|Year : 2021 | Volume
| Issue : 4 | Page : 219-225
Effects of patient and seizure-related factors on drug load in seizure-free patients with idiopathic generalized epilepsy
Fulya Eren, Günay Gül
Department of Neurology, University of Health Sciences, Bakırkoy Prof. Dr. Mazhar Osman Mental Health and Neurology Training and Research Hospital, Istanbul, Turkey
|Date of Submission||21-May-2021|
|Date of Decision||10-Aug-2021|
|Date of Acceptance||30-Aug-2021|
|Date of Web Publication||29-Dec-2021|
Bakırköy Prof. Dr. Mazhar Osman Research and Training Hospital for Neurology, Neurosurgery and Psychiatry, Neurology Clinic, Istanbul
Source of Support: None, Conflict of Interest: None
Introduction: Idiopathic generalized epilepsies (IGEs) include four different epilepsy syndromes and IGE have mostly a good response to antiepileptic drugs (AEDs). The most common IGE subgroup is juvenile myoclonic epilepsy (JME). It generally responds well to low doses of AEDs; however, some patients need higher doses of medication. In this study was hypothesized that patient and epilepsy characteristics of seizure-free patients with high drug load might differ from those with low drug load. For this purpose, it was aimed to compare patients with JME and patients with other generalized epilepsies (non-JME IGE) regarding these factors concerning drug load. Patients and Methods: The records of the epilepsy outpatient clinic from 2010 to 2020 were retrospectively evaluated for patients with IGEs. Patients without any epileptic seizures in the last year were accepted as seizure-free. Drug load is calculated by dividing the prescribed daily dose by defined daily dose (PDD/DDD). A total drug load (TDL) equal to one and greater was considered as a high TDL (≥1, high-TDL group), where a drug load of below one was considered as a low TDL (<1, low-TDL group). The high-TDL and low-TDL groups in patients with JME and non-JME IGE were compared in terms of sociodemographic characteristics, personal and family histories, duration of epilepsy, seizure characteristics, epilepsy syndromes, electroencephalography findings, and AEDs and doses. Results: In this study, 119 patients (69 females, 50 males) with a mean age of 30.11 (range, 18–65) years were included. The mean age of onset and duration of the disease was 16.21 (range, 3–47) years and 13.6 (1–45) years, respectively. Sixty-three of the patients were diagnosed as having JME, and 56 patients were diagnosed as having non-JME IGE (39 with generalized tonic-clonic seizures alone, 17 juvenile absence epilepsy). According to the TDL, 35 patients were classified in the low-TDL group and 84 patients in the high-TDL group. The age of disease onset was higher in the non-JME IGE group (P = 0.027). Triple-type seizures were significantly more common in the JME group (P < 0.001). No statistically significant differences were found between the low- and high-TDL groups regarding patient and epilepsy characteristics in the JME and non-JME IGE groups. Conclusion: Most seizure-free patients had low-TDL in the JME and non-JME IGE groups. No association was observed in the JME and non-JME IGE groups regarding the total AED load.
Keywords: Drug load, epilepsy, genetic generalized epilepsy, idiopathic generalized epilepsy, seizure freedom
|How to cite this article:|
Eren F, Gül G. Effects of patient and seizure-related factors on drug load in seizure-free patients with idiopathic generalized epilepsy. Neurol Sci Neurophysiol 2021;38:219-25
|How to cite this URL:|
Eren F, Gül G. Effects of patient and seizure-related factors on drug load in seizure-free patients with idiopathic generalized epilepsy. Neurol Sci Neurophysiol [serial online] 2021 [cited 2022 May 19];38:219-25. Available from: http://www.nsnjournal.org/text.asp?2021/38/4/219/334047
| Introduction|| |
Idiopathic generalized epilepsies (IGE) include four different epilepsy syndromes: Juvenile myoclonic epilepsy (JME), childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), and IGE with generalized tonic–clonic seizures alone (GTCS-a). In 2017, the International League Against Epilepsy (ILAE) recommended that IGEs should be named “genetically generalized epilepsies,” but the term IGE is widely used. IGEs constitute 15%–20% of all epilepsies. Its incidence is 2.9–14.8/100,000 per year., Despite the well-defined syndromes, they can still be misdiagnosed. History, physical examination, and electroencephalography (EEG) findings should be evaluated together for an accurate diagnosis and classification.
