Randomized controlled study comparing the efficacy of rapid and slow withdrawal of antiepileptic drugs during long-term video-EEG monitoring.

OBJECTIVE: Antiepileptic drugs (AEDs) are routinely withdrawn during long-term video-electroencephalography (EEG) monitoring (LTM), to record sufficient number of seizures. The efficacy of rapid and slow AED taper has never been compared in a randomized control trial (RCT), which was the objective of this study. METHODS: In this open-label RCT, patients aged 2-80 years with drug-resistant epilepsy (DRE) were randomly assigned (1:1) to rapid and slow AED taper groups. Outcome assessor was blinded to the allocation arms. Daily AED dose reduction was 30% to 50% and 15% to <30% in the rapid and slow taper groups, respectively. The primary outcome was difference in mean duration of LTM between the rapid and slow AED taper groups. Secondary outcomes included diagnostic yield, secondary generalized tonic-clonic seizure (GTCS), 4- and 24- hour seizure clusters, status epilepticus, and need for midazolam rescue treatment. The study was registered with Clinical Trial Registry-India (CTRI/2016/08/007207). RESULTS: One hundred forty patients were randomly assigned to rapid (n = 70) or slow taper groups (n = 70), between June 13, 2016 and February 20, 2017. The difference in mean LTM duration between the rapid and slow taper groups was -1.8 days (95% confidence interval [CI] -2.9 to -0.8, P = .0006). Of the secondary outcome measures, time to first seizure (2.9 ± 1.7 and 4.6 ± 3.0 days in the rapid and slow taper groups respectively, P = .0002) and occurrence of 4-hour seizure clusters (11.9% and 2.9% in the rapid and slow taper groups, respectively, P = .04) were statistically significant. None of the other safety variables were different between the 2 groups. LTM diagnostic yield was 95.7% and 97.1%, in rapid and slow taper groups respectively (P = .46). SIGNIFICANCE: Rapid AED tapering has the advantage of significantly reducing LTM duration over slow tapering, without any serious adverse events.

Long-term outcome of seizure-free patients and risk factors of relapse following antiepileptic drug withdrawal.

OBJECTIVE: This study aimed to investigate the long-term outcome in seizure-free patients and to explore the risk factors of seizure relapse following antiepileptic drug (AED) withdrawal. METHODS: This study included 161 patients who had been seizure-free for at least 2 years. These patients were monitored over a follow-up period of at least 3 years or until seizure relapse after AED withdrawal. Patients were grouped into a seizure-free group and a relapse group. Risk factors of seizure relapse were analyzed. RESULTS: During the follow-up period, 72 patients (44.7%) relapsed while 89 patients (55.3%) did not. The average time of relapse was 19.12 ±â€¯27.17 months after the initiation of AED withdrawal, and majority of cases occurred within the first 24 months of AED withdrawal (73.6%). Univariate analysis showed that the likelihood of relapse was higher in patients with uncontrolled seizures beyond the first 6 months of AED therapy initiation, patients with a history of perinatal injury, patients with multiple seizure types, and patients who had been treated with a combination of AEDs. Multiple logistic regression analysis revealed that uncontrolled seizures beyond the first 6 months of AED treatment and a history of perinatal injury were independent risk factors of seizure relapse. CONCLUSION: In the majority of cases, epilepsy relapse occurred within the first two years after the initiation of AED withdrawal. The independent risk factors of seizure relapse were uncontrolled seizures beyond the first 6 months of AED therapy and cases with a history of perinatal injury.

Long-term seizure outcome in 211 patients with focal cortical dysplasia.

