Late-onset temporal lobe epilepsy with unilateral mesial temporal sclerosis and cognitive decline: a diagnostic dilemma.

We present a patient with new onset temporal lobe epilepsy and cognitive decline in his sixth decade with unilateral hippocampal atrophy on structural brain imaging, compatible with mesial temporal sclerosis. This unusual clinical scenario presented a challenging differential diagnosis since it may overlap with primary cognitive disorders, including early-onset Alzheimer's disease and some forms of frontotemporal dementia, and the recently elucidated syndrome of non-paraneoplastic limbic encephalitis associated with voltage-gated potassium channel antibodies.

A randomised controlled trial examining the longer-term outcomes of standard versus new antiepileptic drugs. The SANAD trial.

OBJECTIVES: To compare clinicians' choice of one of the standard epilepsy drug treatments (carbamazepine or valproate) versus appropriate comparator new drugs. DESIGN: A clinical trial comprising two arms, one comparing new drugs in carbamazepine and the other with valproate. SETTING: A multicentre study recruiting patients with epilepsy from hospital outpatient clinics. PARTICIPANTS: Patients with an adequately documented history of two or more clinically definite unprovoked epileptic seizures within the last year for whom treatment with a single antiepileptic drug represented the best therapeutic option. INTERVENTIONS: Arm A was carbamazepine (CBZ) versus gabapentin (GBP) versus lamotrigine (LTG) versus oxcarbazepine (OXC) versus topiramate (TPM). Arm B valproate (VPS) versus LTG versus TPM. MAIN OUTCOME MEASURES: Time to treatment failure (withdrawal of the randomised drug for reasons of unacceptable adverse events or inadequate seizure control or a combination of the two) and time to achieve a 12-month remission of seizures. Time from randomisation to first seizure, 24-month remission of seizures, incidence of clinically important adverse events, quality of life (QoL) outcomes and health economic outcomes were also considered. RESULTS: Arm A recruited 1721 patients (88% with symptomatic or cryptogenic partial epilepsy and 10% with unclassified epilepsy). Arm B recruited 716 patients (63% with idiopathic generalised epilepsy and 25% with unclassified epilepsy). In Arm A LTG had the lowest incidence of treatment failure and was statistically superior to all drugs for this outcome with the exception of OXC. Some 12% and 8% fewer patients experienced treatment failure on LTG than CBZ, the standard drug, at 1 and 2 years after randomisation, respectively. The superiority of LTG over CBZ was due to its better tolerability but there is satisfactory evidence indicating that LTG is not clinically inferior to CBZ for measures of its efficacy. No consistent differences in QoL outcomes were found between treatment groups. Health economic analysis supported LTG being preferred to CBZ for both cost per seizure avoided and cost per quality-adjusted life-year gained. In Arm B for time to treatment failure, VPS, the standard drug, was preferred to both TPM and LTG, as it was the drug least likely to be associated with treatment failure for inadequate seizure control and was the preferred drug for time to achieving a 12-month remission. QoL assessments did not show any between-treatment differences. The health economic assessment supported the conclusion that VPS should remain the drug of first choice for idiopathic generalised or unclassified epilepsy, although there is a suggestion that TPM is a cost-effective alternative to VPS. CONCLUSIONS: The evidence suggests that LTG may be a clinical and cost-effective alternative to the existing standard drug treatment, CBZ, for patients diagnosed as having partial seizures. For patients with idiopathic generalised epilepsy or difficult to classify epilepsy, VPS remains the clinically most effective drug, although TPM may be a cost-effective alternative for some patients. Three new antiepileptic drugs have recently been licensed in the UK for the treatment of epilepsy (levetiracetam, zonisamide and pregabalin), therefore these drugs should be compared in a similarly designed trial.

Efficacy of carbamazepine and valproate as monotherapy for early epilepsy and single seizures.

In the Multi-Centre Study of Early Epilepsy and Single Seizures (MESS), patients were randomly allocated to immediate or delayed antiepileptic drug treatment. For time to first seizure recurrence, MESS provides strong evidence of an effect for carbamazepine as monotherapy but mixed evidence of an effect for valproate.

A meta-analysis of individual patient responses to lamotrigine or carbamazepine monotherapy.

