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Background Vascular prevention trials typically use dichotomous event outcomes although this may be inefficient statistically and gives no indication of event severity. We assessed whether ordinal outcomes would be more efficient and how to best analyse them. Methods Chief investigators of vascular prevention randomised controlled trials that showed evidence of either benefit or harm, or were included in a systematic review that overall showed benefit or harm, shared individual participant data from their trials. Ordered categorical versions of vascular event outcomes (such as stroke and myocardial infarction) were analysed using 15 statistical techniques and their results then ranked, with the result with the smallest p-value given the smallest rank. Friedman and Duncan’s multiple range tests were performed to assess differences between tests by comparing the average ranks for each statistical test. Results Data from 35 trials (254,223 participants) were shared with the collaboration. 13 trials had more than two treatment arms, resulting in 59 comparisons. Analysis approaches (Mann Whitney U, ordinal logistic regression, multiple regression, bootstrapping) that used ordinal outcome data had a smaller average rank and therefore appeared to be more efficient statistically than those that analysed the original binary outcomes. Conclusions Ordinal vascular outcome measures appear to be more efficient statistically than binary outcomes and provide information on the severity of event. We suggest a potential role for using ordinal outcomes in vascular prevention trials.

For Japanese patients with non-valvular atrial fibrillation (NVAF), the risk of stroke and major bleeding events was assessed by using the CHADS

Tumefactive demyelinating lesions (TDLs) can mimic brain tumors on radiological images. TDLs are often referred to as tumefactive multiple sclerosis (TMS), but the heterogeneous nature and monophasic course of TDLs do not fulfill clinical and magnetic resonance imaging (MRI) criteria for multiple sclerosis. Redefining TDLs, TMS and other inflammatory brain lesions is essential for the accurate clinical diagnosis of extensive demyelinating brain lesions. We retrospectively analyzed MRI from nine TDL cases that underwent brain biopsy. Patterns of gadolinium enhancement on MRI were categorized as homogenous, inhomogeneous, patchy and diffuse, open ring or irregular rim, and were compared with pathological hallmarks including demyelination, central necrosis, macrophage infiltration, angiogenesis and perivascular lymphocytic cuffing. All cases had coexistence of demyelinating features and axonal loss. Open-ring and irregular rim patterns of gadolinium enhancement were associated with macrophage infiltrations and angiogenesis at the inflammatory border. An inhomogeneous pattern of gadolinium enhancement was associated with perivascular lymphocytic cuffing. Central necrosis was seen in cases of severe multiple sclerosis and hemorrhagic leukoencephalopathy. These results suggest that the radiological features of TDLs may be related to different pathological processes, and indicate that MRI may be useful in understanding their pathophysiology. Further investigation is needed to determine the precise disease entity of these inflammatory demyelinating brain lesions.

The CHADS2 and CHA2DS2-VASc scores, that is, ischemic stroke risk indices for patients having atrial fibrillation (AF), may also be useful as bleeding risk indices. Japanese patients with AF, who routinely took oral antithrombotic agents were enrolled from a prospective, multicenter study. The CHADS2 and CHA2DS2-VASc scores were assessed based on information at entry. Scores of 0, 1 and ⩾2 were defined as the low, intermediate and high ischemic risk categories, respectively, for each index. Of 1221 patients, 873 took warfarin, 114 took antiplatelet agents and 234 took both. The annual incidence of ischemic stroke was 0.76% in the low-risk category, 1.46% in the intermediate-risk category and 2.90% in the high-risk category by CHADS2 scores, and 1.44, 0.42 and 2.50%, respectively, by CHA2DS2-VASc scores. The annual incidence of major bleeding in each category was 1.52, 2.19 and 2.25% by CHADS2, and 1.44, 1.69 and 2.24% by CHA2DS2-VASc. After multivariate adjustment, the CHADS2 was associated with ischemia (odds ratio 1.76, 95% confidence interval 1.03-3.38 per 1-category increase) and the CHA2DS2-VASc tended to be associated with ischemia (2.18, 0.89-8.43). On the other hand, associations of the indices with bleeding were weak. In conclusion, bleeding risk increased gradually as the CHADS2 and CHA2DS2-VASc scores increased in Japanese antithrombotic users, although the statistical impact was rather weak compared with their predictive power for ischemic stroke.

Although aspirin has been widely prescribed for the prevention of cardiovascular events, its risk of gastrointestinal complications is of great concern. Despite expectations for such, few data are available on the prevalence or incidence of gastrointestinal complications in aspirin users in Japan. The Management of Aspirin-induced GastroIntestinal Complications (MAGIC) is the first attempt at collaboration among cardiologists, neurologists, and gastroenterologists to obtain such findings. We aim to share all about the MAGIC study. The MAGIC is a prospective cohort study involving patients taking low-dose aspirin (81 mg to 325 mg per day) for longer than 1 month. Participants are recruited from multiple disease categories, including those with coronary artery disease, cerebrovascular disease, atrial fibrillation, and other cardiovascular conditions requiring antithrombotic therapy. Its duration of follow-up is 1 year. At baseline and 1 year follow-up, all participants will undergo endoscopic examination. The primary outcome is upper gastrointestinal complications, classified as erosions, ulcers, and bleeding. Secondary outcomes include LANZA score, non-fatal cardiovascular events, any bleeding, cancer, and death. 1,533 participants were entered in the MAGIC cohort. By underlying disease, about 45% of them had coronary artery diseases, followed by cerebrovascular diseases (35%), atrial fibrillation (10%) and other cardiovascular diseases (10%). The MAGIC study will yield important findings with regard to the prevalence and incidence of gastrointestinal complications and related risk factors for low-dose aspirin users. It may also report that use of anti-secretory agents such as proton pump inhibitors reduces the risk of such complications.

