Influence of Statin Pretreatment on Initial Neurological Severity and Short-Term Functional Outcome in Acute Ischemic Stroke Patients: The Fukuoka Stroke Registry.

BACKGROUND: Statins have neuroprotective effects against ischemic stroke. However, associations between pre-stroke statin treatment and initial stroke severity and between the treatment and functional outcome remain controversial. This study aimed at determining these associations in ischemic stroke patients. METHODS: Among patients registered in the Fukuoka Stroke Registry from June 2007 to October 2014, 3,848 patients with ischemic stroke within 24 h of onset, who had been functionally independent before onset, were enrolled in this study. Ischemic stroke was classified as cardioembolic or non-cardioembolic infarction. Primary and secondary study outcomes were mild neurological symptoms defined as a National Institutes of Health Stroke Scale score of ≤4 on admission and favorable functional outcome defined as a modified Rankin Scale score of ≤2 at discharge, respectively. Multivariable logistic regression models were used to quantify associations between pre-stroke statin treatment and study outcomes. RESULTS: Of all 3,848 participants, 697 (18.1%) were taking statins prior to the stroke. The frequency of mild neurological symptoms was significantly higher in patients with pre-stroke statin treatment (64.1%) than in those without the treatment (58.3%, p < 0.01). Multivariable analysis showed that pre-stroke statin treatment was significantly associated with mild neurological symptoms (OR 1.31; 95% CI 1.04-1.65; p < 0.01). Sensitivity analysis in patients with dyslipidemia (n = 1,998) also showed the same trend between pre-stroke statin treatment and mild neurological symptoms (multivariable-adjusted OR 1.26; 95% CI 0.99-1.62; p = 0.06). In contrast, the frequency of favorable functional outcome was not different between patients with (67.0%) and without (65.3%) the treatment (p = 0.40). Multivariable analysis also showed no significant association between pre-stroke statin treatment and favorable functional outcome (OR 1.21; 95% CI 0.91-1.60; p = 0.19). Continuation of statin treatment, however, was significantly associated with favorable functional outcome among patients with pre-stroke statin treatment (multivariable-adjusted OR 2.17; 95% CI 1.16-4.00; p = 0.02). CONCLUSIONS: Pre-stroke statin treatment in ischemic stroke patients was significantly associated with mild neurological symptoms within 24 h of onset. Pre-stroke statin treatment per se did not significantly influence the short-term functional outcome; however, continuation of statin treatment during the acute stage of stroke seems to relate with favorable functional outcome for patients with pre-stroke statin treatment.

Day-by-Day Blood Pressure Variability and Functional Outcome After Acute Ischemic Stroke: Fukuoka Stroke Registry.

BACKGROUND AND PURPOSE: The relationship between blood pressure (BP) variability and functional outcome in patients with acute ischemic stroke remains unclear. This study aimed to elucidate whether in-hospital day-by-day BP variability is associated with functional outcome after acute ischemic stroke. METHODS: Using the Fukuoka Stroke Registry, we included 2566 patients with a first-ever ischemic stroke who had been functionally independent before the onset and were hospitalized within 24 hours. BP was measured daily, and its variability was assessed by SD, coefficients of variance, and variations independent of mean. Poor functional outcome was assessed by modified Rankin Scale scores ≥3 at 3 months. RESULTS: After adjustment for multiple confounding factors including age, sex, risk factors, stroke features, baseline severity, thrombolytic therapy, antihypertensive agents, and mean BP, day-by-day BP variability during the subacute stage (4-10 days after onset) was independently associated with a poor functional outcome (multivariable-adjusted odds ratios [95% confidence interval] in the top versus bottom quartile of systolic BP variability, 1.51 [1.09-2.08] for SD; 1.63 [1.20-2.22] for coefficients of variance; 1.64 [1.21-2.24] for variations independent of mean). Similar trends were also observed for diastolic BP variability. These trends were unchanged in patients who were not treated with antihypertensive drugs. In contrast, no association was found between indices of BP variability during the acute stage and functional outcome after adjusting for potential confounders. CONCLUSIONS: These data suggest that intraindividual day-by-day BP variability during the subacute stage is associated with the 3-month functional outcome after acute ischemic stroke.