OBJECTIVE: To compare the effects of carbamazepine and lamotrigine monotherapy for people with partial onset seizures or generalized onset tonic-clonic seizures. METHODS: A systematic review and meta-analysis using data on individual patients from randomized trials comparing lamotrigine with carbamazepine monotherapy. The review draws on the search strategy developed for the Cochrane Epilepsy Group, which searches MEDLINE and the Cochrane Controlled Trials register, and hand searches relevant journals. The outcomes considered were time to antiepileptic drug withdrawal, which would usually be for either inadequate seizure control or unacceptable adverse effects, time to first seizure, and 6-month remission. RESULTS: Five randomized trials were identified containing data for 1,384 participants. Time to treatment withdrawal significantly improved with lamotrigine compared to carbamazepine (hazard ratio 0.55, 95% CI 0.35 to 0.84, random effects), while time to first seizure (hazard ratio 1.14, 95% CI 0.92 to 1.43, fixed effects) and seizure freedom at 6 months (relative risk 0.92, 95% CI 0.81 to 1.04, fixed effects) favor carbamazepine although the results are not significant. CONCLUSIONS: Lamotrigine is significantly less likely to be withdrawn than carbamazepine, but results for time to first seizure suggest a nonsignificant trend that carbamazepine may be superior in terms of seizure control. Trials were of too short a duration to measure clinically important efficacy outcomes such as time to 12-month remission. Current industry-sponsored trials fail to adequately inform clinical practice and further more clinically relevant trials are needed in which longer-term outcomes are assessed before the place of lamotrigine in the treatment of epilepsy is defined.

An association between type 1 diabetes and idiopathic generalized epilepsy.

OBJECTIVE: Idiopathic generalized epilepsies (IGEs) account for approximately 30% of all patients with epilepsy. Both the IGEs and type 1 diabetes mellitus (T1D) represent serious worldwide problems, because of related medical and social management costs. Clinical experience suggested the two conditions were seen in individuals more frequently than might be expected by chance. METHODS: We compared the population prevalence of T1D in 15- to 30-year-olds to a cohort of 518 15- to 30-year-olds with IGE. RESULTS: We found a highly significant excess of T1D in our IGE cohort, with an odds ratio of 4.4 (95% confidence interval, 2.1-9.2). INTERPRETATION: Our results suggest that the prevalence of T1D is increased by a factor of four in young adults with IGE. To our knowledge, this is the first published association between the two conditions and expands the diseases known to be associated with T1D.

Zonisamide add-on for drug-resistant partial epilepsy.

BACKGROUND: The majority of people with epilepsy have a good prognosis and their seizures can be well controlled with the use of a single antiepileptic agent, but up to 30% develop refractory epilepsy, especially those with partial seizures. In this review we summarize the current evidence regarding zonisamide, when used as an add-on treatment for drug-resistant partial epilepsy. OBJECTIVES: To evaluate the effects of zonisamide when used as an add-on treatment for people with drug-resistant partial epilepsy. SEARCH STRATEGY: We searched the Cochrane Epilepsy Group Specialized Register (August 2005), the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 3, 2005). In addition, we contacted Eisai Limited (makers and licensees of zonisamide) and experts in the field to seek any ongoing/unpublished studies. SELECTION CRITERIA: Randomized placebo controlled add-on trials of zonisamide in people with drug-resistant partial epilepsy. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion and extracted data. Outcomes were: (1) 50% or greater reduction in total seizure frequency; (2) treatment withdrawal; (3) adverse events. Primary analyses were intention-to-treat. Summary relative risks (RRs) were estimated for each outcome. MAIN RESULTS: Four trials (850 participants) were included. The overall RR with 95% confidence intervals (CIs) for 50% reduction in seizure frequency compared to placebo for 300 to 500 mg/day of zonisamide was 2.44 (95% CI 1.81 to 3.30). The RR for any dose zonisamide (100 to 500 mg per day) was 2.35 (1.74 to 3.17). Two trials provide evidence of a dose response relationship for this outcome. The RR for treatment withdrawal for 300 to 500 mg/day zonisamide compared to placebo was 1.64 (1.20 to 2.26), and for 100 to 500 mg per day was 1.47 (1.07 to 2.02). The CIs of the following adverse effects indicate that they are significantly associated with zonisamide: ataxia 4.50 (99% CI 1.05 to 19.22); dizziness 1.77 (99% CI 1.00 to 3.12); somnolence 1.96 (99% CI 1.12 to 3.44); agitation 2.37 (99% CI 1.00 to 5.64); and anorexia 3.00 (99% CI 1.31 to 6.88). AUTHORS' CONCLUSIONS: Zonisamide has efficacy as an add-on treatment in people with drug-resistant partial epilepsy. Minimum effective and maximum tolerated doses cannot be identified. The trials reviewed were of 12 week duration and results cannot be used to confirm longer periods of effectiveness in seizure control. The results cannot be extrapolated to monotherapy or to people with other seizure types or epilepsy syndromes.

