PON1 Q192R is associated with high platelet reactivity with clopidogrel in patients undergoing elective neurointervention: A prospective single-center cohort study.

BACKGROUND AND PURPOSE: The impact of the paraoxonase-1 (PON1) polymorphism, Q192R, on platelet inhibition in response to clopidogrel remains controversial. We aimed to investigate the association between carrier status of PON1 Q192R and high platelet reactivity (HPR) with clopidogrel in patients undergoing elective neurointervention. METHODS: Post-clopidogrel platelet reactivity was measured using a VerifyNow® P2Y12 assay in P2Y12 reaction units (PRU) for consecutive patients before the treatment. Genotype testing was performed for PON1 Q192R and CYP2C19*2 and *3 (no function alleles), and *17. PRU was corrected on the basis of hematocrit. We investigated associations between factors including carrying ≥1 PON1 192R allele and HPR defined as original and corrected PRU ≥208. RESULTS: Of 475 patients (232 men, median age, 68 years), HPR by original and corrected PRU was observed in 259 and 199 patients (54.5% and 41.9%), respectively. Carriers of ≥1 PON1 192R allele more frequently had HPR by original and corrected PRU compared with non-carriers (91.5% vs 85.2%, P = 0.031 and 92.5% vs 85.9%, P = 0.026, respectively). In multivariate analyses, carrying ≥1 PON1 192R allele was associated with HPR by original (odds ratio [OR] 1.96, 95% confidence interval [CI] 1.03-3.76) and corrected PRU (OR 2.34, 95% CI 1.21-4.74) after adjustment for age, sex, treatment with antihypertensive medications, hematocrit, platelet count, total cholesterol, and carrying ≥1 CYP2C19 no function allele. CONCLUSIONS: Carrying ≥1 PON1 192R allele is associated with HPR by original and corrected PRU with clopidogrel in patients undergoing elective neurointervention, although alternative results related to other genetic polymorphisms cannot be excluded.

[A Case of Neuromyelitis Optica Spectrum Disorder Who Relapsed Under Oral Corticosteroid Treatment with Multiple Cerebrospinal Lesions and Severe Neurological Deficits].

We present a case of a 59-year-old female who had been treated for optic neuritis 2 years before being transferred to our hospital. She had been positive for anti-AQP4 antibodies. No cerebrospinal lesions were observed, and based on the diagnosis of neuromyelitis optica spectrum disorder (NMOSD), 5 mg/day oral prednisolone was continued for 2 years. Acute lower back pain and urinary retention appeared on day X. On day X + 1, consciousness disturbance (JCS level II) and paraplegia appeared, and she was transferred to our hospital. Neck stiffness, paraplegia, and urinary retention were present. A cerebrospinal fluid examination revealed mononucleosis-dominant pleocytosis (1,232 cells/µl). Brain magnetic resonance imaging (MRI) showed multiple lesions around the ventricles and corpus callosum, and spinal MRI revealed a longitudinally extensive transverse myelitis lesion (C2-Th5). A relapse of NMOSD was diagnosed and steroid pulse therapy was started, but the symptoms progressed and quadriplegia and coma occurred. Head MRI showed new deep white matter lesions around the ventricles. Plasma exchange was added after the second steroid pulse. The patient's consciousness gradually improved, and spontaneous movement of the left upper limb eventually appeared. We experienced a case of NMOSD that relapsed with multiple cerebrospinal lesions despite corticosteroid therapy, but plasmapheresis therapy was effective.

Clopidogrel response predicts thromboembolic events associated with coil embolization of unruptured intracranial aneurysms: A prospective cohort study.

