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Background: The “1-3-6-12-day rule” for starting direct oral anticoagulants (DOACs) in patients with nonvalvular atrial fibrillation after acute ischemic stroke or transient ischemic attack recommends timings that may be later than used in clinical practice. We investigated more practical optimal timing of DOAC initiation according to stroke severity. Methods: The combined data of prospective registries in Japan, Stroke Acute Management with Urgent Risk-factor Assessment and Improvement-nonvalvular atrial fibrillation (September 2011 to March 2014) and RELAXED (February 2014 to April 2016) were used. Patients were divided into transient ischemic attack and 3 stroke subgroups by the National Institutes of Health Stroke Scale score: mild (0–7), moderate (8–15), and severe (≥16). The early treatment group was defined as patients starting DOACs earlier than the median initiation day in each subgroup. Outcomes included a composite of recurrent stroke or systemic embolism, ischemic stroke, and severe bleeding within 90 days. Six European prospective registries were used for validation. Results: In the 1797 derivation cohort patients, DOACs were started at median 2 days after transient ischemic attack and 3, 4, and 5 days after mild, moderate, and severe strokes, respectively. Stroke or systemic embolism was less common in Early Group (n=785)—initiating DOACS within 1, 2, 3, and 4 days, respectively—than Late Group (n=1012) (1.9% versus 3.9%; adjusted hazard ratio, 0.50 [95% CI, 0.27–0.89]), as was ischemic stroke (1.7% versus 3.2%, 0.54 [0.27–0.999]). Major bleeding was similarly common in the 2 groups (0.8% versus 1.0%). On validation, both ischemic stroke (2.4% versus 2.2%) and intracranial hemorrhage (0.2% versus 0.6%) were similarly common in Early (n=547) and Late (n=1483) Groups defined using derivation data. Conclusions: In Japanese and European populations, early DOAC initiation within 1, 2, 3, or 4 days according to stroke severity seemed to be feasible to decrease the risk of recurrent stroke or systemic embolism and no increase in major bleeding. These findings support ongoing randomized trials to better establish the optimal timing of DOAC initiation.

Background and Purpose— We assessed whether lower-dose alteplase at 0.6 mg/kg is efficacious and safe for acute fluid-attenuated inversion recovery-negative stroke with unknown time of onset. Methods— This was an investigator-initiated, multicenter, randomized, open-label, blinded-end point trial. Patients met the standard indication criteria for intravenous thrombolysis other than a time last-known-well >4.5 hours (eg, wake-up stroke). Patients were randomly assigned (1:1) to receive alteplase at 0.6 mg/kg or standard medical treatment if magnetic resonance imaging showed acute ischemic lesion on diffusion-weighted imaging and no marked corresponding hyperintensity on fluid-attenuated inversion recovery. The primary outcome was a favorable outcome (90-day modified Rankin Scale score of 0–1). Results— Following the early stop and positive results of the WAKE-UP trial (Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke), this trial was prematurely terminated with 131 of the anticipated 300 patients (55 women; mean age, 74.4±12.2 years). Favorable outcome was comparable between the alteplase group (32/68, 47.1%) and the control group (28/58, 48.3%; relative risk [RR], 0.97 [95% CI, 0.68–1.41]; P =0.892). Symptomatic intracranial hemorrhage within 22 to 36 hours occurred in 1/71 and 0/60 (RR, infinity [95% CI, 0.06 to infinity]; P >0.999), respectively. Death at 90 days occurred in 2/71 and 2/60 (RR, 0.85 [95% CI, 0.06–12.58]; P >0.999), respectively. Conclusions— No difference in favorable outcome was seen between alteplase and control groups among patients with ischemic stroke with unknown time of onset. The safety of alteplase at 0.6 mg/kg was comparable to that of standard treatment. Early study termination precludes any definitive conclusions. Registration— URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02002325.

Objective Stroke-associated pneumonia (SAP) is a comorbidity of ischemic stroke related to clinical outcomes. Early enteral nutrition (EEN; within 48 hours) reduces the incidence of infection and length of intensive care unit (ICU)/hospital stay. The relationship between EEN and critical care outcomes, including SAP, in patients with ischemic stroke has been insufficiently studied. Methods We recruited 499 patients in this retrospective observational study. We evaluated SAP incidence within 14 days from admission. Patients were divided into an EEN group and a late EN group (LEN; start later than EEN). We compared groups regarding background and length of ICU/hospital stay. Results EN was started within 48 hours in 236 patients. SAP was diagnosed in 94 patients (18.8%), with most in the LEN group (28.1% vs. 8.5%). Median [interquartile range] lengths of hospitalization (22 [12–30] days vs. 35 [20–45] days) and ICU stay (4 [2–5] days vs. 6 [3–8] days) were longer in the LEN group. EEN reduced the incidence of SAP. By contrast, consciousness disturbance and worsening consciousness level increased the SAP incidence. Increased age and National Institutes of Health Stroke Scale score were associated with start of prolonged EN. Conclusions We found that EEN may reduce SAP risk.

Computed tomography angiography (CTA) immediately after diagnosis of intracerebral hematoma (ICH) on noncontrast CT in the emergency room has benefits, which consist of early diagnosis of secondary ICH and prediction of hematoma growth using the spot sign in primary ICH, but CTA also involves possible risks of acute kidney injury (AKI) and adverse reactions. The purpose of this study was to evaluate the benefits and risks of CTA. A total of 1423 consecutive adult patients diagnosed with ICH who were admitted within 3 days of onset between 2010 and 2017 were retrospectively analyzed. Of 1082 patients undergoing CTA, 162 patients (15.0%) showed secondary ICH, and the sensitivity of CTA for secondary ICH was 95.7%. Of 920 patients with primary ICH, a logistic regression model using the spot sign and four other previously reported risk factors (antiplatelet agents, anticoagulants, interval from onset to arrival, hematoma volume) with an area under the curve (AUC) of 0.787 significantly improved model performance to predict hematoma growth compared with a model using the same four factors without the spot sign (AUC: 0.697) (DeLong's test: P = 0.0002). Rates of AKI occurrence were 9.0% and 9.8% in patients with and without CTA, respectively. The odds ratio of AKI in patients with CTA adjusted by reported risk factors was 1.16 (95% confidence interval: 0.72-1.95, P = 0.5548). Emergency CTA following noncontrast CT in patients with ICH could be useful for early diagnosis of secondary ICH and prediction of hematoma growth using the spot sign in primary ICH with little risk.

