Liver fibrosis index is associated with functional outcome among acute ischemic stroke patients.

INTRODUCTION: The fibrosis-4 (FIB-4) index and the fibrosis-5 (FIB-5) index are noninvasive markers of liver fibrosis in patients with nonalcoholic fatty liver disease. Although liver fibrosis a potential risk factor for stroke development, it is uncertain whether liver fibrosis influences stroke outcomes. We investigated the associations between these two indices and stroke patient outcomes and compared their predictive accuracy. METHODS: We conducted a double-center, hospital-based, retrospective study. Consecutive acute ischemic stroke patients (n=2399) were analyzed. We calculated the FIB-4 index and the FIB-5 index and evaluated their relationships with poor stroke outcome, which was defined as a modified Rankin Scale score of 3-6 at three months after stroke. We evaluated the ability of each index to predict stroke outcome according to cutoff values calculated from receiver operating characteristic (ROC) curves. RESULTS: Of 2399 recruited patients, 1549 patients (mean age, 73 years) were analyzed. The FIB-4 index and FIB-5 index had similar areas under their ROC curves for predicting stroke outcome (FIB-4 index, 0.675 and FIB-5 index, 0.683, P=0.334). The cutoff points of the FIB-4 index and FIB-5 index according to the ROC analysis were associated with poor stroke outcome in the multivariable analyses (odds ratio [OR] 2.23, 95 % confidence interval [CI] 1.72-2.89, OR 1.93, 95 % CI 1.47-2.54, respectively). CONCLUSIONS: Liver fibrosis scores may be useful for predicting outcomes in patients with acute stroke. The FIB-4 and FIB-5 indices should be considered comprehensive tools for assessing the outcome risk after ischemic stroke.

[Clinical features of acyclovir encephalopathy without acute kidney injury].

INTRODUCTION: Few reports have described acyclovir (ACV) encephalopathy without acute kidney injury (AKI). OBJECTIVE: This study clarified the clinical features of ACV encephalopathy without AKI compared to that with AKI. METHODS: Creatinine (Cre) levels were measured on admission. After admission, Cre was measured in a timely manner for the first seven hospital days. The minimum Cre level in these measurements was then determined. ACV encephalopathy was defined when two criteria were met: 1) neurological symptoms appeared after valacyclovir (VACV) administration, and 2) neurological symptoms improved after VACV discontinuation. AKI was defined when the Cre level on admission was >1.5 times higher than the minimum Cre level. The subjects were divided into AKI and non-AKI groups based on these findings. RESULTS: Eighteen patients had ACV encephalopathy (5 males, mean age 81.3±5.5 years old). All patients were prescribed VACV 3,000 mg/day. The minimum Cre was 1.93±1.76 mg/dL. AKI occurred in 10 (56.6%) patients. VACV was discontinued in all patients, and emergency hemodialysis treatment was administered in 10 (55.6%) patients. All patients recovered. Compared to the AKI group, the non-AKI group had a lower history of taking a Ca-blocker (33.3% vs 80.0%, p=0.092), a lower rate of emergency dialysis (16.9% vs 70.0%, p=0.059) and a longer time to clinical improvement (3.67±1.86 vs 2.20±0.63 days, p=0.073). CONCLUSION: ACV encephalopathy without AKI is characterized by a low rate of emergency dialysis, which may be linked to a prolonged duration of symptoms.

[Analysis of factors leading to brain MRI lesions in Wernicke's encephalopathy].

[Objective] To investigate association between Wernicke encephalopathy (WE) and brain MRI. [Subjects] 26 patients (7 females, mean age 63.9 ± 12.7 years) with WE admitted to our department between May 2008 and September 2022. [Methods] Wernicke's encephalopathy in patients with MRI lesions was defined as "MRI-positive group" (MPG), and those without MRI lesions as "MRI-negative group" (MNG). The following parameters were assessed between the two groups: age, sex, alcoholism, neurological symptoms, vitamin B1, lymphocyte, total cholesterol, albumin, and outcome at discharge. [Results] There were 17 patients in MPG. Compared to MNG, MPG had lower rates of alcohol abuse (10.0% vs 77.8%, P = 0.025), lower vitamin B1 (median 10.0 |ng/ml vs 29.0 |ng/ml, P < 0.001), and more vitamin B1 treatment dose (median 1900 |mg vs 600 |mg, P = 0.016). [Conclusion] Alcoholic WE may be overlooked if the focus is solely on brain MRI findings.

