Appropriate use of generic and branded antiseizure medications in epilepsy: Updated recommendations from the Italian League Against Epilepsy (LICE).

Generic drugs are increasingly used to treat many diseases including epilepsy. The growing importance of generic antiseizure medications (ASMs) has led the ASMs commission of the Italian League Against Epilepsy (LICE) to review current evidence in the literature about efficacy and safety of these products. Recommendations from other scientific organizations have also been considered to provide an update of the LICE position about their utilization (List of Recommendations). Compared with the previous literature review, randomized controlled trials assessing bioequivalence among branded drugs and generics are currently available. Although some contrasting results have been reported, brand-to-generic switching was effective and tolerable in real-life settings, with similar adverse event ratios. Based on these findings, LICE concluded that, conforming to the rigorous regulation of USA and EU markets, generic ASMs are not inferior to the respective branded, providing a cost advantage for patients starting or replacing monotherapy or add-on, and for those with incomplete seizure control. Branded-to-generic (and vice versa) switching is not recommended (although applicable) during seizure remission, as well as the generic-to-other generic switching. Other recommendations focus on the appropriateness of therapeutic drug monitoring (TDM) when switching is required, paying attention to avoiding the erroneous switch between modified and immediate-release formulations during dispensation. Finally, to support patients' compliance, they should be assured of generics' safety and efficacy and carefully informed with practical advice, particularly when the switching is associated with aspect modifications (e.g. color and shape changes) of the pill or the packaging.

Defining the electroclinical phenotype and outcome of PCDH19-related epilepsy: A multicenter study.

OBJECTIVE: PCDH19-related epilepsy is an epileptic syndrome with infantile onset, characterized by clustered and fever-induced seizures, often associated with intellectual disability (ID) and autistic features. The aim of this study was to analyze a large cohort of patients with PCDH19-related epilepsy and better define the epileptic phenotype, genotype-phenotype correlations, and related outcome-predicting factors. METHODS: We retrospectively collected genetic, clinical, and electroencephalogram (EEG) data of 61 patients with PCDH19-related epilepsy followed at 15 epilepsy centers. All consecutively performed EEGs were analyzed, totaling 551. We considered as outcome measures the development of ID, autistic spectrum disorder (ASD), and seizure persistence. The analyzed variables were the following: gender, age at onset, age at study, genetic variant, fever sensitivity, seizure type, cluster occurrence, status epilepticus, EEG abnormalities, and cognitive and behavioral disorders. Receiver operating characteristic curve analysis was performed to evaluate the age at which seizures might decrease in frequency. RESULTS: At last follow-up (median = 12 years, range = 1.9-42.1 years), 48 patients (78.7%) had annual seizures/clusters, 13 patients (21.3%) had monthly to weekly seizures, and 12 patients (19.7%) were seizure-free for ≥2 years. Receiver operating characteristic analysis showed a significant decrease of seizure frequency after the age of 10.5 years (sensitivity = 81.0%, specificity = 70.0%). Thirty-six patients (59.0%) had ID and behavioral disturbances. ASD was present in 31 patients. An earlier age at epilepsy onset emerged as the only predictive factor for ID (P = 0.047) and ASD (P = 0.014). Conversely, age at onset was not a predictive factor for seizure outcome (P = 0.124). SIGNIFICANCE: We found that earlier age at epilepsy onset is related to a significant risk for ID and ASD. Furthermore, long-term follow-up showed that after the age of 10 years, seizures decrease in frequency and cognitive and behavioral disturbances remain the primary clinical problems.

Severity and burden of partial-onset seizures in a phase III trial of eslicarbazepine acetate.

