Higher Frequency of Premature Atrial Contractions Correlates With Atrial Fibrillation Detection after Cryptogenic Stroke.

BACKGROUND: Covert atrial fibrillation (AF) is a major cause of cryptogenic stroke. This study investigated whether a dose-dependent relationship exists between the frequency of premature atrial contractions (PACs) and AF detection in patients with cryptogenic stroke using an insertable cardiac monitor (ICM). METHODS: We enrolled consecutive patients with cryptogenic stroke who underwent ICM implantation between October 2016 and September 2020 at 8 stroke centers in Japan. Patients were divided into 3 groups according to the PAC count on 24-hour Holter ECG: ≤200 (group L), >200 to ≤500 (group M), and >500 (group H). We defined a high AF burden as above the median of the cumulative duration of AF episodes during the entire monitoring period. We evaluated the association of the frequency of PACs with AF detection using log-rank trend test and Cox proportional hazard model and with high AF burden using logistic regression model, adjusting for age, sex, CHADS2 score. RESULTS: Of 417 patients, we analyzed 381 patients with Holter ECG and ICM data. The median age was 70 (interquartile range, 59.5-76.5), 246 patients (65%) were males, and the median duration of ICM recording was 605 days (interquartile range, 397-827 days). The rate of new AF detected by ICM was higher in groups with more frequent PAC (15.5%/y in group L [n=277] versus 44.0%/y in group M [n=42] versus 71.4%/y in group H [n=62]; log-rank trend P<0.01). Compared with group L, the adjusted hazard ratios for AF detection in groups M and H were 2.11 (95% CI, 1.24-3.58) and 3.23 (95% CI, 2.07-5.04), respectively, and the adjusted odds ratio for high AF burden in groups M and H were 2.57 (95% CI, 1.14-5.74) and 4.25 (2.14-8.47), respectively. CONCLUSIONS: The frequency of PACs was dose-dependently associated with AF detection in patients with cryptogenic stroke.

Current progress in microRNA profiling of circulating extracellular vesicles in amyotrophic lateral sclerosis: A systematic review.

INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease affecting upper and lower motor neurons, leading to death resulting mainly from respiratory failure, for which there is currently no curative treatment. Underlying pathological mechanisms for the development of ALS are diverse and have yet to be elucidated. Non-invasive testing to isolate circulating molecules including microRNA to diagnose ALS has been reported, but circulating extracellular vesicle (EV)-derived microRNA has not been fully studied in the ALS population. METHODS: A systematic literature review to explore studies investigating the profile of microRNAs in EVs from blood samples of ALS patients was carried out according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guideline. RESULTS: Eleven studies including a total of 263 patients with ALS were included in the present systematic review. The majority of patients had sporadic ALS, though a small number of patients with ALS having genetic mutations were included. Seven studies used plasma-derived EVs, and the remaining four studies used serum-derived EVs. RNA sequencing or microarrays were used in eight studies, and quantitative PCR was used in eight studies, of which five studies used RNA sequencing or microarrays for screening and quantitative PCR for validation. There was overlap of miR-199a-3p and miR-199a-5p in three studies. CONCLUSIONS: Overall, the systematic review addressed the current advances in the profiling of microRNAs in circulating EVs of ALS patients. Blood samples, isolation of EVs, and microRNA analysis were diverse. Although there was an overlap of miR-199a-3p and miR-199a-5p, collection of further evidence is warranted.

C-Reactive Protein, Interleukin-6, and Vascular Recurrence After Stroke: An Individual Participant Data Meta-Analysis.

