Changes in hormone and lipid levels in male patients with focal seizures when switched from carbamazepine to lacosamide as adjunctive treatment to levetiracetam: A small phase IIIb, prospective, multicenter, open-label trial.

Treatment with enzyme-inducing antiepileptic drugs (AEDs) such as carbamazepine (CBZ) can lead to changes in reproductive, endocrine, and lipid parameters, resulting in clinical symptoms for some patients. Previous studies indicate that these changes can be reversed by switching to a nonenzyme-inducing AED. Lacosamide is a newer-generation AED, not known to induce or strongly inhibit cytochrome P450 (CYP450) enzymes. In this phase IIIb, prospective, multicenter, open-label, single-arm trial (NCT01375374), the serum concentrations of CYP-related reproductive hormones, thyroid hormones, and lipids were assessed in otherwise healthy male patients with focal seizures (N=11), before and after a switch from CBZ (600-1200mg/day at baseline) to lacosamide (target dose: 400mg/day by the end of titration) as adjunctive treatment to the nonenzyme-inducing AED levetiracetam (LEV, stable dosage of >1000mg/day throughout). Cross titration took place over 4weeks, followed by an 8-week maintenance period. Serum measurements were conducted at baseline and at the end of maintenance. The median serum sex-hormone-binding globulin (SHBG) concentration was towards the higher end of the normal range at baseline and decreased following the switch (61.7 to 47.5nmol/L, N=10, p=0.027 by Wilcoxon signed-rank test). Free androgen index (100×testosterone/SHBG) and free thyroxine serum concentration increased (25.4 to 36.4 and 13.0 to 14.9pmol/L, respectively, both N=10 and p=0.002). At baseline, the median progesterone serum concentration was below the normal range (0.7nmol/L), whereas median cholesterol and low-density lipoprotein concentrations were above the normal range (5.5 and 3.6mmol/L, respectively). By the end of maintenance, all measured parameters were within the normal range. The safety and tolerability profile of lacosamide was consistent with that observed in previous studies. Furthermore, antiseizure efficacy appeared to be maintained, suggesting that deinduction of CYP enzymes following a switch from CBZ to lacosamide as adjunctive therapy to LEV is feasible within 8weeks and is associated with normalization of serum parameters.

A systematic review of the epidemiology of pediatric autoimmune encephalitis: disease burden and clinical decision-making.

Background: Autoimmune encephalitis (AIE) comprises a group of rare, immune system-mediated conditions. Clinical manifestations among children are not well-characterized, and there are challenges in testing and diagnosis. This can result in treatment delays, which has been found to correlate with poorer long-term outcomes. This challenge is exacerbated by the scarcity of epidemiological reporting of AIE. The objective of this systematic literature review (SLR) was to identify studies reporting epidemiological data on AIE in children. Methods: MEDLINE, Embase, the Cochrane Library, and the University of York Centre for Reviews and Dissemination (CRD) were searched in May 2023 for studies reporting on the epidemiology of AIE in children. These were supplemented with additional searches of conference proceedings, gray literature, and the reference lists of identified SLRs. Quality of studies was assessed using a modified version of the Joanna Briggs Institute (JBI) Checklist for Prevalence Studies. Results: Forty-three publications reporting on 41 unique studies were included. Nine studies reported incidence estimates of different subtypes of AIE, with only one reporting the incidence of overall AIE in children ≤ 18 years, estimated at 1.54 per million children per year in the Netherlands. Three studies reported the incidence of pediatric N-methyl-D-aspartate receptor (NMDAR)-AIE [in United Kingdom (UK), Hong Kong, and Denmark]. The other studies reported incidence data for selected populations. Conclusion: This SLR highlights a paucity of epidemiology data for AIE in children, which is likely reflective of difficulties in testing and diagnosis. There is a clear need for further research and awareness of these challenges in clinical practice to avoid treatment delays and improve patient outcomes. A deeper understanding of the epidemiology of AIE will help determine the worldwide burden of disease and inform research, health policies and clinical decision-making.

Memantine effects measured with the Relevant Outcome Scale for Alzheimer's disease in an open-label, single-arm, multicenter clinical study.