[A case of bilateral middle cerebellar peduncle infarction with hot cross bun sign].

A 71-year-old man with hypertension and diabetes mellitus presented to our hospital because he felt lightheaded. Diffusion-weighted images (DWI) on brain MRI showed high signal lesions in the left cerebellar hemisphere and the right pons. The diagnosis of cerebellar infarction was made, but he refused treatment. One month later, he came to our hospital because his body leaned to the left. Neurological examination revealed dysarthria and cerebellar truncal ataxia. An electrocardiogram showed atrial fibrillation. DWI on brain MRI showed high signal lesions in the bilateral cerebellar hemispheres and middle cerebellar peduncles (MCP). Dabigatran 300 |mg/day was administered for cardiogenic cerebral embolism. On the 12th day of onset, he was transferred to a rehabilitation hospital. At 72 years old, T2*-weighted images on brain MRI showed hot cross bun sign (HCBs) in the pons. We considered that HCBs were caused by antegrade or retrograde degeneration (or both) of pontine infarcts and bilateral MCP infarcts in the pontine cerebellar tract. It seemed preferable to use T2*-weighted images or proton density-weighted images rather than T2-weighted images to detect HCBs. When HCBs is detected, it should be noted that HCBs can be caused by bilateral MCP infarcts in addition to multiple system atrophy.

[A case of a young woman with bilateral medial medullary infarcts caused by varicella-zoster virus vasculopathy without skin rash].

The patient, a 36-year-old female, had no previous history of shingles. She was admitted to the hospital due to nausea and lightheadedness. Upon admission, she was diagnosed with bilateral medial medullary infarcts. She received treatment with intravenous edaravone and argatroban, as well as antiplatelet therapy with aspirin and clopidogrel. However, her dysphagia, dysarthria, and paraplegia worsened. Due to changes in the lesion of the basilar artery on brain |MRA, we suspected the possibility of basilar artery dissection, and discontinued antiplatelet therapy. Subsequent imaging studies suggested vasculitis. After examining the cerebrospinal fluid, we diagnosed varicella-zoster virus (VZV) vasculopathy. Based on this diagnosis, we administered steroid pulse therapy for three days, started intravenous acyclovir, and resumed antithrombotic therapy with clopidogrel. Prednisone was administered for five days. Biochemical tests revealed an elevated D-dimer level. Due to the presence of lower extremity venous thrombus, clopidogrel was replaced with apixaban. The acyclovir infusion was discontinued due to observed acyclovir-induced neutropenia. These treatments improved neurological symptoms, circumflex thickening of the basilar artery, and contrast effects in the same area. On the 70th day, the patient was transferred to the hospital for rehabilitation. It is important to consider VZV angiopathy as a potential cause of juvenile cerebral infarction accompanying progressive basilar artery stenosis, regardless of the presence or absence of a skin rash.

[Diagnostic predictive factors in listeria meningitis].

PURPOSE: The purpose of this study was to elucidate the diagnostic predictive factors of listeria meningitis. SUBJECTS AND METHOD: Twenty-eight patients with bacterial meningitis (age; 65.9 ± 14.8 years, 11 female) who were admitted to Chikamori Hospital from October 1, 2006 to December 31, 2021 were included. Bacterial meningitis was defined as cerebrospinal fluids (CSF) pleocytosis with evidence of bacterial infection in CSF or blood. The blood and CSF data were reviewed for analysis. RESULTS: 9 patients were diagnosed as listeria meningitis, 19 patients were in non-listeria meningitis. Multiple logistic regression analysis showed that higher CSF lymphocyte ratio was significantly associated with listeria meningitis (Odds ratio 1.123, 95% Confidence interval 1.006-1.2155, P = 0.039). CSF lymphocyte ratio of 30% or more was found to predict listeria meningitis with a sensitivity of 55.6% and a specificity of 100%. CONCLUSION: CSF lymphocyte ratio may be useful for differentiating between listeria meningitis and non-listeria meningitis.

[Wernicke encephalopathy with lesions in the bilateral abducens nuclei: a case report].

