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- MATERIALS AND METHODS
Summary: Purpose: To study factors associated with discontinuation of antiepileptic drugs (AEDs) in idiopathic generalized epilepsy (IGE) and symptomatic/cryptogenic localization-related epilepsy (S/CLRE)
Methods: For the IGE study, 71 patients who were able to discontinue their AED (discontinued-IGE group) were compared to 71 patients who continued AED therapy (continued-IGE group) and 20 patients with seizure relapse after discontinuing AED (relapsed-IGE group). For S/CLRE, 90 patients who were able to discontinue AED (discontinued-S/CLRE group) were compared to 90 patients who continued AED (continued-S/CLRE group) and 76 patients with benign childhood epilepsy with centrotemporal spikes who were able to discontinue AED (discontinued-BECTS group).
Results: Compared to the continued-IGE group, the discontinued-IGE group showed a weaker seizure propensity, better response to AEDs, more frequent epileptiform discharge suppression, and lower frequency of generalized tonic–clonic seizures (GTCs). Compared to the relapse-IGE group, the discontinued-IGE group had more frequent epileptiform discharge suppression. The discontinued-S/CLRE group showed a weaker seizure propensity, better response to AEDs, more frequent epileptiform discharge suppression, and less frequent symptomatic signs compared to the continued-S/C LRE group. Notably, the age at epilepsy onset was not a critical factor for discontinuing AEDs in both IGE and S/CLRE. Although the discontinued-S/CLRE group had more frequent symptomatic signs, older age at epilepsy onset and less frequent epileptiform discharge suppression than the discontinued-BECTS group, no difference was found in seizure propensity and response to AEDs between the two groups.
Conclusions: Seizure propensity, epileptiform discharge, and response to AEDs should be considered to predict the possibility of terminating AED therapy in IGE or S/CLRE. In addition, attention should be paid to seizure pattern in IGE and symptomatic signs in LRE.
Review of the clinical courses of epilepsies shows that intractable epilepsies are not as common as previously suspected (1–3), and the majority of patients with epilepsy achieve remission with antiepileptic drug (AED) therapy (4). Seizure remission is reported to occur early in 70–80% of patients in whom seizures develop for the first time (5). Several modes of epilepsy outcome are known; for example, spontaneous seizure remission, seizure remission followed by discontinuation of AED, seizure remission with AED therapy, and an intractable course despite AED therapy (5). During the early phase of AED therapy, predicting the outcome of epilepsy and the possibility of discontinuing the AED is important to plan a future career or to avoid the adverse effect of the AED (2, 6–8).
Many variables have been studied as predictors of favorable outcome after discontinuing AEDs, including age at epilepsy onset, seizure patterns, frequency of seizures, EEG findings, duration of seizure remission before discontinuing AEDs, neuroimaging findings, and the coexistence of cognitive and neurological deficits (9–13). Studies also have confirmed that benign childhood epilepsy with centrotemporal spikes (BECTS) remits before adulthood, and idiopathic epilepsy has a better prognosis than symptomatic epilepsy (14,15). However, the critical role of the epileptic syndrome in discontinuation of AEDs has not adequately been addressed. Previously identified favorable predictors for discontinuation of AEDs usually do not differentiate useful factors among different epileptic syndromes from those useful in predicting within a particular epileptic syndrome. We previously reported the clinical features of patients with idiopathic generalized epilepsy (IGE) and symptomatic/cryptogenic localization-related epilepsy (S/CLRE) who discontinued AEDs after seizure remission (14). The present study investigated intra-syndrome factors that influence discontinuation of AEDs for IGE and S/CLRE, compared to control groups.
MATERIALS AND METHODS
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- MATERIALS AND METHODS
AEDs were discontinued, as of 1994, after seizure remission in 337 (4%) of 8,469 patients seen for the first time at the outpatient clinic of our epilepsy center from 1975 to 1985. The epilepsy classification of patients who discontinued AEDs were IGE in 71 (21%) patients, idiopathic localization related-epilepsy in 77 (23%), S/CLRE in 90 (27%), and unclassifiable epilepsy in 99 (29%). The term unclassifiableepilepsy designates a type of epilepsy with insufficient information to classify it as an epileptic syndrome. Five percent of patients with IGE, 76% of patients with idiopathic localization related-epilepsy, and 2% of patients with S/CLRE discontinued AEDs.
Idiopathic generalized epilepsy
Three groups of patients with IGE were studied (Table 1). Seventy-one patients (33 men and 38 women) who were able to discontinue AEDs (discontinued-IGE group) were compared to 71 patients (34 men and 37 women) who continued AED therapy (continued-IGE group) and 20 patients (seven men and 13 women) with seizure relapsed after discontinuing AEDs (relapse-IGE group). The continued-IGE group was composed of consecutive patients in chronologic order of first presentation at our epilepsy center from 1975. The relapse-IGE group was identified from patients who visited our center for the first time from 1975 to 1985.
