Mucosal-Associated Invariant T Cells Are Involved in Acute Ischemic Stroke by Regulating Neuroinflammation.

Background Mucosal-associated invariant T (MAIT) cells have been associated with inflammation in several autoimmune diseases. However, their relation to ischemic stroke remains unclear. This study attempted to elucidate the role of MAIT cells in acute ischemic stroke in mice. Methods and Results We used MR1 knockout C57BL/6 (MR1-/-) mice and wild-type littermates (MR1+/+). After performing a transient middle cerebral artery occlusion (tMCAO), we evaluated the association with inflammation and prognosis in the acute cerebral ischemia. Furthermore, we analyzed the tMCAO C57BL/6 mice administered with the suppressive MR1 ligand and the vehicle control. We also evaluated the infiltration of MAIT cells into the ischemic brain by flow cytometry. Results showed a reduction of infarct volume and an improvement of neurological impairment in MR1-/- mice (n=8). There was a reduction in the number of infiltrating microglia/macrophages (n=3-5) and in their activation (n=5) in the peri-infarct area of MR1-/- mice. The cytokine levels of interleukin-6 and interleukin-17 at 24 hours after tMCAO (n=3-5), and for interleukin-17 at 72 hours after tMCAO (n=5), were lower in the MR1-/- mice. The administration of the suppressive MR1 ligand reduced the infarct volume and improved functional impairment (n=5). Flow cytometric analysis demonstrated there was a reduction of MAIT cells infiltrating into the ischemic brain at 24 hours after tMCAO (n=17). Conclusions Our results showed that MAIT cells play an important role in neuroinflammation after focal cerebral ischemia and the use of MAIT cell regulation has a potential role as a novel neuroprotectant for the treatment of acute ischemic stroke.

Metabolic endotoxemia promotes neuroinflammation after focal cerebral ischemia.

Lipopolysaccharide (LPS) is a major component of the outer membrane of Gram-negative bacteria and a potent inflammatory stimulus for the innate immune response via toll-like receptor (TLR) 4 activation. Type 2 diabetes is associated with changes in gut microbiota and impaired intestinal barrier functions, leading to translocation of microbiota-derived LPS into the circulatory system, a condition referred to as metabolic endotoxemia. We investigated the effects of metabolic endotoxemia after experimental stroke with transient middle cerebral artery occlusion (MCAO) in a murine model of type 2 diabetes (db/db) and phenotypically normal littermates (db/+). Compared to db/+ mice, db/db mice exhibited an altered gut microbial composition, increased intestinal permeability, and higher plasma LPS levels. In addition, db/db mice presented increased infarct volumes and higher expression levels of LPS, TLR4, and inflammatory cytokines in the ischemic brain, as well as more severe neurological impairments and reduced survival rates after MCAO. Oral administration of a non-absorbable antibiotic modulated the gut microbiota and improved metabolic endotoxemia and stroke outcomes in db/db mice; these effects were associated with reduction of LPS levels and neuroinflammation in the ischemic brain. These data suggest that targeting metabolic endotoxemia may be a novel potential therapeutic strategy to improve stroke outcomes.

Cervico-shoulder dystonia following lateral medullary infarction: a case report and review of the literature.

BACKGROUND: Secondary cervical dystonia is induced by organic brain lesions involving the basal ganglia, thalamus, cerebellum, and brain stem. It is extremely rare to see cervical dystonia induced by a medullary lesion. CASE PRESENTATION: We report a case of an 86-year-old Japanese woman who developed cervical dystonia following lateral medullary infarction. She developed sudden-onset left upper and lower extremity weakness, right-side numbness, and dysarthria. Brain magnetic resonance imaging revealed an acute ischemic lesion involving the left lateral and dorsal medullae. A few days after her stroke, she complained of a taut sensation in her left neck and body, and cervico-shoulder dystonia toward the contralateral side subsequently appeared. Within a few weeks, it disappeared spontaneously, but her hemiplegia remained residual. CONCLUSIONS: To date, to the best of our knowledge, there has been only one reported case of cervical dystonia associated with a single medullary lesion. It is interesting to note the similarities in the clinical characteristics of the previously reported case and our patient: the involvement of the dorsal and caudal parts of the medullary and associated ipsilateral hemiplegia. The present case may support the speculation that the lateral and caudal regions of the medulla may be the anatomical sites responsible for inducing cervical dystonia.

Deep cerebral venous thrombosis mimicking influenza-associated acute necrotizing encephalopathy: a case report.