Background: The present study aimed to clarify the association between left atrial (LA) size and ischemic events after ischemic stroke or transient ischemic attack (TIA) in patients with nonvalvular atrial fibrillation (NVAF). Methods: Acute ischemic stroke or TIA patients with NVAF were enrolled. LA size was classified into normal LA size, mild LA enlargement (LAE), moderate LAE, and severe LAE. The ischemic event was defined as ischemic stroke, TIA, carotid endarterectomy, carotid artery stenting, acute coronary syndrome or percutaneous coronary intervention, systemic embolism, aortic aneurysm rupture or dissection, peripheral artery disease requiring hospitalization, or venous thromboembolism. Results: A total of 1,043 patients (mean age, 78 years; 450 women) including 1,002 ischemic stroke and 41 TIA were analyzed. Of these, 351 patients (34%) had normal LA size, 298 (29%) had mild LAE, 198 (19%) had moderate LAE, and the remaining 196 (19%) had severe LAE. The median follow-up duration was 2.0 years (interquartile range, 0.9–2.1). During follow-up, 117 patients (11%) developed at least one ischemic event. The incidence rate of total ischemic events increased with increasing LA size. Severe LAE was independently associated with increased risk of ischemic events compared with normal LA size (multivariable-adjusted hazard ratio, 1.75; 95% confidence interval, 1.02–3.00). Conclusion: Severe LAE was associated with increased risk of ischemic events after ischemic stroke or TIA in patients with NVAF.

Moyamoya disease (MMD) is well known to be caused by insufficient cerebral vascular formation. However, the essential pathogenesis has not yet been identified. Using our recently developed technique of generating vasculogenic and anti-inflammatory cultures, we investigated endothelial progenitor cell (EPC) expansion and differentiation under the cytokine milieu generated by the peripheral blood mononuclear cells (PBMNCs) of the operated and non-operated MMD patients. EPC colony forming assay of the cultured PBMNCs disclosed the decline of the definitive EPC colony numbers in the both MMD patients. The level of interleukin-10 (IL-10) was lower in secretory cytokines from the cultured PBMNCs of MMD patients than that in that of controls using a cytometric bead array. The addition of human recombinant IL-10 to PBMNCs cultured from MMD patients restored the EPC colony forming potential of MMD PBMNCs. Following phorbol myristate acetate stimulation of the cultured PBMNCs, flow cytometry revealed a decrease in intracellular IL-10 storage in the main cell populations of the PBMNCs cultured from MMD patients relative to those cultured from controls. The present data provide the expected mechanism of vascular malformation in MMD pathogenesis originated from the insufficient production of IL-10 secreting cells from PBMNCs fostering EPC expansion and differentiation.

Background and aim We determined to investigate the incidence and clinical impact of new cerebral microbleeds after intravenous thrombolysis in patients with acute stroke. Methods The THAWS was a multicenter, randomized trial to study the efficacy and safety of intravenous thrombolysis with alteplase in patients with wake-up stroke or unknown onset stroke. Prescheduled T2*-weighted imaging assessed cerebral microbleeds at three time points: baseline, 22–36 h, and 7–14 days. Outcomes included new cerebral microbleeds development, modified Rankin Scale (mRS) ≥3 at 90 days, and change in the National Institutes of Health Stroke Scale (NIHSS) score from 24 h to 7 days. Results Of all 131 patients randomized in the THAWS trial, 113 patients (mean 74.3 ± 12.6 years, 50 female, 62 allocated to intravenous thrombolysis) were available for analysis. Overall, 46 (41%) had baseline cerebral microbleeds (15 strictly lobar cerebral microbleeds, 14 mixed cerebral microbleeds, and 17 deep cerebral microbleeds). New cerebral microbleeds only emerged in the intravenous thrombolysis group (seven patients, 11%) within a median of 28.3 h, and did not additionally increase within a median of 7.35 days. In adjusted models, number of cerebral microbleeds (relative risk (RR) 1.30, 95% confidence interval (CI): 1.17–1.44), mixed distribution (RR 19.2, 95% CI: 3.94–93.7), and cerebral microbleeds burden ≥5 (RR 44.9, 95% CI: 5.78–349.8) were associated with new cerebral microbleeds. New cerebral microbleeds were associated with an increase in NIHSS score ( p = 0.023). Treatment with alteplase in patients with baseline ≥5 cerebral microbleeds resulted in a numerical shift toward worse outcomes on ordinal mRS (median [IQR]; 4 [3–4] vs. 0 [0–3]), compared with those with Conclusion New cerebral microbleeds developed within 36 h in 11% of the patients after intravenous thrombolysis, and they were significantly associated with mixed-distribution and ≥5 cerebral microbleeds. New cerebral microbleeds development might impede neurological improvement. Furthermore, cerebral microbleeds burden might affect the effect of alteplase.

Advanced glycation end products play a key role in the pathophysiology of schizophrenia. Cognitive impairment is one of the central features of schizophrenia; however, the association between advanced glycation end products and cognitive impairment remains unknown. This study investigated whether advanced glycation end products affect the cognitive domain in patients with schizophrenia. A total of 58 patients with chronic schizophrenia were included in this cross-sectional study. Plasma advanced glycation end products were measured using high-performance liquid chromatography (HPLC). Neuropsychological and cognitive functions were assessed using the Wechsler Adult Intelligence Scale, Third Version, and the Wisconsin Card Sorting Test Keio-FS version. Multiple regression analysis adjusted for age, sex, body mass index, educational years, daily dose of antipsychotics, and psychotic symptoms revealed that processing speed was significantly associated with plasma pentosidine, a representative advanced glycation end product (standardized β = -0.425; p = 0.009). Processing speed is the cognitive domain affected by advanced glycation end products. Considering preceding evidence that impaired processing speed is related to poor functional outcome, interventions targeted at reducing advanced glycation end products may contribute to promoting recovery of patients with schizophrenia as well as cognitive function improvement.