Table 1. Summary of idiopathic generalized epilepsy
| ||Discontinued-IGE group||Relapse-IGE group||Continued-IGE group|
|Male/female||M 33/ F 38||M 7/F13||M 34/F 37|
|Age at epilepsy onset (yr)||10.17 ± 5.51 (n = 71)||12.76 ± 6.66 (n = 20)||11.6 ± 4.81 (n = 71)|
|Duration from epilepsy onset to the last seizure (yr)|| 5.38 ± 4.46 (n = 71)|| 7.27 ± 6.73 (n = 19)||20.67 ± 11.37 (n = 71)a|
|Age at the last seizure (yr)||15.55 ± 6.74 (n = 71)||19.45 ± 11.55 (n = 20)||32.27 ± 13.01 (n = 71)a|
|Age at AED discontinuation (yr)||24.51 ± 7.08 (n = 71)||26.00 ± 11.73 (n = 20)|| |
|Duration from epilepsy onset to AED discontinuation (yr)||14.34 ± 5.21 (n = 71)||13.23 ± 7.74 (n = 20)|| |
|Duration of epilepsy (yr)|| ||34.41 ± 9.67 (n = 71)b,c|
|Length of seizure-free period before AED discontinuation (yr)|| 9.16 ± 4.30 (n = 71)|| 8.07 ± 4.23 (n = 20)|| |
|Length of AED reduction period (yr)|| 4.29 ± 2.83 (n = 50)|| 2.78 ± 2.20 (n = 15)|| |
|Epilepsy syndrome (subdivision of IGE)|
| Childhood absence epilepsy||16/71 (22.54%)||1/20 (5%)||6/71 (8.45%)a|
| Juvenile absence epilepsy||2/71 (2.82%)||0||0|
| Juvenile myoclonic epilepsy||10/71 (14.08%)||4/20 (20%)||6/71 (8.45%)|
| Epilepsy with grand mal seizures on awakening||3/71 (4.23%)||2/20 (10%)||7/71 (9.86%)|
| Other generalized idiopathic epilepsies not defined above||40/71 (56.34%)||13/20 (65%)||52/71 (73.24%)b|
|No. of patients with generalized tonic clonic seizure||64/71 (90.14%)||20/20 (100%)||71/71 (100%)a|
|Frequency of seizures except for absence|
| More than once a day||0||0||1/71 (1.41%)|
| Once or more than once a week but less than once a day||0||1/20 (5%)||6/71 (8.45%)b|
| Once or more than once a month but less than once a week||1/71 (1.41%)||3/20 (15%)||17/71 (23.94%)a|
| Less than once a month||53/71 (74.65%)||15/20 (75%)||35/71 (49.30%)a|
|No. of patients with epileptic discharge suppression at discontinuing AED||60/71 (85.91%)||12/20 (60%)b||36/71 (50.70%)a|
|Period of epileptic discharge suppression before discontinuing AED (yr)|| 5.20 ± 3.81 (n = 60)|| 3.32 ± 3.42 (n = 11)|| |
|Age at epileptic discharge suppression (yr)||18.68 ± 7.42 (n = 60)|| 21.5 ± 7.95 (n = 15)||35.77 ± 10.84 (n = 35)a|
|No. of AED at the last seizure (no. of patients with monotherapy)|| 2.27 ± 0.99 (16/71 = 22.53%)|| 2.56 ± 0.98 (3/18 = 16.67%)|| |
|No. of AEDs at discontinuation (no. of patients with monotherapy)||1.04 ± 0.20 (3/71 = 95.77%)||1.15 ± 0.49 (18/20 = 90%)|| |
|No. of AEDs at present (no. of patients with monotherapy)|| || 1.42 ± 0.65 (66.20%)a|
|No. of patients with febrile convulsions||23/71 (32.39%)||4/20 (20%)||23/71 (32.39%)|
|No. of patients with convulsion in third-degree relatives||19/71 (26.76%)||9/20 (45%)||33/71 (46.48%)|
|Follow-up period (yr)|| 2.58 ± 2.04 (n = 70)|| 21.9 ± 4.41 (n = 16)|| |
|Duration from AED discontinuation to seizure relapse (yr)|| ||2.08 ± 2.91|| |
Symptomatic/cryptogenic localization-related epilepsy
First, 90 patients (55 men and 35 women) with S/CRLE who were able to discontinue AEDs (discontinued-S/CLRE group) were compared to 90 patients (49 men and 41 women) with S/CRLE who continued AEDs (continued-S/C LRE group) and 76 patients (39 men and 37 women) with BECTS who were able to discontinue AEDs (discontinued-BECTS group). Patients with idiopathic localization-related epilepsy designated by the International Classification of Epilepsies and Epileptic Syndromes published in 1989 (16) were excluded from the discontinued-S/CLRE and continued-S/CLRE groups. All patients in the discontinued-S/CLRE and continued-S/CLRE groups were confirmed to have focal epileptiform discharges in our EEG examinations.
