Intravenous tissue plasminogen activator therapy for an acute ischemic stroke patient with later diagnosed unilateral moyamoya syndrome.

We report the use of intravenous tissue plasminogen activator (t-PA) therapy in a 38-year-old patient who was later diagnosed with unilateral moyamoya syndrome. The patient had a sudden onset of unconsciousness, vomiting, dysarthria, and tetraparesis. A neurologic examination revealed consciousness disturbance, right central facial nerve palsy, dysarthria, and tetraparesis with bilateral exotropia and horizontal gaze palsy. A magnetic resonance imaging scan on admission did not reveal fresh cerebral infarction or hemorrhage, but magnetic resonance angiography revealed severe stenosis at the terminal portion of left internal carotid artery, the anterior cerebral arteries, and the right vertebral artery. We suspected infarction of brain stem. The patient was treated with intravenous t-PA approximately 2.5 hours after onset, and the patient demonstrated a remarkable recovery 1 day after onset and had only a minimal deficit at discharge (12 days after onset). Cerebral angiography 7 days after onset confirmed the diagnosis of moyamoya disease. The present case suggests that therapeutic intravenous t-PA may be applicable for an acute ischemic stroke patient coexisting with moyamoya disease after careful evaluation and discussion with patient and family.

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.

Localized lesions on MRI in a case of hypertensive brainstem encephalopathy.

We report a case of hypertensive brainstem encephalopathy (HBE) with unusual magnetic resonance imaging (MRI) findings. A 67-year-old woman presented with high blood pressure and stupor as the only symptoms. MRI revealed lesions localized in the area from the upper medulla oblongata to the lower pons with high fluid-attenuated inversion recovery (FLAIR) and T2-weighted signal intensity, but these were not seen in the whole brainstem and there were no accompanying occipital lobe changes. To our knowledge, no similar case has been reported. The lesions and symptoms dramatically improved after normalization of blood pressure. Severe hypertension that exceeded the range of autoregulation may have resulted in segmental vasodilatation and the increased vascular permeability may have lead to vasogenic edema in the localized areas of the brainstem.

Estimation of the Presence of Small Dense Lipoprotein Cholesterol in Acute Ischemic Stroke.

Small dense low-density lipoprotein (sdLDL) is an established risk factor in ischemic heart disease. However, its clinical significance in acute ischemic stroke (AIS) is uncertain. This study evaluates the prognostic value of the presence of sdLDL in patients with AIS by determining whether it contributes to clinical outcome or not. We studied 530 consecutive patients admitted within the first 48 hours after onset of ischemic stroke and 50 corresponding controls. Serum lipid parameters were measured on admission by standard laboratory methods. The percentage of AIS patients with sdLDL was significantly higher than the one of matched controls with sdLDL. Concerning comparisons between AIS patients with or without sdLDL, the percentages of males and patients with histories of smoking, hypertension, and cardiovascular disease were significantly higher in AIS patients with sdLDL. Concerning the grade of severity, modified Rankin Scale (mRS) on discharge was significantly higher in AIS patients with sdLDL. On logistic regression analysis, age (OR=2.29, P<0.001), male gender (OR=0.49, P<0.01), history of atrial fibrillation (OR=3.46, P<0.001), and the presence of sdLDL (OR=1.59, P<0.05) were significantly associated with poor prognosis (mRS on discharge >3). Our study showed that the presence of sdLDL might be independently associated with a poor prognosis after AIS.

Temporal profile of stem cell division, migration, and differentiation from subventricular zone to olfactory bulb after transient forebrain ischemia in gerbils.