International audience; BACKGROUND: Patients who have had a stroke with unknown time of onset have been previously excluded from thrombolysis. We aimed to establish whether intravenous alteplase is safe and effective in such patients when salvageable tissue has been identified with imaging biomarkers. METHODS: We did a systematic review and meta-analysis of individual patient data for trials published before Sept 21, 2020. Randomised trials of intravenous alteplase versus standard of care or placebo in adults with stroke with unknown time of onset with perfusion-diffusion MRI, perfusion CT, or MRI with diffusion weighted imaging-fluid attenuated inversion recovery (DWI-FLAIR) mismatch were eligible. The primary outcome was favourable functional outcome (score of 0-1 on the modified Rankin Scale [mRS]) at 90 days indicating no disability using an unconditional mixed-effect logistic-regression model fitted to estimate the treatment effect. Secondary outcomes were mRS shift towards a better functional outcome and independent outcome (mRS 0-2) at 90 days. Safety outcomes included death, severe disability or death (mRS score 4-6), and symptomatic intracranial haemorrhage. This study is registered with PROSPERO, CRD42020166903. FINDINGS: Of 249 identified abstracts, four trials met our eligibility criteria for inclusion: WAKE-UP, EXTEND, THAWS, and ECASS-4. The four trials provided individual patient data for 843 individuals, of whom 429 (51%) were assigned to alteplase and 414 (49%) to placebo or standard care. A favourable outcome occurred in 199 (47%) of 420 patients with alteplase and in 160 (39%) of 409 patients among controls (adjusted odds ratio [OR] 1·49 [95% CI 1·10-2·03]; p=0·011), with low heterogeneity across studies (I(2)=27%). Alteplase was associated with a significant shift towards better functional outcome (adjusted common OR 1·38 [95% CI 1·05-1·80]; p=0·019), and a higher odds of independent outcome (adjusted OR 1·50 [1·06-2·12]; p=0·022). In the alteplase group, 90 (21%) patients were severely disabled or died (mRS score 4-6), compared with 102 (25%) patients in the control group (adjusted OR 0·76 [0·52-1·11]; p=0·15). 27 (6%) patients died in the alteplase group and 14 (3%) patients died among controls (adjusted OR 2·06 [1·03-4·09]; p=0·040). The prevalence of symptomatic intracranial haemorrhage was higher in the alteplase group than among controls (11 [3%] vs two [\textless1%], adjusted OR 5·58 [1·22-25·50]; p=0·024). INTERPRETATION: In patients who have had a stroke with unknown time of onset with a DWI-FLAIR or perfusion mismatch, intravenous alteplase resulted in better functional outcome at 90 days than placebo or standard care. A net benefit was observed for all functional outcomes despite an increased risk of symptomatic intracranial haemorrhage. Although there were more deaths with alteplase than placebo, there were fewer cases of severe disability or death. FUNDING: None.

Background and Purpose: We determined to identify patients with unknown onset stroke who could have favorable 90-day outcomes after low-dose thrombolysis from the THAWS (Thrombolysis for Acute Wake-Up and Unclear-Onset Strokes With Alteplase at 0.6 mg/kg) database. Methods: This was a subanalysis of an investigator-initiated, multicenter, randomized, open-label, blinded–end point trial. Patients with stroke with a time last-known-well >4.5 hours who showed a mismatch between diffusion-weighted imaging (DWI) and fluid-attenuated inversion recovery were randomly assigned (1:1) to receive alteplase at 0.6 mg/kg intravenously or standard medical treatment. The patients were dichotomized by ischemic core size or National Institutes of Health Stroke Scale score, and the effects of assigned treatments were compared in each group. The efficacy outcome was favorable outcome at 90 days, defined as a modified Rankin Scale score of 0 to 1. Results: The median DWI-Alberta Stroke Program Early CT Score (ASPECTS) was 9, and the median ischemic core volume was 2.5 mL. Both favorable outcome (47.1% versus 48.3%) and any intracranial hemorrhage (26% versus 14%) at 22 to 36 hours were comparable between the 68 thrombolyzed patients and the 58 control patients. There was a significant treatment-by-cohort interaction for favorable outcome between dichotomized patients by ASPECTS on DWI ( P =0.026) and core volume ( P =0.035). Favorable outcome was more common in the alteplase group than in the control group in patients with DWI-ASPECTS 5 to 8 (RR, 4.75 [95% CI, 1.33–30.2]), although not in patients with DWI-ASPECTS 9 to 10. Favorable outcome tended to be more common in the alteplase group than in the control group in patients with core volume >6.4 mL (RR, 6.15 [95% CI, 0.87–43.64]), although not in patients with volume ≤6.4 mL. The frequency of any intracranial hemorrhage did not differ significantly between the 2 treatment groups in any dichotomized patients. Conclusions: Patients developing unknown onset stroke with DWI-ASPECTS 5 to 8 showed favorable outcomes more commonly after low-dose thrombolysis than after standard treatment. Registration: URL: https://www.clinicaltrials.gov ; Unique Identifier: NCT02002325. URL: https://www.umin.ac.jp/ctr ; Unique Identifier: UMIN000011630.

Despite the high frequency of depression in the first year following stroke, few studies have predicted risk of depression after the acute and subacute stroke periods. The aim of this study was to identify, in the acute and subacute periods, measures that would predict major depression during the first year after stroke.Study subjects were inpatients with ischemic stroke aged 20-85 years within 6 weeks of onset. Patients were evaluated at baseline and at 3, 6, 9, and 12 months. Patients were diagnosed with major depression using the Structured Clinical Interview for DSM-IV. The severity of depressive symptoms was measured with the Patient Health Questionnaire-9 (PHQ-9) and the Montgomery-Åsberg Depression Rating Scale (MADRS).Of the 152 potential patients who met inclusion criteria, 49 had follow-up evaluations; one patient with major depression in the acute and subacute periods was excluded from the analysis. Among the remaining 48 patients, the number of those with major depression during the first year of stroke onset was five (10.4%). Patients who developed major depression had significantly more depressive symptoms in the acute and subacute stroke phase as assessed by both the PHQ-9 and MADRS. Patients with PHQ-9 scores ≥9 in the acute and subacute stroke phases were significantly more likely to develop major depression in a chronic phase of stroke.The self-administered PHQ-9 can identify patients in the acute and subacute stroke periods who are at increased risk for developing major depression during the first year after stroke.

We report an 82-year-old man with recurrence of Mikulicz’s disease accompanied with mononeuritis multiplex. On admission, both upper eyelids, the salivary gland, the dorsum of the left hand and both legs were swollen. Neurological examination showed motor weakness of distal limbs (manual muscle testing 3/5) and decreased touch, pain and vibration sensation of the dorsum of the left hand and both legs. Deep tendon reflex in both legs was also decreased. We diagnosed Mikulicz’s disease based on high serum immunoglobulin (Ig)G4 (630 mg/dl, 26.1% of total IgG) and lacrimal gland biopsy findings. Clinical symptoms and motor conduction study findings improved after steroid therapy. However, tapering of the steroid dose resulted in recurrence two years later. Steroid therapy is usually effective for IgG4-related neuropathy, and we found that an increase of steroid dose was effective to treat the recurrence. But, in general, a suitable maintenance dose of steroid in combination with an immunosuppressant may be necessary to prevent relapse.

