Introduction

Epilepsy is the second common neurologic disorder after stroke. Epilepsy affects about 0.5% to 1% of the world's population and about 700 thousand people have been diagnosed in Iran. Epilepsy can occur in all age groups, ethnicities and genders. The age adjusted annual epilepsy rate is 29-53 per 100,000. The highest age-specific incidence rates of epilepsy pertain to children and the elderly. About 50% of all the epilepsy cases emerge during childhood or early adolescence. The incidence rates of this condition are slightly higher in men than in women (1-3). Epilepsy is a condition defined as transient nervous signs caused by abnormal synchronous and paroxysmal neuronal electrical activity in the cerebral cortex, leading to a variety of clinical states. The occurrence of each of these signs depends on the brain damage focus and the epileptic discharge depletion site (4). It is caused by an extensive list of idiopathic, symptomatic and cryptogenic etiologies. In the idiopathic type, causes are genetic and begin during childhood. The symptomatic type is the result of a specific brain damage. The cryptogenic type is still lacking a cause (2). The definition proposed by the International League Against Epilepsy (ILAE) for refractory epilepsy is "the failure of adequate trials of two tolerated and appropriately chosen and used antiepileptic  schedule drugs selected as the antiepileptic medication therapy of choice (whether as mono or in combination) to achieve sustainable seizure freedom" (3). When no curable causes can be found for resistant seizures, and the seizures are not progressive due to any neurodegenerative diseases and cannot be controlled despite two years of medication therapy either, the patient should be assessed for the helpfulness of surgical operations (1).

The majority of refractory epilepsies are caused by a temporal lobe sclerosis (75% of the cases) and the Lennox-Gastaut syndrome (50% of the cases). Resistance may reach 90% in  patients  with  hippocampal sclerosis accompanied with focal dysgenesis or other abnormal disorders (5). The prognostic factors of refractory epilepsy include: (1) high density of seizures (the number of seizures experienced each time) before beginning the treatment  (2), prolonged history of poor seizure control (3), early onset of seizures (4), having more than one type of seizure, (5) frequent seizures after beginning the treatment (6), previous causes (such as head trauma and infection) (7), particular structural disorders (such as cortical dysplasia and hippocampal sclerosis) (8), special EEG abnormalities, (9) mental retardation (10), accompanying psychiatric disorders (11), abnormal neurological examination results (12) and history of permanent epilepsy (6). Epileptic patients suffer from problems such as isolation, dependence, psychiatric disorders, celibacy, unemployment and a poor quality of life. Although antiepileptic medications (especially new ones) have relatively controlled seizures, their side-effects cause serious problems and occasionally exacerbate the seizures as well (5).

Refractory epilepsy entails numerous complications for the patients and their families. Patients who do not respond to or who respond only partially to antiepileptic medications experience debilitating seizures leading to neurological, psychological and social complications with a subsequent reduced quality of life and increased disability and mortality (6). Nasehi et al. (2010) conducted a study in Mofid hospital of Tehran in order to assess the factors affecting the response to treatment in children with refractory epilepsy and concluded that a refractory epilepsy that is secondary to an underlying disease clearly affects the patients' response to treatment and increases the likelihood of not responding to the medical treatments at all (7). A study conducted by Shnayder et al. in 2008-2010 in in Russia aimed to assess cases of refractory epilepsy with different severities, the exact number of drug-resistant samples hardly  reached one third of the total sample population after the modification of the treatment (26.6%). The proper method of reducing refractory cases among these samples was therefore to use a dedicated approach for the treatment of each patient (8). In a study conducted by French et al. (2007) in the Hospital of the University of Pennsylvania in Philadelphia entitled "Refractory epilepsy: A clinical review", the results obtained showed that despite the abundance of new antiepileptic medications introduced to the market over the past 10 years, refractory epilepsy is still highly prevalent, and according to the available epidemiological data, the condition becomes refractory in 20% to 40% of newly diagnosed epilepsy patients. Prognostic factors of epilepsy include the type of epilepsy, associated syndromes, etiology, frequency history and the frequency and concentration of seizures. Environmental factors (such as trauma) and genetic factors may also affect the response to treatment with antiepileptic medications. Resistance to treatment is therefore a multi-factorial phenomenon (9). The present study was therefore conducted to assess the prevalence of refractory epilepsy and examine its associated factors so as to collect a basic set of data that can be used for making decisions about evidence-based treatment approaches and the appropriate management of epileptic patients with the ultimate aim of improving quality of life in these patients.

