First European long-term experience with the orphan drug rufinamide in childhood-onset refractory epilepsy

ObjectiveRecently, we published the first postmarketing European experience with rufinamide (RUF) in a retrospective 12-week observational study. This follow-up report summarizes the long-term effectiveness and tolerability of RUF after 18 months for the same patient sample.MethodsIn total, 52 of 60 initially included patients from eight centers in Germany and Austria (45 children and 15 adults aged 1–50 years) with various severe and inadequately controlled epilepsy syndromes continued treatment with RUF after the initial 3-month observation period (mean final dose: 38.2 ± 17.3 mg/kg/day). Efficacy was assessed by seizure frequency evaluated by comparison with baseline frequency. Tolerability was evaluated by analysis of parental report of adverse events and laboratory tests. Responders were defined as patients who achieved a 50% or greater decrease in countable seizures within 18 months of initiating RUF therapy.ResultsMean overall duration of RUF treatment was 14.5 months (range: 3–18 months). Retention rate, defined as the percentage of patients still taking RUF after 18 months, was 41.7% (n = 25/60). The overall response rate after 18 months was 26.7% (16/60 patients). The highest response rates were found in the subgroup of patients with Lennox–Gastaut syndrome (LGS, 35.5%) and in patients with other generalized epilepsy syndromes. Complete seizure control was maintained in one patient (1.6%). A total of 73 adverse events were reported in 37 of 60 patients. The most frequently occurring adverse events were fatigue (18.3%), vomiting (15.0%), and loss of appetite (10.0%). Only 4 new adverse events were reported after week 12. No serious adverse events were observed.ConclusionsThe present data suggest that RUF is efficacious and well tolerated in the long-term treatment of children and adults with various epilepsy syndromes and difficult-to-control seizures.     

Ketogenic diet in adolescents and adults with epilepsy

PurposeThe ketogenic diet is an alternative treatment for patients with refractory epilepsy. Most studies to date report dietary response in children. There are limited data evaluating the efficacy of the ketogenic diet in adults. This is a report of the long-term outcome in a largely adult population of patients treated with the ketogenic diet for epilepsy.MethodTwenty-nine adult and adolescent patients (mean age 32 years, range 11–51) were initiated on the ketogenic diet and followed until diet discontinuation. Clinical response and adverse effects were noted during the duration of the diet.ResultsFifty-two percent of patients had a significant reduction in seizure frequency on the ketogenic diet, including 45% with ≥50% reduction in seizure frequency. Thirty-one percent had no improvement, seven percent were unable to successfully initiate the diet, and 10% had a >50% increase in seizure frequency. The diet was continued for a mean of 9 months (range 0.13–35 months), with five patients completing ≥23 months. There was a trend toward better response and better tolerability/longer duration in patients with symptomatic generalized epilepsy. The diet was generally well-tolerated, but undesired weight loss and constipation were the most frequent adverse effects.ConclusionThe ketogenic diet can be used safely in the adult and adolescent population, with a response rate similar to those seen in children. Patient with symptomatic generalized epilepsy may be particularly good candidates for this type of dietary treatment.     

Rufinamide in refractory childhood epileptic encephalopathies other than Lennox–Gastaut syndrome

Background: To report on the first multicenter Italian experience with rufinamide as adjunctive drug in children, adolescents and young adults with refractory childhood‐onset epileptic encephalopathies other than Lennox–Gastaut syndrome. Methods: Thirty‐eight patients (19 males, 19 females), aged between 4 and 34 (mean 13.7 ± 8.3, median 12.5), all affected by different types of childhood‐onset refractory epileptic encephalopathies other than Lennox–Gastaut syndrome, were treated with rufinamide as adjunctive drug for a mean period of 11.4 months (range 3–26 months). Results: Fifteen of 38 patients (39.5%) had a ≥50% seizure reduction in countable seizures. Complete seizure freedom was achieved in one of these patients (2.6%). Three patients (7.9%) had a 25–49% seizure reduction, whilst seizure frequency remained unchanged in 15 (39.5%) and increased in five patients (13.1%). Eleven patients (28.9%) reported adverse side effects. Vomiting was reported in five patients (13.1%); drowsiness, decreased appetite and irritability with migraine manifested in other four patients. They were transient and mild in all cases. Conclusion: Rufinamide may be an effective and well‐tolerated adjunctive drug for the treatment of refractory childhood‐onset epileptic encephalopathies other than Lennox–Gastaut syndrome. Rufinamide was most effective in patients with drop‐attacks and (bi)frontal spike–wave discharges.     