There are few studies regarding functional outcome and lesion extent on diffusion-weighted MRI (DWI) in patients with posterior circulation (PC) infarction. The aim of our study was to assess whether a newly proposed posterior circulation Alberta Stroke Program Early CT Score (pc-ASPECTS) on DWI is useful for predicting functional outcome in PC patients. One hundred thirty-two patients with first-ever ischemic stroke in the posterior circulation within 24 h of onset who were admitted to our hospital were enrolled in the study. We compared background characteristics, vital signs, laboratory data, and MRI findings between favorable (F) and unfavorable (U) outcome groups at 3 months, according to the modified Rankin Scale (mRS). The F and U groups were defined as having a mRS of 0-2 and 3-6, respectively. pc-ASPECTS was scored by DWI obtained 12-36 h after onset. Ninety-eight patients (74.2%) were classified into the F group and 34 patients (25.8%) into the U group. On univariate analysis, F group patients were younger, had lower National Institutes of Health Stroke Scale (NIHSS) score at entry, and a lower rate of early neurological deterioration (END) and cardioembolic stroke than U group patients. On MRI, F group patients had lower leukoaraiosis and medial temporal atrophy score and higher pc-ASPECTS score on DWI compared to U group patients. Multiple logistic regression analysis revealed NIHSS (p < 0.001), END (p = 0.0057), pc-ASPECTS (p < 0.001), and leukoaraiosis (p = 0.0091) as independent predictors of functional outcome. pc-ASPECTS appears to be a powerful marker for predicting functional outcome, along with clinical severity and END. Leukoaraiosis may also be an independent predictor of functional outcome.

Objectives Instead of the mismatch in MRI between the perfusion-weighted imaging (PWI) lesion and the smaller diffusion-weighted imaging (DWI) lesion (PWI-DWI mismatch), clinical-DWI mismatch (CDM) has been proposed as a new diagnostic marker of brain tissue at risk of infarction in acute ischemic stroke. The Alberta Stroke Program Early CT Score (ASPECTS) has recently been applied to detect early ischemic change of acute ischemic stroke. The present study applies the CDM concept to DWI data and investigated the utility of the CDM defined by the NIH Stroke Scale (NIHSS) and ASPECTS in patients with non-lacunar anterior circulation infarction. Methods Eighty-seven patients with first ever ischemic stroke within 24 hours of onset with symptoms of non-lacunar anterior circulation infarction with the NIHSS score ≥ 8 were enrolled. Initial lesion extent was measured by the ASPECTS on DWI within 24 hours, and initial neurological score was measured by the NIHSS. As NIHSS ≥ 8 has been suggested as a clinical indicator of a large volume of ischemic brain tissue, and the majority of patients with non-lacunar anterior infarction with score of NIHSS < 8 had lesions with ASPECTS ≥ 8 on DWI, so CDM was defined as NIHSS ≥ 8 and DWI-ASPECTS 8 ≥ . We divided patients into matched and mismatched patient groups, and compared them with respect to background characteristics, neurological findings, laboratory data, radiological findings and outcome. Results There were 35 CDM-positive patients (P group, 40.2%) and 52 CDM-negative patients (N group , 59.8%). P group patients had a higher risk of early neurological deterioration (END) than N group patients (37.1% vs 13.5%, p < 0.05), which were always accompanied by lesion growth defined by 2 or more points decrease on ASPECTS (36 to 72 hours after onset on CT). The NIHSS at entry were significantly lower in the P group, but there was no difference in the outcome at three months measured by the modified Rankin Scale. However, CDM was not an independent predictor of END by multiple logistic regression analysis. Conclusions Patients with CDM had high rate of early neurological deterioration and lesion growth. CDM defined as NIHSS ≥ 8 and DWI-ASPECTS ≥ 8 can be another marker for detecting patients with tissue at risk of infarction, but more work is needed to clarify whether this CDM method is useful in acute stroke management.