OBJECTIVE: The objective of this study was to compare posttreatment seizure severity in a phase III clinical trial of eslicarbazepine acetate (ESL) as adjunctive treatment of refractory partial-onset seizures. METHODS: The Seizure Severity Questionnaire (SSQ) was administered at baseline and posttreatment. The SSQ total score (TS) and component scores (frequency and helpfulness of warning signs before seizures [BS]; severity and bothersomeness of ictal movement and altered consciousness during seizures [DS]; cognitive, emotional, and physical aspects of postictal recovery after seizures [AS]; and overall severity and bothersomeness [SB]) were calculated for the per-protocol population. Analysis of covariance, adjusted for baseline scores, estimated differences in posttreatment least square means between treatment arms. RESULTS: Out of 547 per-protocol patients, 441 had valid SSQ TS both at baseline and posttreatment. Mean posttreatment TS for ESL 1200 mg/day was significantly lower than that for placebo (2.68 vs 3.20, p<0.001), exceeding the minimal clinically important difference (MCID: 0.48). Mean DS, AS, and SB were also significantly lower with ESL 1200 mg/day; differences in AS and SB exceeded the MCIDs. The TS, DS, AS, and SB were lower for ESL 800 mg/day than for placebo; only SB was significant (p=0.013). For both ESL arms combined versus placebo, mean scores differed significantly for TS (p=0.006), DS (p=0.031), and SB (p=0.001). CONCLUSIONS: Therapeutic ESL doses led to clinically meaningful, dose-dependent reductions in seizure severity, as measured by SSQ scores. CLASSIFICATION OF EVIDENCE: This study presents Class I evidence that adjunctive ESL (800 and 1200 mg/day) led to clinically meaningful, dose-dependent seizure severity reductions, measured by the SSQ.

Prospective, case-control study on the effect of pregnancy on seizure frequency in women with epilepsy.

To evaluate if pregnancy induces a change in seizure frequency and in percentage of subjects remaining seizure-free. This is a prospective case-control study conducted in our tertiary epilepsy centre. Controls were matched 2:1 with the cases for relevant clinical parameters. Cases had to be referred to our centre for at least 9 months before-pregnancy, during pregnancy and the-9-months-after-birth. Controls were followed for the correspondent periods of time: named respectively control period 1-2-3. Seizure frequency was defined as "improved" if there was a 50 % of reduction, "worsened" if there was a 50 % of increase, and "unchanged" in the rest of cases. We recruited 36 cases and 72 controls [in both group mean age was 28 years, partial epilepsy (80.6 %), generalized epilepsy (19.4 %)]; 30 cases and 60 controls were seizure-free before pregnancy and in period 1, respectively. During pregnancy 72 % of cases remained "unchanged" while 8 and 19 % respectively "improved" and "worsened"; moreover, there was no statistical difference in the number of seizure-free patients and in the monthly seizure frequencies. No differences were found in controls. In this prospective case-control study, pregnancy does not affect seizure frequency in women with epilepsy.

Reliability of clinical diagnosis of dystonia.

BACKGROUND: There is only one small single-center study on the reliability of the diagnosis of focal dystonia. The aim of this study was to assess the inter-rater reliability of dystonia diagnosis among neurologists with different professional experience. METHODS: Twenty-nine adults (18 with dystonia, 9 with other movement disorders, and 2 healthy controls) were videotaped while undergoing neurological examination and during the process of collecting information on the history of their condition. Each case was diagnosed by 35 blind raters (12 general neurologists, 21 neurology residents, and 2 experts in movement disorders) from different hospitals. Sensitivity and specificity were calculated confronting raters with the gold standard (the caring physician). Inter-rater agreement was measured by the Kappa statistic. RESULTS: Specificity and sensitivity were 95.2 and 66.7%, 76.3 and 75.2%, 84.6 and 71.6% for experts, general neurologists, and residents, respectively. Kappa values on dystonia diagnosis ranged from 0.30 to 0.46. The agreement was moderate for experts and residents (0.40-0.60) and fair for general neurologists (0.20-0.40). Kappas were the highest among experts for cranial and laryngeal dystonia (0.61-1), but not for cervical dystonia (0.37). CONCLUSIONS: The diagnosis of dystonia is difficult and only partially mirrors a physician's background.

Withdrawal of antiepileptic drugs: guidelines of the Italian League Against Epilepsy.