Effect of Rikkunshi‐to on appetite loss found in elderly dementia patients: a preliminary study

Background: Functional gastrointestinal symptoms are frequently found in elderly dementia patients. In such a case, we attempt treatment by the administration of antidepressants or second‐generation antipsychotics. However, these medications have a risk of side‐effects. In the present study, we carried out oral administration of Rikkunshi‐to to elderly dementia patients with appetite loss, and examined its effects on food intake. Methods: Six elderly dementia patients were recruited from inpatients. They showed appetite loss, but no organic abnormalities of the gastrointestinal organs. These patients were given Rikkunshi‐to, at 7.5 g per day, t.i.d. for 4 weeks. We examined the food intake, weight, total protein, albumin and potassium in plasma before administration and for 4 weeks after administration. In statistical analyses, the percentage of food consumed for 4 weeks was analyzed by anova . We also examined the side‐effects of Rikkunshi‐to. Results: In patient 3, we stopped investigation after 3 weeks because of the development of cholecystitis. The values of 4 weeks in patient 3 were calculated as the mean values of 4 weeks in the other five patients. anova and Tukey's multiple comparison showed a marginally significant difference in weight between before Rikkunshi‐to was given and 4 weeks after. In change of food intake, there were no significant differences between before Rikkunshi‐to was given and 1 day after, 1 day and 2 days after, 2 days and 3 days after, 3 days and 1 week after, and 1 week and 2 weeks after; however, there were significant increases in food intake between other times. With regard to the side‐effects, mild lower limb oedema appeared in the two patients. Conclusion: In the present study, we showed the effect of Rikkunshi‐to in improving appetite loss in elderly dementia patients. The present study suggests that Rikkunshi‐to might be useful in improving functional appetite loss in elderly dementia patients, because there are no serious side‐effects.     

Adjunctive pregabalin for uncontrolled partial-onset seizures: findings from a prospective audit

Stephen LJ, Parker P, Kelly K, Wilson EA, Leach V, Brodie MJ. Adjunctive pregabalin for uncontrolled partial‐onset seizures: findings from a prospective audit.
Acta Neurol Scand: 2011: 124: 142–145.
© 2011 John Wiley & Sons A/S. Aims – Pregabalin (PGB) was licensed in Europe as an add‐on antiepileptic drug (AED) for the treatment of partial‐onset seizures in 2004. This audit assessed the response to adjunctive PGB in patients with uncontrolled seizures. Methods – PGB was titrated in 135 patients [73 men; 62 women, aged 18–76 (median 44 years) until one of the following occurred: ≥6 months’ seizure freedom, ≥50% or <50% seizure reduction over 6 months; PGB withdrawal because of adverse effects, lack of efficacy or both. Results – Of the 135 patients, 14 (10.4%) became seizure‐free for ≥6 months (median PGB dose 300 mg/day; range 75–600 mg). A ≥ 50% seizure reduction occurred in 33 (24.4%) patients; 20 (14.8%) had <50% reduction. PGB was withdrawn in 68 (50.4%) (40 adverse effects, seven lack of efficacy and 21 both). Commonest problems resulting in withdrawal were sedation (n = 18), weight gain (n = 14) and ataxia (n = 9). There was a positive correlation between increasing dose and weight gain (r = 0.42, P = 0.045). Conclusions – Add‐on PGB benefited 50% of patients, but only 10% achieved 6 months’ seizure freedom. Adverse effects, most commonly sedation, dose‐related weight gain and ataxia, led to drug discontinuation by 45%. Prospective audits of novel AEDs are a useful adjunct to randomized, controlled trials in managing epilepsy.     