BACKGROUND: Anti-inflammatory therapies reduce recurrent vascular events in coronary disease. Existing studies have reported highly conflicting findings for the association of blood inflammatory markers with vascular recurrence after stroke leading to uncertainty about the potential of anti-inflammatory therapies after stroke and no consensus about the utility of measurement of inflammatory markers in current guidelines. METHODS: We investigated the association between hsCRP (high-sensitivity C-reactive protein), IL-6 (interluekin-6), and recurrent major adverse cardiovascular events (MACE), and stroke from individual participant data from 8420 patients with ischemic stroke/transient ischemic attack from 10 prospective studies. We did within-study multivariable regression analyses and then combined adjusted risk ratio (RR) by random-effects meta-analysis. RESULTS: During 18 920 person-years of follow-up, 1407 (16.7% [95% CI, 15.9-17.5]) patients had MACE and 1191 (14.1% [95% CI, 13.4-14.9]) patients had recurrent stroke. On bivariate analysis, baseline IL-6 was associated with MACE (RR, 1.26 [95% CI, 1.10-1.43]) and recurrent stroke (RR, 1.18 [95% CI, 1.05-1.32]), per unit increase logeIL-6. Similar associations were observed for hsCRP (MACE RR, 1.19 [95% CI, 1.09-1.29]; recurrent stroke RR, 1.12 [95% CI, 1.04-1.21], per unit increase logehsCRP). After adjustment for vascular risk factors and treatment, independent associations remained with MACE (IL-6, RR, 1.12 [95% CI, 1.04-1.21]; hsCRP, RR, 1.09 [95% CI, 1.04-1.15]) and recurrent stroke (IL-6, RR, 1.09 [95% CI, 1.00-1.19]; hsCRP, RR, 1.05 [95% CI, 1.00-1.11]). Comparing the top with the bottom quarters (Q4 versus Q1), IL-6 (RR, 1.35 [95% CI, 1.09-1.67]) and hsCRP (RR, 1.31 [95% CI, 1.07-1.61]) were associated with MACE after adjustment. Similar results were observed for recurrent stroke for IL-6 (RR, 1.33 [95% CI, 1.08-1.65]) but not hsCRP (RR, 1.16 [95% CI, 0.93-1.43]). CONCLUSIONS: Blood markers of inflammation were independently associated with vascular recurrence after stroke, strengthening the rationale for randomized trials of anti-inflammatory therapies for secondary prevention after ischemic stroke/TIA.

P-wave terminal force in lead V1 and atrial fibrillation burden in cryptogenic stroke with implantable loop recorders.

Implantable loop recorders (ILRs) are useful for the detection of atrial fibrillation (AF) in patients with cryptogenic stroke (CS). P-wave terminal force in lead V1 (PTFV1) is associated with AF detection; however, data on the association between PTFV1 and AF detection using ILRs in patients with CS are limited. Consecutive patients with CS with implanted ILRs from September 2016 to September 2020 at eight hospitals in Japan were studied. PTFV1 was calculated by 12-lead ECG before ILRs implantation. An abnormal PTFV1 was defined as ≥ 4.0 mV × ms. The AF burden was calculated as a proportion based on the duration of AF to the total monitoring period. The outcomes included AF detection and large AF burden, which was defined as ≥ 0.5% of the overall AF burden. Of 321 patients (median age, 71 years; male, 62%), AF was detected in 106 patients (33%) during the median follow-up period of 636 days (interquartile range [IQR], 436-860 days). The median time from ILRs implantation to AF detection was 73 days (IQR, 14-299 days). An abnormal PTFV1 was independently associated with AF detection (adjusted hazard ratio, 1.71; 95% confidence interval [CI], 1.00-2.90). An abnormal PTFV1 was also independently associated with a large AF burden (adjusted odds ratio, 4.70; 95% CI, 2.50-8.80). In patients with CS with implanted ILRs, an abnormal PTFV1 is associated with both AF detection and a large AF burden.Clinical Trial Registration Information: UMIN Clinical Trials Registry 000044366.

Recurrent embolic stroke associated with adenomyosis: A single case report and literature review.

INTRODUCTION: Uterine adenomyosis is a benign disorder in which endometrial glands and stroma are present within the myometrium. There have been several case reports of cerebral infarction associated with adenomyosis, but their clinical characteristics, optimal treatment, and prognosis have not been systematically reviewed. METHODS: A case of cerebral infarction with adenomyosis is reported, and a comprehensive systematic literature search using the PubMed database was conducted. RESULTS: A 42-year-old woman, previously diagnosed with adenomyosis, developed multiple cerebral infarctions during menstruation. Her CA125 level was 293 U/mL, and treatment with edoxaban 30 mg was started. Seven days after hospital discharge, she had her subsequent menstrual period and then developed a recurrent stroke. Her CA125 level was 743 U/mL on readmission. A hysterectomy was performed, and the patient has had no further stroke recurrence. A systematic review identified 19 cases with cerebral infarction associated with adenomyosis, including the present case. The patients' clinical characteristics included young age (44.7 ± 6.2 years), stroke development during menstruation (85%), multiple infarctions affecting ≥ 3 vessel territories (39%), and high levels of CA125 and D-dimer (810.6 ± 888.4 U/mL, and 10.3 ± 18.6 µg/mL, respectively). Antithrombotic therapy was given to 14 patients, but recurrent stroke occurred in 5 (36%) patients. Hysterectomy was conducted in 5 and 4 patients with initial and recurrent stokes, respectively, and there were no further recurrences thereafter. CONCLUSION: Cerebral infarction associated with adenomyosis has specific clinical characteristics. Antithrombotic therapy was insufficient, and hysterectomy should particularly be considered in cases of recurrent stroke.

