Cerebrospinal fluid biomarkers in patients with epilepsy in Alzheimer's disease: a nation-wide study

Alzheimer’s disease is the most common neurodegenerative dementia. A subset of Alzheimer’s disease patients develop epilepsy. The risk is higher in young-onset Alzheimer’s disease, but pathophysiological mechanisms remain elusive. The purpose of this study was to assess biomarkers reflecting neurodegeneration in Alzheimer’s disease patients with and without epilepsy. By cross-referencing the largest national laboratory database with Swedish national patient registers, we could identify cerebrospinal fluid biomarker results from 17901 Alzheimer’s disease patients, and compare levels of neurofilament light, glial fibrillary acidic protein, total tau, phosphorylated tau, and amyloid beta 42 in patients with (n = 851) and without epilepsy. The concentrations of total tau and phosphorylated tau were higher in Alzheimer’s disease patients with epilepsy than Alzheimer’s disease patients without epilepsy and amyloid beta 42 levels were significantly lower in Alzheimer’s disease patients with epilepsy. No differences in the levels of neurofilament light and glial fibrillary acidic protein were observed. Our study suggests that epilepsy is more common in Alzheimer’s disease patients with more pronounced Alzheimer’s pathology, as determined by the CSF biomarkers. Further studies are needed to investigate the biomarker potential of these CSF markers as predictors of epilepsy course or as indicators of epileptogenesis in Alzheimer’s disease

Infections in status epilepticus: A retrospective 5-year cohort study

AbstractPurposeStatus epilepticus (SE) has attracted renewed interest lately, and efforts are made to optimize every treatment stage. For refractory SE, optimal supporting care involves mechanical ventilation and intensive care unit (ICU) admission. Infections often complicate SE and recently a single-centre observational study demonstrated an association between infections and poor short-term outcome of SE in a cohort of severely ill patients. We have here attempted to replicate those findings in a different cohort.MethodWe performed a retrospective observational study and included all patients with a diagnosis of SE during 2008–2012 at a Swedish tertiary referral centre.ResultsThe cohort consisted of 103 patients (53% female, 47% male, median age 62 years, range 19–87 years). In house mortality was less than 2 and 70% of the patients’ were discharged home. The most common aetiologies of SE were uncontrolled epilepsy (37%) and brain tumours (16%). A total of 39 patients suffered infections during their stay. Presence of infection was associated with mechanical ventilation (OR 3.344, 95% CI 1.44–7.79) as well as not being discharged home (OR2.705, 95% CI 1.14–6.44), and duration of SE was significantly longer in patients with infection (median 1 day vs. 2.5 days, p<0.001).ConclusionWe conclude that the previously described association between infections, a longer SE duration, and an unfavourable outcome of SE seems valid also in SE of less severe aetiology

Neurofilament light, glial fibrillary acidic protein, and tau in a regional epilepsy cohort: High plasma levels are rare but related to seizures

OBJECTIVE: Higher levels of biochemical blood markers of brain injury have been described immediately after tonic-clonic seizures and in drug-resistant epilepsy, but the levels of such markers in epilepsy in general have not been well characterized. We analyzed neurofilament light (NfL), glial fibrillary acidic protein (GFAP), and tau in a regional hospital-based epilepsy cohort and investigated what proportion of patients have levels suggesting brain injury, and whether certain epilepsy features are associated with high levels. METHODS: Biomarker levels were measured in 204 patients with an epilepsy diagnosis participating in a prospective regional biobank study, with age and sex distribution correlating closely to that of all patients seen for epilepsy in the health care region. Absolute biomarker levels were assessed between two patient groups: patients reporting seizures within the 2 months preceding inclusion and patients who did not have seizures for more than 1 year. We also assessed the proportion of patients with above-normal levels of NfL. RESULTS: NfL and GFAP, but not tau, increased with age. Twenty-seven patients had abnormally high levels of NfL. Factors associated with such levels were recent seizures (p = .010) and epileptogenic lesion on radiology (p = .001). Levels of NfL (p = .006) and GFAP (p = .032) were significantly higher in young patients (1 year. NfL and GFAP correlated weakly with the number of days since last seizure (NfL: rs  = -.228, p = .007; GFAP: rs  = -.167, p = .048) in young patients. NfL also correlated weakly with seizure frequency in the last 2 months (rs  = .162, p = .047). SIGNIFICANCE: Most patients with epilepsy do not have biochemical evidence of brain injury. The association with seizures merits further study; future studies should aim for longitudinal sampling and examine whether individual variations in NfL or GFAP levels could reflect seizure activity