OBJECTIVE: Periprocedural thromboembolic events are a serious complication associated with coil embolization of unruptured intracranial aneurysms. However, no established clinical rule for predicting thromboembolic events exists. This study aimed to clarify the significance of adding preoperative clopidogrel response value to clinical factors when predicting the occurrence of thromboembolic events during/after coil embolization and to develop a nomogram for thromboembolic event prediction. METHODS: In this prospective, single-center, cohort study, we included 345 patients undergoing elective coil embolization for unruptured intracranial aneurysm. Thromboembolic event was defined as the occurrence of intra-procedural thrombus formation and postprocedural symptomatic cerebral infarction within 7 days. We evaluated preoperative clopidogrel response and patients' clinical information. We developed a patient-clinical-information model for thromboembolic event using multivariate analysis and compared its efficiency with that of patient-clinical-information plus preoperative clopidogrel response model. The predictive performances of the two models were assessed using area under the receiver-operating characteristic curve (AUC-ROC) with bootstrap method and compared using net reclassification improvement (NRI) and integrated discrimination improvement (IDI). RESULTS: Twenty-eight patients experienced thromboembolic events. The clinical model included age, aneurysm location, aneurysm dome and neck size, and treatment technique. AUC-ROC for the clinical model improved from 0.707 to 0.779 after adding the clopidogrel response value. Significant intergroup differences were noted in NRI (0.617, 95% CI: 0.247-0.987, p < .001) and IDI (0.068, 95% CI: 0.021-0.116, p = .005). CONCLUSIONS: Evaluation of preoperative clopidogrel response in addition to clinical variables improves the prediction accuracy of thromboembolic event occurrence during/after coil embolization of unruptured intracranial aneurysm.

Recurrent Cerebral Venous Thrombosis Treated with Direct Oral Anticoagulants in a Japanese Man with Hereditary Protein C Deficiency.

We herein report a case involving a 32-year-old Japanese man with recurrent cerebral venous thrombosis due to hereditary protein C deficiency. He was admitted to our hospital with impaired consciousness. Brain magnetic resonance imaging demonstrated high intensities diffusely along the bilateral sulci and magnetic resonance venography revealed left transverse sinus and superior sagittal sinus stenoses. His father had a history of cerebral infarction and venous thrombosis. The protein C activity level examined by chromogenic synthetic substrate assay was markedly reduced. He was diagnosed with protein C deficiency, and a genetic analysis revealed a heterozygous mutation at exon 3 c.199G>A,p.Glu67Lys on the protein C gene. Four months later, at his second admission, he had transient aphasia, and his protein C activity was under 10%. We switched warfarin to the direct oral anticoagulants edoxaban. He remains fully recovered with no adverse events after the administration of edoxaban for a year. Direct oral anticoagulants may be a new tool for treating cerebral venous thrombosis due to hereditary protein C deficiency.

Modified diffusion-weighted imaging-Alberta Stroke Program Early Computed Tomography Score including deep white matter lesions predicts symptomatic intracerebral hemorrhage following intravenous thrombolysis.

The Alberta Stroke Program Early Computed Tomography Score (ASPECTS) is widely used for the assessment of early ischemic changes (EICs) before thrombolysis. However, for symptomatic intracerebral hemorrhage (sICH) following intravenous recombinant tissue plasminogen activator (rt-PA), the prediction abilities of CT-ASPECTS, diffusion-weighted imaging (DWI)-ASPECTS, and DWI-ASPECTS including EICs in deep white matter (DWI-ASPECTS + W) are unclear. We investigated associations between each score and sICH following intravenous rt-PA. Data from consecutive patients who received intravenous rt-PA for acute ischemic stroke from 2005 to 2015 in four hospitals were retrospectively screened. We included data from patients who had undergone both CT and magnetic resonance imaging before thrombolysis and without evidence of posterior circulation stroke. We analyzed the ability of CT-ASPECTS, DWI-ASPECTS, and DWI-ASPECTS + W to predict sICH, accompanied by an increase in the National Institutes of Health Stroke Scale (NIHSS) score of ≥ 4 within the initial 36 h. Of 455 patients (273 men, median 75 years old), sICH occurred in 15 patients (3.3%). Receiver operating characteristics curve analysis showed that the optimal cut-offs of CT-ASPECTS, DWI-ASPECTS, and DWI-ASPECTS + W for predicting sICH were ≤ 9 (sensitivity 60.0%, specificity 59.8%, c-statistic 0.625), ≤ 6 (sensitivity 53.3%, specificity 80.9%, c-statistic 0.718), and ≤ 8 (sensitivity 86.7%, specificity 55.9%, c-statistic 0.756), respectively. A DWI-ASPECTS + W of ≤ 8 was independently associated with sICH (odds ratio 5.21, 95% confidence interval 1.30-35.31) after adjustment for pretreatment with antithrombotic agents, pretreatment NIHSS score, and large artery occlusions. DWI-ASPECTS + W predicted sICH in patients with acute anterior circulation stroke receiving intravenous rt-PA.