High-risk patent foramen ovale and elderly in cryptogenic stroke.

BACKGROUND: High-risk patent foramen ovale (PFO) could be pathological in cryptogenic stroke (CS), but its clinical characteristics have not been fully studied, especially in elderly patients. METHODS: Patients with CS were enrolled in the CHALLENGE ESUS/CS registry, a multicenter registry of CS patients undergoing transesophageal echocardiography. Clinical characteristics were compared among three groups: high-risk PFO group, large shunt PFO (≥25 microbubbles) or PFO with atrial septal aneurysm (ASA); right-to-left shunt (RLS) group, RLS including PFO with <25 microbubbles or without ASA; and no-RLS group. RESULTS: In total, 654 patients were analyzed: 91, 221, and 342 in the high-risk PFO, RLS, and no-RLS groups, respectively. In multinomial logistic regression analysis, the male sex (odds ratio [OR] 1.825 [1.067-3.122]) was independently associated with high-risk PFO, but hypertension (OR, 0.562 [0.327-0.967]), multiple infarctions (OR, 0.601 [0.435-0.830]), and other cardioaortic embologenic risks (OR, 0.514 [0.294-0.897]) were inversely associated with high-risk PFO compared with non-RLS. In 517 patients aged ≥60 years, multiple infarctions (OR, 0.549 [0.382-0.788]) and other cardioaortic embologenic risks (OR, 0.523 [0.286-0.959]) were inversely associated with high-risk PFO. CONCLUSIONS: High-risk PFO had specific clinical characteristics and possible mechanistic associations, and this trend was consistent among CS patients aged ≥60 years. CLINICAL TRIAL REGISTRATION INFORMATION: http://www.umin.ac.jp/ctr/ (UMIN000032957).

Association of blood eicosapentaenoic acid levels with intracerebral hemorrhage during the COVID-19 pandemic: preliminary experience from a single-center in Japan.

BACKGROUND: The COVID-19 pandemic has forced lockdowns and declarations of states of emergency, resulting in marked changes to daily life such as dietary habits in many countries. Though serum omega-3 polyunsaturated fatty acids levels have been shown to be useful markers for recurrent vascular events or worse prognosis in cardiovascular diseases and ischemic stroke, the relationship between serum omega-3 PUFA levels and the occurrence of intracerebral hemorrhage has essentially been unknown. We explored the association of serum omega-3 polyunsaturated fatty acids with intracerebral hemorrhage during the COVID-19 pandemic. METHODS: Participants comprised patients admitted to Juntendo University Hospital (Tokyo, Japan) with intracerebral hemorrhage between January 1, 2016 and April 30, 2020. Clinical characteristics including serum omega-3 polyunsaturated fatty acid levels were compared between patients developing intracerebral hemorrhage during the period from January 1, 2016 to February 29, 2020, and the subsequent COVID-19 pandemic period (March 1 to April 30, 2020). Clinical characteristics independently related to intracerebral hemorrhage during the COVID-19 pandemic were analyzed by comparing these two cohorts of intracerebral hemorrhage patients in different periods. RESULTS: A total of 103 patients (age, 67.0 ± 13.9 years; 67 males) with intracerebral hemorrhage were enrolled. Intracerebral hemorrhage developed in 91 patients before and 12 patients during the COVID-19 pandemic. Monthly averages of intracerebral hemorrhage patients admitted to our hospital during and before the COVID-19 pandemic were 6 and 1.82, respectively. Serum eicosapentaenoic acid levels were significantly lower in intracerebral hemorrhage patients during the COVID-19 pandemic than before (31.87 ± 12.93 µg/ml vs. 63.74 ± 43.29 µg/ml, p = 0.007). Multiple logistic regression analysis showed that, compared to before the COVID-19 pandemic, dyslipidemia (odds ratio 0.163, 95% confidence interval 0.031-0.852; p = 0.032) and eicosapentaenoic acid levels (odds ratio 0.947, 95% confidence interval 0.901-0.994; p = 0.029) were associated with intracerebral hemorrhage during the COVID-19 pandemic. CONCLUSIONS: From our preliminary results, low eicosapentaenoic acid levels were linked with intracerebral hemorrhage during the COVID-19 pandemic. Low levels of eicosapentaenoic acid might be an endogenous surrogate marker for intracerebral hemorrhage during the COVID-19 pandemic.