Neurosarcoidosis Presenting with Prominent Periventricular White-Matter Lesions during Steroid Treatment for Autoimmune Hepatitis.

A 63-year-old woman under treatment of autoimmune hepatitis presented with headache, memory loss, and somnolence. Three months before admission, the patient experienced liver inflammation relapse after prednisolone (PSL) cessation. Consequently, PSL was resumed and then tapered. Cerebrospinal fluid (CSF) examination showed lymphocytic pleocytosis with remarkably reduced glucose and elevated angiotensin-converting enzyme and soluble interleukin-2 receptor levels. Magnetic resonance imaging (MRI) revealed prominent bilateral periventricular white-matter lesions, hydrocephalus, ischemic stroke with gadolinium enhancement of frontoparietal and basilar meninges on contrast-enhanced fluid-attenuated inversion recovery. Magnetic resonance angiography (MRA) showed narrowing of the bilateral middle cerebral arteries. Based on these findings, we diagnosed the patient with neurosarcoidosis. Re-increment of PSL improved the neurological symptoms, CSF findings, and abnormalities found on MRI and MRA. This case suggests that neurosarcoidosis may occur as a complication of some autoimmune diseases during immunotherapy administration.

Epstein-Barr Virus-Associated Encephalopathy Presenting with Nonconvulsive Status Epilepticus in an Immunosuppressive State.

Epstein-Barr virus (EBV) infection is occasionally accompanied by central nervous system (CNS) complications, particularly in immunosuppressed patients. However, the symptoms and clinical features of EBV infection in the CNS are rather heterogeneous and remain unknown. We herein describe the first reported adult case manifesting nonconvulsive status epilepticus (NCSE), possibly associated with reactivation of EBV in an immunosuppressive state. A 63-year-old man with a history of acute myeloid leukemia and taking immunosuppressants was admitted due to progressively impaired consciousness without any focal neurological signs, including paralysis or convulsions. Arterial spin labeling magnetic resonance imaging (ASL-MRI) and brain perfusion single-photon emission computed tomography showed hyperperfusion in the right temporal region, despite no morphological abnormalities in other MRI sequences. White blood cell counts, EBV viral load, and virus-capsid antigen IgG in cerebrospinal fluid were elevated. We diagnosed him with EBV-associated encephalopathy presenting with NCSE. Administration of levetiracetam, an antiepileptic, improved the consciousness and the abnormal hyperperfusion. This case suggests a new concept of EBV-associated encephalopathy leading to epilepsy, particularly in immunosuppressed patients.

[A case of recurrent transient global amnesia showing different symptom duration and MRI findings].

A 66-year-old man was admitted to our department with anterograde amnesia. He was diagnosed with transient global amnesia (TGA) because of the symptom lasting for several hours and no abnormal findings on MRI and EEG. About a year after the episode, he recurred amnesia lasting only for 20 minutes. MRI diffusion weighted image (DWI) revealed a small hyperintense signal in the right hippocampus, while there was no abnormality on EEG. We diagnosed him with recurrent TGA. This case may be interesting in that symptom duration and MRI-DWI finding are much different between two attacks of TGA.

Polymorphisms in the lymphotoxin alpha gene and the risk of ischemic stroke in the Japanese population. The Fukuoka Stroke Registry and the Hisayama Study.