A 35-year-old Japanese man had been treated for alcoholism until 6 months before coming to our hospital, after which he discontinued treatment for alcoholism. He noticed dizziness from two weeks ago. He visited our hospital because his dizziness was worsened and he noticed diplopia from two days ago. Physical examination revealed bilateral abducens nerve palsy, decreased limb tendon reflex, and ataxia. His blood vitamin B1 level was 16 ng/ml (normal range 24-66 ng/ml). FLAIR images on brain MRI showed high signal intensity lesions in the bilateral abducens nuclei and mammillary body. We diagnosed him as Wernicke encephalopathy (WE) with lesions in the bilateral abducens nuclei. Treatment with thiamine rapidly resulted in improvement of his neurological symptoms and MRI findings. He was discharged from our department on the 10th hospitalization day. Previous reports have shown that abducens nerve palsy and horizontal gaze evoked nystagmus may occur in the early state of WE. This case report highlights the importance to comprehend the atypical MRI findings of WE to treat a patient at the early stage.

[Diuretics-induced beriberi polyneuropathy: a case report].

A 56-year-old man with an unbalanced diet who preferred chicken was admitted to the hospital because of heart failure. He was treated with diuretics for heart failure, but muscle weakness in bilateral lower extremities appeared and gradually worsened. He was transferred to our hospital for weakness of bilateral lower extremities. Physical examination revealed mild disturbance of consciousness, pitting edema, weakness of bilateral lower extremities, and areflexia. Based on his current medical history and physical examinations, we considered him to have beriberi neuropathy. Treatment with thiamine rapidly resulted in improvement of his neurological symptoms. His blood vitamin B1 level was 12 ng/ml (normal range 24-66 ng/ml). We diagnosed him with diuretic-induced beriberi neuropathy. Previous reports have shown that diuretic treatment excretes vitamin B1 in the urine. His report represents a case for neurologists to consider to treat with vitamin B1 for beriberi neuropathy when muscle weakness is observed during treatment for heart failure receiving diuretics.

Predictors of Stroke Outcome Extracted from Multivariate Linear Discriminant Analysis or Neural Network Analysis.

AIM: The prediction of functional outcome is essential in the management of acute ischemic stroke patients. We aimed to explore the various prognostic factors with multivariate linear discriminant analysis or neural network analysis and evaluate the associations between candidate factors, baseline characteristics, and outcome. METHODS: Acute ischemic stroke patients (n=1,916) with premorbid modified Rankin Scale (mRS) scores of 0-2 were analyzed. The prediction models with multivariate linear discriminant analysis (quantification theory type II) and neural network analysis (log-linearized Gaussian mixture network) were used to predict poor functional outcome (mRS 3-6 at 3 months) with various prognostic factors added to age, sex, and initial neurological severity at admission. RESULTS: Both models revealed that several nutritional statuses and serum alkaline phosphatase (ALP) levels at admission improved the predictive ability. Of the 1,484 patients without missing data, 560 patients (37.7%) had poor outcomes. The patients with poor outcomes had higher ALP levels than those without (294.3±259.5 vs. 246.3±92.5 U/l, P＜0.001). Multivariable logistic analyses revealed that higher ALP levels (1-SD increase) were independently associated with poor stroke outcomes after adjusting for several confounding factors, including the neurological severity, malnutrition status, and inflammation (odds ratio 1.21, 95% confidence interval 1.02-1.49). Several nutritional indicators extracted from prediction models were also associated with poor outcome. CONCLUSION: Both the multivariate linear discriminant and neural network analyses identified the same indicators, such as nutritional status and serum ALP levels. These indicators were independently associated with functional stroke outcome.

Clinical characteristics and tumor markers in ischemic stroke patients with active cancer.

