Kortaro Tanaka

Ambivalent aspects of interleukin-6 in cerebral ischemia: inflammatory versus neurotrophic aspects

Interleukin-6 (IL-6) is pleiotropic cytokine involved in many central nervous system disorders including stroke, and elevated serum IL-6 has been found in acute stroke patients. IL-6 is implicated in the inflammation, which contributes to both injury and repair process after cerebral ischemia. However, IL-6 is one of the neurotrophic cytokines sharing a common receptor subunit, gp130, with other neurotrophic cytokines, such as leukemia inhibitory factor (LIF) and ciliary neurotrophic factor. The expression of IL-6 is most prominently identified in neurons in the peri-ischemic regions, and LIF expression shows a similar pattern. The direct injection of these cytokines into the brain after ischemia can reduce ischemic brain injury. The cytokine receptors are localized on the neuron surface, suggesting that neurons are the cytokine target. The major IL-6 downstream signaling pathway is JAK—STAT, and Stat3 activation occurs mainly in neurons during postischemic reperfusion. Further investigation is necessary to clarify the exact role of Stat3 signaling in neuroprotection. Taken together, the information suggests that IL-6 plays a double role in cerebral ischemia, as an inflammatory mediator during the acute phase and as a neurotrophic mediator between the subacute and prolonged phases.

Chronic Kidney Disease and CHADS2 Score Independently Predict Cardiovascular Events and Mortality in Patients With Nonvalvular Atrial Fibrillation

Chronic kidney disease is a risk factor for cardiovascular events, but how it relates to the prognosis associated with clinical risk factors for thromboembolism in patients with nonvalvular atrial fibrillation (AF) is not well known. Estimated glomerular filtration rate (eGFR), score for congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, and stroke/transient ischemic attack (CHADS(2)), and clinical outcomes of cardiovascular events were determined in 387 patients with nonvalvular AF (mean age 66 years, 289 men, mean follow-up 5.6 ± 3.2 years). Decreased eGFR (<60 ml/min/1.73 m(2)) combined with CHADS(2) score ≥2 was associated with higher all-cause (12.9% vs 1.4% per year, hazard ratio [HR] 6.9, p <0.001) and cardiovascular (6.5% vs 0.2% per year, HR 29.7, p <0.001) mortalities compared to preserved eGFR (≥60 ml/min/1.73 m(2)) combined with CHADS(2) score <2. This was also true for rates of cardiac events (cardiac death, nonfatal myocardial infarction, or hospitalization for worsening of heart failure, 10.4% vs 1.3% per year, HR 8.9, p <0.001), ischemic stroke (3.6% vs 0.2% per year, HR 11.0, p <0.001), and cardiovascular events (cardiac events and ischemic stroke, 13.6% vs 1.5% per year, HR 8.3, p <0.001). On multivariate analysis, CHADS(2) score ≥2, decreased eGFR, and male gender independently predicted all-cause mortality. In conclusion, combined eGFR and CHADS(2) score could be an independent powerful predictor of cardiovascular events and mortality in patients with nonvalvular AF. Long-term mortality, cardiac events, and stroke risk were >8 times higher when decreased eGFR (<60 ml/min/1.73 m(2)) was present with higher CHADS(2) score (≥2).

Myasthenia gravis accompanied by alopecia areata: clinical and immunogenetic aspects.

The purpose of this study was to evaluate the clinical characteristics of patients who had both myasthenia gravis (MG) and alopecia areata (AA). Clinical information was retrospectively collected for 159 Japanese patients with MG. Human leukocyte antigen (HLA)‐DQB1 and DRB1 alleles were determined by genotyping. Of 159 MG patients, six (3.7%) developed AA after the onset of MG and thymectomy. The prevalence of AA in MG patients was higher than that reported in Caucasians. The frequencies of bulbar involvement, myasthenic crisis, and thymoma were significantly higher in MG patients with AA than in those without (P = 0.007, 0.004, and 0.006, respectively). All but one patient with AA had advanced stage thymoma. Three patients with a severe form of AA (alopecia totalis) had additional autoimmune diseases: myocarditis, myositis, and pure red cell aplasia. DRB1*0901 and DQB1*0303 tended to be more frequently detected in the six MG patients with AA than in the 82 patients without it. In conclusion, a subset of MG patients who have severe neuromuscular symptoms and thymoma develop AA several years after thymectomy.

