Topiramate Effectiveness as Add-on Therapy in Bulgarian Patients with Drug-resistant Epilepsy

Introduction: There are no reliable prospective studies on the effectiveness of topiramate in Bulgarian adult patients with drugresistant epilepsy. Aim: The aim of the study was to conduct an open, prospective study on various aspects of topiramate (TPM) effectiveness in Bulgarian patients with drug-resistant epilepsy. Patients and methods: The study included patients with epilepsy who attended the Clinic of Neurology at the University Hospital in Plovdiv, Bulgaria. Patients completed diaries for seizure frequency, seizure severity, and adverse events. There were regular documented visits at 3 or 6 months during the first year of TPM treatment and at 6 months afterwards, with a dynamic assessment of seizure frequency, severity, adverse events, and EEG recordings. Results: TPM was used as an add-on treatment in 120 patients (69 males, mean age 37 years). There was a relatively mild and stable dynamic improvement of seizure severity, a satisfactory seizure frequency reduction in 37% of participants, a stable mean seizure frequency reduction (47%) from month 6 to month 24 of treatment and a stable responder rate (48-51%) during the same period. New seizure types (focal with impaired awareness with/without evolution to bilateral tonic-clonic seizures) occurred in 5 patients. There were adverse events (dizziness/vertigo, irritability, speech disturbances, memory impairment, concentration problems, tremor, loss of appetite and weight, weakness, numbness, bradypsychia, confusion, visual hallucinations, sleepiness, insomnia, headache, itching, unstable gait, nausea, and vomiting) in 20% of patients. Conclusions: TPM treatment is associated with low and stable improvement of seizure severity, good and stable improvement of seizure frequency, possible worsening of seizure control and appearance of new seizure types, good safety and tolerability.


INTRODUCTION
Topiramate (TPM) is a newer-generation antiepileptic drug (AED) with several mechanisms of action: interaction with GABA, reduction of the effect of excitatory neurotransmitters through blockage of glutamatergic kainate and AMPA receptors, inhibition of calcium and sodium channels, carboanhydrase inhibition. TPM has been confirmed as Folia Medica I 2020 I Vol. 62 I No. 4 a monotherapy and add-on therapy drug in patients with focal seizures with and without evolution to bilateral tonic-clonic seizures and generalized tonic-clonic seizures in patients above 2 years of age, as well as add-on therapy in children and adults with Lennox-Gastaut syndrome. The favourable pharmacokinetics, lack of enzyme induction activity, and limited drug interactions have been proven as other advantages explaining the frequent usage of TPM in the medical practice. Some disadvantages requiring special attention are: the necessity of slow up-titration and the poorer tolerability with typical and frequent adverse events -cognitive disturbances, loss of weight, nephrolithiasis.
Seizure frequency dynamics is the main efficacy outcome reported by investigators from randomized, double-blind, placebo-controlled, and open prospective studies about the add-on treatment with TPM. Dose-dependent variations have been reported in 27% to 52% of responders in randomized, double-blind, placebo-controlled studies 1-8 and up to 82% in patients with focal seizures, up to 75% in patients with generalized tonic-clonic seizures, and up to 67% in patients with absences in open prospective studies. [9][10][11][12][13][14] Attention has not been focused on seizure severity, as well as on the correlation of seizure frequency and severity dynamics with demographics and clinical findings. There are no reliable prospective studies on the effectiveness of TPM in Bulgarian adult patients with drug-resistant epilepsy. Therefore, the conduction of an open, prospective study on various aspects of effectiveness of add-on therapy with TPM 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 TPM effectiveness in Bulgarian patients with drug-resistant epilepsy.

