Management of antiepileptic drugs following epilepsy surgery: a review

The favourable impact of surgery for intractable epilepsy on seizures is well documented. However, few studies have determined what changes in antiepileptic drug (AED) therapy occur following surgery. Alterations in AED blood levels in the immediate postoperative period can result in breakthrough seizures. In long term follow-up, one-third to one-half of seizure-free patients after temporal lobectomy, the most common type of epilepsy surgery, still require AED treatment which usually has been reduced from polytherapy to monotherapy. In our study of 93 patients followed two years after temporal lobectomy, polytherapy decreased from 78% before surgery to 14% postoperatively, while medication was discontinued in 44%. Early reduction from polytherapy to monotherapy can often be carried out in the immediate postoperative period but the most appropriate timing of cessation of AED treatment has yet to be determined. Patients undergoing extratemporal resections and other forms of epilepsy surgery associated with less favourable postoperative seizure control may achieve comparatively less reduction in antiepileptic medication. We generally do not recommend stopping AEDs prior to one year after surgery.     

First, do no harm: the risks of overtreating children with epilepsy

BACKGROUND: Although overtreatment with antiepileptic drugs contributes to the morbidity associated with epilepsy, many children still are overtreated. OBJECTIVE: To evaluate if the withdrawal of at least one antiepileptic drug (AED) in children with refractory epilepsy using polytherapy enable a better seizure control. METHOD: This was a prospective study. Children with refractory epilepsy using at least two AEDs were included. Once the patient, or guardian, agreed to participate in the study, one or more AED were slowly tapered off. The remaining AEDs dosages could be adjusted as needed, but a new AED could not be introduced. RESULTS: Fifteen patients were evaluated, three girls; ages ranging from 3 to 18 (mean=8.7 years). After at least one AED withdrawal, two (13.5%) patients became seizure free, seizures improved >50% in 5 (33.5%) patients, did not change in 5 (33.5%), and seizure frequency became worse in 3 (20%). Adverse events improved in 12 patients (80%). CONCLUSION: The withdrawal of at least one AED is a valuable option in the treatment of selected children with refractory epilepsy.     

Complaints associated with the use of antiepileptic drugs: results from a community-based study.

BACKGROUND: Few data exist with respect to the occurrence of chronic side effects due to antiepileptic drugs (AED) in routine clinical practice. OBJECTIVE: To evaluate the prevalence of subjective complaints which patients with epilepsy regard as side effects of their AED treatment in a community-based population. METHODS: Cross-sectional study. Subjects were identified through the database of AED-use in the pharmacies in a suburban area in The Netherlands. Respondents completed a brief questionnaire about their epilepsy, including a checklist with 30 complaints, which are common in AED users. RESULTS: We present data of 346 responding adults with treated epilepsy from a population of 107,000 adult inhabitants. Eighty percent was using monotherapy, with few patients taking new AEDs. Almost 60% of the patients reported complaints probably due to side effects in at least three domains. General CNS-related side effects were reported most often; memory problems (21.4% of the patients) and fatigue (20.3%) were dominant. Polytherapy was associated with more side effects than monotherapy. We identified differences in profiles of complaints between valproate, carbamazepine and phenytoin monotherapy. Complaints were not substantially associated with ongoing seizures or other treatment factors. CONCLUSIONS: The majority of patients taking AEDs for epilepsy think they have side effects form their drugs, even when seizures were in remission and when monotherapy was used. Our findings suggest a need to improve monitoring of complaints of side effects of AEDs and to explore the feasibility of interventions aimed at reduction of such complaints in everyday clinical practice.     

Primary generalized epilepsy: a risk factor for seizures in labor and delivery?