The Italian League Against Epilepsy has issued evidence-based guidelines to help practicing physicians in their decision to stop or withhold antiepileptic drugs (AEDs) in patients achieving a prolonged period of seizure freedom. Six adult and two child neurologists, divided into four pairs, critically appraised 128 published reports and provided graded recommendations answering 15 key questions: length of the seizure-free period after treatment initiation, difference in seizure-free periods in children and adults, electroencephalography (EEG) pattern at the time of discontinuation, etiology of epilepsy, seizure type(s), patient's age and sex, family history of epilepsy, history of febrile seizures, epilepsy syndrome, seizure frequency before entering remission, duration of active epilepsy, tapering period, number and type of AEDs taken at time of discontinuation, combination of risk factors for recurrence, and length of patient monitoring after treatment discontinuation. Based on the available data, the following recommendations can be outlined: (1) antiepileptic treatment might be discontinued after a minimum period of 2 years of seizure freedom; shorter seizure-free periods are associated to a higher risk of relapse; (2) in children, AED discontinuation could be considered after less than two seizure-free years because of a marginally higher risk of relapse for early withdrawal; (3) factors, such as abnormal EEG (including epileptiform abnormalities) at the time of treatment discontinuation, a documented etiology of seizures (including mental retardation, perinatal insults, and abnormal neurologic examination), partial seizures, or an older age at disease onset, enhance the risk of relapse; however, patients should not be encouraged to withhold treatment unless a combination of two or more of these factors is present; (4) female sex, family history of epilepsy, history of febrile seizures, disease length/severity, and number and type of drugs taken should not influence the decision to stop treatment; (5) epilepsy syndrome should be always included in the decision process; (6) slow (at least 6 months) AED discontinuation should be encouraged; in any case the duration of the tapering period should be tailored to the patient's needs and preference; and (7) patient discontinuing treatment should be followed for no <2 years. As a general habit, the decision to stop treatment should be discussed and shared with each patient, taking into account social and personal complications of a seizure relapse and the medical complications of chronic AED treatment.

Epileptic seizures, movement disorders, and breathing disturbances in Rett syndrome: diagnostic relevance of video-polygraphy.

Epileptic seizures, movement disorders and breathing disturbances may be observed in Rett syndrome, and correct diagnosis is mandatory for the management. We evaluated the usefulness of video-polygraphy in the differential diagnosis between epileptic and non-epileptic paroxysmal events in eight patients with Rett syndrome. Based on video analysis, myoclonic seizures were usually misdiagnosed as movement disorders and stereotypies; the events identified by parents as generalized tonic-clonic seizures included episodes of motor activity and breathing abnormality. Myoclonic seizures aggravated by inappropriate treatment were evident in four patients; hyperventilation and apnea during wakefulness were present in all patients, while central sleep apneas were present in one patient; sinus tachycardia and cardiac arrhythmias emerged in six patients; cortical myoclonus was disclosed in five patients. In Rett syndrome, video-polygraphy is essential in characterizing the clinical features of paroxysmal events, determining autonomic dysfunctions, documenting myoclonic motor phenomena, and evaluating the responses to the treatment of epilepsy.

Ictal video-polygraphic features of perioral myoclonia with absences.

There have been few case reports of perioral myoclonia with absences (POMA) because of the lack of video-polygraphic recordings clarifying the electroencephalogram (EEG)-electromyogram (EMG) correlations. We describe one of the first video-polygraphic studies of POMA in a patient who underwent repeated and prolonged split-screen video-polygraphic recordings. The ictal EEG showed generalized and irregular discharges of spikes or multiple spikes and slow waves, while two concomitant EMG patterns appeared: (1) a rhythmic enhancement of the orbicularis oris and masseter muscles on both sides with minimal asymmetry corresponding to perioral movements, and (2) a progressive increment in muscular tone in the mylohyoideus muscle corresponding to oroalimentary automatisms. Myoclonic jerks were inconstantly time-locked to the spike component of the spike-wave complex. The evidence of a complex pattern of activation of the facial muscles suggests that the involvement of subcortical central pattern generators, related to masticatory activity, through the disinhibitory effect of the spike-wave discharge is a possible pathophysiological mechanism underlying POMA.

Early versus late remission in a cohort of patients with newly diagnosed epilepsy.