Broad-spectrum antiepileptic drugs (AEDs) are used in the treatment of IGE, excluding CAE, and a good response to AEDs is observed. Long-term drug therapy is recommended, and drug resistance is reported at rates between 7% and 15%.,
The most common and well-known IGE subgroup is JME. It generally responds well to low doses of AEDs, and seizures are under control in 80%–90% of patients; however, some patients need higher doses of medication. Many factors have been suggested to affect seizure control in these patients. Coexistence of myoclonus, absence, and GTCS, presence of family history, focal EEG abnormalities, and a history of psychiatric diseases are some of the predictive factors.,,
The defined daily dose (DDD) is a standardized definition proposed by the World Health Organization (WHO) in 1996 for use in drug studies. Drug load is calculated by dividing the prescribed daily dose (PDD) by DDD (PDD/DDD). Seizure freedom is achieved with different doses of AEDs, with different drug combinations. There are limited studies related to the factors determining drug load in patients. In a study, it was suggested that patients with JME with high drug load had a positive family history and focal anomalies in EEG; other IGEs did not show the same features.
It was hypothesized that patient and epilepsy characteristics of seizure-free patients with high drug load might differ from those with low drug load. Accordingly, it was aimed to compare patients with JME and patients with other generalized epilepsies (non-JME IGE) regarding these factors in relation to drug load.
| Patients and Methods|| |
The protocol of this study was approved by the Ethics Committee of the Instution must be written on 15.03.2021 with the number “2021-06-28.”
The records of the epilepsy outpatient clinic from 2010 to 2020 were retrospectively evaluated for patients with IGE in accordance with the criteria recommended in the ILAE 2017 classification. Among these, 224 IGE records were identified. Episodes were documented with reference to seizure dairies at the last visit. According to the definition by the ILAE, in this study, seizure freedom was considered at least three times the interval of the longest previous interseizure duration (determined from seizures occurring within the past 12 months), or 12 months, whichever was longer. According to the ILAE guideline, 139 patients who were seizure-free were identified. Patients with at least 1 year of follow-up and at least one outpatient visit in the last year were included. Patients aged under 18 years, those diagnosed as having mental retardation, with abnormal foci that may be associated with seizure in magnetic resonance imaging, and patients with insufficient records were excluded, which left 119 patients for further analyses.
Sociodemographic characteristics, personal and family history, duration of epilepsy, seizure characteristics, epilepsy syndromes, EEG findings, and AEDs and doses were documented. Patients who presented with all GTCS, myoclonus, and absence type seizures were defined as having “triple-type seizures.”
The first EEG with diagnostic features was used. In our EEG laboratory, routine EEGs are performed with the patients awake for 30 min. Intermittent photic stimulation and hyperventilation are used as activation methods.
PDD was the total daily drug dose for each AED, recorded in the last visit of the patient. For the DDD of each drug, the values in the lists published by the WHO were used. DDD values were published as 1.5 g for valproic acid, 1.5 g for levetiracetam, 0.3 g for lamotrigine, and 0.3 g for topiramate. Drug load was calculated by dividing PDD by DDD (PDD/DDD) for each drug. Total drug load (TDL) was the sum of all drug loads in patients using more than one AED. A TDL equal to one and greater (≥1, high-TDL group) was considered as a high TDL, and a drug load of below one (<1, low-TDL group) was considered as a low TDL.
The sociodemographic and clinical characteristics of patients with JME and non-JME IGE and patients with drug burden ≥1 and <1 were compared.
Statistical analyses were performed using the SPSS software (version 26, IBM, New York, USA). Descriptive statistical methods (mean and standard deviation in groups with normal distribution, median, and range in groups without normal distribution) were used for reporting. The independent t-test for parametric values and the Chi-square test for nonparametric values were used when comparing groups. A P < 0.05 was considered statistically significant.
| Results|| |
In this study, 119 patients (69 females, 50 males) with a mean age of 30.11 (range, 18–65) years were included. The mean age of onset and duration of the disease was 16.21 (range, 3–47) years and 13.6 (range, 1–45) years, respectively. Sixty-three patients were diagnosed as having JME, and 56 patients were diagnosed as having non-JME IGE (39 with GTCS-a, 17 with JAE).
