The long-term effects of heated tobacco product exposure on the central nervous system in a mouse model of prodromal Alzheimer's disease.

Heated tobacco products (HTPs) have emerged as novel alternatives to conventional cigarettes (CCs), marketed by the tobacco industry as having a reduced potential for harm. Nevertheless, a significant dearth of information remains regarding the long-term effects of HTPs on the central nervous system (CNS). Here, we sought to shed light on the repercussions of prolonged exposure to HTPs on the CNS, employing a mouse model mimicking prodromal Alzheimer's disease (AD). Our study entailed subjecting App knock-in mice to 16 weeks of HTP exposure, administered 5 days per week, with serum cotinine concentration serving as confirmation of HTP exposure within this model. Histological analysis, aimed at assessing amyloid pathology, unveiled a minimal impact attributable to HTPs. However, exploration of differentially expressed genes in the cerebral cortex, using unadjusted p values, indicated an association between HTP exposure and non-inflammatory pathways, specifically linked to neurohypophyseal and neuropeptide hormone activity within the CNS. Of note, similar results have already been observed after exposure to CCs in vivo. Our study not only contributes insights into the potential non-inflammatory effects of HTPs within the context of AD pathogenesis but also underscores the significance of continued research to comprehend the full scope of their impact on the CNS.

On-scene time delays for epileptic seizures in developed community-based integrated care system regions.

BACKGROUND: Delayed on-scene time by emergency medical services (EMS) can have detrimental effects on critical cases for people with epilepsy (PWE). In preparation for a super-aged society, a Community-based Integrated Care System is crucial to manage healthcare costs. However, sufficient coordination irrespective of sociomedical changes among medical providers is challenging. AIM: This study aimed to evaluate on-scene time delays in the treatment of PWE, identify factors associated with such delays, and clarify regional differences. The focus was on the volume of acute care beds in regions with a developed Community-based Integrated Care System. METHODS: This population-based observational study evaluated on-scene time delays in the treatment of PWE across six major cities in western Japan between 2017 and 2021. In addition, we also evaluated the association between regional differences focusing on volume of acute care beds ("Reduced region" and "Preserved region", as cities with numbers of acute care beds per 1,000 people below and above the national average, respectively) along with sociomedical factors associated with on-scene time delays. RESULTS: This study included 8,737 PWE transported by EMS, with a mean on-scene time for EMS ranging from 12.9 ± 6.8 min to 21.7 ± 10.6 min. On-scene time delays were evident in Reduced regions, with an increase of 1.45 min (95 % confidence interval 0.86-2.03 min, p < 0.001). A high total EMS call volume independently influenced on-scene time delays during the middle period of the pandemic in Reduced regions. CONCLUSION: Optimal coordination must be facilitated to ensure the effective functioning of the Community-based Integrated Care System, particularly during unusual circumstances.

Apolipoprotein E genotype-dependent accumulation of amyloid ß in APP-knock-in mouse model of Alzheimer's disease.

Apolipoprotein E4 (APOE4), the strongest risk factor for late-onset Alzheimer's disease (AD), has been revealed to cause greater accumulation of extracellular amyloid ß (Aß) aggregates than does APOE3 in traditional transgenic mouse models of AD. However, concerns that the overexpression paradigm might have affected the phenotype remain. Amyloid precursor protein (APP)-knock-in (KI) mice, incorporating APP mutations associated with AD development, offer an alternative approach for overproducing pathogenic Aß without needing overexpression of APP. Here, we present the results of comprehensive analyses of pathological and biochemical traits in the brains of APP-KI mice harboring APP-associated familial AD mutations (APPNL-G-F/NL-G-F mice) crossed with human APOE-KI mice. Immunohistochemical and biochemical analyses revealed the APOE genotype-dependent increase in Aß pathology and glial activation, which was evident within 8 months in the mouse model. These results suggested that this mouse model may be valuable for investigating APOE pathobiology within a reasonable experimental time frame. Thus, this model can be considered in investigating the interaction between APOE and Aß in vivo, which may not be addressed appropriately by using other transgenic mouse models.

Paradoxical effects of levetiracetam in people with epilepsy with rhythmic epileptiform discharges.