A multicentre comparative trial of sodium valproate and carbamazepine in adult onset epilepsy. Adult EPITEG Collaborative Group.

The long-term efficacy and safety of sodium valproate and carbamazepine in adult outpatients with newly diagnosed primary generalised or partial and secondarily generalised seizures were compared in a randomised, open, multicentre study at 22 neurology outpatient clinics. Patients were randomised to oral sodium valproate (Epilim EC enteric coated 200 mg tablets twice daily, n = 149) or oral carbamazepine (100 mg twice daily increasing to 200 mg twice daily in week 2, n = 151) and followed up for three years. If clinically necessary, dosages were regularly increased until seizures were controlled or toxicity developed. Sodium valproate and carbamazepine controlled both primary generalised and partial seizures equally effectively overall. Significantly more patients on sodium valproate than carbamazepine (126/140 (90%) v 105/141 (75%), p = 0.001) remained on randomised treatment for at least six months. Skin rashes occurred significantly more often in carbamazepine recipients than in sodium valproate recipients (11.2% v 1.7%, p < 0.05) and carbamazepine was associated with a higher withdrawal rate because of adverse events (15% v 5% on sodium valproate) in the first six months of treatment. There was no difference between the drugs in the rate of withdrawal because of poor seizure control at any stage, regardless of seizure type. At the end of the three year trial period, over 70% of the available patients were still on randomised treatment or had recently stopped treatment after achieving full seizure control. Sodium valproate and carbamazepine were both associated with a high degree of overall seizure control regardless of seizure type and both have good long-term tolerability in adult patients with newly diagnosed epilepsy. Recommendations are made for a higher initial dosage regime for sodium valproate in partial seizures.     

Adult‐onset photosensitivity: clinical significance and epilepsy syndromes including idiopathic (possibly genetic) photosensitive occipital epilepsy

To evaluate the clinical associations of adult‐onset photosensitivity, we studied the clinical and EEG data of patients who were referred due to a possible first seizure and who had a photoparoxysmal response on their EEG. Patients with clinical evidence of photosensitivity before the age of 20 were excluded. Of a total of 30 patients, four had acute symptomatic seizures, two had vasovagal syncope, and 24 were diagnosed with epilepsy. Nine of the 24 patients had idiopathic (genetic) generalized epilepsies and predominantly generalized photoparoxysmal response, but also rare photically‐induced seizures, while 15 had exclusively, or almost exclusively, reflex photically‐induced occipital seizures with frequent secondary generalization and posterior photoparoxysmal response. Other important differences included a significantly older age at seizure onset and paucity of spontaneous interictal epileptic discharges in patients with photically‐induced occipital seizures; only a quarter of these had occasional occipital spikes, in contrast to the idiopathic (genetic) generalized epilepsy patients with typically generalized epileptic discharges. On the other hand, both groups shared a positive family history of epilepsy, common seizure threshold modulators (such as tiredness and sleep deprivation), normal neurological examination and MRI, a generally benign course, and good response to valproic acid. We demonstrated that photosensitivity can first occur in adult life and manifest, either as idiopathic (possibly genetic) photosensitive occipital epilepsy with secondary generalization or as an EEG, and less often, a clinical/EEG feature of idiopathic (genetic) generalized epilepsies. Identification of idiopathic photosensitive occipital epilepsy fills a diagnostic gap in adult first‐seizure epileptology and is clinically important because of its good response to antiepileptic drug treatment and fair prognosis.     

