Perampanel for the treatment of epilepsy with genetic aetiology: Real-world evidence from the PERMIT Extension study.

Genetic factors contribute to the aetiology of epilepsy in >50% of cases, and information on the use of antiseizure medications in people with specific aetiologies will help guide treatment decisions. The PERMIT Extension study pooled data from two real-world studies (PERMIT and PROVE) to investigate the effectiveness and safety/tolerability of perampanel (PER) when used to treat people with focal and generalised epilepsy in everyday clinical practice. This post-hoc analysis of PERMIT Extension explored the use of PER when used to treat individuals presumed to have epilepsy with a genetic aetiology. Assessments included retention rate (evaluated at 3, 6 and 12 months), effectiveness (responder and seizure freedom rates; evaluated at 3, 6, 12 months and the last visit [last observation carried forward) and tolerability (adverse events [AEs]). Of the 6822 people with epilepsy included in PERMIT Extension, 1012 were presumed to have a genetic aetiology. The most common genetic aetiologies were idiopathic generalised epilepsy (IGE; 58.2%), tuberous sclerosis (1.1%), Dravet syndrome (0.8%) and genetic epilepsy with febrile seizures plus (GEFS+; 0.5%). Retention rates at 3, 6 and 12 months in the total genetic aetiology population were 89.3%, 79.7% and 65.9%, respectively. In the total genetic aetiology population, responder rates at 12 months and the last visit were 74.8% and 68.3%, respectively, and corresponding seizure freedom rates were 48.9% and 46.5%, respectively. For the specific aetiology subgroups, responder rates at 12 months and the last visit were, respectively: 90.4% and 84.4% (IGE), 100% and 57.1% (tuberous sclerosis), 100% and 71.4% (Dravet syndrome), and 33.3% and 20.0% (GEFS+). Corresponding seizure freedom rates were, respectively: 73.1% and 64.6% (IGE), 33.3% and 22.2% (tuberous sclerosis), 20.0% and 28.6% (Dravet syndrome), and 0% and 0% (GEFS+). The incidence of AEs was 46.5% for the total genetic aetiology population, 48.8% for IGE, 27.3% for tuberous sclerosis, 62.5% for Dravet syndrome, and 20% for GEFS+. Tolerability findings were consistent with PER's known safety profile. PER was effective and generally well tolerated when used in individuals with a presumed genetic epilepsy aetiology in clinical practice. PER was effective across a wide range of genetic aetiologies.

Individualised prediction of drug resistance and seizure recurrence after medication withdrawal in people with juvenile myoclonic epilepsy: A systematic review and individual participant data meta-analysis.

Background: A third of people with juvenile myoclonic epilepsy (JME) are drug-resistant. Three-quarters have a seizure relapse when attempting to withdraw anti-seizure medication (ASM) after achieving seizure-freedom. It is currently impossible to predict who is likely to become drug-resistant and safely withdraw treatment. We aimed to identify predictors of drug resistance and seizure recurrence to allow for individualised prediction of treatment outcomes in people with JME. Methods: We performed an individual participant data (IPD) meta-analysis based on a systematic search in EMBASE and PubMed - last updated on March 11, 2021 - including prospective and retrospective observational studies reporting on treatment outcomes of people diagnosed with JME and available seizure outcome data after a minimum one-year follow-up. We invited authors to share standardised IPD to identify predictors of drug resistance using multivariable logistic regression. We excluded pseudo-resistant individuals. A subset who attempted to withdraw ASM was included in a multivariable proportional hazards analysis on seizure recurrence after ASM withdrawal. The study was registered at the Open Science Framework (OSF; https://osf.io/b9zjc/). Findings: Our search yielded 1641 articles; 53 were eligible, of which the authors of 24 studies agreed to collaborate by sharing IPD. Using data from 2518 people with JME, we found nine independent predictors of drug resistance: three seizure types, psychiatric comorbidities, catamenial epilepsy, epileptiform focality, ethnicity, history of CAE, family history of epilepsy, status epilepticus, and febrile seizures. Internal-external cross-validation of our multivariable model showed an area under the receiver operating characteristic curve of 0·70 (95%CI 0·68-0·72). Recurrence of seizures after ASM withdrawal (n = 368) was predicted by an earlier age at the start of withdrawal, shorter seizure-free interval and more currently used ASMs, resulting in an average internal-external cross-validation concordance-statistic of 0·70 (95%CI 0·68-0·73). Interpretation: We were able to predict and validate clinically relevant personalised treatment outcomes for people with JME. Individualised predictions are accessible as nomograms and web-based tools. Funding: MING fonds.

Adjunctive brivaracetam - A prospective audit of outcomes from an epilepsy clinic.