BACKGROUND AND PURPOSE: Lymphotoxin alpha (LTA), one of the tumor necrosis factor family proteins, is an important proinflammatory cytokine and appears to play a putative role in the inflammatory process of atherosclerosis. Recent genetic studies have suggested that variations in the gene encoding LTA, which affect its expression and biological function, may contribute to the development of vascular diseases. We conducted a case-control study to clarify the association of LTA gene polymorphisms with ischemic stroke in a large Japanese population. METHODS: Genotyping for LTA A252G and C804A polymorphisms was achieved by a rapid-cycle polymerase chain reaction and melting curve analysis using fluorescent probes in 1,044 incident cases of ischemic stroke recruited from the Fukuoka Stroke Registry and 1,044 age- and sex-matched control subjects recruited from the Hisayama Study. RESULTS: The overall distribution of allele and genotype for each polymorphism was similar between stroke patients and control subjects. The allele frequencies of 252G and 804A were slightly lower in stroke patients than in control subjects; however, conditional logistic regression analysis adjusted for potential risk factors found no association between the risk of ischemic stroke and either polymorphism. In terms of stroke subtype, we also found no association of these polymorphisms with any subtypes of ischemic stroke. CONCLUSIONS: Neither the A252G nor C804A polymorphism of the LTA gene was associated with stroke overall and any subtypes of ischemic stroke in the Japanese population.

A case of hearing loss and quadriplegia after a pontine hemorrhage.

We herein describe the case of a 50-year-old female who developed a pontine hemorrhage with consciousness disturbance and quadriplegia. Her respiratory condition was so bad that she needed to be intubated and put on artificial respiration. After her consciousness and respiratory condition gradually recovered, we noticed that she had developed a bilateral hearing loss. The auditory brain stem response test revealed only I waves on both sides, thus suggesting that her hearing loss had been caused by an injury to the hearing-conducting pathway including the cochlear nuclei. In this case, the hematoma extended from the lower to the upper part of pons and, furthermore, it was also located broadly in the dorsal part of the pons. As a result, the cochlear nuclei and corpus trapezoideum appeared to have been destroyed by the hematoma. However, since most cases with a brain stem hemorrhage showing bilateral hearing loss tend to be in a severe condition, this condition is often easy to overlook. We should therefore carefully evaluate patients' reaction to hearing stimulation to avoid overlooking any hearing loss in such patients.

Cardiovascular events occur independently of high on-aspirin platelet reactivity and residual COX-1 activity in stable cardiovascular patients.

Several studies have indicated that approximately 25 % of patients treated with aspirin exhibit high on-treatment platelet reactivity (HTPR), which is potentially associated with cardiovascular events (CVEs). However, this association is still controversial, since the mechanisms by which HTPR contributes to CVEs remain unclear and a no standardised definition of HTPR has been established. To determine whether HTPR is associated with CVE recurrence and what type of assay would best predict CVE recurrence, we conducted a multicentre prospective cohort study of 592 stable cardiovascular outpatients treated with aspirin monotherapy for secondary prevention. Their HTPR was determined by arachidonic acid- or collagen-induced aggregation assays using two different agonist concentrations. Residual cyclooxygenase (COX)-1 activity was assessed by measuring serum thromboxane (TX)B2 or urinary 11-dehydro TXB2. Shear-induced platelet thrombus formation was also examined. We followed all patients for two years to evaluate how these seven indexes were related to the recurrence of CVEs (cerebral infarction, transient ischaemic attack, myocardial infarction, unstable angina, revascularisation, other arterial thrombosis, or cardiovascular death). Of 583 patients eligible for the analysis, CVEs occurred in 69 (11.8 %). A Cox regression model identified several classical risk factors associated with CVEs. However, neither HTPR nor high residual COX-1 activity was significantly associated with CVEs, even by applying cut-off values suggested in previous reports or a receiver-operating characteristic analysis. In conclusion, recurrence of CVEs occurred independently of HTPR and residual COX-1 activity. Thus, our findings do not support the use of platelet or COX-1 functional testing for predicting clinical outcomes in stable cardiovascular patients.

[A case of cardioembolic brain infarction in arrhythmogenic right ventricular dysplasia].

