Kazuhiro Takamatsu

Trends in oral anticoagulant choice for acute stroke patients with nonvalvular atrial fibrillation in Japan: The SAMURAI-NVAF Study

Background Large clinical trials are lack of data on non-vitamin K antagonist oral anticoagulants for acute stroke patients. Aim To evaluate the choice of oral anticoagulants at acute hospital discharge in stroke patients with nonvalvular atrial fibrillation and clarify the underlying characteristics potentially affecting that choice using the multicenter Stroke Acute Management with Urgent Risk-factor Assessment and Improvement-NVAF registry (ClinicalTrials.gov NCT01581502). Method The study included 1192 acute ischemic stroke/transient ischemic attack patients with nonvalvular atrial fibrillation (527 women, 77·7 ± 9·9 years old) between September 2011 and March 2014, during which three nonvitamin K antagonist oral anticoagulant oral anticoagulants were approved for clinical use. Oral anticoagulant choice at hospital discharge (median 23-day stay) was assessed. Results Warfarin was chosen for 650 patients, dabigatran for 203, rivaroxaban for 238, and apixaban for 25. Over the three 10-month observation periods, patients taking warfarin gradually decreased to 46·5% and those taking nonvitamin K antagonist oral anticoagulants increased to 48·0%. As compared with warfarin users, patients taking nonvitamin K antagonist oral anticoagulants included more men, were younger, more frequently had small infarcts, and had lower scores for poststroke CHADS2, CHA2DS2-VASc, and HAS-BLED, admission National Institutes of Health stroke scale, and discharge modified Rankin Scale. Nonvitamin K antagonist oral anticoagulants were started at a median of four-days after stroke onset without early intracranial hemorrhage. Patients starting nonvitamin K antagonist oral anticoagulants earlier had smaller infarcts and lower scores for the admission National Institutes of Health stroke scale and the discharge modified Rankin Scale than those starting later. Choice of nonvitamin K antagonist oral anticoagulants was independently associated with 20-day or shorter hospitalization (OR 2·46, 95% CI 1·87–3·24). Conclusions Warfarin use at acute hospital discharge was still common in the initial years after approval of nonvitamin K antagonist oral anticoagulants, although nonvitamin K antagonist oral anticoagulant users increased gradually. The index stroke was milder and ischemia-risk indices were lower in nonvitamin K antagonist oral anticoagulant users than in warfarin users. Early initiation of nonvitamin K antagonist oral anticoagulants seemed safe.

Clinical features of SCA36 A novel spinocerebellar ataxia with motor neuron involvement (Asidan)

Objective: To characterize the phenotype of spinocerebellar ataxia type 36 (SCA36), a novel dominant disorder (nicknamed “Asidan”) caused by a hexanucleotide GGCCTG repeat expansion in intron 1 of the NOP56 gene. Methods: We investigated the clinical, genetic, and neuropathologic characteristics of 18 patients with SCA36. We performed histologic evaluation of a muscle biopsy specimen from 1 patient with SCA36, and neuropathologic evaluation of an autopsied brain from another patient with SCA36. Results: The (GGCCTG)n expansion was found in 18 ataxic patients from 9 families. The age at onset of ataxia was 53.1 ± 3.4 years, with the most frequent symptoms being truncal ataxia (100% of patients), ataxic dysarthria (100%), limb ataxia (93%), and hyperreflexia (79%). Tongue fasciculation and subsequent atrophy were found in 71% of cases, particularly in those of long duration. Skeletal muscle fasciculation and atrophy of the limbs and trunk were found in 57% of cases. Lower motor involvement was confirmed by EMG and muscle biopsy. The neuropathologic study revealed significant cerebellar Purkinje cell degeneration with obvious loss of lower motor neurons. Immunohistochemical analysis showed that NOP56 was localized to the nuclei of various neurons. Cytoplasmic or intranuclear inclusion staining of NOP56, TDP-43, and ataxin-2 was not observed in the remaining neurons. Conclusions: This is the first description of the unique clinical features of SCA36, a relatively pure cerebellar ataxia with progressive motor neuron involvement. Thus, SCA36 is a disease that stands at the crossroads of SCA and motor neuron disease.