The sociodemographic and clinical characteristics are shown in [Table 1]. AEDs used were documented as valproic acid, lamotrigine, levetiracetam, and topiramate in different doses, alone or in combination. Sixteen patients were under polytherapy (11 in the low-TDL group and five in the high-TDL groups). According to the TDL, 84 patients were classified in the low-TDL group and 35 patients in the high-TDL group [Table 2]. The PDDs for each AED was as follows: Valproic acid 858.9 ± 377.7 mg, lamotrigine 179.6 ± 128.5 mg, levetiracetam 1537.9 ± 739.8 mg, and topiramate 471.4 ± 680 mg. Drug loads are summarized in [Table 2].
|Table 1: Sociodemographic and clinical features of patients with juvenile myoclonic epilepsy and nonjuvenile myoclonic epilepsy idiopathic generalized epilepsies|
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|Table 2: Drug loads of patients with juvenile myoclonic epilepsy and nonjuvenile myoclonic epilepsy idiopathic generalized epilepsies|
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The age of disease onset was higher in the non-JME IGE group (P = 0.027). Myoclonus was observed in all patients with JME and six in the non-JME IGE group (P < 0.001). Triple-type seizures were significantly more common in the JME group (P < 0.001). The disease duration, family history, sensitivity to photic and hyperventilation stimulation in EEG were higher in the JME group, and focal anomalies in EEG were higher in the non-JME group. However, these differences were not found to be statistically significant.
Juvenile myoclonic epilepsy group
The total number of patients with low drug load was 41 (low-TDL), and the number of patients with high drug load was 22 (high-TDL). The mean TDL was 0.51 ± 0.2 in the low-TDL group and 1.65 ± 1.3 in the high-TDL group (P < 0.001). No statistically significant differences were found between the low- and high-TDL groups regarding patient and epilepsy characteristics [Table 3].
|Table 3: Comparison of low-total drug load and high-total drug load groups in patients with juvenile myoclonic epilepsy|
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Nonjuvenile myoclonic epilepsy idiopathic generalized epilepsy group
The total number of patients with low drug load was 43 (low-TDL), and the number of patients with a high drug load was 13 (high-TDL). The mean TDL was 0.5 ± 0.2 in the low-TDL group and 1.69 ± 0.8 in the high-TDL group (P < 0.001). No statistically significant differences were found between the low- and high-TDL groups regarding patient and epilepsy characteristics [Table 4].
|Table 4: Comparison of low-total drug load and high-total drug load groups in patients with nonjuvenile myoclonic epilepsy idiopathic generalized epilepsies|
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| Discussion|| |
In this study, it was hypothesized that the sociodemographic and epilepsy characteristics of patients with high TDL might differ from those with low TDL in patients with JME and non-JME IGE. According to our results, being on a high or low AED doses showed no difference regarding these characteristics. It was found that the age of disease onset was higher in the non-JME IGE group, and the number of patients with triple-type seizures was higher among patients with JME.
The age of onset in IGEs varies according to the syndrome, and most patients are diagnosed before the age of 25 years. JME is usually diagnosed between 8 and 25 years; JAEs most commonly begin in puberty and young adulthood. CAE peaks at the age of 6–8 years and 12 years. GTCS-a can start in childhood and is mostly diagnosed in the second decade. Studies are showing that early-onset age is associated with poor prognosis in IGEs. It is known that between 8.5% and 28% of all IGEs are diagnosed with late-onset. No correlation between clinical and EEG features with late-onset has been reported. In our study, it was observed that the age of onset was higher in non-JME. This was thought to be related to the absence of patients with CAE, the low number of patients with JAE, and the natural history of other non-JME IGEs. No statistically significant difference was observed between the syndrome groups regarding TDL and age of onset.
JME is characterized by myoclonus, and GTCS accompanies in 90% of patients and absence seizures in 30%. JAE is characterized by absence seizures and GTCS accompanies in 80% of patients and myoclonus in 15%–20%. Myoclonus and absence are typically not observed in GTCS-a. Triple-type seizures, consisting of myoclonus, absence, and GTCS, were found to be higher in JMEs than in non-JME IGEs. Studies are reporting a poor prognosis in patients with triple-type seizure patterns in IGE., This was not supported in our data. The rate of triple-type seizure patterns was similar in both the low- and high-TDL groups, regardless of the syndrome.