Baseline platelet count may predict short-term functional outcome of cerebral infarction.

BACKGROUND AND AIMS: Platelets play an important role in homeostasis however, they have also been associated with increased mortality after myocardial infarction. In the present study, we investigated whether platelet count is associated with differences in the short-term prognosis at the time of hospital discharge and early neurological deterioration in ischemic stroke patients. METHODS: Patients with ischemic stroke were enrolled from among 661 cerebrovascular disease patients admitted between January 2018 and December 2020. Patients who received hyperacute treatment, had a pre-onset modified Rankin scale (mRS) ≥ 3, transient ischemic attack, or active malignant disease were excluded. The platelet count was divided into quartiles (Q1-4) according to the number of patients, and the relationship between platelet count and prognosis was assessed using multivariable analysis. RESULTS: In total, 385 patients were included in the study. Regarding the functional outcome by platelet count, there was a significant increase in mRS ≥ 3 at discharge in the Q4 (range: 243-1327 × 109/L, p = 0.013, ORs: 1.674, 95%CI: 1.253-6.681) group compared to the Q3 (range: 205-242 × 109/L) group even after adjusting for factors with P < 0.2 in univariate analysis. Furthermore, the frequency of neurological deterioration (NIHSS ≥ 4) within 1 week was significantly lower in the Q3 group than in the Q1 (range; 19-173 × 109/L) and Q4 groups even after adjustment (Q1; p = 0.020 ORs: 6.634, 95%CI: 1.352-32.557, Q4; p = 0.007 ORs: 8.765, 95%CI: 1.827-42.035). CONCLUSION: Platelet count at onset may affect the prognosis of cerebral infarction and early neurological deterioration. This study may help clarify the pathogenesis of cerebral infarction to improve prognosis.

Impact of D-dimer for pathologic differentiation on transesophageal echocardiography in embolic stroke of undetermined source: a single-center experience.

BACKGROUND: Embolic stroke of undetermined source (ESUS) encompasses diverse embologenic mechanisms, which transesophageal echocardiography (TEE) is critical to detect. Specific markers related to each embolic source in ESUS is not fully studied. We focused on D-dimer levels, and explored the association of D-dimer with potential embolic sources (PES) identified on TEE in ESUS. METHODS: Consecutive patients with ESUS were included in this study. Clinical characteristics including D-dimer levels were compared between ESUS patients with and without TEE, and among none of, one, and at least two PES in ESUS patients undergoing TEE. Factors related to elevation of D-dimer were analyzed. RESULTS: A total of 211 patients (age, 69.3 ± 13.2 years; 149 males) with ESUS were enrolled. Of these, 115 received TEE, displaying significantly younger age and lower D-dimer levels than patients without TEE (P < 0.05), and 20 (17%), 61 (53%), and 34 (30%) patients were classified into none of, one, and ≥ two PES, respectively. On multiple logistic regression analysis, D-dimer levels were related to one PES (odds ratio [OR]: 9.01; 95% confidence interval [CI]: 1.00-81.51; P = 0.050) and PES ≥ two (OR: 9.76; 95% CI: 1.07-88.97; P = 0.043). Right-to-left shunt (RLS) with deep venous thrombosis (DVT)(OR: 13.94; 95% CI: 1.77-109.99; P = 0.012) and without DVT (OR: 3.90; 95% CI: 1.20-12.70; P = 0.024) were associated with elevation of D-dimer. CONCLUSIONS: D-dimer levels were higher in patients with PES. Among PES, RLS, with and without DVT, were associated with increase of D-dimer in ESUS.

Cerebral artery dissection secondary to antiphospholipid syndrome: A report of two cases and a literature review.