Pharmacokinetic-pharmacodynamic assessment of topiramate dosing regimens for children with epilepsy 2 to <10 years of age

Purpose: To identify and validate the efficacious monotherapy dosing regimen for topiramate in children aged 2 to <10 years with newly diagnosed epilepsy using pharmacokinetic–pharmacodynamic (PK–PD) modeling and simulation bridging. Methods: Several models were developed in pediatric and adult populations to relate steady‐state trough plasma concentrations (C_min ) of topiramate to the magnitude of clinical effect in monotherapy and adjunctive settings. These models were integrated to derive and support the monotherapy dosing regimen for pediatric patients. Key Findings: A two‐compartmental population PK model with first‐order absorption described the time course of topiramate C_min as a function of dosing regimen. Disposition of topiramate was related to age, body weight, and use of various concomitant antiepileptic drugs. The PK–PD model for monotherapy indicated that the hazard of time to first seizure decreased with increasing C_min and time since randomization. Higher baseline seizure frequency increased risk for seizures. Age did not significantly influence hazard of time to first seizure after randomization to monotherapy. For adjunctive therapy, the distribution of drug and placebo responses was not significantly different among age groups. Based on the available PK–PD modeling data, the dosing regimen expected to achieve a 65–75% seizure freedom rate after 1 year for pediatric patients age 2–10 years is approximately 6–9 mg/kg per day. Significance: This analysis indicated no difference in PK–PD of topiramate between adult and pediatric patients. Effects of indication and body weight on PK were adequately integrated into the model, and monotherapy dosing regimens were identified for children 2–10 years of age.     

E-mail management of the modified Atkins Diet for adults with epilepsy is feasible and effective

Purpose: The modified Atkins Diet (MAD) is an effective dietary treatment for children with epilepsy. However, adults may have limited access to this therapy because of lack of availability of dietitian or nutrition support or familiarity with the diet by their treating neurologist. This study was designed to investigate the tolerability and efficacy of the MAD administered solely via e‐mail to adults with pharmacoresistant epilepsy. Methods: A prospective, open‐label, proof‐of‐principle 3‐month study design was employed. Adults were enrolled, instructed on how to self‐administer a 20 g carbohydrate per day MAD, and followed by the investigators only via e‐mail. There were no clinic visits or dietitian contacts during the study period. Key Findings: Twenty‐five participants (median age 30 years [range 18–66 years], 68% female) consented and 22 started the MAD. The median prior anticonvulsants was 5 (range 2–10) and seizure frequency was 5 per week (range 1–140). Urinary ketosis was achieved in 21 participants (95%), of which 16 (76%) reported at least 40 mg/dl (moderate). Twenty‐one participants (95%) remained on the MAD at 1 month and 14 (64%) at 3 months. After 1 month, 9 (41%) had >50% seizure reduction including one (5%) with >90% seizure reduction using intent‐to‐treat analysis. After 3 months, 6 (27%) had >50% seizure reduction including 3 (14%) with >90% seizure reduction. The mean ketogenic ratio was 1.1:1 (fat:carbohydrates and protein) for those who provided a MAD food record at follow‐up. Over the study period, the median number of e‐mails sent by the participants was 6 (range 1–19). The most frequent side effect was weight loss. Significance: E‐mail administration of the MAD to adults with refractory epilepsy appears to be feasible and effective. Therefore, when dietitian or physician support is limited for adult patients with epilepsy, remote access via telemedicine could provide an alternative.     

Felbamate for refractory absence seizures

We treated 10 patients (aged 5–37 years) with medically refractory absence seizures with felbamate (FBM). Average duration of absence seizures was 16.2 years. All patients continued to have absence seizures at maximally tolerated doses of valproic acid and/or ethosuximide. At maximal FBM dosage (45 mg/kg/day or 3,600 mg/day), there was at least a 65% reduction in absence seizure frequency in eight patients; in four, there was a > 95% reduction. Mean duration of FBM therapy is 16.2 months (range, 5–31 months). Nine patients remain on FBM. Two patients are on FBM monotherapy; seven others are on FBM and one or two other antiepileptic drugs. FBM was discontinued in one patient who developed severe insomnia followed by a return to baseline absence seizure frequency after an initial good response, and an increase in generalized tonic-clonic seizures (GTCS). Three other patients also had a history of GTCS; in one there has been no significant change, whereas two have not had a GTCS during FBM therapy. Eight patients continue to have a clinically meaningful reduced absence seizure frequency, and eight patients reported fewer adverse effects with their current regimen including FBM. Tachyphylaxis to the antiabsence efficacy was observed in four cases. These preliminary findings suggest that FBM is useful in treating absence seizures.     

