Antiepileptic Drug Treatment After Temporal Lobe Epilepsy Surgery: A Randomized Study Comparing Carbamazepine and Polytherapy

Temporal lobectomy is an effective treatment in selected patients with medically intractable temporal lobe epilepsy (TLE). Postoperative antiepileptic drug (AED) treatment guidelines have not been established, and patients are often treated with polytherapy postoperatively. We prospectively randomized 40 patients undergoing temporal lobectomy to monotherapy with carbamazepine (CBZ, 20) or to continuation of their presurgical polytherapy (20) to assess the efficacy and safety of each regimen during the first year after operation. No significant differences between groups were noted with respect to seizure recurrence rate and type or time of recurrence. Patients in the polytherapy group had a 30% incidence of drug-related side effects as compared with only 10% in the CBZ group. These results suggest that after temporal lobectomy for intractable epilepsy, patients can be safely treated with CBZ monotherapy and that treatment with multiple AEDs is not necessary.     

Withdrawal of antiepileptic medications following epilepsy surgery

We followed 104 patients to determine the prognosis for antiepileptic medication withdrawal following anterior temporal lobectomy for complex partial seizures. Thirty-nine of the 104 patients underwent a trial of complete medication withdrawal following a minimum 1-year seizure-free postoperative period. The likelihood of remaining seizure-free in these 39 patients was 77% at 1 year, 72% at 2 years, and 66% at 3 years. A prolonged duration of epilepsy prior to surgery significantly increased the risk for recurrent seizures. These findings suggest that patients who remain seizure-free following surgery for temporal lobe complex partial seizures have a good prognosis for remaining seizure-free following anti-epileptic medication withdrawal.     

Challenging epilepsy with antiepileptic pharmacotherapy in a tertiary teaching hospital in Sri Lanka

The goal of antiepileptic drug (AED) therapy is to achieve a seizure-free state and eliminate the medical and psychosocial risks of recurrent seizures. Burden of epilepsy on the economy of a country may be largely due to the expenditure on AEDs. The adverse effects may influence the compliance to AEDs and effective control of epilepsy. We determined the pattern of AED use, the degree of epileptic control achieved and the adverse effects experienced by the epileptics in a Tertiary Teaching Hospital in Sri Lanka. Carbamazepine was found to be the most frequently used AED. Monotherapy was used on 70.8% of subjects. 86.27% of the study sample had achieved effective control of epilepsy with a 50% or more reduction in seizure frequency. Of them 72.64% were on monotherapy and they were either on carbamazepine, sodium valproate, phenytoin sodium or phenobarbitone. None of the new AEDs were prescribed to these patients. 50.9% on monotherapy and 51.5% on polytherapy reported adverse effects. Somnolence followed by headache was found to be the most frequently reported adverse effects by those on monotherapy and polytherapy both. This study shows that most epileptics can be effectively managed with the conventional AEDs with clinical monitoring.     

Seizure recurrence after planned discontinuation of antiepileptic drugs in seizure-free patients after epilepsy surgery: a review of current clinical experience

PURPOSE: Although epilepsy surgery, especially temporal lobe epilepsy surgery, is well established to control seizures in patients remaining on antiepileptic drug (AED) treatment, less information is available about how many seizure-free surgical patients will relapse after discontinuation of AEDs under medical supervision. METHODS: A literature review yielded six retrospective clinical observations. RESULTS: After planned discontinuation of AEDs in patients rendered seizure free after epilepsy surgery, most often various forms of temporal lobe surgery, the mean percentage recurrence rate in adults in four studies was 33.8%[95% confidence interval (CI), 32.4-35.2%], with maximum follow-up ranging from 1 to 5 years. Seizure recurrence increased during the follow-up of 1 to 3 years and occurred within 3 years of AED discontinuation. In one study of children with temporal lobe epilepsy, the recurrence rate was 20%. More than 90% of adult patients with seizure recurrence regained seizure control with reinstitution of previous AED therapy. Seizure recurrence was unaffected by the duration of postoperative AED treatment; as a consequence, delaying discontinuation beyond 1 to 2 years of complete postoperative seizure control seems to have no added benefit. The occurrence of rare seizures or auras after surgery did not eliminate the possibility of eventual successful AED discontinuation. CONCLUSIONS: AED discontinuation is associated with a seizure recurrence in one in three patients rendered seizure free by epilepsy surgery. These results will be useful in counseling patients about discontinuing AED treatment after successful epilepsy surgery.     