The stage of neurogenesis can be divided into three steps: proliferation, migration, and differentiation. To elucidate their detailed relations after ischemia, the three steps were comprehensively evaluated, in the subventricular zone (SVZ) through the rostral migratory stream (RMS) to the olfactory bulb (OB), in adult gerbil brain after 5 minutes of transient forebrain ischemia. Bromodeoxyuridine (BrdU), highly polysialylated neural cell adhesion molecule (PSA-NCAM), neuronal nuclear antigen (NeuN), and glial fibrillary acidic protein (GFAP) were used as markers for proliferation, migration, and differentiation, respectively. The number of BrdU-labeled cells that coexpressed PSA-NCAM and the size of PSA-NCAM-positive cell colony increased in the SVZ with a peak at 10 d after transient ischemia. In the RMS, the number of BrdU-labeled cells that coexpressed PSA-NCAM increased, with a delayed peak at 30 d, when the size of RMS itself became larger and the number of surrounding GFAP-positive cells increased. In the OB, BrdU + NeuN double positive cells were detected at 30 and 60 d. NeuN staining and terminal deoxynucleotidyl dUTP nick-end labeling staining showed no neuronal cell loss around the SVZ, and in the RMS and the OB after transient ischemia. These findings indicate that transient forebrain ischemia enhances neural stem cell proliferation in the SVZ without evident neuronal cell loss, and has potential neuronal precursor migration with activation of GFAP-positive cells through the RMS to the OB.

Three steps of neural stem cells development in gerbil dentate gyrus after transient ischemia.

The stage of neurogenesis can be divided into three steps: proliferation, migration, and differentiation. To elucidate detailed relations between these three steps after ischemia, the authors evaluated the three steps in the adult gerbil dentate gyrus (DG) after 5 minutes of transient global ischemia using bromodeoxyuridine (BrdU), highly polysialylated neural cell adhesion molecule (PSA-NCAM), and neuronal nuclear antigen (NeuN) and glial fibrillary acidic protein (GFAP) as markers for proliferation, migration, and differentiation, respectively. Bromodeoxyuridine-labeled cells increased approximately sevenfold, and PSA-NCAM-positive cells increased approximately threefold in the subgranular zone (SGZ) with a peak 10 days after ischemia. Bromodeoxyuridine-labeled cells with PSA-NCAM expression were first detected both in the SGZ and the granule cell layer (GCL) 20 days after ischemia and gradually decreased after that, whereas BrdU-labeled cells with NeuN gradually increased in the GCL until 60 days after ischemia. A few BrdU-labeled cells with GFAP expression were detected in DG after ischemia; no PSA-NCAM-positive cells with GFAP expression were detected, but the radial processes of glial cells were partly in contact with PSA-NCAM-positive cell bodies and dendrites. These results suggest that neural stem cell proliferation begins at the SGZ, and that the cells then migrate into the GCL and differentiate mainly into neuronal cells. The majority of these three steps finished in 2 months after transient global ischemia.

Coordinate expression of survival p-ERK and proapoptotic cytochrome c signals in rat brain neurons after transient MCAO.

In order to determine possible coordinate expression of major survival and proapoptotic signals, immunofluorescent analyses for phosphorylated ERK (p-ERK) and cytochrome c were carried out after 90 min of transient middle cerebral artery occlusion (MCAO) in rats. Strong induction of p-ERK was primarily expressed in the ischemic penumbra, while that of cytosolic cytochrome c signal was strongly induced in the ischemic core from 3 min to 3 h of reperfusion. The double-stained cells with strong p-ERK/weak cytochrome c became most apparent at 3 min primarily expressed in the ischemic penumbra, whereas the cells with weak p-ERK/strong cytochrome c were predominantly found in the ischemic core at 3 h. The proportion of double positive cells among the total number of single positive cells decreased in the ischemic core, and increased in the ischemic penumbra. These findings suggest that the coordinate expression of p-ERK and cytochrome c is fundamentally involved in cell survival or death at the early stage of reperfusion, and that they could play roles in different temporal and spatial profiles.

Cooperative expression of survival p-ERK and p-Akt signals in rat brain neurons after transient MCAO.

In order to determine possible coordinate expression of major survival signals, immunofluorescent analyses for phosphorylated ERK (p-ERK) and phosphorylated Akt (p-Akt) were carried out after 90 min of transient middle cerebral artery occlusion (MCAO) in rats. p-Akt single positive cells (E-/A+) were found in the sham control brains with weak signal intensity. The levels of both survival signals concurrently increased from 1 to 3 h after the reperfusion with the peak at 1 h, and the signals were much stronger in the ischemic penumbra (IP) than ischemic core (IC). The number of E-/A+ cells was larger in both the IC and IP than that of p-ERK single positive cells (E+/A-). The E+/A- cells were primarily expressed at 1 h in the IP. The number of p-ERK plus p-Akt double positive cells (E+/A+) peaked at 1 h, and the intensity was much stronger in the IP than IC. These findings suggest that p-ERK and p-Akt play independent roles, respectively as emergency or maintenance signal for survival at an early stage after reperfusion, and that both signals were cooperatively expressed especially in the IP.