Rufinamide in children and adults with Lennox–Gastaut syndrome: First Italian multicenter experience

This is the first multicenter Italian experience with rufinamide as an adjunctive drug in children, adolescents and adults with Lennox–Gastaut syndrome.The patients were enrolled in a prospective, add-on, open-label treatment study from 11 Italian centers for children and adolescent epilepsy care. Forty-three patients (26 males, 17 females), aged between 4 and 34 years (mean 15.9 ± 7.3, median 15.0), were treated with rufinamide for a mean period of 12.3 months (range 3–21 months). Twenty patients were diagnosed as cryptogenic and 23 as symptomatic. Rufinamide was added to the baseline therapy at the starting dose of 10 mg/kg body weight, evenly divided in two daily doses and then increased by 10 mg/kg approximately every 3 days up to a maximum of 1000 mg/day in children aged ≥4 years with a body weight less than 30 kg. In patients more than 30 kg body weight, rufinamide could be titrated up to 3200 mg/day.After a mean follow-up period of 12.3 months (range 3–21 months), the final mean dose of rufinamide was 33.5 mg/kg/24 h (range 11.5–60) if combined to valproic acid, and of 54.5 mg/kg/24 h (range 21.8–85.6) without valproic acid. The response rate (≥50% decrease in countable seizures) was 60.5% (26 of 45 patients) in total; 51.1% experienced a 50–99% reduction in seizure frequency and complete seizure control was achieved in the last 4 weeks follow-up by 9.3% of patients. Two patients (4.7%) had a 25–50% seizure reduction, while seizure frequency remained unchanged in 13 (30.2%) and increased in 2 (4.7%). Reliable data for atypical absence seizures and myoclonic seizures were not available, as these are usually impossible to count.Ten patients (23.2%) reported adverse side effects, while taking rufinamide. They were generally mild and transient and most frequently included vomiting, drowsiness, irritalibility and loss of appetite.In conclusion, rufinamide as an adjunctive therapy reduced the number of drop attacks and major motor seizures in about 60% of patients with Lennox–Gastaut syndrome and produced only mild or moderate adverse side effects.     

Body mass index in adults with intellectual disability: distribution, associations and service implications: a population-based prevalence study

Background Previous studies of weight problems in adults with intellectual disability (ID) have generally been small or selective and given conflicting results. The objectives of our large‐scale study were to identify inequalities in weight problems between adults with ID and the general adult population, and to investigate factors associated with obesity and underweight within the ID population. Methods We undertook a population‐based prevalence study of 1119 adults with ID aged 20 and over on the Leicestershire Learning Disability Register who participated in a programme of universal health checks and home interviews with their carers. We performed a cross‐sectional analysis of the register data and compared the observed and expected prevalences of body mass index categories in the ID and general populations using indirect standardisation for age. We used logistic regression to evaluate the association of a range of probable demographic, physical, mental and skills attributes with obesity and underweight. Results In those aged 25 and over, the standardised morbidity ratio (SMR) for obesity was 0.80 (95% CI 0.64–1.00) in men and 1.48 (95% CI 1.23–1.77) in women. The SMR for underweight was 8.44 (95% CI 6.52–10.82) in men and 2.35 (95% CI 1.72–3.19) in women. Among those aged 20 and over, crude prevalences were 20.7% for obesity, 28.0% for overweight, 32.7% for normal weight and 18.6% for underweight. Obesity was associated with living independently/with family, ability to feed/drink unaided, being female, hypertension, Down syndrome and the absence of cerebral palsy. Underweight was associated with younger age, absence of Down syndrome and not taking medication. Conclusion Obesity in women and underweight in both men and women was more common in adults with ID than in the general population after controlling for differences in the age distributions between the two populations. The associated factors suggest opportunities for targeting high‐risk groups within the ID population for lifestyle and behaviour modification.     

