Neurological adverse events of new generation sodium blocker antiepileptic drugs. Meta-analysis of randomized, double-blinded studies with eslicarbazepine acetate, lacosamide and oxcarbazepine

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Verso una definizione delle “near-death experiences”: dimensioni fisiologiche, psicologiche e culturali

Riassunto: Il fenomeno delle “near-death experiences” (NDE), esperienze soggettive intense e profonde, è caratterizzato dalla percezione di essere in una dimensione diversa da quella ordinaria, di aver abbandonato il proprio corpo e, con esso, la dimensione spazio-temporale del mondo fisico. Il termine NDE è utilizzato per indicare esperienze simili occorse in condizioni cliniche molto diverse, ad esempio l’arresto cardiaco, il coma, lo svenimento o l’assunzione di sostanze psicotrope. In questo lavoro si considerano esclusivamente quelle esperienze sperimentate in condizioni di prossimità alla morte. Il fenomeno viene discusso confrontando gli elementi più comunemente presenti nelle NDE di soggetti occidentali con quelli riportati da soggetti di altre culture. Le varie esperienze pre-morte sono discusse in funzione dei contenuti riportati e delle modalità con cui si sono verificate. Infine, lo stato di coma è stato valutato come condizione di “near-death” nell’ottica di considerare la morte come un processo.Parole chiave: Near-death Experiences; Cultura; Coscienza; Memoria; Arresto cardiaco; Coma Towards a definition of “near-death experiences”: Physiologic, psychologic and cultural dimensionsAbstract: The phenomenon of near-death experiences (NDE), intense and profound subjective experiences, is characterized by the perception of being in a different dimension from the ordinary one, of having abandoned one’s body and, with it, the space-time dimension of the physical world. The term NDE has been used to indicate similar experiences that occurred in very different clinical conditions, namely cardiac arrest, coma, fainting, use of psychotropic substances, etc. In what follows will be considered only experiences taking place in conditions of proximity to death. The phenomenon will be discussed comparing elements most commonly present in NDEs of Western subjects with those reported by subjects from other cultures. The various near-death experiences will be discussed in according to the contents reported and the ways in which they occurred. Finally, the state of coma was considered as a near-death condition under the assumption of death as a process.Keywords: Near-Death Experiences; Culture; Consciousness; Memory; Cardiac Arrest; Com

Stimulation of S1PR5 with A-971432, a selective agonist, preserves blood-brain barrier integrity and exerts therapeutic effect in an animal model of Huntington's disease

Huntington's disease (HD) is themost common neurodegenerative disorder for which no effective cure is yet available. Although several agents have been identified to provide benefits so far, the number of therapeutic options remains limited with only symptomatic treatment available. Over the past few years, we have demonstrated that sphingolipid-based approachesmay open the door to newandmore targeted treatments for the disease. In this study, we investigated the therapeutic potential of stimulating sphingosine-1-phosphate (S1P) receptor 5 by the new selective agonist A-971432 (provided by AbbVie) in R6/2mice, a widely used HD animalmodel. Chronic administration of low-dose (0.1mg/kg) A-971432 slowed down the progression of the disease and significantly prolonged lifespan in symptomatic R6/2mice. Such beneficial effects were associated with activation of pro-survival pathways (BDNF, AKT and ERK) and with reduction of mutant huntingtin aggregation. A-971432 also protected blood-brain barrier (BBB) homeostasis in the same mice. Interestingly, when administered early in the disease, before any overt symptoms, A-971432 completely protected HDmice fromthe classic progressivemotor deficit and preserved BBB integrity. Beside representing a promising strategy to take into consideration for the development of alternative therapeutic options for HD, selective stimulation of S1P receptor 5may be also seen as an effective approach to target brain vasculature defects in the disease

Markerless Analysis of Articulatory Movements in Patients With Parkinson's Disease