BACKGROUND: Acute necrotizing encephalopathy is one of the most devastating neurological complications of influenza virus infection. Acute necrotizing encephalopathy preferentially affects the thalamus bilaterally, as does deep cerebral venous thrombosis, which can lead to misdiagnosis. CASE PRESENTATION: A 52-year-old Japanese woman infected with seasonal influenza B virus presented to the emergency care unit in our hospital with progressive alteration of her level of consciousness. Bilateral thalamic lesions were demonstrated by magnetic resonance imaging, leading to a tentative diagnosis of acute necrotizing encephalopathy. However, she had deep cerebral venous thrombosis, and the presence of diminished signal and enlargement of deep cerebral veins on T2*-weighted imaging contributed to a revised diagnosis of deep cerebral venous thrombosis. Anticoagulant therapy was initiated, leading to her gradual recovery, with recanalization of the deep venous system and straight sinus. CONCLUSIONS: To the best of our knowledge, these results represent the first report of deep cerebral venous thrombosis associated with influenza infection. It is clinically important to recognize that deep cerebral venous thrombosis, although rare, might be one of the neurological complications of influenza infection. In the presence of bilateral thalamic lesions in patients with influenza infection, deep cerebral venous thrombosis should be considered in addition to acute necrotizing encephalopathy. Delays in diagnosis and commencement of anticoagulant therapy can lead to unfavorable outcomes.

Analysis of the Usefulness of the WORSEN Score for Predicting the Deterioration of Acute Ischemic Stroke.

BACKGROUND: Early neurological worsening is associated with increased mortality and long-term functional disability. We developed the WORSEN score for predicting whether patients with stroke will deteriorate during the week after stroke onset and investigated its usefulness. PATIENTS AND METHODS: We retrospectively investigated the cases of 478 patients who were admitted to Juntendo University Hospital between April 2007 and March 2009. Neurological deterioration was defined as a worsening of 4 points or higher on the National Institute of Health Stroke Scale score within 1 week of admission. Based on a previous study, we developed the WORSEN score, which was derived from the following factors: wrong (poor) blood sugar control (W), old myocardial infarction (O), radiological findings (R), infarct size (S), elevated low-density lipoprotein cholesterol (E), and neurological findings (N). Next, we investigated the utility of this scoring system in 456 other patients who were admitted to Juntendo University Hospital and Juntendo Urayasu Hospital between October 2013 and December 2014. RESULTS: First, we checked the utility of the WORSEN score for detecting worsening in cases of stroke. In the first patient group, deterioration was noted in 32.5% of the patients with scores higher than 3 points (sensitivity: .704 and specificity: .744). For checking reproductivity on using the second group, deterioration was detected in 36.1% of the patients with WORSEN scores higher than 3 points (sensitivity: .740 and specificity: .835). CONCLUSIONS: Careful attention should be paid to patients with acute stroke with high WORSEN scores. The WORSEN score might become a valuable tool for detecting the neurological deterioration of ischemic stroke.

Emerging Risk Factors for Recurrent Vascular Events in Patients With Embolic Stroke of Undetermined Source.

BACKGROUND AND PURPOSE: Underlying embolic causes diagnosed by transesophageal echocardiography could be implicated in mechanisms of embolic stroke of undetermined source. We aimed to explore factors, including underlying embolic causes, related to recurrent vascular events in embolic stroke of undetermined source. METHODS: Patients who fulfilled the diagnostic criteria for embolic stroke of undetermined source and whose potential embolic sources were examined by transesophageal echocardiography were included. Recurrent vascular events, including ischemic stroke, cardiovascular and peripheral artery diseases, and vascular death, were retrospectively analyzed. Cox proportional hazards regression analysis was used to explore factors, including clinical characteristics, embolic causes on transesophageal echocardiography, and the Calcification in the Aortic Arch, Age, Multiple Infarction score (CAM), based on the degree of aortic arch calcification on chest radiograph (0-3 points), age (≥70 years; 1 point), and multiple infarctions on magnetic resonance imaging (multiple infarcts in 1, 2, or ≥3 territories of large intracranial arteries, 1, 2, or 3 points) associated with recurrent vascular events. RESULTS: A total of 177 patients (age, 64.1±14.2 years; 127 men) were enrolled. Thirty-one patients had recurrent vascular events (follow-up, 3.5±2.7 years; annualized rate, 5.0% per person-year). Among embolic causes on transesophageal echocardiography, incidence of recurrent vascular events was high in patients with large aortic arch plaques (7.5% per person-year). Diabetes mellitus (hazard ratio, 2.56; 95% confidence interval, 1.23-5.32; P=0.012) and CAM score grade (hazard ratio, 2.29; 95% confidence interval, 1.11-4.72; P=0.026) predicted recurrent vascular events. CONCLUSIONS: History of diabetes mellitus and the CAM score could be novel risk factors for recurrent vascular events in embolic stroke of undetermined source.

Exendin-4 Inhibits Matrix Metalloproteinase-9 Activation and Reduces Infarct Growth After Focal Cerebral Ischemia in Hyperglycemic Mice.