Materials and Methods

The present observational, descriptive-analytic, cross-sectional study was conducted on the entire population of epilepsy patients admitted to a teaching hospital associated with Islamic Azad University of Mashhad in the North East of Iran in 2014 collected through simple, purposive and non-random sampling. A checklist was designed to register the personal details of participants, including their gender, age, duration of the disease, type of epilepsy, medications used and the monthly frequency of seizures. Since the study aimed to examine refractory epilepsy, the type of epilepsy (i.e. refractory or non-refractory) was identified. Patients who experienced more than one seizure per month despite their use of two medications at the right dose for a period of one year were considered as the cases of refractory epilepsy. Also the accompanying symptoms were then recorded in the checklist. The study inclusion criteria consisted of being older than fifteen in age (in children under 15, epilepsy is classified as pediatric), having epilepsy based on the criteria proposed by the ILAE. The exclusion criteria consisted of having acute symptomatic seizures (caused by acute conditions such as hypoglycemia and tramadol poisoning, and etc. which are different from seizures secondary to underlying diseases such as vascular malformation or space-occupying lesions and abscesses), having psychogenic epilepsy. Eligible patients were briefed on the study objectives and then submitted their informed consent. Participants were then interviewed and examined by a neurologist and underwent imaging and EEG. Patients diagnosed with pseudo-seizures using diagnostic and statistical manual of mental/behavioral disorders as cases of conversion disorder were excluded (10).

Tables and appropriate statistical indicators such as the Mean±Standard deviation were used in describing the data and the Likelihood Ratio Chi-Square test was used to analyze the nominal scale data. In cases  where more  than  20%  of the expected frequencies of the tables were below 5 (Cochran), Fisher's Exact test was used. The one-sample Kolmogorov-Smirnov (the revised Lilliefors version) test was used to ensure the normality of the data (where the data were discrete or qualitative or the sample size was below 30). Appropriate parametric tests such as the student T-test were used when the normality of the data was confirmed, and if it was not confirmed, the Mann-Whitney U test was used instead. Analysis was performed in SPSS software version 22. The significance level was considered as p<0.05.  (The values less than 0.05 identified with an asterisk (٭) and values less than 0.01 with a double-asterisk (٭٭).

Results

The present study was conducted on 171 epileptic patients. Patients were in the age range of 16 to 58 and had a mean age of 28±9 years. As for the gender distribution of the patients, 88 (37.5%) participants were men and 83 (31.3%) women. A total of 59 patients (34.5%) had refractory epilepsy. The statistical tests showed that refractory epilepsy was not significantly related to the patients' age (t-test=0.06 and p=0.947) or gender (likelihood ratio=0.72 and p=0.424). According to the results obtained, the mean duration of disease in patients with refractory epilepsy was 14.5±8.4 years, which was significantly greater compared to in patients with controlled epilepsy (11±8.8 years; t-test=2.5 and p*=0.013). There was a significant difference between two groups in terms of the monthly frequency of seizures, which was 7.15±8.4 in the refractory group and 0.29±7 in the controlled group (t-test=6.3 and p٭٭=0.0001). Table 1 shows the frequency of refractory epilepsy in each type of seizure. In each seizure type group there wasn’t any significant difference in the frequency of controlled and uncontrolled epilepsy except for mixed epilepsy in which, controlled seizure was more prevalent  (p=0.04).