Possible Roles of Extracellular Vesicles in the Pathogenesis and Interventions of Immune-Mediated Central Demyelinating Diseases.

Multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) are two of the most devastating immune-mediated central demyelinating disorders. NMOSD was once considered as a variant of MS until the discovery of an antibody specific to the condition. Despite both MS and NMOSD being considered central demyelinating disorders, their pathogenesis and clinical manifestations are distinct, however the exact mechanisms associated with each disease remain unclear. Extracellular vesicles (EVs) are nano-sized vesicles originating in various cells which serve as intercellular communicators. There is a large body of evidence to show the possible roles of EVs in the pathogenesis of several diseases, including the immune-mediated central demyelinating disorders. Various types of EVs are found across disease stages and could potentially be used as a surrogate marker, as well as acting by carrying a cargo of biochemical molecules. The possibility for EVs to be used as a next-generation targeted treatment for the immune-mediated central demyelinating disorders has been investigated. The aim of this review was to comprehensively identify, compile and discuss key findings from in vitro, in vivo and clinical studies. A summary of all findings shows that: 1) the EV profiles of MS and NMOSD differ from those of healthy individuals, 2) the use of EV markers as liquid biopsy diagnostic tools appears to be promising biomarkers for both MS and NMOSD, and 3) EVs are being studied as a potential targeted therapy for MS and NMOSD. Any controversial findings are also discussed in this review.

Relationships between intracranial arterial dolichoectasia and small vessel disease in patients with ischaemic stroke: a systematic review and meta-analysis.

BACKGROUND: Intracranial arterial dolichoectasia (IADE) is a common arterial finding of dilation, elongation, or both, affecting large intracranial vessels, and associated with vascular risk factors, including hypertension. Associations of IADE with neuroimaging cerebral small vessel disease (CSVD) may be relevant for diagnosis and prognosis in patients with stroke. The study aimed to conduct an updated systematic review and meta-analysis of observational studies to investigate the relationships of IADE with well-defined CSVD markers in patients with ischaemic stroke. METHODS: We systematically searched PubMed, Embase, and Scopus for studies on IADE in ischaemic stroke patients with fulfilling predefined inclusion criteria. We pooled data to conduct a meta-analysis to compare the prevalence of SVD markers between patients with and without IADE groups using risk ratios (RRs) and 95% confidence intervals (CIs). RESULTS: From 157 retrieved abstracts, we included six studies from seven publications comprising 6102 patients with ischaemic stroke. The mean age of patients was 52.8 years, and 3691 (60.5%) were male. IADE was diagnosed in 11.4% (95% CI 8.9-13.9) (761) of included patients; 51.8% (3160) had hypertension. Compared to patients without IADE, individuals diagnosed with IADE had a significantly increased prevalence of lacune (RR 1.67, 95% CI 1.36-2.06, P < 0.01, I2 = 0.00%), cerebral microbleeds (CMBs) (RR 2.56, 95% CI 1.53-4.28, P < 0.01, I2 = 84.95%) and white matter hyperintensities (WMHs) (RR 2.17, 95% CI 1.84-2.56, P < 0.01, I2 = 0.00%). CONCLUSIONS: In patients with ischaemic stroke, IADE is associated with a higher prevalence of CSVD markers, including lacunes, CMBs, and WMHs. Further studies are needed to clarify the mechanisms underlying these associations and their potential relevance for the understanding, diagnosis, and treatment of CSVD.

The diagnostic tests and functional outcomes of acute ischemic stroke or transient ischemic attack in young adults: A 4-year hospital-based observational study.