Nemaline myopathy is a rare disorder defined by the presence of nemaline rods in muscle fibers. Adult forms are known as sporadic late-onset nemaline myopathy (SLONM) [1, 2]. We report the first case of SLONM associated with primary Sjogren’s syndrome (PSjS). A 58-year-old woman without family history of musculoskeletal disease presented with progressive muscle weakness over the course of 2 years. She had severe difficulty walking and holding her head up, and was unable to rise from a chair. She also presented with dry eyes and mouth. Laboratory investigations revealed normal CK, absence of anti-AChR antibodies, and negative viral serology, including HIV. Level of IgG was mildly elevated without monoclonal gammopathy of undetermined significance (MGUS). Anti-SS-A/Ro antibodies were elevated at 295 U/ml. A salivary-gland-biopsy revealed lymphocytic sialoadenitis. Electromyography revealed myopathic motor unit potentials with fibrillation potentials and positive sharp waves (PSW) in the four limbs. Nerve conduction studies were normal. Left-quadriceps-muscle-biopsy revealed variation of muscle fiber diameter with scattered atrophic fibers, and no inflammatory cell infiltration. On hematoxylin-eosinstaining, some muscle fibers contained eosinophilic granules. Modified Gomori-trichrome-stained section showed variable rods in more than half of the muscle fibers. Only a few rods were crisply rod-shaped and many were somewhat irregular and punctuate. Severely affected fibers were small and occasionally vacuolated. NADH-TR-stained section revealed lobulated fibers, many of them were type 1 fibers. Fiber type proportions were normal. Electronmicroscopic image showed variable rods, some arising from the Z-discs (Fig. 1). No amyloid was detected. Genetic analysis was not performed. A diagnosis of SLONM with PSjS was made. Neck weakness and sicca syndrome were improved with prednisolone. Residual weakness was improved with intravenous immunoglobulin (IVIg, 0.4 g/kg/day for 5 days). She was eventually able to walk with a cane and rise from a chair without assistance. Fibrillation potentials and PSW in electromyography disappeared. Anti-SS-A/Ro antibodies were decreased at 49.9 U/ml. Symptomatic myopathy in PSjS is rarely reported in association with hypothyroidism or renal tubular acidosis [3–5]. Myositis is noted in secondary SjS patients, although muscle biopsy findings are quite variable. In our patient, these conditions were excluded by laboratory examinations. Etiology of SLONM is unclear. Because some cases of SLONM are associated with MGUS [2, 6, 7], and some occur in the early immunocompetent period of HIV infection [8, 9], an immune dysregulation or an unrecognized viral trigger have been suspected [2, 10]. Our patient developed muscle weakness and sicca syndrome simultaneously, which improved with immunotherapy. Nemaline rods were the predominant findings and features of other etiologies were absent. We believe the primary diagnosis to be SLONM, and suspect that immunological abnormalities may have played a role in the development of both PSjS and SLONM. HIV-associated SLONM has been noted to respond to therapy with prednisone or plasmapheresis [11–13], or a combination of IVIg [14], whereas a concomitant MGUS leads to a very poor prognosis [2]. However, two patients with non-HIV SLONM/MGUS were recently reported to M. Suzuki (&) Y. Shimizu M. Takeuchi M. Kobayashi M. Iwata S. Uchiyama Department of Neurology, Tokyo Women’s Medical University, 8-1 Kawadacho Shinjuku-ku, Tokyo 162-8666, Japan e-mail: suzukimiki@nij.twmu.ac.jp

Background: Fundamental cytological changes of amyotrophic lateral sclerosis (ALS) were looked for by comparing relatively preserved Onuf’s nucleus (ON) and severely affected neighboring motor neuron groups (dorsolateral alpha motoneurons (DL) and other anterior horn neurons (OAH)). The second sacral segments from 11 ALS patients and 5 controls were initially quadruple-labeled for phosphorylated and non-phosphorylated TAR DNA-binding protein of 43 kDa (TDP43), and p62 with DAPI to identify TDP43-related changes. After digital recording of these fluorescence data encompassing the entire specimen at a high resolution, the same sections were stained with Kluver-Barrera method to obtain their exact bright-field counterparts. This novel approach facilitated exact identification of ON. Furthermore, this cell to cell comparison enabled to correlate quantitative indices of the neuronal cell bodies: perimeter, area and circularity index (CI) i.e. the ratio of (perimeter/2π) divided by the square root of (area/π), which decreases with dendritic retraction, overall number of neurons and inclusions. Results: In addition to known preservation of ON neuron number relative to DL and OAH, size reduction of ON neurons was not significant even in the advanced stage. Significant size reduction in DL was counteracted in the presence of TDP43-positive inclusions. Early increase of neuronal size in OAH was further enhanced by the presence of TDP43-positive inclusions. Even with these heterogeneous cytopathological changes, a decrease in CI was consistent in all groups at an early phase and was correlated with neuronal loss. Conclusions: Among variable cytological changes of ALS, a decrease in CI is a consistent early feature shared between non-atrophic ON neurons and other anterior horn neurons with either decreased (DL) or even increased (OAH) size and profounder neuronal loss. This decrease in CI, representative of dendritic retraction, is fundamental to ALS pathogenesis, not necessarily linked to cell size and pathological inclusions.

Recently, it has been established that aspirin significantly reduces the risk of vascular events such as stroke, myocardial infarction and vascular death.[1] The aim of this study was to examine the ex vivo effects of d-indobufen on platelet aggregation and thromboxane A2 (TXA2) production in patients with cerebrovascular disease with a view to its potential as an alternative to aspirin in the prevention of cerebrovascular events.