PATIENTS AND METHODS
This is an open prospective study with a possibility of using available detailed retrospective information about some participants. It included 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 obtaining approval from the Local Ethics Committee of 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. A signed informed consent form; 2. A consent of the patient and relatives about giving the required information and medical records; 3. Age ≥ 18 years; 4. A diagnosis of epilepsy; 5. Good compliance of patients to recommended treatment; 6. A stable dose of concomitant AEDs in the recent 3 months; 7. A period of prospective observation of at least 3 months; 8. A completed diary about seizure frequency and severity, and adverse events; 10. Regular documented visits at 3 or 6 months during the first year of treatment and at 6 months or 1 year afterwards, with dynamic assessment of seizure frequency, severity, adverse events, and EEG recordings. The criteria for AEDs choice are in conformity with the indications approved by the National Drug Agency.
Data were collected by a trained neurologist specialized in epilepsy through examination of the patients' medical documentation and a detailed interview about the disease onset, heredity, concomitant diseases, type and etiology of epilepsy, seizure type, frequency and severity, treatment with AEDs, efficacy of TPM, and adverse events from treatment. The seizure frequency dynamics was based on information from patients' seizure diaries. Seizure severity was estimated on the basis of information about seizure duration, traumatism during seizures, duration of consciousness loss, severity of postictal manifestations. Adverse events from treatment were assessed as type, severity (mild, moderate, severe), and duration based on reports from patients and relatives, a standardized interview based on the Bulgarian version of the Liverpool Adverse Events profile validated by Kuzmanova et al. 15 , a physical, and neurological status examination at every visit.
Data were analysed using STATA (Stata Corp., College Station, TX, USA) and SPSS v. 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 were given in percentages. The principal outcomes were: clinical efficacy (effect on seizure frequency and severity, treatment duration and reasons for withdrawal, new seizure types, treatment changes), and tolerability (adverse events). The association of dynamics in seizure frequency and severity with demographics, and clinical findings was tested by means of χ 2 test and Friedman test. The level of significance was set at p<0.05.

RESULTS
The total number of patients diagnosed with epilepsy who attended the Clinic of Neurology between 2003 and 2016 was 1259 (in-and outpatients). TPM was used in 120 patients aged 18 to 65 years (mean age 37±13.36 years). The onset of epilepsy varied from 1 day to 54 years of age, mean age onset 16±13.69 years. The mean epilepsy duration varied from 2 to 60 years, mean duration was 22±12.7 years. The observation continued from 5 days to 144 months, (mean duration 37±29.67 months). The commonest dosage of TPM was 200 or 300 mg/d, mean dosage 224±7.99 mg/d. The demographic and clinical characteristics of study participants are presented in Table 1.
The assessment of seizure frequency up to 24 months of TPM treatment is presented in Table 2. The most significant improvement of the seizure frequency was observed at 6 months of treatment followed by retention of a high responder rate of about 50% (48.33% at 6 months, 56.5% at 12 months, 51.3% at 24 months) and gradual increase of the percentage of patients without seizures up to 14.5% ( Table 2). The statistical analysis of the results confirmed that there was no significant decrease in the seizure frequency between month 6 and month 12, and between month 6 and month 24 (Friedman Test = 3.32, p>0.05). We found the following dynamics in the mean seizure frequency reduction -46.93% at 6 months, 49.14% at 12 months, and 47.31% at 24 months. Therefore, regarding seizure frequency, the efficacy of TPM was good and stable for the study period.
The seizure frequency improvement by TPM monotherapy or various combinations of TPM with other AEDs at the end of the study is presented in Table 3. In one case, the investigational drug was added to another AEM and then the other one was withdrawn in a short period of time due to inefficacy.
At the end of the study the seizure frequency was increased in 23 (19.3%) participants, there was no or unsatisfactory improvement (seizure frequency reduction <50%) in 52 (43.7%) patients. Responders were 44 (37%) patients -17 (14.3%) were with seizure reduction >75%, 8 (6.7%) -without seizures. The final seizure frequency reduction correlated with a low initial seizure frequency (χ 2 =11.21, p<0.05). Responders were the participants with a low initial seizure frequency (1 to 11 seizures/year -66.7%) and those with very frequent (daily) seizures at the study baseline (53.3%). The final seizure frequency reducti-on did not correlate with any other clinical or demographic findings (p>0.05).
There was a modification of the seizure type in a small number of patients: a manifestation of focal seizures with impaired awareness in 2 patients with generalized epilepsy and of GTCS in 1 patient with focal epilepsy at 6 months of study, focal seizures with/without impaired awareness in one patient with generalized epilepsy at 36 months of study, focal seizures with impaired awareness in one patient with focal seizures without impaired awareness and generalized tonic-clonic seizures at 60 months of study.
In 6 patients, TPM was stopped very early (before 6 months of treatment), at 6 months of treatment TPM was stopped in 5 other patients, at 12 months -in 4 patients, at 24 months -in none, at 36 months -in 3 patients, and at 48 months in 2 patients. Therefore, we found a gradual decrease of the percentage of patients continuing TPM treatment, i.e. the retention rate was 90.83% at 6 months, 87.5% at 12 and 24 months, 85% at 36 months, 83.33% at 48 months, the decrease being significant during the first 6 months.
The total duration of TPM treatment was 4377 months. The total duration of effectiveness was 2456 months, therefore TPM was effective in 56.11% of the treatment time of Folia Medica I 2020 I Vol. 62 I No. 4

