Juvenile myoclonic epilepsy (JME) is the most common syndrome within the idiopathic generalized epilepsy spectrum, manifested by myoclonic and generalized tonic-clonic seizures and spike-and-wave ...discharges (SWDs) on electroencephalography (EEG). Currently, the pathophysiological concepts addressing SWD generation in JME are still incomplete. In this work, we characterize the temporal and spatial organization of functional networks and their dynamic properties as derived from high-density EEG (hdEEG) recordings and MRI in 40 JME patients (25.4 ± 7.6 years, 25 females). The adopted approach allows for the construction of a precise dynamic model of ictal transformation in JME at the cortical and deep brain nuclei source levels. We implement Louvain algorithm to attribute brain regions with similar topological properties to modules during separate time windows before and during SWD generation. Afterwards, we quantify how modular assignments evolve and steer through different states towards the ictal state by measuring characteristics of flexibility and controllability. We find antagonistic dynamics of flexibility and controllability within network modules as they evolve towards and undergo ictal transformation. Prior to SWD generation, we observe concomitantly increasing flexibility (F(1,39) = 25.3, corrected p < 0.001) and decreasing controllability (F(1,39) = 55.3, p < 0.001) within the fronto-parietal module in γ-band. On a step further, during interictal SWDs as compared to preceding time windows, we notice decreasing flexibility (F(1,39) = 11.9, p < 0.001) and increasing controllability (F(1,39) = 10.1, p < 0.001) within the fronto-temporal module in γ-band. During ictal SWDs as compared to prior time windows, we demonstrate significantly decreasing flexibility (F(1,14) = 31.6; p < 0.001) and increasing controllability (F(1,14) = 44.7, p < 0.001) within the basal ganglia module. Furthermore, we show that flexibility and controllability within the fronto-temporal module of the interictal SWDs relate to seizure frequency and cognitive performance in JME patients. Our results demonstrate that detection of network modules and quantification of their dynamic properties is relevant to track the generation of SWDs. The observed flexibility and controllability dynamics reflect the reorganization of de−/synchronized connections and the ability of evolving network modules to reach a seizure-free state, respectively. These findings may advance the elaboration of network-based biomarkers and more targeted therapeutic neuromodulatory approaches in JME.
•JME patients display distinct and overlapping network communities before and during SWDs.•Flexibility and controllability exhibit antagonistic dynamics before and during SWDs.•Flexibility and controllability dynamics are detectable in γ- and β-bands.•Detection of network communities and their properties is relevant to track SWD generation.
Summary Background Three small trials suggest that intravenous immunoglobulin can affect biomarkers and symptoms of mild-to-moderate Alzheimer's disease. We tested the safety, effective dose, and ...infusion interval of intravenous immunoglobulin in such patients. Methods We did a multicentre, placebo-controlled phase 2 trial at seven sites in the USA and five in Germany. Participants with probable Alzheimer's disease aged 50–85 years were randomly assigned (by a computer-generated randomisation sequence, with block sizes of eight) to infusions every 4 weeks (0·2, 0·5, or 0·8 g intravenous immunoglobulin per kg bodyweight, or placebo) or infusions every 2 weeks (0·1, 0·25, or 0·4 g/kg, or placebo). Patients, caregivers, investigators assessing outcomes, and staff at imaging facilities and the clinical research organisation were masked to treatment allocation, but dispensing pharmacists, the statistician, and the person responsible for final PET analyses were not. Treatment was masked with opaque pouches and infusion lines. The primary endpoint was median area under the curve (AUC) of plasma amyloid β (Aβ)1–40 between the last infusion and the final visit (2 weeks or 4 weeks depending on infusion interval) in the intention-to-treat population. The trial is registered at ClinicalTrials.gov ( NCT00812565 ) and controlled-trials.com ( ISRCTN64846759 ). Findings 89 patients were assessed for eligibility, of whom 58 were enrolled and 55 included in the primary analysis. Median AUC of plasma Aβ1–40 was not significantly different for intravenous immunoglobulin compared with placebo for five of the six intervention groups (–18·0 range −1347·0 to 1068·5 for 0·2 g/kg, −364·3 –5834·5 to 1953·5 for 0·5 g/kg, and −351·8 –1084·0 to 936·5 for 0·8 g/kg every 4 weeks vs −116·3 –1379·0 to 5266·0 for placebo; and −13·8 –1729·0 to 307·0 for 0·1 g/kg, and −32·5 –1102·5 to 451·5 for 0·25 g/kg every 2 weeks vs 159·5 51·5 to 303·0 for placebo; p>0·05 for all). The difference in median AUC of plasma Aβ1–40 between the 0·4 g/kg every 2 weeks group (47·0 range −341·0 to 72·5) and the placebo group was significant (p=0·0216). 25 of 42 (60%) patients in the intervention group versus nine of 14 (64%) receiving placebo had an adverse event. Four of 42 (10%) patients in the intravenous immunoglobulin group versus four of 14 (29%) receiving placebo had a serious adverse event, including one stroke in the intervention group. Interpretation Intravenous immunoglobulin may have an acceptable safety profile. Our results did not accord with those from previous studies. Longer trials with greater power are needed to assess the cognitive and functional effects of intravenous immunoglobulin in patients with Alzheimer's disease. Funding Octapharma AG.
