Increased serum alkaline phosphatase and early neurological deterioration in patients with atherothrombotic brain infarction attributable to intracranial atherosclerosis.

OBJECTIVE: The purpose of this study was to determine whether increased alkaline phosphatase (ALP) was associated with early neurological deterioration (END) in patients with atherothrombotic brain infarction (ATBI) attributable to intracranial atherosclerosis (ICAS) or not. METHODS: We analyzed data derived from 70 patients (47 men; mean age, 72.4 ± 12.8 years) with symptomatic ICAS who were admitted within 3 days of ATBI onset between April 2013 and December 2018. We defined END as an increase of ≥2 in the National Institutes of Health Stroke Scale scores during the first 72 h of hospitalization. RESULTS: Eleven (15.7%) patients had END. Serum ALP levels on admission were significantly higher among patients with, than without END (median [interquartile range], 296 [233-338] vs. 216 [187-262] U/L, p = .0081). CONCLUSION: Increased serum ALP levels on admission may be able to predict developing END in patients with symptomatic ICAS.

Long-read sequencing identifies GGC repeat expansions in NOTCH2NLC associated with neuronal intranuclear inclusion disease.

Neuronal intranuclear inclusion disease (NIID) is a progressive neurodegenerative disease that is characterized by eosinophilic hyaline intranuclear inclusions in neuronal and somatic cells. The wide range of clinical manifestations in NIID makes ante-mortem diagnosis difficult1-8, but skin biopsy enables its ante-mortem diagnosis9-12. The average onset age is 59.7 years among approximately 140 NIID cases consisting of mostly sporadic and several familial cases. By linkage mapping of a large NIID family with several affected members (Family 1), we identified a 58.1 Mb linked region at 1p22.1-q21.3 with a maximum logarithm of the odds score of 4.21. By long-read sequencing, we identified a GGC repeat expansion in the 5' region of NOTCH2NLC (Notch 2 N-terminal like C) in all affected family members. Furthermore, we found similar expansions in 8 unrelated families with NIID and 40 sporadic NIID cases. We observed abnormal anti-sense transcripts in fibroblasts specifically from patients but not unaffected individuals. This work shows that repeat expansion in human-specific NOTCH2NLC, a gene that evolved by segmental duplication, causes a human disease.

[Acute myelitis associated with anti-neutral glycolipid antibody].

A 48-year-old man with rapid onset of fever elevation developed acute myelitis over a period of a week. MRI of the spinal cord revealed a longitudinal T2-hyperintense intraspinal lesion extending from C6 to Th8 level. Clinical symptoms and findings resolved with immunotherapy. In serological analysis, no antibodies related to various collagen diseases, anti-aquaporin-4 (AQP4) antibody and anti-myelin oligodendrocyte glycoprotein (MOG) antibody were detected. Anti-lactosylceramide (LacCer) antibodies were detected in the acute phase of serum and cerebrospinal fluid, with titers showing decrements in the recovery phase. The present case supports the notion that acute myelitis can occur as an anti-neutral glycolipid antibody-related disorder. Anti-neutral glycolipid antibodies should be examined in future pertinent cases of myelitis.

[Cerebellar and brainstem hypoperfusion in Bickerstaff's brainstem encephalitis: a case report].

A 16-year-old healthy male experienced gastrointestinal symptoms and 9 days later developed fever, headache, numbness of the left hand, and disturbance of consciousness with rapid deterioration to a comatose state. These clinical symptoms resolved after treatment with steroid pulse, plasma exchange, and intravenous immunoglobulin. Along with the recovery, ophthalmoplegia and ataxia were observed. These symptoms and the detection of a high titer of serum anti-GQ1b immunoglobulin G autoantibodies led to the diagnosis of Bickerstaff's brainstem encephalitis (BBE). Brain 123I-IMP SPECT indicated hypoperfusion of the brainstem and bilateral cerebellar cortex during the acute phase, which increased during the recovery phase. This finding is indicative of reversible dysfunction in the cerebellar cortex and brainstem in the acute phase of BBE.