OBJECTIVE: The Relevant Outcome Scale for Alzheimer's disease (ROSA) is a novel, valid, and reliable instrument for multidimensional assessment of Alzheimer's disease (AD) symptoms across all severity stages. The ROSA and four standard instruments -- the Alzheimer's disease Assessment Scale-cognitive (ADAS-cog), Severe Impairment Battery (SIB), Disability Assessment for Dementia (DAD), and the Neuropsychiatric Inventory (NPI) -- were used in an open-label, multicenter, single-arm clinical study to assess treatment-induced changes in cognitive, functional, and behavioral symptoms in patients with AD at different severity stages. METHODS: A total of 451 patients were treated with memantine (initiated at 5 mg/day and up-titrated with 5 mg weekly to a final dose of 20 mg/day) for 12 weeks. The study endpoints comprised changes from baseline in the scores of the ROSA, ADAS-cog, SIB, DAD, and NPI as well as global changes on the Clinical Global Impression of Change (CGI-C). Analyses were performed for the overall population and by AD severity stage (early, middle, late). RESULTS: The ROSA scores increased significantly after a 12-week treatment in all study groups except for early stage. Mean changes in the ADAS-cog score indicated a trend towards worsening in early and middle stages. Non-significant changes were shown by the SIB, NPI, and DAD assessments at week 12. The CGI-C demonstrated 'minimal improvement' or 'no change' for most of the patients. Overall, memantine treatment was safe and well tolerated. CONCLUSION: The results demonstrated the ROSA feasibility in daily practice for assessment of memantine effects over time in patients with moderate and late AD.

Attack phenotypes and disease course in pediatric MOGAD.

Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is an autoimmune demyelinating condition that affects children differently than adults. We performed a literature review to assess the presentation and clinical course of pediatric MOGAD. The most common initial phenotype is acute disseminated encephalomyelitis, especially among children younger than five years, followed by optic neuritis (ON) and/or transverse myelitis. Approximately one-quarter of children with MOGAD have at least one relapse that typically occurs within three years of disease onset and often includes ON, even if ON was not present at onset. Clinical risk factors for a relapsing course have not been elucidated.

Detecting treatment effects with combinations of the ADAS-cog items in patients with mild and moderate Alzheimer's disease.

OBJECTIVE: When complex cognitive functions are measured with multi-item scales like the Alzheimer's Disease Assessment Scale - cognitive subscale (ADAS-cog), it seems valuable information can be lost due to combination of the ADAS-cog items results into a total score. We hypothesized, that an analysis of the results of different ADAS-cog item combinations may reveal drug treatment effects in distinct cognitive domains and/or enhance the sensitivity to detect such treatment effects. Here, we present a novel approach called 'subsetting analysis' for assessment of drug treatment effects with multi-item scales, like the ADAS-cog. METHODS: The subsetting approach is a mathematical algorithm designed to select and group scale items in a subset detecting drug treatment effects in a particular study population. The approach was applied in a post-hoc analysis of ADAS-cog results from two randomized, placebo-controlled and double-blind clinical trials with memantine in mild to moderate Alzheimer's disease (AD). The subsetting analysis of the ADAS-cog combined database aimed at selecting the scale items showing no worsening at study end compared to baseline due to memantine treatment in mild AD (Mini-Mental State Examination (MMSE >19)) patients. RESULTS: Two ADAS-cog subsets were finally revealed by the analysis: a subset of five ADAS-cog items, identified as most sensitive to memantine effects in mild AD patients, and a subset of six ADAS-cog items shown to detect significant memantine effects in moderate AD patients. CONCLUSION: The subsetting approach of analyzing ADAS-cog data is a powerful alternative for gaining information about drug effects on cognitive performance in mild and moderate AD patients.

Treatment options for subjective tinnitus: self reports from a sample of general practitioners and ENT physicians within Europe and the USA.