Cognitive and affective impairments of a novel SCA/MND crossroad mutation Asidan

Background:  A variety of hereditary spinocerebellar ataxia (SCA) develops a broad spectrum of both ataxia and non‐ataxia symptoms. Cognitive and affective changes are one such non‐ataxia symptoms, but have been described only in hereditary SCAs with exonic CAG gene expansion.

Three-month risk-benefit profile of anticoagulation after stroke with atrial fibrillation: The SAMURAI-Nonvalvular Atrial Fibrillation (NVAF) study

Aims This study was performed to determine the short-term risk-benefit profiles of patients treated with oral anticoagulation for acute ischemic stroke or transient ischemic attack using a multicenter, prospective registry. Methods A total of 1137 patients (645 men, 77 ± 10 years old) with acute ischemic stroke/transient ischemic attack taking warfarin (662 patients) or non-vitamin K antagonist oral anticoagulants (dabigatran in 205, rivaroxaban in 245, apixaban in 25 patients) for nonvalvular atrial fibrillation who completed a three-month follow-up survey were studied. Choice of anticoagulants was not randomized. Primary outcome measures were stroke/systemic embolism and major bleeding. Results Both warfarin and non-vitamin K antagonist oral anticoagulants were initiated within four days after stroke/transient ischemic attack onset in the majority of cases. Non-vitamin K antagonist oral anticoagulant users had lower ischemia- and bleeding-risk indices (CHADS2, CHA2DS2-VASc, HAS-BLED) and milder strokes than warfarin users. The three-month cumulative rate of stroke/systemic embolism was 3.06% (95% CI 1.96%–4.74%) in warfarin users and 2.84% (1.65%–4.83%) in non-vitamin K antagonist oral anticoagulant users (adjusted HR 0.96, 95% CI 0.44–2.04). The rate of major bleeding was 2.61% (1.60%–4.22%) and 1.11% (0.14%–1.08%), respectively (HR 0.63, 0.19–1.78); that for intracranial hemorrhage was marginally significantly lower in non-vitamin K antagonist oral anticoagulant users (HR 0.17, 0.01–1.15). Major bleeding did not occur in non-vitamin K antagonist oral anticoagulant users with a CHADS2 score <4 or those with a discharge modified Rankin Scale score ≤2. Conclusions Stroke or systemic embolism during the initial three-month anticoagulation period after stroke/transient ischemic attack was not frequent as compared to previous findings regardless of warfarin or non-vitamin K antagonist oral anticoagulants were used. Intracranial hemorrhage was relatively uncommon in non-vitamin K antagonist oral anticoagulant users, although treatment assignment was not randomized. Early initiation of non-vitamin K antagonist oral anticoagulants during the acute stage of stroke/transient ischemic attack in real-world clinical settings seems safe in bleeding-susceptible Japanese population.

Seizures after intracerebral hemorrhage; risk factor, recurrence, efficacy of antiepileptic drug

OBJECTIVE This study aimed to determine the risk factors for recurrent post stroke seizure (PSS) and the efficacy of anti-epileptic drugs (AED) in patients having intracerebral hemorrhage (ICH) with initial seizure. METHODS/SUBJECTS A total of 1920 consecutive patients with ICH from 2004 to 2012 were investigated retrospectively. The relationships among the baseline clinical and radiological data, administration of AED, and incidence of initial and recurrent PSS were evaluated using multiple logistic regression analysis. RESULTS Seizures occurred in 127 (6.6%) of the 1920 patients, displaying statistically significant relationships with cortical involvement of a cerebral lesion (P<0.001), non-hypertensive ICH (P<0.001), younger age (P<0.001), and severe neurological deficits (P<0.001). Early (4.3%) and late seizure (2.3%) had no significant relationship with the development of recurrent PSS. Larger volume of hematoma was the only independent factor associated with recurrence of PSS (OR 1.03; 95% CI 1.00-1.05; P=0.027). A Kaplan Meier survival analysis revealed that AED treatment had a poor association with recurrence of PSS (P=0.750). CONCLUSIONS Larger volume of hematoma was predictive of recurrence of PSS. AED therapy had poor association with preventing the recurrence of PSS.