Multiple sclerosis is a neurological disorder in which the myelin sheaths of axons are damaged by the immune response. We report here a three-dimensional structural analysis of brain and spinal cord tissues of a mouse model of multiple sclerosis, known as experimental autoimmune encephalomyelitis (EAE). EAE-induced mice were raised with or without administration of fingolimod, which is used in the treatment of multiple sclerosis. Brains and spinal cords dissected from the EAE mice were lyophilized so as to reconstitute the intrinsic contrast of tissue elements, such as axons, in X-ray images. Three-dimensional structures of the brain hemispheres and spinal cords of the EAE mice were visualized with synchrotron radiation microtomography. Microtomographic cross sections reconstructed from the X-ray images revealed dilation of capillary vessels and vacuolation in the spinal cord of the EAE mice. Vacuolation was also observed in the cerebellum, suggesting that the neuroinflammatory response progressed in the brain. The vessel networks and vacuolation lesions in the spinal cords were modelled by automatically tracing the three-dimensional image in order to analyze the tissue structures quantitatively. The results of the analysis indicated that the distribution of vacuolations was not uniform but three-dimensionally localized. The mean vessel diameter showed a linear correlation with the clinical score, indicating that vasodilation is relevant to paralysis severity in the disease model. We suggest that vasodilation and vacuolation are related with neurological symptoms of multiple sclerosis., 22 pages, 5 figures, 1 table

Although myo-inositol pyrophosphates such as diphosphoinositol pentakisphosphate (InsP7) are important in biology, little quantitative information is available regarding their presence in mammalian organisms owing to the technical difficulties associated with accurately detecting these materials in biological samples. We have developed an analytical method whereby InsP7 and its precursor inositol hexakisphosphate (InsP6) are determined directly and sensitively using tandem mass spectrometry coupled with hydrophilic interaction liquid chromatography (HILIC). InsP6 and InsP7 peak symmetry is influenced greatly by the buffer salt composition and pH of the mobile phase used in HILIC analysis. The use of 300 mM ammonium carbonate (pH 10.5) as an aqueous mobile phase resolves InsP6 and InsP7 on a polymer-based amino HILIC column with minimal peak tailing. Method validation shows that InsP6 and InsP7 can be quantitated from 20-500 pmol with minimal intra-day/inter-day variance in peak area and retention time. The concentration of InsP6 in C57BL/6J mouse brain (40.68 ± 3.84 pmol/mg wet weight) is successfully determined. HILIC‒MS/MS analysis using HEK293 culture cells confirms previous observations that InsP7 is induced by NaF treatment and ectopic expression of InsP6K2, a primary kinase for InsP7 synthesis. Furthermore, this analysis reveals the abundance of InsP6 (50.46 ± 18.57 pmol/106 cells) and scarcity of InsP7 in human blood cells. The results demonstrate that HILIC‒MS/MS analysis can quantitate endogenous InsP6 and InsP7 in mouse and human samples, and we expect that the method will contribute to further understanding of InsP7 functions in mammalian pathobiology.

BACKGROUND We determined the 2-year long-term risk-benefit profile in patients with stroke or transient ischemic attack (TIA) receiving warfarin or direct oral anticoagulants (DOACs) for nonvalvular atrial fibrillation (NVAF) using a prospective, multicenter, observational registry in Japan.Methods and Results:NVAF patients within 7 days after onset of ischemic stroke/TIA were enrolled in 18 stroke centers. Outcome measures included ischemic and bleeding events and death in the 2-year follow-up period. We enrolled 1,116 patients taking either warfarin (650 patients) or DOACs (466 patients) at acute hospital discharge. DOAC users were younger and had lower National Institutes of Health Stroke Scale, CHADS2and discharge modified Rankin Scale scores than warfarin users (P

Stroke-associated pneumonia (SAP) is a frequent complication in acute ischemic stroke (IS) patients, especially those receiving tube feeding (TF). In this retrospective study, we investigated whether or not cilostazol, a pluripotent phosphodiesterase III-specific inhibitor with anti-platelet and vasculogenic effects, can prevent SAP in these patients and reduce their duration of stay in intensive care unit/hospitalization. We recruited 158 IS patients receiving TF. Patients' characteristics (including age, gender, past history), National Institute of Health Stroke Scale and serum albumin level on admission, concomitant medications associated with SAP prevention (including cilostazol), and stroke characteristics (bilateral subcortical white matter lesion, brainstem involvement, large infarction, and asymptomatic hemorrhagic infarction) were compared between the SAP(-) and SAP(+) groups. Cilostazol was more frequently used in the SAP(-) group (20.8% vs. 6.1%, p

Background: We aimed to clarify associations between pre-admission risk scores (CHADS2, CHA2DS2-VASc, and HAS-BLED) and 2-year clinical outcomes in ischemic stroke or transient ischemic attack (TIA) patients with non-valvular atrial fibrillation (NVAF) using a prospective, multicenter, observational registry. Methods: From 18 Japanese stroke centers, ischemic stroke or TIA patients with NVAF hospitalized within 7 days after onset were enrolled. Outcome measures were defined as death/disability (modified Rankin Scale score ≥3) at 2 years, 2-year mortality, and ischemic or hemorrhagic events within 2 years. Results: A total of 1,192 patients with NVAF (527 women; mean age, 78 ± 10 years), including 1,141 ischemic stroke and 51 TIA, were analyzed. Rates of death/disability, mortality, and ischemic or hemorrhagic events increased significantly with increasing pre-admission CHADS2 (p for trend p for trend = 0.024 for events), CHA2DS2-VASc (p for trend p for trend = 0.004 for death/disability, p for trend p for trend = 0.024 for events) scores. Pre-admission CHADS2 (OR per 1 point, 1.52; 95% CI 1.35–1.71; p p p = 0.016 for events), CHA2DS2-VASc (1.55, 1.41–1.72, p < 0.001; 1.21, 1.12–1.30, p < 0.001; 1.17, 1.07–1.27, p < 0.001; respectively), and HAS-BLED (1.33, 1.17–1.52, p < 0.001; 1.23, 1.10–1.38, p < 0.001; 1.18, 1.05–1.34, p = 0.008; respectively) scores were independently associated with all outcome measures. Conclusions: In ischemic stroke or TIA patients with NVAF, all pre-admission risk scores were independently associated with death/disability at 2 years and 2-year mortality, as well as ischemic or hemorrhagic events within 2 years.

We report a case of eosinophilic granulomatosis with polyangiitis (EGPA; formerly known as Churg-Strauss syndrome) complicated by perforation of the small intestine and necrotizing cholecystitis. A 69-year-old man with a history of bronchial asthma was admitted with mononeuritis multiplex. The laboratory findings included remarkable eosinophilia. He was treated with corticosteroids and his laboratory indices showed improvement; however, his functional deficits remained. His neuropathy gradually improved after the addition of intravenous immunoglobulin (IVIG). He was subsequently treated with oral prednisolone (40 mg/day) as maintenance therapy. Within a month after finishing IVIG, he developed perforation of the small intestine and necrotizing cholecystitis. Intestinal perforation has often been reported as a gastrointestinal complication of EGPA. In contrast, cholecystitis is a rare complication. We report this case because the manifestation of more than one complication is extremely rare. Gastrointestinal symptoms may be a complication of EGPA itself and/or immunosuppressive treatment.