Study of Hemostatic Biomarkers in Acute Ischemic Stroke by Clinical Subtype

BACKGROUND We studied the usefulness of hemostatic biomarkers in assessing the pathology of thrombus formation, subtype diagnosis, prognosis in the acute phase of cerebral infarction, and differences between various hemostatic biomarkers. METHODS Our study included 69 patients with acute cerebral infarction who had been hospitalized within 2 days of stroke onset. Fibrin monomer complex (FMC), soluble fibrin (SF), D-dimer, thrombin-antithrombin III complex, fibrinogen, antithrombin III, and fibrin/fibrinogen degradation products (FDPs) were assayed as hemostatic biomarkers on days 1, 2, 3, and 7 of hospitalization. RESULTS In the cardioembolic (CE) stroke group, FMC and SF levels were significantly higher on days 1 and 2 of hospitalization, and D-dimer levels were significantly higher on day 1 of hospitalization, compared to the noncardioembolic (non-CE) stroke group. FDP levels were significantly higher at all times in the CE group compared to the non-CE group. Neither the National Institute of Health Stroke Scale (NIHSS) used during hospitalization nor the modified Rankin Scale (mRS) used at discharge found any significant correlations to hemostatic biomarkers, but the NIHSS score during hospitalization was significantly higher in the CE group than in the non-CE group. CONCLUSIONS Measurements of hemostatic biomarkers, such as FMC, SF, and D-dimer on the early stage of cerebral infarction are useful for distinguishing between CE and non-CE stroke.

One-year atherothrombotic vascular events rates in outpatients with recent non-cardioembolic ischemic stroke: The EVEREST (Effective Vascular Event REduction after STroke) registry

BACKGROUND Patients with recent ischemic stroke may have higher risk of atherothrombosis than stable patients with established vascular events. Our aims were to investigate 1-year atherothrombotic vascular event rates and to assess the risk factors for recurrent ischemic stroke in this population. METHODS This prospective cohort study was conducted between January 2007 and July 2009 at 313 hospitals in Japan. Outpatients who were at least 45 years of age and who had received oral antiplatelet therapy were enrolled within 2 weeks to 6 months from the last onset of noncardioembolic ischemic stroke. At 12 ± 3 months after enrollment, data on presence/absence of atherothrombotic vascular events were collected. The primary endpoint was the occurrence of fatal or nonfatal ischemic stroke. RESULTS A total of 3452 patients were enrolled, and 3411 patients who had baseline data were included in the analysis. The 1-year event rate was 3.81% (95% confidence interval 3.15-4.48%) for fatal or nonfatal ischemic stroke and 0.84% (95% confidence interval 0.52-1.15%) for all-cause mortality. The annual rate of recurrent ischemic stroke was significantly higher in patients who had ischemic stroke at least twice than in patients who had first-ever ischemic stroke (5.02% vs 3.59%; P = .0313). In the multivariable Cox regression analysis, recurrent ischemic stroke was significantly associated with age (P = .0033), the presence of diabetes (P = .0129), and waist circumference ≥80 cm (P = .0056). CONCLUSIONS Patients with recent ischemic stroke have a higher risk of stroke recurrence than stable patients enrolled in the REduction of Atherothrombosis for Continued Health (REACH) registry even though they received antiplatelet therapy. The rigorous management of risk factors is needed.