BACKGROUND AND OBJECTIVES: Ischemic strokes in young adults have been a significant concern due to various potential etiologies and had substantial clinical and public health impacts. We aimed to study the diagnostic tests, etiologies, and functional outcomes of acute ischemic stroke (AIS) and transient ischemic attack (TIA) in young adult patients. METHODS: The data were retrieved from the Chiang Mai University Hospital Stroke Registry between January 2018 and December 2021. Consecutive AIS or TIA patients were included if they were 18-50 years and had no stroke mimics. Study outcomes were proportions of positive diagnostic tests, and 90-day modified Rankin Scale (mRS). RESULTS: Of 244 enrolled patients, 59.0% (n = 144) were male, and 38.1% (n = 93) were aged 18-40, classified as the younger age group. There was a high incidence of diabetes (24.5%) and dyslipidemia (54.3%) among patients aged 41-50, associated with small-vessel occlusion and large-artery atherosclerosis stroke classification in this age group. Patients aged 18-40 years had more other determined etiologies (39.8%), with hypercoagulability (8.2%), arterial dissection (7.8%), and cardiac sources (6.6%) being the first three causes, which were associated with higher anticoagulant treatment. The cerebrovascular study, cardiac evaluation using echocardiography, and antiphospholipid syndrome testing were commonly performed, of which computed tomography angiography provided a high proportion of positive results (80.3%). 76.3% of young adult patients had excellent functional outcomes (mRS 0-1) with a median mRS of 0 (interquartile range 0-1) at 90-day follow-up. CONCLUSIONS: Stroke of other determined etiology remained the common cause of stroke in young adults, and most affected individuals had excellent clinical outcomes. Blood tests for arterial hypercoagulability and noninvasive vascular and cardiac evaluations are encouraged in selected patients to determine the stroke etiology and guide for appropriate preventive strategies.

Serum NT-proBNP level for predicting functional outcomes after acute ischemic stroke.

N-terminus pro-brain natriuretic peptide (NT-proBNP) has been studied and recognized as a biomarker of cardiac thrombogenicity and stroke risk. However, the association between NT-proBNP and functional outcomes following acute ischemic stroke is still debated. This study aimed to investigate whether serum NT-proBNP level is associated with functional outcomes in acute ischemic stroke individuals. This prospective cohort study included patients diagnosed with acute ischemic stroke, and serum NT-proBNP levels were measured within 72 h. At 3 months, all patients were followed up for a modified Rankin Scale (mRS), and logistic regression models were used to evaluate the association of NT-proBNP on the primary outcome, in which a score of 3-6 was classified as an unfavorable functional outcome. Sixty-seven patients were enrolled in the study, and 23 (34.3%) patients were identified with an unfavorable functional outcome. Elevated serum NT-proBNP levels (> 100 pg/mL) were observed in 57 (85.1%) patients, and the Youden index demonstrated a cutpoint estimation of poor outcomes at 476 pg/mL with 74% sensitivity and 63% specificity. Multivariate regression analysis showed an elevation of NT-proBNP above the cutpoint level was an independent predictor for unfavorable functional outcomes, odds ratio 3.77, 95% confidence interval (1.04-13.62), P = 0.04. The present study demonstrated that elevated serum NT-proBNP levels were expected among acute ischemic stroke patients and represented the risk of unfavorable functional outcomes, suggesting that NT-proBNP might be a useful biomarker for predicting prognosis after ischemic stroke.

A Simplified Risk Score to Predict In-Hospital Newly-Diagnosed Atrial Fibrillation in Acute Ischemic Stroke Patients.

Purpose: Atrial fibrillation (AF) is a significant cause of stroke, and newly diagnosed AF (NDAF) is typically detected in the early period of stroke onset. We aimed to identify the factors associated with in-hospital NDAF in acute ischemic stroke patients and developed a simplified clinical prediction model. Methods: Patients with cryptogenic stroke aged 18 years or older who were admitted between January 2017 and December 2021 were recruited. NDAF was determined by inpatient cardiac telemetry. Univariable and multivariable regression analyses were used to evaluate the factors associated with in-hospital NDAF. The predictive model was developed using regression coefficients. Results: The study enrolled 244 eligible participants, of which 52 NDAFs were documented (21.31%), and the median time to detection was two days (1-3.5). After multivariable regression analysis, parameters significantly associated with in-hospital NDAF were elderly (>75 years) (adjusted Odds ratio, 2.99; 95% confident interval, 1.51-5.91; P = 0.002), female sex (2.08; 1.04-4.14; P = 0.04), higher admission national institute of health stroke scale (1.04; 1.00-1.09; P = 0.05), and presence of hyperdense middle cerebral artery sign (2.33; 1.13-4.79; P = 0.02). The area under the receiver operating characteristic curve resulted in 0.74 (95% CI 0.65-0.80), and the cut-point of 2 showed 87% sensitivity and 42% specificity. Conclusion: The validated and simplified risk scores for predicting in-hospital NDAF primarily rely on simplified parameters and high sensitivity. It might be used as a screening tool for in-hospital NDAF in stroke patients who initially presumed cryptogenic stroke.