Increased pulse wave velocity in patients with acute lacunar infarction doubled the risk of future ischemic stroke.

The aim of this study was to determine whether pulse wave velocity (PWV), a marker of vascular endothelial impairment and arteriosclerosis, predicts future ischemic stroke in patients who developed acute lacunar infarction. Patients with a first-ever ischemic stroke due to acute lacunar infarction were enrolled in this study. An oscillometric device (Form PWV/ABI; Omron Colin, Tokyo, Japan) was used to measure brachial-ankle PWV 1 week after stroke onset. Patients were followed for at least 5 years. The main end point of the study was recurrent ischemic stroke. Event-free survival was analyzed using Kaplan-Meier plots and log-rank tests. The risk of recurrent ischemic stroke was estimated using the Cox proportional-hazards model. Of the 156 patients (61% male, mean age: 69.2±11.3 years) assessed in this study, 29 developed recurrent ischemic stroke. The median brachial-ankle PWV value was 20.4 m s-1. Patients with high PWV values had a greater risk of recurrent ischemic stroke than patients with low PWV values (28% vs. 15%, P=0.08). Kaplan-Meier curve analysis showed that patients with high PWV values had a less favorable (that is, free of recurrent ischemic stroke) survival time (P=0.015). A multivariate Cox proportional-hazards model identified high PWV as an independent predictor of recurrent ischemic stroke after adjusting for age, sex and blood pressure (hazard ratio 2.35, 95% confidence interval, 1.02-5.70, P=0.044). In patients with acute lacunar infarction, a high PWV predicts a twofold greater risk of future ischemic stroke, independent of patient age, sex and blood pressure levels.

A homozygous mutation of VWA3B causes cerebellar ataxia with intellectual disability.

BACKGROUND: Hereditary cerebellar ataxia constitutes a heterogeneous group of neurodegenerative disorders, occasionally accompanied by other neurological features. Genetic defects remain to be elucidated in approximately 40% of hereditary cerebellar ataxia cases in Japan. We attempted to identify the gene responsible for autosomal recessive cerebellar ataxia with intellectual disability. METHODS: The present study involved three patients in a consanguineous Japanese family. Neurological examination and gene analyses were performed in all family members. We performed genome-wide linkage analysis including single nucleotide polymorphism arrays, copy-number variation analysis and whole exome sequencing. To clarify the functional alteration resulting from the identified mutation, we performed cell viability assay of cultured cells expressing mutant protein. RESULTS: One homozygous region shared among the three patients on chromosomes 2p16.1-2q12.3 was identified. Using whole exome sequencing, six homozygous variants in genes in the region were detected. Only one variant, VWA3B c.A1865C, results in a change of a highly conserved amino acid (p.K622T) and was not present in control samples. VWA3B encodes a von Willebrand Factor A Domain-Containing Protein 3B with ubiquitous expression, including the cerebellum. The viability of cultured cells expressing the specific K622T mutation was proved to decrease through the activation of apoptotic pathway. CONCLUSIONS: Mutated VWA3B was found to be likely associated with cerebellar degeneration with intellectual disability. Although a rare cause of cerebellar degeneration, these findings indicate a critical role for VWA3B in the apoptosis pathway in neuronal tissues.

Comparison of arteriosclerotic indicators in patients with ischemic stroke: ankle-brachial index, brachial-ankle pulse wave velocity and cardio-ankle vascular index.