Topiramate in children with west syndrome: a retrospective multicenter evaluation of 100 patients

The aim of this study is to investigate the efficacy and tolerability of topiramate in a large number of children with West syndrome. The authors performed a retrospective, questionnaire-based data collection in specialized epilepsy units in Germany. Patients with West syndrome and hypsarrhythmia could be included if topiramate treatment had started at an age of < or =3 years. Data of 100 patients were evaluated. Nearly all patients were severely affected and had been treated with multiple antiepileptic drugs with insufficient effect. Topiramate was introduced at a median age of 11.9 months. The median starting dosage was 1.6 mg/kg body weight per day, increased to a median maximum dosage of 12.0 mg/kg. Sixty-one patients received between 1 and 3 antiepileptic drugs in addition to topiramate. The median daily dose considered by the attending physicians to be most effective regarding seizure reduction was 10 mg/kg. A significant reduction in the number of seizures per week was achieved. A total of 17.5% of patients became free of seizures, and in 47%, the seizure frequency decreased by at least 50%. Hypsarrhythmia or status-like electroencephalography patterns remitted in 18 of 83 cases. Side effects were reported in 25% of children and included mostly sedation, loss of appetite, weight loss, and metabolic acidosis. These side effects were statistically related to the number of additional antiepileptic drugs but not to the topiramate dosage. In 17% of patients, topiramate treatment was discontinued because of side effects and in a further 4% because of worsening of seizures. In 44% of patients, treatment was continued for more than 3 months. In conclusion, the data suggest that topiramate is a useful drug in treating West syndrome. However, because of the inherent limitations of the retrospective study design, future prospective controlled studies should be performed.     

Levetiracetam as add-on therapy in generalised epilepsies.

Levetiracetam is highly effective as add-on treatment in refractory partial-onset seizures but there are only limited data supporting its benefit in generalised epilepsies. We have reviewed the clinical records of 25 consecutive adult patients with generalised epilepsies (84% females; mean age 34 (range 16-75) years) prescribed levetiracetam for at least six months. The epilepsy was considered idiopathic in 22 patients (88%)--including 13 with juvenile myoclonic epilepsy--and symptomatic in three. Most patients (68%) reported some improvement in seizure frequency on levetiracetam including 16% who became seizure free. Levetiracetam was generally well tolerated although 11/25 (44%) of patients reported some tiredness, weight change or rash. Levetiracetam was stopped in five patients, four because of side effects and one though lack of efficacy. In four cases, pre-existing antiepileptic medication was withdrawn, leaving levetiracetam as monotherapy. We conclude that levetiracetam is a useful add-on treatment for patients with refractory generalised epilepsies.     

Clobazam‐treated patients with Lennox‐Gastaut syndrome experienced fewer seizure‐related injuries than placebo patients during trial OV‐1012

Drop seizures are especially problematic in patients with Lennox‐Gastaut syndrome (LGS) because of their potential for serious injury. In this post hoc analysis of phase 3 OV‐1012 data, a medical review was conducted of seizure‐related injuries based on Medical Dictionary for Regulatory Activities (MedDRA) preferred terms from all adverse event (AE) listings. Patients receiving clobazam experienced fewer seizure‐related injuries than those receiving placebo (8.9% all clobazam dosages vs. 27.1% placebo, p ≤ 0.05). Significant differences in the rates of seizure‐related injuries were observed for the medium‐ and high‐dosage clobazam treatment groups (4.8% and 10.2%, respectively, p ≤ 0.05). A total of 50 of 53 AEs considered seizure‐related were mild or moderate in intensity; 3 severe AEs occurred in the placebo group (fall, contusion, and jaw fracture). A single serious AE (jaw fracture, which required hospitalization and surgery) occurred in a placebo‐treated patient. Most injuries resolved by the end of the study. This analysis indicates that the reduction in drop‐seizure frequency achieved with clobazam provides a clinically meaningful benefit, a reduced likelihood of experiencing seizure‐related injuries.     

