MRI-Guided Thrombolysis for Stroke with Unknown Time of Onset.

BACKGROUND: Under current guidelines, intravenous thrombolysis is used to treat acute stroke only if it can be ascertained that the time since the onset of symptoms was less than 4.5 hours. We sought to determine whether patients with stroke with an unknown time of onset and features suggesting recent cerebral infarction on magnetic resonance imaging (MRI) would benefit from thrombolysis with the use of intravenous alteplase. METHODS: In a multicenter trial, we randomly assigned patients who had an unknown time of onset of stroke to receive either intravenous alteplase or placebo. All the patients had an ischemic lesion that was visible on MRI diffusion-weighted imaging but no parenchymal hyperintensity on fluid-attenuated inversion recovery (FLAIR), which indicated that the stroke had occurred approximately within the previous 4.5 hours. We excluded patients for whom thrombectomy was planned. The primary end point was favorable outcome, as defined by a score of 0 or 1 on the modified Rankin scale of neurologic disability (which ranges from 0 [no symptoms] to 6 [death]) at 90 days. A secondary outcome was the likelihood that alteplase would lead to lower ordinal scores on the modified Rankin scale than would placebo (shift analysis). RESULTS: The trial was stopped early owing to cessation of funding after the enrollment of 503 of an anticipated 800 patients. Of these patients, 254 were randomly assigned to receive alteplase and 249 to receive placebo. A favorable outcome at 90 days was reported in 131 of 246 patients (53.3%) in the alteplase group and in 102 of 244 patients (41.8%) in the placebo group (adjusted odds ratio, 1.61; 95% confidence interval [CI], 1.09 to 2.36; P=0.02). The median score on the modified Rankin scale at 90 days was 1 in the alteplase group and 2 in the placebo group (adjusted common odds ratio, 1.62; 95% CI, 1.17 to 2.23; P=0.003). There were 10 deaths (4.1%) in the alteplase group and 3 (1.2%) in the placebo group (odds ratio, 3.38; 95% CI, 0.92 to 12.52; P=0.07). The rate of symptomatic intracranial hemorrhage was 2.0% in the alteplase group and 0.4% in the placebo group (odds ratio, 4.95; 95% CI, 0.57 to 42.87; P=0.15). CONCLUSIONS: In patients with acute stroke with an unknown time of onset, intravenous alteplase guided by a mismatch between diffusion-weighted imaging and FLAIR in the region of ischemia resulted in a significantly better functional outcome and numerically more intracranial hemorrhages than placebo at 90 days. (Funded by the European Union Seventh Framework Program; WAKE-UP ClinicalTrials.gov number, NCT01525290; and EudraCT number, 2011-005906-32 .).

Feasibility of peripheral nerve MR neurography using diffusion tensor imaging adapted to skeletal muscle disease.

Background Diffusion tensor imaging (DTI) of peripheral nerves may provide additional information about nerve involvement in muscular disorders, but is considered difficult due to different optimal scan parameters tailored to magnetic resonance (MR) signal properties of muscle and neural tissues. Purpose To assess the feasibility of sciatic nerve DTI using two different approaches of region of interest (ROI)-localization in DTI scans with b-values 500 s/mm2, in participants with muscular disorders and in controls. Material and Methods DTI of the thigh was conducted on a 3T system in ten patients (6 men, 4 women; mean age =54 ± 15 years) with neuromuscular disorders and ten controls. T1-weighted (T1W) images were co-registered to fractional anisotropy (FA) color-encoded images. The apparent diffusion coefficient (ADC), FA, and fiber track length (FTL) were analyzed by two operators using a freehand ROI and a single-point ROI covering the sciatic nerve. Interclass correlation coefficient (ICC) and Bland-Altman analysis were used for evaluation of inter-operator and inter-technical agreement, respectively. Results Three-dimensional visualization of sciatic nerve fiber was achievable using both techniques. The ICC of DTI metrics showed excellent inter-operator agreement both in patients and controls. Bland-Altman analysis revealed good agreement of both techniques. A maximum FTL was achieved using the single-point ROI technique, but with a lower inter-operator agreement (ICC = 0.99 vs. 0.83). The ADC and maximum FTL were significantly decreased in patients compared to controls. Conclusion Both ROI localization techniques are feasible to analyze the sciatic nerve in the setting of muscular disease. A maximum FTL is reached using the single-point ROI, however, at the cost of lower inter-operator agreement.

Silent Brain Infarctions and Leukoaraiosis in Patients With Retinal Ischemia: A Prospective Single-Center Observational Study.