BACKGROUND AND PURPOSE: Admission hyperglycemia is an independent risk factor for poor outcome of ischemic stroke. Amelioration of hyperglycemia by insulin has not been shown to improve the poststroke outcome. Glucagon-like peptide 1 receptor agonists, which modulate glucose levels by stimulating insulin secretion, have been shown to exert cytoprotective effects by inhibiting inflammation and oxidative stress. This study aimed to evaluate whether the glucagon-like peptide 1 receptor agonist exendin-4 could reduce glucose levels and exert protective effects after acute focal ischemia in hyperglycemic mice. METHODS: Hyperglycemia was induced by intraperitoneal injection of dextrose 15 minutes before transient middle cerebral artery occlusion was performed for 60 minutes using an intraluminal thread. We assessed 4 groups: (1) normal glucose (vehicle control), (2) induced hyperglycemia, (3) induced hyperglycemia with insulin treatment, and (4) induced hyperglycemia with exendin-4 treatment. Neurovascular injuries in brains from each group were evaluated 24 hours and 7 days post ischemia. RESULTS: Hyperglycemia significantly increased infarct volume (36.3±1.20 versus 26.9±1.28; P<0.001), brain edema (P<0.05), and hemorrhagic transformation compared with control (P<0.001). This increase in infarct volume was associated with increased blood-brain barrier disruption and matrix metalloproteinase-9 activation. Exendin-4, but not insulin, attenuated matrix metalloproteinase-9 activation, proinflammatory cytokine (tumor necrosis factor-α) release, and biomarkers of oxidative stress and showed significant inhibition of infarct growth at 24 hours (23.6±0.97 versus 36.3±1.20; P<0.001) and at 7 days after ischemia (21.0±0.92 versus 29.3±1.41; P<0.001). CONCLUSIONS: Treatment with exendin-4 could be a potentially useful therapeutic option for treatment of acute ischemic stroke with transient hyperglycemia.

Impact of BNP on cryptogenic stroke without potential embolic sources on transesophageal echocardiography.

BACKGROUND: Clinical characteristics are important for determining the etiologies of embolic stroke, including patent foramen ovale and complex aortic plaques demonstrated on transesophageal echocardiography (TEE). This study sought to analyze the clinical signs of cryptogenic stroke (CS) without such embolic etiologies and to examine the association between CS and brain natriuretic peptide (BNP), which is currently unknown. METHODS: Patients with CS after routine examinations who underwent TEE were included in this single-center observational study. Patients were classified into the potential embolic sources (PES) group (patients having PES on TEE) and the no potential embolic source (NPES) group. Patients were also categorized according to the tertile of BNP. RESULTS: A total of 158 patients (age, 64.0 ± 13.9 years; 119 males) with CS were enrolled. The PES group had 108 (68%) patients, and the NPES group had 50 (32%). Hypertension was more common, and glucose, D-dimer, and BNP were higher in the NPES than in the PES group (p<0.05). NPES was independently associated with high-BNP tertile (OR: 5.61; 95% CI: 1.91 to 16.44; p=0.002). CONCLUSIONS: BNP, an indicator of cardioembolism, was closely associated with NPES. Cardiogenic mechanisms may be implicated in the etiology of CS without potential embolic etiologies on TEE.

Rosuvastatin may stabilize atherosclerotic aortic plaque: transesophageal echocardiographic study in the EPISTEME trial.

OBJECTIVE: Large atheromatous aortic plaques (AAPs) have been associated with ischemic stroke. There is little evidence to guide the therapeutic strategy for ischemic stroke associated with large AAPs. This study sought to analyze the temporal profile of AAPs after rosuvastatin therapy in Japanese patients with acute ischemic stroke. METHODS: The Efficacy of Post-stroke Intensive Rosuvastatin Treatment for aortogenic Embolic stroke (EPISTEME) trial was a prospective, randomized, open-label study. Acute ischemic stroke patients with dyslipidemia and AAPs ≥4-mm-thick on transesophageal echocardiography (TEE) were enrolled and randomly allocated to either the group treated with 5 mg/day rosuvastatin or the control group. The primary endpoint was the changes in volume and composition of AAPs on repeat TEE after 6 months. High-echoic plaque area was analyzed using binary images. RESULTS: A total of 24 Japanese patients (rosuvastatin 12; control 12) were included in the primary analysis. Rosuvastatin substantially reduced low-density lipoprotein cholesterol (LDL-C) compared to control (-42.1% vs. 1.4%, P < 0.001). Percent changes of high-echoic plaque areas were significantly increased in the rosuvastatin group, while they were decreased in the control group (65.8% vs -14.7%, P < 0.001). There was a significant linear correlation between percent increase in high-echoic plaque area and LDL-C decrease (r=-0.434, P=0.002). CONCLUSION: Treatment with 5-mg rosuvastatin for 6 months might induce atheromatous aortic plaque stabilization together with marked LDL-C reduction in Japanese patients with ischemic stroke, which could provide evidence on which to base the therapeutic strategy for aortogenic brain embolism.