Objectives: A large percentage of patients with Parkinson's disease have hypokinetic dysarthria, exhibiting reduced peak velocities of jaw and lips during speech. This limitation implies a reduction of speech intelligibility for such patients. This work aims at testing a cost-effective markerless approach for assessing kinematic parameters of hypokinetic dysarthria. Study design: Kinematic parameters of the lips are calculated during a syllable repetition task from 14 Parkinsonian patients and 14 age-matched control subjects. Methods: Combining color and depth frames provided by a depth sensor (Microsoft Kinect), we computed the three-dimensional coordinates of main facial points. The peak velocities and accelerations of the lower lip during a syllable repetition task are considered to compare the two groups. Results: Results show that Parkinsonian patients exhibit reduced peak velocities of the lower lip, both during the opening and the closing phase of the mouth. In addition, peak values of acceleration are reduced in Parkinsonian patients, although with significant differences only in the opening phase with respect to healthy control subjects. Conclusions: The novel contribution of this work is the implementation of an entirely markerless technique capable to detect signs of hypokinetic dysarthria for the analysis of articulatory movements during speech. Although a large number of Parkinsonian patients have hypokinetic dysarthria, only a small percentage of them undergoes speech therapy to increase their articulatory movements. The system proposed here could be easily implemented in a home environment, thus, increasing the percentage of patients who can perform speech rehabilitation at home

Mesenchymal stem cell secretome and extracellular vesicles for neurodegenerative diseases: Risk-benefit profile and next steps for the market access

Neurodegenerative diseases represent a growing burden on healthcare systems worldwide. Mesenchymal stem cells (MSCs) have shown promise as a potential therapy due to their neuroregenerative, neuroprotective, and immunomodulatory properties, which are, however, linked to the bioactive substances they release, collectively known as secretome. This paper provides an overview of the most recent research on the safety and efficacy of MSC-derived secretome and extracellular vesicles (EVs) in clinical (if available) and preclinical models of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, Huntington's disease, acute ischemic stroke, and spinal cord injury. The article explores the biologically active substances within MSCsecretome/EVs, the mechanisms responsible for the observed therapeutic effects, and the strategies that may be used to optimize MSC-secretome/EVs production based on specific therapeutic needs. The review concludes with a critical discussion of current clinical trials and a perspective on potential future directions in translating MSCsecretome and EVs into the clinic, specifically regarding how to address the challenges associated with their pharmaceutical manufacturing, including scalability, batch-to-batch consistency, adherence to Good Manufacturing Practices (GMP) guidelines, formulation, and storage, along with quality controls, access to the market and relative costs, value for money and impact on total expenditure

Are Patients With Schizophrenia Spectrum Disorders More Prone to Manifest Nocebo-Like-Effects? A Meta-Analysis of Adverse Events in Placebo Groups of Double-Blind Antipsychotic Trials

Background: Antipsychotic clinical trials use to present adverse events (AEs) for the drug under evaluation to treat schizophrenia. Interestingly, patients who receive the placebo during antipsychotic trials often report several AEs, but little is known about the essence of these negative effects in patients with schizophrenia spectrum disorders (SCD). In the present meta-analysis, we evaluated the relationship between the level of psychiatric symptomatology expressed as Positive and Negative Syndrome Scale (PANSS) scores and the rates of AEs reported in the placebo arms of double-blind clinical trials, for commonly prescribed atypical antipsychotic medications.Methods: We selected 58 clinical trials describing AEs in SCD placebo groups, which compared atypical antipsychotic medications with placebo. A total of 6,301 placebo-treated patients were considered. AE profiles of the class were clusterized using MedDRA classification and analysed using a meta-regression approach.Results: In the placebo arms the proportions of patients with any AE was 66.3% (95% CI: 62.7–69.8%). The proportion of withdrawal of patients treated with placebo because of AEs was 7.2% (95% CI: 5.9–8.4%). Interestingly, the AEs in the placebo arms corresponded to those of the antipsychotic-atypical-medication-class against which the placebo was compared. Namely, using meta-regression analysis we found an association between the level of psychiatric symptomatology measured with PANSS scores and higher AEs reported as nervous system (p = 0.020) and gastrintestinal disorders (p = 0.004). Moreover, the level of a higher psychiatric symptomatology expressed with PANSS scores was also related with higher AEs associated with psychiatric symptoms (p = 0.017).Conclusion: These findings emphasise that the AEs in placebo arms of clinical trials of antipsychotic medications were substantial. Importantly, a higher level of psychiatric symptomatology makes SCD patients more prone to express AEs, thus contributing to possible drop-outs and to a lower adherence to treatments. These results are consistent with the expectation theory of placebo and nocebo effects