The ankle-brachial index (ABI), brachial-ankle pulse wave velocity (baPWV) and cardio-ankle vascular index (CAVI) are surrogate markers of arteriosclerosis. However, their roles in patients with acute ischemic stroke remain unclear. From October 2003 to September 2011, we enrolled patients with arteriosclerotic ischemic stroke (AIS) exhibiting large infarcts attributed to large-artery atherosclerosis (LAA) or deep subcortical infarcts (mainly lacunar infarcts) attributed to small-artery disease (SAD). Outpatients without a history of stroke served as controls (CTL). We divided the study period into two terms and assessed patients using two different oscillometric devices (Form PWV/ABI, Omron Colin; and VaSera VS-1500, Fukuda Denshi) in each term. One-way analysis of variance and age- and sex-adjusted analysis of covariance were used to compare the three groups. We analyzed 842 patients. The ABI was significantly lower in the LAA (n = 102) group than in the SAD (n = 280) and CTL (n = 460) groups. The baPWV was significantly higher in the LAA and SAD groups than in the CTL group. The CAVI gradually increased in the order of CTL, SAD and LAA. The cutoff values of baPWV and CAVI for detection of AIS were 18.3 m s(-1) (odds ratio (OR): 6.09, 95% confidence interval (CI): 3.97-9.62, P < 0.01) and 9.5 (OR: 1.44, 95% CI: 1.24-1.70, P < 0.001), respectively. Among the three indicators, a lower ABI indicated advanced atherosclerosis associated with LAA, and an increased baPWV more closely indicated AIS. An increased CAVI may indicate the degree of vessel stiffness due to arteriosclerosis.

Spinocerebellar ataxia type 36 exists in diverse populations and can be caused by a short hexanucleotide GGCCTG repeat expansion.

OBJECTIVE: Spinocerebellar ataxia 36 (SCA36) is an autosomal-dominant neurodegenerative disorder caused by a large (>650) hexanucleotide GGCCTG repeat expansion in the first intron of the NOP56 gene. The aim of this study is to clarify the prevalence, clinical and genetic features of SCA36. METHODS: The expansion was tested in 676 unrelated SCA index cases and 727 controls from France, Germany and Japan. Clinical and neuropathological features were investigated in available family members. RESULTS: Normal alleles ranged between 5 and 14 hexanucleotide repeats. Expansions were detected in 12 families in France (prevalence: 1.9% of all French SCAs) including one family each with Spanish, Portuguese or Chinese ancestry, in five families in Japan (1.5% of all Japanese SCAs), but were absent in German patients. All the 17 SCA36 families shared one common haplotype for a 7.5 kb pairs region flanking the expansion. While 27 individuals had typically long expansions, three affected individuals harboured small hexanucleotide expansions of 25, 30 and 31 hexanucleotide repeat-units, demonstrating that such a small expansion could cause the disease. All patients showed slowly progressive cerebellar ataxia frequently accompanied by hearing and cognitive impairments, tremor, ptosis and reduced vibration sense, with the age at onset ranging between 39 and 65 years, and clinical features were indistinguishable between individuals with short and typically long expansions. Neuropathology in a presymptomatic case disclosed that Purkinje cells and hypoglossal neurons are affected. CONCLUSIONS: SCA36 is rare with a worldwide distribution. It can be caused by a short GGCCTG expansion and associates various extracerebellar symptoms.

Functional independence measure scores predict level of long-term care required by patients after stroke: a multicenter retrospective cohort study.

PURPOSE: To examine whether Functional Independence Measure (FIM) scores on admission can predict the future care levels of patients after acute stroke. METHODS: In this multicenter retrospective cohort study, we enrolled post-acute stroke patients and assessed stroke subtypes, self-care abilities using FIM scores, and discharge destination. Patients' care levels were assessed according to the Long-Term Care Insurance (LTCI) system (0-5: slight impairment to bedridden), the national insurance plan for care in Japan, at discharge. We divided patients into two groups according to LTCI care levels (0-2 versus 3-5) to compare their clinical characteristics using multivariate logistic regression analysis. The trial was registered with the UMIN Clinical Trials Registry (UMIN000012653). RESULTS: Of the 1261 patients (47% female, mean age 75 years), 492 (39%) fulfilled LTCI care levels 0-2. FIM scores on admission were significantly correlated with LTCI care levels (p < 0.001). On multivariate analysis, age and FIM scores on admission were found to be independent predictors of LTCI care levels 0-2. CONCLUSIONS: FIM scores on admission after stroke can independently predict later care requirements. Early prediction of LTCI care levels may contribute to the early supported discharge and improve the efficiency of healthcare planning. Implications for Rehabilitation There is a clear relationship between Functional Independence Measure (FIM) scores and the care levels certified by the Long-Term Care Insurance (LTCI) system, a national healthcare and insurance system in Japan. FIM scores on admission can predict future LTCI care levels required for patients after acute stroke. Early prediction of LTCI care levels may contribute to early supported discharge, improve the efficiency of stroke management and assist healthcare planning.