The provision of epilepsy care across Europe 2017 : a 17-year follow-up survey

OBJECTIVE: To assess the resources available in the provision of epilepsy care across Europe and the developments since the International League Against Epilepsy (ILAE) survey published in 2003 (data collected in 2000).METHODS: An updated online version of the European Epilepsy Services Inventory was distributed to all European chapters of the ILAE (N = 47) and responses were obtained from 33 chapters (response rate 70%). To assess trends and allow comparisons with the survey published in 2003, the responding countries were divided into 4 groups (Western, Central, Southern, and Eastern). Responses from European Union (EU) member states are reported as a subgroup (N = 23), since the current survey is a part of the EU‐funded European Study on the Burden and Care of Epilepsy (ESBACE, www.esbace.eu).RESULTS: The total number of physicians involved in epilepsy care had increased since 2000, with the largest increase seen for neurologists. The gap between the best‐ and the least‐provided areas with regard to the competence of the providers had diminished. However, the density of comprehensive multidisciplinary epilepsy teams had not changed to any greater degree. The main problems reported by the chapters were to a large extent the same as in 2000 and included lack of specialists and specialist care, lack or underuse of epilepsy surgery, and problems regarding financing and resource allocation. Several chapters also highlighted problems with healthcare structure and organization.SIGNIFICANCE: Although there have been some improvements concerning the availability of care for people with epilepsy in Europe over the last 17 years, there are still a number of problem areas with little improvement or where there are important regional differences.European Union (Directorate General for Health and Food safety), Grant/Award Number: 2014/1/1995648peer-reviewe

Potential for improved retention rate by personalized antiseizure medication selection: A register-based analysis

Objective: The first antiseizure medication (ASM) is ineffective or intolerable in 50% of epilepsy cases. Selection between more than 25 available ASMs is guided by epilepsy factors, but also age and comorbidities. Randomized evidence for particular patient subgroups is seldom available. We asked whether register data could be used for retention rate calculations based on demographics, comorbidities, and ASM history, and quantified the potential improvement in retention rates of the first ASM in several large epilepsy cohorts. We also describe retention rates in patients with epilepsy after traumatic brain injury and dementia, patient groups with little available evidence. Methods: We used medical, demographic, and drug prescription data from epilepsy cohorts from comprehensive Swedish registers, containing 6380 observations. By analyzing 381 840 prescriptions, we studied retention rates of first- and second-line ASMs for patients with epilepsy in multiple sclerosis (MS), brain infection, dementia, traumatic brain injury, or stroke. The rank of retention rates of ASMs was validated by comparison to published randomized control trials. We identified the optimal stratification for each brain disease, and quantified the potential improvement if all patients had received the optimal ASM. Results: Using optimal stratification for each brain disease, the potential improvement in retention rate (percentage points) was MS, 20%; brain infection, 21%; dementia, 14%; trauma, 21%; and stroke, 14%. In epilepsy after trauma, levetiracetam had the highest retention rate at 80% (95% confidence interval [CI] = 65–89), exceeding that of the most commonly prescribed ASM, carbamazepine (p\ua0=.04). In epilepsy after dementia, lamotrigine (77%, 95% CI = 68–84) and levetiracetam (74%, 95% CI = 68–79) had higher retention rates than carbamazepine (p\ua0=.006 and p\ua0=.01, respectively). Significance: We conclude that personalized ASM selection could improve retention rates and that national registers have potential as big data sources for personalized medicine in epilepsy

Antiepileptogenesis after Stroke - Trials and Tribulations: Methodological Challenges and Recruitment Results of a Phase II Study with Eslicarbazepine Acetate.

