Use of perampanel oral suspension for the treatment of refractory and super-refractory status epilepticus.

INTRODUCTION: Status epilepticus (SE) is a medical emergency associated with a significant risk of disability and death. The treatment of SE follows a step-wise approach, with limited data on ideal antiseizure medications (ASMs) for refractory and super refractory SE (RSE/SRSE). Perampanel (PER), an AMPA receptor antagonist, has shown promise in animal models but still has limited data in humans. This study tried to evaluate optimal dosage and safety of PER in RSE and SRSE patients. MATERIALS AND METHODS: We retrospectively analysed 17 adult patients with RSE (1) or SRSE (16) treated with PER. Demographic and clinical data, including EEG patterns, ASMs administered, PER dosages, and PER plasma concentrations, were collected. For patients receiving a 24 mg PER loading dose (full dose group), the following treatment regimen was applied: 24 mg per day for 48 h following by 16 mg per day. The response to PER was assessed based on electroencephalographic (EEG) improvement from high to low epileptiform activity or from low to the absence of epileptiform activities. Safety was evaluated monitoring hepatic and renal function. RESULTS: A response rate of 58.82 % was observed, with significantly higher responses in the full dose group (81.82 %) compared to those receiving PER doses below 24 mg (low dose group) (16.67 %) (p-value = 0.004; OR 0.044, 95 % CI 0.003 to 0.621, p = 0.021). No other clinical factors significantly influenced treatment response. Hepatic enzymes become elevated in most patients (70.59 %) but spontaneously decreased. DISCUSSION: Our findings suggest that a 24 mg PER dose administered for 48 h may be more effective in managing RSE and SRSE compared to doses below 24 mg, potentially due to pharmacokinetic factors. CONCLUSION: More robust data on PER in RSE and SRSE, including standardized dosing procedures and plasma level monitoring are needed. PER's potential benefits should be explored further, particularly in patients with RSE and SRSE.

[A guide to psychiatric prescribing in pregnancy, postpartum and breastfeeding]. / Guide de prescription psychiatrique pendant la grossesse, le postpartum et l'allaitement.

Perinatal psychopharmacology is an emerging specialty that is gradually developing alongside perinatal psychiatry. The management of psychiatric disorders during the perinatal period is a challenge for perinatal practitioners due to the multiple changes occurring during this crucial period. This little-known specialty still suffers from inappropriate considerations on the impact of psychotropic treatments on the mother and the infant during pregnancy and postpartum, which can promote a deficiency in perinatal psychic care. However, the risks associated with insufficient management of mental health are major, impacting both the mental and physical health of the mother and the infant. In this paper, we propose a perinatal psychopharmacology prescription guide based on available scientific evidence and international and national recommendations. We thus propose a decision-making process formalized on simple heuristics in order to help the clinician to prescribe psychotropic drugs during the perinatal period.

The effects of education in psychiatry on attitudes towards antidepressants in nursing students: A cross-sectional study.

BACKGROUND: Stigma associated with depression and antidepressants is strong among the general population but also among patients and health professionals. OBJECTIVES: This cross-sectional study is aimed at: 1) evaluating the knowledge and attitude towards antidepressant by nursing student; 2) exploring the association between instruction in psychiatry and representation of depression and antidepressants. PARTICIPANTS: 2037 undergraduate students from 10 French nursing schools were invited to participate in 2017, 1475 (73%) completed the questionnaire. METHODS: The self-report questionnaire included the Drug Attitude Inventory (DAI) and questions about representation on depression and antidepressant. Four groups of students were built: 1) pre-teaching group (PT) as a reference group, 2) clinical training in psychiatry (CT), 3) receiving mental health theoretical education (TE), 4) receiving both (CT + TE). RESULTS: The mean (standard deviation) DAI score was negative: -1.9 (±4.4) with only 40% of the nursing students conveying a positive attitude towards antidepressant. A combination of CT and TE was associated with a more positive attitude towards antidepressant in comparison with the PT condition. The CT + TE group was more prone to view antidepressants as effective and safe. CONCLUSION: There is strong stigma against depression/antidepressants among nursing student. Education combined with clinical experiences in psychiatry improved these representations.