We examined the relationship between hemifacial spasm (HFS; a form of cranio-cervical dystonia) and chronic primary headache, including tension-type headache (TTH). We also examined whether botulinum toxin A (BoNT/A) therapy for HFS ameliorates concomitant TTH.Fifty-one HFS patients receiving BoNT/A therapy were recruited. Patients' characteristics (including age, gender, chronic headache history, exercise habits, stiff neck, cervical spondylolysis history), stress factors, worsening/new onset of headache associated with HFS, and dose of BoNT/A were examined. We diagnosed headache types according to The International Classification of Headache Disorders, 3rd edition, beta. Numerical Rating Scale (NRS) and Headache Impact Test-6 (HIT-6) scores for headache severity were compared between the 6-week baseline before BoNT/A therapy and 6-week follow-up after BoNT/A therapy.Of 51 patients with HFS, 17 (33.3%) reported worsening or new onset of headache (especially TTH) associated with HFS (Group-S), and 34 were not aware of headache (Group-N). Twelve patients (70.6%) in group-S reported improvement of headache after BoNT/A therapy. NRS (from 7 [5-9] to 0 [0-5], p0.01) and HIT-6 (from 55 [54-64] to 44 [36-52], p0.001) scores were significantly improved after BoNT/A therapy. Logistic regression analysis revealed significant interaction between TTH associated with HFS and the presence of stress factors (odds ratio 43.11: 2.95-629.39, p0.001) and history of chronic headache (odds ratio 28.53: 2.96-275.10, p0.001).Primary headache, especially TTH, is associated with HFS. BoNT/A therapy for HFS may also be indirectly effective for treatment of TTH.

Background and Purpose— We assessed whether the presence, number, and distribution of cerebral microbleeds (CMBs) on pre-intravenous thrombolysis MRI scans of acute ischemic stroke patients are associated with an increased risk of intracerebral hemorrhage (ICH) or poor functional outcome. Methods— We performed an individual patient data meta-analysis, including prospective and retrospective studies of acute ischemic stroke treated with intravenous tissue-type plasminogen activator. Using multilevel mixed-effects logistic regression, we investigated associations of pre-treatment CMB presence, burden (1, 2–4, ≥5, and >10), and presumed pathogenesis (cerebral amyloid angiopathy defined as strictly lobar CMBs and noncerebral amyloid angiopathy) with symptomatic ICH, parenchymal hematoma (within [parenchymal hemorrhage, PH] and remote from the ischemic area [remote parenchymal hemorrhage, PHr]), and poor 3- to 6-month functional outcome (modified Rankin score >2). Results— In 1973 patients from 8 centers, the crude prevalence of CMBs was 526 of 1973 (26.7%). A total of 77 of 1973 (3.9%) patients experienced symptomatic ICH, 210 of 1806 (11.6%) experienced PH, and 56 of 1720 (3.3%) experienced PHr. In adjusted analyses, patients with CMBs (compared with those without CMBs) had increased risk of PH (odds ratio: 1.50; 95% confidence interval: 1.09–2.07; P =0.013) and PHr (odds ratio: 3.04; 95% confidence interval: 1.73–5.35; P P =0.014), PH ( P =0.013), and PHr ( P 10 CMBs independently predicted poor 3- to 6-month outcome (odds ratio: 1.85; 95% confidence interval: 1.10–3.12; P =0.020; and odds ratio: 3.99; 95% confidence interval: 1.55–10.22; P =0.004, respectively). Conclusions— Increasing CMB burden is associated with increased risk of ICH (including PHr) and poor 3- to 6-month functional outcome after intravenous thrombolysis for acute ischemic stroke.

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Background and Purpose— We aimed to compare outcomes of ischemic stroke patients with nonvalvular atrial fibrillation between earlier and later initiation of direct oral anticoagulants (DOACs) after stroke onset. Methods— From data for 1192 nonvalvular atrial fibrillation patients with acute ischemic stroke or transient ischemic attack in a prospective, multicenter, observational study, patients who started DOACs during acute hospitalization were included and divided into 2 groups according to a median day of DOAC initiation after onset. Outcomes included stroke or systemic embolism, major bleeding, and death at 3 months, as well as those at 2 years. Results— DOACs were initiated during acute hospitalization in 499 patients in median 4 (interquartile range, 2–7) days after onset. Thus, 223 patients (median age, 74 [interquartile range, 68–81] years; 78 women) were assigned to the early group (≤3 days) and 276 patients (median age, 75 [interquartile range, 69–82] years; 101 women) to the late (≥4 days) group. The early group had lower baseline National Institutes of Health Stroke Scale score and smaller infarcts than the late group. The rate at which DOAC administration persisted at 2 years was 85.2% overall, excluding patients who died or were lost to follow-up. Multivariable Cox shared frailty models showed comparable hazards between the groups at 2 years for stroke or systemic embolism (hazard ratio, 0.86 [95% CI, 0.47–1.57]), major bleeding (hazard ratio, 1.39 [95% CI, 0.42–4.60]), and death (hazard ratio, 0.61 [95% CI, 0.28–1.33]). Outcome risks at 3 months also did not significantly differ between the groups. Conclusions— Risks for events including stroke or systemic embolism, major bleeding, and death were comparable whether DOACs were started within 3 days or from 4 days or more after the onset of nonvalvular atrial fibrillation–associated ischemic stroke or transient ischemic attack. Registration— URL: https://www.clinicaltrials.gov . Unique identifier: NCT01581502.

We have previously reported that inositol hexakisphosphate kinase (InsP6K)2 mediates cell death. InsP6K2 is abundantly expressed in anterior horn cells of the mammalian spinal cord. We investigated the role of InsP6K2 in spinal cords of patients with amyotrophic lateral sclerosis (ALS). Autopsy specimens of lumbar spinal cords from ten patients with sporadic ALS and five non-neurological disease patients (NNDPs) were obtained. We performed quantitative real-time PCR, immunostaining, and western blotting for InsP6K1, InsP6K2, InsP6K3, protein kinase B (Akt), casein kinase 2 (CK2), and 90-kDa heat-shock protein (HSP90). In contrast to InsP6K1 and InsP6K3 mRNA expression, InsP6K2 levels in anterior horn cells of the spinal cord were significantly increased in ALS patients compared to NNDPs. In ALS patients, InsP6K2 translocated from the nucleus to the cytoplasm. However, we observed a decrease in HSP90, CK2, and Akt activity in ALS patients compared to NNDPs. A previous study reported that InsP6K2 activity is suppressed after binding to HSP90 and subsequent phosphorylation and degradation by CK2, thus decreasing InsP6K2 activity. However, InsP7, which is generated by InsP6K2, can compete with Akt for PH domain binding. Consequently, InsP7 can inhibit Akt phosphorylation. Our results suggest that InsP6K2 is activated in the spinal cord of patients with ALS and may play an important role in ALS by inducing cell death mechanisms via Akt, CK2, and HSP90 pathways.