OBJECTIVE: Focal cortical dysplasia (FCD) is currently recognized as the most common cause of neocortical pharmacoresistant epilepsy. Epilepsy surgery has become an increasingly successful treatment option. Herein, the largest patient cohort reported to date is analyzed regarding long-term outcome and factors relevant for long-term seizure control. METHODS: Two hundred eleven children and adults undergoing epilepsy surgery for histologically proven FCD and a follow-up period of 2-12 years were analyzed regarding the longitudinal course of seizure control, effects of FCD type, localization, magnetic resonance imaging (MRI), timing of surgery, and postoperative antiepileptic treatment. RESULTS: After 1 year, Engel class I outcome was achieved in 65% of patients and the percentage of seizure-free patients remained stable over the following (up to 12) years. Complete resection of the assumed epileptogenic area, lower age at surgery, and unilobar localization were positive prognostic indicators of long-term seizure freedom. Seizure recurrence was 12% after the first year, whereas 8% achieved late seizure freedom either following additional introduction of antiepileptic drugs (AEDs) (4%), a reoperation (2%), or a running down phenomenon (2%). Thirty-nine percent of patients had a reduction of AED from polytherapy to monotherapy or a complete cessation of AED treatment. Late seizure relapse was seen in nine patients during reduction of AEDs (i.e., in 12% of all patients with AED tapering); in four of them seizures persisted after reestablishment of antiepileptic medication. SIGNIFICANCE: Postoperative long-term seizure outcome was favorable in patients with FCD and remained stable in 80% of patients after the first postoperative year. Several preoperative factors revealed to be predictive for the postoperative outcome and may help in the preoperative counseling of patients with FCD and in the selection of ideal candidates for epilepsy surgery.

Time to relapse after epilepsy surgery in children: AED withdrawal policies are a contributing factor.

AIM: It was recently suggested that early postoperative seizure relapse implicates a failure to define and resect the epileptogenic zone, that late recurrences reflect the persistence or re-emergence of epileptogenic pathology, and that early recurrences are associated with poor treatment response. Timing of antiepileptic drugs withdrawal policies, however, have never been taken into account when investigating time to relapse following epilepsy surgery. METHODS: Of the European paediatric epilepsy surgery cohort from the "TimeToStop" study, all 95 children with postoperative seizure recurrence following antiepileptic drug (AED) withdrawal were selected. We investigated how time intervals from surgery to AED withdrawal, as well as other previously suggested determinants of (timing of) seizure recurrence, related to time to relapse and to relapse treatability. Uni- and multivariable linear and logistic regression models were used. RESULTS: Based on multivariable analysis, a shorter interval to AED reduction was the only independent predictor of a shorter time to relapse. Based on univariable analysis, incomplete resection of the epileptogenic zone related to a shorter time to recurrence. Timing of recurrence was not related to the chance of regaining seizure freedom after reinstallation of medical treatment. CONCLUSION: For children in whom AED reduction is initiated following epilepsy surgery, the time to relapse is largely influenced by the timing of AED withdrawal, rather than by disease or surgery-specific factors. We could not confirm a relationship between time to recurrence and treatment response. Timing of AED withdrawal should be taken into account when studying time to relapse following epilepsy surgery, as early withdrawal reveals more rapidly whether surgery had the intended curative effect, independently of the other factors involved.

Early versus late antiepileptic drug withdrawal following temporal lobectomy.

PURPOSE: To compare the seizure outcome following early and late complete antiepileptic drug (AED) withdrawal following anterior temporal lobectomy (ATL) for mesial temporal lobe epilepsy (MTLE). METHOD: All the patients who were seizure free for one year following ATL were offered early or late AED withdrawal. AEDs were discontinued starting at one year in those who opted for early withdrawal. Patients who opted for late withdrawal were continued on single AED for three years following surgery before attempting complete discontinuation. RESULTS: Of the 135 study patients, 65 opted for early AED withdrawal and 70 for late withdrawal. The mean postoperative follow-up duration was 10.4 ± 1.3 (Range, 8-12) years. At three years following surgery, seizure recurrence occurred in 23 (35.4 %) patients in the early withdrawal group and in 10 (14.3 %) patients in late withdrawal group (p = 0.005; relative risk [RR], 2.48; 95 % confidence interval [CI], 1.28-4.80). At last follow-up, 27 (41.5 %) patients in the early withdrawal group and 26 (37.1 %) in late withdrawal group had recurrence (p = 0.60; RR, 1.12, 95 % CI, 0.74-1.70). At last followup, 80 (59.3 %) patients were off AEDs. During the terminal one year, 123 (91 %) patients were seizure free, similar in the two groups. CONCLUSIONS: This nonrandomized controlled study suggests that early complete AED withdrawal starting one year following ATL is associated with a higher risk of early seizure recurrence. However, long term seizure outcome is similar in early and late AED withdrawal groups.