OBJECTIVE: Brivaracetam (BRV), is licensed in Europe as adjunctive treatment, and in the United States of America as adjunctive and monotherapy for focal seizures with or without secondary generalization in adults, adolescents, and children ≥4 years. As BRV becomes available globally, this prospective audit was undertaken to gain an understanding of how best to use the anti-seizure medication (ASM) in the everyday clinical setting. METHODS: Brivaracetam was started by patients ≥16 years with difficult-to-control epilepsy at Glasgow epilepsy clinics following a 12-week baseline on stable ASM doses. Target dosing was 200 mg/day. Review occurred every 12-16 weeks until 1 of 4 end-points occurred: seizure freedom for ≥6 months on a given BRV dose; ≥50% (responder) or <50% (marginal benefit) seizure reduction over 6 months compared with baseline on the highest tolerated BRV dose; withdrawal of BRV due to lack of efficacy, adverse effects, or both. RESULTS: An end-point has been reached by 108 patients (38 men, 70 women; median age 45 years), 88 with focal-onset seizures and 20 with genetic generalized epilepsies (GGEs). Of these, 71 (65.7%) have benefitted from BRV, including 23 (21.3%) who have been seizure free for ≥6 months on a median BRV dose of 100 mg/day (range 25-200 mg/day). A further 18 (16.7%) were classified as responders and 30 (27.8%) showed marginal benefit. Brivaracetam benefitted 16 (80.0%) patients with GGEs, 5 becoming seizure free. Generalized tonic-clonic seizures, absences, and myoclonic seizures were completely controlled in 4 (25%) patients with juvenile myoclonic epilepsy. Brivaracetam monotherapy was established in 12 patients, 3 of whom had GGEs. Levetiracetam (LEV) had previously been prescribed in 53 patients who had discontinued the ASM due to lack of efficacy, side effects, or both. Adjunctive BRV benefitted 34 (64.2%) of these patients. Brivaracetam was withdrawn in 37 (34.3%) patients, (23 side effects, 4 lack of efficacy, 10 both). Sedation was the commonest side effect leading to BRV withdrawal (n = 14; 13.0%). Psychiatric side effects resulted in BRV discontinuation in 9 (8.3%) patients. SIGNIFICANCE: Brivaracetam has efficacy for a range of seizure types and syndromes in a wide range of doses. The ASM can produce positive outcomes in patients who have failed LEV. Post-marketing studies remain a useful tool to evaluate the efficacy and tolerability of novel ASMs in everyday clinical practice.

Pharmacological Management of the Genetic Generalised Epilepsies in Adolescents and Adults.

Common genetic generalised epilepsy syndromes encountered by clinicians include childhood and juvenile absence epilepsies, juvenile myoclonic epilepsy and generalised tonic-clonic seizures on awakening. Treatment of these syndromes involves largely the use of broad-spectrum antiseizure drugs. Those effective for the generalised epilepsies include sodium valproate, phenobarbital, ethosuximide, clobazam, clonazepam, lamotrigine, levetiracetam, topiramate, zonisamide and, more recently, perampanel and brivaracetam. Results from the few rigorous studies comparing outcomes with drugs for genetic generalised epilepsies show valproate to be the most effective. The majority of patients with genetic generalised epilepsy syndromes will become seizure free on antiseizure monotherapy; those for whom control proves elusive may benefit from combination regimens. Early counselling regarding management may assist the patient to come to terms with their diagnosis and improve long-term outcomes. Treatment can be lifelong in some individuals, although others may remain seizure free without medication. Choice of antiseizure medication depends on the efficacy for specific seizure types, as well as tolerability. For patients prescribed comedication, drug interactions should be considered. In particular, for young women taking oral hormonal contraceptives, ≥ 200 mg/day of topiramate can decrease the circulating concentration of ethinylestradiol and ≥ 12 mg/day of perampanel can induce levonorgestrel metabolism. The use of valproate in women of childbearing potential is limited by associated teratogenic and neurodevelopmental effects in offspring. Given that valproate is often the antiseizure drug of choice for genetic generalised epilepsies, this creates a dilemma for patients and clinicians. Decision making can be aided by comprehensive assessment and discussion of treatment options. Psychiatric comorbidities are common in adolescents and adults with genetic generalised epilepsies. These worsen the prognosis, both in terms of seizure control and quality of life. Attendant lifestyle issues can impact significantly on the individual and society. Frontal lobe dysfunction, which can present in patients with juvenile myoclonic epilepsy, can adversely affect the long-term outlook, regardless of the nature of seizure control. Ongoing management requires consideration of psychosocial and behavioural factors that can complicate diagnosis and treatment. An assured supportive attitude by the neurologist can be an important contributor to a positive outcome. The mechanisms underlying genetic generalised epilepsies, including genetic abnormalities, are unclear at present. As the pathophysiology is unravelled, this may lead to the development of novel therapies and improved outcomes for patients with these syndromes.

