Reduction of intracerebral hemorrhage by rivaroxaban after tPA thrombolysis is associated with downregulation of PAR-1 and PAR-2.

This study aimed to assess the risk of intracerebral hemorrhage (ICH) after tissue-type plasminogen activator (tPA) treatment in rivaroxaban compared with warfarin-pretreated male Wistar rat brain after ischemia in relation to activation profiles of protease-activated receptor-1, -2, -3, and -4 (PAR-1, -2, -3, and -4). After pretreatment with warfarin (0.2 mg/kg/day), low-dose rivaroxaban (60 mg/kg/day), high-dose rivaroxaban (120 mg/kg/day), or vehicle for 14 days, transient middle cerebral artery occlusion was induced for 90 min, followed by reperfusion with tPA (10 mg/kg/10 ml). Infarct volume, hemorrhagic volume, immunoglobulin G leakage, and blood parameters were examined. Twenty-four hours after reperfusion, immunohistochemistry for PARs was performed in brain sections. ICH volume was increased in the warfarin-pretreated group compared with the rivaroxaban-treated group. PAR-1, -2, -3, and -4 were widely expressed in the normal brain, and their levels were increased in the ischemic brain, especially in the peri-ischemic lesion. Warfarin pretreatment enhanced the expression of PAR-1 and PAR-2 in the peri-ischemic lesion, whereas rivaroxaban pretreatment did not. The present study shows a lower risk of brain hemorrhage in rivaroxaban-pretreated compared with warfarin-pretreated rats following tPA administration to the ischemic brain. It is suggested that the relative downregulation of PAR-1 and PAR-2 by rivaroxaban compared with warfarin pretreatment might be partly involved in the mechanism of reduced hemorrhagic complications in patients receiving rivaroxaban in clinical trials. © 2016 Wiley Periodicals, Inc.

Effects of Pretreatment with Warfarin or Rivaroxaban on Neurovascular Unit Dissociation after Tissue Plasminogen Activator Thrombolysis in Ischemic Rat Brain.

BACKGROUND: Warfarin and rivaroxaban are highly effective in reducing stroke risk in patients with atrial fibrillation (AF). However, their effects on anticoagulation and neurovascular unit (NVU) change remain elusive. In this study, we assessed the risks and benefits of pre-treatment with warfarin or rivaroxaban after tissue-type plasminogen activator (tPA) thrombolysis in ischemic rat brain. METHODS: Pre-treatment with warfarin (.2 mg/kg/day), low dose rivaroxaban (60 mg/kg/day), high dose rivaroxaban (120 mg/kg/day) or vehicle was performed for 2 weeks, transient middle cerebral artery occlusion (tMCAO) was induced for 90 min, then followed by reperfusion with tPA. At 24 hours (h) after reperfusion, we observed the changes of matrix metalloproteinase-9 (MMP-9), tissue factor, caspase 3 and NVU dissociation. RESULTS: Prothrombin time (PT) was significantly prolonged in the warfarin and rivaroxaban pretreated groups. MMP-9 expression greatly increased in the warfarin group, and this was reduced in the rivaroxaban groups compared with the vehicle group. Tissue factor expression remarkably decreased in the warfarin and rivaroxaban groups. The number of caspase 3-positive cells had no difference among all the groups. Marked dissociations between astrocyte foot processes and the basal lamina or pericytes were observed in the warfarin pretreated group, but such dissociations were improved in the rivaroxaban groups. CONCLUSIONS: Our present study shows that pre-treatment with rivaroxaban was noninferior to warfarin in the anticoagulation, but a lower risk of NVU dysfunction and dissociation after tPA treatment in rivaroxaban. This finding could partly explain the mechanism of reducing hemorrhagic complications by rivaroxaban in clinical studies.

Phase II Trial of Intravenous Low-Dose Granulocyte Colony-Stimulating Factor in Acute Ischemic Stroke.