PURPOSE: Women in the United States who have epilepsy give birth to about 20000 newborns every year. Because seizures during late gestation and delivery may seriously affect the fetus, and because primary generalized tonic-clonic (GTC) seizures may occur during labor and delivery in 1-2% of women with epilepsy, we attempted to define the rate, risks, and causes of seizures during labor and delivery. METHODS: To characterize seizures during labor and delivery, we retrospectively analyzed 89 consecutive pregnancies of women with epilepsy on antiepileptic drugs (AEDs). Six epileptologists in our group had treated these patients. We confirmed data and acquired new information by telephone for 83.1% of the pregnancies, and categorized the women as having primary generalized or partial epilepsy. Most of the patients (78%) were on monotherapy during pregnancy; 20% took two AEDs, and 3% took three AEDs during that period. RESULTS: Seizures during labor and delivery occurred in 4/32 (12.5%) patients with primary generalized epilepsy, but in none of the 57 women with partial epilepsy (P<0.05). None of the 38 patients with therapeutic AED levels before labor and delivery had seizures, compared to 3/37 (8.1%) of the subtherapeutic group. However, drug levels were taken at variable times in relation to delivery, limiting their value. Also, the levels sampled were both total and free levels; the latter would be more helpful to determine the adequacy of AED drug coverage. CONCLUSIONS: Maintaining therapeutic AED levels during the last trimester may help prevent seizures during labor and delivery, especially in women with generalized epilepsy. Women with epilepsy who had subtherapeutic AED levels and had been seizure-free may be at-risk for seizures during labor and delivery. Our sample was small, and a random sampling bias may have affected the results.     

Characteristics of patients initiated on the new antiepileptic drugs: a PADS study

Whereas randomized controlled trials remain a standard for evaluating and comparing efficacy and safety of the new antiepileptic drugs (AEDs), postmarketing drug research offers a useful means of comparing efficacy and safety of new AEDs. However, differences in baseline characteristics of patients in different drug groups create the potential for bias in drug comparison studies. In this study, baseline demographic characteristics of 1,386 patients initiating lamotrigine (LTG), tiagabine (TGB), or topiramate (TPM) were compared to identify patient characteristics that may influence AED use in epilepsy patients. Data were collected at 14 epilepsy centers and included medications, seizure types and syndromes, and prior adverse events. There were 402 patients in the LTG group, 725 TPM, and 259 TGB. The groups differed both in their number of concurrent AEDs (p<0.001) and in their number of prior AEDs (p<0.01). There was no difference in proportion with partial versus generalized epilepsy syndromes. The groups differed in the proportions of patients with complex partial seizures (p=0.049), primary generalized tonic-clonic seizures (p=0.01), and myoclonic seizures (p=0.03). Baseline behavioral adverse event rate was lowest in patients initiating TPM (p<0.01); LTG patients had the lowest rate of prior AED-related rash (p=0.02). There was no relationship between AED assignment and patient age, age of epilepsy onset, epilepsy duration, institutionalization status, gender, or psychiatric history. Numerous epidemiological differences were identified among patients placed on the new AEDs, including current and prior AED profiles, seizure types, and prior adverse event history. Accounting for these differences is of crucial importance because they may bias conclusions of nonrandomized post-marketing trials comparing the drugs.     

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.     

Neurodevelopmental effects of antiepileptic drugs

Although the vast majority of children born to women with epilepsy are normal, these children are at increased risk for both anatomic and cognitive impairments. Current evidence suggests that the defects are the result of in utero antiepileptic drug (AED) exposure combined with a genetic predispositon. However, the exact mechanisms underlying these effects remain to be delineated. AED polytherapy increases the risk, but it remains uncertain if specific AEDs pose an overall greater threat. Most women with epilepsy cannot avoid AEDs during pregnancy because of the greater risks posed by seizures to the mother and fetus. Therefore, current recommendations emphasize definitive diagnosis and the use of AED monotherapy at the lowest effective dose if treatment is indicated. Prenatal folate and multivitamins should also be given routinely to women of childbearing age who require AED therapy.     

Generic substitution in the treatment of epilepsy: Patient and physician perceptions

Generic substitution of branded antiepileptic drugs (AEDs) has sparked recent debates. We sought to understand perceptions about generic AED substitution and how these guide prescribing. Surveys were conducted among 550 adult patients with self-reported epilepsy and 606 physicians who treat patients with epilepsy. Physicians (88%) were concerned about an increase in breakthrough seizures in patients switched from a brand AED to a generic or among generics. Two-thirds of physicians and 34% of patients have linked breakthrough seizures to generic AED substitution. Physicians (75%) and patients (65%) were also concerned about efficacy. About half of physicians were extremely/very likely to request that brand AEDs not be substituted with a generic. In conclusion, perceptions among physicians and patients do not align with the FDA position that generic AEDs have the same clinical effect and safety profile as branded AEDs. Additional investigation on bioequivalence may help address ongoing concerns and inform policy-making decisions.     

