Publications by authors named "E Bernd Ringelstein"

492 Publications

Reversible Edema in the Penumbra Correlates With Severity of Hypoperfusion.

Stroke 2021 May 13:STROKEAHA120033071. Epub 2021 May 13.

Department of Neurology, University Hospitals Leuven, Belgium (L.S., A.W., R. Lemmens).

Background And Purpose: We aimed to investigate fluid-attenuated inversion recovery changes in the penumbra.

Methods: We determined core and perfusion lesions in subjects from the WAKE-UP trial (Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke) and AXIS 2 trial (Granulocyte Colony-Stimulating Factor in Patients With Acute Ischemic Stroke) with perfusion- and diffusion-weighted imaging at baseline. Only subjects with a mismatch volume >15 mL and ratio >1.2 were included. We created voxel-based relative fluid-attenuated inversion recovery signal intensity (rFLAIR SI) maps at baseline and follow-up. We studied rFLAIR SI in 2 regions of interest: baseline penumbra (baseline perfusion lesion-[core lesion+voxels with apparent diffusion coefficient <620 10 mm/s]) and noninfarcted penumbra (baseline perfusion lesion-follow-up fluid-attenuated inversion recovery lesion) at 24 hours (WAKE-UP) or 30 days (AXIS 2). We analyzed the association between rFLAIR SI and severity of hypoperfusion, defined as time to maximum of the residue function.

Results: In the baseline penumbra, rFLAIR SI was elevated (ratio, 1.04; =1.7×10; n=126) and correlated with severity of hypoperfusion (Pearson r, 0.03; <1.0×10; n=126). In WAKE-UP, imaging at 24 hours revealed a further increase of rFLAIR SI in the noninfarcted penumbra (ratio, 1.05 at 24 hours versus 1.03 at baseline; =7.1×10; n=43). In AXIS 2, imaging at 30 days identified reversibility of the rFLAIR SI (ratio, 1.02 at 30 days versus 1.04 at baseline; =1.5×10; n=26) since it was no longer different from 1 (ratio, 1.01 at 30 days; =0.099; n=26).

Conclusions: Penumbral rFLAIR SI increases appear early after stroke onset, correlate with severity of hypoperfusion, further increase at 24 hours, and are reversible by 30 days. Registration: URL:; Unique identifier: NCT01525290. URL:; Unique identifier: NCT00927836.
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May 2021

Imaging Markers of Brain Frailty and Outcome in Patients With Acute Ischemic Stroke.

Stroke 2021 Mar 28;52(3):1004-1011. Epub 2021 Jan 28.

Stroke Division (V.T.), The Florey Institute of Neuroscience and Mental Health.

Background And Purpose: Functional outcome after stroke may be related to preexisting brain health. Several imaging markers of brain frailty have been described including brain atrophy and markers of small vessel disease. We investigated the association of these imaging markers with functional outcome after acute ischemic stroke.

Methods: We retrospectively studied patients with acute ischemic stroke enrolled in the AXIS-2 trial (AX200 in Ischemic Stroke Trial), a randomized controlled clinical trial of granulocyte colony-stimulating factor versus placebo. We assessed the ratio of brain parenchymal volume to total intracerebral volumes (ie, the brain parenchymal fraction) and total brain volumes from routine baseline magnetic resonance imaging data obtained within 9 hours of symptom onset using the unified segmentation algorithm in SPM12. Enlarged perivascular spaces, white matter hyperintensities, lacunes, as well as a small vessel disease burden, were rated visually. Functional outcomes (modified Rankin Scale score) at day 90 were determined. Logistic regression was used to test associations between brain imaging features and functional outcomes.

Results: We enrolled 259 patients with a mean age of 69±12 years and 46 % were female. Increased brain parenchymal fraction was associated with higher odds of excellent outcome (odds ratio per percent increase, 1.078 [95% CI, 1.008-1.153]). Total brain volumes and small vessel disease burden were not associated with functional outcome. An interaction between brain parenchymal fraction and large vessel occlusion on excellent outcome was not observed.