BACKGROUND: Granulocyte colony-stimulating factor (G-CSF) has shown neuroprotective and neurogenerative activities in experimental studies, and our previous phase I clinical study suggested the safety and potential efficacy of low-dose G-CSF in acute ischemic stroke patients. The present phase II trial is aimed to evaluate the effect of G-CSF administration on neurological function and infarct volume, compared with a placebo group. METHODS: Forty-nine acute ischemic stroke patients (29 males, 20 females; 71 ± 10 years) within 24 hours after onset were recruited. Eligible patients were randomized 2:2:1 to receive G-CSF 150 µg/body/day, G-CSF 300 µg/body/day, and placebo, respectively. We evaluated clinical outcome in terms of the National Institutes of Health Stroke Scale, the modified Rankin Scale, and the Barthel Index at 90 days after onset, together with changes in infarct volume on magnetic resonance imaging. RESULTS: We found no serious adverse event, including change in leukocyte levels, which remained below 31,000/µL, at 150 and 300 µg G-CSF/body/day. Clinical outcome scores did not show any significant difference among the 3 groups. Chronological changes in infarct volume also showed no significant difference. CONCLUSIONS: G-CSF was well-tolerated at 150 and 300 µg/body/day in patients with acute ischemic stroke. However, administration of G-CSF at both 150 and 300 µg/body/day neither contributed to functional recovery nor reduced infarct volume at 3 months after onset, compared with the control group. The apparent lack of effectiveness may have been due to the small sample size. A trial of combination therapy with recombinant tissue plasminogen activator and G-CSF is planned.

Neurovascular protection by telmisartan via reducing neuroinflammation in stroke-resistant spontaneously hypertensive rat brain after ischemic stroke.

Telmisartan is a highly lipid-soluble angiotensin receptor blocker (ARB), which improves insulin sensitivity and reduces triglyceride levels and, thus, is called metabo-sartan. We examined the effects of telmisartan on neurovascular unit (N-acetylglucosamine oligomer [NAGO], collagen IV, and glial fibrillary acidic protein [GFAP]) and neuroinflammation (matrix metalloproteinase-9 [MMP-9] and inflammasome) in brain of stroke-resistant spontaneously hypertensive rat (SHR-SR). At 12 weeks of age, SHR-SR received transient middle cerebral artery occlusion (tMCAO) for 90 minutes and were divided into the following 3 groups, that is, vehicle group, low-dose telmisartan group (.3 mg/kg/d), and high-dose telmisartan group (3 mg/kg/d, postoral). Immunohistologic analysis at ages 6, 12, and 18 months showed progressive decreases of NAGO-positive endothelium and collagen IV-positive basement membrane and progressive increases of MMP-9-positive neurons, GFAP-positive astrocytes, and NLRP3-positive inflammasome in the cerebral cortex of vehicle group. Low-dose telmisartan reduced such changes without lowering blood pressure (BP), and high-dose telmisartan further improved such changes with lowering BP. The present findings suggest that a persistent hypertension caused a long-lasting inflammation after tMCAO in SHR-SR, which accelerated neurovascular disruption and emergent inflammasome, and that telmisartan greatly reduced such inflammation and protected the neurovascular unit via its pleiotropic effects in living hypertensive rat brain after ischemic stroke.

High Incidence of Dementia Conversion than Stroke Recurrence in Poststroke Patients of Late Elder Society.

BACKGROUND: This study investigated the incidence of current poststroke dementia (PSD), the annual conversion ratio into PSD, and the risk factors for conversion. METHODS: In a 4.8-year follow-up period, 112 poststroke patients (ischemic stroke and intracerebral hemorrhage) were retrospectively investigated in cognitive examinations. They were categorized into 3 subgroups: converters into PSD, nonconverters who maintained their normal cognitive functions, and reverters who recovered to the normal mentality range. The clinical and demographic characteristics of these 3 subgroups were analyzed. RESULTS: Among all 112 poststroke patients (61.6% male, 73.6 ± 10.4 years old), 16.1% had PSD. During the follow-up period, a part of the normal baseline mentality group (83.9% of 112 original patients) newly developed PSD (subdivided into converters) with an annual conversion rate of 7.6%. The reversion rate from the baseline PSD group was 11.3%. There were significant differences in age (P < .05), baseline mini-mental state examination scores (P < .05), body mass index (P < .05), and periventricular and deep white matter hyperintensity grades (P < .05 and P = .01, respectively) between converters and nonconverters. The annual rate of stroke recurrence was only 2.2% in all stroke subtypes. CONCLUSIONS: In comparison with stroke recurrence (2.2%), 7.6% of the annual PSD conversion rate was very high. Therefore, prevention of direct conversion into PSD without stroke recurrence may be another important aspect of poststroke clinics, especially in late elder society.