Diffusion tensor imaging and magnetic resonance spectroscopy of transient cerebral white matter lesions in X-linked Charcot-Marie-Tooth disease

BACKGROUND X-linked Charcot-Marie-Tooth disease (CMTX) is a common inherited axonal or mixed axonal-demyelinating neuropathy. The disease is caused by mutations in the GJB1 gene encoding the gap junction protein connexin32, which is expressed in both Schwann cells in the peripheral nervous system and oligodendrocytes in the central nervous system. Several reports have described CMTX patients presenting with transient and recurrent central nervous system (CNS) symptoms with transient white matter lesions in the brain. PATIENTS We describe a man with CMTX who presented with transient CNS symptoms and abnormal cerebral white matter lesions in MRI. He was subjected to a detailed MRI examination using two specialized techniques, diffusion tensor imaging (DTI) and magnetic resonance spectroscopy (MRS). RESULTS In the early stage of his CNS symptoms, MRS studies revealed reduced N-acetyl-aspartate (NAA) levels in deep white matter, and DTI revealed reduced fractional anisotropy within lesions. Interestingly, these reductions began to recover from day 19 after admission, and follow-up DTI and MRS studies on day 101 revealed a reversal of the abnormalities. CONCLUSION The findings of reversible reductions in fractional anisotropy and NAA levels in our patient suggest reversible axonal damage associated with deficient oligodendrocyte gap junctions.

Effects of Meteorological Conditions on the Risk of Ischemic Stroke Events in Patients Treated with Alteplase—HEWS-tPA

BACKGROUND Predicting a day that presents a high risk for the occurrence of ischemic stroke events may enable health professionals to prepare for emergency stroke therapy more properly. We evaluated the association between meteorological conditions and the frequency of ischemic stroke events in Japanese patients. METHODS Ischemic stroke patients (n = 299) who were treated with alteplase at 9 stroke hospitals in 3 restricted areas were examined. The daily rates of ischemic stroke events were compared with the daily mean thermo-hydrological index (THI), the atmospheric pressure, and the daily changes of these variables for the 6 days preceding an ischemic stroke event using Poisson regression analysis. RESULTS We trisected onset days based on the THI (low-temperature, intermediate-temperature, and high-temperature), atmospheric pressure (low-pressure, intermediate-pressure, and high-pressure), changes in THI for preceding 6 days from the previous day (cooler, unchanged-temperature, and warmer), and changes in atmospheric pressure (decreased-pressure, unchanged-pressure, and increased-pressure). The frequency of ischemic stroke was significantly higher on low-temperature or high-pressure days (risk ratio, 1.398, P = .022; risk ratio, 1.374, P = .039), on warmer-temperature days, and when atmospheric pressure varied from the day before (P < .05). There were significantly lower risks for ischemic stroke events on cooler-temperature days, and higher risks were associated with a variation in atmospheric pressure 3 days before the onset from 4 days before (P < .05). CONCLUSIONS There were higher risks for ischemic stroke events associated with low ambient temperature, high atmospheric pressure, increased temperature, and varied atmospheric pressure. Also, atmospheric pressure variation 3 days before may be associated.