There is currently no evidence to support the use of antiseizure medications to prevent unprovoked seizures following stroke. Experimental animal models suggested a potential antiepileptogenic effect for eslicarbazepine acetate (ESL), and a Phase II, multicentre, randomised, double-blind, placebo-controlled study was designed to test this hypothesis and assess whether ESL treatment for 1 month can prevent unprovoked seizures following stroke. We outline the design and status of this antiepileptogenesis study, and discuss the challenges encountered in its execution to date. Patients at high risk of developing unprovoked seizures after acute intracerebral haemorrhage or acute ischaemic stroke were randomised to receive ESL 800 mg/day or placebo, initiated within 120 hours after primary stroke occurrence. Treatment continued until Day 30, then tapered off. Patients could receive all necessary therapies for stroke treatment according to clinical practice guidelines and standard of care, and are being followed up for 18 months. The primary efficacy endpoint is occurrence of a first unprovoked seizure within 6 months after randomisation ('failure rate'). Secondary efficacy assessments include occurrence of a first unprovoked seizure during 12 months after randomisation and during the entire study; functional outcomes (Barthel Index original 10-item version; National Institutes of Health Stroke Scale); post-stroke depression (Patient Health Questionnaire-9; PHQ-9); and overall survival. Safety assessments include evaluation of treatment-emergent adverse events; laboratory parameters; vital signs; electrocardiogram; suicidal ideation and behaviour (PHQ-9 question 9). The protocol aimed to randomise approximately 200 patients (1:1), recruited from 21 sites in seven European countries and Israel. Despite the challenges encountered, particularly during the COVID-19 pandemic, the study progressed and included a remarkable number of patients, with 129 screened and 125 randomised. Recruitment was stopped after 30 months, the first patient entered in May 2019, and the study is ongoing and following up on patients according to the Clinical Trial Protocol

Научно-исследовательская, культурно-массовая, физкультурно-спортивная и общественная деятельность студентов как факторы успешности их учебно-познавательного процесса

Материалы IV Респ. науч.-метод. конф., посвящ. 120-летию со дня рождения П. О. Сухого, Гомель, 29–30 окт. 2015 г

Dissociated Representations of Pleasant and Unpleasant Olfacto-Trigeminal Mixtures: An fMRI Study

How the pleasantness of chemosensory stimuli such as odorants or intranasal trigeminal compounds is processed in the human brain has been the focus of considerable recent interest. Yet, so far, only the unimodal form of this hedonic processing has been explored, and not its bimodal form during crossmodal integration of olfactory and trigeminal stimuli. The main purpose of the present study was to investigate this question. To this end, functional magnetic resonance imaging (fMRI) was used in an experiment comparing brain activation related to a pleasant and a relatively unpleasant olfacto-trigeminal mixture, and to their individual components (CO2 alone, Orange alone, Rose alone). Results revealed first common neural activity patterns in response to both mixtures in a number of regions: notably the superior temporal gyrus and the caudate nucleus. Common activations were also observed in the insula, although the pleasant mixture activated the right insula whereas the unpleasant mixture activated the left insula. However, specific activations were observed in anterior cingulate gyrus and the ventral tegmental area only during the perception of the pleasant mixture. These findings emphasized for the firs time the involvement of the latter structures in processing of pleasantness during crossmodal integration of chemosensory stimuli