Management of epilepsy in women.

Epilepsy is a common neurological condition in women worldwide. Hormonal changes occurring throughout a woman's life can influence and be influenced by seizure mechanisms and antiepileptic drugs, presenting unique management challenges. Effective contraception is particularly important for women with epilepsy of childbearing potential because of antiepileptic drug-related teratogenicity and hormonal interactions; although studies reveal many women do not receive contraceptive and preconceptual counselling. Management challenges in this population include the higher risk of pregnancy complications and peripartum psychiatric problems than in women without epilepsy. Research is needed to clarify the precise role of folic acid supplementation in prevention of congenital malformations in children born to women with epilepsy. To optimise treatment of low bone density in women with epilepsy, studies investigating bone densitometry frequency and calcium and vitamin D supplements are required. Understanding of the mechanisms linking seizures and the menopause will help to develop effective therapeutic strategies, and advances in managing epilepsy could improve quality of life for women with this condition.

Brivaracetam: a novel antiepileptic drug for focal-onset seizures.

Brivaracetam (BRV), the n-propyl analogue of levetiracetam (LEV), is the latest antiepileptic drug (AED) to be licensed in Europe and the USA for the adjunctive treatment of focal-onset seizures with or without secondary generalization in patients aged 16 years or older. Like LEV, BRV binds to synaptic vesicle protein 2A (SV2A), but BRV has more selective binding and a 15- to 30-fold higher binding affinity than LEV. BRV is more effective than LEV in slowing synaptic vesicle mobilization and the two AEDs may act at different binding sites or interact with different conformational states of the SV2A protein. In animal models, BRV provides protection against focal and secondary generalized seizures and has significant anticonvulsant effects in genetic models of epilepsy. The drug undergoes first-order pharmacokinetics with an elimination half-life of 7-8 h. Although BRV is metabolized extensively, the main circulating compound is unchanged BRV. Around 95% of metabolites undergo renal elimination. No dose reduction is required in renal impairment, but it is recommended that the daily dose is reduced by one-third in hepatic dysfunction that may prolong half-life. BRV has a low potential for drug interactions. The efficacy and tolerability of adjunctive BRV in adults with focal-onset seizures have been explored in six randomized, placebo-controlled studies. These showed significant efficacy outcomes for doses of 50-200 mg/day. The most common adverse events reported were headache, somnolence, dizziness, fatigue and nausea. Patients who develop psychiatric symptoms with LEV appear to be at risk of similar side effects with BRV, although preliminary data suggest that these issues are likely to be less frequent and perhaps less severe. As with all AEDs, a low starting dose and slow titration schedule help to minimize side effects and optimize seizure control and thereby quality of life.

Psychiatric side effects and antiepileptic drugs: Observations from prospective audits.

Psychiatric comorbidities are common in people with epilepsy. A retrospective study of characteristics associated with withdrawal due to psychiatric side effects was undertaken in patients with treated epilepsy participating in prospective audits with new antiepileptic drugs (AEDs). A total of 1058 treated patients with uncontrolled seizures (942 focal-onset seizures, 116 generalized genetic epilepsies [GGEs]) participated in eight prospective, observational audits from 1996 to 2014. These patients were prescribed adjunctive topiramate (n=170), levetiracetam (n=220), pregabalin (n=135), zonisamide (n=203), lacosamide (n=160), eslicarbazepine acetate (n=52), retigabine (n=64), or perampanel (n=54). Doses were titrated according to efficacy and tolerability to optimize zeizure outcomes and reduce side effects. Psychiatric comorbidities were recorded prior to and after the addition of each AED. At baseline, patients with focal-onset seizures (189 of 942; 20.1%) were statistically more likely to have psychiatric diagnoses compared to patients with GGEs (14 of 116, 12.1%; p=0.039). Following adjunctive AED treatment, neuropsychiatric adverse effects led to AED withdrawal in 1.9-16.7% of patients. Patients with a pre-treatment psychiatric history (22 of 209; 10.5%) were statistically more likely to discontinue their new AED due to psychiatric issues compared to patients with no previous psychiatric diagnosis (50 of 849; 5.9%; p=0.017). Patients receiving sodium channel blocking AEDs (4 of 212, 1.9%) were statistically less likely to develop intolerable psychiatric problems, compared to those on AEDs possessing other mechanisms of action (68 of 846, 8.0%; p=0.012). Depression was the commonest problem, leading to discontinuation of AEDs in 2.8% (n=30) patients. Aggression was statistically more common in men (11 of 527, 2.1%) compared to women (1 of 531, 0.2%; p=0.004). Patients with learning disability (12 of 122, 9.8%; p=0.0015) were statistically less likely to have psychiatric issues prior to adjunctive AED treatment compared to other patients (208 of 936, 22.2%), but there were no statistically significant differences once the new AEDs were added (8 of 122 patients with learning disability, 6.6%; 64 of 936 other patients, 6.8%). Awareness of these issues may assist clinicians in avoiding, identifying and treating psychiatric comorbidities in people with epilepsy.

