Do neurologists agree in diagnosing drug resistance in adults with focal epilepsy?

OBJECTIVE: To evaluate interrater agreement in categorizing treatment outcomes and drug responsiveness status according to the International League Against Epilepsy (ILAE) definition of drug-resistant epilepsy. METHODS: A total of 1053 adults with focal epilepsy considered by the investigators to meet ILAE criteria for drug resistance were enrolled consecutively at 43 centers and followed up prospectively for 18-34 months. Treatment outcomes for all antiepileptic drugs (AEDs) used up to enrollment (retrospective assessment), and on an AED newly introduced at enrollment, were categorized by individual investigators and by 2 rotating members of a 16-member expert panel (EP) that reviewed the patient records independently. Interrater agreement was tested by Cohen's kappa (k) statistics and rated according to Landis and Koch's criteria. RESULTS: Agreement between EP members in categorizing outcomes on the newly introduced AED was almost perfect (90.1%, k = 0.84, 95% confidence interval [CI] 0.80-0.87), whereas agreement between the EP and individual investigators was moderate (70.4%, k = 0.57, 95% CI 0.53-0.61). Similarly, categorization of outcomes on previously used AEDs was almost perfect between EP members (91.7%, k = 0.83, 95% CI 0.81-0.84) and moderate between the EP and investigators (68.2%, k = 0.50, 95% CI 0.48-0.52). Disagreement was related predominantly to outcomes considered to be treatment failures by the investigators but categorized as undetermined by the EP. Overall, 19% of patients classified as having drug-resistant epilepsy by the investigators were considered by the EP to have "undefined responsiveness." SIGNIFICANCE: Interrater agreement in categorizing treatment outcomes according to ILAE criteria ranges from moderate to almost perfect. Nearly 1 in 5 patients considered by enrolling neurologists to be "drug-resistant" were classified by the EP as having "undefined responsiveness.

Association of intronic variants of the KCNAB1 gene with lateral temporal epilepsy.

The KCNAB1 gene is a candidate susceptibility factor for lateral temporal epilepsy (LTE) because of its functional interaction with LGI1, the gene responsible for the autosomal dominant form of LTE. We investigated association between polymorphic variants across the KCNAB1 gene and LTE. The allele and genotype frequencies of 14 KCNAB1 intronic SNPs were determined in 142 Italian LTE patients and 104 healthy controls and statistically evaluated. Single SNP analysis revealed one SNP (rs992353) located near the 3'end of KCNAB1 slightly associated with LTE after multiple testing correction (odds ratio=2.25; 95% confidence interval 1.26-4.04; P=0.0058). Haplotype analysis revealed two haplotypes with frequencies higher in cases than in controls, and these differences were statistically significant after permutation tests (Psim=0.047 and 0.034). One of these haplotypes was shown to confer a high risk for the syndrome (odds ratio=12.24; 95% confidence interval 1.32-113.05) by logistic regression analysis. These results support KCNAB1 as a susceptibility gene for LTE, in agreement with previous studies showing that this gene may alter susceptibility to focal epilepsy

Unilateral catalepsy in non-convulsive status epilepticus

Catalepsy is defined as a loss of motor and it is listed among the clinical features associated with catatonic syndrome and may occur in association with both psychiatric and neurological disorders. Isolated catalepsy represents a much rarer phenomenon, and has been occasionally reported due to focal brain injuries (e.g. strokes) involving either cortical or subcortical regions. Here, we describe the case of an 81-year-old man presenting with isolated unilateral catalepsy as the main manifestation of focal non-convulsive status epilepticus, ipsilateral to the cataleptic limbs. To our knowledge, this is the first report of ictal catalepsy, which highlights the need to consider epilepsy in the diagnostic algorithm for both hyper- and hypokinetic movement disorders

Open label, long-term, pragmatic study on levetiracetam in the treatment of juvenile myoclonic epilepsy.