The longer term outcome of children born to mothers with epilepsy.

OBJECTIVES: To determine the prevalence of cognitive delay and possible associated dysmorphic features in children exposed to antiepileptic drugs (AEDs) in utero. DESIGN: Retrospective study of children born to mothers with epilepsy. SETTING: Regional epilepsy clinics in Liverpool and Manchester, UK. PARTICIPANTS: Children aged between 6 months and 16 years born to mothers with epilepsy. MAIN OUTCOME MEASURES: Structured interviews, hospital records, clinical examination, and psychometric tests (Wechsler) were used to assess exposure and intelligence quotient (IQ). Blinded assessment of photographs was used to score children with characteristic dysmorphic features. RESULTS: A total of 249 children aged 6 and over were studied: 41 were exposed to sodium valproate, 52 to carbamazepine, 21 to phenytoin, 49 to polytherapy, and 80 were unexposed. Mean verbal IQ was significantly lower in the valproate group compared to unexposed and other monotherapy groups. Multiple regression analysis showed that both valproate exposure and frequent tonic-clonic seizures in pregnancy were significantly associated with a lower verbal IQ despite adjusting for other confounding factors. There was a significant negative correlation between dysmorphic features and verbal IQ in children exposed to valproate. CONCLUSIONS: This study identifies valproate as a drug carrying potential risks for developmental delay and cognitive impairment and is the first to suggest that frequent tonic-clonic seizures have a similar effect. Our results need to be interpreted with caution given their retrospective nature. Women with epilepsy need careful counselling about individual risk benefit of AED treatment before pregnancy.

A comparison of adult onset and "classical" idiopathic generalised epilepsy.

OBJECTIVES: To report the characteristics of a population of patients with idiopathic generalised epilepsy (IGE) with age of onset over 20 years, and compare them with patients with "classical" IGE. METHODS: Data were collected from a computerised database of all patients with IGE attending a regional adult epilepsy clinic. Demographic data, epilepsy characteristics, and treatment outcomes were recorded. RESULTS: 72 patients with IGE of a total population of 844 had an age of onset over 20 years (8.5%). There was similar incidence of family history of epilepsy, EEG findings, and remission rates between those with a younger and older age of onset of IGE. There was a lower incidence of previous febrile convulsions in patients with adult onset. There were fewer patients with absence seizures in the adult onset group (15.3% v 46.4% in the "classical" group). CONCLUSIONS: IGE with onset later than the third decade was rare in the population studied. Prolonged EEG in selected patients may be helpful in diagnosing adult onset IGE, but the diagnosis of epilepsy remains clinical. Adult onset IGE shares many features with "classical" IGE, including EEG findings and prognosis, and is likely to represent a genetic epilepsy.

The relationship between treatment with valproate, lamotrigine, and topiramate and the prognosis of the idiopathic generalised epilepsies.