Semantic Knowledge Influences Prewired Hedonic Responses to Odors

Background Odor hedonic perception relies on decoding the physicochemical properties of odorant molecules and can be influenced in humans by semantic knowledge. The effect of semantic knowledge on such prewired hedonic processing over the life span has remained unclear. Methodology/Principal Findings The present study measured hedonic response to odors in different age groups (children, teenagers, young adults, and seniors) and found that children and seniors, two age groups characterized by either low level of (children) or weak access to (seniors) odor semantic knowledge, processed odor hedonics more on the basis of their physicochemical properties. In contrast, in teenagers and young adults, who show better levels of semantic odor representation, the role of physicochemical properties was less marked. Conclusions/Significance These findings demonstrate for the first time that the biological determinants that make an odor pleasant or unpleasant are more powerful at either end of the life span

Adhesion molecules and synapse remodeling during motoneuron regeneration

Spinal motoneurons integrate a vast synaptic input and are the final conveyors of motor commands to skeletal muscle. Motoneuron regeneration includes altered contacts between the motoneuron and several other cell types. The severed axon elongates along Schwann cells in the nerve, while other types of glia interact closely with lesioned motoneurons in the spinal cord. Simultaneously, cell contacts are disrupted when synapses are lost from lesioned motoneurons in a process called synaptic stripping. The aim of this thesis project was to identify potential mediators of cell interactions during motoneuron regeneration, with special emphasis on molecules that could be of importance for synaptic remodeling. A reduced expression of cell adhesion molecules has been speculated to be involved in synaptic stripping of motoneurons. Over the last years, several such molecules have been described which influence formation and maintenance of synapses, and also mediate adhesion in other events that occur during motoneuron regeneration, such as axon guidance and myelination. We demonstrate that peripheral axotomy of sciatic motoneurons results in altered expression of several cell adhesion molecules, many of which are previously unstudied in this context. Some of these changes indicate possible involvement of the molecules in synapse elimination, whereas other molecules may be involved in other regenerative events. Specifically, the expression of nectin-1 and -3 increased in lesioned motoneurons, as did the expression of nectin-3-binding necl-5. Nectin proteins did not localize to synapses on spinal motoneurons, but instead to neuronal processes and glia, both within the spinal cord and in the lesioned sciatic nerve. Immunoreactivity for N-cadherin localized to synapses on the surface of motoneurons and was reduced after sciatic nerve transection (SNT). Motoneuron expression of mRNA encoding N-cadherin was not altered after axotomy, and immunoreactivity for the molecule increased in the severed nerve. Axotomy also resulted in altered expression of SynCAM3/necl-1 and SynCAM4/necl-4 in the nerve, which indicates possible involvement of these molecules in remyelination. SynCAM1/necl-2, SynCAM2/necl-3, and neuroligin (NLG) -2 and -3 were expressed by unlesioned motoneurons, and SynCAM immunoreactivity localized to synapses on motoneuron cell bodies. In vitro these molecules have synapse-inducing properties, and following SNT, expression of SynCAM1 and NLG2 and -3 decreased rapidly, prior to loss of staining for synaptophysin in the motoneuron pool. SynCAM1 expression correlated to loss and return of synapses in regeneration after SNT. NLG expression decreased to a smaller degree after sciatic nerve crush than after SNT, although the loss of synapses was similar in both lesion models. Finally, while this work was ongoing, complement-tagging of CNS synapses for removal was demonstrated to occur in the visual system. We investigated whether complement could be involved also in synapse removal from axotomized motoneurons. Complement C3-/- mice displayed reduced synaptic stripping after lesion, a larger upregulation of growth-associated protein 43 in motoneurons, and a more rapid restoration of motor function. We conclude that the motoneuron response to axotomy involves downregulation of several synaptic adhesion molecules. Expression of SynCAM1 correlates closely to the loss and return of synapses but the magnitude of the downregulation of NLGs does not seem to reflect the magnitude of the loss of synapses. Contact with the distal nerve stump may stimulate expression of NLGs, but does not seem to influence that of SynCAM1. Expression of NLGs and SynCAM1 does not seem to be the sole determinant of the elimination of synapses, since the expression pattern of these molecules was similar in mice with altered synaptic stripping and wild type mice. We also conclude that complement C3 is required for normal synapse elimination. Thus, complement may be a potential target in therapeutic attempts to preserve synaptic circuits