In a meta-analysis that compiled studies on the prognosis of IGE, it was reported that evaluation methods of EEG were markedly heterogeneous, and conclusions were inconsistent. It is known that focal anomalies, as well as generalized EEG anomalies, can be seen in patients with IGE which causes late or misdiagnosis. In two studies conducted by Matsuoka and Szaflarski it was shown that focal anomalies were associated with poor prognosis. However, several studies opposed this association.,, Another study reported that there was no significant association between focal EEG anomalies and age of epilepsy onset, history of birth, developmental stages, and history of febrile convulsions. Focal anomalies were observed in 19.3% of our patients. The presence of focal anomalies was reported to be significantly associated with higher AED load for seizure freedom in patients with JME but not in patients with non-JME IGE in a single study with a smaller patient cohort. This finding was not supported in our results. We observed no association of TDL with focal anomalies in either group.
DDD, which was defined by the WHO, is a useful standardization method for drug studies and guides physician drug choice. Although DDD alone is a valuable tool to compare patients using different AEDs, it is still insufficient to compare patients on mono or polytherapy. To overcome this difficulty, TDL is used to compare polytherapy. We also used this method in our study. Brodie et al. reported in 2013 that patients using <50% or 75% of DDD had a lower rate of seizure freedom, and polytherapy remains ineffective if the first AED was admitted at a low dose. Therefore, it was suggested that the definition of resistant epilepsy should be revised by the ILAE in accordance with DDDs. However, in a study conducted on 1282 patients with epilepsy in 2016, it was reported that most seizure-free patients were using AEDs at a rate of ≤75% DDD. It was not shown that low drug load was less effective than high drug load, and it could not be concluded that high drug load was related to seizure freedom. In our study, a PDD reaching or exceeding the DDD (≥1) was defined as a high dose. We observed that 70.5% of the patients were in the low-TDL group, which supports the idea that low-dose AEDs may be enough to provide seizure freedom in patients with IGE who are considered to have a better prognosis than those with other epilepsy syndromes.
In the literature, the highest remission ratio reported on IGE ranges from 64.6% to 81.4%., Studies are reporting that CAE and JAE have better remission rates than JME in long-term follow-up., In our study, a high drug load was found in 53.6% of patients with JME and 30.2% of patients with non-JME IGE. Although the difference was not statistically significant, the tendency of JME requiring a high dose for seizure-freedom was noted, in accordance with the literature.
IGEs are a group of heterogeneous clinical syndromes. It has been demonstrated that there is a genetic predisposition, especially by twin studies. Studies are suggesting that polygenic interactions, single gene variants, and Mendelian inheritance play a role in etiology. In a study conducted by Gesche et al., family history was found positive in 27.3% of patients with IGE. However, no association was found between clinical phenotype and treatment response when comparing familial and nonfamilial patients. In a study that evaluated 37 patients according to drug load, high drug load was reported to be associated with a family history among patients with JME. In our study, 31.9% of all patients, 25% of patients with non-JME IGE, and 38.9% of patients with JME had a positive family history. This difference between the groups was not statistically significant.
The are several limitations of this study. The retrospective nature of the study may be associated with selection bias. We included all consecutive patients admitted for treatment to decrease this effect. Seizure-freedom is an indirect method to address the minimum drug dose that prevents seizures. Patients with pseudo drug resistance may have been included in this cohort and affected results. In this study, awake EEG was used to report epileptiform anomalies instead of sleep EEG, which is more sensitive.
There are numerous studies in the literature on patients with IGE with diverse methodologies. Although there is a considerable consensus on clinical features, diagnosis, and treatment approaches, data on prognostic factors are inconsistent. Studies on the drug load of AEDs are lacking.
| Conclusion|| |
In this study, patient and seizure characteristics in seizure-free patients with IGE were studied. Most seizure-free patients had low-TDL in the JME and non-JME IGE groups. No association was observed regarding the total AED load in either group. AED dose below 1 TDL may be sufficient for seizure freedom in patients with IGE. Further studies investigating other patients and epilepsy-related characteristics are required to reveal factors that affect the drug load needed to achieve seizure freedom.
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Conflicts of interest
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[Table 1], [Table 2], [Table 3], [Table 4]