Prospective audit with adjunctive perampanel: Preliminary observations in focal epilepsy.

PURPOSE: Perampanel (PER) was first licensed in the United Kingdom in 2012 for the adjunctive treatment of focal seizures with or without secondary generalization in adults and children over 12years of age. It has recently also been approved for use as add-on therapy for patients with primary generalized tonic-clonic seizures. This prospective audit reports preliminary outcomes with adjunctive PER in patients with focal-onset seizures in everyday clinical practice using a standard design. METHODS: To date, 54 patients (38 males, 16 females; 21-65years, median: 48years) have completed the study. The median monthly seizure frequency was 4 (range: 1-60). At baseline, patients were taking a median of 2 other antiepileptic drugs (range: 1-4 drugs), with their seizures having previously failed to improve on a median of 3 schedules (range: 1-15 schedules). After 12weeks of stable dosing, PER was added, aiming at a target range of 6-12mg/daily. Review took place every 6-8weeks until one of 4 endpoints was reached: seizure freedom for ≥6months on a given PER dose, ≥50% (responder) or <50% (marginal effect) seizure reduction over 6months, compared with the prospective baseline, on the highest tolerated PER dose, or withdrawal of PER due to a lack of efficacy or side effects. RESULTS: Three (5.6%) patients have remained seizure-free, with 8 (14.8%) demonstrating a ≥50% response and a further 17 (31.5%) reporting a marginal effect. Of the 26 (48.1%) dropping out of PER treatment, 21 (38.9%) did so because of side effects. The commonest problems were nausea, vomiting, ataxia, dizziness, and sedation. Overall, 6 (11%) patients developed neuropsychiatric problems, with 3 reporting irritability and/or aggression. Two patients had substantial weight gain, and another patient suffered recurrent falls. Treatment with enzyme-inducing AEDs had no effect on PER dosing in patients responding to PER or withdrawing due to side effects. SIGNIFICANCE: These data support the value of adjunctive PER in some patients with pharmacoresistant epilepsy in everyday clinical practice.

Adjunctive lacosamide--5 years' clinical experience.

PURPOSE: In 2008, lacosamide (LCM) was licensed in Europe for the adjunctive treatment of focal-onset seizures. At that time a prospective audit was initiated at the Western Infirmary to assess outcomes with this antiepileptic drug (AED) in everyday clinical practice. METHODS: A total of 160 patients (74 M; 86 F, aged 14-74 years [median 42 years]) with uncontrolled focal-onset seizures (median monthly frequency 1; range 1-300) were started on LCM. After 12 weeks on stable AED doses (median 1 AED; range 1-4), LCM was added and the dose titrated as appropriate with a target range of 200-400 mg/day. Review took place every 6-8 weeks until 1 of 4 end-points was reached: seizure freedom for 6 months on a given LCM dose; ≥50% (responder) or <50% (marginal benefit) seizure reduction over 6 months compared with baseline on the highest tolerated LCM dose; withdrawal of LCM due to lack of efficacy, side effects, or both. RESULTS: Of the 160 patients, 35 (21.9%) remained seizure-free for at least 6 months on a stable LCM dose, while 35 (21.9%) had a ≥50% reduction in seizure frequency and 54 (33.7%) reported a marginal benefit. Five patients became seizure-free on LCM monotherapy following withdrawal of their initial treatment. Outcomes were similar for patients taking LCM with traditional sodium blocking agents (n=56; 43 [76%] continued LCM) compared to those who also received AEDs with other mechanisms (n=84; 64 [76%] continued LCM). LCM was discontinued in 36 (22.5%) patients because of lack of efficacy (n=24, 15%) or side effects (n=12; 7.5%). Commonest side effects leading to withdrawal were nausea and vomiting, dizziness, sedation, headaches, tremor, and ataxia, particularly for patients also taking sodium valproate. CONCLUSION: LCM is a well-tolerated and effective AED for focal-onset seizures with or without secondary generalisation, regardless of concomitant treatment. Commonest dose-related side effects were neurotoxic in nature.

Prospective audits with newer antiepileptic drugs in focal epilepsy: insights into population responses?