Discontinuing antiepileptic drugs in long-standing idiopathic generalised epilepsy.

BACKGROUND: Once adults with long-standing idiopathic generalised epilepsy have achieved stable seizure remission, patients or physicians may attempt to discontinue their antiepileptic drug treatment. To date, risk of subsequent seizure relapse across the four idiopathic generalised epilepsy syndromes is largely unknown, and so are the clinical variables associated. METHODS: For this retrospective observational study, 256 adult outpatients with idiopathic generalised epilepsy were evaluated. Data were obtained from outpatient charts and, if possible, from additional telephone or mail interviews. RESULTS: In 84 patients (33%), antiepileptic medication was discontinued at least once. Median patient age at antiepileptic drug withdrawal was 33 years, and median duration of subsequent follow-up was 20 years. Seizures recurred in 46% of patients after a median latency of 11 months. Following multivariable analysis, seizure relapse was independently associated with short duration of seizure remission beforehand. If medication was withdrawn after < 5 years of seizure freedom, two-thirds of patients had a seizure relapse, while among those in remission for ≥ 5 years, only one-third relapsed. CONCLUSIONS: Discontinuation of antiepileptic drug treatment can be successful in every other adult with long-standing idiopathic generalised epilepsy. Short duration of prior seizure remission appears to be a relevant predictor of seizure recurrence.

Characteristics of Seizure and Antiepileptic Drug Utilization in Outpatients With Autoimmune Encephalitis.

Autoimmune encephalitis (AE) is one kind of encephalitis that associates with specific neuronal antigens. Most patients with AE likely suffer from seizures, but data on the characteristics of seizure and antiepileptic drugs (AEDs) utilization in this patient group remains limited. This study aimed to report the clinical status of seizure and AEDs treatment of patients with AE, and to evaluate the relationship between AEDs discontinuation and seizure outcomes. Patients with acute neurological disorders and anti-N-methyl-D-aspartate receptor (NMDAR), γ-aminobutyric acid B receptor (GABABR), leucine-rich glioma inactivated 1, or contactin-associated protein-like 2 (CASPR2) antibodies were included. As patients withdrew from AEDs, they were divided into the early withdrawal (EW, AEDs used ≤3 months) and late withdrawal (LW, AEDs used >3 months) groups. Seizure remission was defined as having no seizures for at least 1 year after the last time when AEDs were administered. Seizure outcomes were assessed on the basis of remission rate. The factors affecting the outcomes were assessed through Spearman analysis. In total, we enrolled 75 patients (39 patients aged <16 years, male/female = 39/36) for follow-up, which included 67 patients with anti-NMDAR encephalitis, 4 patients with anti-GABABR encephalitis, 2 patients with anti-voltage-gated potassium channel encephalitis, and 2 patients with coexisting antibodies. Among the 34 enrolled patients with anti-NMDAR encephalitis who were withdrawn from AEDs, only 5.8% relapse was reported during the 1-year follow-up, with no significant difference in the percentage of relapse between the EW and LW groups (P = 0.313). Fifteen patients (an average age of 6.8, 14 patients with anti-NMDAR encephalitis and 1 patient with anti-CASPR2 encephalitis) presented seizure remission without any AEDs. Seventy five percent of patients with anti-GABABR antibodies developed refractory seizure. Other risk factors which contributed to refractory seizure and seizure relapse included status epilepticus (P = 0.004) and cortical abnormalities (P = 0.028). Given this retrospective data, patients with AE have a high rate of seizure remission, and the long-term use of AEDs may not be necessary to control the seizure. Moreover, seizures in young patients with anti-NMDAR encephalitis presents self-limited. Patients with anti-GABABR antibody, status epilepticus, and cortical abnormalities are more likely to develop refractory seizure or seizure relapse.