Long-term seizure outcome and antiepileptic drug treatment in surgically treated temporal lobe epilepsy patients: a controlled study

PURPOSE: To evaluate the long-term impact of surgical treatment on seizure outcome and antiepileptic drug (AED) use in patients with pharmacoresistant temporal lobe epilepsy (TLE). METHODS: Comparison of seizure outcome and AED us in operated-on TLE patients (n=148) and nonsurgically treated TLE patients (n=94) at a baseline visit and a follow-up visit after a mean period of 4.8 years. RESULTS: At follow-up, 44.6% of the surgical patients and 4.3% of the nonsurgical patients had been continuously seizure- free since the baseline visit (including the immediate postoperative period). A further 17.6% of the operated-on and 3.2% of the not operated-on patients had been seizure-free for at least the previous year; 37.8% of the surgical and 92.5% of the nonsurgical patients had had seizures during the previous 12 months (p < 0.001). Of the surgical patients, 8.8% versus none of the nonsurgical patients were AED free at follow-up; 55.4% versus 20.2% were receiving monotherapy, and 35.8% versus 79.8% were receiving polytherapy (p < 0.001). Mean number of AEDs and mean change in number of AEDs were significantly more favorable in operated-on than in non-operated-on patients. Further subgroup analysis revealed that not only the continuously seizure-free surgical patients, but also the operated-on patients with ongoing seizures took fewer AEDs than their respective non-operated-on counterparts. CONCLUSIONS: This controlled study for the first time provides comprehensive information on long-term seizure outcome and AED use in surgical TLE patients. It shows a more favorable seizure outcome and AED use in the surgically treated patients. The latter holds true even for the not seizure-free patient subgroup.     

How safe is it to withdraw antiepileptic drugs following successful surgery for mesial temporal lobe epilepsy?

Purpose: To investigate the feasibility of antiepileptic drug (AED) withdrawal following anterior temporal lobectomy (ATL) and to identify the predictors of post withdrawal seizure recurrence. Methods: We prospectively studied the seizure outcome of 310 consecutive patients, who were followed for a minimum of 5 years following ATL for medically refractory mesial temporal lobe epilepsy. In seizure‐free patients, we started AED tapering at 3 months in patients on duotherapy/polytherapy and at 1 year after ATL for those on monotherapy. We used Kaplan‐Meier survival curves to estimate the probability of seizure recurrence and complete AED discontinuation, and compared the attributes of recurred and nonrecurred groups of patients by univariate and multivariate logistic regression analyses. Key Findings: Immediately after ATL, 197 patients were on duotherapy and 101 were on monotherapy. We attempted AED withdrawal in 258 patients (83.2%). Sixty‐four patients (24.8%) had seizure recurrence while reducing AEDs. Of 26 patients who had seizure recurrence after complete AED withdrawal, 24 (92.3%) again became seizure‐free after restarting the AEDs. Absence of hippocampal sclerosis on pathologic examination and abnormal postoperative electroencephalogram (EEG) predicted seizure recurrence on multivariate analysis. At the end of follow‐up duration of 8.0 ± 2.0 years, 163 patients (52.6%) were AED free. The cumulative probability of achieving AED‐free status among patients in whom AED withdrawal was attempted, was 44% at fourth year, 65% at sixth year, 71% at eighth year, and 77% at 10th year after ATL. Significance: AED withdrawal can be safely attempted following successful ATL. Seizure recurrences are few and can be managed easily.     

Kaplan-Meier analysis on seizure outcome after epilepsy surgery: do gender and race influence it?