Preseptal and Pretarsal Botulinum Toxin Injection in Hemifacial Spasm and Blepharospasm: A 10-Year Comparative Study.

Purpose: Preseptal and pretarsal botulinum toxin injections are approved for treatment of hemifacial spasm and blepharospasm. However, the long-term data is limited. We compared the efficacy, safety, and costs between preseptal and pretarsal injection in hemifacial spasm and blepharospasm. Patients and Methods: The data were retrieved between 2011 and 2021. Consecutive hemifacial spasm and blepharospasm botulinum toxin patients were categorized as preseptal or pretarsal. Study outcomes were the difference in pre-and post-treatment modified Jankovic scale, self-reporting scales, time-related treatment, safety, and cost. Results: Of 152 botulinum toxin-injected patients, 117 (77.0%) patients had hemifacial spasm and 35 (33.0%) patients had blepharospasm. Analysis included data pertinent to 1665 injections in hemifacial spasm (920 preseptal and 745 pretarsal) and 527 injections in blepharospasm (210 preseptal and 317 pretarsal). The difference between pre-and post-treatment modified Jankovic scale was lower in the preseptal group than in the pretarsal group in both hemifacial spasm and blepharospasm (1.5±0.8 vs 1.8±0.6, P-value <0.001 and 1.8±0.8 vs 3.1±0.9, P-value <0.001). There was no difference in duration of maximum response in hemifacial spasm between groups, while the blepharospasm with preseptal had a longer duration than blepharospasm with pretarsal. The preseptal injection was associated with more adverse events overall than the pretarsal (9.4% vs 5.2%, P-value <0.001). The total dose and cost per session in the preseptal group is lower for onabotulinum toxin but higher for abobotulinum toxin. Conclusion: Pretarsal injections reduced symptom severity with fewer side effects. Further studies on the pharmacoeconomics of both techniques are required.

Impact of dabigatran dose on drug levels in asian patients with atrial fibrillation or venous thromboembolism: evidence from pharmacological to clinical outcomes.

Dabigatran is commonly used in atrial fibrillation (AF) or venous thromboembolism (VTE). However, there was limited data on dabigatran levels in Asian patients. This study aimed to investigate plasma levels of dabigatran 110 mg (D110) or 150 mg (D150) twice daily and their impact on clinical outcomes in Thai patients. This was a prospective cohort study including patients who were diagnosed with AF or VTE and were prescribed either D110 or D150. Plasma dabigatran levels were measured using the diluted thrombin time method. All patients were observed for bleeding and thrombotic complications for 12 months after enrollment. Ninety patients were included in the study (45 in the D110 group and 45 in the D150 group). For the D110 group, there was no significant difference in trough and peak levels in patients with creatinine clearance (CrCl) < 50 ml/min compared to those with CrCl ≥ 50 ml/min. For the D150 group, patients with CrCl < 50 ml/min had significantly higher trough and peak levels compared to those with CrCl ≥ 50 ml/min (P = 0.016 for trough, P = 0.005 for peak). Multivariate regression analysis showed females and low CrCl were independent risk factors for high dabigatran levels. Most patients (83.33%) who experienced bleeding complications had peak levels within the expected range. D150 was associated with higher plasma dabigatran levels, especially in those with impaired renal function.

Outcomes of asymptomatic recombinant tissue plasminogen activator associated intracranial hemorrhage.