Waist circumference has been shown to be a better predictor of cardiovascular risk than body mass index (BMI). Our case-control study aimed to evaluate the contribution of obesity and abdominal fat ...mass to the risk of stroke and transient ischemic attacks (TIA).
We recruited 1137 participants: 379 cases with stroke/TIA and 758 regional controls matched for age and sex. Associations between different markers of obesity (BMI, waist-to-hip ratio, waist circumference and waist-to-stature ratio) and risk of stroke/TIA were assessed by using conditional logistic regression adjusted for other risk factors.
BMI showed a positive association with cerebrovascular risk which became nonsignificant after adjustment for physical inactivity, smoking, hypertension, and diabetes (odds ratio 1.18; 95% CI, 0.77 to 1.79, top tertile versus bottom tertile). Markers of abdominal adiposity were strongly associated with the risk of stroke/TIA. For the waist-to-hip ratio, adjusted odds ratios for every successive tertile were greater than that of the previous one (2nd tertile: 2.78, 1.57 to 4.91; 3rd tertile: 7.69, 4.53 to 13.03). Significant associations with the risk of stroke/TIA were also found for waist circumference and waist-to-stature ratio (odds ratio 4.25, 2.65 to 6.84 and odds ratio 4.67, 2.82 to 7.73, top versus bottom tertile after risk adjustment, respectively).
Markers of abdominal adiposity showed a graded and significant association with risk of stroke/TIA, independent of other vascular risk factors. Waist circumference and related ratios can better predict cerebrovascular events than BMI.
Objective
To report the interim results of the PERPRISE study (Study 509; NCT04202159), which is evaluating perampanel as the only adjunctive anti‐seizure medication (ASM) in adults with focal to ...bilateral tonic–clonic seizures (FBTCS) or primary generalized tonic–clonic seizures (GTCS).
Methods
PERPRISE is an ongoing 12‐month multicenter, prospective, observational, non‐interventional study of perampanel in a real‐world setting in Germany. Patients are aged ≥18 years with FBTCS or GTCS due to focal or idiopathic generalized epilepsy. Perampanel, as an adjunctive therapy to ASM monotherapy (‘add‐on therapy’) or as a substitute for one ASM in dual therapy (‘substitution therapy’), is prescribed in line with its SmPC. The Interim Analysis Set comprises the first 100 patients who received ≥1 dose of perampanel and attended or discontinued prior to the ~6‐month visit. Interim endpoints include retention rate, measures of effects on seizure frequency, and treatment‐emergent adverse events (TEAEs).
Results
One hundred patients were included in the Interim Analysis Set (add‐on, n = 43 43.0%; substitution, n = 55 55.0%; unknown, n = 2). The 6‐month retention rate was 78.0% (add‐on, 83.7%; substitution, 72.7%). For the overall population with GTCS and/or FBTCS, seizure‐freedom rate at 6 months was 58.8% (add‐on, 72.2%; substitution, 47.9%) and 50% responder rate at 6 months was 82.6% (add‐on, 89.2%; substitution, 76.6%). Retention rates and seizure outcomes were better with perampanel as an early‐line treatment than as a late‐line treatment. TEAEs were reported by 48 patients (48.0%), most commonly dizziness (n = 9), fatigue (n = 7), and irritability (n = 7). Sixteen patients (16.0%) withdrew from perampanel treatment due to TEAEs.