Background We aimed to develop quality indicators (QIs) related to primary and comprehensive stroke care and examine the feasibility of their measurement using the existing Diagnosis Procedure Combination (DPC) database. Methods and results We conducted a systematic review of domestic and international studies using the modified Delphi method. Feasibility of measuring the QI adherence rates was examined using a DPC-based nationwide stroke database (396,350 patients admitted during 2013-2015 to 558 hospitals participating in the J-ASPECT study). Associations between adherence rates of these QIs and hospital characteristics were analyzed using hierarchical logistic regression analysis. We developed 17 and 12 measures as QIs for primary and comprehensive stroke care, respectively. We found that measurement of the adherence rates of the developed QIs using the existing DPC database was feasible for the 6 QIs (primary stroke care: early and discharge antithrombotic drugs, mean 54.6% and 58.7%; discharge anticoagulation for atrial fibrillation, 64.4%; discharge antihypertensive agents, 51.7%; comprehensive stroke care: fasudil hydrochloride or ozagrel sodium for vasospasm prevention, 86.9%; death complications of diagnostic neuroangiography, 0.4%). We found wide inter-hospital variation in QI adherence rates based on hospital characteristics. Conclusions We developed QIs for primary and comprehensive stroke care. The DPC database may allow efficient data collection at low cost and decreased burden to evaluate the developed QIs.

Objective:\ud It is not known whether patients with atrial fibrillation (AF) with ischemic stroke despite oral anticoagulant therapy are at increased risk for further recurrent strokes or how ongoing secondary prevention should be managed.\ud \ud Methods:\ud We conducted an individual patient data pooled analysis of 7 prospective cohort studies that recruited patients with AF and recent cerebral ischemia. We compared patients taking oral anticoagulants (vitamin K antagonists [VKA] or direct oral anticoagulants [DOAC]) prior to index event (OACprior ) with those without prior oral anticoagulation (OACnaive ). We further compared those who changed the type (ie, from VKA or DOAC, vice versa, or DOAC to DOAC) of anticoagulation (OACchanged ) with those who continued the same anticoagulation as secondary prevention (OACunchanged ). Time to recurrent acute ischemic stroke (AIS) was analyzed using multivariate competing risk Fine-Gray models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs).\ud \ud Results:\ud We included 5,413 patients (median age = 78 years [interquartile range (IQR) = 71-84 years]; 5,136 [96.7%] had ischemic stroke as the index event, median National Institutes of Health Stroke Scale on admission = 6 [IQR = 2-12]). The median CHA2 DS2 -Vasc score (congestive heart failure, hypertension, age≥ 75 years, diabetes mellitus, stroke/transient ischemic attack, vascular disease, age 65-74 years, sex category) was 5 (IQR = 4-6) and was similar for OACprior (n = 1,195) and OACnaive (n = 4,119, p = 0.103). During 6,128 patient-years of follow-up, 289 patients had AIS (4.7% per year, 95% CI = 4.2-5.3%). OACprior was associated with an increased risk of AIS (HR = 1.6, 95% CI = 1.2-2.3, p = 0.005). OACchanged (n = 307) was not associated with decreased risk of AIS (HR = 1.2, 95% CI = 0.7-2.1, p = 0.415) compared with OACunchanged (n = 585).\ud \ud Interpretation:\ud Patients with AF who have an ischemic stroke despite previous oral anticoagulation are at a higher risk for recurrent ischemic stroke despite a CHA2 DS2 -Vasc score similar to those without prior oral anticoagulation. Better prevention strategies are needed for this high-risk patient group.

Human T-lymphotropic virus type I (HTLV-I) is a retrovirus associated with adult T-cell lymphoma (ATL) and HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). In addition to HAM/TSP and ATL, HTLV-I-associated encephalopathy and cerebellar involvement have been reported. We report a case of an 87-year-old Japanese woman presenting with progressive dysarthria and gait disturbance. Neurological examination showed word-finding difficulty, scanning speech, saccadic eye movements, ocular dysmetria, gaze-evoked nystagmus and bilateral dysmetria. There was no motor weakness or spasticity. HTLV-I antibody was detected in both her serum and cerebrospinal fluid. Cerebrospinal fluid neopterin (57 pg/mL) and IgG index (3.27) were significantly elevated. MRI showed cerebellar swelling. She was finally diagnosed with HTLV-I associated cerebellitis. Two courses of high-dose intravenous methylpredonine therapy attenuated cerebellar ataxia and cerebellar swelling. It suggests that cerebellitis can result from HTLV-I infection, regardless of the existence of ATL or HAM/TSP.

The clinical features of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) are not uniform. We herein report a male patient with unusual MELAS-like encephalopathy who had been experiencing isolated recurrent stroke-like episodes since he was 33 years old without any particular family history. Despite an extensive investigation, he had no other signs suggestive of MELAS. Although the muscle pathology showed a normal appearance, a mitochondrial genome sequence analysis of the biopsied muscle revealed a heteroplasmic m.10158T>C mutation in the mitochondrial complex I subunit gene, MT-ND3. To prevented further deterioration of the higher brain function, the early diagnosis and treatment of mitochondrial stroke-like episodes is important.

We report the case of a 69-year-old woman with proximal limb muscle weakness, who received post-operative chemotherapy for uterine cancer. Her serum creatinine kinase level was high (10,779 mg/dL) and a muscle biopsy from her left biceps revealed various sizes of muscle fibers accompanied by necrotic and regenerating fibers. She was positive for anti-3 hydroxy-3-methylglutary-coenzyme A reductase (anti-HMGCR) antibodies, but negative for anti-signal recognition particle (anti-SRP) antibodies. She was diagnosed with immune-mediated necrotizing myopathy (IMNM) and treated with prednisolone. Our findings indicate that not only drug-induced myopathy but also paraneoplastic myopathy can be involved in the pathogenesis of IMNM.

We aimed to validate the diagnostic utility of enzyme-linked immunosorbent assay (ELISA) for the detection of anti-neurofascin (NF) 155 antibody in 191 patients with chronic inflammatory demyelinating polyneuropathy (CIDP). Human NF155-based ELISA clearly distinguished between anti-NF155 antibody-positive and -negative sera. Fifteen CIDP patients (8%) were IgG4 anti-human NF155 antibody-positive, which were confirmed by western blot, cell-based assay and immunohistochemical study. None of disease controls or healthy subjects had positive results. Clinical presentation of IgG4 anti-NF155 antibody-positive patients was consistent with those in previous reports. This ELISA combined with determination of the IgG4 subclass is useful in screening for anti-NF155 antibodies.