PURPOSE: To count patients with newly diagnosed epilepsy entering early and late remission and to identify prognostic predictors of late remission. METHODS: Children and adults with previously untreated epilepsy from two Italian tertiary centers (Monza, Bari) were the study population. All patients received monotherapy at treatment start; drug choice and schedule were left to the physician's judgment. A retrospective audit was performed and the following prognostic predictors were identified: age, gender, putative etiology, first electroencephalography (EEG) record, neurologic and psychiatric examination, disease duration at diagnosis, seizure type(s) and number prior to starting treatment, epilepsy syndrome, and first antiepileptic drug. Early remission was defined by 2-year seizure control immediately after treatment start. Late remission was defined by 2-year seizure control achieved at least 24 months after treatment start. Prognostic predictors were assessed by logistic regression analysis, adjusting for age, gender, and center. RESULTS: One hundred seventy-four women and 178 men (mean age 31.5 years) were included and followed for 2399.6 person-years. The cumulative time-dependent probability of 2-year remission was 56.3% at 2 years after treatment start, and 62.6, 69.4, and 79.5% at 3, 5, and 10 years. One hundred fifteen patients (23.0%) achieved early remission and 38 patients (10.8%) achieved late remission. The interaction between partial seizures and number of seizures prior to treatment was the only independent predictor of late remission. DISCUSSION: The course of epilepsy and the chance of remission are together a complex and dynamic process, possibly explained by the diversity of the mechanisms underlying drug response and the use of an increasing number of drugs.

A novel de novo SCN1A missense mutation in Severe Myoclonic Epilepsy Borderland.

In this report we describe a novel missense SCN1A mutation in a patient affected by Severe Myoclonic Epilepsy Borderland (SMEB). This three and a half year-old female patient experienced prolonged febrile seizures at the age of 14 months, followed by generalized tonic-clonic seizures, atonic seizures, atypical absences almost in a cluster and triggered by fever. Cognitive and motor development was normal. The case was suggestive for SMEB. SCN1A analysis revealed an unknown de novo point mutation: a heterozygous replacement of nucleotide G with nucleotide T in position 4183 of the coding region of the gene (c.4183 G>T) in exon 21. This mutation causes the replacement of aspartic acid with tyrosine in 1395 (p.D1396Y). Even if other SCN1A missense mutations localized in the same region are associated to SMEB, a definite genotype-phenotype correlation has not yet been found, probably because other factors are involved in the pathogenesis of this type of epilepsy.

Combination treatment of Glatiramer Acetate and Minocycline affects phenotype expression of blood monocyte-derived dendritic cells in Multiple Sclerosis patients.

The effects of Glatiramer Acetate (GA) in combination with Minocycline (MIN), a second-generation tetracycline, have been investigated on the course of EAE in mice, resulting in a significant reduction in disease severity and burden with attenuation of the inflammation, axonal loss and demyelination. Here we investigate the effects of combination therapy with GA and MIN on the induction, maturation and phenotyping of blood monocyte-derived dendritic cells (DCs) in Multiple Sclerosis (MS) patients. Hence the expressions of HLA-DR, CD11c, CD83 and CD1a were studied by flow cytometric analysis on immature (iDCs) and mature DCs (mDCs) from untreated and GA treated MS patients. Thirteen relapsing-remitting MS patients and 13 healthy controls (HCs) were included in the study. Ten of the MS patient group were re-tested after a 2 month period of GA treatment. The marker expressions on DC from untreated MS and HCs were studied in vitro in the absence or presence of GA and GA+MIN; and on DCs from GA treated MS patients without and with the in vitro addition of MIN. We found that in vitro GA alone or in combination with MIN downregulated DCs antigen presentation capability (HLA-DR), whereas the combination treatment only affected also myeloid DCs activation (CD83) in both MS and HCs. Prolonged GA treatment (in vivo for 2 months) affected antigen presentation capability by DCs, whereas when treated in vitro with MIN these cells also tended to reduce activation marker expression and myeloid phenotype acquisition (CD11c). The present data demonstrate possible combination effects of GA and MIN on peripheral blood monocyte-derived DCs in MS patients.

Tolerability of adjunctive eslicarbazepine acetate according to concomitant lamotrigine or carbamazepine use: A subgroup analysis of three phase III trials in adults with focal (partial-onset) seizures.

