Aim: Diabetic polyneuropathy is the most described complication in patients with diabetes mellitus. A significant percentage of these patients experience disabling neuropathic pain (painful diabetic polyneuropathy). Small nerve fibers are primarily responsible for peripheral nociception, but objectively assessing its function is challenging. The primary objective of this study was to explore the task execution and outcomes of intra-epidermal electrical stimulation technique that combines nociceptive detection thresholds (NDT) and evoked potentials (EPs) in patients with diabetes. We compared the results of diabetic patients, both with and without painful diabetic polyneuropathy, with those of healthy controls to explore potential clinically relevant information.
Methods: The NDT-EP method was applied to 38 patients with diabetes (18 with and 20 without chronic painful neuropathy) and 38 age- and sex-matched healthy controls. Individual mean NDTs, psychometric slopes, EP amplitudes, and the effect of the stimuli on EP amplitudes were analyzed and compared between groups using linear regression.
Results: The findings revealed significantly lower detection rates, higher NDTs, and lower psychometric slopes in patients with painful diabetic polyneuropathy than in healthy controls. Both patient groups significantly exhibited lower mean EP amplitudes than healthy controls, which were not linked to pulse amplitudes but influenced by stimulus detection.
Conclusions: This study showed altered NDT-EP outcomes in patients with painful diabetic polyneuropathy. Whereas the task execution, NDTs, and psychometric slopes may provide valuable insights into small fiber dysfunction, pulse amplitudes seemed not differently encoded in neurophysiological responses to intra-epidermal electrical stimulation near the detection threshold compared to controls. Future studies should investigate whether the altered NDT-EP outcomes could quantify small fiber dysfunction in patients with diabetes mellitus. We recommend further exploration of NDT-EP measures in other patient groups with nociceptive dysfunction.
Aim: Seizure and epilepsy adverse events (AEs) can occur following vaccination. For epilepsy AEs, they are generally expected to only occur at background population frequencies without associations with immunizations. The Vaccine AEs Reporting System (VAERS) collects a subset of AEs experienced by vaccinees, including multiple epilepsy related AEs. This study examines the possibility of immunization associated epilepsy AEs in VAERS occurring above background rates.
Methods: Herein, VAERS is retrospectively examined for epilepsy and seizure AEs following immunizations (AEFIs). Reported AEFIs are normalized by total AEFIs for each vaccine. VAERS data is examined by vaccine type, vaccine source, vaccinee gender, and age-stratified for infants.
Results: Association signals for examined epilepsy and seizure AEFIs are identified for multiple vaccines when compared to other vaccines with normalized frequencies above expected population background frequencies. Normalized epilepsy AEFI frequencies for children less than 1 year are higher than children aged 1 year for several vaccines. For pairs of matched vaccines from different manufacturers, statistically different epilepsy AEFI normalized frequencies were observed. These matched pairs for multiple vaccines implicate likely vaccine contaminations (e.g., endotoxins) as likely candidates for causing elevated epilepsy and seizure AEFIs.
Conclusions: Based on the reported results, delaying some immunizations of a small set of vaccines until children are 1 year of age is predicted to reduce epilepsy AEFI occurrences for these vaccines. For several vaccines, statistically significant differences in epilepsy AEFI normalized frequencies were detected for the same (or similar) vaccine from different manufacturers; this suggests that possible manufacturing contaminant(s) (e.g., endotoxins) as the likely causative agent(s) for observed epilepsy AEFIs above background rates. Eliminating or reducing these possible contaminants is predicted to reduce the observed associations closer to background population levels observed for other vaccines with very low epilepsy AEFI normalized frequencies.
Glioblastoma multiforme (GBM) is the most common malignant primary central nervous system (CNS) tumor. It presents an aggressive pattern, with a tendency for intracranial progression despite optimal treatment. On the other hand, metastases and manifestations outside the CNS are exceptional, and very few cases have been described. The authors submitted a case of a 48-year-old male diagnosed with a left parietooccipital GBM isocitrate dehydrogenase (IDH) wild-type, non-methylated O6-methylguanine-DNA methyltransferase (MGMT). Six months after surgical treatment, followed by a chemotherapy (CT) and radiotherapy scheme, he developed a few subcutaneous erythematous nodules within the surgical scar. A punch biopsy confirmed the histopathology of GBM. The CT scan showed concomitant intracranial progression. We ruled out systemic metastases. As the performance status was good [Karnofsky Performance Status 90 (KPS 90)] and the subcutaneous implants were growing rapidly, limiting the quality of life, we decided to perform palliative surgery to remove the implants. The result was good. Unfortunately, the patient worsened during the following week, after ruling out medical complications, we attributed the worsening to cerebral tumor swelling, revealed in the CT scan, as unresponsive to steroids. He passed away a few days later. Based on the analysis of our case, we intend to provide useful information for the approach to this peculiar manifestation of GBM.
Aim: Patients with tuberous sclerosis complex (TSC) which is caused by hyperactivation of mechanistic target of rapamycin complex 1 (mTORC1) often show giant cells in the brain. These giant cells are thought to be involved in epileptogenesis, but the underlying mechanisms are unknown. In this study, we focused on mTORC1 activation and γ-amino butyric acid (GABA)ergic signaling in somatostatin-expressing inhibitory neurons (SST-INs) using TSC-related epilepsy model mice.
Methods: We analyzed the 8-week-old Tsc2 conditional knockout (Tsc2 cKO) mice, which have epileptic seizures that are cured by sirolimus, an mTORC1 inhibitor. After the occurrence of epileptic seizures was confirmed, Tsc2 cKO mice were treated with vehicle or sirolimus. Then, their brains were investigated by hematoxylin and eosin staining, immunohistochemical staining and immunoblotting assay.