Strategies to prevent overtreatment with antiepileptic drugs in patients with epilepsy

Overtreatment is defined here as an unnecessary and excessive drug load in the management of epilepsy leading to a suboptimal risk-to-benefit balance. Pharmacological overtreatment can often be prevented by deciding and counselling carefully about the need for antiepileptic drugs (AEDs) given the limitations of current AEDs. Although AEDs will reduce the incidence of seizures, they have no demonstrated ability to prevent epilepsy in patients at risk or to modify the course of epilepsy in patients following the first seizure. In addition, starting AEDs may not be necessary for control of epileptic seizures induced by precipitation or predisposing factors or for benign epilepsies with rare or mild seizures. Start monotherapy with the chosen first-line AED, initially at low doses titrating up to the low maintenance dose. Avoid drug loading (except for emergency treatment). If seizures continue, titrate to the limit of tolerability which will however, achieve additional seizure control in approximately 20% of patients. If, as in many patients, dosing to the limit of tolerability is not beneficial, the dose should be reduced. Switching to an average dose of another first line AED is another option to prevent overtreatment. Avoid drug overload during add-on therapy by slowly reducing the dose of the first drug in patients having adverse effects, ideally by an amount that the patient does not experience any further adverse effects, if possible, before adding another drug. If the patient does not benefit unequivocally from two-drug therapy within 3 months (and approximately 75% will not benefit), slowly transfer to monotherapy of the second drug and start with a newly chosen AED for add-on. To counteract the propensity to overmedication in chronic epilepsy is not easy. Great benefits, without loss of seizure control, are often gained by slowly reducing the overall drug load.     

Generic substitution in the treatment of epilepsy: patient and physician perceptions

Generic substitution of branded antiepileptic drugs (AEDs) has sparked recent debates. We sought to understand perceptions about generic AED substitution and how these guide prescribing. Surveys were conducted among 550 adult patients with self-reported epilepsy and 606 physicians who treat patients with epilepsy. Physicians (88%) were concerned about an increase in breakthrough seizures in patients switched from a brand AED to a generic or among generics. Two-thirds of physicians and 34% of patients have linked breakthrough seizures to generic AED substitution. Physicians (75%) and patients (65%) were also concerned about efficacy. About half of physicians were extremely/very likely to request that brand AEDs not be substituted with a generic. In conclusion, perceptions among physicians and patients do not align with the FDA position that generic AEDs have the same clinical effect and safety profile as branded AEDs. Additional investigation on bioequivalence may help address ongoing concerns and inform policy-making decisions.     

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.     

Postictal serum levels of antiepileptic drugs for detection of noncompliance

Medication noncompliance (NC) is thought to be a major cause of insufficient seizure control. In an explorative study we investigated whether postictal serum levels (PISLs) of antiepileptic drugs (AEDs) are a reliable indicator of NC. Young adults with epilepsy on a stable AED regimen were asked to contact medical service as soon as possible when a seizure occurred to obtain serum levels of their AEDs. PISLs were compared with the mean value of two routine serum levels of the same medication. PISLs lower than 50% of the individual reference value were regarded as an indicator of NC. PISL samples in 61 seizures of 52 patients treated mainly with carbamazepine, valproic acid, or lamotrigine were evaluated. A drop in serum levels >50% indicating NC was noted in 44.3% of the seizures. Determination of PISLs seems to be a simple and useful method for detecting or ruling out irregular intake patterns as a cause of "breakthrough" seizures.     

Women with Epilepsy: Must Contraception and Pregnan Add to the Burden of Epilepsy?

Summary: In addition to seizure control, women with epilepsy face particular complications associated with menstruation, fertility, contraception, pregnancy, and breastfeeding. With traditional long-term antiepileptic drug (AED) therapy there is a risk of menstrual irregularities, contraceptive failure, and adverse pregnancy outcome. Many women intentionally discontinue AED therapy during pregnancy because of concerns about the risk of fetal malformation and effects on fetal growth and development. However, trauma resulting from seizures is the leading cause of maternal and fetal death in women with epilepsy. In addition, mothers are concerned about the presence of AEDs in breast milk and therefore tend to choose bottle feeding. Clearly, a balance must be achieved between seizure control for the mother and exposure of the fetus or infant to AEDs. Tiagabine (TGB) is a new AED which acts by inhibiting uptake of the neurotransmitter γ-aminobutyric acid into glial cells. Animal studies show that TGB has no toxic effects either on reproductive function or on the developing fetus, although there is still insufficient evidence to permit conclusions from human studies. TGB does not induce hepatic metabolism, and a study in healthy volunteers indicates no interaction with oral contraceptives. It is hoped that the availability of new AEDs such as TGB, with the promise of a better safety profile and a lower propensity for drug interactions, will alleviate the burden for women with epilepsy.     