OBJECTIVE: To evaluate and compare the effects of concomitant lamotrigine (LTG) or carbamazepine (CBZ) on the incidence of treatment-emergent adverse events (TEAEs) in patients taking adjunctive eslicarbazepine acetate (ESL) for focal (partial-onset) seizures (FS). METHODS: These post-hoc analyses of data pooled from three randomized, double-blind, placebo-controlled studies of adjunctive ESL (BIA-2093-301, -302 and -304) included adults (≥16 years) with FS refractory to 1-3 antiepileptic drugs (AEDs). Patients were randomized equally to placebo, ESL 400 mg (Studies 301 and 302 only), 800 mg, or 1200 mg once daily (8-week baseline, 2-week titration, and 12-week maintenance periods). TEAEs, TEAEs leading to discontinuation, and serious AEs (SAEs) were evaluated in patients taking, or not taking, LTG (excluding those taking CBZ or phenytoin [PHT]; i.e., the +LTG and -LTG/-CBZ subgroups), or CBZ (excluding those taking LTG or PHT; i.e., the +CBZ and -LTG/-CBZ subgroups) at baseline. RESULTS: LTG was used concomitantly by 248 patients (+LTG; placebo, n = 81; ESL, n = 167) and CBZ by 613 patients (+CBZ; placebo, n = 172; ESL, n = 441); 361 patients were taking neither LTG nor CBZ (-LTG/-CBZ; placebo, n = 109; ESL, n = 252). The overall incidence of TEAEs with ESL (any dose) was numerically higher for +CBZ (77%) than for +LTG (73%) or -LTG/-CBZ (68%; statistical significance not tested). Among patients taking ESL, dizziness, diplopia, and vomiting were reported more frequently in the +CBZ subgroup (30%, 14%, and 10%, respectively) than in the +LTG (16%, 8%, 5%) or -LTG/-CBZ (11%, 3%, 5%) subgroups. The overall incidence of TEAEs leading to discontinuation with ESL was higher for +CBZ (21%) than for +LTG (13%) or -LTG/-CBZ (15%). Dizziness leading to discontinuation with ESL was reported more frequently in the +CBZ subgroup than in the +LTG or -LTG/-CBZ subgroups (9%, 3%, and 3%, respectively). The overall incidence of SAEs in patients taking ESL was comparable across subgroups (+LTG, 5%; +CBZ, 6%; -LTG/-CBZ, 5%). The results were similar when evaluating placebo-adjusted incidences. CONCLUSION: There was a potential pharmacodynamic interaction between AEDs with a putatively similar mechanism of action, with a seemingly lesser interaction between ESL and LTG versus ESL and CBZ. If combining ESL with LTG or CBZ, clinicians should be aware of the potential risk for an increased incidence of TEAEs typically associated with voltage-gated sodium channel inhibitors (e.g., dizziness, blurred vision, vertigo, diplopia, headache, or vomiting).

Individualised prediction model of seizure recurrence and long-term outcomes after withdrawal of antiepileptic drugs in seizure-free patients: a systematic review and individual participant data meta-analysis.