A Novel tDCS Sham Approach Based on Model-Driven Controlled Shunting

Abstract Background Transcranial direct current stimulation (tDCS), a non-invasive brain stimulation technique able to transiently modulate brain activity, is surging as one of the most promising therapeutic solutions in many neurological and psychiatric disorders. However, profound limitations exist in current placebo (sham) protocols that limit single- and double-blinding, especially in non-naive subjects. Objective /hypothesis: To ensure better blinding and strengthen reliability of tDCS studies and trials, we tested a new optimization algorithm aimed at creating an "active" sham tDCS condition (ActiSham hereafter) capable of inducing the same scalp sensations perceived during real stimulation, while preventing currents from reaching the cortex and cause changes in brain excitability. Methods A novel model-based multielectrode technique —optimizing the location and currents of a set of small electrodes placed on the scalp— was used to control the relative amount of current delivered transcranially in real and placebo multichannel tDCS conditions. The presence, intensity and localization of scalp sensations during tDCS was evaluated by means of a specifically designed questionnaire administered to the participants. We compared blinding ratings by directly addressing subjects' ability to discriminate across conditions for both traditional (Bifocal-tDCS and -Sham, using sponge electrodes) and our novel multifocal approach (both real Multifocal-tDCS and ActiSham). Changes in corticospinal excitability were monitored based on Motor Evoked Potentials (MEPs) recorded via concurrent Transcranial Magnetic Stimulation (TMS) and electromyography (EMG). Results Subjects perceived Multifocal-tDCS and ActiSham similarly in terms of both scalp sensations and their localization on the scalp, whereas traditional Bifocal stimulation was rated as more painful and annoying compared to its Sham counterpart. Additionally, differences in scalp localization were reported for active/sham Bifocal-tDCS. As for MEPs amplitude, a main effect of stimulation was found when comparing Bifocal-Sham and ActiSham (F(1,13)= 6.67, p=.023), with higher MEPs amplitudes after the application of Bifocal-Sham. Conclusions Compared to traditional Bifocal-tDCS, ActiSham offers better participants' blinding by inducing very similar scalp sensations to those of real Multifocal tDCS both in terms of intensity and localization, while not affecting corticospinal excitability

Tolerability of new antiepileptic drugs:a network meta-analysis

Objective: The objective of this study was to perform a comparative assessment of tolerability of all licensed new antiepileptic drugs (AEDs) through a network meta-analysis (NMA) including all placebo-controlled double-blind clinical trials (RCTs) in all conditions in which these drugs have been tested. Methods: NMA with a frequentist approach was used to compare proportions of patients withdrawing because of adverse events (AEs). Analyses were conducted for all therapeutic doses pooled and specifically for high therapeutic doses. Patients treated with non-therapeutic doses of each drug were excluded. Results: A total of 195 RCTs were included in the current analysis, comprising a total of 28,013 patients treated with AEDs and 17,908 patients treated with placebo. RCTs included in the analysis were 8 for brivaracetam; 5 for eslicarbazepine; 22 for gabapentin; 7 for lacosamide; 14 for levetiracetam; 14 for lamotrigine; 6 for oxcarbazepine; 9 for perampanel; 50 for pregabalin; 5 for tiagabine; 36 for topiramate; 7 for zonisamide; 4 for gabapentin-extended formulation (ER); 2 each for levetiracetam-ER, lamotrigine-ER, and topiramate-ER; and 1 each for oxcarbazepine-ER and pregabalin-ER. Brivaracetam, gabapentin, gabapentin-ER, and levetiracetam had a significantly lower withdrawal rate compared to several other AEDs, while eslicarbazepine, lacosamide, oxcarbazepine, and topiramate had a higher withdrawal rate. Perampanel, lamotrigine, pregabalin, tiagabine, and zonisamide showed an intermediate pattern of tolerability. Additional analysis has been conducted through selection of highly recommended doses for each drug. This analysis has roughly confirmed results of head to head comparisons of the all-dose analysis, with some exceptions. A further analysis has been conducted after exclusion of RCTs in which patients were allocated to the therapeutic dose of the experimental drug without titration, and it failed to show clinically important differences. Significance: Relevant differences in short-term tolerability of AEDs have been observed between AEDs. Brivaracetam, gabapentin, and levetiracetam show the best tolerability profile while other AEDs are at higher risk for intolerable adverse effects