Optimal timing and differential significance of postoperative awake and sleep EEG to predict seizure outcome after temporal lobectomy.

OBJECTIVE: To evaluate the prognostic value of postoperative EEGs to estimate post anterior temporal lobectomy (ATL) seizure outcome. METHODS: We studied postoperative EEGs in 325 consecutive patients who had minimum five years of post-ATL followup. Interictal epileptiform discharges (IEDs) present only during sleep were classified as sleep IEDs. We defined favorable final-year outcome as no seizures during the final one year and favorable absolute-postoperative outcome as no seizures during the entire postoperative period. RESULTS: At mean follow-up of 7.3 ±â€¯1.8 years, 281 (86.5%) patients had favorable final-year outcome while 161 (49.5%) had favorable absolute-postoperative outcome. IEDs on three months and one year EEG were associated with unfavorable outcomes while IEDs at 7th day had no association with outcomes. Sleep record increased the yield of IEDs by 30% at each time-point without compromising predictive value. EEG at one year predicted the risk of seizure recurrence on drug withdrawal. CONCLUSION: While EEG at three months and at one-year after ATL predicted seizure outcome, EEG at 7th day was not helpful. Sleep record increases the sensitivity of postoperative EEG without compromising specificity. SIGNIFICANCE: Both awake and sleep EEG provide useful information in postoperative period following ATL.

A classification system for verifying the long-term efficacy of resective surgery for drug-resistant seizures.

OBJECTIVE: To verify the long-term efficacy of resective surgery, we created a classification system in which strictly defined patterns of postoperative seizure emergence are incorporated as basic components and the seizure states throughout the entire follow-up period are assessed comprehensively. METHODS: In our system, Class I has three subclasses (A-C); subclasses A and B are identical to Engel I-A and I-B, respectively. Subclass C comprises patients whose disabling seizures remit within the first 2 years postoperatively. Patients in Class II have only 1-3 days with disabling seizures throughout follow-up after the first 2 years. Patients in Class III have a maximum of 3 seizure days annually, and those in Class IV have ≥4 seizure days annually after the first 2 years. Classes II-IV each have 2 subclasses (A and B): subclass A, late recurrence (i.e., the first seizure occurs after 2 years postoperatively); and subclass B, early recurrence (i.e., first seizure within 2 years). In 646 patients who underwent resective surgery (temporal lobe resection, 74.6%) and were followed for at least 8 years (mean, 14.6 years), we analyzed three patterns of postoperative seizures: early remission, late recurrence, and occasional seizures. In addition, we investigated the differences between the long-term seizure outcomes of the cohort as determined according to our system and the Engel scale. RESULTS: Overall, 52.9% of the cohort experienced at least one disabling seizure postoperatively throughout the follow-up period; in 1/3 of these patients, the first seizure occurred after 2 years. In 73.8% of the 80 patients who manifested the running-down phenomenon, seizure remission occurred within the first 2 years. In addition, 36.7% of the 283 patients who had disabling seizures after 2 years experienced only 1-3 seizure days. Engel Class I-C included about 30% of the patients who had ≥4 seizure days after 2 years. The long-term seizure outcomes, determined according to our system, were: Class I, 56.2% (C, 9.1%) of the overall cohort; Class II, 16.1% (A, 11.0%); and Class III/IV, 27.7% (A, 6.6%). CONCLUSION: Our system clarifies the actual effect of resective surgery more precisely than the Engel scale and thus may be useful for comparing outcomes between different surgical procedures or for identifying potential risk factors predicting unfavorable outcome.

Effective withdrawal of antiepileptic drugs in premonitoring admission to capture seizures during limited video-EEG monitoring.