Dissociative increase of oligodendrocyte progenitor cells between young and aged rats after transient cerebral ischemia.

To investigate the effect of aging on the oligodendrocyte progenitor cells (OPCs) after cerebral ischemia, neuron-glia antigen 2 (NG2) chondroitin sulfate proteoglycan was examined at 1, 3 and 7 days after 90 min of transient middle cerebral artery occlusion in young and aged brains. The number of NG2 positive cells increased in the ischemic penumbra at 3 and 7 days after reperfusion, while those decreased in the ischemic core. At 7 days, the number of NG2 positive cells was significantly greater in the young than the aged brains, and the processes of NG2 positive cells enlarged and were highly branched in the young than the aged brains. These results suggest that the young brain showed a higher potential of proliferation and process branching of OPCs than the aged brains.

Modification of a fiber protein in an adenovirus vector improves in vitro gene transfer efficiency to the mouse microglial cell line.

In microglia, it is difficult to introduce exogenous genes of interest even by recombinant adenovirus vectors (Ad) which can infect with high efficiency only to the cells expressing coxackievirus and adenovirus receptors (CAR). We found a lack of CAR expression in primary cultured murine microglia (PCMG) and its immortalized cell line MG5 by reverse transcription-polymerase chain reaction. In order to improve the efficiency of gene transfer, we generated a novel Ad (Ad-RGD) by an incorporation of the Arg-Gly-Asp motif (RGD) containing peptide in the HI loop of the viral fiber knob domain, which enables the virus to contact target cells through alpha V integrins which are known to be ubiquitously expressed on the surface of mammalian cells. Ad-RGD showed a remarkable improvement (13-18-fold) in the delivery of Escherichia coli LacZ gene in MG5 cells and a moderate increase in PCMG cells under the treatment with granulocyte-macrophage colony stimulating factor. These results suggest that Ad-RGD may be a potent tool for the delivery of genes to microglia activated by optimum stimulation, and thus analyzing the function of microglia with utilization of MG5 and PCMG cells.

Potentiation of Akt and suppression of caspase-9 activations by electroacupuncture after transient middle cerebral artery occlusion in rats.

Electroacupuncture (EA) is an effective curative method for diseases including cerebral ischemia. In the current study, we investigated the effects of EA treatment on the activations of survival Akt and proapoptotic caspase-9 after 90 min of transient middle cerebral artery occlusion (tMCAO) in rat. Immunoreactivity of phospho-Akt (p-Akt) increased in the ipsilateral hemisphere after tMCAO with a peak at 8 h, and EA enhanced the Akt expression both in the number and the staining strength mainly in the ischemic penumbra (IP) at 8 and 24 h. Cleaved caspase-9 was strongly induced at 8 h in IP, which was suppressed with EA. The number of terminal deoxynucleotidyl transferase-mediated uridine 5' triphosphate-biotin nick end labelling positive cells reduced at 24 h in the cerebral cortex. These results suggest that EA potentiated the Akt and suppressed the caspase-9 activations, and may have a potential to reduce the number of neuronal cells undergoing apoptotic cell death.

Extension of ischemic therapeutic time window by a free radical scavenger, Edaravone, reperfused with tPA in rat brain.