PURPOSE: Patients with juvenile myoclonic epilepsy (JME) may be resistant or show adverse effects to valproate. We present a multicenter, prospective, long-term, open-label study evaluating the efficacy and safety of levetiracetam in JME. METHODS: Patients with newly diagnosed (10) or resistant/intolerant to previous AEDs JME (38) were enrolled. After a 8 week baseline period, levetiracetam was titrated in 2 weeks to 500 mg b.i.d. and then increased up to 3000 mg/day according to the patient's response. Efficacy parameters were: number of seizure-free patients, number of days with myoclonus (DWM), and monthly frequency of generalised tonic-clonic (GTC) seizures. Adverse events were recorded. RESULTS: The overall mean dose of levetiracetam was 2208 mg/day. The mean study period was 19 (range 0.3-38) months. Five patients dropped out. 11/38 (28.9%) patients with add-on treatment and 5/10 (50%) newly diagnosed patients were seizure-free for a mean period of 17.2 (+/-8.8) months. Eighteen patients (37.5%) were without myoclonia, and 35 (72.9%) had no GTC seizures over the study period. The mean monthly frequency of DWM and of GTC seizures in the entire group was significantly reduced after levetiracetam. Five patients complained of side effects. CONCLUSIONS: This open-label study suggests levetiracetam may be effective and well tolerated in resistant cases of JME or may become a reasonable alternative to valproate in newly diagnosed patients

Flexible dosing of adjunctive zonisamide in the treatment of adult partial-onset seizures: a non-comparative, open-label study (ZEUS).

OBJECTIVES: To assess the efficacy and tolerability of zonisamide in a study allowing flexible dosing in a more diverse and less refractory population than assessed in randomized controlled trials. METHODS: This 19-week, non-comparative study of adjunctive zonisamide included 281 adults who had at least four partial-onset seizures within 8 weeks on one or two antiepileptic drugs. Alterations to zonisamide doses were allowed after titration, except during two fixed-dose periods (weeks 10-13 and 16-19). RESULTS: At the end of the second fixed-dose period (median dose 300 mg/day), the median reduction in monthly seizure frequency was 33.3-41.1%; > or =50% responder rate was 40.9-44.2%; and seizure freedom rate was 15.0-15.9%, depending on the analysis used. The most common adverse events were fatigue (16.7%) and somnolence (15.3%). CONCLUSIONS: Zonisamide demonstrated efficacy in a setting more reflective of clinical practice and was generally well tolerated

The Photoparoxysmal Response Reflects Abnormal Early Visuomotor Integration In The Human Motor Cortex

Background: Visual-paired associative stimulation (V-PAS) is a transcranial magnetic stimulation (TMS) technique able to investigate long-term potentiation (LTP) and depression (LTD)-like plasticity in the primary motor cortex (M1) arising through early visuomotor integration. Objective/hypothesis: Abnormal early visuomotor integration might contribute to the pathophysiology of intermittent photic stimulation (IPS)-induced photoparoxysmal response (PPR). Methods: We applied V-PAS in 25 healthy subjects (HS), 25 PPR-positive patients, with and without idiopathic generalized epilepsy (IGE), and 8 PPR-negative patients with IGE. V-PAS consisted of primary visual area activation achieved by visual evoked potentials coupled with TMS-induced M1 activation at 100 ms interstimulus interval (ISI) (V-PAS100). Before and after V-PAS, we measured changes in motor evoked potentials (MEPs). We compared MEPs after 1 Hz repetitive TMS (rTMS) and 0.25 Hz-V-PAS100. To examine possible V-PAS-induced after-effects at other ISIs, we delivered V-PAS at 40 (V-PAS40) and 140 ms ISIs (V-PAS140). To clarify whether V-PAS100 increases parieto-/premotor-to-M1 connectivity, before and after V-PAS100, we examined MEPs evoked by paired-pulse techniques. Results: V-PAS100 increased MEPs more in PPR-positive patients than in HS. PPR-negative patients had normal response to V-PAS100. 1 Hz-rTMS, 0.25 Hz-V-PAS100 and V-PAS40 elicited similar responses in HS and PPR-positive patients, whereas V-PAS140 induced stronger after-effects in PPR-positive patients than HS. After V-PAS, MEPs elicited by facilitatory paired-pulse protocols decreased similarly in HS and PPR-positive patients. Conversely, MEPs elicited by inhibitory protocols decreased in HS, whereas in PPR-positive patients, they turned from inhibition to facilitation. Conclusion: We suggest that abnormal early visuomotor integration contributes to the pathophysiology of PPR