Acceptability, attitudes and knowledge towards Transcranial Magnetic Stimulation (TMS) among psychiatrists in France.

BACKGROUND: Non-invasive brain stimulation techniques are becoming a part of psychiatrists' therapeutic arsenal. Proof of TMS effectiveness and its indications are becoming clearer. While international recommendations exist, and many countries have already recognized the use of these techniques, the French situation is peculiar since no recommendation has been published by the High Authority of Health. Consequently, those techniques are not reimbursed by the healthcare service, few practitioners are trained, some are criticized for using it, and practices remain very heterogeneous. It is therefore important to investigate what slows down the development of these techniques. The objective of this study was to determine the acceptability of TMS by psychiatrists and to analyze the factors influencing it. METHOD: A sample of psychiatrists was recruited in order to complete an online quantitative acceptability study using a four variable domain model (utility, intention of use, facility, risk) allowing an acceptability score calculation. RESULT: Four hundreds and seventy-six observations were included in the analysis. Regarding the main objective, the overall TMS acceptability score was high for 47.2% of psychiatrists, average for 40.6% and low for 12.1% of them. The main factors influencing it were theoretical orientation (psychoanalytic vs neurobiological) and training level (only one in three psychiatrists acknowledge having been trained in this technique). DISCUSSION: The majority of practitioners consider TMS to be a credible alternative to current therapies, especially for depressive disorders. Yet psychiatrists are uninformed and poorly trained in these techniques and report very clearly a desire for more training and information. Our study highlights a significant lack of training that negatively impacts the accessibility of these techniques.

Methods for analysis of brain connectivity: An IFCN-sponsored review.

The goal of this paper is to examine existing methods to study the "Human Brain Connectome" with a specific focus on the neurophysiological ones. In recent years, a new approach has been developed to evaluate the anatomical and functional organization of the human brain: the aim of this promising multimodality effort is to identify and classify neuronal networks with a number of neurobiologically meaningful and easily computable measures to create its connectome. By defining anatomical and functional connections of brain regions on the same map through an integrated approach, comprising both modern neurophysiological and neuroimaging (i.e. flow/metabolic) brain-mapping techniques, network analysis becomes a powerful tool for exploring structural-functional connectivity mechanisms and for revealing etiological relationships that link connectivity abnormalities to neuropsychiatric disorders. Following a recent IFCN-endorsed meeting, a panel of international experts was selected to produce this current state-of-art document, which covers the available knowledge on anatomical and functional connectivity, including the most commonly used structural and functional MRI, EEG, MEG and non-invasive brain stimulation techniques and measures of local and global brain connectivity.

[Assessment of mood disorders by passive data gathering: The concept of digital phenotype versus psychiatrist's professional culture]. / Évaluation des troubles thymiques par l'étude des données passives : le concept de phénotype digital à l'épreuve de la culture de métier de psychiatre.

OBJECTIVES: The search for objective clinical signs is a constant practitioners' and researchers' concern in psychiatry. New technologies (embedded sensors, artificial intelligence) give an easier access to untapped information such as passive data (i.e. that do not require patient intervention). The concept of "digital phenotype" is emerging in psychiatry: a psychomotor alteration translated by accelerometer's modifications contrasting with the usual functioning of the subject, or the graphorrhea of patients presenting a manic episode which is replaced by an increase of SMS sent. Our main objective is to highlight the digital phenotype of mood disorders by means of a selective review of the literature. METHOD: We conducted a selective review of the literature by querying the PubMed database until February 2017 with the terms [Computer] [Computerized] [Machine] [Automatic] [Automated] [Heart rate variability] [HRV] [actigraphy] [actimetry] [digital] [motion] [temperature] [Mood] [Bipolar] [Depression] [Depressive]. Eight hundred and forty-nine articles were submitted for evaluation, 37 articles were included. RESULTS: For unipolar disorders, smartphones can diagnose depression with excellent accuracy by combining GPS and call log data. Actigraphic measurements showing daytime alteration in basal function while ECG sensors assessing variation in heart rate variability (HRV) and body temperature appear to be useful tools to diagnose a depressive episode. For bipolar disorders, systems which combine several sensors are described: MONARCA, PRIORI, SIMBA and PSYCHE. All these systems combine passive and active data on smartphones. From a synthesis of these data, a digital phenotype of the disorders is proposed based on the accelerometer and the GPS, the ECG, the body temperature, the use of the smartphone and the voice. This digital phenotype thus brings into question certain clinical paradigms in which psychiatrists evolve. CONCLUSION: All these systems can be used to computerize the clinical characteristics of the various mental states studied, sometimes with greater precision than a clinician could do. Most authors recommend the use of passive data rather than active data in the context of bipolar disorders because automatically generated data reduce biases and limit the feeling of intrusion that self-questionnaires may cause. The impact of these technologies questions the psychiatrist's professional culture, defined as a specific language and a set of common values. We address issues related to these changes. Impact on psychiatrists could be important because their unity seems to be questioned due to technologies that profoundly modify the collect and process of clinical data.