Rivaroxaban and apixaban reduce hemorrhagic transformation after thrombolysis by protection of neurovascular unit in rat.

BACKGROUND AND PURPOSE: This study aimed to assess the risk and benefit of tissue-type plasminogen activator treatment after oral anticoagulation with rivaroxaban or apixaban compared with warfarin or placebo. METHODS: Pretreatment with warfarin (0.2 mg/kg per day), rivaroxaban (2 mg/kg per day), apixaban (10 mg/kg per day), or vehicle (0.5% carboxymethyl cellulose sodium salt) was performed for 7 days. Transient middle cerebral artery occlusion was then induced for 120 minutes, followed by reperfusion with tissue-type plasminogen activator (10 mg/kg per 10 mL). Clinical parameters, including cerebral infarction volume, hemorrhagic volume, and blood coagulation, were examined. Twenty-four hours after reperfusion, markers for the neurovascular unit at the peri-ischemic lesion were immunohistochemically examined in brain sections, and matrix metalloproteinase-9 activity was measured by zymography. RESULTS: The paraparesis score was significantly improved in the rivaroxaban-pretreated group compared with the warfarin-pretreated group. Intracerebral hemorrhage was observed in the warfarin-pretreated group, and this was reduced in the rivaroxaban and apixaban-pretreated groups compared with the vehicle group. Marked dissociation of astrocyte foot processes and the basal lamina or pericytes was observed in the warfarin-pretreated group, and this was improved in the rivaroxaban and apixaban-pretreated groups. Furthermore, activation of matrix metalloproteinase-9 in the ipsilateral warfarin-pretreated brain was greatly reduced in rivaroxaban- and apixaban-pretreated rats. CONCLUSIONS: This study shows a lower risk of intracerebral hemorrhage after tissue-type plasminogen activator treatment in rats with ischemic stroke that are pretreated with rivaroxaban and apixaban compared with pretreatment with warfarin. Reducing neurovascular dissociation by rivaroxaban and apixaban compared with warfarin could partly explain a reduction in hemorrhagic complications reported in clinical studies.

Reducing hemorrhagic complication by dabigatran via neurovascular protection after recanalization with tissue plasminogen activator in ischemic stroke of rat.

This study assesses the risks and benefits of tissue plasminogen activator (tPA) treatment under oral anticoagulation with dabigatran compared with warfarin or vehicle control in transient middle cerebral artery occlusion (tMCAO). After pretreatment with warfarin (0.2 mg/kg/day), dabigatran (20 mg/kg/day), or vehicle (0.5% carboxymethyl cellulose sodium salt) for 7 days, tMCAO was induced for 120 min, followed by reperfusion and tPA (10 mg/kg/10 ml). Clinical parameters, including cerebral infarction volume, hemorrhagic volume, and blood coagulation, were examined. At 24 hr after reperfusion, markers for the neurovascular unit at the peri-ischemic lesion were immunohistochemically examined in brain sections, and MMP-9 activity was measured by zymography. Paraparesis and intracerebral hemorrhage volume were significantly improved in the dabigatran-pretreated group compared with the warfarin-pretreated group. A marked dissociation between astrocyte foot processes and the basal lamina or pericyte was observed in the warfarin-pretreated group, which was greatly improved in the dabigatran-pretreated group. Furthermore, a remarkable activation of MMP-9 in the ipsilateral warfarin-pretreated rat brain was greatly reduced in dabigatran-pretreated rats. The present study reveals that the mechanism of intracerebral hemorrhage with warfarin-pretreatment plus tPA in ischemic stroke rats is the dissociation of the neurovascular unit, including the pericyte. Neurovascular protection by dabigatran, which was first shown in this study, could partially explain the reduction in hemorrhagic complication by dabigatran reported from clinical study.

Neurovascular protection of cilostazol in stroke-prone spontaneous hypertensive rats associated with angiogenesis and pericyte proliferation.