BACKGROUND: Intracranial hemorrhage (ICH) is the most devastating complication of recombinant tissue plasminogen activator (rtPA) treatment in acute ischemic stroke patients. Data on rtPA-associated asymptomatic ICH (aICH) are limited. OBJECTIVES: To determine the incidence, risk factors, characteristics, management, and clinical outcome of rtPA-associated aICH. METHODS: The data were retrieved from the Chiang Mai University Hospital Stroke Registry between 1995 and 2019. Consecutive ischemic stroke patients were included if they were 18 or older and received rtPA. Study outcomes were the incidence and characteristics of aICH, management, 90-day modified Rankin scale (mRS), National Institute of Health Stroke Scale (NIHSS), Barthel index, and all-cause mortality. RESULTS: Of 725 rtPA treated patients, 166 (16.0%, 95% confidence interval [CI] 13.4-18.9) had aICH, 50 (6.9%, 95% CI 5.2-9.0) had symptomatic ICH (sICH). Patients with aICH had more hemorrhagic infarctions (HI) compared to sICH (81.9% vs 2.0%, P-value < 0.001). Fresh Frozen Plasma and cryoprecipitate were the most common blood products used to reverse the anticoagulant effect in sICH. Craniotomy was performed in 1% and 60% of patients who had aICH and sICH. At 90 days, patients who had aICH had poorer clinical outcomes (mRS, NIHSS and Barthel index) as compared to those without ICH. Compared to non-ICH patients, aICH patients were associated with increased risk of 90-day mortality, the hazard ratio (HR), 3.7, 95% CI 1.6-8.9. CONCLUSIONS: The rtPA-associated aICH increased the risk of morbidity and mortality outcomes. Further treatment consensus, guideline generation, or clinical trials focusing on the treatment of rtPA-associated aICH may be required.

Cerebral venous sinus thrombosis in immune thrombocytopenia patients treated with thrombopoietin receptor agonist: Case reports and literature review.

Introduction and importance: Cerebral venous sinus thrombosis is an uncommon adverse event in immune thrombocytopenia (ITP) patients treated with thrombopoietin receptor agonists (TPO-RAs). Case presentation: We reported two cases of cerebral venous sinus thrombosis after eltrombopag administration. The first case is a 29-year-old ITP woman who recently initiated eltrombopag one month before admission. She presented with progressive headache, visual disturbance, and nausea for six days with unremarkable physical examination except for bilateral optic disc edema. She was treated with enoxaparin and switched to edoxaban when discharged. The second case is a 75-year-old man with a history of vaccine-induced ITP. He was initially treated with dexamethasone and eltrombopag. One month later, he developed acute cerebral venous thrombosis with hemorrhagic infarction in the bilateral frontal lobes. Even though he was treated with intravenous heparin, his status was not improved. He received the best supportive care. Discussion: The pathophysiology of TPO-RAs-associated cerebral venous sinus thrombosis remained unclear but might associate with platelet activation. Most cases of cerebral venous sinus thrombosis occur within two months, thus closed platelet monitoring is important. Conclusion: Careful use and closed monitoring might prevent this event. Indications of initiation and tapering must be considered before TPO-RAs administration. Off-label use may enhance TPO-RA side effects.

Factors Associated with Unfavorable Functional Outcomes After Intravenous Thrombolysis in Patients with Acute Ischemic Stroke.

Purpose: Intravenous thrombolysis (IVT) has become a standard treatment for eligible ischemic stroke patients. However, functional outcomes after receiving IVT varied widely. Hence the primary goal of this study is to identify characteristics related to poor outcomes. Patients and Methods: The study enrolled acute ischemic stroke patients aged 18 or older who received IVT within 4.5 hours after onset between January 2018 and December 2020. The data were retrospectively collected from medical records. The patients were classified as having an excellent (0-2) or poor (3-6) outcomes based on the 90-day modified Rankin Scale (mRS). Univariable and multivariable logistic regression analyses were used to evaluate the results. The predictive model was determined and developed the score using regression coefficients. The prediction power was validated using the area under the receiver operating characteristic curve analysis. Results: The study included 138 eligible participants. Forty-eight patients had unfavorable functional outcomes. With multivariable logistic regression analysis, factors significantly associated with poor outcomes were age (adjusted odds ratio (AOR), 1.03; 95% confidence interval (CI), 0.99-1.07; P = 0.05), diabetes (3.96; 1.61-9.37; P = 0.003), admission National Institute of Health Stroke Scale (NIHSS) (1.08; 1.01-1.15; P = 0.02) and initial Alberta Stroke Program Early Computed Tomography Score (ASPECTS) (0.56; 0.37-0.86; P = 0.009). The predictive model developed from the findings demonstrated good discrimination power (AuROC 0.803, 95% CI 0.728-0.877). Conclusion: The current study found that older age, diabetes, atrial fibrillation, higher admission NIHSS, and lower ASPECTS on the initial NCCT brain were related to unfavorable functional outcomes following IVT and served as good predictors of patient functional outcomes.