BACKGROUND: Tinnitus affects about 10-15% of the general population and risks for developing tinnitus are rising through increased exposure to leisure noise through listening to personal music players at high volume. The disorder has a considerable heterogeneity and so no single mechanism is likely to explain the presence of tinnitus in all those affected. As such there is no standardized management pathway nor singly effective treatment for the condition. Choice of clinical intervention is a multi-factorial decision based on many factors, including assessment of patient needs and the healthcare context. The present research surveyed clinicians working in six Westernized countries with the aims: a) to establish the range of referral pathways, b) to evaluate the typical treatment options for categories of subjective tinnitus defined as acute or chronic, and c) to seek clinical opinion about levels of satisfaction with current standards of practice. METHODS: A structured online questionnaire was conducted with 712 physicians who reported seeing at least one tinnitus patients in the previous three months. They were 370 general practitioners (GPs) and 365 ear-nose-throat specialists (ENTs) from the US, Germany, UK, France, Italy and Spain. RESULTS: Our international comparison of health systems for tinnitus revealed that although the characteristics of tinnitus appeared broadly similar across countries, the patient's experience of clinical services differed widely. GPs and ENTs were always involved in referral and management to some degree, but multi-disciplinary teams engaged either neurology (Germany, Italy and Spain) or audiology (UK and US) professionals. For acute subjective tinnitus, pharmacological prescriptions were common, while audiological and psychological approaches were more typical for chronic subjective tinnitus; with several specific treatment options being highly country specific. All therapy options were associated with low levels of satisfaction. CONCLUSIONS: Despite a large variety of treatment options, the low success rates of tinnitus therapy lead to frustration of physicians and patients alike. For subjective tinnitus in particular, effective therapeutic options with guidelines about key diagnostic criteria are urgently needed.

Safety and efficacy of adjunctive lacosamide in Chinese and Japanese adults with epilepsy and focal seizures: A long-term, open-label extension of a randomized, controlled trial.

This Phase III, long-term, open-label extension (OLE) trial (EP0009; NCT01832038) was conducted to evaluate the long-term safety, tolerability, and efficacy of adjunctive lacosamide (100-400 mg/day) in Chinese and Japanese people with epilepsy (PWE) (16-70 years) who had completed a double-blind, randomized, placebo-controlled trial of adjunctive lacosamide (EP0008; NCT01710657). PWE entered the OLE trial on 200 mg/day lacosamide and up to 3 concomitant antiseizure medications. Dose adjustments were permitted to optimize tolerability and seizure reduction. Safety variables were treatment-emergent adverse events (TEAEs) and discontinuations due to TEAEs. Efficacy variables were percent change in focal seizure frequency per 28 days from Baseline of the double-blind trial, ≥50 % and ≥75 % responder rates, seizure-freedom, and proportion of PWE on lacosamide monotherapy. Overall, 473 PWE (74.0 % Chinese and 26.0 % Japanese) were enrolled; 238 (50.3 %) PWE completed the trial and 235 (49.7 %) discontinued, most commonly due to lack of efficacy (81 [17.1 %]), adverse events (55 [11.6 %]), and consent withdrawn (49 [10.4 %]). During the trial, PWE received lacosamide for a median of 1016.0 days (∼3 years), with a total exposure of 1454.8 person-years; 321 (67.9 %) PWE received lacosamide for >24 months, and 246 (52.0 %) for >36 months. The median modal dose of lacosamide was 300 mg/day. Overall, 410/473 (86.7 %) PWE reported TEAEs, 244 (51.6 %) had a TEAE that was considered drug-related, and 49 (10.4 %) discontinued due to a TEAE. The most common TEAEs (≥20 % of PWE) were nasopharyngitis, dizziness, and upper respiratory tract infection. The median reduction in focal seizure frequency per 28 days from Baseline was 57.1 %, and the ≥50 % and ≥75 % responder rates were 57.1 % (269/471) and 29.7 % (140/471), respectively. Among PWE who completed 12, 24, and 36 months of treatment, the 12-, 24-, and 36-month seizure-freedom rates were 3.5 % (13/375), 3.4 % (11/321), and 2.0 % (5/247), respectively. Among PWE exposed to lacosamide for ≥6 months and ≥12 months, the proportions of PWE that maintained continuous monotherapy for ≥6 months and ≥12 months were 5.0 % (21/421) and 5.0 % (19/378), respectively. Overall, lacosamide was well-tolerated as long-term adjunctive therapy in Chinese and Japanese PWE and uncontrolled focal seizures, with improvements in seizure reduction maintained over 36 months of treatment.

Subtype-specific dendritic Ca(2+) dynamics of inhibitory interneurons in the rat visual cortex.