Despite the availability of a wide range of new antiepileptic drugs (AEDs), there is little evidence that their introduction has substantially altered outcomes. This paper reviews data from 5 consecutive prospective audits with new AEDs using similar methodology. Prospective audits with topiramate (TPM; n=135), levetiracetam (LEV; n=136), zonisamide (ZNS; n=141), pregabalin (PGB; n=135), and lacosamide (LCM; n=160) were undertaken in treated patients with uncontrolled partial-onset seizures. Follow-up continued until one of four endpoints was reached: seizure freedom for ≥6months on unchanged dosing; ≥50% reduction (responder) in seizure frequency on the highest tolerated dose compared with baseline; <50% seizure frequency reduction (marginal response) compared with baseline in patients wishing to continue treatment with the new AED; or withdrawal due to lack of efficacy, side effects, or both. A greater proportion of seizure-free patients occurred with LEV (23.5%), LCM (21.9%), and TPM (20.7%) than with ZNS (12.8%) and PGB (10.4%). A higher percentage discontinued treatment with ZNS (41.8%) and PGB (50.4%) than with LEV (32.4%), TPM (31.1%), and LCM (22.5%). Most seizure-free patients responded to the new agent as first or second add-on (TPM 96%; LEV 97%; ZNS 89%; PGB 86%; LCM 97%) often at modest or moderate dosing (TPM 68%, ≤200mg/day; LEV 63%, ≤1000mg/day; ZNS 61%, ≤100mg/day; PGB 86%, ≤300mg/day; LCM 74%, ≤200mg/day). With <10% of patients discontinuing all AEDs due to lack of efficacy, tolerability was the major factor influencing the number of patients remaining on treatment. Lacosamide was the best (77% patients continued treatment), while PGB was the worst (50% continued treatment) tolerated AED. Overall, seizure freedom was achieved in <25% of patients in each audit, mainly as a first or second add-on, with best tolerated AEDs producing a higher number of good outcomes. Seizures in very few patients with drug-resistant epilepsy, as defined by the International League Against Epilepsy task force, responded to any of the 5 newer AEDs. These data support the suggestion that the introduction of modern agents has not importantly impacted the outcomes in refractory epilepsy.

Uncontrolled epilepsy is not necessarily the same as drug-resistant epilepsy: differences between populations with newly diagnosed epilepsy and chronic epilepsy.

BACKGROUND: A proportion of patients with seemingly "uncontrolled" epilepsy could still control their epilepsy with further pharmacological manipulations. It is possible that their epilepsy might not be truly "drug-resistant". We audited the patients with "uncontrolled epilepsy" using the recent ILAE definition of drug-resistant epilepsy. METHODS: Patients with newly diagnosed epilepsy at Glasgow and patients with chronic epilepsy treated in Hong Kong were independently assessed at their last clinic visit. If the patient was not seizure-free, the epilepsy was considered "uncontrolled". In this latter situation, if the patient had adequate trials of two or more tolerated, appropriately chosen, and appropriately used AED schedules, the epilepsy was classified as "drug-resistant" in accordance with the ILAE definition. If not, the outcome was classified as "undefined", and the reason(s) for this was documented. RESULTS: In the newly diagnosed cohort with uncontrolled epilepsy (n=311), outcome was "undefined" in 175 (56%). The most common reasons were trying just one AED usually at the patient's behest (n=68; 39%); intermittent compliance (60; 34%); adverse effects at low dosage (51; 29%); inadequate dosing (49; 28%); social issues such as imprisonment, alcohol, and recreational drug use (34; 19%); psychiatric problems affecting documentation, attendance, etc. (32; 18%); patient choice accepting less than optimal control (14; 8%); and seizure freedom of less than 12 months (12.7%). In the chronic cohort of 194 patients with uncontrolled epilepsy, drug responsiveness was "undefined" in just 79 (41%). The most common reasons were inadequate use of the AED(s) (35; 44%), followed by a lack of information on treatment response in the medical records (18; 23%) and failure of only one adequately used AED (11; 14%). CONCLUSION: Uncontrolled epilepsy is not necessarily the same as drug-resistant epilepsy. Efforts should be made to understand why a patient is not seizure-free so that appropriate adjustment in AED regimen can be taken to enable the patient to attain long-term seizure freedom.

Antiepileptic drug monotherapy versus polytherapy: pursuing seizure freedom and tolerability in adults.