Roles of humanin and derivatives on the pathology of neurodegenerative diseases and cognition.

BACKGROUND: Alzheimer's disease (AD), Parkinson's disease (PD), and age-related macular degeneration (AMD) are common among neurodegenerative diseases, but investigations into novel therapeutic approaches are currently limited. Humanin (HN) is a mitochondrial-derived peptide found in brain tissues of patients with familial AD and has been increasingly investigated in AD and other neurodegenerative diseases. SCOPE OF REVIEW: In this review, we summarize and discuss the effects of HN on the pathology of neurodegenerative diseases and cognition based on several studies from preclinical to clinical models. The association between cardiac ischemia-reperfusion (I/R) injury and brain are also included. Findings from in vitro studies and those involving mice provide the most fundamental information on the impact of HN and its potential association with clinical studies. MAJOR CONCLUSIONS: HN plays a considerable role in countering the progression and neuropathology of AD. Inhibition and reduction of oxidative stress and neuroinflammation of the original amyloid hypothesis is the mainstay mechanism. Multiple intracellular mechanisms will be elucidated, including those involved in the anti-apoptotic signaling cascades, the insulin signaling pathway, and mitochondrial function, and especially autophagic activity. These beneficial roles are also found following cardiac I/R injury. Cognitive improvement was found to be related to maintenance of synaptic integrity and neurotransmitter modulation. Small humanin-like peptide 2 demonstrates the neuroprotective effects in PD and AMD via prevention of mitochondrial loss. GENERAL SIGNIFICANCE: Comprehensive knowledge of HN effects on cognition and neurodegenerative diseases emphasizes its potential to treat a viable disease, as it ameliorates the pathogenesis of the disease.

Conglomerate ring and tract-like enhancement lesions: Neuroimaging in Listeria monocytogenes brain abscess.

This report aims to describe a characteristic neuroimaging of Listeria monocytogenes brain abscess in predisposed patients. A 56-year-old man presented with fever and headache for 3 weeks. Cerebrospinal fluid (CSF) revealed pleocytosis with lymphocytosis, high protein, and low glucose. Both hemoculture and CSF culture yielded L monocytogenes. Another case is a 23-year-old woman with systemic lupus erythematosus, who presented with fever, headache and left hemiparesis. CSF showed pleocytosis with polymorphonuclear cells predominance and low glucose. Hemoculture positive for L monocytogenes. Their MRI brain revealed conglomerate ring and tract-like enhancement lesions at the right parietotemporal lobe. The patients were diagnosed with L monocytogenes brain abscess. They received a high dose of ceftriaxone and ampicillin for 6 weeks. The clinical and MRI at the end of treatment was a substantial improvement. Our information can help the physician concern about this pathogen in patients who presented with brain abscess and had these MRI findings.

PM2.5 exposure in association with AD-related neuropathology and cognitive outcomes.

Particulate matter with a diameter of less than 2.5 µm or PM2.5 is recognized worldwide as a cause of public health problems, mainly associated with respiratory and cardiovascular diseases. There is accumulating evidence to show that exposure to PM2.5 has a crucial causative role in various neurological disorders, the main ones being dementia and Alzheimer's disease (AD). PM2.5 can activate glial and microglial activity, resulting in neuroinflammation, increased intracellular ROS production, and ultimately neuronal apoptosis. PM2.5 also causes the alteration of neuronal morphology and synaptic changes and increases AD biomarkers, including amyloid-beta and hyperphosphorylated-tau, as well as raising the levels of enzymes involved in the amyloidogenic pathway. Clinical trials have highlighted the correlation between exposure to PM2.5, dementia, and AD diagnosis. This correlation is also displayed by concordant evidence from animal models, as indicated by increased AD biomarkers in cerebrospinal fluid and markers of vascular injury. Blood-brain barrier disruption is another aggravated phenomenon demonstrated in people at risk who are exposed to PM2.5. This review summarizes and discusses studies from in vitro, in vivo, and clinical studies on causative relationships of PM2.5 exposure to AD-related neuropathology. Conflicting data are also examined in order to determine the actual association between ambient air pollution and neurodegenerative diseases.