Arterial stiffness and progressive neurological deficit in patients with acute deep subcortical infarction.

BACKGROUND AND PURPOSE: The mechanism of progressive neurological deficit (PND) in patients with ischemic stroke remains unclear. The aim of this study was to clarify whether arterial stiffness, a marker of vascular endothelial impairment and arteriosclerosis, is associated with PND in patients with acute deep subcortical infarction. METHODS: We evaluated 156 consecutive first-ever ischemic stroke patients with acute deep subcortical infarction. PND was defined as an increment of ≥2 points in the National Institute of Health Stroke Scale score or an increase of ≥1 point in the limb weakness score within 7 days of stroke onset. Patients were assessed for risk factors, and infarct size was measured on initial diffusion-weighted magnetic resonance imaging. We measured brachial-ankle pulse wave velocity (baPWV) as a marker of arterial stiffness. We divided patients into 2 groups according to the presence or absence of PND to compare their clinical characteristics. RESULTS: Fifty-two patients (33%) had PND, and baPWV was significantly higher in patients with than in those without PND. The baPWV cut-off value for PND was 18.24 m/s, with 90% sensitivity and 47% specificity. In multivariable logistic regression analysis, high baPWV (≥18.24 m/s; odds ratio, 8.22; 95% confidence interval, 2.55-31.9), large infarct size (≥15 mm; odds ratio, 2.76; 95% confidence interval, 1.01-7.92), and ≥3 infarct slices on serial axial diffusion-weighted imaging (odds ratio, 3.38; 95% confidence interval, 1.22-10.0) were independently associated with PND. CONCLUSIONS: Arterial stiffness indicated by baPWV is independently associated with PND in patients with acute deep subcortical infarction.

Association between silent brain infarct and arterial stiffness indicated by brachial-ankle pulse wave velocity.

OBJECTIVE: The aim of this hospital-based cohort study was to clarify the independent association between silent brain infarct (SBI) and arterial stiffness indicated by brachial-ankle pulse wave velocity (baPWV) including the cutoff value for SBI. METHODS: We studied 240 consecutive patients (mean age 69 years) with no history of stroke. We assessed the presence of SBI, white matter hyperintensities (WMHs), and risk factors. Arterial stiffness was evaluated using baPWV. We measured the intima-media thickness of the common carotid artery (CCAIMT) using carotid ultrasonography. We divided patients into two groups according to the presence or absence of SBI, and compared clinical characteristics between the two groups. RESULTS: In multivariable analysis, increased baPWV [by 1 m/s; odds ratio (OR) 1.13, 95% confidence interval (CI) 1.02-1.25] was independently associated with SBI. The baPWV cutoff value for SBI was 17.49 m/s. Patients with baPWV≥17.49 m/s had a higher possibility of the presence of SBI (OR 2.30, 95% CI 1.02-5.34) compared with patients with baPWV <17.49 m/s. Furthermore, the adjusted OR for the presence of SBI of the combination of baPWV≥17.49 m/s and CCAIMT≥1.1 mm (OR 2.73, 95% CI 1.24-6.11) was higher compared with that of baPWV≥17.49 m/s (OR 2.47, 95% CI 1.11-5.65). CONCLUSION: Arterial stiffness is independently associated with SBI. Measurement of baPWV can indicate the presence of SBI, especially in patients with baPWV≥17.49 m/s.

Silent brain infarct is independently associated with arterial stiffness indicated by cardio-ankle vascular index (CAVI).