Safety and tolerability of TPM treatment
There were adverse events from treatment in 24 (20%) of the study participants, without any correlation with the TPM dosage (χ 2 =16.71, p>0.05). The distribution of patients with somatic and CNS-associated adverse events ac-cording to the TPM dosage is presented in Table 5. More detailed information about adverse events is included in Table 6.
The commonest adverse events were: loss of appetite and weight -in 10 (8.33%), asthenia -in 6 (5%), sleepiness -in 4 (3.33%) patients. The severity of adverse events was most frequently moderate and severe and they were associated with treatment termination in some patients. The most severe adverse events associated with treatment termination were: asthenia, sleepiness, and speech disturbances. Some adverse events (visual hallucinations, memory impairment, loss of appetite and weight) were manifested later than treatment beginning. We did not confirm a correlation of adverse events with demographic and clinical factors.

DISCUSSION
In our study, TPM was used as an add-on treatment in 120 patients (mean age 37 years) with long duration epilepsy with predominant severe and frequent focal, a combination of focal and generalized and generalized tonic-clonic seizures, refractory to the prescribed, usually combined treatment with a variety of AEDs. There was a relatively mild and stable dynamic improvement of the seizure severity. These results could not be compared with other studies for the lack of literature data.
The described satisfactory seizure frequency reduction in 37% of the participants (6.7% seizure free), the stable mean seizure frequency reduction (46.93-47.31%) from 6 months to 24 months of the study, as well as the high and stable responder rate (48.3-51.3%) during the same period, The percentage of our study participants with worse seizure control, without improvement or minimal efficacy, is not a small one (19.3% and 43.7% respectively), and suggests focusing attention in future studies, moreover the lack of efficacy is the reason for TPM treatment termination in 15% of study participants. The appearance of new seizure types in 5 patients (focal seizures with impaired awareness with/without evolution to bilateral tonic-clonic seizures), raises 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.
The following combinations of TPM with other AEDs were more frequent: 1. VPA + TPM (31.09%) -27.03% responders; 2. OCBZ + TPM -(11.76%) -no responders; 3. CBZ + TPM (11.75%) -with low efficacy (14.29% responders). There was a significant decrease of the percentage of patients continuing TPM treatment to 90.83% at 6 months followed by a retention rate of 87.5% at 12 and 24 months, and a mild decrease to 83.33% at 48 months of study. We found only one retrospective study with 470 patients in literature focusing attention on the retention rate of TPM. Bootsma et al. reported a significantly higher and quicker decrease of TPM retention rate -from 53% at the end of the first year to 30% after 4 years, mainly because of adverse events and/or inefficacy. 18 TPM showed good safety and tolerability in our study participants. The frequency of reported adverse events (20%) is similar to the literature data, they are usually with moderate severity and become a cause of treatment termination in a similar percentage of patients -16.6%. 2,[16][17][18][19][20][21] The most severe adverse events associated with treatment termination were: asthenia, sleepiness, and speech disturbances. The most severe adverse events, which were manifested early in some participants and were associated with a rapid termination of TPM treatment were: asthenia, sleepiness, and speech disturbances. Most adverse events are similar to the ones reported in literature and are not associated with a higher TPM dose. 2,5,6,9,10,[16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31] Loss of appetite (10 patients), asthenia (6 patients) and sleepiness (4 patients) were the more frequent adverse events. Unusual adverse events were found in 3 patients -hands tremor (in 1 patient, with moderate severity), insomnia (in 1 patient, severe), and mild, transient itching (in 1 patient). They could result in TPM termination in some patients and necessitate attention for the possibility of manifestation in the medical practice.

CONCLUSIONS
TPM treatment is characterized with: low and stable improvement of seizure severity, good and stable reduction of seizure frequency, a possibility of worsening of seizure control, possible appearance of new seizure types, good safety and tolerability. Future studies are needed with an emphasis on seizure control worsening by TPM treatment, new seizure type manifestations in the course of treatment, and correlations of efficacy and adverse events from treatment with patients' demographic and clinical characteristics.