Cancer-associated ischemic stroke (CAS) refers to a hypercoagulation disorder related to malignant tumors, especially adenocarcinoma. Carbohydrate antigen (CA) 125 is a mucinous serum marker that might reflect hypercoagulation status, but the association between CA 125 and CAS is unclear across various types of cancer. The aim of this study was to investigate the associations among tumor markers, coagulation markers, and clinical factors in acute ischemic stroke (AIS) patients with active cancer. Consecutive AIS patients with active cancer (a diagnosis or ongoing active therapy for cancer within 6 months) were prospectively enrolled at four hospitals. D-dimer, C-reactive protein (CRP), carcinoembryonic antigen (CEA), CA19-9, and CA 125 levels were measured. Of 120 AIS patients with active cancer, 47 were diagnosed with CAS. CA 125 had the strongest correlations with D-dimer and CRP (ρ = 0.543, p < 0.001 and ρ = 0.452, p < 0.001, respectively). The areas under the receiver-operating characteristic curves for the diagnosis of CAS were 0.812 (95% CI 0.718-0.878) for CA 125, 0.714 (95% CI 0.602-0.801) for CEA, and 0.663 (95% CI 0.552-0.759) for CA 19-9. Multivariable analysis revealed that CA 125 levels in the highest quartile (OR 2.91, 95% CI 1.68-5.53), multiple lesions in multiple vascular territories observed on diffusion-weighted imaging, the absence of dyslipidemia, and the absence of atrial fibrillation were independently associated with CAS. Increased CA 125 levels, which indicate hypercoagulability, were useful for diagnosing CAS in AIS patients with active cancer.

Increased Serum Alkaline Phosphatase and Functional Outcome in Patients with Acute Ischemic Stroke Presenting a Low Ankle-Brachial Index.

AIMS: Elevated serum alkaline phosphatase (ALP) levels are associated with an increased risk of cerebrocardiovascular diseases. However, the associations of ALP with peripheral arterial disease (PAD) and outcomes in patients with acute ischemic stroke (AIS) are not well-known. METHODS: We examined the association between ALP levels and the ankle-brachial index (ABI) in 2111 consecutive patients with AIS. A poor functional outcome was defined as a modified Rankin Scale (mRS) score of 3-6 at 3 months after stroke. A low ABI was defined as a value of ≤ 0.9. RESULTS: Of the total cohort, 482 patients (22.8%) had a low ABI. ALP levels were higher in patients with a low ABI than in those without (p＜0.001). The multivariable logistic analysis revealed that quartiles of ALP levels were significantly associated with a low ABI (odds ratio [OR]: 1.20, 95% confidence interval [CI]: 1.08-1.33). Of the 1322 patients with a premorbid mRS score of 0-2, 434 patients (32.8%) had a poor outcome. The multivariable analysis revealed that elevated serum ALP levels and a low ABI were independently associated with poor stroke outcomes after adjustment for baseline characteristics (OR: 1.21, 95% CI: 1.07-1.38, and OR: 2.00, 95% CI: 1.40-2.84, respectively). CONCLUSIONS: Increased serum ALP levels are significantly associated with a low ABI. These indicators are independent prognostic factors for poor stroke outcomes at 3 months.

Short-term or long-term outcomes for stroke patients with cancer according to biological markers.

BACKGROUND: Although hypercoagulability using D-dimer levels may be a useful marker for predicting outcomes in ischemic stroke patients with cancer, other biological markers for predicting outcomes are unclear. We aimed to investigate the associations between several biological markers and short-term or long-term outcomes among ischemic stroke patients with cancer. METHODS: Consecutive acute ischemic stroke patients with cancer (n = 309) were registered. Biological markers such as hemoglobin, albumin, C-reactive protein and D-dimer levels were assessed. Stroke outcomes, namely, a 3-month modified Rankin Scale score indicating poor functional outcome (mRS score of 3-6) and 1-year survival, were assessed. RESULTS: Of the 277 patients who could be assessed for 3 months outcome, 131 patients (47.3%) had a poor outcome at 3 months. Multivariable analysis revealed that increased D-dimer levels and decreased albumin levels were independently associated with poor stroke outcomes (adjusted odds ratio [aOR]: 1.04, 95% confidence interval [CI]: 1.00-1.08, and aOR: 0.50, 95% CI: 0.31-0.80, respectively). Of 309 patients, 70 patients (22.7%) died during the follow-up period (median, 241 days). Multivariate Cox proportional hazard analyses showed that high D-dimer levels and hypoalbuminemia were independently associated with mortality (adjusted hazard ratio [aHR]: 2.65, 95% CI: 1.37-5.12, and aHR: 2.29, 95% CI: 1.21-4.49, respectively). The effect of each biological marker on mortality was notably observed among patients with active cancer but not among those with nonactive cancer. CONCLUSION: Low albumin levels were independently associated with short- and long-term outcomes, as were D-dimer levels, in acute ischemic stroke patients with cancer.