Vertebral artery dissection in patients with autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited renal cystic disease, and it is associated with various extrarenal manifestations, including vascular complications, such as intracranial aneurysms, and aortic root dilatation and aneurysms. However, intracranial arterial dissection has rarely been reported. We herein report the cases of 2 patients with ADPKD who developed a vertebral artery (VA) dissection. Dissection was also observed on the other side of the VA and in the internal carotid artery in the first and second patient, respectively. Both patients also had a history of hypertension, which is frequently accompanied by ADPKD, and their serum creatinine levels were normal. Our report supports the importance of considering ADPKD as one of the possible pathogenic factors in arterial dissection.

Motor-dominant polyneuropathy due to IgM monoclonal antibody against disialosyl gangliosides in a patient with mantle cell lymphoma.

A rapidly progressive motor-dominant neuropathy associated with IgM monoclonal antibody against gangliosides with disialosyl residues, GD3, GD1b, GT1b, and GQ1b, in a 60-year-old Japanese man with mantle cell lymphoma is reported. Plasma exchange and chemotherapy for mantle cell lymphoma were performed for the neuropathy and mantle cell lymphoma. After therapy, the motor neuropathy dramatically improved concurrently with substantial reduction of the antibody activities especially in reaction to GD1b. This is the first case report of neuropathy with anti-disialosyl IgM antibodies associated with mantle cell lymphoma, and plasma exchange and chemotherapy were effective.

Rationale and design of the EPISTEME trial: efficacy of post-stroke intensive rosuvastatin treatment for aortogenic embolic stroke.

BACKGROUND: Large atheromatous aortic plaques (AAPs) are associated with stroke recurrence. Rosuvastatin is a potent lipid-lowering agent and suppresses carotid and coronary artery atherosclerosis. It is unclear whether rosuvastatin has anti-atherogenic effects against AAPs in stroke patients. We designed a clinical trial in stroke patients to analyze changes in AAPs after rosuvastatin treatment using repeated transesophageal echocardiography (TEE). METHODS: This trial is a prospective randomized open label study. Inclusion criteria were patients were ischemic stroke with hypercholesterolemia and AAPs ≥ 4 mm in thickness. The patients are randomly assigned to either a group treated with 5 mg/day rosuvastatin or a control group. Primary endpoint is the changes in volume and composition of AAPs after 6 months using transesophageal echocardiography (TEE). Biochemical findings are analyzed. By using repeated TEE and binary image analysis, we will be able to compare the dynamic changes in plaque composition of AAPs before and after therapy in the two groups. CONCLUSIONS: The EPISTEME trial will provide information on the changes in plaque volume and composition achieved by improvement of lipid profiles with rosuvastatin therapy in stroke patients with aortic atherosclerosis. The results of the study may provide evidence for a therapeutic strategy for aortogenic brain embolism. This study is registered with UMIN-CTR (UMIN000010548).

Temporal changes of ulcerative plaques in the aortic arch in recurrent stroke patients.

BACKGROUND: Ulcerative aortic plaques (UAPs) are considered a major source of brain embolism. However, whether UAPs contribute to a specific stroke mechanism remains unknown. METHODS: Three consecutive patients with recurrent embolic stroke underwent repeated transesophageal echocardiography (TEE) examinations after their initial and recurrent strokes. RESULTS: All 3 patients had UAPs. Between TEEs, different morphologies of UAPs were found in cases 1 and 2, and case 3 maintained advanced UAPs with no significant morphological alteration. Case 3 underwent repeated contrast-enhanced computed tomographic examinations after each stroke event, which showed newly developed, uneven, ulcerative plaques in the aortic arch after recurrent stroke. CONCLUSIONS: Repeated TEE showed dynamic changes of UAPs in recurrent stroke patients and supported the diagnosis of aortogenic brain embolism.

Recurrent embolic strokes associated with vertical atlantoaxial subluxation in a patient with rheumatoid arthritis: a case report and review of literature.

We report a 78-year-old woman with rheumatoid arthritis who developed recurrent embolic cerebellar strokes associated with vertical atlantoaxial subluxation (AAS). On contrast angiography, the bilateral vertebral arteries (VAs) were occluded between the C1 and C2 levels, and the distal parts of bilateral VA were supplied by the collateral circulations. Dynamic cerebral angiography and carotid duplex ultrasonography showed that blood flow was substantially decreased in the left VA and left posterior inferior cerebellar artery on cervical anteflexion. It is suggested that vertical AAS reduced the blood flow of collateral circulation in the left VA with cervical anteflexion and might be a cause of recurrent ischemic stroke.