Results: As in TSC patients, giant cells with hyperactivation of mTORC1 were found in the cerebral cortex of Tsc2 cKO mice. These giant cells were mainly SST-INs in the cortical layers 4/5. Giant cells showed decreased expression of GABA type A receptor subunit α1 (GABAAR-α1) compared with normal size cells in control mice and Tsc2 cKO mice. In addition, decreased GABAAR-α1 expression was also confirmed by immunoblotting assay of the whole cerebral cortex. In the cerebral cortex of sirolimus-treated Tsc2 cKO mice, whose epileptic seizures were cured, decreased GABAAR-α1 expression was recovered to the same level as in control mice.
Conclusions: These results suggest that the epileptic seizures in Tsc2 cKO mice are caused by the deregulation of GABAergic signaling through mTORC1 activation of SST-INs localized in cortical layers 4/5.
Glioblastoma multiforme (GBM) is characterized by its infiltrative growth pattern and high recurrence rate despite treatment. While local progression within the central nervous system (CNS) is the rule, manifestations outside the CNS, particularly skin and subcutaneous metastases, are very infrequent and seldom reported in the literature. The authors reviewed the current understanding of this rare condition, with the main purpose of giving visibility to its clinical presentation and prognostic implications, thus improving clinical management and encouraging research in this area. A PubMed, Cochrane Library, and EMBASE search from database inception through March 2024 was conducted. In this way, we compiled a total of thirty-five cases in our review. As far as we know, our work gathers the largest number of patients with this condition. Remarkably, we observed that the typical presentation of soft-tissue high-grade glioma metastases is the finding of subcutaneous erythematous nodules in patients previously operated on for a primary CNS tumor, within the craniotomy site and nearby, mostly in the first year after the initial surgery. It was also noted that there is a trend of developing a concomitant CNS recurrence and/or other metastases in different locations, either simultaneously or subsequently. From here, we propose some possible mechanisms that explain the extracranial spread of GBM. We concluded that a poor outcome is expected from the diagnosis of skin and subcutaneous metastases: the mean overall survival was 4.38 months. Yet, assessing individual characteristics is always mandatory; a palliative approach seems to be the best option for the majority of cases.
Melatonin is widely available as a dietary supplement and/or medicine for sleep. It is an endogenous hormone produced in the pineal gland of the brain, with metabolites providing additional beneficial mechanisms such as supporting long-term memory. Melatonin is well known as a hormone that plays a role in the circadian rhythm (sleep cycle), but additional mechanisms such as antioxidant, and anti-inflammatory activity are elucidated from animal research models. This article discusses melatonin supplementation and the current understanding of how it may provide benefits beyond the use as a sleep aid including a review of the evidence in how it may aid in mitigating components of cognitive decline.
Aim: We aimed to undertake a small study comparing buccal midazolam and rectal diazepam in the emergency out-of-hospital treatment of prolonged or serial epileptic seizures in children. We wanted to see if the parent/carer could not only administer the emergency medication but also document the timings and outcomes of the trial. We also aimed to demonstrate parental preference for either treatment.
Methods: This was an open-label, randomised, cross-over clinical trial. The primary outcome was parental preference, secondary outcomes included therapeutic success (seizure stopped within 10 minutes of treatment with no relapse in the next 24 hours), and adverse events. Research Ethics Committee approval and appropriate written informed consent were obtained for all participants. Identical convenient age-related doses of buccal midazolam and rectal diazepam were used: for those aged 6 to < 12 months, 2.5 mg was prescribed; for those aged 1 to < 5 years, 5 mg; 5 to < 10 years, 7.5 mg; 10 years and over, 10 mg. Appropriate randomisation and statistical methods were used.
Results: Twelve children, three males, aged 2.5–8 (median 5) years, including 10/12 with developmental delay or intellectual impairment completed the trial. Each participant had between 2–4 types of epileptic seizure, was taking 2–3 different regular antiseizure medications, and had been previously on 2–9 (median 3) regular other antiseizure medications in the past. Nine of twelve parents preferred buccal midazolam, 1/12 preferred rectal diazepam (P < 0.05). Therapeutic success was seen in 7/12 participants with either treatment. No respiratory depression was seen in this small trial.
Conclusions: Buccal midazolam was clearly preferred to rectal diazepam by parents. This small study was not powered to show a difference in efficacy and adverse effects. The study did show that the cross-over design with parents recording trial data, including data for the outcome measures was feasible.
Depression is characterized by affective symptoms and neuropsychological deficits. After treatment, affective symptoms frequently remit, but cognitive alterations may remain affecting the lives of people and having an impact on health, economy, and societies. The present work describes the methods, procedures, and equipment for a randomized three-arm controlled experiment designed to measure the effects of exergames on executive functions (EFs) under depression. EFs are complex cognitive functions that are essential for organizing information, planning an action, reasoning, decision-making, and problem-solving. Literature shows that EFs are compromised in depression, affecting daily-life activities and other cognitive domains. To conduct the experiment, depressed middle-aged adults will be randomly distributed into three experimental groups: an intervention group training with exergames, an active control group training only with cognitive video games, and a passive control group or wait-list. EFs are evaluated at three different time points: pre-post intervention, and three months follow-up, using the Wisconsin Card Sorting Test (WCST). Researchers will collect cognitive-behavioral and neural information [event-related potentials (ERPs)]. Results will be explored by performing analysis of variance to compare the outcomes of the diverse groups at the three different time points, understanding the benefits of exergames in terms of EFs under depression. The study of simultaneous multidomain interventions in depression holds promise for the development of novel approaches, to implementing psychological and neuropsychological health [this experiment is part of a registered clinical trial entitled “MUDgame” (ClinicalTrials.gov identifier NCT06536530). Registered on August 2024, https://clinicaltrials.gov/study/NCT06536530].