Objective: Withdrawal of antiepileptic drugs (AEDs) is commonly applied to capture seizures in video-EEG (vEEG) monitoring for patients with infrequent but intractable seizures. Because of the half-life of AEDs, AED withdrawal during only vEEG tends to be inadequate to provoke seizures within the vEEG admission. We hypothesize that prewithdrawal of long-half-life AEDs in premonitoring admission (PMA) is safe and effective to capture seizures in the limited time of vEEG. We determined the effect of half-life on the interval between AED withdrawal and seizure occurrence. Methods: We collected 87 patients with three criteria: (1) seizure occurrence ≤3 per month; (2) AEDs ≥2; (3) AED withdrawal during their admission, among 126 consecutive patients who underwent vEEG in the Department of Neurosurgery, Hiroshima University Hospital between 2011 and 2014. We divided patients into two groups on the basis of half-life of AED: Group A (23 patients) with phenobarbital (PB) and/or zonisamide (ZNS); Group B (64 patients) with other AEDs. In Group A, PB and ZNS were withdrawn during 4-day PMA before vEEG started. Further AED withdrawal was performed during vEEG, depending on the seizure occurrence. Results: The number of AEDs on admission was significantly higher in Group A (2-6, 3.5 ± 0.9; range, mean ±SD) than in Group B (2-5, 2.8 ± 0.8) (p < 0.01). All 23 Group A patients and 13 (20%) Group B patients underwent AED withdrawal during PMA. Seizures occurred during PMA in two patients in both Group A (9%) and Group B (15%). The first seizure occurred significantly longer after the start of withdrawal in Group A (6.1 ± 2.0 days) than in Group B (2.8 ± 1.3 days) (p < 0.01). Seizures were equally captured between both groups: 96% in Group A and 92% in Group B during vEEG. Significance: For epilepsy patients who are treated with PB and/or ZNS, we recommend the planning of AED withdrawal during PMA before the start of vEEG to succeed in capturing seizures during the limited time of vEEG monitoring.

Antiepileptic drug therapy and recommendations for withdrawal in patients with seizures and epilepsy due to neurocysticercosis.

INTRODUCTION: Neurocysticercosis (NCC) is a leading causes of secondary epilepsy worldwide. There is increasing evidence on the epileptogenic role of NCC, and the presence of edema, calcified scars, gliosis and hippocampal sclerosis support this phenomenon. AREAS COVERED: We summarized principles of antiepileptic drug (AED) therapy as well as risk factors associated with seizure recurrence after AED withdrawal in patients with NCC. Expert commentary: First-line AED monotherapy is effective as a standard approach to control seizures in most NCC patients. Risks and benefits of AED withdrawal have not been systematically studied, and this decision must be individualized. However, a seizure-free period of at least two years seem prudent before attempting withdrawal. Risk factors for seizure recurrence after AED withdrawal include a history of status epilepticus, poor seizure control during treatment, neuroimaging evidence of perilesional gliosis, hippocampal sclerosis and calcified lesions, as well as persistence of paroxysmal activity in the EEG.

Withdrawal of antiepileptic drugs improves psychomotor speed after childhood epilepsy surgery.

This retrospective study evaluates the impact of postoperative antiepileptic drug (AED) withdrawal on psychomotor speed in seizure-free children, operated for medically refractory epilepsy. Post-surgical medication policy and neuropsychological assessments (performed shortly before and 6, 12 and 24 months after surgery), were evaluated in 57 children (32 female, median age at surgery 13 years). Patients were divided into a withdrawal (n=29) and a no-withdrawal group (n=28). Scores of four psychomotor tests performed at 12 and 24 months after surgery were compared with those of postoperative baseline measurements, performed 6 months after surgery. At 24 months, the withdrawal group had improved significantly more than the no-withdrawal group on three of four tests; reaction time to light (p=0.031), reaction time to sound (p=0.045) and tapping (p=0.003). At 12 months, a non-significant tendency in the same direction was found for both reaction time tests. Drug withdrawal after surgery improves psychomotor speed and may unleash the potential for cognitive improvement.