Stroke is the major cause of death and decrease in the activities of daily living. This study sought to evaluate the effects of commonly used antiplatelet drugs on spontaneous cerebral infarction in relation to neurovascular protection associated with angiogenesis and pericyte proliferation. Stroke-prone spontaneously hypertensive rats (SHR-SP) were treated with vehicle, aspirin, clopidogrel, or cilostazol from 8 to 10 weeks of age. The interaction of neurovascular components among endothelial cells, pericytes, and astrocytic endfeet were immunohistochemically examined in brain sections. Angiogenesis associated with vascular endothelial growth factor receptor 2 (VEGFR2) and pericyte proliferation were also examined immunohistochemically. The expression and activity of matrix metalloproteinase 9 (MMP-9) were assessed immunohistochemically and by gelatin zymography. Among the antiplatelet drugs, cilostazol preserved the neurovascular unit (NVU) by preventing astrocytic endfeet or pericytes from pathological detachment found in the vehicle and aspirin treatment. Cilostazol also inhibited the expression and activity of MMP-9, which led to protection of the NVU. Furthermore, in the periinfarct area, cilostazol increased VEGFR2 expression, promoting angiogenesis through proliferation of pericytes. The present study showed a strong protection of NVU integrity by cilostazol and the promotion of angiogenesis by stimulating both endothelial VEGFR2 expression and pericyte proliferation. In addition to the antioxidative effect, these pleiotropic effects of cilostazol contribute to reduce spontaneous infarct volume and preserve motor and cognitive function in SHR-SP.

Pericyte protection by edaravone after tissue plasminogen activator treatment in rat cerebral ischemia.

Pericytes play a pivotal role in contraction, mediating inflammation and regulation of blood flow in the brain. In this study, changes of pericytes in the neurovascular unit (NVU) were examined in relation to the effects of exogenous tissue plasminogen activator (tPA) and a free radical scavenger, edaravone. Immunohistochemistry and Western blot analyses showed that the overlap between platelet-derived growth factor receptor ß-positive pericytes and N-acetylglucosamine oligomers (NAGO)-positive endothelial cells increased significantly at 4 days after 90 min of transient middle cerebral artery occlusion (tMCAO). The number of pericytes and the overlap with NAGO decreased with tPA but recovered with edaravone 4 days after tMCAO with proliferation. Thus, tPA treatment damaged pericytes, resulting in the detachment from astrocytes and a decrease in glial cell line-derived neurotrophic factor secretion. However, treatment with edaravone greatly improved tPA-induced damage to pericytes. The present study demonstrates that exogenous tPA strongly damages pericytes and destroys the integrity of the NVU, but edaravone treatment can greatly ameliorate such damage after acute cerebral ischemia in rats.

Synergistic neuroprotective effects of combined treatment with olmesartan plus azelnidipine in stroke-prone spontaneously hypertensive rats.

An angiotensin 2 type 1 receptor blocker, olmesartan, and a calcium channel blocker, azelnidipine, possess not only an antihypertensive effect but also an antioxidative effect and other beneficial effects. In the present study, we examined the efficacy of olmesartan and azelnidipine monotherapy (2 mg/kg or 10 mg/kg each) and their combination therapy (1 mg/kg each) on stroke-prone spontaneously hypertensive rats (SHR-SP) in relation to oxidative stress, inflammation, and the neurovascular unit. In comparison with the vehicle group, body weight, regional cerebral blood flow, and motor function were preserved, whereas systolic blood pressure and diastolic blood pressure decreased in the five drug-treatment groups. Spontaneous infarct volume decreased with the low-dose combination of olmesartan plus azelnidipine and with the high-dose olmesartan, with a further decrease in the high-dose azelnidipine group. In addition, these drugs dose-dependently reduced oxidative stresses, proinflammatory molecules, and well-preserved components of the neurovascular unit. The low-dose combination of olmesartan plus azelnidipine showed a better effect than the low-dose olmesartan or azelnidipine monotherapy. The present study shows that the low-dose combination of olmesartan plus azelnidipine demonstrates a greater synergistic benefit than monotherapy with a low-dose of olmesartan or azelnidipine in SHR-SP for preventing spontaneous infarct volume, reducing oxidative stresses and proinflammatory molecules, and imparting neurovascular protection. In addition, a high-dose of olmesartan showed a greater benefit without the lowering of blood pressure, probably because of the antioxidative and anti-inflammatory effects. A high dose of azelnidipine showed the best benefit, probably because of the two effects mentioned above related to the lowering of blood pressure.

Long-term amelioration of telmisartan on metabolic syndrome-related molecules in stroke-resistant spontaneously hypertensive rat after transient middle cerebral artery occlusion.