OBJECTIVE: To examine a large population with idiopathic generalised epilepsy (IGE), and estimate the overall remission rates for the IGEs and subsyndromes in a clinic based sample. Remission rates on valproate, lamotrigine, topiramate, and combinations of these antiepileptic drugs were estimated and factors predicting outcome examined. METHODS: All patients with IGE were identified from a computerised database and EEG records at large adult and paediatric epilepsy clinics. Data were recorded retrospectively on demographics and clinical information, seizure types and syndrome diagnosis, antiepileptic drug treatment details, and remission rates. RESULTS: 54.3% of 962 patients had achieved a one year period of remission; this was most likely with valproate monotherapy (52.1%), with lower rates for lamotrigine and topiramate (16.7% and 34.6%, respectively). The combination of valproate and lamotrigine achieved a remission rate of 15.3%. The factor most predictive of a response to a particular antiepileptic drug regimen was the rank order in which it was given. Relapse rate was high (79.9%) after antiepileptic drug withdrawal in remission, particularly with juvenile myoclonic epilepsy (93.6%). CONCLUSIONS: Valproate may be the most effective antiepileptic drug in the treatment of the IGEs. Combination therapy should be initiated if an adequate trial of valproate monotherapy is not effective, rather than switching to alternative monotherapy. Antiepileptic drug treatment needs to be lifelong in many adult patients with IGE.

Security issues in the electronic transmission of prescriptions.

The UK government has stated within its plan of reform for the National Health Service that a secure system for the Electronic Transfer of Prescriptions will be available by 2004. The objectives of this paper are to highlight the significant barriers faced in securing an ETP system, to provide a critical analysis of the security mechanisms in the models currently being piloted and to suggest an alternative revised model which overcomes the identified deficiencies and security hurdles. To identify the significant security issues relevant to the adoption of ETP, the authors have combined their analysis of present prescription processing practice with their knowledge of computer security. The authors identify and describe how the issues of patient confidentiality, authorization, identity authentication, audit, scalability, availability and reliability are significant barriers to the adoption of ETP, particularly if they effect ease of use. The paper's contribution to the field of ETP is to suggest solutions to each of the identified security issues and to combine the solutions together in a revised and developed model.

Topiramate, carbamazepine and valproate monotherapy: double-blind comparison in newly diagnosed epilepsy.

OBJECTIVES: To compare topiramate (TPM) with investigator's choice of carbamazepine (CBZ) or valproate (VPA) for initial treatment in patients with newly diagnosed epilepsy. MATERIAL AND METHODS: In patients with epilepsy diagnosed within previous 3 months, investigators selected CBZ (600 mg/day) or VPA (1250 mg/day) as preferred therapy based on the patient's clinical presentation. Based on investigators' treatment choice, patients (n=613) were assigned to the CBZ or VPA treatment branch. Within each branch, patients were randomized to double-blind treatment with the traditional antiepileptic drugs (CBZ or VPA), TPM 100 mg/day, or TPM 200 mg/day. Patients continued double-blind treatment until exiting the study or until 6 months after last patient randomized. RESULTS: No statistically significant differences between fixed doses of TPM and CBZ or VPA were observed in efficacy measures: time to exit, time to first seizure, and the proportion of patients seizure-free during the last 6 months of treatment. TPM 100 mg/day was associated with the fewest discontinuations due to adverse events. CONCLUSION: In patients with newly diagnosed epilepsy, an initial target dose of TPM 100 mg/day is at least as effective as therapeutic doses of CBZ and VPA.

Hypersensitivity reactions to carbamazepine: characterization of the specificity, phenotype, and cytokine profile of drug-specific T cell clones.

Administration of carbamazepine (CBZ) causes hypersensitivity reactions clinically characterized by skin involvement, eosinophilia, and systemic symptoms. These reactions have an immune etiology; however, the role of T cells is not well defined. The aim of this study was to characterize the specificity, phenotype, and cytokine profile of CBZ-specific T cells derived from hypersensitive individuals. Proliferation of blood lymphocytes was measured using the lymphocyte transformation test. CBZ-specific T cell clones were generated by serial dilution and characterized in terms of their cluster of differentiation and T cell receptor V beta phenotype. Proliferation, cytotoxicity, and cytokine secretion were measured by [(3)H]thymidine incorporation, (51)Cr release, and enzyme-linked immunosorbent assay, respectively. HLA blocking antibodies were used to study the involvement of antigen-presenting cells. The specificity of the drug T cell receptor interaction was studied using CBZ metabolites and other structurally related compounds. Lymphocytes from hypersensitive patients (stimulation index: 32.1 +/- 24.2 [10 microg ml(-1)]) but not control patients (stimulation index: 1.2 +/- 0.4 [10 microg ml(-1)]) proliferated upon stimulation with CBZ. Of 44 CBZ-specific T cell clones generated, 10 were selected for further analysis. All 10 clones were either CD4+ or CD4+/CD8+, expressed the alpha beta T cell receptor, secreted IFN-gamma, and were cytotoxic. T-cell recognition of CBZ was dependent on the presence of HLA class II (DR/DQ)-matched antigen-presenting cells. The T cell receptor of certain clones could accommodate some CBZ metabolites, but no cross-reactivity was seen with other anticonvulsants or structural analogs. These studies characterize drug-specific T cells in CBZ-hypersensitive patients that are phenotypically different from T cells involved in other serious cutaneous adverse drug reactions.