OBJECTIVE: To elucidate the incidence and risk factors for paradoxical effects (i.e., increased seizure frequency, increased seizure severity, or onset of new seizure types) of levetiracetam (LEV) in people with epilepsy (PWE) and identify the usefulness of electroencephalography (EEG) in predicting these effects. METHODS: We examined data for consecutive PWE treated with LEV. All PWE underwent EEG and magnetic resonance imaging (MRI) before LEV administration. We also evaluated the incidence of paradoxical LEV effects and conducted multivariate logistic regression analyses to identify the associated factors. RESULTS: In total, 210 (66.2%) of 317 PWEs treated in our department had a history of LEV use. The incidence of paradoxical LEV effects was 5.2% (n = 11) and was significantly associated with a high LEV dose (p = 0.029), high seizure frequency (p = 0.005), temporal lobe epilepsy (p = 0.004), focal awareness seizure (p = 0.004), focal impaired awareness seizure (p = 0.007), spike (p = 0.015), rhythmic epileptiform discharges (REDs; p = 0.003), and MRI-identified focal cortical dysplasia (FCD; p < 0.0001). Multivariate analyses revealed that REDs (odds ratio [OR] = 5.35, p = 0.048, 95% confidence interval [CI]: 1.01-28.21) were independently associated with paradoxical LEV effects. CONCLUSIONS: Paradoxical LEV effects occurred in PWE, particularly in those with drug-resistant focal epilepsy. Furthermore, the occurrence of REDs in EEG was an independent factor associated with the paradoxical effects of LEV in PWE.

On-scene time delays for epileptic seizures in emergencies during a social pandemic: A population-based study.

OBJECTIVES: The on-scene time of Emergency Medical Services (EMS), including time for hospital selection, is critical for people in an emergency. However, the outbreak of the novel coronavirus disease 2019 (COVID-19) led to longer delays in providing immediate care for individuals with non-COVID-19-related emergencies, such as epileptic seizures. This study aimed to examine factors associated with on-scene time delays for people with epilepsy (PWE) with seizures needing immediate amelioration. MATERIALS & METHODS: We conducted a population-based retrospective cohort study for PWE transported by EMS between 2016 and 2021. We used data from the Hiroshima City Fire Service Bureau database, divided into three study periods: "Pre period", the period before the COVID pandemic (2016-2019); "Early period", the early period of the COVID pandemic (2020); and "Middle period", the middle period of the COVID pandemic (2021). We performed linear regression modeling to identify factors associated with changes in EMS on-scene time for PWE during each period. In addition, we estimated the rate of total EMS call volume required to maintain the same on-scene time for PWE transported by EMS during the pandemic expansion. RESULTS: Among 2,205 PWE transported by EMS, significant differences in mean age and prevalence of impaired consciousness were found between pandemic periods. Total EMS call volume per month for all causes during the same month <5,000 (-0.55 min, 95% confidence interval [CI] -1.02 - -0.08, p = 0.022) and transport during the Early period (-1.88 min, 95%CI -2.75 - -1.00, p < 0.001) decreased on-scene time, whereas transport during the Middle period (1.58 min, 95%CI 0.70 - 2.46, p < 0.001) increased on-scene time for PWE transported by EMS. The rate of total EMS call volume was estimated as 0.81 (95%CI -0.04 - 1.07) during the expansion phase of the pandemic to maintain the same degree of on-scene time for PWE transported by EMS before the pandemic. CONCLUSIONS: On-scene time delays on PWE in critical care settings were observed during the Middle period. When the pandemic expanded, the EMS system required resource allocation to maintain EMS for time-sensitive illnesses such as epileptic seizures. Timely system changes are critical to meet dramatic social changes.

Immediate and 6-month seizure outcomes following first and second SARS-CoV2 mRNA vaccinations: A multicenter study with a nationwide survey.

OBJECTIVE: This study aimed to identify seizure outcomes in people with epilepsy (PWE) following severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) messenger RNA vaccination. METHODS: We examined PWE (n = 332, age ≥ 14 years) treated in four tertiary hospitals between 2021 and 2022 to assess the incidence of seizure worsening following vaccination using closed questions. We identified the clinical factors associated with worsening and 6-month vaccination outcomes. We also conducted a nationwide survey on self-reported seizure worsening using open questions, to which 261 general practitioners from 99 institutes contributed. RESULTS: Of the 282 PWE vaccinated in the four hospitals, 16 (5.7%) exhibited seizure worsening; most of them emerged within 48 h of vaccination and were not sustained. Thus, all PWE were at baseline condition 6 months after their vaccination. PWE with seizure worsening were more significantly associated with focal impaired awareness seizures (p < 0.001), high seizure frequency (p = 0.025), and drug-resistant epilepsy (p = 0.007) at baseline compared to PWE without worsening. Multivariate logistic regression analysis revealed that focal impaired awareness seizures were independently associated with worsening (odds ratio, 7.0; 95% confidence interval, 1.50-32.77). A nationwide survey of 5156 PWE data (real-world data) confirmed an extremely low incidence rate of self-reported seizure worsening (0.43%). SIGNIFICANCE: Some PWE, particularly refractory focal epilepsy, exhibit seizure worsening. However, the worsening events were infrequent, non-sustainable, and probably under-reported by PWE, suggesting that there is little evidence that worsening seizures discourage current and future vaccinations.