Significance
The interim analysis of PERPRISE offers insight into the real‐world use of perampanel in Germany, including for the first time, clinical practice data from patients with GTCS and switching ASMs within a dual therapy. Further data from PERPRISE will be of value to inform clinical decision‐making in this patient cohort.
Plain Language Summary
Patients with epilepsy often take more than one medication for seizure control. This 12month study looked at patients in Germany receiving perampanel as only add‐on medication. The interim analysis shows, that at 6 months, over 70% of the 100 patients continued to use perampanel; 59% experienced no seizures during treatment with perampanel, and in 83%, seizure frequency was reduced by half. Side effects occurred in 48% of patients (most commonly dizziness, fatigue, and irritability) and caused 16% to withdraw from the study. Overall, perampanel was a suitable as only add‐on medication for patients with epilepsy.
To investigate prokinetic and antidepressive effects of rasagiline in de novo Parkinson disease (PD).
Patients with newly diagnosed PD with comorbid untreated depression were randomly assigned to ...rasagiline monotherapy 1 or 2 mg/d. Unified Parkinson's Disease Rating Scale Part 2 (Activity of Daily Living) and Part 3 (Motor Function), and Hamilton Depression Rating Scale (HDRS) assessments were carried out by a blinded investigator in each patient at baseline and after 8 weeks of rasagiline treatment.
Both groups showed equal motor improvement at the end point. The improvements of HDRS score and activity of daily living were significantly more pronounced with rasagiline, 2 mg/d, than rasagiline, 1 mg/d (P = 0.0002). The treatment with rasagiline, 2 mg/d, improved symptoms in all HDRS core depression symptoms and specifically those not considered to be influenced by motor function: mood, guilt, psychic anxiety, and hypochondria.
Our results suggest that antidepressive effect seen in higher dosage of rasagiline may be not related to the motor improvement.
Neuromuscular disorders are rare diseases with a chronic and debilitating course. Unfortunately, data on the health-related quality of life (HRQoL) in neuromuscular diseases are limited. The ...objective of this multicentre cross-sectional study was to compare the HRQoL in patients with amyotrophic lateral sclerosis (ALS), facioscapulohumeral muscular dystrophy (FSHD) and myasthenia gravis (MG) and to identify the determinants of the HRQoL in these diseases. We recruited 91 consecutive outpatients with ALS (
n
= 37), FSHD (
n
= 17) or MG (
n
= 37) in seven specialized German health centres. The HRQoL was determined using the 36-Item Short Form Health Survey (SF-36) and the EuroQol (EQ-5D). Independent predictors of the HRQoL were identified using multiple regression analysis. The HRQoL in all domains of the SF-36, except for bodily pain, was significantly reduced. The domains related to physical health (physical functioning, physical role) were most affected. The EQ-5D-index score was most reduced in ALS (0.54) and least reduced in MG (0.89). Independent predictors of a reduced HRQoL were disease severity and depression in ALS, and disease severity, depression, older age and increased body-mass index in MG. The patterns of HRQoL-impairment in neuromuscular disorders share some common features, such as a more pronounced reduction in the HRQoL related to physical health, but there are a number of disease-specific features that should be considered in outcomes of clinical trials and treatment guidelines. In addition to the treatment of motor symptoms, greater attention should be paid to the treatment of depression, which was found to be among the independent predictors of the HRQoL in ALS and MG.