INTRODUCTION: Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by thromboembolic events, including ischemic stroke or complications in pregnancy, and the presence of antiphospholipid antibodies. Cervical artery dissection (CAD) is not an uncommon cause of stroke in young adults. The concomitant presence of APS and CAD is extremely rare. METHODS: Two cases with APS who developed acute ischemic strokes related to CAD are reported. A comprehensive systematic literature search using the PubMed database was also conducted. RESULTS: In Case 1, a 36-year-old woman who had been diagnosed with systemic lupus erythematosus and had been repeatedly positive for lupus anticoagulant tests developed an ischemic stroke caused by a vertebral artery dissection (VAD). After admission, she had a recurrent ischemic stroke, followed by considerable changes in steno-occlusive lesions of the vertebrobasilar artery system. In Case 2, a 36-year-old man developed multiple brain infarcts due to bilateral VAD with aneurysmal formations and associated with pulmonary embolism. The anticardiolipin antibody titer was repeatedly elevated after stroke. The literature review identified 8 patients with CAD associated with APS, involving the internal carotid artery in 6 patients and the middle cerebral artery and vertebral artery in 1 patient each. The patients were predominantly young and female, infrequently had atherosclerotic vascular risk factors, and were positive for various antiphospholipid antibodies. CONCLUSIONS: The current report described two rare cases of ischemic stroke caused by CAD secondary to APS, along with a review of the literature; the patients displayed characteristic clinical manifestations, implying specific mechanisms for cerebral artery disorders secondary to APS.

Extensive leukoencephalopathy associated with idiopathic capillary leak syndrome: report of a case with neuropathology.

INTRODUCTION: Idiopathic systemic capillary leak syndrome (ISCLS) is a rare cryptogenic disorder characterized by recurrent hemoconcentration, hypoalbuminemia, edema, and hypotension due to extravascular fluid leakage. This is the first report that details uncommon extensive leukoencephalopathy caused by ISCLS upon a neuropathological investigation. CASE REPORT: A 68-year-old female had recurrent episodes of hemoconcentration, hypoalbuminemia, and generalized edema and was diagnosed with ISCLS. After 9 years, brain magnetic resonance imaging (MRI) incidentally revealed extensive leukoencephalopathy without neurological deficits. Thorough examinations ruled out other disorders, and the cerebral involvement due to ISCLS was finally diagnosed. Three years later, she developed an acute-onset coma and status epilepticus together with hypotension and hemoconcentration, which were compatible with ISCLS recurrence. Electroencephalogram and MRI were correlated with a seizure arising from the left hemisphere. Extensive leukoencephalopathy did not show notable changes for 3 years. Although treatment for ISCLS recurrence temporally improved hemoconcentration and consciousness, consciousness worsened again by marked edema of the left hemisphere, and she died of cerebral herniation. A brain autopsy revealed straggly perivascular plasma leakage around the small vessels of the deep white matter, which supported that the leukoencephalopathy was caused by ISCLS. Widespread myelin pallor and decreased axonal density with sparse astrogliosis and microgliosis were observed in the cerebral white matter and corresponded with a chronic change in the MRI. CONCLUSION: Current radiological and pathological observations revealed that frequent perivascular leakages could cause chronic leukoencephalopathy, were linked with the development of systemic capillary leakage in ISCLS, and provided insights into the mysterious pathophysiology.

The Clonal Population of Trichophyton equinum from Dermatophytoses of Japanese Racehorses.

Trichophyton equinum is a zoophilic dermatophyte that is frequently isolated from horse dermatophytosis and rare infections in humans. In the present study, molecular and physiological testing were performed on T. equinum isolates from dermatophytoses of Japanese racehorses to assess genotype and phenotype patterns of these strains. Comparative nucleotide sequence analysis showed that internal transcribed spacer (ITS) region sequences amplified from all Japanese isolates were 99.5% identical to T. equinum reference strains. ITS sequences amplified among the isolates were 100% (BT2) showed that isolates were 100% identical and harbored a "T" single nucleotide polymorphism at position 18. The sequences of ß-tubulin (BT2) showed that isolates were 100% identical to T. equinum reference strains. The MAT1-2 allele was detected by PCR in all seven isolates, whereas none of the isolates contained the MAT1-1 allele. All isolates grew only on Trichophyton Agar 5 and did not grow on Trichophyton Agar 1 and 4, indicating nicotinic acid requirement. These results suggest that Japanese T. equinum isolates are derived from a clonal population.

Antifungal susceptibility of dermatophytes from racehorses in Japan.