PURPOSE OF REVIEW: Despite the availability of many new antiepileptic drugs (AEDs), only around 50% of people with epilepsy will become seizure free on their first drug. This article explores treatment options and issues influencing whether AEDs should be substituted or combined in the remainder of the patient population. RECENT FINDINGS: Prior to the introduction of novel AEDs, it was generally opined that combining traditional agents did not necessarily lead to an improvement in seizure control and might increase the propensity for side effects. Newer AEDs, many with different mechanisms of action, have increased the potential for polytherapy regimens, although robust data to support or refute this therapeutic strategy are sparse. It seems sensible to substitute rather than combine when the first AED produces an idiosyncratic reaction, is poorly tolerated at a low/moderate dose or shows no efficacy. Polytherapy may be preferred if the patient tolerates their first or second AED well, but with a suboptimal response, particularly when there is an identifiable anatomical substrate for the seizures. AED selection requires consideration of many factors some of which are discussed in this study. SUMMARY: There are no definitive answers on whether to combine or substitute AEDs. Different strategies are required for different scenarios in different patients.

Antiepileptic drug combinations--have newer agents altered clinical outcomes?

In 2000, 332 (20.5%) of 1617 patients registered with the Western Infirmary Epilepsy Unit required antiepileptic drug (AED) polytherapy to remain seizure-free for at least 1 year. The analysis was repeated 10 years later. Of 2379 seizure-free patients, 20.4% (n=486 - 254 women, 232 men, aged 18-95 years [median age 49 years]) were receiving combination therapy. Two AEDs were taken by 395 (81.3%) patients in 2010, and by 287 (86.4%) in 2000. Sodium valproate with lamotrigine was the commonest of 64 successful pairings. As a combination, mean daily doses of both AEDs were lower (n=96; sodium valproate 1200 mg, lamotrigine 155 mg) than when sodium valproate was taken with carbamazepine or levetiracetam (n=42; 1621 mg; p<0.001), and lamotrigine was combined with topiramate or levetiracetam (n=33; 430 mg; p<0.001), suggesting possible synergism. In 2010, a higher percentage of patients (n=85) remained seizure-free on 3 AEDs (17.5% in 2010, 12.7% in 2000) in 57 separate regimens. Only 0.9% (n=3) of patients in 2000, and 1.2% (n=6) in 2010 responded to 4 AEDs. Levetiracetam (n=109; 10.2%) and topiramate (n=81; 7.6%) were the newer agents most commonly represented in successful combinations. These data tend to imply that drug substitution rather than addition has largely led to these marginally improved results. In the last decade, when used as adjunctive therapies, newer agents appear not to have impacted substantially on the likelihood of producing seizure freedom. An alternative approach to AED development may be required to change this disappointing scenario.

Adjunctive lacosamide in clinical practice: sodium blockade with a difference?

Lacosamide (LCM) was licensed in the United Kingdom in 2008 for the adjunctive treatment of partial-onset seizures. It exerts its effect by enhancing sodium channel slow inactivation. This article reports preliminary outcomes with adjunctive LCM in the everyday clinical setting. To date, 113 patients (57 males, 56 females; aged range=18-74 years, median=39 years) with uncontrolled partial-onset seizures (monthly frequency range=1-300, median=4) have been included in the audit. Patients were taking 1-4 (median=1) antiepileptic drugs (AEDs), having previously tried 1-12 (median 3) drug schedules. After 12 weeks on stable AED dosing, LCM was added, aiming at an initial target range of 200-400mg/day. Review took place every 6-8 weeks until one of four endpoints was reached: seizure freedom for ≥6 months on a given LCM dose; ≥50% (responder) or <50% (marginal benefit) seizure reduction over 6 months compared with baseline on the highest tolerated LCM dose; withdrawal of LCM because of lack of efficacy, side effects, or both. An endpoint has been reached by 65 (57.5%) patients so far. Seventeen (26.2%) have remained seizure free on a median daily LCM dose of 100mg (range=50-300 mg). Patients were more likely to become seizure free when LCM was used as a first add-on (15/36, 41.7%), compared with a later treatment schedule (1/27, 3.7%, P=0.001). With appropriate dose manipulation, patients taking traditional sodium blockers (5/26, 19.2%) were as likely to become seizure free as those taking AEDs with other mechanisms of action only (11/37, 29.7%). Fifty percent or greater seizure reduction was achieved in an additional 16 (24.6%) patients (1 monotherapy); 18 (27.7%) reported marginal benefit. Two patients were established on LCM monotherapy (one seizure free, one responder). Patients remaining on LCM were as likely to also be taking sodium blockers only (23/27, 85.1%) as AEDs with other mechanisms (26/36, 72.2%). LCM was withdrawn in 14 patients (12.3% of ongoing patients, 21.5% of those at an endpoint; 10 for side effects, 4 for lack of efficacy). The most common side effects leading to withdrawal were sedation, ataxia, and dizziness. Of the 10 with side effects, only 2 patients took concomitant sodium blockers. Patients on sodium valproate were more likely to discontinue LCM (8/21, P=0.018) than those also taking other AEDs; 5 of the 8 did so because of side effects and 3 because of lack of efficacy. In patients with partial-onset seizures, LCM is an effective and well-tolerated adjunctive AED when combined with appropriate doses of traditional sodium blockers, as well as agents with other mechanisms of action. Seizure freedom was more likely when LCM was used as a first add-on compared with a later treatment schedule. Patients also taking sodium valproate were significantly more likely to discontinue LCM compared with those taking other AEDs. These data suggest that the pharmacological effect of LCM differs importantly from that of AEDs that influence fast inactivation of the sodium channel.