The Ca(2+) increase in dendrites that is evoked by the backpropagation of somatic action potentials (APs) is involved in the activity-dependent modulation of dendritic and synaptic functions that are location dependent. In the present study, we investigated dendritic Ca(2+) dynamics evoked by backpropagating APs (bAPs) in four subtypes of inhibitory interneurons classified by their spiking patterns: fast spiking (FS), late spiking (LS), burst spiking (BS), and regular-spiking nonpyramidal (RSNP) cells. Cluster analysis, single-cell RT-PCR, and immunohistochemistry confirmed the least-overlapping nature of the grouped cell populations. Somatic APs evoked dendritic Ca(2+) transients in all subtypes of inhibitory interneurons with different spatial profiles along the tree: constantly linear in FS and LS cells, increasing to a plateau in BS cells and bell-shaped in RSNP cells. The increases in bAP-evoked dendritic Ca(2+) transients brought about by the blocking of A-type K(+) channels were similar in whole dendritic trees of each subtype of inhibitory interneurons. However, in RSNP cells, the increases in the distal dendrites were larger than those in the proximal dendrites. On cholinergic activation, nicotinic inhibition of bAP-evoked dendritic Ca(2+) transients was observed only in BS cells expressing cholecystokinin and vasoactive intestinal peptide mRNAs, with no muscarinic modulation in all subtypes of inhibitory interneurons. Cell subtype-specific differential spatial profiles and their modulation in bAP-evoked dendritic Ca(2+) transients might be important for the domain-specific modulation of segregated inputs in inhibitory interneurons and differential control between the excitatory and inhibitory networks in the visual cortex.

Treatment effects of Memantine on language in moderate to severe Alzheimer's disease patients.

BACKGROUND: Language impairment is one of the most troublesome manifestations of Alzheimer's disease (AD). The objective of this post hoc analysis was to assess the treatment effects of Memantine on language in patients with moderate to severe AD, using the recently developed Severe Impairment Battery-Language (SIB-L) scale. METHODS: From a combined database including four Memantine clinical trials in moderate-to-severe AD, we analyzed 801 patients with SIB-L scores of <38 and Mini-Mental State Examination scores of <15. Patients were treated with either 20 mg Memantine per day or placebo. Mean changes in SIB-L scores from baseline were calculated. For responder analyses, a change in SIB-L score greater than or equal to the SIB-L measurement error of 3.7 points was considered a clinically relevant response. RESULTS: The mean change from baseline in SIB-L score at week 12 and weeks 24/28 (study end) significantly favored Memantine over placebo treatment (P < .0001 and P = .0182, respectively). Overall, more Memantine-treated patients than placebo-treated patients benefited from treatment. The effect was especially pronounced in patients with substantial language impairment on the SIB-L (baseline score,

Severe Impairment Battery Language scale: a language-assessment tool for Alzheimer's disease patients.

BACKGROUND: Communication problems are common in Alzheimer's disease (AD) patients, but instruments to assess these symptoms are limited. Our objective was to create a new scale, based on the language subscale of the Severe Impairment Battery (SIB), as a sensitive and reliable measurement of treatment effects on language performance. METHODS: All 24 items of the SIB language subscale were chosen for analysis. Baseline scores of 1320 moderate-to-severe patients (Mini-Mental State Examination [MMSE] score, <15), from a combined AD database of four Memantine clinical trials (Study Codes: IE-2101, MEM-MD-01, MEM-MD-02, and MRZ-9605), were used for item reduction according to a standard principal components factor analysis. All items with loadings >0.5 on the identified factors were selected for inclusion in the new language scale. Correlations with existing AD scales were examined. RESULTS: The analysis indicated six factors, with 21 of 24 items showing loadings >0.5. The resulting 21-item SIB Language (SIB-L) scale exhibited high internal consistency (Cronbach's alpha = 0.809). The maximal SIB-L score was 41 points, with a measurement error of 3.7 points. The stratification of baseline SIB-L scores (mean, 31.7; SD, 8.4) by MMSE scores (mean, 9.7; SD, 3.3) showed a high variance in SIB-L scores. This confirms that patients with a low MMSE score can possess preserved language abilities. The SIB-L scale did not exhibit substantial floor-and-ceiling effects. CONCLUSIONS: The new SIB-L is a fast (<15 minutes) and easily administered scale with favorable psychometric characteristics for assessing language impairment and treatment effects on the language performance of patients with moderate to severe AD.