BACKGROUND: Luliconazole (LCZ) is an imidazole antifungal medication that exhibits excellent activity against dermatophytes. As a topical cream and lotion (approved for human use), LCZ has demonstrated a broad spectrum of activity against human dermatophytoses. OBJECTIVES: This is the first study to investigate the in vitro susceptibility of clinical isolates from horse dermatophytoses to LCZ. ANIMALS: No animals were used in this study. METHODS AND MATERIALS: In the present study, the in vitro susceptibilities of clinical isolates of dermatophytes to LCZ, clotrimazole (CTZ), miconazole (MCZ) and terbinafine (TRF) were investigated using the Clinical & Laboratory Standards Institute M38-A2 test. RESULTS: The minimum inhibitory concentrations (MICs) for all 16 clinical isolates of Trichophyton equinum, Microsporum equinum/canis and M. gypseum for LCZ were <0.03 mg/L. The MICs of all isolates were <0.03-0.5 mg/L for CTZ, 0.03-16 mg/L for MCZ and <0.03-1 mg/L for TRF. CONCLUSIONS: LCZ demonstrated a broad spectrum of activity against clinical isolates from horse dermatophytoses. We consider that LCZ will become the primary antifungal agent for treating horse dermatophytosis.

Cardiac and Echocardiographic Markers in Cryptogenic Stroke with Incidental Patent Foramen Ovale.

OBJECTIVE: Some cardiac abnormalities could be a substrate for potential embolic source in cryptogenic stroke (CS). We evaluated whether cardiac and echocardiographic markers were associated with CS in patients with incidental patent foramen ovale (PFO) as defined using the Risk of Paradoxical Embolism (RoPE) score. MATERIALS AND METHODS: Among 677 patients enrolled in a multicenter observational CS registry, 300 patients (44%) had PFOs detected by transesophageal echocardiography. They were classified into probable PFO-related stroke (RoPE score>6, n = 32) and stroke with incidental PFO (RoPE score≤6, n = 268) groups, and clinical characteristics, laboratory findings, cardiac and echocardiographic markers (i.e. brain natriuretic peptide, left atrial [LA] diameter, ejection fraction, early transmitral flow velocity/early diastolic tissue Doppler imaging velocity [E/e'], LA appendage flow velocity, spontaneous echo contrast, atrial septal aneurysm, substantial PFO, and aortic arch plaques), stroke recurrence, and excellent outcome (modified Rankin scale score <2) at discharge were compared. Risk factors for low RoPE scores were determined using multiple logistic regression analysis. RESULTS: Higher brain natriuretic peptide levels (p = 0.032), LA enlargement (p < 0.001), higher E/e' (p = 0.001), lower LA appendage flow velocity (p < 0.001), non-substantial PFO (p = 0.021), and aortic arch plaques (p = 0.002) were associated with the low RoPE score group. Patients with high RoPE scores had excellent outcomes (58% versus 78%, p = 0.035). LA enlargement (age- and sex-adjusted odds ratio, 1.15; 95 % confidence interval, 1.00-1.32; p = 0.039) was an independent predictor of low RoPE scores. CONCLUSIONS: Abnormal cardiac substrate could be associated with CS occurrence in a subset of patients with PFO. Patients with CS who had incidental PFO may be at risk of cardioembolism.

The effects of A1/A2 astrocytes on oligodendrocyte linage cells against white matter injury under prolonged cerebral hypoperfusion.

As oligodendrocyte precursor cells (OPCs) are vulnerable to ischemia, their differentiation to oligodendrocytes (OLG) is impaired in chronic cerebral hypoperfusion. Astrocyte-OLG interaction is important for white matter homeostasis. Recently, reactive astrocytes were separated into two types, A1 (cytotoxic) and A2 (neurotrophic). However, their role in prolonged cerebral hypoperfusion remains unclear. We analyzed the effects of interaction between A1-A2 astrocytes and OPC-OLG under hypoperfusion, focusing on mitochondrial migration. As an in vivo model, chronic hypoperfusion model mice were created by bilateral common carotid artery stenosis (BCAS) using microcoils. As a matching in vitro study, rat primary cells were cocultured with a nonlethal concentration of CoCl2 . At 28 days after hypoperfusion, the number of OPC and astrocytes increased, whereas that of OLG decreased. Increased astrocytes were mainly A1-like astrocytes; however, the number of A2-like type decreased. In cell culture, OPC differentiation was interrupted under mimic chronic ischemia, but improved after astrocyte-conditioned medium (ACM) was added. However, injured-ACM was unable to improve OPC maturation. Incubation with CoCl2 changed astrocytes from A2-like to A1-like, and mitochondrial migration was also reduced. A Trkß agonist was able to maintain astrocytes from A1-like to A2-like even under hyperperfused conditions, and aided in OPC maturation and memory impairment via mitochondrial migration and drug effects in cell culture study and BCAS model. The reduction of A1-like astrocytes protects against white matter injury. Trkß agonists may play an important role in the impairment under chronic ischemic conditions. Mitochondrial migration may be a broad therapeutic strategy for cerebrovascular diseases. MAIN POINTS: Prolonged cerebral hypoperfusion leads to impaired oligodendrocyte (OLG) maturation and increased numbers of A1 astrocytes. Mitochondria migration maintained A2 astrocyte morphology, mature OLG, and myelinated white matter in vivo/vitro.