The continued-S/CLRE group was composed of consecutive patients in chronologic order of first presentation at our epilepsy center from 1975. The discontinued-BECTS group was selected from patients with idiopathic localization-related epilepsy including a patient with childhood epilepsy with occipital paroxysms and 76 patients with BECTS. AEDs were discontinued after seizure remission during the same period as the discontinued-S/CLRE group.
Medical records were reviewed retrospectively. The variables analyzed included etiologic and hereditary factors, neurological and mental status, age and duration related to epilepsy and AED therapy, seizure types and epileptic syndromes, EEG findings, and AED therapy, as shown in Tables 1 and 2.
Table 2. Summary of localization-related epilepsy
|Male/female||M 55/ F 35||M 49/ F41||M 39/ F 37|
|Age at onset of epilepsy (yr)||8.82 ± 7.57 (n = 90)||10.75 ± 8.06 (n = 90)||6.26 ± 2.72 (n = 76)|
|Duration from epilepsy onset to the last seizure (yr)||5.18 ± 4.97 (n = 90)||31.85 ± 9.46 (n = 90)a||3.57 ± 2.30 (n = 76)|
|Age at the last seizure (yr)||14.00 ± 10.41 (n = 90)||42.61 ± 10.67 (n = 90)a||9.71 ± 2.63 (n = 76)|
|Age at AED discontinuation (yr)||22.27 ± 10.75 (n = 90)||−||16.76 ± 2.88 (n = 76)|
|Duration from epilepsy onset to AED discontinuation (yr)||13.41 ± 5.48 (n = 90)||−||10.37 ± 3.60 (n = 76)|
| Duration of epilepsy (yr)|| ||35.72 ± 7.78a,c|| |
|Length of seizure-free period before AED discontinuation (yr)||8.45 ± 3.78 (n = 90)||−||6.93 ± 2.96 (n = 76)|
|Length of AED reduction period (yr)||3.85 ± 2.15 (n = 70)||−||3.53 ± 2.28 (n = 67)|
|No. of patients with generalized tonic-clonic seizure||61/89 (68.54%)||68/90 (75.56%)||36/76 (47.37%)a|
|Frequency of seizures|
| More than once a day||1/87 (1.15%)||12/90 (13.33%)a||1/75 (1.33%)|
| Once or more than once a week but less than once a day||0||19/90 (21.11%)a||0|
| Once or more than once a month but less than once a week||9/87 (10.35%)||42/90 (46.67%)a||11/75 (14.67%)|
| Less than once a month||77/87 (88.51%)||17/90 (18.89%)a||63/75 (84.00%)|
|No. of patients with epileptic discharge suppression at discontinuing AED||74/88 (84.09%)||14/90 (15.56%)a||69/74 (93.24%)a|
|Period of epileptic discharge suppression before discontinuing AED (yr)||3.72 ± 3.01 (n = 76)||−||3.62 ± 2.24 (n = 69)|
|Age at epileptic discharge suppression (yr)||19.00 ± 10.55 (n = 84)||42.36 ± 11.33 (n = 14)a||13.57 ± 3.35 (n = 74)a|
|No. of AEDs at the last seizure (no. of patients with monotherapy)|| 2.36 ± 1.07 (21/88 = 23.86%)||−||2.25 ± 1.05 (21/76 = 27.63%)|
|No. of AEDs at discontinuation (no. of patients with monotherapy)|| 1.07 ± 0.29 (85/90 = 94.44%)||−||1.04 ± 0.20 (73/76 = 96.05%)|
|No. of AEDs at present (no. of patients with monotherapy)|| || 2.79 ± 1.23 (14.44%)a|| |
|No. of patients with convulsion in third-degree relatives||29/90 = 32.22%||20/90 (22.22%)||24/76 (31.58%)|
|No. of patients with etiology||27/89 (30.33%)||49/89 (55.06%)a||0a|
|No. of patients with neurological deficit||3/90 (3.33%)||14/89 (15.73%)a||0 |
|No. of patients with mental retardation||7/90 (7.78%)||27/90 (30.00%)a||0b|
|No. of patients with lesions in MRI or CT||19/75 (25.33%)||70/88 (79.55%)a||0 (n = 68)a|
|Follow-up period (yr)|| 2.61 ± 3.11||24.69 ± 2.20||2.01 ± 2.15|
Data were analyzed by the χ2 test for independence, the Fisher's exact probability test, and the Mann–Whitney U test.