Levetiracetam monotherapy--outcomes from an epilepsy clinic.

INTRODUCTION: Levetiracetam (LEV) is a broad spectrum antiepileptic drug (AED) with a unique mechanism of action. This retrospective audit explores outcomes in patients commenced on LEV monotherapy at the Epilepsy Unit at the Western Infirmary, Glasgow, Scotland from 1st January 2001 until 30th June 2009. METHODS: LEV monotherapy was started in 228 patients (89 men, 139 women, aged 12-81 years [median 28 years]). Of these, 161 (70.6%) had partial-onset seizures, 59 (25.9%) had idiopathic generalized epilepsies (35 primary generalized tonic-clonic seizures [PGTCS], 20 juvenile myoclonic epilepsy, 4 juvenile absence epilepsy), and 8 (3.5%) had unclassified GTCS. Initial dosing was 250 mg twice daily for 2 weeks, followed by 500 mg twice daily. Patients were reviewed every 6-8 weeks. If required, the LEV dose was titrated in 500 mg increments to a maximum tolerated or effective dose. RESULTS: In total, 112 (49.1%) patients remained seizure-free for ≥1 year on a median LEV dose of 1000 mg/day (range 500-3000 mg/day). Patients were more likely to achieve seizure freedom with LEV as a first monotherapy (81 of 149 [54.4%]), as opposed to switching from another AED (31 of 79 [39.2%]; p=0.03). In this latter group, seizure freedom was more likely in those who switched after failing their 1st or 2nd AED (n=39 of 64 [60.9%]), compared to later in the treatment schedule (n=2 of 15 [13.3%]; p=0.029). Patients reporting <5 seizures (70 of 118) prior to starting LEV were more likely to become seizure-free than those with ≥5 seizures (42 of 110; p=0.001). Thirty-six (15.8%) patients had a ≥50% seizure reduction over 1 year; 43 (18.9%) were classified as having a <50% improvement, but elected to continue on LEV. The drug was withdrawn in 37 (16.2%) patients (30 side effects, 7 lack of efficacy). Eighteen (7.9%) patients reported intolerable neuropsychiatric symptoms (7 aggression, 7 mood swings, 2 irritability, 2 depression). Other side effects leading to drug withdrawal included sedation (n=5) and lethargy (n=4). CONCLUSION: Seizure freedom was achieved in around half the patients on a median LEV dose of 1000 mg/day. This was more likely to occur in those taking the drug as first monotherapy, and in those with <5 pre-treatment seizures. Around 50% of those who discontinued LEV due to side effects developed neuropsychiatric symptoms.

Pharmacotherapy of epilepsy: newly approved and developmental agents.

This article discusses seven newly available antiepileptic drugs (AEDs) and agents in phase III development. Lacosamide, licensed as an adjunctive treatment for partial-onset seizures, primarily acts by enhancing sodium channel slow inactivation. At daily doses of 200-600 mg, the drug significantly reduced partial-onset seizures in adults with refractory epilepsy. The most common adverse effects are CNS related. Rufinamide, available as adjunctive treatment for seizures associated with Lennox-Gastaut syndrome, has an unclear mechanism of action, although it does block voltage-dependent sodium channels. Coadministration of valproic acid significantly increases rufinamide circulating concentrations. The drug has been shown to have efficacy for partial-onset, primary generalized tonic-clonic, tonic-atonic, absence and atypical absence seizures. Adverse effects are mainly somnolence, nausea and vomiting. Eslicarbazepine acetate, a carbamazepine analogue, was recently licensed as adjunctive treatment for partial-onset seizures. Eslicarbazepine acetate acts at voltage-gated sodium channels, although the precise mechanism of action is unclear. The drug had efficacy for partial-onset seizures in three randomized, double-blind, placebo-controlled studies, using 400, 800 or 1200 mg/day. Adverse effects include dizziness and somnolence. Retigabine (ezogabine) exerts its anticonvulsant effect through the opening of neuronal voltage-gated potassium channels. Following significant seizure reduction rates at dosages of 600, 900 and 1200 mg/day, license applications have been submitted for its use as adjunctive treatment for patients with partial-onset seizures. Dose-related adverse effects include somnolence, confusion and dizziness. Brivaracetam is the n-propyl analogue of levetiracetam. Mixed results have been obtained in phase III studies in patients with partial-onset seizures, and further trials in children, patients with photosensitive epilepsy and patients with partial-onset seizures are ongoing. Dizziness, headache and somnolence are the most common adverse effects reported. Perampanel was designed as an AMPA-type glutamate receptor antagonist. Following encouraging results from phase II studies in patients with refractory partial-onset seizures, recruitment for phase III trials is almost complete. Ganaxolone is a neurosteroid with potent antiepileptic activity that modulates GABA(A) receptors in the CNS. Ganaxolone has shown promise in a variety of seizure types. Dizziness and somnolence have been reported in some patients. The availability of new AEDs has widened the choices for clinicians treating patients with epilepsy. However, given the minimal improvement in prognosis and disappointing efficacy outcomes in double-blind, placebo-controlled, dose-ranging regulatory trials, it seems unlikely that these novel agents will have a major impact on outcomes for people with epilepsy.