Ischemic Stroke Mortality Is More Strongly Associated with Anemia on Admission Than with Underweight Status

BACKGROUND Underweight patients have recently been reported as a group with a high risk of poststroke death. Anemia also increases mortality rates in stroke patients. However, the causal associations between body weight and anemia resulting in stroke-related death remain unclear. We examined the association of weight status and hemoglobin levels with 3-month mortality after ischemic stroke. METHODS The study enrolled all consecutive patients with acute ischemic stroke and no history of stroke admitted to our hospital between January 2010 and December 2013. The patients were categorized into 4 body mass index (BMI) categories (underweight, normal-weight, overweight, and obese). Anemia was evaluated according to the World Health Organization criteria (men, <13 g/dL; women, <12 g/dL). RESULTS A total of 1733 acute ischemic stroke patients (149 underweight, BMI < 18.5 kg/m2; 1076 normal-weight, BMI = 18.5-24.9 kg/m2; 436 overweight, BMI = 25-29.9 kg/m2; and 72 obese, BMI > 30 kg/m2) were included. Death within 3 months occurred in 65 patients (underweight, 10.1%; normal-weight, 3.4%; overweight, 2.3%; and obese, 5.6%). Compared to nonanemic patients, those with anemia (n = 329, 19.0%) had lower BMI (21.8 kg/m2 versus 23.7 kg/m2, P <.001) and higher mortality rates (9.1% versus 2.5%, P <.001). Underweight status was associated with 3-month mortality after adjusting for age, sex, comorbidities, and initial stroke severity. However, in the models that included laboratory findings, it was anemia status (odds ratio, 2.81; 95% confidence interval, 1.46-5.43), not underweight status, that was independently associated with 3-month mortality. CONCLUSION Anemia on admission was associated with stroke mortality independent of underweight status.

Acute ischemic stroke associated with nephrotic syndrome: Incidence and significance — Retrospective cohort study

We report 10 cases with arterial ischemic stroke (AIS) with nephrotic syndrome (NS), and clarified its incidence and clinical characteristics. The patients having albumin less than 3.0 g/dl and serum cholesterol greater than 250 mg/dl at the same time were retrospectively screened from 11,161 cases of stroke. Furthermore, the patients of AIS showing heavy proteinuria were selected. The 10 cases were diagnosed as AIS with NS. Its incidence was 0.09% of all kinds of stroke and 0.12% of AIS. Their subtypes were 6 large-artery atherosclerosis, 3 small-vessel occlusion, and 1 cardioembolism. We carried out a retrospective cohort study to assess the association between NS and atherosclerosis progression in AIS patients. Seven AIS patients with NS due to diabetic nephropathy (cases; NS group) were compared with patients with AIS and diabetes mellitus (DM) without NS (control group). Control group subjects were matched in a 2:1 ratio to cases by age, sex, use of medications for DM, and hemoglobin A1c (HbA1c) level. The NS group had high cerebral artery atherosclerosis scores, especially in the anterior circulation. The NS group demonstrated atherosclerosis of the internal carotid and lower extremity arteries, although there were no statistical differences between the two groups. Study subjects had high serum fibrinogen and D-dimer levels, suggesting that AIS patients with NS have a greater degree of hypercoagulability than AIS patients without NS.

Potential multisystem degeneration in Asidan patients

OBJECTIVE To evaluate a potential multisystem involvement of neurodegeneration in Asidan, in addition to cerebellar ataxia and signs of motor neuron disease. METHODS We compared the new Asidan patients and those identified in previous studies with Parkinsons disease (PD, n=21), and progressive supranuclear palsy (PSP, n=13) patients using 123I-2β-Carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl) nortropane (123I-FP-CIT) dopamine transporter single photon emission computed tomography (DAT-SPECT) and 123I-metaiodobenzylguanidine (MIBG) myocardial scintigraphy (Asidan, DAT: n=10; MIBG: n=15). RESULTS Both the PD and PSP groups served as positive controls for DAT decline. The PD and PSP groups served as a positive and negative control, respectively, of MIBG decline in the early phase H/M ratio. Of the Asidan patients, 60.0% showed DAT decline without evident parkinsonian features and 6.7% showed impaired MIBG in only the delayed phase H/M ratio. Combined with a normal range of the early phase H/M ratio, this phenotype was newly named Declined DAT Without Evident Parkinsonism (DWEP). INTERPRETATION The results of present study including DWEP suggest a wider spectrum of neurodegeneration for extrapyramidal and autonomic systems in Asidan patients than expected, involving cerebellar, motor system and cognitive functioning.