CD8+ T-cell encephalitis mimicking PRES in AIDS: a case report.

BACKGROUND: Diverse mechanisms including infections, autoimmune inflammatory reactions, neoplasms, and degeneration are involved in the central nervous system in cases of acquired immune deficiency syndrome. In such cases, it is difficult to determine the precise pathogenesis by radiological examination and laboratory testing. CASE PRESENTATION: We report a 37-year-old Japanese woman who had untreated hypertension and gender identity disorder and had been taking testosterone injections since she was 19 years old. She developed a headache and visual field deficits together with elevated blood pressure. According to radiological findings, she was initially suspected as having posterior reversible encephalopathy syndrome in the right parieto-occipital lobe with reversible cerebral vasoconstriction syndrome. Human immunodeficiency virus antibody was positive and the CD4+ T-lymphocyte count was 140 cells/µl. Therefore, antiretroviral therapy was started. Antiretroviral therapy suppressed the activity of acquired immune deficiency syndrome but worsened her visual symptoms and expanding radiological lesions. Brain biopsy led to the diagnosis of CD8+ encephalitis, and she also fulfilled the diagnosis of paradoxical immune reconstitution inflammatory syndrome. Corticosteroid therapy alleviated her symptoms. CONCLUSIONS: This is a rare case of CD8+ encephalitis, with an exacerbation owing to paradoxical immune reconstitution inflammatory syndrome after antiretroviral therapy, which radiologically mimicked posterior reversible encephalopathy syndrome. Corticosteroid therapy was effective; thus, it is important to provide a pathological diagnosis in such cases.

Pleiotropic Effects of Exosomes as a Therapy for Stroke Recovery.

Stroke is the leading cause of disability, and stroke survivors suffer from long-term sequelae even after receiving recombinant tissue plasminogen activator therapy and endovascular intracranial thrombectomy. Increasing evidence suggests that exosomes, nano-sized extracellular membrane vesicles, enhance neurogenesis, angiogenesis, and axonal outgrowth, all the while suppressing inflammatory reactions, thereby enhancing functional recovery after stroke. A systematic literature review to study the association of stroke recovery with exosome therapy was carried out, analyzing species, stroke model, source of exosomes, behavioral analyses, and outcome data, as well as molecular mechanisms. Thirteen studies were included in the present systematic review. In the majority of studies, exosomes derived from mesenchymal stromal cells or stem cells were administered intravenously within 24 h after transient middle cerebral artery occlusion, showing a significant improvement of neurological severity and motor functions. Specific microRNAs and molecules were identified by mechanistic investigations, and their amplification was shown to further enhance therapeutic effects, including neurogenesis, angiogenesis, axonal outgrowth, and synaptogenesis. Overall, this review addresses the current advances in exosome therapy for stroke recovery in preclinical studies, which can hopefully be preparatory steps for the future development of clinical trials involving stroke survivors to improve functional outcomes.

Cerebral Microbleeds and Chronic Kidney Disease in Acute Ischemic Stroke Patients with Atrial Fibrillation.