Foramen ovale recordings: a presurgical investigation in epilepsy.

The aim of our study was to determine when foramen ovale recordings add useful information to scalp EEG recordings and magnetic resonance imaging (MRI) with hippocampal measurements. We evaluated the outcome of 79 patients with non-lesional partial epilepsy with presumed temporal seizure onset. Ictal foramen ovale recordings were performed in 16 patients with normal MRI ('MRI-negative group') and 41 patients with lateralizing MRI but non-lateralizing scalp EEG ('discordant group'). 22 patients with concordant MRI and scalp EEG were not investigated with foramen ovale recordings ('concordant group'). The seizure-free rate was higher in concordant than discordant patients despite additional investigation with foramen ovale electrodes (71 and 55% seizure free, respectively). No useful localizing information was added with foramen ovale recordings in MRI-negative patients.

The legacy of vigabatrin in a regional epilepsy clinic.

OBJECTIVES: To review all patients who had received vigabatrin at the Walton Centre to determine the incidence of visual field defect, seizure outcome if vigabatrin had been stopped, and adherence to guidelines on the use of vigabatrin in clinical practice. METHODS: Retrospective review of 583 patients prescribed vigabatrin at any time between 1989 and 2001 from a regional and satellite epilepsy clinic. Data were collected on dose and duration of treatment, results of quantitative perimetry, and reasons for, and outcome of, discontinuation. RESULTS: The visual fields were abnormal with no alternative cause in 42 of the 98 tested (43%). There was no clear relation between the cumulative dose of vigabatrin received and the occurrence of a visual field abnormality. Fifty patients continued taking vigabatrin, and a further 84 were lost to follow up while taking vigabatrin. In 75 patients who had stopped vigabatrin due to a visual field abnormality or concern over this potential adverse effect, the seizure control was no different or had improved in 66 (88%), while it had deteriorated in only 7 (9%). CONCLUSIONS: This study confirms the previously reported high incidence of asymptomatic visual field defects associated with vigabatrin. Many patients taking vigabatrin may not have been counselled about the risks, and there are significant cost implications in tracing and assessing those patients lost to follow up. Switching over to another antiepileptic drug usually does not result in deterioration in seizure control, but in clinical practice an individual risk to benefit ratio needs to be taken into consideration.

Zonisamide add-on for drug-resistant partial epilepsy.

BACKGROUND: The majority of people with epilepsy have a good prognosis and their seizures can be well controlled with the use of a single antiepileptic agent, but up to 30 per cent develop refractory epilepsy, especially those with partial seizures. In this review we summarize the current evidence regarding zonisamide, when used as an add-on treatment for drug-resistant partial epilepsy. OBJECTIVES: To evaluate the effects of zonisamide when used as an add-on treatment for people with drug -resistant partial epilepsy. SEARCH STRATEGY: We searched the Cochrane Epilepsy Group trial register (14/12/01), the Cochrane Controlled Trials Register (Cochrane Library Issue 4, 2001). In addition, we contacted Dainippon and Elan Pharma (makers and licensees of zonisamide) and experts in the field to seek any ongoing studies or unpublished studies. SELECTION CRITERIA: Randomized placebo controlled add-on trials of zonisamide in people with drug-resistant partial epilepsy. DATA COLLECTION AND ANALYSIS: Two reviewers independently selected trials for inclusion and extracted relevant data. Outcomes were: (a) fifty per cent or greater reduction in total seizure frequency; (b) treatment withdrawal (any reason); (c) adverse events. Primary analyses were intention to treat. Summary odds ratios (ORs) were estimated for each outcome. MAIN RESULTS: Three trials (499 participants) were included. The overall odds ratio (OR, 95% Confidence Interval (CI)) for 50 per cent reduction in seizure frequency compared to placebo was 2.07(1.36 to 3.15) for a 400mg/day dose of zonisamide. When the full treatment period of 12 weeks was considered for all three trials including varied rates of titration to 400mg/day the OR compared to placebo was 2.72(95% CI 1.74 to 4.25). There was insufficient evidence to support a dose response relationship for this outcome. The OR for treatment withdrawal was 1.74(95% CI 1.03 to 2.95). The 99% CI for the following side effects indicate that they are significantly associated with zonisamide: ataxia 3.94(1.23 to 12.57); somnolence 2.11(1.11 to 3.98); agitation 3.52(1.26 to 9.68); agitation and irritability 2.43(1.04 to 5.66) and anorexia 2.98(1.38 to 6.42). REVIEWER'S CONCLUSIONS: Zonisamide has efficacy as an add-on treatment in people with drug-resistant partial epilepsy. Minimum effective and maximum tolerated doses cannot be identified. The trials reviewed were of 12 week duration and results cannot be used to confirm longer periods of effectiveness in seizure control. The results cannot be extrapolated to monotherapy or to people with other seizure types or epilepsy syndromes.