Changes in drug load during lacosamide combination therapy: A noninterventional, observational study in German and Austrian clinical practice.

INTRODUCTION: Effects of antiepileptic drug (AED) load changes in patients with focal seizures have not been well evaluated. METHODS: SP1065 (NCT01673282) was a noninterventional, prospective, observational study conducted in a clinical practice setting. Patients (aged ≥18 years) with focal seizures were enrolled within 7 days of being prescribed adjunctive lacosamide. Observation period was ~6 months. Drug load was assessed using percentage change in ratio of actual prescribed dose and World Health Organization defined daily dose (DDD) for concomitant AEDs and all AEDs (including lacosamide). Subgroups were defined for patients with at least one concomitant sodium channel-blocking AED (SCB [+]) and those without (SCB [-]). RESULTS: A total of 311 patients were assessed for safety, 302 for measurement of drug load, and 240 for effectiveness. Ratio of AED dose to DDD decreased for concomitant AEDs (-9.6%) and increased for all AEDs (including lacosamide; 15.5%). Median reduction in focal seizure frequency per 28 days was 100% (range: -100, 2275.8). 70.4% and 61.7% of patients had a ≥50% or ≥75% reduction in seizure frequency, respectively; 50.8% became seizure-free. In the SCB (+) subgroup (n = 149), ratio of AED dose to DDD decreased for concomitant AEDs (-15.0%) and increased for all AEDs (10.7%). In the SCB (-) subgroup (n = 153), ratio of AED dose to DDD decreased for concomitant AEDs (-4.4%) and increased for all AEDs (20.2%). Fifty-seven patients (18.3%) reported ADRs, most commonly dose >400 mg/d (7.1%). Seventeen patients (5.5%) had ADRs leading to discontinuation. SIGNIFICANCE: Addition of lacosamide resulted in reduction of concomitant AED drug load regardless of whether concomitant AEDs were SCB (+) or SCB (-). These results indicate that addition of lacosamide in patients with focal seizures could allow clinicians to withdraw or reduce the dose of less well-tolerated or less effective AEDs.

Safety and tolerability of lacosamide monotherapy in the elderly: A subgroup analysis from lacosamide trials in diabetic neuropathic pain.

Objective: To assess the safety profile of lacosamide monotherapy in elderly (≥65 years) subjects with diabetic neuropathic pain (DNP). Methods: Of 1,863 DNP subjects in double-blind, randomized, placebo-controlled trials of lacosamide monotherapy (NCT00861445, NCT00235469, NCT00238524, NCT00135109, NCT00350103), 502 were elderly. Safety data from elderly subjects were compared with that of younger subjects (<65 years) within these DNP trials. It should be noted that lacosamide is approved for the treatment of focal (partial-onset) seizures; it is not approved/recommended for the treatment of DNP. Results: Overall, cardiovascular diseases were prevalent in the DNP population, as was the use of cardiac, blood pressure, diabetes, and cholesterol-lowering medications among both young and elderly subjects. The most frequently reported adverse events (AEs) for lacosamide monotherapy (200, 400, and 600 mg/day combined) in elderly versus younger subjects were dizziness (16.2% vs. 13.2%), nausea (10.0% vs. 9.4%), and headache (8.0% vs. 8.7%). Incidences of cardiac disorder AEs were higher in elderly versus younger subjects receiving placebo (6.2% vs. 3.9%), lacosamide 200 (4.8% vs. 3.3%), lacosamide 400 (7.0% vs. 4.1%), and lacosamide 600 mg/day (7.7% vs. 4.0%). Discontinuation rates because of any AE in the elderly versus younger subjects were similar for placebo (8.8% vs. 7.0%) and lacosamide 200 mg/day (9.6% vs. 11.9%) and higher for lacosamide 400 (25.1% vs. 10.8%) and lacosamide 600 mg/day (52.7% vs. 28.3%). Significance: Lacosamide monotherapy was well tolerated in elderly subjects with DNP, with an overall AE profile consistent with that reported in epilepsy trials.

Efficacy and safety of adjunctive lacosamide for the treatment of partial-onset seizures in Chinese and Japanese adults: A randomized, double-blind, placebo-controlled study.