Efficacy and Safety of Ultrahigh-Dose Methylcobalamin in Early-Stage Amyotrophic Lateral Sclerosis: A Randomized Clinical Trial.

Importance: The effectiveness of currently approved drugs for amyotrophic lateral sclerosis (ALS) is restricted; there is a need to develop further treatments. Initial studies have shown ultrahigh-dose methylcobalamin to be a promising agent. Objective: To validate the efficacy and safety of ultrahigh-dose methylcobalamin for patients with ALS enrolled within 1 year of onset. Design, Setting, and Participants: This was a multicenter, placebo-controlled, double-blind, randomized phase 3 clinical trial with a 12-week observation and 16-week randomized period, conducted from October 17, 2017, to September 30, 2019. Patients were recruited from 25 neurology centers in Japan; those with ALS diagnosed within 1 year of onset by the updated Awaji criteria were initially enrolled. Of those, patients fulfilling the following criteria after 12-week observation were eligible for randomization: 1- or 2-point decrease in the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) total score, a percent forced vital capacity greater than 60%, no history of noninvasive respiratory support and tracheostomy, and being ambulatory. The target participant number was 64 in both the methylcobalamin and placebo groups. Patients were randomly assigned through an electronic web-response system to methylcobalamin or placebo. Interventions: Intramuscular injection of methylcobalamin (50-mg dose) or placebo twice weekly for 16 weeks. Main Outcomes and Measures: The primary end point was change in ALSFRS-R total score from baseline to week 16 in the full analysis set. Results: A total of 130 patients (mean [SD] age, 61.0 [11.7] years; 74 men [56.9%]) were randomly assigned to methylcobalamin or placebo (65 each). A total of 129 patients were eligible for the full analysis set, and 126 completed the double-blind stage. Of these, 124 patients proceeded to the open-label extended period. The least square means difference in ALSFRS-R total score at week 16 of the randomized period was 1.97 points greater with methylcobalamin than placebo (-2.66 vs -4.63; 95% CI, 0.44-3.50; P = .01). The incidence of adverse events was similar between the 2 groups. Conclusions and Relevance: Results of this randomized clinical trial showed that ultrahigh-dose methylcobalamin was efficacious in slowing functional decline in patients with early-stage ALS and with moderate progression rate and was safe to use during the 16-week treatment period. Trial Registration: ClinicalTrials.gov Identifier: NCT03548311.

Increased blood pressure variability during the subacute phase in patients with ischemic stroke presenting with a low ankle-brachial index.

AIM: This study aimed to evaluate the associations of blood pressure (BP) variability in patients with ischemic stroke during the subacute phase using ambulatory blood pressure monitoring and the ankle-brachial index (ABI). METHODS: We retrospectively examined 831 consecutive patients (women 44.8%, mean age 76 ± 12 years) with acute ischemic stroke who underwent 24-h ambulatory blood pressure monitoring during the subacute phase of stroke (median 9 days from onset) and an ABI examination. BP variability was evaluated by assessing the standard deviation and coefficient of variation of systolic BP and diastolic BP. A low ABI was defined as an ABI <0.9. RESULTS: Of the 831 patients, 201 (24.2%) had a low ABI. Older age, lower body mass index, diabetes mellitus, chronic kidney disease, atrial fibrillation and a higher National Institutes of Health Stroke Scale score at admission were independently associated with a low ABI. The patients with a low ABI had a higher mean 24-h diastolic BP, higher standard deviation of both BP measurements (systolic BP and diastolic BP) and a higher coefficient of variation in both BP measurements than those with a higher ABI. According to the multivariable linear regression analysis, a low ABI was independently associated with increased BP variability (a high standard deviation or coefficient of variation of both BP measurements) after adjusting for baseline confounders. CONCLUSIONS: A low ABI was associated with increased BP variability during the subacute ischemic phase. Geriatr Gerontol Int 2020; 20: 448-454.

Increased blood pressure variability during the subacute phase of ischemic stroke is associated with poor functional outcomes at 3 months.