The costs of acute stroke care, length of hospital stay (LOS), and outcome in patients with cardioembolic stroke or cardioembolic transient ischemic attacks (TIA) were investigated with the aim of ...estimating the clinical and health-economic impacts of cerebral cardioembolism. The study population consisted of 511 consecutive patients with the diagnosis of ischemic stroke (
n
= 379) or TIA (
n
= 132) treated at the Department of Neurology, Philipps University, Marburg. Cerebral cardioembolism was defined according to the criteria of the Cerebral Embolism Task Force. Clinical status was assessed by means of Barthel index (BI) and modified Rankin Scale. Costs were calculated using a bottom-up approach. All costs (in Euros) were inflated to the 2008 level. Compared to non-cardioembolic stroke (
n
= 278) patients, patients who had suffered cardioembolic stroke (
n
= 101) had more severe clinical deficits on admission (BI 46.3 ± 27.0 vs. 59.3 ± 34.1;
P
< 0.01), worse recovery (BI on discharge 59.2 ± 28.9 vs. 73.1 ± 33.4;
P
< 0.01), and increased LOS (12.6 ± 5.7 vs. 10.0 ± 7.8 days;
P
< 0.01). The latter also required a relatively higher daily resource utilization due to increased expenses for personnel and diagnostics. Mean costs of acute care for patients with cardioembolic stroke € 4890 per patient (95% confidence interval 4460–5200) were significantly higher than those for patients with non-cardioembolic stroke € 3550 (95% confidence interval 3250–3850);
P
< 0.01. The clinical and health-economic impact of cardiogenic cerebral embolism on stroke care is considerable. Patients with cardioembolic stroke/TIA are more severely impaired, and they require longer hospital treatment and increased resource utilization. Costs of acute care of cardioembolic stroke/TIA patients may exceed those of non-cardioembolic stroke/TIA by up to 40%.
Abstract Introduction Daridorexant was approved by FDA and EMA for the treatment of chronic insomnia. It is a new dual orexin-receptor anatgonist, which demonstrated its clinical efficacy and safety ...in randomized controlled trials. The real-world data including its influence on the health-related quality of life (HrQol) are not yet available. In this prospective observational study we investigate the influence of daridorexant on HrQol in patients with chronic insomnia. Methods Patients with chronic insomnia diagnosed following the DSM V criteria were included in the observational study in terms of the Mainz Sleep Registry (MAINZ-SLEEPREG). All patients received the standard dosis of daridorexant of 50mg/night. The evaluation of clinical parameters and HrQoL was performed before, as well as three and six months after the initiation of daridorexant. The collected night-time efficacy endpoints included wake time after sleep onset (WASO), latency to persistent sleep (LPS), total sleep time and self-reported total sleep time. The EuroQol5D (EQ5D Index and EQVAS: visual analogue scale) was used to evaluate HrQol. Results Study participants (n=63) were 52.7±11.0 years old and 58.7% of them were females. All applied night-time efficacy measures (WASO, LPF, total sleep and self-reported sleep time) showed a significant improvement by approximately 20-40% at the time points after three and six months (p< 0.05). At the follow-up after three and six months the EQ5D Index values (0.71±0.17 and 0.72±0.15, correspondingly) improved on daridorexant by 18% in comparison to baseline (0.61±0.17, p< 0.05). Similar increase of HrQol was observed on EQVAS (62.2±16.5 at baseline versus 73.9±19.8 and 74.6±18.9, p< 0.05). Conclusion The data from this real-word study shows that daridorexant not only significantly improves the night-time sleep of patients with chronic insomnia but it also increases their HrQol. These findings encourage farther real-world studies to investigate the role of daridorexant in the treatment of chronic insomnia in broader populations. Support (if any)
Neuromuscular disorders (NMD) are chronic devastating diseases. The aim of this multicenter cross-sectional study was to evaluate the socioeconomic impact of three NMDs in Germany. Patients (
n
... = 107) with amyotrophic lateral sclerosis (ALS), myasthenia gravis (MG) or facioscapulohumeral muscular dystrophy (FSHD) were recruited consecutively in seven centers in Germany. The health-economic data were collected using a “bottom-up” approach consisting of comprehensive questionnaires and patient diaries. Costs were evaluated from the societal perspective in 2009 Euros (EUR). Total annual costs from the societal perspective were EUR 36,380 (95% CI 27,090–47,970) per patient in ALS, EUR 26,240 (95% CI 17,770–37,940) in FSHD and EUR 14,950 (95% CI 10,470–21,730) in MG. The main components of costs were the expenditures of health insurance and the loss of productivity of patients and their caregivers. The following independent cost-driving factors were identified: disease severity, assistance in activities of daily living (ADL), dementia and younger age in ALS, disease severity in FSHD and assistance in ADL, disease severity and assistance in ADL in MG. The socioeconomic burden of NMDs in Germany is considerable. Further studies evaluating both the health-economic and clinical effects of NMD treatment as well as disease management programs and benchmarking activities are necessary.
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