OBJECTIVE: To evaluate the efficacy and safety of adjunctive lacosamide treatment in Chinese and Japanese adults with uncontrolled focal (partial-onset) seizures (POS), with or without secondary generalization. METHODS: A 24-week, randomized, double-blind, placebo-controlled study (EP0008; NCT01710657) was conducted in patients (aged 16-70 years) with uncontrolled POS and taking 1-3 concomitant antiepileptic drugs from 72 sites across China and Japan. Following an 8-week Baseline period, randomized patients received lacosamide 200mg/day (100mg twice daily), 400mg/day (200mg twice daily), or placebo for 4-week Titration and 12-week Maintenance periods. The primary efficacy variable was the change in POS frequency per 28days from Baseline to Maintenance. RESULTS: Overall, 692 patients were screened; 548 were randomized to placebo (n=184), lacosamide 200mg/day (n=183), or lacosamide 400mg/day (n=181); 485 (88.5%) completed the study. The median change (range) in POS frequency per 28days from Baseline to Maintenance was -3.33 (-754.3 to 165.2), -4.50 (-97.5 to 28.2), and -1.22 (-93.0 to 39.8) in the lacosamide 200mg/day, 400mg/day, and placebo groups, respectively. Significant percentage reductions in POS frequency over placebo per 28days from Baseline to Maintenance were observed for lacosamide 200mg/day (29.4% [95% CI 18.7-38.7%], p<0.001) and 400mg/day (39.6% [30.5-47.6%], p<0.001). Higher ≥50% and ≥75% responder and seizure freedom rates were observed in lacosamide-treated patients vs placebo. Treatment-emergent adverse events reported by ≥10% of all lacosamide-treated patients occurring at ≥2% difference compared with placebo were dizziness (25.9% vs 9.2%) and somnolence (10.2% vs 3.8%). Dose-proportional pharmacokinetics were consistent with earlier global pivotal trials. CONCLUSIONS: Adjunctive lacosamide (200 and 400mg/day) was efficacious in reducing POS frequency in Chinese and Japanese patients with a safety and tolerability profile consistent with the three global pivotal studies.

Phase sensitivity of synaptic modifications in oscillating cells of rat visual cortex.

Synaptic modifications depend on the amplitude and temporal relations of presynaptic and postsynaptic activation. The interactions among these variables are complex and hard to predict when neurons engage in synchronized high-frequency oscillations in the beta and gamma frequency range, as is often observed during signal processing in the cerebral cortex. Here we investigate in layer II/III pyramidal cells of rat visual cortex slices how synapses change when synchronized, oscillatory multifiber activity impinges on postsynaptic neurons during membrane potential (V(m)) oscillations at 20 and 40 Hz. Synapses underwent long-term potentiation (LTP) when EPSPs coincided with the peaks of the V(m) oscillations but exhibited long-term depression (LTD) when EPSPs coincided with the troughs. The induction of LTP but not of LTD was NMDA receptor dependent, required additional activation of muscarinic receptors in older animals, and persisted in a kainate-driven increased conductance state. Thus, even when neuronal networks engage in high-frequency oscillations, synaptic plasticity remains exquisitely sensitive to the timing of discharges. This is an essential prerequisite for theories which assume that precise synchronization of discharges serves as signature of relatedness in distributed processing.

Efficacy and safety of lacosamide as first add-on or later adjunctive treatment for uncontrolled partial-onset seizures: A multicentre open-label trial.