Bilateral Subthalamic Deep Brain Stimulation for Camptocormia Associated with Parkinson’s Disease

Background: Few multiple case studies of the effects of deep brain stimulation for camptocormia associated with Parkinson’s disease have been reported. Although deep brain stimulation was in some cases not effective against camptocormia, it is unclear in which types of patients it was effective in treating camptocormia. Objective: We treated 4 Parkinson’s disease patients with camptocormia and evaluated their paraspinal muscle status by computed tomography to specify the characteristics of cases of effective treatment. Methods: The 2 female and 2 male patients in this study were 60–69 years old, with a disease duration from onset to surgery of 7–13 years and a follow-up period of 18–40 months. The electrodes were implanted bilaterally in the subthalamic nuclei. Results: Camptocormia was improved in 3 cases, and was unchanged in the remaining case although other parkinsonian symptoms improved. The computed tomography number of paraspinal muscle in the unimproved patient was much smaller than that in the improved patients. Conclusions: A relationship may exist between improvement of camptocormia and severity of paraspinal muscle degeneration.

Detection of autoantibody against extracellular epitopes of N-methyl-D-aspartate receptor by cell-based assay.

The concept of anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, a severe, potentially lethal, treatment-responsive disorder, mediated by autoantibodies against NMDAR was proposed. Because paraneoplastic anti-NMDAR encephalitis has a better prognosis after tumor resection and immunotherapy, rapid quantitative systems for detecting functional autoantibodies against extracellular epitopes of NMDAR are necessary. To detect autoantibodies recognizing extracellular epitopes of NMDAR, we stably expressed mutant NMDAR that decreases Ca(2+) permeability on a heterologous cell surface without any antagonist. Serum and CSF samples from patients were analysed using the cells expressing mutant NMDAR subunits by immunocytochemistry and on-cell Western analysis using live cells stably expressing mutant NMDAR. Furthermore, we were able to express mutant GluRζ1(NR1, GluN1) subunit of NMDAR alone on the cell surface and obtained direct evidence of the presence of autoantibodies recognizing extracellular epitopes of GluRζ1 and the induction of internalization by autoantibodies in serum and CSF from patients. The specificity of on-cell Western analysis was improved at 37°C. The combination of this rapid quantitative assay using our on-cell western analysis, detailed analysis of extracellular epitopes of NMDAR, and internalization assay of NMDAR will be valuable for the diagnosis, evaluation of clinical treatments, and follow-up of anti-NMDAR encephalitis.

Effects of Edaravone on Muscle Atrophy and Locomotor Function in Patients with Ischemic Stroke A Randomized Controlled Pilot Study

AbstractBackground and Objective: Stroke patients with severe leg paralysis are often bedridden in the acute and subacute phase, which increases the risk of disuse muscle atrophy in the chronic phase. The evidence to date indicates that oxidative stress plays an important role in the mechanism of disuse muscle atrophy. Therefore, the aim of this study was to determine if long-term radical scavenger treatment with edaravone following an acute stroke prevents the progression of disuse muscle atrophy and improves leg locomotor function in the chronic phase. Methods: This randomized controlled pilot study was conducted at 19 acute stroke and rehabilitation centers across Japan. Forty-seven ischemic stroke patients with at least leg motor weakness admitted within 24 hours of onset were randomly assigned to receive continuous intravenous infusions of edaravone 30 mg twice daily for 3 days (short-term group) or 10–14 days (long-term group). The primary endpoints of the study included the degree of leg disuse muscle atrophy, as measured by the percentage change from baseline in femoral muscle circumference 15 cm above the knee, and the improvement in leg locomotor function, as assessed by the maximum walking speed over 10 m, 3 months after the onset of stroke. Results: Three-month follow-up was completed by a total of 41 patients (21 in the short-term group and 20 in the long-term group). On admission, there was no significant difference in the severity of stroke or the grade of leg paresis between the two treatment groups. The grade of disuse muscle atrophy and incidence of gait impairment 3 weeks after stroke onset were also similar between the short- and long-term groups. However, disuse muscle atrophy of the paretic and non-paretic legs was significantly less severe in the long-term versus the short-term treatment group (3.6±5.9% and 1.5±6.0% vs 8.3±5.2% and 5.7±6.4%; p<0.01 and p<0.05) 3 months after stroke onset. Additionally, the maximum walking speed over a distance of 10 m was significantly greater in the long-term group (98±67 vs 54±55 cm/sec; p<0.05). Conclusion: Edaravone treatment for up to 14 days suppresses the progression of disuse muscle atrophy and improves leg locomotor function to a greater extent than shorter-term treatment in acute stroke patients. This suggests that the management of stroke may be improved with long-term edaravone therapy by providing myoprotective effects that ameliorate functional outcome in the chronic phase.

