Thrombolysis for Acute Wake-Up and Unclear-Onset Strokes with Alteplase at 0.6 mg/kg in Clinical Practice: THAWS2 Study.

INTRODUCTION: The aim of this study was to determine the safety and efficacy of intravenous (IV) alteplase at 0.6 mg/kg for patients with acute wake-up or unclear-onset strokes in clinical practice. METHODS: This multicenter observational study enrolled acute ischemic stroke patients with last-known-well time >4.5 h who had mismatch between DWI and FLAIR and were treated with IV alteplase. The safety outcomes were symptomatic intracranial hemorrhage (sICH) after thrombolysis, all-cause deaths, and all adverse events. The efficacy outcomes were favorable outcome defined as an mRS score of 0-1 or recovery to the same mRS score as the premorbid score, complete independence defined as an mRS score of 0-1 at 90 days, and change in NIHSS at 24 h from baseline. RESULTS: Sixty-six patients (35 females; mean age, 74 ± 11 years; premorbid complete independence, 54 [82%]; median NIHSS on admission, 11) were enrolled at 15 hospitals. Two patients (3%) had sICH. Median NIHSS changed from 11 (IQR, 6.75-16.25) at baseline to 5 (3-12.25) at 24 h after alteplase initiation (change, -4.8 ± 8.1). At discharge, 31 patients (47%) had favorable outcome and 29 (44%) had complete independence. None died within 90 days. Twenty-three (35%) also underwent mechanical thrombectomy (no sICH, NIHSS change of -8.5 ± 7.3), of whom 11 (48%) were completely independent at discharge. CONCLUSIONS: In real-world clinical practice, IV alteplase for unclear-onset stroke patients with DWI-FLAIR mismatch provided safe and efficacious outcomes comparable to those in previous trials. Additional mechanical thrombectomy was performed safely in them.

Magnetic Resonance Imaging-Guided Thrombolysis (0.6 mg/kg) Was Beneficial for Unknown Onset Stroke Above a Certain Core Size: THAWS RCT Substudy.

BACKGROUND AND PURPOSE: We determined to identify patients with unknown onset stroke who could have favorable 90-day outcomes after low-dose thrombolysis from the THAWS (Thrombolysis for Acute Wake-Up and Unclear-Onset Strokes With Alteplase at 0.6 mg/kg) database. METHODS: This was a subanalysis of an investigator-initiated, multicenter, randomized, open-label, blinded-end point trial. Patients with stroke with a time last-known-well >4.5 hours who showed a mismatch between diffusion-weighted imaging (DWI) and fluid-attenuated inversion recovery were randomly assigned (1:1) to receive alteplase at 0.6 mg/kg intravenously or standard medical treatment. The patients were dichotomized by ischemic core size or National Institutes of Health Stroke Scale score, and the effects of assigned treatments were compared in each group. The efficacy outcome was favorable outcome at 90 days, defined as a modified Rankin Scale score of 0 to 1. RESULTS: The median DWI-Alberta Stroke Program Early CT Score (ASPECTS) was 9, and the median ischemic core volume was 2.5 mL. Both favorable outcome (47.1% versus 48.3%) and any intracranial hemorrhage (26% versus 14%) at 22 to 36 hours were comparable between the 68 thrombolyzed patients and the 58 control patients. There was a significant treatment-by-cohort interaction for favorable outcome between dichotomized patients by ASPECTS on DWI (P=0.026) and core volume (P=0.035). Favorable outcome was more common in the alteplase group than in the control group in patients with DWI-ASPECTS 5 to 8 (RR, 4.75 [95% CI, 1.33-30.2]), although not in patients with DWI-ASPECTS 9 to 10. Favorable outcome tended to be more common in the alteplase group than in the control group in patients with core volume >6.4 mL (RR, 6.15 [95% CI, 0.87-43.64]), although not in patients with volume ≤6.4 mL. The frequency of any intracranial hemorrhage did not differ significantly between the 2 treatment groups in any dichotomized patients. CONCLUSIONS: Patients developing unknown onset stroke with DWI-ASPECTS 5 to 8 showed favorable outcomes more commonly after low-dose thrombolysis than after standard treatment. Registration: URL: https://www.clinicaltrials.gov; Unique Identifier: NCT02002325. URL: https://www.umin.ac.jp/ctr; Unique Identifier: UMIN000011630.