PURPOSE: To evaluate the efficacy and safety of lacosamide administered as either first add-on or later add-on antiepileptic drug (AED) therapy for patients with uncontrolled partial-onset seizures (POS). METHODS: In this open-label, multicentre trial, patients with POS initiated oral lacosamide (titrated to 400 mg/day) either as add-on to first AED monotherapy, or as later add-on to 1-3 concomitant AEDs after ≥ 2 previous AEDs. The primary efficacy variable was the proportion of patients achieving seizure freedom for the first 12 weeks of the 24-week Maintenance Phase. RESULTS: 456 patients received ≥ 1 dose of lacosamide (96 as first add-on, 360 as later add-on). In the first add-on cohort, 27/72 (37.5%) patients completed 12 weeks treatment and remained seizure-free; 18/68 (26.5%) remained seizure-free after 24 weeks. 64/91 (70.3%) patients achieved ≥ 50% reduction in seizure frequency during maintenance treatment. This was accompanied by a mean 7.1 ± 16.00 point improvement from Baseline in the Quality of Life Inventory in Epilepsy (QOLIE-31-P) total score for 24-week completers, with improvement reported in all subscales. Most common treatment-emergent adverse events (TEAEs) were dizziness (31.3%) and headache (13.5%). In the later add-on cohort, 39/261 (14.9%) and 29/249 (11.6%) patients remained seizure-free after completing 12 and 24 weeks' treatment, respectively. 178/353 (50.4%) patients achieved ≥ 50% reduction in seizure frequency during maintenance treatment. Mean change in QOLIE-31-P total score was 4.8 ± 14.74 points among 24-week completers. Common TEAEs were dizziness (33.6%), somnolence (15.0%) and headache (11.4%). CONCLUSIONS: Lacosamide initiated as first add-on treatment was efficacious and well tolerated in patients with uncontrolled POS.

Sustained effects of once-daily memantine treatment on cognition and functional communication skills in patients with moderate to severe Alzheimer's disease: results of a 16-week open-label trial.

The present study evaluated the effects of once-daily memantine (20 mg) treatment on cognition and communication in patients with moderate to severe Alzheimer's disease (AD). In a multicenter, single-arm open-label study, outpatients diagnosed with AD (MMSE < 20; n = 97) were titrated from 5 mg to 20 mg once-daily memantine over 4 weeks. Once-daily memantine treatment (20 mg) was then continued for 8 weeks, followed by a 4-week wash-out period. The primary efficacy endpoint was the change from baseline in the Consortium to Establish a Registry for Alzheimer's Disease -Neuropsychological Battery (CERAD-NP) total score. Secondary efficacy endpoints included change from baseline in Functional Communication Language Inventory (FLCI) and ADCS-ADL19 total score, and the response from baseline in Clinical Global Impression of Change (CGI-C). The CERAD-NP total score improved significantly after 12 weeks of once-daily memantine treatment compared with baseline (5.9 ± 8.8; p < 0.0001). The FLCI total score improved significantly after 12 weeks compared with baseline (4.4 ± 6.8; p < 0.0001). These significant improvements were already observed after 4 and 8 weeks of once-daily memantine treatment and persisted after a 4-week wash-out period. ADCS-ADL19 total scores showed only slight increases from baseline, and CGI-C indicated that the majority of patients experienced an improvement or stabilization of the disease after 12 weeks. At least one Treatment-Emergent Adverse Event was reported by 38 (39.2%) patients. In patients with moderate to severe AD, once-daily memantine (20 mg) treatment significantly improved cognition and functional communication and was found to have a favorable safety and tolerability profile.

Validation of the relevant outcome scale for Alzheimer's disease: a novel multidomain assessment for daily medical practice.

INTRODUCTION: The Relevant Outcome Scale for Alzheimer's Disease (ROSA) is a new observer rating instrument recently developed for routine medical practice. The validity and reliability of ROSA as well as sensitivity to changes due to intervention were examined in an open-label, single-arm, multicenter clinical study in patients with Alzheimer's disease (AD). METHODS: The study enrolled 471 patients with a diagnosis of AD consistent with the criteria of the National Institute of Neurological and Communicative Disease and Stroke/Alzheimer's Disease and Related Disorders Association or with the Diagnostic and Statistical Manual Disorders criteria for dementia of Alzheimer's type. Following assessments of the ROSA and other standard assessments (Alzheimer's Disease Assessment Scale - cognitive subscale, Severe Impairment Battery, Neuropsychiatric Inventory, and Disability Assessment for Dementia), patients were treated with memantine for 12 weeks. Factor analysis of the baseline ROSA total scores was performed based on the principal components method using the varimax orthogonal rotational procedure. The psychometric analyses of the ROSA included internal consistency, test-retest reliability, inter-rater reliability, construct validity, and responsiveness to changes over time. RESULTS: All items showed adequate factor loadings and were retained in the final ROSA as Factor 1 (all items related to cognition, communication, function, quality of life and caregiver burden) and Factor 2 (all behavior items). The ROSA demonstrated high internal consistency (Cronbach's α = 0.93), test-retest reliability (intraclass correlation coefficient = 0.93), and inter-rater reliability (intraclass correlation coefficient = 0.91). The correlation coefficients between the ROSA and each of the validated scales ranged between 0.4 and 0.7, confirming the ROSA construct validity. Nonsubstantial floor and ceiling effects were found in middle and late disease stages, whereas a small ceiling effect was observed in the early stage. The ROSA responsiveness to change was high (responsiveness index ≥0.8) for all severity stages. CONCLUSIONS: The ROSA is a valid and reliable instrument to aid medical practitioners in sensitively assessing AD-relevant symptoms over time in their clinical practice.