Membrane lipidomics in schizophrenia patients: a correlational study with clinical and cognitive manifestations.

Schizophrenia is a severe mental condition in which several lipid abnormalities-either structural or metabolic-have been described. We tested the hypothesis that an abnormality in membrane lipid composition may contribute to aberrant dopamine signaling, and thereby symptoms and cognitive impairment, in schizophrenia (SCZ) patients. Antipsychotic-medicated and clinically stable SCZ outpatients (n=74) were compared with matched healthy subjects (HC, n=40). A lipidomic analysis was performed in red blood cell (RBC) membranes examining the major phospholipid (PL) classes and their associated fatty acids (FAs). Clinical manifestations were examined using the positive and negative syndrome scale (PANSS). Cognitive function was assessed using the Continuous Performance Test, Salience Attribution Test and Wisconsin Card Sorting Test. Sphingomyelin (SM) percentage was the lipid abnormality most robustly associated with a schizophrenia diagnosis. Two groups of patients were defined. The first group (SCZ c/SM-) is characterized by a low SM membrane content. In this group, all other PL classes, plasmalogen and key polyunsaturated FAs known to be involved in brain function, were significantly modified, identifying a very specific membrane lipid cluster. The second patient group (SCZ c/SM+) was similar to HCs in terms of RBC membrane SM composition. Compared with SCZ c/SM+, SCZ c/SM- patients were characterized by significantly more severe PANSS total, positive, disorganized/cognitive and excited psychopathology. Cognitive performance was also significantly poorer in this subgroup. These data show that a specific RBC membrane lipid cluster is associated with clinical and cognitive manifestations of dopamine dysfunction in schizophrenia patients. We speculate that this membrane lipid abnormality influences presynaptic dopamine signaling.

Channel interpolation in TMS-EEG: a quantitative study towards an accurate topographical representation.

The co-registration of transcranial magnetic stimulation and electroencephalography (TMS-EEG) is emerging as a successful technique for causally exploring cortical mechanisms and connections. However, various artefacts could affect TMS-EEG signals. Correct artefacted channels reconstruction is crucial to obtain accurate topographical representation and consequently accurate inverse problem solution, in order to map in a proper way the global brain responses after the stimulation of one particular brain region of interest. In this paper, we discuss the problem of artefacted channels interpolation in TMS-EEG signals. Aim of the study was to investigate two different interpolation methods evaluating their performance in two datasets: one constituted by 19 EEG channels montage (low-density spatial resolution) and the other one by 60 EEG channels montage (high-density spatial resolution). In addition, these evaluations took place in two different contexts of application: after the averaging of TMS Evoked Potentials (TEPs) in a time interval to obtain a global information in the considered range, and at fixed latencies 100 ms and 300 ms after the TMS stimulus. The results showed that the global reconstruction error was lower at fixed latencies for the high-density electrodes spatial resolution montage.

Non-invasive electrical and magnetic stimulation of the brain, spinal cord, roots and peripheral nerves: Basic principles and procedures for routine clinical and research application. An updated report from an I.F.C.N. Committee.