Adverse effects of carbamazepine,phenytoin, valproate and lamotrigine monotherapy in epileptic adult Chinese patients

Objective

Antiepileptic drugs (AEDs) have been widely used in patients with epilepsy but the adverse effects in adult Chinese patients have not been investigated. This study evaluated the adverse effects of four commonly prescribed AED monotherapies with carbamazepine (CBZ), phenytoin (PHT), valproate (VPA), and lamotrigine (LTG) in adult Chinese patients with epilepsy.

Methods

The prospective open-label clinical trial was conducted at the Chongqing Epilepsy Center. The study enrolled 505 adults with newly diagnosed epilepsy, including generalized tonic–clonic (n = 110), partial and partial secondarily generalized (n = 395) seizures. Patients were evaluated by two clinicians at the Center and were prescribed one type of AED monotherapy with CBZ, PHT, VPA or LTG for a 24-month period. An adverse effect profile, as well as efficacy of monotherapy, was obtained through a face-to-face interview with the patient at each visit. A physical examination and routine laboratory tests were performed during a clinical screening.

Results

A total of 62.6% (316/505) patients successfully completed the AED monotherapy study: 64.3% of those receiving CBZ, 55.9%—PHT, 61.5%—VPA, and 66.2%—LTG. However, 34.7% of the patients discontinued the AED monotherapy because of unsatisfactory seizure control. Overall, 18% of patients experienced adverse effects: for CBZ (25/168; 14.9%), PHT (18/59; 30.5%), VPA (32/192; 16.7%) and LTG (16/86; 18.6%). The most common drug-related adverse events included gastrointestinal disturbances, loss of appetite and nausea, weight gain and fatigue/tiredness. Tremor and nystagmus occurred in some patients receiving PHT and VPA. Two CBZ, one PHT and four LTG patients (n = 7) discontinued the study due to rash.

Conclusion

Adult Chinese patients with epilepsy accepted and tolerated monotherapy with CBZ, PHT, VPA, and LTG. No fatal adverse events occurred. Unsatisfactory seizure control was a primary reason for withdrawal from the AED monotherapy study.     

Long‐term add‐on pregabalin treatment in patients with partial‐onset epilepsy: Pooled analysis of open‐label clinical trials

Purpose: To evaluate the safety, tolerability, and efficacy of long‐term pregabalin as add‐on therapy for patients with poorly controlled partial seizures. Methods: Analysis of data from six long‐term clinical trials involving 2,061 patients receiving open‐label pregabalin 75–600 mg/day adjunctive therapy for partial onset epilepsy refractory to multiple antiepileptic drugs. Results: Total pregabalin exposure was 3,877 person‐years. The mean duration of pregabalin treatment was 534 days (range 0.3–8 years) and 59% completed 1 year. One‐third of patients discontinued for lack of efficacy. The most common dose was ≥300 mg/day; over half took ≥450 mg/day. There was a mean reduction in the 28‐day seizure rate of 25–40%, and more than 40% of all patients had a ≥50% reduction in seizures from baseline during the last 3 months of treatment. Twelve percent of all patients had a 6‐month period continuously free of seizures. In the last year, 6% were seizure‐free for the entire year. Pregabalin was generally well‐tolerated and the safety profile favorable in patients treated for up to several years, with an adverse event (AE) profile similar to short‐term placebo‐controlled trials. Common AEs included CNS symptoms (dizziness, somnolence, headache, and asthenia), accidental injury, and weight gain. CNS AEs tended to be mild and transient. Rates of sudden unexpected death in epilepsy (SUDEP), mortality, cancer, and status epilepticus were within the expected range for this population. Conclusions: Adjunctive pregabalin was effective, generally well tolerated, and safe in the long‐term treatment of partial seizures, and provided clinically meaningful seizure reduction and freedom without evidence of tolerance over 2 years of follow‐up.     