OBJECTIVE: To evaluate seizure outcome following epilepsy surgery for patients with temporal lobe epilepsy and evaluate is gender and race/ethnicity influence it. METHODS: Data were obtained from the discharge database of the University of Alabama at Birmingham, Epilepsy Center, between 1985 and 2001. The sample consisted of all patients with a primary diagnosis of medically intractable temporal lobe epilepsy (TLE) who underwent anterior temporal lobectomy. Seizure recurrence was tabulated at 7 days, 2 months, 6 months, 1, 2, 3, 4, 5, and 6 years following surgery. Logistic regression analysis was used to model the presence of seizure recurrence after anterior temporal lobectomy for all patients. Kaplan-Meier analysis was done to obtain estimates and 95% CIs of seizure freedom from baseline. Baseline variables--age at surgery, age at seizure onset, sex, side of resection, immediate postoperative seizures, and pathology results--were assessed as potential predictors of each outcome by comparing the survival curves within each variable with a log rank test. RESULTS: Three hundred sixty-eight patients underwent surgical treatment for TLE, mean age of 30.2 years. Thirty-five patients were African American, 43% were men. Immediate postoperative seizures were seen in 23 patients, while seizure recurrence occurred in 27.3% patients within a year after surgery, and in 33.6% within 6 years. Logistic regression results showed no differences between African Americans and whites, between males and females. The occurrence of immediate postoperative seizures was a strong predictor of late seizure recurrence only at 1 year after surgery. CONCLUSIONS: The occurrence of seizures in the immediate postoperative period is a strong predictor of later seizure recurrence. Sex and race/ethnicity do not appear to be predictors of long-term outcome following surgery for temporal lobe epilepsy.     

Factors related to successful antiepileptic drug withdrawal after anterior temporal lobectomy for medial temporal lobe epilepsy.

OBJECTIVE: To assess the rate of successful antiepileptic drug (AED) discontinuation, prognostic factors and proper time of AED withdrawal after surgery for medial temporal lobe epilepsy (MTLE). METHODS: We reviewed 171 consecutive patients who underwent resective surgery for MTLE. All patients were followed up for more than two postoperative years. AEDs were slowly tapered with an individualized schedule for each patient. Outcome status was determined from medical records and telephone interviews. RESULTS: 41.2% of patients experienced no seizure recurrence. 34.5% discontinued medication without seizure recurrence for more than 2 years at final assessment. Multivariate analysis revealed that an age greater than 30 years at surgery and postoperative AED reduction before 10 months increased the risk of recurrence [hazard ratio (HR) 2.1, 95% confidence interval (CI) 1.1-3.9 and HR 2.5, CI 1.1-5.8]. CONCLUSIONS: Resective surgery for MTLE brings seizure remission without AED to one-third of patients. Postoperative AED tapering is recommended after at least 10 months. Younger age at surgery is a good predictive factor of remission after MTLE surgery.     

Discontinuation of antiepileptic drugs after successful epilepsy surgery

OBJECTIVE: To evaluate the frequency and risk factors for seizure recurrence subsequent to antiepileptic drug (AED) withdrawal in patients who underwent surgical treatment for intractable partial epilepsy and were rendered seizure-free. METHODS: The outcome of discontinuation of AED medication was studied retrospectively in 210 consecutive patients who were rendered seizure-free after epilepsy surgery performed between 1989 and 1993. RESULTS: Medical therapy was reduced in 96 patients and discontinued in 84 patients. The seizure recurrence rate after complete AED withdrawal was 14% and 36% at 2 and 5 years. In contrast, only 3% and 7% of the 30 patients who did not alter AED treatment after surgery had recurrent seizures in the same time intervals. After AED discontinuation, seizures tended to recur more often in patients with normal preoperative MRI studies compared with those with focal pathology. However, this difference did not reach significance. Intraoperative electrocorticography, extent of surgical resection, postoperative EEG, and seizure-free duration after surgery were not predictive of seizure outcome after AED withdrawal. CONCLUSIONS: AED withdrawal was associated with seizure recurrence in a significant portion of patients rendered seizure-free by epilepsy surgery. Patients with a normal preoperative MRI study showed a tendency for higher seizure recurrence, whereas the duration of seizure-free postoperative AED treatment interval did not significantly influence the seizure recurrence rate. These results will prove useful in counseling patients about discontinuing AED treatment after successful epilepsy surgery.     