Telmisartan is expected to ameliorate not only hypertension, but also metabolic syndrome as a metabosartan. We examined the effects of telmisartan on metabolic syndrome-related molecules such as insulin receptor (IR), peroxisome proliferator-activated receptor gamma (PPAR-γ), and angiotensin 2 type 1 receptor (AT1R) in stroke-resistant spontaneously hypertensive rat (SHR-SR) after transient middle cerebral artery occlusion (tMCAO), by administering telmisartan at either 0 (vehicle), .3 mg/kg/day (low dose), or 3 mg/kg/day (high dose), postoperatively, from 3 months of age and performed immunohistologic analysis at 6, 12, and 18 months of age. Compared with the vehicle group, the 2 telmisartan groups dose dependently decreased the number of IR- and AT1R-positive neurons in the cerebral cortex in the ipsilateral cerebral cortex from 6 to 18 months after tMCAO. On the other hand, the number of PPAR-γ-positive neurons increased in a dose-dependent manner in the 2 telmisartan groups from 6 to 18 months. The present study suggests that telmisartan dose-dependently ameliorated metabolic syndrome-related changes in the poststroke brain of SHR-SR with a direct protective effect (low dose) and an additive benefit, an antihypertensive effect at a high dose, for long-term protection after tMCAO.

Strong reduction of low-density lipoprotein receptor/apolipoprotein E expressions by telmisartan in cerebral cortex and hippocampus of stroke resistant spontaneously hypertensive rats.

BACKGROUND: Telmisartan is a unique angiotensin II type 1 receptor blocker with a partial peroxisome proliferator-activated receptor-γ (PPARγ) agonistic property to exert not only antihypertensive effect but also antimetabolic syndrome effect. METHODS: We examined the long-term effect of telmisartan on cholesterol transport-related proteins (low-density lipoprotein receptor [LDL-R]/apolipoprotein E [ApoE]) and microtubule-associated proteins 2 (MAP2) in the brains of stroke resistant spontaneously hypertensive rats (SHR-SRs), which were divided into 3 experiment groups including vehicle group (SHR/Ve), low-dose telmisartan group (SHR/Low, .3 mg/kg/day), and high-dose telmisartan group (SHR/High, 3 mg/kg/day). RESULTS: The numbers of LDL-R- and immuno-ApoE-positive neurons increased in both cerebral cortex and hippocampus of SHR/Ve throughout 6, 12, and 18 months of age, compared with age-matched normotensive Wistar rats. On the other hand, telmisartan significantly reduced the numbers of LDL-R- and ApoE immuno-positive neurons in both cerebral cortex and hippocampus, with similar effectiveness in the SHR/Low group without blood pressure (BP) lowering to BP lowering (SHR/High). The decrease of MAP2-positive neuron in SHR/Ve was recovered by telmisartan in both cerebral cortex and hippocampus. CONCLUSIONS: These findings suggest that a long-term treatment with telmisartan directly improved neuronal lipid metabolism in the cerebral cortex and hippocampus of SHR-SR, mainly improving LDL-R and ApoE metabolism (SHR/Low) with a small additive benefit by BP lowering (SHR/High), which could provide a preventative approach in patients with hypertension at risk of Alzheimer disease.

A novel useful tool of computerized touch panel-type screening test for evaluating cognitive function of chronic ischemic stroke patients.

Cognitive and affective impairments are important non-motor features of ischemic stroke (IS) related to white-matter hyperintensity, including periventricular hyperintensity (PVH). To confirm the usefulness of a novel computerized touch panel-type screening test, we investigated cognitive and affective functioning among 142 IS patients and 105 age-and gender-matched normal control subjects. Assessment using the mini-mental state examination, Hasegawa Dementia Scale-Revised, and frontal assessment battery revealed reduced cognitive function in IS patients, with the most severe reduction exhibited by cardiogenic embolism patients, followed by lacunar infarction patients, and atherothrombotic infarction patients. Our novel touch panel screening test revealed a similar pattern of results. In addition, PVH grading, classified using Fazekas' magnetic resonance imaging method, was also correlated with cognitive decline and touch panel screening test performance. In contrast, affective function, assessed with the 15-item Geriatric Depression Scale, vitality index, and apathy scale, was not significantly decreased in IS, and did not correlate with touch panel screening test results or PVH, although the number of microbleeds was correlated with apathy scale results. The present findings revealed that IS and PVH grading were significantly correlated with decline in general cognitive status (mini-mental state examination and Hasegawa Dementia Scale-Revised) and frontal lobe function (frontal assessment battery). Performance on all touch panel screening tests was correlated with IS and PVH grading, but was largely independent of depression or apathy. Touch panel screening tests were easily understood and performed by almost all patients with mild cognitive and motor dysfunction, due to visually clear images and simple methods not involving detailed manual-handling tasks such as writing. Touch panel screening tests may provide a useful tool for the early screening of cognitive function.