A longitudinal seizure outcome following the COVID-19 pandemic in 2020 and 2021: Transient exacerbation or sustainable mitigation.

OBJECTIVE: To study the longitudinal seizure outcomes of people with epilepsy (PWE) following the acute and chronic phases of the coronavirus disease 2019 (COVID-19) pandemic. METHODS: Consecutive PWE who were treated at the epilepsy center of Hiroshima University Hospital between 2018 and 2021 were enrolled. We evaluated the incidence of seizure frequency increase or decrease following the pandemic during observational periods in 2020 and 2021. Data between 2018 and 2019 were used as a control set. The sustainability of the altered seizure frequency condition was evaluated throughout the study period. We analyzed the clinical, psychological, and social factors associated with PWE with seizure exacerbation or amelioration. RESULTS: Among the 223 PWE who were evaluated (mean age 37.8 ± 16.3 years), seizure frequency increased for 40 (16.8%) and decreased for 34 (15.2%) after the pandemic began. While seizure exacerbation tended to be a transient episode during 2020, seizure amelioration was likely to maintain excellent status over the observation periods; the sustainability of the altered seizure frequency condition was more prominent for amelioration than exacerbation (p < 0.001). Seizure exacerbation was significantly associated with "no housemate" (odds ratio [OR] 3.37; p = 0.045) and "comorbidity of insomnia" (OR 5.80; p = 0.004). Conversely, "structural abnormality of MRI" (OR 2.57; p = 0.039) and "two-generation householding" (OR 3.70; p = 0.004) were independently associated with seizure amelioration. CONCLUSION: This longitudinal observation confirmed that seizure exacerbation and amelioration emerged during the COVID-19 pandemic. The COVID-19 pandemic has shed light on the stark difference that social support systems can make on outcomes for PWE.

A case of repetitive seizures following immune checkpoint inhibitor therapy as a feature of autoimmune encephalitis.

Pembrolizumab, an immune-checkpoint inhibitor (ICI), is a humanized monoclonal antibody that binds to programmed cell death-1 receptor (PD-1) and thereby inhibits binding to its ligand, which inhibits the suppression of activated T cells by cancer cells, resulting in enhancing antitumour immunity. Although several cases of encephalitis have been reported as immune-related adverse effects of ICIs, epilepsy has not been reported following ICI treatment. We describe the case of an elderly woman with bladder carcinoma who experienced two episodes of generalized seizures after treatment with pembrolizumab. The episodes were atypical of encephalitis, because the seizures were completely responsive to AEDs and the CSF parameters normalized completely without immunotherapy. Since interictal EEG revealed persistent epileptic discharges after the seizures, pembrolizumab was considered to have induced a chronic state of epileptogenicity as the possible pathology, with a clinical picture similar to that of autoimmune epilepsy. The possibility that ICIs may cause an immune-related adverse effect, such as a chronic epileptic condition, should be considered, since ICIs are used widely.

Pomalidomide-associated progressive multifocal leukoencephalopathy in multiple myeloma: cortical susceptibility-weighted imaging hypointense findings prior to clinical deterioration.

Although there are several case reports of progressive multifocal leukoencephalopathy (PML) in multiple myeloma (MM), there are few reports of cases associated with pomalidomide. Here, we report the case of a 69-year-old female who had received 41 cycles of pomalidomide and dexamethasone treatment for relapsed/refractory IgG-κ MM presented with right-hand weakness; she was diagnosed as pomalidomide-associated PML. Fluid-attenuated inversion recovery (FLAIR) on admission showed high signals in the bilateral front-parietal lobe white matter, with multiple punctate lesions in the vicinity of the main lesions. These punctate pattern findings on FLAIR were similar to that of natalizumab-associated PML. Susceptibility weighted imaging (SWI) showed hypointense rims within the cortex at unaffected sites, in the initial stages. Subsequently, the clinical manifestations deteriorated, and the FLAIR images showed new hyperintense white matter lesions at the sites where cortical SWI hypointense rims were detected on the initial MRI examination. Our patient's serial MRI findings suggest that cortical SWI hypointense rims appear prior to the visible demyelinating white matter lesions in patients with PML.