A prospective audit of adjunctive zonisamide in an everyday clinical setting.

This audit examined outcomes for 203 patients prescribed zonisamide (ZNS) for various uncontrolled seizure types at a specialist outpatient service. Forty-two (20.7%) patients achieved 6 months of seizure freedom, and an additional 37 (18.2%) had a 50% seizure reduction for 6 months on a stable ZNS dose. Seizure freedom was more likely in patients with primary generalized (24/61, 39%) than in those with partial-onset (18/141, 12.7%) seizures (P<0.001). Eight patients (5 seizure free) were maintained on ZNS monotherapy. More patients became seizure free with ZNS as monotherapy or first add-on, compared with those in whom ZNS was the second, third, or fourth adjunctive drug (P=0.001). Seizure freedom was less likely in patients treated with hepatic enzyme-inducing agents (13/113, 11.5%) than in those receiving noninducing AEDs (24/82, 29.3%) (P=0.002). ZNS was discontinued in 72 (35.5%) patients largely because of side effects (n=58, 28.6%). Commonest complaints leading to withdrawal were sedation (n=14), nausea and vomiting (n=13), neuropsychiatric symptoms (n=12), rash (n=6), and weight loss (n=6). Around 80% of patients who became seizure free on ZNS or had the drug withdrawn did so on a dose 200mg. ZNS is an effective broad-spectrum AED that can also produce a range of dose-dependent and idiosyncratic side effects.

Selection of antiepileptic drugs in adults.

Epilepsy affects approximately 50 million people worldwide, with an annual incidence of 50 to 70 cases per 100,000 population. The condition can strike at any time of life, with an immediate impact on everyday activities and routine. Key to optimal management is swift referral to an epilepsy specialist, appropriate investigation, and timely institution of antiepileptic drug therapy. In the past 20 years, the explosion of 13 new agents into the marketplace has greatly increased the potential for therapeutic intervention. This article explores the rationale for treatment selection in adults with epilepsy.

Binasal visual field defects are not specific to vigabatrin.

This study investigated the visual defects associated with the antiepileptic drug vigabatrin (VGB). Two hundred four people with epilepsy were grouped on the basis of antiepileptic drug therapy (current, previous, or no exposure to VGB). Groups were matched with respect to age, gender, and seizure frequency. All patients underwent objective assessment of electrophysiological function (wide-field multifocal electroretinography) and conventional visual field testing (static perimetry). Bilateral visual field constriction was observed in 59% of patients currently taking VGB, 43% of patients who previously took VGB, and 24% of patients with no exposure to VGB. Assessment of retinal function revealed abnormal responses in 48% of current VGB users and 22% of prior VGB users, but in none of the patients without previous exposure to VGB. Bilateral visual field abnormalities are common in the treated epilepsy population, irrespective of drug history. Assessment by conventional static perimetry may neither be sufficiently sensitive nor specific to reliably identify retinal toxicity associated with VGB.

Management of a first seizure. Special problems: adults and elderly.

A first seizure out of a clear blue sky can be a major life-changing event. Careful history-taking and appropriate investigation together with a clear explanation provided to patient and family are an essential requirement. Although for most patients, pharmacotherapy can be withheld and events awaited, there are circumstances where introduction of antiepileptic drug (AED) therapy should be considered. Medical causes of seizures should also be sought and treated. In addition, a first seizure in HIV-positive patients and in those with underlying neurocysticercosis should usually provoke the introduction of AED therapy. Particular problems can occur in patients with a single episode of provoked status epilepticus, a first tonic-clonic seizure during pregnancy and, particularly, an unprovoked event in older and learning disabled people. Treatment following a first seizure should balance risk factors for recurrence with the informed opinion of the patients and their family.