Thrombolysis With Alteplase at 0.6 mg/kg for Stroke With Unknown Time of Onset: A Randomized Controlled Trial.

Background and Purpose- We assessed whether lower-dose alteplase at 0.6 mg/kg is efficacious and safe for acute fluid-attenuated inversion recovery-negative stroke with unknown time of onset. Methods- This was an investigator-initiated, multicenter, randomized, open-label, blinded-end point trial. Patients met the standard indication criteria for intravenous thrombolysis other than a time last-known-well >4.5 hours (eg, wake-up stroke). Patients were randomly assigned (1:1) to receive alteplase at 0.6 mg/kg or standard medical treatment if magnetic resonance imaging showed acute ischemic lesion on diffusion-weighted imaging and no marked corresponding hyperintensity on fluid-attenuated inversion recovery. The primary outcome was a favorable outcome (90-day modified Rankin Scale score of 0-1). Results- Following the early stop and positive results of the WAKE-UP trial (Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke), this trial was prematurely terminated with 131 of the anticipated 300 patients (55 women; mean age, 74.4±12.2 years). Favorable outcome was comparable between the alteplase group (32/68, 47.1%) and the control group (28/58, 48.3%; relative risk [RR], 0.97 [95% CI, 0.68-1.41]; P=0.892). Symptomatic intracranial hemorrhage within 22 to 36 hours occurred in 1/71 and 0/60 (RR, infinity [95% CI, 0.06 to infinity]; P>0.999), respectively. Death at 90 days occurred in 2/71 and 2/60 (RR, 0.85 [95% CI, 0.06-12.58]; P>0.999), respectively. Conclusions- No difference in favorable outcome was seen between alteplase and control groups among patients with ischemic stroke with unknown time of onset. The safety of alteplase at 0.6 mg/kg was comparable to that of standard treatment. Early study termination precludes any definitive conclusions. Registration- URL: https://www.clinicaltrials.gov; Unique identifier: NCT02002325.

Association of a Subperiosteal Hematoma With Minor Injury.

An intraorbitalsubperiosteal hematoma is a rare clinical entity that is usually caused by head trauma. The authors experienced a patient involving an intraorbital hemorrhage that was associated with minor injury in the forehead and that required surgical decompression. The authors describe this rare case involving an intraorbitalsubperiosteal hematoma that occurred in a conscious young boy who had no remarkable head injury and who had sudden onset of proptosis. Three-dimensional computed tomography, which was conducted with a volume-rendering method, was very useful, and the transorbital approach that was used to remove the hematoma was very effective. The patient showed good recovery. The pathogenesis of the intraorbitalsubperiosteal hemorrhage could not be fully explained, and, thus, the authors suggest that a possible pathogenesis involved the migration of the hemorrhage from the forehead into the intraorbital region.

Reduced incidence of cardiovascular disease in patients with type 2 diabetes through the integrated improvement of diabetes care by comparing two prospective observational cohorts in real-world clinical practice (JDDM 72).

AIM: To investigate whether any reduction in all-cause mortality and cardiovascular disease morbidity was found over the decade in type 2 diabetes on real-world practice. METHODS: A prospective observational study was performed by following two independent cohorts recruited in 2004 (n = 3286, Cohort 1) and 2014 (n = 3919, Cohort 2). The primary outcome was a composite of onset of cardiovascular disease and death. Cox proportional hazards analysis was used to explore any difference between Cohort 2 and Cohort 1 for the composite endpoints and cardiovascular disease after adjustment for covariates and accumulation of five risks (smoking, HbA1c, blood pressure, lipids, and albuminuria) outside target ranges. RESULTS: During the 8-year follow-up, 391 (11.9%) and 270 (6.9%) primary outcomes, and 270 (8.2%) and 161 (4.1%) cardiovascular diseases occurred in Cohort 1 and Cohort 2, respectively. Cohort 2 (vs. Cohort 1) exhibited a significant risk reduction for composite endpoints (HR 0.73, 95% CI 0.62 to 0.86) and cardiovascular disease (HR 0.64, 95% CI 0.52 to 0.79), and similarly exhibited a significant reduction independent of the accumulation of the five risks. CONCLUSIONS: The significant reduction of Cohort 2 for cardiovascular disease independent of the baseline covariates suggests an integrated effect delivered by the recent treatment advances.