These guidelines provide an up-date of previous IFCN report on "Non-invasive electrical and magnetic stimulation of the brain, spinal cord and roots: basic principles and procedures for routine clinical application" (Rossini et al., 1994). A new Committee, composed of international experts, some of whom were in the panel of the 1994 "Report", was selected to produce a current state-of-the-art review of non-invasive stimulation both for clinical application and research in neuroscience. Since 1994, the international scientific community has seen a rapid increase in non-invasive brain stimulation in studying cognition, brain-behavior relationship and pathophysiology of various neurologic and psychiatric disorders. New paradigms of stimulation and new techniques have been developed. Furthermore, a large number of studies and clinical trials have demonstrated potential therapeutic applications of non-invasive brain stimulation, especially for TMS. Recent guidelines can be found in the literature covering specific aspects of non-invasive brain stimulation, such as safety (Rossi et al., 2009), methodology (Groppa et al., 2012) and therapeutic applications (Lefaucheur et al., 2014). This up-dated review covers theoretical, physiological and practical aspects of non-invasive stimulation of brain, spinal cord, nerve roots and peripheral nerves in the light of more updated knowledge, and include some recent extensions and developments.

Does an intraneural interface short-term implant for robotic hand control modulate sensorimotor cortical integration? An EEG-TMS co-registration study on a human amputee.

PURPOSE: Following limb amputation, central and peripheral nervous system relays partially maintain their functions and can be exploited for interfacing prostheses. The aim of this study is to investigate, for the first time by means of an EEG-TMS co-registration study, whether and how direct bidirectional connection between brain and hand prosthesis impacts on sensorimotor cortical topography. METHODS: Within an experimental protocol for robotic hand control, a 26 years-old, left-hand amputated male was selected to have implanted four intrafascicular electrodes (tf-LIFEs-4) in the median and ulnar nerves of the stump for 4 weeks. Before tf-LIFE-4s implant (T0) and after the training period, once electrodes have been removed (T1), experimental subject's cortico-cortical excitability, connectivity and plasticity were tested via a neuronavigated EEG-TMS experiment. RESULTS: The statistical analysis clearly demonstrated a significant modulation (with t-test p < 0.0001) of EEG activity between 30 and 100 ms post-stimulus for the stimulation of the right hemisphere. When studying individual latencies in that time range, a global amplitude modulation was found in most of the TMS-evoked potentials; particularly, the GEE analysis showed significant differences between T0 and T1 condition at 30 ms (p < 0.0404), 46 ms (p < 0.0001) and 60 ms (p < 0.007) latencies. Finally, also a clear local decrement in N46 amplitude over C4 was evident. No differences between conditions were observed for the stimulation of the left hemisphere. CONCLUSIONS: The results of this study confirm the hypothesis that bidirectional neural interface could redirect cortical areas -deprived of their original input/output functions- toward restorative neuroplasticity. This reorganization strongly involves bi-hemispheric networks and intracortical and transcortical modulation of GABAergic inhibition.

[Bipolar disorders and comorbid anxiety: prognostic impact and therapeutic challenges]. / Troubles bipolaires et troubles anxieux comorbides : impact pronostique et enjeux therapeutiques.

INTRODUCTION: Anxiety disorders are among the main psychiatric conditions co-occuring with bipolar disorders. Many clinical and epidemiological studies have found much higher prevalence rates of generalized anxiety disorder, social phobia, obsessive-compulsive disorder, panic disorder and post-traumatic stress disorder in bipolar patients than in the general population, regardless of age. In the National Comorbidity Survey for instance, the diagnosis of at least one anxiety disorder was made for nearly 90% of bipolar subjects. Several issues arise from this high comorbidity, such as the way anxiety disorders alter the course and prognosis of the mood disorder, and challenge typical therapeutic strategies. This article reviews data on clinical and therapeutical significance of such comorbidity. LITERATURE FINDINGS: Many studies point out the poorer outcome for bipolar patients with co-occurring anxiety symptoms: apart from the alarming increase of suicidal ideas and suicide attempts, authors have found a shorter duration of euthymia, more comorbid addictions, mixed states and rapid cycling, and lower response to treatments. This is the reason why monitoring the suicidal risk in those bipolar patients with co-occurring anxiety disorders is of critical importance. From a physiopathological standpoint, the precise links between both pathologies remains unclear. The frequency of this comorbidity and its significance on long term prognosis stands in sharp contrast with the very few therapeutic studies conducted in this indication so far. Pharmacological approaches are strongly limited by the risk of mood switching under antidepressants and drug dependence on anxiolytics such as benzodiazepines. Nevertheless, there is emerging evidence of the interest of atypical antipsychotics such as olanzapine and mood stabilisers such as lamotrigine to control anxiety symptoms in bipolar patients. There is weaker evidence for other molecules. Taking into account other therapeutic approaches than the pharmacological approach appears accurate. Psychosocial interventions such as cognitive-behavioral therapies or psychoeducation appear essential to improve in a correct way the global functioning and quality of life of these patients.