BACKGROUND: People with epilepsy who became seizure-free while taking antiepileptic drugs might consider discontinuing their medication, with the possibility of increased quality of life because of the elimination of adverse events. The risk with this action, however, is seizure recurrence. The objectives of our study were to identify predictors of seizure recurrence and long-term seizure outcomes and to produce nomograms for estimation of individualised outcomes. METHODS: We did a systematic review and meta-analysis, and identified eligible articles and candidate predictors, using PubMed and Embase databases with a last update on Nov 6, 2014. Eligible articles had to report on cohorts of patients with epilepsy who were seizure-free and had started withdrawal of antiepileptic drugs; articles also had to contain information regarding seizure recurrences during and after withdrawal. We excluded surgical cohorts, reports with fewer than 30 patients, and reports on acute symptomatic seizures because these topics were beyond the scope of our objective. Risk of bias was assessed using the Quality in Prognosis Studies system. Data analysis was based on individual participant data. Survival curves and proportional hazards were computed. The strongest predictors were selected with backward selection. Models were converted to nomograms and a web-based tool to determine individual risks. FINDINGS: We identified 45 studies with 7082 patients; ten studies (22%) with 1769 patients (25%) were included in the meta-analysis. Median follow-up was 5·3 years (IQR 3·0-10·0, maximum 23 years). Prospective and retrospective studies and randomised controlled trials were included, covering non-selected and selected populations of both children and adults. Relapse occurred in 812 (46%) of 1769 patients; 136 (9%) of 1455 for whom data were available had seizures in their last year of follow-up, suggesting enduring seizure control was not regained by this timepoint. Independent predictors of seizure recurrence were epilepsy duration before remission, seizure-free interval before antiepileptic drug withdrawal, age at onset of epilepsy, history of febrile seizures, number of seizures before remission, absence of a self-limiting epilepsy syndrome, developmental delay, and epileptiform abnormality on electroencephalogram (EEG) before withdrawal. Independent predictors of seizures in the last year of follow-up were epilepsy duration before remission, seizure-free interval before antiepileptic drug withdrawal, number of antiepileptic drugs before withdrawal, female sex, family history of epilepsy, number of seizures before remission, focal seizures, and epileptiform abnormality on EEG before withdrawal. Adjusted concordance statistics were 0·65 (95% CI 0·65-0·66) for predicting seizure recurrence and 0·71 (0·70-0·71) for predicting long-term seizure freedom. Validation was stable across the individual study populations. INTERPRETATION: We present evidence-based nomograms with robust performance across populations of children and adults. The nomograms facilitate prediction of outcomes following drug withdrawal for the individual patient, including both the risk of relapse and the chance of long-term freedom from seizures. The main limitations were the absence of a control group continuing antiepileptic drug treatment and a consistent definition of long-term seizure freedom. FUNDING: Epilepsiefonds.

Evidence for a rapid action of levetiracetam compared to topiramate in refractory partial epilepsy.

The objective of this observational study was to compare the efficacy of levetiracetam and topiramate during the first 15 days of add-on treatment in adults with refractory partial epilepsy. Two cohorts of patients with > or =3 simple or complex partial seizures with or without secondary generalisation per month over an 8-week baseline period received levetiracetam or topiramate in two distinct phases, in addition to standard antiepileptic treatment. During the first 15 days of the therapy, levetiracetam was added at the dosage of 250 mg b.i.d. or topiramate at 25mg o.i.d. Efficacy parameters included number of seizure-free days (SFDs), mean and percent reduction in seizure frequency (in general and by type), and number of seizure-free patients in the first 15 days of treatment compared to last 15 days of the baseline period. Sixty-one patients received levetiracetam and 61 topiramate. The general characteristics of the two treatment groups were similar. The total number of SFDs during 15 days before treatment was 637 with levetiracetam and 621 with topiramate; in the 15-day evaluation period the SFDs increased to 748 (17.4%) and 668 (7.6%), respectively (ANOVA, p<0.05). Twenty-six patients (42.6%) taking levetiracetam were seizure free compared to 10 (16.4%) receiving topiramate (chi-square, p=0.003). This open-label non-controlled study suggests an early efficacy of levetiracetam as add-on therapy in patients with refractory partial epilepsy: these results appear to confirm previous indications of a rapid onset of action and seem to suggest first evaluation of the patient at the dose of 500 mg/day before increasing to the considered minimum standard dose of 1000 mg/day, as some patients could respond to the starting dose.

Intravenous lacosamide in seizure emergencies: Observations from a hospitalized in-patient adult population.

PURPOSE: to evaluate the efficacy and safety of intravenous (IV) lacosamide (LCM) in the treatment of seizure clusters (SC) and status epilepticus (SE) in hospitalized adult patients. METHODS: we prospectively analyzed treatment response, seizure outcome, and adverse effects of IV LCM in 38 patients with seizure emergencies (15 with SC, 23 with SE) during a hospital stay. The loading dose of IV LCM was 200-400mg and the maintenance dose was 200-400mg daily. Response to IV LCM was evaluated within 20min, 4h and 24h of LCM infusion. RESULTS: an acute anti-seizure effect after IV LCM was especially evident when it was first used - (SC) or second line (established SE) treatment. In particular, 87% of SC patients (13/15) and 80% of established SE (8/10) demonstrated response to LCM treatment, while no patients with super-refractory SE (0/8) responded to IV LCM according to our criteria. The loading of IV LCM was well tolerated, with mild adverse effects (2/38 temporary dizziness). In most patients, during and after administration of the loading dose of IV LCM a temporary (30min-1h) sedation was observed. No ECG and laboratory values-changes were documented in any of the patients. CONCLUSIONS: LCM is an effective and well-tolerated treatment when used to treat SC in hospitalized adult patients. As add-on therapy, it may be useful to stop seizure activity in patients with focal SE not responding to first/second-line intravenous AEDs.