Background Granulocyte colony-stimulating factor (G-CSF) has shown neuroprotective and neurogenerative activities in experimental studies, and our previous phase I clinical study suggested the safety and potential efficacy of low-dose G-CSF in acute ischemic stroke patients. The present phase II trial is aimed to evaluate the effect of G-CSF administration on neurological function and infarct volume, compared with a placebo group. Methods Forty-nine acute ischemic stroke patients (29 males, 20 females; 71 ± 10 years) within 24 hours after onset were recruited. Eligible patients were randomized 2:2:1 to receive G-CSF 150 µg/body/day, G-CSF 300 µg/body/day, and placebo, respectively. We evaluated clinical outcome in terms of the National Institutes of Health Stroke Scale, the modified Rankin Scale, and the Barthel Index at 90 days after onset, together with changes in infarct volume on magnetic resonance imaging. Results We found no serious adverse event, including change in leukocyte levels, which remained below 31,000/µL, at 150 and 300 µg G-CSF/body/day. Clinical outcome scores did not show any significant difference among the 3 groups. Chronological changes in infarct volume also showed no significant difference. Conclusions G-CSF was well-tolerated at 150 and 300 µg/body/day in patients with acute ischemic stroke. However, administration of G-CSF at both 150 and 300 µg/body/day neither contributed to functional recovery nor reduced infarct volume at 3 months after onset, compared with the control group. The apparent lack of effectiveness may have been due to the small sample size. A trial of combination therapy with recombinant tissue plasminogen activator and G-CSF is planned.

Background: The WAKE-UP trial recently revealed the efficacy of magnetic resonance imaging (MRI)-based intravenous thrombolysis with alteplase at 0·9 mg/kg in acute ischemic stroke patients with unknown time of onset. We assessed whether lower-dose alteplase at 0·6 mg/kg is efficacious and safe in patients under the same conditions. Methods: This was an investigator-initiated, multicenter, randomized, open-label, blinded-endpoint trial. Patients met the standard indication criteria for intravenous thrombolysis other than a time last-known-well >4·5 h (e.g., wake-up stroke). Patients were randomly assigned (1:1) to receive alteplase at 0·6 mg/kg or standard medical treatment if MRI showed acute ischemic lesion on diffusion-weighted imaging and no marked corresponding hyperintensity on FLAIR. The primary outcome was a favorable outcome (90-day modified Rankin Scale score of 0-1). Findings: Following the early stop and positive results of the WAKE-UP trial, this trial was prematurely terminated with 131 of the anticipated 300 patients (55 women; mean age: 74·4±12·2 years; median National Institutes of Health Stroke Scale score: 7; interquartile range: 4-13). Favorable outcome was comparable between the alteplase group (32/68, 47·1%) and the control group (28/58, 48·3%) (relative risk (RR), 0·97; 95% confidence interval (CI), 0·68 to 1·41; p=0·892). Symptomatic intracranial hemorrhage within 22-36 h occurred in 1/71 (1·4%) and 0/60 (RR, infinity; 95%CI, 0·06 to infinity; p=1·0), respectively. Death at 90 days occurred in 2/71 (2·8%) and 2/60 (3·3%) (RR, 0·85; 95%CI, 0·06 to 12·58; p=1·0), respectively. Interpretation: No difference in favorable outcome was seen between alteplase and control groups among ischemic stroke patients with unknown time of onset. The safety of alteplase at 0·6 mg/kg was comparable to that of standard treatment. Early study termination precludes any definitive conclusions, and additional research may be warranted. Trial Registration: This trial was registered with ClinicalTrials.gov NCT02002325 and UMIN 000011630. Funding Statement: This trial was funded mainly by the Japan Agency for Medical Research and Development (AMED) (JP16ek0210025h and JP18ek0210091h), and the Ministry of Health, Labour, and Welfare, and partly by the Intramural Research Fund for Cardiovascular Diseases of National Cerebral and Cardiovascular Center (H23-4-3; maintenance of the administration infrastructure for international multicenter studies of clinical stroke; P. I., K. Toyoda), and the Mihara Cerebrovascular Disorder Research Promotion Fund. Declaration of Interests: MK reports honoraria from Bayer, BMS/Pfizer, Daiichi-Sankyo and Nippon Boehringer Ingelheim, scientific advisory board from Ono, and research supports from Takeda, Daiichi-Sankyo, Nippon Boehringer Ingelheim, Astellas, Pfizer and Shionogi, outside the submitted work. RI reports personal fees from Bayer, personal fees from Bristol-Myers Squibb, personal fees from Daiichi-Sankyo, personal fees from Boehringer Ingelheim, personal fees from Pfizer, personal fees from Stryker, personal fees from Medtronic, personal fees from Otsuka Pharmaceutical, personal fees from GE, grants from Tohoku Fukushi University, personal fees from Tanabe Mitsubishi , personal fees from Johnson and Johnson, outside the submitted work. TI reports grants from Ogaki Tokusyukai Hospital, grants from GlaxoSmithKline K.K., outside the submitted work. YN reports personal fees from Bayer, Bristol-Myers Squibb, Eisai, Daiichi Sankyo, Mochida, Ono, and Takeda, outside the submitted work. YO reports personal fees from Boehringer Ingelheim, personal fees from Bayer, personal fees from Pfizer, personal fees from Daiichi-Sankyo, personal fees from Bristol Myer Squibb, personal fees from Otsuka, outside the submitted work. NS reports personal fees from Otsuka, outside the submitted work. SY reports personal fees from Medtronic, personal fees from Stryker, personal fees from Kaneka Medics, personal fees from Otsuka Pharmaceutical, during the conduct of the study; personal fees from Boehringer-Ingelheim, personal fees from Daiichi Sankyo, personal fees from Pfizer, personal fees from Bayer, personal fees from Sanofi, personal fees from Bristol-Meyers, outside the submitted work. TU reports personal fees from Boehringer Ingelheim, personal fees from Bristol-Myers Squibb, personal fees from AstraZeneca K.K., personal fees from Bayer Pharmaceutical Co., Ltd., personal fees from Otsuka Pharmaceutical Co., Ltd., personal fees from Takeda Pharmaceutical Co., Ltd., personal fees from Mitsubishi-Tanabe Pharma Co., Ltd, personal fees from UCB Japan Co., Ltd., personal fees from Kowa Shinyaku Co., Ltd., personal fees from Sumitomo Dainippon Pharma Co., Ltd., personal fees from Astellas Pharma Inc., personal fees from AbbVie GK, personal fees from Medtronic Japan Co., Ltd., personal fees from Eisai Co., Ltd., personal fees from Daiichi Sankyo Co., Ltd., personal fees from CSL Behring, personal fees from Japanese Physical Therapy Association, outside the submitted work. MI reports grants from Shimadzu Corporation, grants and personal fees from Otsuka Pharmaceutical Company Ltd., personal fees from Daiichi Sankyo Company Ltd., personal fees from Pfizer Inc., personal fees from Eisai, outside the submitted work. TK reports personal fees from Bayer Yakuhin Ltd, grants and personal fees from Daiichi Sankyo Co Ltd, grants and personal fees from Chugai Pharmaceutical Co Ltd, grants from Takeda Pharmaceutical Co Ltd, grants from Eisai Co Ltd, grants from Astellas Pharma Inc, grants from MSD KK, grants from Mitsubishi Tanabe Pharma Co, outside the submitted work. Dr. Sasaki reports personal fees from Mitsubishi Tanabe, personal fees from Bayer, personal fees from Astellas, personal fees from Ono Pharma, personal fees from Mediphysics, personal fees from Actelion, personal fees from Ezai, personal fees from FujiFilm, personal fees from Daiichi Sankyo, personal fees from Nippon Boehlinger Ingelheim, personal fees from Otsuka, personal fees from Chugai, grants and personal fees from Hitachi, grants from Actelion, grants from GE Healthcare, outside the submitted work. KK reports personal fees（honoraria for lecture presentations） from Bayer Yakuhin. KM reports personal fees and other from Bayer Yakuhin, personal fees from Otsuka Pharmaceutical, personal fees from Boehringer-Ingelhaem, personal fees from Mitsubishi Tanabe Pharma Cooperation, outside the submitted work; and personal fees (honoraria for seminar presentation) and other (Advisory Board) from AstraZeneca; personal fees (honoraria for seminar presentation) from Pfizer, Japan Stryker, Dai-ichi Sankyo, Astellas Pharma, Nippon Chemiphar and Fuji Film RI Pharma; and other (Advisory Board) from CSL Behring, Medico's Hirata, EPS Corporation, HEALIOS K.K. and T-PEC Corporation. KT reports personal fees from Daiichi-Sankyo, personal fees from Bayer Yakuhin, personal fees from Brystol-Meyers-Squibb, personal fees from Nippon Behringer Ingerheim, outside the submitted work. None of the other authors have any conflicts of interest to declare. Ethics Approval Statement: The trial protocol was approved by the Ministry of Health, Labour, and Welfare, Japan to perform a treatment not covered by the national health insurance system. The trial was approved by the local ethics committee or institutional review board at each participating center. Patients or their relatives provided written informed consent according to ethical regulations.