It is still unclear whether silent brain infarct (SBI) and white-matter hyperintensities (WMHs) on magnetic resonance imaging (MRI) scans are associated with cardio-ankle vascular index (CAVI), a novel parameter of arterial stiffness. We studied 220 consecutive patients (mean age, 69 years) without a history of stroke or transient ischemic attack. Patients were assessed for the presence of SBI, WMHs and risk factors. Arterial stiffness was evaluated using CAVI. Patients were categorized into one of two groups according to the presence or absence of SBI and WMHs, and clinical characteristics were compared between the two groups. CAVI was significantly higher in patients with SBI or in patients with WMHs than in those without those respective findings. The CAVI cutoff values for detection of SBI and WMHs were 9.2 and 8.9, respectively. On multivariable analyses, CAVI, a one point increase in CAVI: odds ratio (OR), 1.25; 95% confidence interval (CI), 1.01-1.56; CAVI ≥9.2: OR, 2.34; 95% CI, 1.16-5.02, was independently associated with SBI, however, CAVI was not independently associated with WMHs. Patients with CAVI ≥9.2 had higher OR for the presence of both SBI and WMHs (OR, 2.57; 95% CI, 1.15-5.98) when compared with patients with CAVI <9.2 after adjustment for age and sex. SBI is independently associated with arterial stiffness indicated by CAVI.

Increased brachial-ankle pulse wave velocity is independently associated with white matter hyperintensities.

BACKGROUND: White matter hyperintensities (WMHs) are a risk factor for stroke. Their etiology is considered to be cerebral microvascular abnormality. However, the association between WMHs and arteriosclerosis is not yet clear. The aim of this hospital-based cohort study was to identify the arteriosclerotic characteristics associated with WMHs. METHODS: We cross-sectionally included 240 consecutive patients with no history of stroke. We measured the brachial-ankle pulse wave velocity (baPWV), ankle brachial pressure index, and intima-media thickness of the common carotid artery, and we performed magnetic resonance brain imaging. WMHs were defined as periventricular hyperintensity (Fazekas grade ≥3) and/or separate deep white matter hyperintense signals (Fazekas grade ≥2). We determined the prevalence of WMHs, silent brain infarction (SBI), hypertension, hypercholesterolemia, diabetes mellitus, ischemic heart disease, and smoking. We compared 2 groups of patients, defined by the presence or absence of WMHs, using multiple logistic regression analyses. RESULTS: In multivariable analysis, SBI (OR 3.38; 95% CI 1.52-7.72), hypertension (OR 2.23; 95% CI 1.03-5.15), female sex (OR 1.95; 95% CI 1.03-3.76), baPWV (OR 1.12; 95% CI 1.02-1.23), and age (OR 1.09; 95% CI 1.04-1.14) were independently associated with WMHs. CONCLUSIONS: An increased baPWV is associated with WMHs. Management of increased baPWV may help to prevent the progression of WMHs and stroke.

Clinical features of a first-ever lacunar infarction in Japanese patients: poor outcome in females.

Lacunar infarction (LI) remains an important stroke subtype in Japan. The aim of this study was to investigate the characteristics of outcome determinants in LI. This study was a single center observational study and included 163 consecutive patients (108 male, 55 female; mean age 69 years). The National Institutes of Health Stroke Scale (NIHSS) score on admission and the modified Rankin scale (mRS) score at discharge were used to evaluate stroke severity. We determined the location of the infarct, the grade of white matter hyperintensity (WMH), and the prevalence of silent brain infarcts, hypertension, hypercholesterolemia, diabetes mellitus, ischemic heart disease, and smoking. We compared 2 groups, good outcome (mRS score 0-2) and poor outcome (mRS score 3-5), using multiple logistic regression analysis. We found significant differences between the 2 groups according to female sex (P = .04), WMH (P = .04), and NIHSS score (P < .001). After multivariate analysis, female sex (odds ratio [OR] = 3.4, 95% confidence interval [CI] = 1.1-11.4; P = .03), and NIHSS score (OR = 2.3, 95% CI = 1.7-3.3; P < .001) were independently associated with poor outcome. Elderly onset, poor outcome, and hypercholesterolemia were more common in female patients, whereas smoking was more prevalent in males. Our data indicate that sex differences exist in Japanese LI patients with regard to risk factors and outcome. The treatment of risk factors based on sex differences is important to the management of LI.