Implications of the Presence of Hyperdense Middle Cerebral Artery Sign in Determining the Subtypes of Stroke Etiology.

BACKGROUND: Identifying stroke subtypes is crucial in choosing appropriate treatment, predicting outcomes, and managing recurrent stroke prevention. OBJECTIVES: To study the association of hyperdense middle cerebral artery sign (HMCAS) on noncontrast computed tomography (NCCT) brain and subtypes of stroke etiology. METHODS: This is a retrospective hypothesis testing study. Patients aged 18 or over who had middle cerebral artery occlusion symptoms with HMCAS with verification on brain NCCT and received intravenous thrombolysis between January 2016 and June 2019 were enrolled. The demographic data, clinical outcomes, stroke subtypes, and characteristics of HMCAS were collected from medical records. RESULTS: Ninety-nine out of 299 enrolled patients presented with HMCAS. The most common stroke subtype was cardioembolism (59%). Of the baseline characteristics, hypertension was more common in cases of large-artery atherosclerosis (LAA) (86.4%), and atrial fibrillation (AF) was the highest in cardioembolism (44.8%). HMCAS disappearance in cardioembolism was lowest compared to LAA and others (63% vs. 91% vs. 94.7%, respectively). The univariable analysis found that HMCAS disappearance is significantly associated with all stroke subtypes (Odds ratio, 95% confidence interval 10.58, 1.31-85.43; P = 0.027 for other and 5.88, 1.24-27.85; P = 0.026 for LAA). Multinomial logistic regression found that body weight and hypertension were associated with the LAA subtype. AF and intracranial hemorrhage (ICH) were associated with cardioembolism. CONCLUSION: The most likely diagnosis from the presence of HMCAS is cardioembolism, but the definite stroke etiologic subtype can not be identified. Combining the patient risk factors, including body weight, hypertension, and AF, with HMCAS and its characteristics will predict stroke subtypes more accurately.

Internal carotid artery and bilateral vertebral arteries dissections associated with amphetamine abuse: Case report.

Arterial dissection is an important cause of stroke in young patients. Various factors influencing arterial dissection included amphetamine abuse and anterior circulation is the majority of stroke locations. We reported the Case of a 40-year-old male patient with chronic amphetamine used since childhood. He had increased the consumption from once a month to every other day in the last year. The patient suffered from acute left-side hemiparesis and neglect. Computed tomography angiography of the brain and neck vessels demonstrated non-atheromatous vasculopathy with a suspected dissection process of the right internal carotid artery and bilateral vertebral arteries. A review of recent data is also provided to clarify the possible mechanism.

The effects of hyperbaric oxygen therapy on the brain with middle cerebral artery occlusion.

Middle cerebral artery occlusion (MCAO) causes focal cerebral hypoperfusion, resulting in cerebral ischemia or ischemic stroke. The main therapeutic approach is to restore an adequate blood flow to the brain via the process of reperfusion. However, rapid reperfusion can itself aggravate brain damage; this adverse effect is known as ischemic/reperfusion (I/R) injury. The pathological conditions that occur after cerebral ischemia and cerebral I/R are microvascular injury, blood-brain barrier dysfunction, post-ischemic inflammation, increased oxidative stress/reactive oxygen species, and a reduction in neuronal survival, leading to brain infarction. Animal and clinical studies on hyperbaric oxygen therapy (HBOT) have recently been carried out, and there is evidence of positive effects on neurological outcomes after cerebral ischemia. However, some evidence has shown that HBOT may not affect the functional recovery after ischemic injury. This review describes the current evidence, both in vivo and clinical data, regarding the potential benefits of HBOT after MCAO and cerebral I/R injury. The contrary data are also discussed to verify the effectiveness of HBOT in stroke outcomes.