Thus far, it is well known that increased blood pressure variability may exacerbate stroke outcomes. Blood pressure in the acute phase would be influenced by both reactive hypertension to stroke and intrinsic blood pressure reactivity. Thus, we aimed to evaluate the association between blood pressure variability and outcomes at 3 months using ambulatory blood pressure monitoring in ischemic stroke patients in the subacute phase after reactive hypertension subsided. We retrospectively examined 626 consecutive patients with acute ischemic stroke who underwent 24-hour ambulatory blood pressure monitoring during the subacute phase of stroke (median, 9 days from onset). The variability in blood pressure was evaluated by assessing the standard deviation and coefficient of variation of systolic and diastolic blood pressure. The primary outcome was functional status at 3 months. A poor outcome was defined as a modified Rankin scale score of 3 or more and a good outcome as 2 or less. We assessed the functional outcome at 3 months in 497 patients (79.4%). The mean systolic and diastolic blood pressure levels were not associated with functional outcome. The multivariable analysis revealed that increases in the standard deviations of systolic and diastolic blood pressure, coefficient of variation of diastolic blood pressure, and morning blood pressure surge were associated with poor outcome. Blood pressure variability during the subacute phase of ischemic stroke can be a useful prognostic indicator of poor functional outcome at 3 months in patients with acute ischemic stroke.

Prognostic role of the controlling nutritional status score in acute ischemic stroke among stroke subtypes.

INTRODUCTION: The association of malnutrition on stroke subtypes has not been well established. We investigated the relationship between malnutrition and functional outcome according to stroke subtypes. METHODS: Acute consecutive ischemic stroke patients (n = 1915, 73 ± 12 years) were analysed. The nutritional status was evaluated using the Controlling Nutritional Status (CONUT) score, which was calculated from the serum albumin level, lymphocyte count, and total cholesterol level; malnutrition was defined as a CONUT score of 5 to 12. A poor outcome was defined as a modified Rankin Scale score ≥ 3 at 3 months. RESULTS: Of the 1518 patients, 113 (7.4%) had malnutrition, and 533 (33.1%) had a poor outcome. Among the patients with cardioembolic stroke and stroke of other etiologies, those with malnutrition had higher rates of poor outcomes than those without. After adjusting for age, sex, and baseline stroke severity, malnutrition was independently associated with poor outcomes in patients with cardioembolic stroke and other stroke etiologies (odds ratio 3.25, 95% confidence interval 1.02-10.4, p = .044; 6.22, 2.71-14.3, p < .001, respectively). CONCLUSIONS: Considering stroke subtype, malnutrition determined using the CONUT score was independently associated with poor outcomes in the patients with cardioembolic stroke or stroke of other etiologies.

Effects of vascular compression on the rostral ventrolateral medulla for blood pressure variability in stroke patients.

BACKGROUNDS: Vascular compression of the rostral ventrolateral medulla (RVLM) has been associated with hypertension or blood pressure (BP) variability. For acute ischemic stroke patients, increased BP variability may cause poor functional outcomes. We tested the hypothesis that RVLM compression was associated with increased BP variability or stroke outcome in acute ischemic stroke patients. METHODS: Acute ischemic stroke patients (n = 622) with 24-h ambulatory BP monitoring during the subacute phase of stroke (median 9 days from onset) were retrospectively studied. Variability in BP was evaluated with the SD and coefficient of variation of SBP and DBP. The morning surge was also evaluated. The presence of RVLM compression was evaluated using time-of-flight three-dimensional MRI. A poor outcome was defined as a modified Rankin Scale score of 3-6 at 3 months. RESULTS: Patients with RVLM compression (n = 213) had significantly higher 24-h SBP mean, 24-h SBP SD, 24-h SBP coefficient of variation, 24-h DBP mean, 24-h DBP SD, and 24-h DBP coefficient of variation values and a higher prevalence of morning surge than those without (n = 409). Multiple regression analysis revealed that RVLM compression was associated with increased SBP variability, DBP variability, and morning surge. Despite the significant association between RVLM compression and BP variability, RVLM compression was not associated with poor stroke outcome. CONCLUSION: Although RVLM compression was closely associated with BP variability in the subacute ischemic stroke phase, an effect of RVLM compression on stroke outcome was not observed.

HTRA1-Related Cerebral Small Vessel Disease: A Review of the Literature.

Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is clinically characterized by early-onset dementia, stroke, spondylosis deformans, and alopecia. In CARASIL cases, brain magnetic resonance imaging reveals severe white matter hyperintensities (WMHs), lacunar infarctions, and microbleeds. CARASIL is caused by a homozygous mutation in high-temperature requirement A serine peptidase 1 (HTRA1). Recently, it was reported that several heterozygous mutations in HTRA1 also cause cerebral small vessel disease (CSVD). Although patients with heterozygous HTRA1-related CSVD (symptomatic carriers) are reported to have a milder form of CARASIL, little is known about the clinical and genetic differences between the two diseases. Given this gap in the literature, we collected clinical information on HTRA1-related CSVD from a review of the literature to help clarify the differences between symptomatic carriers and CARASIL and the features of both diseases. Forty-six symptomatic carriers and 28 patients with CARASIL were investigated. Twenty-eight mutations in symptomatic carriers and 22 mutations in CARASIL were identified. Missense mutations in symptomatic carriers are more frequently identified in the linker or loop 3 (L3)/loop D (LD) domains, which are critical sites in activating protease activity. The ages at onset of neurological symptoms/signs were significantly higher in symptomatic carriers than in CARASIL, and the frequency of characteristic extraneurological findings and confluent WMHs were significantly higher in CARASIL than in symptomatic carriers. As previously reported, heterozygous HTRA1-related CSVD has a milder clinical presentation of CARASIL. It seems that haploinsufficiency can cause CSVD among symptomatic carriers according to the several patients with heterozygous nonsense/frameshift mutations. However, the differing locations of mutations found in the two diseases indicate that distinct molecular mechanisms influence the development of CSVD in patients with HTRA1-related CSVD. These findings further support continued careful examination of the pathogenicity of mutations located outside the linker or LD/L3 domain in symptomatic carriers.

[A rare case of Streptococcus salivarius meningitis in elderly].

An 80-year-old man who had chronic heart failure and atrial fibrillation was refered to our hospital because of acute onset of fever and consciousness disturbance. Neurological examinations revealed deteriorated consciousness, nuchal rigidity and Kernig's sign. A lumber puncture yielded clouded fluid with a WBC 11,200/µl (polynuclear cell 94%), 758 mg/dl of protein, 1 mg/dl of glucose, 0.007 of cerebrospinal fluid-blood glucose ratio and Gram positive cocci. Diffusion-weighted images on brain MRI showed no signal intensity in bilateral ventricles at admission. He was treated with ceftriaxon, vancomycin and ampicillin. Streptococcus salivarius (S. salivarius) was isolated from blood and cerebrospinal fluid. He responded promptly to antibiotics therapy, and within 5 days, he became lucid and afebrile. S. salivarius was sensitive for ceftriaxone, vancomycin and ampicillin. After Day 6, he was treated with ceftriaxone only. We diagnosed his condition as S. salivarius meningitis. He discharged from our hospital at Day 22. Many cases of S. salivarius meningitis were occurred in second and fifth decade. But elderly case was rare. Neurologist should consider that elderly case with bacterial meningitis was caused by S. salivarius.

[A rare case of Streptococcus agalactiae meningitis in previously healthy adult].

A 39-year-old previously healthy man was referred to our hospital because of acute onset of fever and consciousness disturbance. Neurological examinations revealed deteriorated consciousness, nuchal rigidity and Kernig's sign. A lumbar puncture yielded clouded fluid with a WBC 1,012/µl (polynuclear cell 96%), 147.3 mg/dl of protein, 44 mg/dl of glucose and Gram positive cocci. At first, he was treated with ceftriaxon and ampicillin. At Day 2, meropenem was added. Streptococcus agalactiae was isolated from blood and cerebrospinal fluid. He responded promptly to antimicrobial therapy, and within 2 days, he became lucid and afebrile. S. agalactiae was sensitive to ceftriaxone, ampicillin and meropenem. After Day 3, he was treated with meropenem only. We diagnosed his condition as S. agalactiae meningitis and was discharged from our hospital at Day 18. Many cases of S. agalactiae meningitis are known to occur in neonates, pregnant women, elderly, and persons with underlying disease such as diabetes, malignant disorders, liver dysfunction. But cases occurring in a previously healthy adult are rare. Neurologists should be aware that S. agalactiae may be cause bacterial meningitis in a previously healthy adults.