Intravenous Alteplase at 0.6 mg/kg for Unknown Onset Stroke with Prior Antithrombotic Medication: THAWS Randomized Clinical Trial.

AIM: This study aimed to assess the potential effect of prior antithrombotic medication for thrombolysis in an unknown onset stroke. METHODS: This was a predefined sub-analysis of the THAWS trial. Stroke patients with a time last known well ＞4.5 h who had a DWI-fluid-attenuated inversion recovery mismatch were randomly assigned (1:1) to receive alteplase at 0.6 mg/kg (alteplase group) or standard medical treatment (control group). Patients were dichotomized by prior antithrombotic medication. RESULTS: Of 126 patients (intention-to-treat population), 40 took antithrombotic medication (24 with antiplatelets alone, 13 with anticoagulants alone, and 3 with both), and the remaining 86 did not before stroke onset. Of these, 17 and 52 patients, respectively, received alteplase, and 23 and 34, respectively, had standard medical treatment. Antithrombotic therapy was initiated within 24 h after randomization less frequently in the alteplase group (12% vs. 86%, p＜0.01). Both any intracranial hemorrhage within 22-36 h (26% vs. 14%) and a modified Rankin Scale score of 0-1 at 90 days (good outcome) (47% vs. 48%) were comparable between the two groups. A good outcome was more common in the alteplase group than in the control group in patients with prior antithrombotic medication [relative risk (RR) 2.25, 95% confidence interval (CI) 1.02-4.99], but it tended to be less common in the alteplase group in those without (RR 0.69, 95% CI 0.46-1.03) (p＜0.01 for interaction). The frequency of any intracranial hemorrhage did not significantly differ between the two groups in any patients dichotomized by prior antithrombotic medication. CONCLUSION: Alteplase appears more beneficial in patients with prior antithrombotic medication.

Skull base training and education using an artificial skull model created by selective laser sintering.

INTRODUCTION: Practicing skull base approaches on cadavers affords the surgeon a chance to learn complex anatomical relationships and to practice surgical skills. However, there are ethical or legal problems in obtaining cadaver material in some countries. In addition, there is always risk of transmitting infections with cadaveric material. In order to get around these problems, we created a whole skull model which reproduces the detailed anatomy within the skull base using a selective laser sintering (SLS) technique. MATERIALS AND METHODS: The first author's head was scanned using multidetector-row computed tomography. The data were reconstructed and converted into the standard triangulation language file system. Powdered material comprised of polyamide nylon and glass beads was laser-sintered in accord with the data derived from the head CT. The model was dissected under a surgical microscope using a high-speed drill, suction, and other surgical instruments. RESULTS AND DISCUSSION: The appearance of both inner and outer cranial surfaces, including sutures, foramens, fissures, and protrusions, were clearly demonstrated. The artificial mastoid did not melt from the heat of the drill when a mastoidectomy was performed. The anatomical structures inside the mastoid and of paranasal sinuses were accurately reproduced in the model. CONCLUSION: The model created using SLS should be very useful for the teaching skull base approaches avoiding the ethical, legal, and infection problems inherent in cadavers.

[Artery-to-artery embolism due to ruptured calcified carotid plaque].

Calcified carotid plaques are thought to be less likely to be symptomatic than non-calcified plaques. We present a patient with an unusual cerebral embolism that appeared as very high density on CT and was ascertained to derive from a calcified plaque. This 46-year-old male was admitted within 1 hr of sudden aphasia onset. The admission CT scan showed multiple high-intensity lesions that appeared like calcification. They were high intensity on MRI FLAIR images. MRA showed occlusion of the posterior trunk of the middle cerebral artery. As we considered cerebral embolism, the patient received heparin followed by warfarin. Routine MRA and DSA detected no abnormality, however, a carotid echogram showed a hyperechoic plaque at the left carotid bifurcation. As the NASCET method indicated 6.5% stenosis, carotid endarterectomy was not indicated. However, the thrombus at the bifurcation gradually enlarged despite adequate medical treatment (PT-INR 2.2 - 2.7) and we decided to surgically remove the calcified plaque, thought to be the embolus source. We removed the plaque content through a defect in the plaque membrane. Intraoperatively we found that the rapidly enlarging lesion was the plaque content rather than a thrombus. Pathologically, calcification was more dominant than atherosclerosis. His postoperative course was good and he required only aspirin. This case was peculiar in that the calcification mimicked a hyperdensity embolus and that the lesion derived from a calcified plaque which is usually stable. Repeat carotid ultrasonography is easy and useful when routine investigation fails to reveal the embolic source.

