of concomitant AEDs at the onset of LEV treatment. 11 LEV showed good safety and tolerability in our study participants. The frequency of reported adverse events (13.3%) was similar to that in the literature data, they were usually with moderate severity and became a cause of treatment termination in a similar percentage of patients (6.7%). [1][2][3][4]12 Unusual adverse events were found in 15 patients -memory impairment, numbness, speech disturbances, pelvic muscles weakness, nightmares, unstable gait, hair loss, skin problems. They could result in LEV termination and necessitate attention for the possibility of manifestation in the medical practice. Most adverse events were similar to the ones reported in literature and were not associated with a higher LEV dose. [1][2][3]5,6,12,[14][15][16][17][18][19][20]

CONCLUSIONS
The results from our study suggest the following advantages of LEV treatment: low and persisting improvement of seizure severity, good and persisting reduction of seizure frequency, a possibility of worsening of seizure control, possible appearance of new seizure types, good safety and tolerability.