3-methyl-1-phenyl-2-pyrazolin-5-one (Edaravone) is a free radical scavenger. We tested the hypothesis that combination treatment of Edaravone and recombinant tissue plasminogen activator (tPA) extends the therapeutic time window. Male Wistar rats were subjected to 1.5-, 3.0- or 4.5-hour middle cerebral artery (MCA) occlusion (MCAO) by a nylon thread. Animals were randomly divided into four groups. The Sham group rats were operated without MCAO and drug injection. In the Vehicle-treated group the same volume of saline was given every 1.5 hours from just after MCAO to just before reperfusion. In the Vehicle + tPA-treated group saline injection was given as above and tPA (5 mg/kg, i.v.) was given once just after reperfusion. Edaravone+tPA-treated group: Edaravone (3 mg/kg, i.v.) was given every 1.5 hours instead of saline and tPA injection as above. Survival rate, infarct size and evidence of apoptosis and hemorrhage were examined in the animals. Combining administration of Edaravone+tPA significantly increased survival rate after 3 hours of transient MCAO, and reduced infarct volume after 1.5 hours of transient MCAO compared with the vehicle or vehicle+tPA groups. In Edaravone+tPA-treated group, the number of terminal deoxynucleotidyl transferase-mediated dUTP-biotin in situ nick end labeling (TUNEL) and 4-hydroxynonenal (4-HNE) positive cells were reduced at 16 hours after 3 hours of transient MCAO, but not in advanced glycation end products (AGEs) and 8-hydroxy-2'-deoxyguanosine (8-OHdG). Hemorrhage rate and the area decreased in the Edaravone+tPA-treated group. The combination therapy of Edaravone+tPA increased survival rate, and reduced the infarct volume and hemorrhage with reduction of lipid peroxidation. Therefore, Edaravone combination is expected to extend the therapeutic time window of tPA in the clinical situation.

Combined ipsilateral oculomotor nerve palsy and contralateral downbeat nystagmus in a case of cerebral infarction.

We report a patient with acute cerebral infarction of the left paramedian thalamus, upper mesencephalon and cerebellum who exhibited ipsilateral oculomotor nerve palsy and contralateral downbeat nystagmus. The site of the infarction was considered to be the paramedian thalamopeduncular and cerebellar regions, which are supplied by the superior cerebellar artery containing direct perforating branches or both the superior cerebellar artery and the superior mesencephalic and posterior thalamosubthalamic arteries. Contralateral and monocular downbeat nystagmus is very rare. Our case suggests that the present downbeat nystagmus was due to dysfunction of cerebellar-modulated crossed oculovestibular fibers of the superior cerebellar peduncle or bilateral downbeat nystagmus with one-sided oculomotor nerve palsy.

A novel mutation of the GAA gene in a patient with adult-onset Pompe disease lacking a disease-specific pathology.

We herein report a novel compound heterozygous mutation of the acid α-glucosidase (GAA) gene in a 23-year-old man with adult-onset Pompe disease. The patient was admitted for respiratory failure and a highly elevated serum level of creatine kinase (CK). His muscle pathology did not show typical vacuolated fibers; however, globular inclusion bodies with acid phosphatase (ACP) activity was observed. A molecular genetic analysis of the GAA gene revealed a novel compound heterozygous mutation, c.1544 T>A (M515K), combined with a previously reported mutation, c.1309 C>T (R437C). The presence of ACP-positive globular inclusion bodies is a useful diagnostic marker for adult-onset Pompe disease, even when typical vacuolated fibers are absent.

A case of fisher-bickerstaff syndrome overlapped by guillain-barré syndrome.

We report a 72-year-old woman with overlapping Miller Fisher syndrome (MFS), Guillain-Barré syndrome (GBS) and Bickerstaff's brainstem encephalitis (BBE). She developed diplopia and unsteady gait a week after an upper respiratory infection on day 1. She had weakness of both upper limbs on day 3 and became drowsy, and her respiratory status worsened on day 5. Neurologic examination revealed ophthalmoplegia, ataxia, symmetrical weakness, areflexia, and consciousness disturbance. We diagnosed her with MFS on day 1, GBS on day 3 and overlapping BBE on day 5. She underwent immunoadsorption therapy and two courses of intravenous immunoglobulin therapy. Ten months after onset, her symptoms had fully recovered. Anti-GM1 IgG, GD1a IgG, GQ1b IgG, and GT1a IgG antibodies were positive. Our case supports the notion that MFS, GBS, and BBE are all part of a continuous clinical spectrum, which is an antibody-mediated process.

Novel Mutations of the GNE Gene in Distal Myopathy with Rimmed Vacuoles Presenting with Very Slow Progression.