[A case of brainstem encephalitis diagnosed by stereotactic biopsy].

Brainstem encephalitis is a rare form of encephalitis which should be differentiated from cerebrovascular and neoplastic diseases. The authors report a case of viral brainstem encephalitis mimicking malignant lymphoma. A 55-year-old female was admitted to our hospital with gradually progressive diplopia and left hemiplegia. CT scan revealed low density lesions in the right globus pallidus and the anterior limb of the internal capsule. MRI demonstrated high intensity signals extending into the right cerebral peduncle, temporal lobe, thalamus and the contralateral thalamus on FLAIR images. Petechial hemorrhages were seen in the affected lesions, but no enhancement was observed following administration of a contrast material. CSF examination revealed mild mononuclear cell dominant pleocytosis. Both early and delayed images of 123I-IMP SPECT revealed marked hot spots corresponding to the lesions on FLAIR images. CT-guided stereotactic biopsy was useful for early diagnosis.

[Serial magnetic resonance angiography in a case with isolated angiitis of the CNS].

Isolated angiitis of the central nervous system (IAC) is an idiopathic type of vasculitis, exclusively affecting small to medium-sized blood vessels of the central nervous system. We report serial angiographical findings, mainly demonstrated with magnetic resonance angiography (MRA) in a case of IAC. A 58-year-old-female came to our hospital because of a sudden headache. Computed tomography (CT) did not show any particular findings. MRA 3 days after the onset revealed diffuse arterial dilatations and segmental stenoses of the middle and anterior cerebral arteries. However, these findings did not lead us to make a diagnosis of IAC. Two days later she was admitted with increased headache and subcortical hemorrhage in the left frontal lobe on CT. Subsequent MRA demonstrated remarkable changes such as dilatated main trunks with segmental stenoses. Steroid pulse therapy was started after definite diagnosis of IAC. She improved gradually and was headache-free 15 days after the onset. Nevertheless, follow-up MRA at 15 days revealed diffusely narrowed anterior and middle cerebral arteries with multiple segmental stenoses. Characteristic findings of angiitis showed improvement at 29 days and had disappeared at 73 days. The patient discontinued corticosteroids and has remained free from headache for the last 7 months.

[Chronological changes in the vasculature and the cerebral blood flow of two patients with isolated angiitis of the central nervous system].

Isolated angiitis of the central nervous system (IAC) is an inflammatory, rare vasculopathy confined to the central nervous system, and the exact etiology has remained uncertain. We report serial changes in the vasculature and the mean cerebral blood flow (mCBF) in two patients with IAC. The first patient, a 58-year-old female, had sudden onset of severe headache and CT 4 days later showed cerebral hemorrhage in the frontal lobe. MRA revealed that the main trunks were dilated on admission, whereas two weeks later, diffuse narrowing of affected arteries occurred in multiple vascular distributions. She required about two months for almost full recovery in MRA findings. Mean CBF during the period of vascular narrowing did not correlate with the form of vasculature, and was much the same as that in the chronic phase. The second patient, a 24-year-old female, presented with severe headache one day after delivery following an uncomplicated pregnancy. MRA findings showed that, at first, segmental stenoses were located only in the peripheral regions of the middle cerebral artery, but this vascular abnormality spread to the anterior, middle and posterior cerebral arteries. She showed almost full recovery in MRA findings after about 3 months. SPECT analysis showed approximately 35% decrease in mCBF compared with that in the chronic phase. In the first case, hyperemia, which was caused by inflammatory cells infiltrating into the brain parenchyma through the vessel wall, contributed to cerebral hemorrhage. On the other hand, in the second case it was presumed that because inflammation was restricted to the vascular wall, mCBF consequently correlated with the form of vasculature. Our experience suggests that IAC has several etiologies.

[Multiple small subcortical infarction required to distinguish from lacunar infarction: evaluation by use of diffusion-weighted imaging].