Ovulatory Function in Epilepsy

Summary Women with epilepsy have lower fertility rates than women without epilepsy. We hypothesized that limbic dysfunction in temporal lobe epilepsy (TLE) alters the release of hypothalamic trophic hormones that secondarily affect release of the pituitary gonadotropins, causing ovulatory failure. We assessed ovulatory function over three consecutive menstrual cycles in 17 women with partial seizures arising from the temporal lobe (TLE), 7 women with primary generalized epilepsy (PGE), and 12 controls. We devised scores to reflect ovulatory function that were based on daily basal body tem perature and monthly serum progesterone levels. Seizure frequency, antiepileptic drugs (AEDs), and depressive symptomatology were also evaluated. Anovulation was more frequent in subjects with TLE (35.3%) than in subjects with PGE (0%) or in controls (8.3%). Anovulatory cycles tended to occur more frequently in subjects with TLE who were treated with polytherapy than in those receiving monotherapy, but this result was not statistically significant. Seizure frequency and symptoms of depression did not affect ovulatory function. Although AED polytherapy may increase the likelihood of anovulation, our results suggest a mechanism of infertility related to temporal lobe dysfunction.     

Early antiepileptic drug reduction following anterior temporal lobectomy for medically intractable complex partial epilepsy.

PURPOSE: To determine the safety, in our practice, of allowing patient preference to influence the timing of antiepileptic drug (AED) reduction, once they became seizure-free after anterior temporal lobectomy (ATL). METHODS: Thirty patients underwent anterior temporal lobectomy for medically intractable complex partial epilepsy at Loma Linda University Medical Center between December 1st 1991 and November 30th 2001. Timing of AED reduction in seizure-free patients was based on patient request. A review of patient records noted seizure status, duration from surgery to AED reduction, AED side effects, seizure recurrence and whether control was regained. RESULTS: Twenty-four (80%) of the 30 patients became seizure-free on their preoperative AEDs after initial ATL; three additional patients after a second operation. AEDs were not reduced in the reoperated patients, the three patients who did not become seizure-free, and in two patients who asked to increase AEDs to control auras. Thus, AEDs were reduced in 22 of the 27 seizure-free patients. Patients were followed an average of 3.4 +/- 2.7 (mean +/- standard deviation) years. AED reduction was initiated 4.6 +/- 7.2 months (range 0-27 months) after surgery. Polytherapy use decreased from 54% preoperatively to 18% at last follow up. Seizures recurred in six patients (27% of 22); three became seizure-free after AED adjustments. CONCLUSIONS: In our practice, using an individualized approach to AED reduction following successful epilepsy surgery resulted in early reduction in AEDs. Our data suggest that early AED reduction can be performed safely and without undue risk of seizure recurrence.     

Antiepileptic drug withdrawal after successful surgery for intractable temporal lobe epilepsy

PURPOSE: To investigate the prognosis related to antiepileptic drug (AED) discontinuation after successful surgery for intractable temporal lobe epilepsy. METHODS: The clinical courses after temporal lobectomies (TLs) were retrospectively analyzed in 88 consecutive patients. All the patients had TLs as the only surgical procedure, and they had been followed up for longer than 3 years. AED discontinuation was attempted if the patient had been seizure free without aura for >or=1 year during the follow-up period. RESULTS: Sixty-six (75%) patients achieved complete seizure freedom for >or=1 year; 28 patients were seizure free immediately after surgery (immediate success); and 38 patients became seizure free after some period of recurrent seizures (delayed success). AED discontinuation was attempted in 60 (91%) of 66 patients with a successful outcome. In 13 (22%) patients, seizure relapse developed during AED reduction (n=60), and in seven (12%) patients after discontinuation of AEDs (n=38). The seizure recurrence rate was not different between the immediate-and delayed-success groups. Among 20 patients with seizure relapse related to AED tapering, nine (45%) of them regained seizure freedom after reinstitution of AED treatment, and AEDs were eventually discontinued in six of them. Seizures that recurred after complete AED discontinuation had a better prognosis than did the seizures that recurred during AED reduction (seizure freedom in 86% vs. 23%). At the final assessment, 54 (61%) patients had been seizure free >or=1 year; 37 without AEDs and 17 with AEDs. The successful discontinuation of AEDs was more frequent for patients with a younger age at the time of surgery and for those patients with shorter disease duration. CONCLUSIONS: Our results suggest that seizure freedom without aura at >or=1 year is a reasonable indication for the attempt at AED discontinuation. The subsequent control of recurrent seizures was excellent, especially if seizures relapsed after the complete discontinuation of AEDs. Younger age at the time of surgery and a shorter disease duration seem to affect successful AED discontinuation for a long-term period.     