BACKGROUND AND PURPOSE: We aimed to determine the incidence of co-occurring cerebral ischemia, extent of cerebral small vessel disease, and vascular risk profile of patients with acute retinal ischemia. METHODS: RETIS (Frequency of Acute Silent Brain Infarction and Systematic Evaluation of Stroke Risk in Retinal Ischemia) was a single-center, prospective, observational study comprising ophthalmologic examination, brain magnetic resonance imaging, and extensive diagnostic work-up of vascular risk factors and stroke cause. Silent brain infarctions were identified on diffusion-weighted imaging, leukoaraiosis was quantified on fluid-attenuated inversion recovery sequences, and carotid artery stenosis was assessed by carotid ultrasound. RESULTS: Of 112 patients with retinal ischemia, 77 (68.8%) had retinal arterial occlusion, and 35 (31.3%) presented with amaurosis fugax. Silent brain infarctions were found in 17 (15.1%) patients. Internal carotid artery stenosis was present in 19 (17.0%) and severe leukoaraiosis in 29 (25.9%) patients. Atrial fibrillation was detected in 14 (12.5%) patients. Patients with silent brain infarctions had higher rates of internal carotid artery stenosis (35.3% versus 13.7%; P=0.029) than those without, whereas leukoaraiosis and vascular risk factors were comparable between groups. Internal carotid artery stenosis was the only significant predictor of silent brain infarctions in multivariate analysis (odds ratio, 4.27; 95% confidence interval, 1.06-17.23). CONCLUSIONS: Silent cerebral ischemia is present in about 1 in 7 patients with retinal ischemia. The high rate of symptomatic internal carotid artery stenosis suggests that large artery atherosclerosis plays a major role in the pathogenesis of acute retinal ischemia.

Stroke lesion volumes and outcome are not different in hemispheric stroke side treated with intravenous thrombolysis based on magnetic resonance imaging criteria.

BACKGROUND AND PURPOSE: Patients with right hemispheric stroke (RHS) have been reported to have fewer good outcomes after thrombolysis. We aimed at evaluating outcome after stroke thrombolysis with regards to the affected hemisphere controlling for stroke lesion volume as a potential confounder. METHODS: We retrospectively analyzed data from a prospective study of patients with acute stroke treated with intravenous tissue-type plasminogen activator, based on magnetic resonance imaging criteria within 6 hours of symptom onset. Neurological deficit was assessed by the National Institutes of Health Stroke Scale. Lesion volume on acute perfusion imaging, diffusion-weighted imaging (DWI) and perfusion imaging/DWI mismatch were measured. Clinical outcome was assessed after 90 days using the modified Rankin Scale, and relation to affected hemisphere was studied by multivariate analysis. RESULTS: Of 173 patients, 55 (32%) presented with RHS, whereas 118 (68%) had left HS. Baseline National Institutes of Health Stroke Scale was lower in RHS (11.7 versus 13.6; P=0.031). There were no differences in DWI lesion volume (11.0 versus 17.8 mL; P=0.519), perfusion imaging lesion volume (98.9 versus 118.3 mL; P=0.395), perfusion imaging/DWI mismatch (60 versus 85.05 mL; P=0.283). Clinical outcome was also comparable for both groups (modified Rankin Scale, 0-1; P=0.327). In multivariate analysis, DWI lesion volume (P<0.001) and age were associated with modified Rankin Scale at day 90, whereas affected hemisphere was not. CONCLUSIONS: We did not find differences between RHS and left HS with regards to stroke lesions volumes or outcome after thrombolysis. Previously reported hemisphere-related differences in stroke outcome may partly results from imbalances in stroke lesion volume between RHS and left HS.

Influence of stroke infarct location on functional outcome measured by the modified rankin scale.

BACKGROUND AND PURPOSE: In the early days after ischemic stroke, information on structural brain damage from MRI supports prognosis of functional outcome. It is rated widely by the modified Rankin Scale that correlates only moderately with lesion volume. We therefore aimed to elucidate the influence of lesion location from early MRI (days 2-3) on functional outcome after 1 month using voxel-based lesion symptom mapping. METHODS: We analyzed clinical and MRI data of patients from a prospective European multicenter stroke imaging study (I-KNOW). Lesions were delineated on fluid-attenuated inversion recovery images on days 2 to 3 after stroke onset. We generated statistic maps of lesion contribution related to clinical outcome (modified Rankin Scale) after 1 month using voxel-based lesion symptom mapping. RESULTS: Lesion maps of 101 patients with middle cerebral artery infarctions were included for analysis (right-sided stroke, 47%). Mean age was 67 years, median admission National Institutes of Health Stroke Scale was 11. Mean infarct volumes were comparable between both sides (left, 37.5 mL; right, 43.7 mL). Voxel-based lesion symptom mapping revealed areas with high influence on higher modified Rankin Scale in regions involving the corona radiata, internal capsule, and insula. In addition, asymmetrically distributed impact patterns were found involving the right inferior temporal gyrus and left superior temporal gyrus. CONCLUSIONS: In this group of patients with stroke, characteristic lesion patterns in areas of motor control and areas involved in lateralized brain functions on early MRI were found to influence functional outcome. Our data provide a novel map of the impact of lesion localization on functional stroke outcome as measured by the modified Rankin Scale.