Cortical plasticity and brain computer interface.

There is increasing evidence to support the concept that adult brain has the remarkable ability to plastically reorganize itself. Brain plasticity involves distinct functional and structural components and plays a crucial role in reorganizing central nervous system's networks after any lesion in order to partly or totally restore lost and/or compromised functions. The idea that a computer can decode brain electromagnetic signals to infer the intentions of a human and then enact those intentions directly through a machine is becoming a reasonable technical possibility. In neurological patients unable to move and to communicate with the external environment, technologies implementing brain-machine interfaces (BMIs) can be of valuable aid and support. The emerging possibility, through neuro-imaging advanced techniques, to clarify some crucial issues underlying brain plasticity will give the possibility to modulate these mechanisms in a BCI-oriented way. This approach may have a tremendous impact in a variety of neuropsychiatric disorders and the clinical advent of this technology will usher in a new era of restorative medicine.

Meibomian gland dysfunction and ocular discomfort in video display terminal workers.

PURPOSE: Meibomian gland dysfunction (MGD) is one of the most common ocular disorders encountered in clinical practice. The clinical manifestations of MGD are related to the changes in the tear film and ocular surface with symptoms of ocular discomfort. In recent years, many surveys have evaluated symptoms associated with the use of Video Display Terminals (VDT), and VDT use is recognized as a risk factor for eye discomfort. The aim of the present study was to determine if the presence of MGD contributes to the signs and symptoms of ocular discomfort during the use of VDT. METHODS: In course of a routine health surveillance programme, a group of 70 subjects fulfilled the inclusion criteria and responded to a questionnaire about symptoms of ocular discomfort. The following ocular tests were performed: tear break-up time, fluorescein corneal stain, and basal tear secretion test. RESULTS: A total of 52 subjects out of 70 (74.3%) had MGD. A statistically significant correlation between the symptoms of ocular discomfort and hours spent on VDT work was observed in the total population (r=0.358; P=0.002; 95% CI 0.13-0.54) and in the group of subjects with MGD (r=0.365; P=0.009; 95% CI 0.103-0.58). Such correlation was not shown in subjects without MGD. CONCLUSIONS: The high prevalence of MGD among the subjects with symptoms of ocular discomfort suggests that this diagnosis should be considered when occupational health practitioners encounter ocular complaints among VDT operators. It appears that MGD can contribute to the development of ocular discomfort in VDT operators.

[Cardiovascular effects of cholinesterase inhibitors in Alzheimer's disease]. / Effets cardio-vasculaires des inhibiteurs de la cholinestérase dans la maladie d'Alzheimer.

INTRODUCTION: In the treatment of mild to moderate Alzheimer's disease, cholinesterase inhibitors (ChEIs) have shown modest clinical benefits. STATE OF THE ART: Use of donepezil, galantamine and rivastigmine is widespread in clinical practice. Although relatively safe, ChEIs are prescribed for a frail population and may have clinically significant adverse drug effects on the cardiovascular system. Arrhythmia and syncope have been reported. Most of the cardiovascular adverse drug reactions to ChEIs might be related to stimulation of the parasympatic nervous system. PERSPECTIVES: Early and accurate recognition of past and present arrhythmia or syncope appears to be essential. Monitoring for pharmacokinetic (cytochromes P450 CYP2D6 or CYP3A4) and pharmacodynamic interactions and a more systematic clinical follow-up are mandatory. In patients with relevant risk factors or with cardiovascular adverse drug reactions a multidisciplinary approach with a cardiologist is required. CONCLUSION: Prevention of cardiac adverse events requires a careful clinical evaluation before the introduction of the ChEIs and an early recognition of cardiac disturbances under treatment.

'Free' copper in serum of Alzheimer's disease patients correlates with markers of liver function.