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- MATERIALS AND METHODS
Previous reports identified diverse risk factors for seizure relapse after discontinuation of AEDs or intractable seizures, including adult- and adolescent-onset epilepsy, occurrence of GTCs and myoclonic seizures with more than one AED, continuation of seizures and epileptiform discharges after initiation of AED therapy, short seizure-free period before discontinuing AEDs, and symptomatic signs in miscellaneous epileptic syndromes (1,3,5,6,10–13,17,18). However, it is necessary to confirm the factors predicting discontinuation of AEDs and seizure relapse after discontinuation of AED by comparing two groups within the same epileptic syndrome; one group that was able to discontinue AEDs and another group that was unable to discontinue AEDs or had seizure relapse after discontinuation of AEDs.
In the IGE study, high seizure frequency, long period until seizure remission, long duration of epilepsy, and persistent epileptiform seizure discharges were factors against discontinuation of AEDs. These indicators seem to show that a strong tendency toward spontaneously recurring seizures (2), and persistent epileptiform discharge are critical factors for the inability of patients with IGE to discontinue AEDs. Patients with infrequent or no GTCs tend to belong to the discontinued-IGE group. Thus, high frequency of GTCs is associated with intractability of IGE. Our results also showed that patients in the discontinued-IGE group achieved seizure remission soon after the beginning of AED therapy. Previous reports have indicated (17) that a long seizure-free state with AED therapy and remission achieved while receiving monotherapy were important factors for successful discontinuation of AEDs, supporting our results that good seizure response to AEDs is favorable for discontinuing AEDs in IGE. Our results for IGE showed no significant difference in the age at epilepsy onset between the discontinued-IGE group and the continued-IGE group. Contrary to previous findings in miscellaneous epilepsies, the age at epilepsy onset did not play an important role as a predictive factor for discontinuation of AEDs in IGE. In summary, strong seizure propensity, persistent epileptiform discharges, poor response to AEDs, and presence of a GTC seizure pattern are seen to be unfavorable factors for discontinuation of AEDs in IGE.
Comparison of the discontinued-IGE group with the relapse-IGE group reveals that the presence of epileptiform discharges at discontinuation of AEDs is a risk factor for seizure relapse, even if other factors are favorable for discontinuing AEDs. Therefore, whether epileptiform discharges persist is a very important index to judge discontinuation of AEDs in patients with IGE. As reported in our previous article (14), only a few of our patients had seizure relapses after AEDs were discontinued. The low incidence of seizure relapse in this series might be due to a very gradual reduction of AEDs, taking sufficient time to observe whether seizures or epileptiform discharges are aggravated (14). Our experience suggests that slow reduction of AEDs, in conjunction with EEG monitoring, is a reasonable method for avoiding seizure relapse after discontinuation of AEDs.
The favorable indices for discontinuation of AEDs identified in S/CLRE cases were low level of seizure tendency and a good response to AEDs, almost the same as those in the discontinued-IGE group. In addition, the discontinued-S/CLRE group had less frequent symptomatic signs compared to the continued-S/CLRE group. Less frequent symptomatic signs in the discontinued-S/CLRE group are reflected by a smaller proportion of patients with etiologic factors, neurological deficits, developmental delay, and brain damage signs on CT or MRI. Thus, symptomatic signs seem to be important factors reflecting difficulty in discontinuing AEDs in S/CLRE. This result is consistent with previous articles reporting that patients with symptomatic factors are associated with difficulty in discontinuing AEDs (3,5,7,9,14). According to previous reports, earlier onset of epilepsy before age 12 years and no history of GTCs are favorable factors in the localization-related epilepsy group (1,3,16,17). In contrast, our results showed no significant difference in the age at epilepsy onset and GTC frequency between the discontinued-S/CLRE group and the continued-S/CLRE group. The present study was conducted by excluding idiopathic location-related epilepsy that started before age 10 years in most patients and was cured before adulthood. The different results between our findings and previous reports on the discontinuation of AEDs in LRE may be due to the criteria for patient selection. Our results also suggest that seizure tendency has an important connection with the discontinuation of AEDs in S/CLRE, but generalization of focal seizures shown by secondarily GTCs has no connection.
Compared to the discontinued-BECTS group, the discontinued-S/CLRE group had more frequent symptomatic signs and a lower rate of epileptiform discharge suppression at time of discontinuation of AEDs, but indices of seizure propensity and response to AEDs were not different between the two groups. The discontinued-S/CLRE group also had widespread distribution of age at epilepsy onset, including patients older than 20 years. These results suggest that, of the factors, low seizure propensity and a good response to AEDs are important for discontinuation of AEDs in S/CLRE.