Reinvestigation and reduction of polytherapy in children with chronic seizures

From October 2001 to October 2003, the authors reviewed all patients with chronic seizures taking antiepileptic drugs for more than 2 years with follow-up at the pediatric neurological clinic. They identified 31 patients who were using 3 or more drugs. Twenty-nine patients agreed to undergo a drug reduction and readjustment. The authors spent a mean period of 14.1 months to either purely reduce the numbers of drugs or introduce a new drug (rational polytherapy) plus removal of some drugs to achieve the end goal of a maximum of 2 or 3 drugs (if necessary). Seizure control in 96.6% of patients (28 of 29 patients) did not worsen after the readjustment and reduction of the antiepileptic drugs. Instead, 65.5% (19 of 29 patients) got better, and 37.9% (11 of 29) were seizure free. The number of antiepileptic drugs before and after adjusting was 3.6 (range, 3-6) to 1.9 (4 monotherapy, 22 duotheray, and 2 triple drugs). The most common combined therapies were sodium valproate/lamotrigine (n = 10) and carbamazepine/ topiramate (n = 5). Although the results could be possibly attributed to the spontaneous remission of the seizures, it was still shown that those patients were overtreated. Serial addition to 3 or more antiepileptic drugs is less likely to lead to seizure freedom for patients with difficult-to-treat epilepsy. On the contrary, polytherapy and some antiepileptic drugs could aggravate seizures. Certain combinations of antiepileptic drugs (rational polytherapy) offer better efficacy to control seizures.     

Suppression of antiepileptic treatment

The present report evaluates the suppression of antiepileptic drugs in a group of 608 epileptics. Conditions for the suppression of antiepileptic treatment included a previous seizure-free period of 5 years under medication, and a careful evaluation of individual social and work-related circumstances. The reduction of medication was realized during a minimum period of 1 year, passing from eventual polytherapy to monotherapy. Of the total 608 epileptics in whom treatment was suppressed, 144 relapses (23.7%) occurred, and 464 (76.3%) patients continued to be seizure-free. A complete remission of the epilepsy was achieved in 14.3% of 3,254 epileptics with an adequate follow-up. Significant risk factors for recurrence included a delay in starting anticonvulsant therapy; symptomatic generalized epilepsy; different types of combined seizures, or atypical absences and/or tonic crisis and/or atonic crisis; or partial complex associated with secondary generalized tonic-clonic seizures; the presence of status epilepticus in the course of the disease and permanent neurologic damage. With the patient's prior agreement, it was possible to suppress anticonvulsant medication in one fourth of nonselected epileptic patients with a possibility of relapse in about 25% of the cases (generally one isolated seizure).     

Spectral EEG During Short-Term Discontinuation of Antiepileptic Medication in Partial Epilepsy

Summary: The effect of short-term discontinuation of antiepileptic drugs (AEDs) on spectral analysis of EEG background activity (spectral EEG) was studied in patients undergoing preoperative evaluation for epilepsy surgery. We also wished to clarify whether AED discontinuation would provide lateralizing evidence in spectral EEGs of patients with temporal lobe epilepsy (TLE). Spectral EEGs were performed in 15 patients receiving their regular medication regimen and again after a 1-week period during AED withdrawal. A subgroup of 9 patients who had previously undergone temporal lobectomies (TLE group) was studied separately. In this group, we evaluated the effect of preceding seizures on spectral EEG derived from temporal neocortical areas. In all patients, spectral EEG changes were detected even after a short-term AED withdrawal. The total amount of absolute delta activity was reduced and occipital peak frequency and relative alpha activity were increased as compared with baseline values. In TLE patients with habitual seizures occurring <20 h before the spectral EEG recording, lateralization was correctly identified by the greater amount of absolute delta activity ipsilateral to the epileptogenic focus. Epileptic seizures are accompanied by subtle focal slowing in spectral EEG for a much longer period than has been assumed. In addition, postictal spectral EEG over the temporal lobes may have lateralizing value. Further studies in larger numbers of patients are needed to evaluate the role of spectral EEG in the preoperative evaluation of patients for temporal lobe surgery.     