Intravenous thrombolysis with neuroprotective therapy by edaravone for ischemic stroke patients older than 80 years of age.

BACKGROUND: Alteplase, a recombinant tissue plasminogen activator (tPA), was approved for patients with acute ischemic stroke within 3 hours of stroke onset in Japan in October 2005 at a dose of 0.6 mg/kg. The aim of this study was to assess the safety and efficacy of alteplase in elderly patients in Japan. METHODS: One hundred twenty-nine consecutive patients who were admitted to our 5 hospital groups and who received intravenous tPA within 3 hours of stroke onset between January 2010 and December 2011 were divided into 2 groups by age (<80 years of age [younger group] and >80 years of age [older group]) and by treatment with or without edaravone. Clinical backgrounds and outcomes were investigated. RESULTS: The National Institutes of Health Stroke Scale score on admission was not different in both groups, but the National Institutes of Health Stroke Scale scores 7 days after stroke onset were significantly higher in the older group (score 8; P < .05) than in the younger group (score 4), and the ratio of patients with a modified Rankin Scale score of 4 to 6 was significantly greater in the older group (41.7%; P < .05) than in the younger group (22.2%). However, there was no difference in asymptomatic and symptomatic intracerebral hemorrhage rates between the younger and older groups (asymptomatic 20.2% v 18.8%; symptomatic 2.6% v 2.1%). Patients with edaravone showed a higher recanalization rate (61.9%; P < .01) and a better modified Rankin Scale score at 3 months poststroke (P < .01) than the nonedaravone group. CONCLUSIONS: These data suggest that intravenous alteplase (0.6 mg/kg) within 3 hours of stroke onset was safe and effective, even for very old patients (≥ 80 years of age), but resulted in poor outcomes relating not to tPA but to aging. In addition, edaravone may be a good partner for combination therapy with tPA to enhance recanalization and reduce hemorrhagic transformation.

Tissue plasminogen activator thrombolytic therapy for acute ischemic stroke in 4 hospital groups in Japan.

In October 2005 in Japan, the recombinant tissue plasminogen activator (tPA) alteplase was approved for patients with acute ischemic stroke within 3 hours of onset at a dose of 0.6 mg/kg. The present study was undertaken to assess the safety and efficacy of alteplase in Japan. Between October 2005 and December 2009, a total of 114 consecutive patients admitted to 4 hospitals received intravenous tPA within 3 hours of stroke onset. Clinical backgrounds and outcomes were investigated. The patients were divided into 2 chronological groups: an early group, comprising 45 patients treated between October 2005 and December 2007, and a later group, comprising 69 patients treated between January 2008 and December 2009. The mean time from arrival at the hospital to the initiation of treatment was significantly reduced in the later group, from 82.6 minutes to 70.9 minutes. Intracerebral hemorrhage (ICH) occurred in 26 patients (22.8%); compared with patients without ICH, these patients had a significantly higher prevalence of cardiogenic embolism (88.5% vs 58.0%); greater warfarin use (26.8% vs 6.8%); higher mean National Institutes of Health Stroke Scale (NIHSS) scores on admission (16 vs 10), at 3 days after admission (14 vs 5), and at 7 days after admission (13.5 vs 3); and a lower Diffusion-Weighted Imaging-Alberta Stroke Program Early CT Score (7.8 vs 9.1). Patients who received edaravone had a higher prevalence of cardiogenic embolism (70.9% vs 36.4%), a higher recanalization rate (77.7% vs 36.4%), and lower NIHSS scores on admission and at 3 and 7 days after admission compared with those who did not receive edaravone. Our data suggest that administration of intravenous alteplase 0.6 mg/kg within 3 hours of stroke onset is safe and effective, that the NIHSS and Diffusion-Weighted Imaging-Alberta Stroke Program Early CT Score are useful predictors of ICH after tPA administration, and that warfarin-treated patients are more likely to develop symptomatic ICH despite an International Normalized Ratio <1.7.

Scheie syndrome diagnosed after cerebral infarction.