Brief antiepileptic drug withdrawal prolongs interval to next seizure

OBJECTIVE: To evaluate the course of seizure control after reinstitution of antiepileptic drugs (AEDs) in patients whose AEDs were discontinued during inpatient EEG-video monitoring. METHODS: The authors studied prospectively patients with intractable epilepsy admitted for EEG-video monitoring with AED withdrawal. They examined seizure diaries in the 2 months preceding admission and recorded the number of seizures during hospitalization and for 2 months after discharge. They also recorded the interval between the last two seizures preceding admission (S-S pre), from the last seizure to admission (S-A), from discharge to the first seizure after discharge (D-S), and between the first and the second seizures following discharge (S-S post). RESULTS: Sixty patients qualified for the study. There was a significant decrease in seizure frequency in the 2 months after discharge compared with baseline (p = 0.02). For patients who had at least two seizures during follow-up, the mean D-S interval was significantly longer than mean S-S pre and S-S post (p < 0.005), whereas the latter two intervals were comparable. Prolongation of D-S was related to duration off AEDs and to the AED restarted, but not to the number or severity of seizures during monitoring. CONCLUSION: Seizure improvement after reinstitution of antiepileptic drugs (AEDs) is due primarily to prolongation of the interval from reinstitution of AEDs to the next seizure. This may reflect increased patient responsiveness to AED therapy after a drug "holiday" and has implications for experimental AED testing in the setting of presurgical evaluation.     

Long term course of childhood epilepsy following relapse after antiepileptic drug withdrawal

OBJECTIVE: To explore the course of epilepsy following relapse after antiepileptic drug (AED) withdrawal. METHODS: Forty two patients were identified with onset of epilepsy in childhood in whom AEDs had been withdrawn after at least 2 years of seizure freedom, and in whom a relapse had occurred. Two patients were lost to follow up. RESULTS: Median follow up after AED withdrawal was 5.9 years (range 1.6-13.2 years). Relapse occurred in more than half of the patients within 6 months of AED withdrawal. At the end of follow up, 12 patients (30%) were seizure free for at least 1 year (mean 10.4 years) without medication; 16 (40%) were seizure free for at least 1 year (mean 5.3 years) with ongoing medication; and 12 patients (30%) were seizure free for less than 1 year with medication. No status epilepticus occurred in any patient after withdrawal. Age at onset, if over the age of 5, combined with normal intelligence were predictive of an excellent outcome; presence of a neurological disorder, and hence symptomatic aetiology, was predictive of poor outcome after a relapse. CONCLUSIONS: Fears that premature withdrawal of AEDs might result in uncontrollable seizures were unsubstantiated in this study. The current practice of withdrawing AEDs in children who have been seizure free for 2 years can be beneficial to most of these patients.     

Comparison of the antiepileptogenic effects of an early long‐term treatment with ethosuximide or levetiracetam in a genetic animal model of absence epilepsy

Purpose: Epilepsy is a heterogeneous syndrome characterized by recurrent, spontaneous seizures; continuous medication is, therefore, necessary, even after the seizures have long been suppressed with antiepileptic drug (AED) treatments. The most disturbing issue is the inability of AEDs to provide a persistent cure, because these compounds generally suppress the occurrence of epileptic seizures without necessarily having antiepileptogenic properties. The aim of our experiments was to determine, in the WAG/Rij model of absence epilepsy, if early long‐term treatment with some established antiabsence drugs might prevent the development of seizures, and whether such an effect could be sustained. Methods: WAG/Rij rats were treated for ～3.5 months (starting at 1.5 months of age, before seizure onset) with either ethosuximide (ETH; drug of choice for absence epilepsy) or levetiracetam (LEV; a broad‐spectrum AED with antiabsence and antiepileptogenic properties). Results: We have demonstrated that both drugs are able to reduce the development of absence seizures, exhibiting antiepileptogenic effects in this specific animal model. Discussion: These findings suggest that absence epilepsy in this strain of rats very likely follows an epileptogenic process during life and that early therapeutic intervention is possible, thereby opening a new area of research for absence epilepsy and AED treatment strategies.