Antikonvulsive Behandlung erwachsener Epilepsiepatienten mit geistiger Behinderung

Management of epilepsies and seizures in learning disabled persons is challenging. Patients with intellectual disabilities (ID) are more likely to experience multiple seizure types and be more refractory to treatment than patients without ID. This justifies the use even of less proven compounds in severely disabled patients with pharmacoresistant epilepsies. Stiripentol (STP) is a new antiepileptic drug (AED) that has been shown to be effective in the treatment of severe myoclonic epilepsy in infancy (Dravet syndrome) but also in other epilepsies, especially those with focal seizures. STP inhibits cytochrome P450 isoenzymes, thus, augmenting concomitant antiepileptic drugs, but also has intrinsic anticonvulsive effects. Between October 2007 and February 2009, 23 adult patients (16 women, 7 men; aged 19 – 47 years) with ID (severe in most cases) and refractory epilepsy were treated with adjunctive STP for 1 to 18 months. Five patients had a marked improvement (>50% decrease in seizures) without displaying adverse effects. In seven patients, treatment with STP had to be ceased on the grounds of insufficient efficacy, in four because of side effects, and in another four for both reasons. The most frequently reported adverse events included neurological symptoms (drowsiness, gait disturbances) and digestive symptoms (nausea, loss of appetite) in equal shares. Three patients developed arterial hypotension under STP. Because of its strong pharmacological interaction with other drugs and its relatively high incidence of adverse events, STP will be prevented from becoming a very broadly applied AED. Nevertheless, STP can be considered when it comes to finding new treatment options for adult patients with pharmacoresistant epilepsies and severe ID.     

Increased adverse events associated with antiepileptic drugs in anti–leucine‐rich glioma‐inactivated protein 1 encephalitis

Anti–leucine‐rich glioma‐inactivated protein 1 (LGI1) encephalitis is a rare autoimmune condition presenting mainly as altered mental state, cognitive dysfunction, and seizure. Antiepileptic drugs (AEDs) are usually initiated to control seizures despite their limited efficacy; however, accumulating clinical experience suggests a high incidence of adverse reactions to AEDs in anti‐LGI1 encephalitis. We reviewed the medical records of patients who were diagnosed with anti‐LGI1 encephalitis to analyze the adverse effects of AEDs in these patients. Among the 20 patients who were treated with AEDs, 10 (50%) changed their AEDs due to adverse cutaneous drug reaction. Eight of them presented with maculopapular eruption, one with drug rash with eosinophilia and systemic symptoms syndrome, and one with eczema. Causative agents mostly consisted of aromatic AEDs. Oxcarbazepine was discontinued in two additional patients due to hyponatremia. Six patients (30%) discontinued their dose of levetiracetam because of psychiatric manifestations including irritability/aggressive behavior (four patients), insomnia (one patient), and depressive mood (one patient). Clinicians should consider adverse cutaneous drug reaction, psychiatric adverse events, and hyponatremia when selecting AEDs for the treatment of anti‐LGI1 encephalitis.     

SODIUM VALPROATE IN the TREATMENT of RESISTANT EPILEPSY

A series of 115 patients was treated with sodium valproate (Epilim) for periods ranging from 6 to 24 months and in dosages ranging from 400 mg to 2400 mg daily. All but six of these patients had intractable epilepsies and had been previously treated unsuccessfully with other anti-epileptic agents. Eighty patients had generalised seizures and 35 had partial seizures which, in 26 cases, were secondarily generalised. Reduction of seizure frequency by over 50 per cent occurred in about 70 per cent of patients with generalised seizures but in only 37 per cent of those with partial seizures. A number of patients reported increased alertness, improvement of mood, increased appetite and improved performance at school. the adverse effects encountered were gastro-intestinal symptoms, weight gain and hair loss.