Retinal hyperreflective foci in Fabry disease.

BACKGROUND: Fabry disease (FD) is an X-linked inherited storage disorder caused by deficiency of lysosomal alpha-Galactosidase A. Here we describe new retinal findings in patients with FD assessed by Spectral domain optical coherence tomography (SD-OCT) and their possible clinical relevance. METHODS: 54 eyes of 27 FD patients and 54 eyes of 27 control subjects were included. The ophthalmic examination included visual acuity testing, tonometry, slit lamp and fundus examination. SD-OCT imaging of the macula was performed in all subjects. Central retinal thickness and retinal nerve fiber layer analysis were quantified. Vessel tortuosity was obtained by a subjective scoring and mathematically calculated. Inner retinal hyperreflective foci (HRF) were quantified, clinically graded and correlated with a biomarker of Fabry disease (lyso-Gb3). RESULTS: In comparison to an age-matched control group, a significant amount of HRF was identified in macular SD-OCT images in FD patients. These HRF were localized within the inner retinal layers. Furthermore, lyso-Gb3 levels correlated significantly with the quantitative evaluation of HRF (p < 0,001). In addition, the vessel tortuosity was remarkably increased in FD patients compared to control persons and correlated significantly with lyso-G3 levels (p = 0.005). A further subanalysis revealed significantly higher HRF and vessel tortuosity scores in male patients with the classic FD phenotype. CONCLUSIONS: The observational, cross sectional, comparative study describes novel intraretinal findings in patients with FD. We were able to identify suspicious HRF within the inner retinal layers. These findings were not accompanied by functional limitations, as visual acuity remained unchanged. However, HRF correlated well with lyso-Gb3, a degradation product of the accumulating protein Gb3 and might potentially indicate Gb3 accumulation within the highly metabolic and densely vascularized macula.

Prevalence of adult Pompe disease in patients with proximal myopathic syndrome and undiagnosed muscle biopsy.

We examined patients with limb-girdle muscle weakness and/or hyper-CKaemia and undiagnosed muscle biopsy for late onset Pompe disease (LOPD). Patients with an inconclusive limb-girdle muscle weakness who presented at our neuromuscular centre between 2005 and 2015 with undiagnosed muscle biopsies were examined by dry blood spot testing (DBS) including determination of the enzyme activity of acid alpha-glucosidase (GAA). In the case of depressed enzyme activity, additional gene testing of the GAA gene was carried out. Of the 340 evaluated muscle biopsies, 69 patients fulfilled the inclusion criteria and were examined with DBS. Among those patients, 76% showed a limb-girdle muscle weakness and 14% showed a hyper-CKaemia. A diagnosis of LOPD could be established in the case of two patients (2.9%) with reduced GAA enzyme activity and proof of mutations in the GAA gene. One of the two patients presents in the muscle biopsy suggestive features of Pompe disease including vacuoles with positive acid phosphatase reaction. In summary, our results show that a muscle biopsy can be helpful in identifying LOPD patients, but vacuolation with glycogen storage can also be absent. An inconspicuous muscle biopsy does not rule out Pompe disease. Consequently, all patients with limb-girdle muscle weakness should be examined by DBS before conducting a muscle biopsy.

Dynamics of regional distribution of ischemic lesions in middle cerebral artery trunk occlusion relates to collateral circulation.

We describe the regional distribution of acute perfusion, diffusion, and final infarct lesions in middle cerebral artery (MCA) trunk occlusion. A total of 31 patients with acute ischemic stroke and MCA trunk occlusion were studied by multiparametric magnetic resonance imaging. Probabilistic maps of lesion distribution were generated. The probability of initial and final infarcts was highest in the central MCA region with decreasing probability toward the periphery where the probability of the tissue at risk of infarction to be saved was highest. The probability of brain regions being involved in acute diffusion lesions and evolving into or escaping from the final infarct relates to the anatomy of arterial blood supply.