Differences between predictive factors for early neurological deterioration due to hemorrhagic and ischemic insults following intravenous recombinant tissue plasminogen activator.

Early neurological deterioration (END) following intravenous recombinant tissue plasminogen activator (rt-PA) treatment is a serious clinical event that can be caused by hemorrhagic or ischemic insult. We investigated the differences in predictive factors for END due to hemorrhagic and END due to ischemic insults. Consecutive patients from four hospitals who received 0.6 mg/kg intravenous rt-PA for acute ischemic stroke were retrospectively recruited. END was defined as a National Institutes of Health Stroke Scale (NIHSS) score ≥ 4 points within 24 h compared with baseline. END was classified into those due to hemorrhagic (ENDh) or ischemic (ENDi) insult based on computed tomography (CT) or magnetic resonance imaging. Risk factors associated with ENDh and ENDi were investigated by comparison with non-END cases. A total of 744 patients (452 men, median 75 years old) were included. END was observed in 79 patients (10.6%), including 22 ENDh (3.0%) and 57 ENDi (7.7%), which occurred within a median of 7 h after treatment. Multivariate analyses showed that higher pretreatment NIHSS score (odds ratio [OR] 1.06, 95% confidence interval [CI] 1.00-1.13) and pretreatment with antiplatelets (OR 2.84, 95% CI 1.08-7.72) were associated with ENDh. Extensive early ischemic change (Alberta Stroke Program Early CT Score ≤ 7 on CT or ≤ 6 on diffusion-weighted imaging; OR 2.80, 95% CI 1.36-5.64) and large artery occlusions (OR 3.09, 95% CI 1.53-6.57) were associated with ENDi. Distinct factors were predictive for the END subtypes. These findings could help develop preventative measures for END in patients with the identified risk factors.

A Visual Task Management Application for Acute Ischemic Stroke Care.

Background: To maximize the effect of intravenous (IV) thrombolysis and/or endovascular therapy (EVT) for acute ischemic stroke (AIS), stroke centers need to establish a parallel workflow on the basis of a code stroke (CS) protocol. At Kokura Memorial Hospital (KMH), we implemented a CS system in January 2014; however, the process of information sharing within the team has occasionally been burdensome. Objective: To solve this problem using information communication technology (ICT), we developed a novel application for smart devices, named "Task Calc. Stroke" (TCS), and aimed to investigate the impact of TCS on AIS care. Methods: TCS can visualize the real-time progress of crucial tasks for AIS on a dashboard by changing color indicators. From August 2015 to March 2017, we installed TCS at KMH and recommended its use during normal business hours (NBH). We compared the door-to-computed tomography time, the door-to-complete blood count (door-to-CBC) time, the door-to-needle for IV thrombolysis time, and the door-to-puncture for EVT time among three treatment groups, one using TCS ("TCS-based CS"), one not using TCS ("phone-based CS"), and one not based on CS ("non-CS"). A questionnaire survey regarding communication problems was conducted among the CS teams at 3 months after the implementation of TCS. Results: During the study period, 74 patients with AIS were transported to KMH within 4.5 h from onset during NBH, and 53 were treated using a CS approach (phone-based CS: 26, TSC-based CS: 27). The door-to-CBC time was significantly reduced in the TCS-based CS group compared to the phone-based CS group, from 31 to 19 min (p = 0.043). Other processing times were also reduced, albeit not significantly. The rate of IV thrombosis was higher in the TCS-based CS group (78% vs. 46%, p = 0.037). The questionnaire was correctly filled in by 34/38 (89%) respondents, and 82% of the respondents felt a reduction in communication burden by using the TCS application. Conclusions: TCS is a novel approach that uses ICT to support information sharing in a parallel CS workflow in AIS care. It shortens the processing times of critical tasks and lessens the communication burden among team members.