Embolic stroke of undetermined source has not been thoroughly investigated in older patients. In this study, we investigated the features of this condition in patients greater than or equal to 80 years of age.All patients with acute ischemic stroke in our hospital underwent diffusion-weighted imaging, magnetic resonance angiography, T2-weighted imaging, and fluid-attenuated inversion recovery sequence imaging. Embolic stroke of undetermined source was defined as a radiologically confirmed nonlacunar brain infarct on diffusion-weighted imaging without (1) extracranial or intracranial atherosclerosis causing greater than or equal to 50% luminal stenosis in arteries supplying the ischemic area, (2) major-risk cardioembolic source, and (3) any other specific cause of stroke. We retrospectively identified consecutive patients hospitalized for acute ischemic stroke who met the embolic stroke of undetermined source diagnostic criteria and investigated patients' baseline and diagnostic findings.We divided 122 consecutive embolic stroke of undetermined source patients (median age: 73 years; 49 men, 73 women) into 2 groups by age at admission. Patients aged greater than or equal to 80 years had higher D-dimer and brain natriuretic peptide levels, more frequent premature atrial complexes/day in 24-hour Holter electrocardiography, and thicker maximum intima media thickness on ultrasound compared with patients aged less than 80 years (P.05, U test).Our results suggest that high admission D-dimer and brain natriuretic peptide levels are associated with age of onset in patients with embolic stroke of undetermined source. Patients aged greater than or equal to 80 years tended to have more frequent premature atrial complexes and thicker maximum intima media thickness compared with patients aged less than 80 years.

We describe the cases of two sisters with spastic paraplegia 11 (SPG11). The younger sister developed relapsing lesions in the brain white matter with enhancement during the acute phase that mimicked multiple sclerosis (MS). The elevation of myelin basic protein in the cerebrospinal fluid (CSF) suggested demyelination, but a normal IgG index, the absence of oligoclonal bands, and the ineffectiveness of steroid treatment indicate that an autoimmune mechanism may not have been involved. In these affected sisters, we identified novel compound heterozygous mutations in the SPG11 gene. Our cases indicate the possible existence of a broader phenotypic spectrum of SPG11 mutations.

We had a case of Emery-Dreifuss muscular dystrophy (EDMD) in an 18-year-old woman who underwent endovascular therapy for a cardioembolic stroke. At 5 years old, she showed a high creatine kinase level and atrial fibrillation on electrocardiography in our hospital. Finally, she was diagnosed as having EDMD by genetic screening that revealed mutations in the LMNA gene (c.810+1GT). Before this event, she received no medications. At 18 years old, she was admitted to our hospital8 hours after the onset of sudden consciousness disturbance. Neurological examination on admission revealed consciousness disturbance and right hemiplegia. Magnetic resonance imaging revealed a cerebral infarction in the left insular cortex and putamen with left internal carotid artery occlusion. We performed endovascular therapy and completely recanalized her left internal carotid artery. Thereafter, her neurological symptoms improved. She was subsequently transferred to a rehabilitation hospital. EDMD is a rare genetic muscular disease that mainly presents with contractures, weakness, and cardiac conduction abnormalities. Although patients with EDMD are young with low CHADS

We present a 48-year-old man with a history of hypertension, who suddenly noticed dysarthria and right hemiparesis. Diffusion-weighted MRI at 1 day after the onset showed a small high-intensity region in the left corona radiata, indicating the acute phase of lacunar infarction. Fluid attenuation inversion recovery images showed extensive hyperintense lesions predominantly in the white matter of the fronto-temporoparietal lobes and pons, indicating posterior reversible encephalopathy syndrome (PRES). In addition, T2*-weighted gradient-echo images showed multiple small round hypointense lesions in white matter and basal ganglia, indicating cerebral microbleeds. This is a rare case of symptomatic lacunar infarction accompanied with both PRES and microbleeds, which may suggest that the pathophysiology of PRES is related to hypertension.

Endothelial progenitor cells (EPCs) participate in endothelial repair and angiogenesis due to their abilities to differentiate into endothelial cells and to secrete protective cytokines and growth factors. Consequently, there is considerable interest in cell therapy with EPCs isolated from peripheral blood to treat various ischemic injuries. Quality and quantity-controlled culture systems to obtain mononuclear cells enriched in EPCs with well-defined angiogenic and anti-inflammatory phenotypes have recently been developed, and increasing evidence from animal models and clinical trials supports the idea that transplantation of EPCs contributes to the regenerative process in ischemic organs and is effective for the therapy of ischemic cerebral injury. Here, we briefly describe the general characteristics of EPCs, and we review recent developments in culture systems and applications of EPCs and EPC-enriched cell populations to treat ischemic stroke.