BACKGROUND: Cerebral microbleeds (CMBs) are associated with the risk of intracerebral hemorrhage in stroke patients with atrial fibrillation (AF). We investigated the association between CMBs and chronic kidney disease (CKD) in patients with acute ischemic stroke and AF. METHODS: We retrospectively examined consecutive patients with acute ischemic stroke and AF who underwent brain gradient-echo T2*-weighted magnetic resonance imaging. The number and distribution (lobar, deep or infratentorial, and mixed) of CMBs were assessed. Kidney function was assessed according to the estimated glomerular filtration rate (eGFR), which was calculated using a modified version of the Modification of Diet in Renal Disease equation. RESULTS: Of the 357 included patients, 105 (29.4%) had CMBs. CKD (eGFR < 60 mL/min/1.73 m2) was found in 131 (36.7%) patients. Patients with CKD showed a higher prevalence of any form of CMB (41.2% versus 22.6%, P < .001), deep or infratentorial CMBs (19.9% versus 9.3%, P < .01), and mixed CMBs (14.5% versus 5.3%, P < .01) than those without CKD. After adjusting for age and other confounding factors, CKD was found to be independently associated with the presence of any form of CMB (odds ratio 1.89, P = .02) and mixed CMBs (odds ratio 3.10, P < .01). Moreover, moderate to severe CKD (eGFR < 45 mL/min/1.73 m2) was independently associated with the presence of multiple CMBs (odds ratio 2.31, P = .04). CONCLUSIONS: CMBs and CKD are common in acute ischemic stroke patients with AF, and CKD may be a risk factor for CMBs. Further longitudinal studies are needed to evaluate whether maintaining kidney function can prevent the development of CMBs.

Analysis of Clinical Symptoms and Brain MRI of Heat Stroke: 2 Case Reports and a Literature Review.

INTRODUCTION: Heat stroke is defined as high body temperature causing multiple organ failure, psychological change, seizure, and consciousness disturbance, which lead to its high mortality rate. However, the involvement of brain injury is rare, and heat-stroke has only been reported in a few case reports or case series. The purpose of this case study was to evaluate the clinical symptoms and radiological features of heat stroke. METHODS: We reviewed our hospital records and previously published reports to find cases of heat stroke. We excluded those with unknown clinical features or radiological findings. RESULTS: We retrieved 2 cases of heat stroke from our hospital, which presented as extensive lesions on brain imaging that led to disseminated intravascular coagulation and death within a few days. In 21 previously reported cases of heat stroke, similar brain lesions were noted. These were classified as infarction/posterior reversible encephalopathy syndrome (PRES)-like lesions. The patients who developed PRES-like lesions and survived often developed cerebellar sequelae. CONCLUSION: The mechanism of heat stroke is presumed to be multifactorial. Ischemic-like lesions result from hypovolemia and unusual coagulation, whereas PRES-like lesions are caused by direct heat and vasogenic edema due to hypercytokinemia. We need to consider the above mentioned conditions when evaluating heat stroke.

CLIPPERS and its mimics: evaluation of new criteria for the diagnosis of CLIPPERS.

OBJECTIVE: To evaluate the accuracy of the recently proposed diagnostic criteria for chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS). METHODS: We enrolled 42 patients with hindbrain punctate and/or linear enhancements (<3 mm in diameter) and tested the CLIPPERS criteria. RESULTS: After a median follow-up of 50 months (IQR 25-82), 13 out of 42 patients were CLIPPERS-mimics: systemic and central nervous system lymphomas (n=7), primary central nervous system angiitis (n=4) and autoimmune gliopathies (n=2). The sensitivity and specificity of the CLIPPERS criteria were 93% and 69%, respectively. Nodular enhancement ( ≥ 3 mm in diameter), considered as a red flag in CLIPPERS criteria, was present in 4 out of 13 CLIPPERS-mimics but also in 2 out of 29 patients with CLIPPERS, explaining the lack of sensitivity. Four out of 13 CLIPPERS-mimics who initially met the CLIPPERS criteria displayed red flags at the second attack with a median time of 5.5 months (min 3, max 18), explaining the lack of specificity. One of these four patients had antimyelin oligodendrocyte glycoprotein antibodies, and the three remaining patients relapsed despite a daily dose of prednisone/prednisolone ≥ 30 mg and a biopsy targeting atypical enhancing lesions revealed a lymphoma. CONCLUSIONS: Our study highlights that (1) nodular enhancement should be considered more as an unusual finding than a red flag excluding the diagnosis of CLIPPERS; (2) red flags may occur up to 18 months after disease onset; (3) as opposed to CLIPPERS-mimics, no relapse occurs when the daily dose of prednisone/prednisolone is ≥ 30 mg; and (4) brain biopsy should target an atypical enhancing lesion when non-invasive investigations remain inconclusive.