Remacemide hydrochloride as an add-on therapy in epilepsy: a randomized, placebo-controlled trial of three dose levels (300, 600 and 1200 mg/day) in a Q.I.D. regimen.

Remacemide hydrochloride is a low-affinity, non-competitive N-methyl-D-aspartic acid (NMDA) receptor channel blocker, under investigation in epilepsy. This double-blind, placebo-controlled, multicentre study assessed the safety and efficacy of remacemide hydrochloride or placebo, as adjunctive therapy, in 252 adult patients with refractory epilepsy who were already taking up to three antiepileptic drugs (including an enzyme-inducer). Patients were randomized to one of three doses of remacemide hydrochloride (300, 600 or 1200 mg /day) or placebo Q.I.D., for up to 15 weeks. An increasing percentage of responders (defined as a reduction in seizure frequency from baseline of > or =50%) was seen with increasing remacemide hydrochloride dose. At 1200 mg /day, 23% of patients were responders compared with 7% on placebo. This difference was significant (P = 0.016), as was the overall difference between treatments (P = 0.038). Adverse events: dizziness, abnormal gait, gastrointestinal disturbance, somnolence, diplopia and fatigue were mild or moderate in severity. Carbamazepine and phenytoin plasma concentrations were well controlled and maintained within target ranges, with no evidence of improved seizure control due to increases in the concentrations of these drugs. A dose-dependent, significant, increase in responders following adjunctive remacemide hydrochloride compared with placebo was observed. Remacemide hydrochloride was well tolerated.

Levetiracetam, oxcarbazepine, remacemide and zonisamide for drug resistant localization-related epilepsy: a systematic review.

OBJECTIVE: To undertake a systematic review and meta-analysis of placebo controlled add-on trials of levetiracetam, oxcarbazepine, remacemide and zonisamide for patients with drug resistant localization related epilepsy. METHODS: We searched Medline, The Cochrane Library and contacted the relevant pharmaceutical companies. Outcomes were 50% or greater reduction in seizure frequency and treatment withdrawal for any reason. Data were synthesised in a meta-analysis. The effect of dose was explored in regression models for levetiracetam and remacemide. RESULTS: We found four trials (1023 patients) of levetiracetam, two (961) of oxcarbazepine, two (388) of remacemide and three (499) of zonisamide. Ignoring dose, the relative risks (95% CI) for a 50% response were 3.78 (2.62-5.44), 2.51 (1.88-3.33), 1.59 (0.91-2.97) and 2.46 (1.61-3.79), respectively. There was evidence for increasing effect with increasing dose for levetiracetam, oxcarbazepine and remacemide. The relative risks for treatment withdrawal were 1.21 (0.88-1.66), 1.72 (1.35-2.18), 1.90 (1.00-3.60) and 1.64 (1.02-2.62), respectively. CONCLUSIONS: These data suggest a useful effect for levetiracetam, oxcarbazepine and zonisamide. Levetiracetam has the more favourable 'responder-withdrawal ratio' followed by zonisamide and oxcarbazepine.