Lacunar infarctions are small lesions caused by occlusion of the deep and penetrating vessels. Occlusion of such vessels are resulted from thrombosis based on atherosclerotic change. However, we occasionally encounter a patient with lacunar infarction seemed to be caused by embolic mechanism, as who has had previous experience of TIA or presented with clinical symptoms suddenly. Diffusion-weighted imaging (DWI) has high accuracy for depicting small ischemic lesions and discrimination of recent infarctions from old ones. We studied frequency, risk factors and stroke mechanism in the territory of penetrating arteries detected on DWI, and sensitivity of ischemic lesions by DWI as compared with conventional MRI images. Fifty-three consecutive patients with lacunar infarction in the territory of penetrating arteries who admitted to our hospital and were studied by DWI within 24 hours. Nine (17.0%) of 53 patients had multiple high signal lesions on DWI. These lesions were found in single arterial territory in 4 patients and in more than 2 territories in 5 patients. It was presumed that stroke mechanisms were artery to artery or cardiogenic embolism. DWI revealed all 38 hyperintensity lesions, while conventional MRI revealed 35 lesions, although the latter was resulted from retrospectively referring to the DWI finding. Therefore, conventional MRI alone might have been difficult to detect multiple lesions. DWI was enable to distinguish embolic infarction from small vessel lacunar infarction, leading to feasible patient management. Therefore, DWI should be performed in all patients with lacunar infarction, even if neurological finding is correspondent with the conventional MRI finding.

[A case of deep cerebral venous thrombosis with sudden convulsion after delivery].

A 25-year-old woman was admitted to our hospital because of convulsions after delivering a baby. Her neurological examination revealed a disturbance of consciousness and weakness in both arms. A brain magnetic resonance imaging scan (MRI) showed thrombosis of the left transverse sinus and many patchy high signals at bilateral basal ganglia and subcortical areas. A digital subtraction angiogram (DSA) of the brain revealed a defect at the left transverse sinus, congestion of the cerebral venous flow at the vein of Galen and vasospastic changes at both posterior cerebral arteries. After treating the patient with a venous infusion of heparin, nicardipine and phenytoin, her neurological deficits improved within a day. When MRI and DSA were repeated 2 weeks later, the abnormal lesions had disappeared. These findings suggest that venous thrombosis and vasospasm had the pathogenesis of eclampsia in this case.

Hyperperfusion syndrome after clipping an unruptured cerebral aneurysm: two case reports.

A 68-year-old woman presented with severe headache 9 days after undergoing successful clipping of a right middle cerebral artery aneurysm. Postoperative imaging revealed increased perfusion and diffuse edema in the right frontotemporal cortex. A 57-year-old woman exhibited perseveration soon after undergoing successful clipping of an anterior communicating artery aneurysm. Postoperative imaging studies revealed increased perfusion and diffuse edema in the left frontal and insular cortex. The symptoms and diffuse edema gradually resolved in both patients. These two cases of hyperperfusion syndrome occurred in a series of 190 patients treated by clipping of unruptured cerebral aneurysms. Hyperperfusion syndrome is a rare complication following aneurysm surgery, especially surgery for unruptured cerebral aneurysms without temporary clipping.

Syringo-subarachnoidal shunting to correct unilateral leg deformity in a child with terminal syringomyelia: case report.

INTRODUCTION: Among cases with terminal syringomyelia, 25% are associated with tethered cord syndrome. As it can be difficult to determine whether the neurological deficits are attributable to a syrinx or to a coexisting occult spinal dysraphism, it is not easy to determine the correct surgical strategy. CASE: We report a 19-month-old girl with an underdeveloped right leg and pes varus detected when she was 1 month old; lumbosacral magnetic resonance imaging (MRI) revealed syringomyelia. She developed recurrent urinary tract infections and consulted our department with a diagnosis of congenital neurogenic bladder. She presented with clubbed equine position, wore a short brace on her underdeveloped right leg, and exhibited limping gait due to shortening of the right leg. There was no anal reflex. The skin on her lower back was normal. MRI study showed that the lower end of the conus medullaris existed at the L3/4 level; central-type syringomyelia was recognized in the conus medullaris at the T12/L1-L2/L3 level. Computed tomography myelography detected no trabeculae causing tethering effects or influx of contrast medium into the syrinx. There was no comorbid disease like hydrocephalus or Chiari malformation. We performed syringo-subarachnoidal shunt by L1-L2 hemilaminectomy. RESULT: Postoperative MRI confirmed shrinkage of the syrinx. One year later, although her perianal sensory loss and bowel and bladder dysfunction remained, her right leg had caught up with the left and at 1 year and 9 months after the procedure there is no discrepancy in her legs and she is able to run without limping.