The teratogenic risk of antiepileptic drug polytherapy

Purpose: To compare the risks of fetal malformation during pregnancy associated with antiepileptic drug (AED) polytherapy and monotherapy. Methods: Statistical analysis of malformation rate and antiepileptic drug exposure data from the Australian Register of Antiepileptic Drugs in Pregnancy, and from the literature. Results: The calculated relative risk (RR) value for AED polytherapy compared with monotherapy was below 1.0 in only 3 of 14 literature publications. In the register, at 1 year postnatally there were fetal malformations in 5.32% of 282 AED polytherapy pregnancies, and in 7.84% of 791 AED monotherapy pregnancies, an RR of 0.68 [95% confidence interval (CI) 0.39–1.17). For pregnancies exposed to valproate, the RR of fetal malformation (0.39, 95% CI 0.20–0.89) was lower in polytherapy (7.26%) than in monotherapy (17.9%); the difference did not depend on valproate dosage. The RR values for fetal malformation were not significantly different for AED polytherapy and monotherapy when valproate was not involved. Logistic regression suggested that coadministration of lamotrigine may have reduced the malformation risk from valproate. Discussion: The fetal hazard of AED polytherapy relative to monotherapy may depend more on the degree of exposure to valproate than on the fact of polytherapy per se. Coadministration with lamotrigine may lower the fetal risk of valproate therapy.     

Childhood epilepsy: Management in resource-limited setting

Objective:

To optimize the use of phenobarbital and/or phenytoin as frontline drugs for treatment of childhood epilepsy.

Design:

Before-and -after study.

Setting:

Epilepsy clinic at paediatric OPD, Sassoon General Hospital, Pune.

Materials and Methods:

Epilepsy is a condition in which seizures are triggered recurrently from within the brain. For epidemiological classification purpose epilepsy is considered to be present when two or more unprovoked seizures occur at an interval greater than twenty four hours apart. Seizures were classified as generalized and partial seizures, with underlying etiology investigated with EEG, CT scan in majority of the patients. Follow - up rate, seizure - control and antiepileptic drugs used among 151 children enrolled as on 31 March 2005 were compared with 106 children with new onset epilepsy enrolled as on February 2006. Eight children with breakthrough convulsion after a seizure free period of five to eighteen months were followed up after injection vitamin D. Nineteen children with poor control of seizures receiving polytherapy with newer antiepileptic drugs were assessed with frontline antiepileptic medication of phenobarbital and/or phenytoin. Serum calcium, phosphorus, alkaline phosphatase were done in seventy two consecutive children with seizure disorder.

Results:

During post protocol period good seizure control was achieved in 84.8% as against 80.7% and use of phenobarbital and/or phenytoin increased to 65.11% from 22.87%. Of the 8 cases with breakthrough seizures seven remained seizure free after vitamin D administration and with no dose enhancement of AED medications of the nineteen. Children receiving polytherapy thirteen children could be successfully switched to phenobarbital and/or phenytoin. Forty four (61%) children had hypocalcemia (less than 9 mg%), fifty seven (79%) children had raised alkaline phosphatase levels (more than 270 IU).

Comments:

Phenobarbital and/or phenytoin have been found to be effective frontline AED. Periodic administration of vitamin D plays a supportive role.     

Relapse risk analysis after drug withdrawal in epileptic children with uncomplicated seizures.

In an attempt to find the risk of relapse and factors predictive of risk of relapse, 97 children with epilepsy, withdrawn from their medication, followed in our outpatient clinic from 1990 to 1995 were included in this study. The overall relapse rate was 20.6%. All relapses occurred within 2 years after withdrawal started. Female gender, age at onset of seizures of more than 2 years, and the duration of withdrawal were found to be significant risk factors in relapse rate following univariate analysis. However, gender was not found to be significant in multivariate analysis. All other factors, including the duration of seizures prior to starting antiepileptic drug (AED) treatment, the number of seizure before the start of AED treatment, the period between AED induction and control of seizures, diagnostic yield from electroencephalogy (EEG) at diagnosis, the number of seizures after the onset of AED therapy, length of seizure-free period, aetiology of the seizures, a history of epilepsy in the immediate family, or previously experienced febrile convulsions were not significant factors in relapse rate. Significant risk factors for relapse rate also significantly affected relapse time. We conclude that when AED therapy is withdrawn from children with uncomplicated epilepsy, as in our patients, the two important risk factors, age at onset of seizures and the duration of withdrawal, can predict a poor prognosis with a higher relapse rate: this needs taking into consideration.