Review of Alzheimer's disease scales: is there a need for a new multi-domain scale for therapy evaluation in medical practice?

INTRODUCTION: The present review of Alzheimer's disease (AD) rating scales aims to outline the need for a new rating scale to be used in routine clinical practice for long-term medical care of AD patients. An ideal scale would be: 1) practical, easy and quick to administer for an experienced clinician; 2) validated for AD; 3) multi-domain: covering the AD-relevant areas of cognition, activities of daily living, behavior, communication/social interaction, and quality of life; 4) applicable to all AD severity stages; 5) able to monitor disease progression; and 6) sensitive to measure therapy effects. METHODS: The National Library of Medicines' MEDLINE database was searched for the years 1981 to September 2008, using a set of keywords aiming to select instruments which cover at least some of the requirements for an ideal practical AD scale for therapy evaluation. Measures for AD staging and screening tests were not considered for review. RESULTS: Of 1,902 articles resulting from the literature search, 68 relevant AD scales were identified. Most of them were scales that predominantly measure the severity of major dysfunctions in particular AD domains. Only five scales met some of the requirements for a practical multi-domain AD scale, but did not possess all required characteristics. CONCLUSIONS: Despite the multitude of AD scales for various purposes, there remains a need for a new multi-domain and easy to administer AD scale for assessment of disease progression and response to therapy in daily medical practice.

Synaptic plasticity in the absence of backpropagating spikes of layer II inputs to layer V pyramidal cells in rat visual cortex.

Use-dependent changes of synaptic transmission are thought to depend on the evaluation of temporal correlations between pre- and postsynaptic excitatory activity. Previous studies have demonstrated long-term potentiation (LTP) in layer V pyramidal cells after coincident pairing of presynaptic excitatory input with postsynaptic depolarizations, evoking backpropagating action potentials (BAPs). Here we paired excitatory layer II input with somatic hyperpolarization, which blocked BAPs in layer V pyramidal cells of rat visual cortex and induced reliable long-term depression (LTD). Upon cholinergic receptor activation, this BAP-independent protocol also induced LTP, which was not dependent on N-methyl-d-aspartate receptor activation, but blocked by metabotropic glutamate receptor (mGluR) antagonists.

Phase dependent sign changes of GABAergic synaptic input explored in-silicio and in-vitro.

Inhibitory interactions play a crucial role in the synchronization of neuronal activity. Here we investigate the effect of GABAergic PSPs on spike timing in cortical neurons that exhibit an oscillatory modulation of their membrane potential. To this end we combined numerical simulations with in-vitro patch-clamp recordings from layer II/III pyramidal cells of the rat visual cortex. Special emphasis was placed on exploring how the reversal potential of the GABAergic synaptic currents (EGABA) and the phase relations of the PSPs relative to the oscillation cycles affect the timing of spikes riding on the depolarizing peaks of the oscillations. The simulations predicted: (1) With EGABA more negative than the oscillation minima PSPs are hyperpolarizing at all phases and thus delay or prevent spikes. (2) With EGABA being more positive than the oscillation maxima PSPs are depolarizing in a phase-independent way and lead to a phase advance of spikes. (3) In the intermediate case where EGABA lies within oscillation maxima and minima PSPs are either hyper- or depolarizing depending on their phase relations to the V(m) oscillations and can therefore either delay or advance spikes. Experiments conducted in this most interesting last configuration with biphasic PSPs agreed with the model predictions. Additional theoretical investigations revealed the effect of these PSP induced shifts in spike timing on synchronization in neuronal circuits. The results suggest that GABAergic mechanisms can assume highly specific timing functions in oscillatory networks.