Pre-admission CHADS2, CHA2DS2-VASc, and R2CHADS2 Scores on Severity and Functional Outcome in Acute Ischemic Stroke with Atrial Fibrillation.

BACKGROUND: We examined the association between pre-admission risk scores and severity on admission and functional outcome in acute ischemic stroke with atrial fibrillation (AF). METHODS: Between September 2011 and April 2014, we retrospectively extracted consecutive ischemic stroke patients with AF whose pre-admission modified Rankin Scale (mRS) score was 2 or less from our prospective database. Pre-admission CHADS2, CHA2DS2-VASc, and R2CHADS2 scores were calculated in each patient, and their association with the National Institutes of Health Stroke Scale (NIHSS) score on admission or unfavorable outcome (mRS ≥ 3 at 3 months from the onset) was assessed. RESULTS: A total of 344 patients (189 were men; age, 77.7 ± 10.0 years) were included in the analysis. The median pre-admission CHADS2, CHA2DS2-VASc, and R2CHADS2 scores were 2, 4, and 4, respectively. NIHSS score on admission was positively correlated with pre-admission CHADS2 (ρ = .116, P = .031), CHA2DS2-VASc (ρ = .166, P = .020), and R2CHADS2 scores (ρ = .106, P = .049). Receiver operating characteristic (ROC) curve analysis revealed that pre-admission CHADS2 score of 2 or more (sensitivity, 80%; specificity, 45%; area under the ROC curve [AUC], .654), CHA2DS2-VASc score of 3 or more (sensitivity, 86%; specificity, 44%; AUC, .683), and R2CHADS2 score of 4 or more (sensitivity, 61%; specificity, 62%; AUC, .657) were associated with unfavorable outcome. The pre-admission CHA2DS2-VASc score was better than the pre-admission CHADS2 score in estimating unfavorable outcome (P = .017). In multivariate analysis, cutoffs of these scores, female sex, higher NIHSS score, and internal carotid artery occlusion were associated with unfavorable outcome. CONCLUSIONS: Pre-admission CHADS2, CHA2DS2-VASc, and R2CHADS2 scores were associated with onset severity and functional outcome in acute ischemic stroke with AF.

Clinical disability progression and platelet GP IIb/IIIa values in patients with atopic myelitis.

We aimed to clarify the disability progression and platelet aggregative function in atopic myelitis (AM). Seventeen AM patients and 35 healthy controls were subjected to clinico-allergological evaluations and glycoprotein IIb/IIIa (GP IIb/IIIa) measurements using a VerifyNow assay system. In AM patients, the disease duration had significant positive correlations with the Kurtzke Expanded Disability Status Scale scores and Sensory Functional Scale scores. The GP IIb/IIIa values were significantly higher in AM patients than in controls as well as in females compared with males. AM is essentially a progressive disease affecting the sensory system, and involves an increased platelet aggregative function.

Wall-eyed bilateral internuclear ophthalmoplegia (WEBINO) syndrome in a patient with neuromyelitis optica spectrum disorder and anti-aquaporin-4 antibody.

This report describes, for the first time, an occurrence of wall-eyed bilateral internuclear ophthalmoplegia (WEBINO) in a 19-year-old female with neuromyelitis optica (NMO) spectrum disorder, who had anti-aquaporin-4 (AQP4) antibody. A high signal intensity lesion on T2-weighted MRI was detected in the midbrain tegmentum adjacent to the aqueduct, and presumably involved the medial longitudinal fasciculus bilaterally at the caudal levels. Plasma exchange resolved both WEBINO syndrome and the midbrain lesion. Although WEBINO syndrome is occasionally reported in multiple sclerosis patients, diagnosis of NMO should not be excluded in patients with WEBINO syndrome, because AQP4 is expressed abundantly around the periaqueductal region.