We report a 45-year-old woman with arrhythmogenic right ventricular dysplasia (ARVD). Because of congestive heart failure and atrial fibrillation, she underwent tricuspid valvular replacement and warfarin was prescribed. She suddenly had dysarthria, left hemiparesis and left hemispatial neglect. After brain CT examination, and cerebral angiography, she was diagnosed as cardiogenic brain embolism and infusion of low molecular heparin was started. On day 25, she suddenly had ventricular tachycardia and died in spite of treatment for arrhythmia. This is the first report of the case of cardiogenic brain embolism following ARVD. In this type of case, we must take care of arrhythmia besides the management of atrial fibrillation and brain infarction.

Effects of hydrochlorothiazide on oxidative stress and pulse pressure in hypertensive patients with chronic stroke: the EMINENT study.

OBJECTIVE: Thiazide diuretics are reported to have antioxidant effects and reduce pulse pressure (PP). The aim of this study was to elucidate whether hydrochlorothiazide additionally exerts such effects in stroke patients under treatment with losartan. METHODS: This study was an open-label, randomized, multicenter study. Patients with a history of chronic stroke and treatment with angiotensin receptor blockers or angiotensin-converting enzyme inhibitors for essential hypertension were enrolled. Fifty-five hypertensive patients were randomly assigned to two groups: those further treated with hydrochlorothiazide and those further treated with non-diuretic antihypertensive drugs. RESULTS: Both groups showed a significant decrease in PP over six months (hydrochlorothiazide group: 67±12 mmHg to 58±12, p<0.001; non-diuretic group: 72±12 to 61±12, p<0.001), although no significant differences were observed between the two groups. The malondialdehyde-modified low-density lipoprotein levels did not change significantly after treatment in either group. CONCLUSION: In this study, hydrochlorothiazide treatment did not provide any additional benefits over non-diuretic antihypertensive drugs in terms of antioxidant effects or reducing PP.

Elafin, a secretory protein, is cross-linked into the cornified cell envelopes from the inside of psoriatic keratinocytes.

Elafin is a serine proteinase inhibitor highly expressed in psoriatic epidermal keratinocytes, but expressed scarcely, if at all, in normal skin. In addition to the proteinase inhibiting domain, elafin contains multiple transglutaminase substrate domains and has been identified as a constituent of the epidermal cornified cell envelope. It also contains a signal peptide sequence, and previous immunoelectron microscopy studies detected elafin in lamellar granules and also in the intercellular spaces. It has not been explained, however, how and when elafin molecules stored in the granules are cross-linked into the cell envelope. In order to elucidate this issue, we performed pre-embedding and postembedding immunoelectron microscopy of elafin and involucrin, another cell envelope constituent, using psoriatic epidermis. Postembedding double immunoelectron microscopy revealed that elafin was within the secretory (lamellar) granules and released into the intercellular spaces when the cell envelope was not formed. In the cells with involucrin-positive cell envelope, elafin immunolabels were localized diffusely within the cells and also along the cell envelope. Pre-embedding immunoelectron microscopy of purified cell envelope from psoriatic scale samples detected involucrin and elafin colocalizing on the cytoplasmic side of the cell envelope. These findings strongly suggest that elafin-containing granules are disintegrated upon the initiation of cell envelope formation, and that elafin is cross-linked on to the involucrin-positive cell envelope from the inside of keratinocytes. It seems that psoriatic keratinocytes utilize elafin as a major component of the cell envelope, consistent with the previously proposed "precursor availability hypothesis".