We report a 41-year-old woman with Scheie syndrome diagnosed after cerebral infarction. She presented with acute onset dysarthria and right upper limb weakness. The neurologic findings revealed dysarthria, right central facial paralysis, mild right hemiparesis, and mild sensory impairment in the right arm and leg. Diffusion-weighted magnetic resonance imaging (MRI) showed subtle high signal lesions in the left corona radiata and posterior limb of the internal capsule. The diagnosis was made by a coarse facial appearance, claw hands, pigmentary degeneration of the bilateral retinas, and a deficiency of the enzymatic activity of lysosomal α-L-iduronidase. The patient was successfully treated with intravenous recombinant tissue plasminogen activator (rtPA) followed by enzyme replacement therapy. The prognosis of this disease would improve with enzyme replacement therapy. It is necessary to be aware of cerebral infarction in patients with Scheie syndrome.

Two Cases of Probable Neuro-Behçet's Disease with Longitudinally Extensive Transverse Myelitis.

We report 2 cases of probable neuro-Behçet's disease (NBD) with longitudinally extensive transverse myelitis (LETM). In both cases, the patients presented paraplegia, as well as sensory, bladder, and rectal disturbances. Magnetic resonance imaging (MRI) of patient 1 showed continuous high signal intensity extending from the midbrain to the entire spinal cord in the central part of the cord on T2-weighted imaging (T2WI). Spinal MRI of patient 2 revealed high signal intensity extending from Th2 to Th10 in the central part of the cord on T2WI. Both patients received high-dose methylprednisolone. A continuous lesion from the midbrain to the entire spinal cord as in patient 1 has not been previously reported. Patient 2 dramatically improved by infliximab therapy. The present cases suggest that NBD should be considered as a differential diagnosis in patients with LETM.

Two Cases of Very-Late-Onset Neuromyelitis Optica Spectrum Disorder (NMOSD) in Patients over the Age of 80.

We report two cases of very-late-onset neuromyelitis optica spectrum disorder (NMOSD) in patients over the age of 80 with transverse myelopathy as the initial manifestation. In both cases, the patients presented with paraplegia and sensory, bladder, and rectal disturbances. Thoracic magnetic resonance imaging showed longitudinal high-intensity signals on a T2-weighted image. The patients received high-dose methylprednisolone. Their serum was positive for anti-AQP4 antibody (cell-based assay) during the clinical course. They were diagnosed with NMOSD and treated with immunoadsorption, plasmapheresis, and followed up with daily prednisolone. Very-late-onset NMOSD in patients over the age of 80 has only rarely been reported. The present cases suggest that NMOSD should be considered for elderly patients presenting with transverse myelitis. Early diagnosis and treatment are important.

Anti-MuSK Antibody-positive Myasthenia Gravis Successfully Treated with Outpatient Periodic Weekly Blood Purification Therapy.

A 37-year-old man with anti-muscle-specific tyrosine kinase (MuSK) antibody-positive myasthenia gravis (MG) presented with subacute progressive dysphagia and muscle weakness of the neck and bilateral upper extremities. Conventional immune-suppressive treatments and high-dose intravenous immunoglobulin were ineffective. He then displayed repeated exacerbations and remissions over the course of two years, despite two to four sessions of plasma exchange (PE) every two months. The patient was successfully treated with outpatient periodic weekly blood purification therapy with alternative PE and double-filtration plasmapheresis using an internal shunt. This case report suggests the benefits of blood purification therapy with an internal shunt against anti-MuSK antibody-positive MG.

Parkinsonism in Association with Dihydropteridine Reductase Deficiency.

We report a 16-year-old man with disorders of tetrahydrobiopterin metabolism due to dihydropteridine reductase (DHPR) deficiency. He revealed moderate mental retardation, parkinsonism, and spastic paralysis with levodopa and 5-hydroxytryptophan (5-HTP) supplementation from the age of 2 months. Brain MRI showed high intensity areas in bilateral frontal and posterior deep white matter on fluid-attenuated inversion recovery (FLAIR). Coronal FLAIR image showed a high signal in bilateral pyramidal tracts. Single photon computed tomography (SPECT) imaging of the dopamine transporter was normal. This imaging indicates no dopaminergic cell loss. Our patient had no motor fluctuations or dyskinesias. Early diagnosis and replacement treatment might lead to a favorable outcome.