Non-ceruloplasmin bound copper ('free') seems slightly elevated in Alzheimer's disease (AD) patients. To test the hypothesis of a correlation between 'free' copper and liver function in AD. We evaluated 51 AD patients and 53 controls through typical tests for chronic liver disease (AST, ALT, gamma-GT, Albumin, prothrombin time - PT-, bilirubins), along with copper, ceruloplasmin, iron, cholesterol in the serum and apolipoprotein E epsilon4 (APOE4) genotype. Absolute serum copper and 'free' copper were higher, albumin was lower and PT longer in AD patients than in controls. 'Free' copper correlated negatively with markers of liver function, in that albumin and albumin/PT ratio (r = -0.43, p = 0.004), and positively with direct bilirubin. Copper and 'free' copper were higher in the APOE4 carriers. These results suggest that abnormalities in copper metabolism might have an effect on liver function in AD.

Neuroimaging experimental studies on brain plasticity in recovery from stroke.

Topographical cortical organization of sensorimotor area has been shown to be highly plastic, altering his configuration in response to training in different tasks in healthy controls and neurological patients. The term ''brain plasticity'' encompasses all possible mechanisms of neuronal reorganization: recruitment of pathways that are functionally homologous to, but anatomically distinct from, the damaged ones (eg, non-pyramidal corticospinal pathways), synaptogenesis, dendritic arborisation and reinforcement of existing but functionally silent synaptic connections (particularly at the periphery of core lesion). The study of neuroplasticity has clearly shown the ability of the developing brain--and of the adult and ageing brain--to be shaped by environmental inputs both under normal conditions (ie, learning) and after a lesion. Neuronal aggregates adjacent, or distant to a lesion in the sensorimotor area can progressively adopt the function of the injured area. Imaging studies indicate that recovery of motor function after a lesion (i.e. stroke) is associated with a progressive change of activation patterns in specific brain structures. Transcranial magnetic stimulation (TMS) and magnetoencephalography (MEG) can detect reshaping of sensorimotor areas; they have a high temporal resolution but have several limitations. TMS can only provide bidimensional scalp maps and MEG depicts three-dimensional spatial characteristics of virtual neural generators obtained by use of a mathematical model of the head and brain. However, the use of objective methods that assess brain reactivity to a physical stimulus (i.e., TMS) or to a sensory input (ie, electrical stimulation to hand and fingers) can integrate information from self-paced motor tasks, because the resolution of abnormal activation over time could be secondary to recovery. Functional MRI (fMRI) and positron emission tomography (PET), on their own, have insufficient time resolution to follow the hierarchical activation of relays within a neural network; however, because of their excellent spatial resolution, they can integrate the findings of TMS and MEG. An integrated approach constitutes, at present, the best way to assess the brain plasticity both under normal conditions and after a lesion.

Conversion from mild cognitive impairment to Alzheimer's disease is predicted by sources and coherence of brain electroencephalography rhythms.

Objective. Can quantitative electroencephalography (EEG) predict the conversion from mild cognitive impairment (MCI) to Alzheimer's disease (AD)? Methods. Sixty-nine subjects fulfilling criteria for MCI were enrolled; cortical connectivity (spectral coherence) and (low resolution brain electromagnetic tomography) sources of EEG rhythms (delta=2-4 Hz; theta=4-8 Hz; alpha 1=8-10.5 Hz; alpha 2=10.5-13 Hz: beta 1=13-20 Hz; beta 2=20-30 Hz; and gamma=30-40) were evaluated at baseline (time of MCI diagnosis) and follow up (about 14 months later). At follow-up, 45 subjects were still MCI (MCI Stable) and 24 subjects were converted to AD (MCI Converted). Results. At baseline, fronto-parietal midline coherence as well as delta (temporal), theta (parietal, occipital and temporal), and alpha 1 (central, parietal, occipital, temporal, limbic) sources were stronger in MCI Converted than stable subjects (P<0.05). Cox regression modeling showed low midline coherence and weak temporal source associated with 10% annual rate AD conversion, while this rate increased up to 40% and 60% when strong temporal delta source and high midline gamma coherence were observed respectively. Interpretation. Low-cost and diffuse computerized EEG techniques are able to statistically predict MCI to AD conversion.