Gene transfer of extracellular superoxide dismutase reduces cerebral vasospasm after subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: Superoxide may play an important role in cerebral vasospasm after subarachnoid hemorrhage (SAH). Our first goal was to determine the effect of gene transfer of extracellular superoxide dismutase (ECSOD) on vasospasm after experimental SAH. Our second goal was to determine whether tissue binding of ECSOD via the heparin-binding domain (HBD) is important for the effect of the enzyme. Thus, we examined effects of gene transfer of ECSOD with the HBD deleted (ECSODDeltaHBD). METHODS: Adenovirus expressing human ECSOD (AdECSOD), ECSODDeltaHBD (AdECSODDeltaHBD), or no transgene (AdBglII) was injected into the cisterna magna of anesthetized rabbits 30 minutes after induction of experimental SAH. Cerebral angiography, an assay for ECSOD activity in cerebrospinal fluid (CSF), and Western blotting for human ECSOD in the basilar artery were performed. RESULTS: Baseline diameter of the basilar artery averaged 0.77+/-0.01 mm (mean+/-SEM) and was similar in all treatment groups. Decreases in diameter of the basilar artery 2 days after SAH were smaller after AdECSOD (11+/-3%; n=10) than after AdBglII (25+/-4%; n=7; P<0.05). ECSOD activity was not detected in CSF before SAH and gene transfer. Of 8 rabbits treated with AdECSOD, in which ECSOD activity in CSF was measured after SAH, 5 animals had detectable ECSOD activity in CSF (46+/-13 U/mL). In these 5 rabbits, the diameter decreased by only 6+/-3%, and ECSOD protein was detected in the basilar artery. After AdECSODDeltaHBD (n=4), despite high levels of ECSOD activity in CSF (91+/-19 U/mL), vessel diameter decreased by 20+/-2%, and no ECSODDeltaHBD protein was detected in the basilar artery. CONCLUSIONS: Gene transfer of ECSOD reduces cerebral vasospasm after experimental SAH. Tissue binding of the enzyme is essential for cerebral vascular effects of ECSOD.

Application and limitations of three-dimensional reconstruction of the epidermal-dermal junction using electron microscopy.

BACKGROUND: Anchoring fibrils were initially described as the arch-like structures that extend from the lamina densa to the sub-lamina densa. Keene et al. proposed a model in which the anchoring fibrils bridge structures called "anchoring plaques", and thus the three-dimensional (3D) structure of the anchoring fibrils remains somewhat controversial. OBJECTIVE: The aim of this study is to elucidate the 3D structure of anchoring fibrils in the skin. METHODS: In the present study, we performed electron microscopic 3D reconstruction of the epidermal-dermal junction, including the anchoring fibrils and hemidesmosomes using a personal computer and NIH-image software. RESULTS: We obtained images showing that anchoring fibrils had both ends inserted into the lamina densa and that interstitial dermal collagen fibers passed through the loops of the anchoring fibrils. "Anchoring plaques" were not observed. Clear images of hemidesmosomal distribution were not obtained due to technical limitations. CONCLUSION: These results suggest that the loops of the anchoring fibrils are the most important primary structures that hold the dermal interstitial collagen fibers and bind the basement membrane to the dermis.

Free radical scavenger, edaravone, in stroke with internal carotid artery occlusion.

BACKGROUND: Edaravone has potent free radical quenching and antioxidant actions. The agent has been recently in commercial use for acute ischemic stroke patients. In this study, we investigated the therapeutic effect of edaravone on severe carotid-territorial stroke. METHODS: Stroke patients with internal carotid artery occlusion and baseline NIH Stroke Scale Score > or =15 were treated for 14 days with drip intravenous infusion of edaravone (n=30) and were compared with a historical control cohort of similar patients (n=31). Glycerol was also administered to all patients in both groups. RESULTS: Infarct volume (P<0.02) and midline shift (P<0.02) on CT performed on day 2 of the patients treated with edaravone were smaller than those without edaravone. For patients with edaravone, infarct volume (P<0.0001) and midline shift (P<0.0001) on days 5-7 were greater than those on day 2. Hemorrhagic transformation of infarcts on day 2 was less severe in patients with than without edaravone (P<0.03). Within 14 days after the onset of stroke, 6 patients with edaravone (20%) and 14 without edaravone (45%) died directly of stroke (P<0.03). Among all patients, only two treated with edaravone were independent without any assistance 8 weeks after the onset. CONCLUSIONS: Edaravone was associated with delayed evolution of infarcts and edema in patients with severe carotid-territorial stroke and decreased mortality during the acute stage. The agent, however, failed to prevent evolution of infarcts and edema on later days, and did not significantly improve functional outcome among the surviving patients.