Differential diagnosis of cerebral infarction using an algorithm combining atrial fibrillation and D-dimer level

We created an algorithm for diagnosing subtypes of cerebral infarction (CI) during the acute stage by combining atrial fibrillation (AF) and D‐dimer levels. One‐hundred and eight patients hospitalized for acute CI were retrospectively analyzed. CI was classified into cardioembolic, atherothrombotic, lacunar infarction or others. Patients were classified in AF group if they had AF on admission or a prior history of AF. This group was diagnosed to suffer cardioembolic infarction. In non‐AF group, cardioembolic infarction was diagnosed when D‐dimer level exceeded the cutoff point determined using a receiver operating curve. Then, usefulness of the algorithm was validated prospectively in 259 consecutive patients with acute CI. For the retrospective group, cardioembolic infarction was found in 82% of the AF group. In non‐AF group, cardioembolic infarction was found in only 2%, when D‐dimer level was <1.6 μg/ml. However, 41% of non‐AF group with atherothrombotic infarction had elevated D‐dimer level (≥1.6 μg/ml). Results for the validation group were similar to those for the retrospective group (sensitivity, 89%; specificity, 66%; positive predictive value, 50%; and negative predictive value, 94%). D‐dimer level in combination with AF can be useful for distinguishing CI subtypes during the acute stage.

Clinical and transesophageal echocardiographic variables for prediction of thromboembolic events in patients with nonvalvular atrial fibrillation at low-intermediate risk

BACKGROUND There is no clear consensus about antithrombotic treatment in atrial fibrillation (AF) patients at low-intermediate thromboembolic risk. Transesophageal echocardiography (TEE) is useful for prediction of thromboembolic events in AF. METHODS AND RESULTS Of 498 patients with nonvalvular AF, incidence of stroke, cardiac events, and mortality was investigated in 280 patients with CHADS(2) score 0 or 1 (mean age 64 years, mean follow-up 6.4 ± 3.1 years). Left atrial abnormality (low left atrial appendage flow, spontaneous echo contrast, or thrombi), complex aortic plaque (mobile, ulcerated, pedunculate, or thickness ≥ 4mm), or both were defined as TEE risk. The incidences of ischemic stroke, cardiovascular events, and death were higher in patients with TEE risk than in those without the risk (2.0%/year vs. 0.5%/year, p<0.05; 4.7%/year vs. 1.9%/year, p<0.01; and 4.7%/year vs. 2.0%/year, p<0.01, respectively). This was also true for patients with CHADS(2) score of 0 (1.7%/year vs. 0.3%/year, p<0.05; 4.1%/year vs. 1.6%/year, p<0.05; and 3.9%/year vs. 1.4%/year, p<0.01; respectively). On multivariate analysis, TEE risk predicted ischemic stroke, cardiovascular events, and mortality independently of clinical variables or CHADS(2) score. CONCLUSIONS TEE could be useful for further stratification of patients with nonvalvular AF stratified at low-intermediate risk (CHADS(2) score 0 or 1) and could indicate who should receive anticoagulation treatment.