Should antiepileptic drugs be withdrawn in seizure-free patients?

Discontinuation of antiepileptic drug (AED) treatment is a valuable option in patients with epilepsy who have been seizure free for 2 years or longer. However, the decision to withdraw AEDs must be based on a balanced view of the overall risk of seizure relapse, the factors most likely to affect that risk, and the medical, emotional and social implications of treatment continuation versus treatment withdrawal. In a critical review of 28 studies accounting for 4571 patients (2758 children, 1020 adults and a combined group of 793), most with at least 2 years of seizure remission, the proportion of patients with relapses during or after AED withdrawal ranged from 12 to 66%. Using life-table analysis, the cumulative probability of remaining seizure-free in children was 66-96% at 1 year and 61-91% at 2 years after withdrawal of AEDs. The corresponding values in adults were 39-74% and 35-57%, respectively. The relapse rate was highest in the first 12 months (especially in the first 6 months) after withdrawal and tended to decrease thereafter. Based on a previously published meta-analysis of data published up to 1992, the pooled relapse risk was 25% (95% CI 21, 30%) at 1 year and 29% (95% CI 24, 34%) at 2 years after AED withdrawal. The factors associated with a higher-than-average risk of seizure relapse included adolescent-onset epilepsy, partial seizures, the presence of an underlying neurological condition, and abnormal EEG findings at the time of AED withdrawal in children. Factors associated with a lower-than-average risk were childhood-onset epilepsy, idiopathic generalised epilepsy and - for children - a normal EEG. Selected epilepsy syndromes (e.g. benign epilepsy with centrotemporal spikes and juvenile myoclonic epilepsy) may be associated with significantly different outcomes after AED withdrawal. All these factors and their combinations may contribute to the development of guidelines for practising physicians to help them in making the best decision related to treatment discontinuation. The decision plan should also take into account social factors (driving license, job and leisure activities) as well as emotional and personal factors, and must be tailored to and discussed with the individual patient and his/her family.

Adjunctive therapy versus alternative monotherapy in patients with partial epilepsy failing on a single drug: a multicentre, randomised, pragmatic controlled trial.

OBJECTIVE: To evaluate the value of alternative monotherapy versus adjunctive therapy in partial epilepsy refractory to single antiepileptic drug (AED) therapy. DESIGN AND METHODS: In a multicentre, parallel-group, open-label study, patients with cryptogenic or symptomatic partial epilepsy not controlled after single or sequential AED monotherapies were randomised to monotherapy with an alternative AED or to adjunctive therapy with a second AED. The AED to be added/substituted and dose adjustments were determined by the physician's best judgement. Patients were followed up until withdrawal from the allocated treatment or for 12 months, whichever first. Outcome measures included proportion of patients continuing on the assigned treatment strategy, proportion of patients seizure-free after achieving the target maintenance dose, and adverse effects rates. Data were analysed by actuarial life tables, Kaplan-Meier survival analysis and Cox proportional hazard regression model. RESULTS: Of a total of 157 patients (including 94 previously exposed to only one AED), 76 were randomised to alternative monotherapy and 81 to adjunctive therapy. The two groups were balanced in clinical characteristics. The 12-month cumulative probability of remaining on the assigned treatment was 55% in patients randomised to alternative monotherapy and 65% in those randomised to adjunctive therapy (P=0.74). The 12-month probability of remaining seizure-free was 14 and 16%, respectively (P=0.74). Adverse effects were similar in the two groups. No significant differences in outcome within or between groups were identified based on etiology of epilepsy and previous AED exposure. CONCLUSIONS: Although these findings should be interpreted with caution due to the low statistical power resulting from the relatively small sample size, alternative monotherapy and adjunctive therapy were associated with similar outcomes. Further work is required to determine whether outcome could be improved through identification of specific AED combinations with synergistic activity.