High blood pressure after acute ischemic stroke is associated with poor clinical outcomes: Fukuoka Stroke Registry.

The relationship between the poststroke blood pressure (BP) and functional outcomes in patients with acute ischemic stroke is still controversial. The aim of the present study was to elucidate the impact of the poststroke BP on the clinical outcomes of acute ischemic stroke. Among the patients in the Fukuoka Stroke Registry, 1874 patients with first-ever acute ischemic stroke (within 24 hours of onset) who had been functionally independent before onset were prospectively enrolled in the present study. The poststroke BP levels were defined as the average values during the 48 hours after onset. The study outcomes were a good neurological recovery, neurological deterioration, and a poor functional outcome. The higher poststroke BP levels were significantly associated with a lower probability of a good neurological recovery and elevated risks of neurological deterioration and a poor functional outcome after adjusting for potential confounding factors. The multivariate-adjusted odds ratios (95% confidence interval) in the highest quintile of systolic BP (versus the lowest quintile as a reference) were 0.51 (0.37-0.71) for a good neurological recovery, 1.92 (1.15-3.27) for neurological deterioration, and 2.51 (1.69-3.74) for a poor functional outcome. Similar associations were observed when we applied the poststroke diastolic BP or pulse pressure. No evidence of the J-curve phenomenon was observed for each association. These results suggest that a high poststroke BP was significantly associated with unfavorable clinical outcomes in patients with acute ischemic stroke. There was no evidence of the J-curve phenomenon between the poststroke BP levels and the clinical outcomes.

Flow volume and cross-sectional area of the extracranial vertebral arteries and its relation to vascular lesions or anatomical variations in the posterior circulation.

We examined whether the time-averaged maximum velocity (TAMV), flow volume (FV) or cross-sectional area (CA) in the vertebral arteries (VA) as determined by ultrasonography was related to vascular lesions or variations in the intracranial part of the posterior circulation. Three hundred nine patients without severe stenosis in the carotid circulation (159 males, 150 females, mean age of 69.1 years) underwent both colour duplex ultrasonography and magnetic resonance angiography (MRA) and were thus analyzed. According to the MRA findings, the patients were divided as follows; 22 patients with severe stenosis in the bilateral PCA or VA or basilar artery (V group) and 287 patients without (N group). The N group was then further divided as follows; 144 patients with no (P0 group); 89 with one (P1) and 54 with both posterior communicating arteries (P2) detected on MRA. TAMV, FV and CA were compared among these groups. Both TAMV and FV of V group were significantly lower than those of N group (35.3 vs. 42.6 cm/sec in TAMV, 98.2 vs. 135.3 mL/min in FV, p < 0.001 and 0.0001, respectively). The FVs and CAs in the P0 through P2 groups were all significantly different according to the number of posterior communicating arteries (149.3 vs. 128.0 vs. 109.8 mL/min, 22.5 vs. 20.2 vs. 16.5 mm2, both p < 0.001) while TAMVs in these groups did not differ substantially. The FV in both VAs were thus found to be related to the vascular lesions or variations in the posterior circulation.

Eccrine squamous syringometaplasia and syringomatous hyperplasia in association with linear scleroderma.

It is now well recognized that syringomatous hyperplasia with squamous syringometaplasia is a type of pseudoepitheliomatous hyperplasia responding to a variety of stimuli. We report a case of linear scleroderma with this process. Histopathology of the lesion showed numerous solid and cystic epithelial structures with squamous metaplasia within typical sclerodermatous skin lesions. Although the pathogenesis of the process remains unclear, dermal-derived growth factors in scleroderma and/or the mechanical effect of sclerosis could stimulate the proliferative response of eccrine epithelium. To the best of our knowledge, the association of syringomatous hyperplasia with eccrine squamous syringometaplasia and linear scleroderma has not been described previously.