We report novel compound heterozygous mutations of the UDP-N-acetylglucosamine-2-epimerase and N-acetylmannosamine kinase (GNE) gene, c.302G>A (p.R101H) and c.617-4A>G, in a Japanese family with distal myopathy with rimmed vacuoles (DMRV) presenting with slow progression. The three patients could stand and walk even 36, 34, and 39 years after onset, respectively, although affected individuals become wheelchair bound on average 12 years after onset of the disease. The clinical spectrum of DMRV seems to be wider than previously thought in terms of both the clinical course and the severity of the disease.

Two cases of possible neuro-Sweet disease with meningoencephalitis as the initial manifestation.

We report 2 cases that were considered to be neuro-Sweet disease. They initially manifested with meningoencephalitis and no skin lesions, and rapidly improved with corticosteroid therapy. In both cases, patients complained of meningitic symptoms such as fever and headache, and HLA-B54 and -Cw1 turned out to be positive over the clinical course. Cerebrospinal fluid analysis showed increased levels of lymphocytes and protein. In case #1, fluid-attenuated inversion recovery (FLAIR), magnetic resonance imaging (MRI) and diffusion-weighted images (DWI) showed high-intensity signals in the right dorsal medulla oblongata, bilateral dorsal midbrain, and left thalamus. In case #2, FLAIR and DWI showed high-intensity signals in the bilateral cerebellar cortex and left caudate nucleus. Symptoms and MRI images were markedly improved in both cases after corticosteroid pulse therapy. According to published diagnostic criteria, these 2 cases were considered possible neuro-Sweet disease. These cases suggest that the combination of meningoencephalitis and HLA specificity is important to consider the possibility of neuro-Sweet disease, even without skin lesions.

Systemic blood pressure profile correlates with cardiac 123I-MIBG uptake in patients with Parkinson's disease.

To examine the correlation between the systemic blood pressure profile and cardiac (123)I-metaiodobenzylguanidine (MIBG) uptake in patients with Parkinson's disease (PD), we monitored circadian blood pressure patterns of 37 PD patients of 49 to 85 years of age (mean, 71.8±8.4 years) using a portable blood pressure monitoring device. The duration of PD was 0.5 to 15 years, and the disability level (modified Hoehn and Yahr stage) ranged from 1.0 to 4.0 (mean, 2.7±0.7). There were 37 age- and sex-matched control subjects. Cardiac MIBG scintigraphy was performed for the 37 PD patients. Based on the nocturnal fall in mean arterial blood pressure (MABP), we classified patients into extreme dippers (nocturnal reduction of MABP >20%), dippers (>10% but <20%), nondippers (<10% but >0%), and inverted dippers (<0%). Average 24-hour MABP values revealed reduced BP variability in PD patients. The percentage nocturnal fall in MABP was significantly different between PD patients and control subjects (p<0.05). Significant correlations were found between % MABP reduction and the heart-to-mediastinum (H/M) ratio on early and delayed images (p<0.01). The UPDR motor score, early and delay H/M ratios were also significantly different between patients who were and were not dippers (p<0.05). The present results reported for the first time a significant correlation between the systemic blood pressure profile and cardiac (123)I-MIBG uptake in patients with PD. The degeneration between the brainstem and the postganglionic neurons of myocardial sympathetic nerves may progress in parallel in patients with PD.

Serial diffusion-weighted MRI and SPECT findings in a Creutzfeldt-Jakob disease patient with V180I mutation.

We report serial changes of diffusion-weighted imaging (DWI) and single photon emission computed tomography (SPECT) in a patient with Creutzfeldt-Jakob disease with V180I mutation (CJD180). DWI abnormalities in our patient were more predominantly observed in the left cerebral cortex than left basal ganglia. Hemilateral abnormalities progressed over 5 months to involve the contralateral side with increasing DWI signals. At 6 months, SPECT showed hypoperfusion in the left parietal and frontal lobes and the hypoperfusion region spread to the bilateral basal ganglia, right parietal and frontal lobes. SPECT imaging revealed marked cerebral blood flow reduction, predominantly in the cerebral cortex corresponding to brain areas with high-intensity DWI signals. During the follow-up period of CJD180, DWI was more sensitive than conventional FLAIR and T2-weighted images (T2WI) to detect and monitor the progression of abnormal hyperintense lesions. We suggest that serial DWI and SPECT findings are useful for not only early diagnosis of CJD but also for monitoring disease progression.