Conclusions: Global brain health, as assessed by brain parenchymal fraction on magnetic resonance imaging, is associated with excellent functional outcome after ischemic stroke. Registration: URL: Unique identifier: NCT00927836.
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March 2021

Impaired Isometric Force Matching in Upper and Lower Limbs Revealed by Quantitative Motor Assessments in Huntington's Disease.

J Huntingtons Dis 2019 ;8(4):483-492

George-Huntington-Institute, Deilmann-Building IV, Technology-Park, Muenster, Germany.

Background: Assessment of motor symptoms in Huntington's disease (HD) is based on the Unified-HD-Rating-Scale-Total-Motor-Score (UHDRS-TMS). Its categorical and rater-dependent nature reduces the ability to detect subtle changes and often placebo effects have been observed in trials. We have previously shown that impairments in isometric force matching can be detected by quantitative motor (Q-Motor) assessments of tongue protrusion forces (glossomotography) in HD.

Objective: We aimed to investigate whether similar impairments in isometric force matching can be detected in tasks assessing hand and foot force coordination and whether correlations with clinical measures and the disease burden score can be found.

Methods: Using a pre-calibrated force transducer, the ability of subjects to generate and maintain isometric forces at different target levels displayed on a monitor was assessed. Target forces applied in the hand were 1.5 and 5 Newton [N] and in feet 1, 5, and 10 N. Subjects with HD (n = 31) and age-matched controls (n = 22) were recruited from the HD out-patient clinic.

Results: All paradigms distinguished controls from HD. The static coefficient of variability (%) was the most robust measure across all matching tasks. Correlations with clinical measures, such as the UHDRS-TMS, TFC, and the DBS were found.

Conclusions: Assessment of hand and foot force matching tasks was feasible and provided quantitative objective measures for severity of motor phenotype in HD. Since both upper and lower extremity motor function are relevant for everyday activities, these measures should be further assessed as candidates for developing functionally meaningful quantitative motor tasks.
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July 2020

KCNC1-related disorders: new de novo variants expand the phenotypic spectrum.

Ann Clin Transl Neurol 2019 07 7;6(7):1319-1326. Epub 2019 Jun 7.

Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.

A recurrent de novo missense variant in KCNC1, encoding a voltage-gated potassium channel expressed in inhibitory neurons, causes progressive myoclonus epilepsy and ataxia, and a nonsense variant is associated with intellectual disability. We identified three new de novo missense variants in KCNC1 in five unrelated individuals causing different phenotypes featuring either isolated nonprogressive myoclonus (p.Cys208Tyr), intellectual disability (p.Thr399Met), or epilepsy with myoclonic, absence and generalized tonic-clonic seizures, ataxia, and developmental delay (p.Ala421Val, three patients). Functional analyses demonstrated no measurable currents for all identified variants and dominant-negative effects for p.Thr399Met and p.Ala421Val predicting neuronal disinhibition as the underlying disease mechanism.
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July 2019

Angioplasty in asymptomatic carotid artery stenosis vs. endarterectomy compared to best medical treatment: One-year interim results of SPACE-2.

Int J Stroke 2019 Mar 15:1747493019833017. Epub 2019 Mar 15.

1 Department of Neurology, University Hospital of Heidelberg, Heidelberg, Germany.

Background: Treatment of individuals with asymptomatic carotid artery stenosis is still handled controversially. Recommendations for treatment of asymptomatic carotid stenosis with carotid endarterectomy (CEA) are based on trials having recruited patients more than 15 years ago. Registry data indicate that advances in best medical treatment (BMT) may lead to a markedly decreasing risk of stroke in asymptomatic carotid stenosis. The aim of the SPACE-2 trial (ISRCTN78592017) was to compare the stroke preventive effects of BMT alone with that of BMT in combination with CEA or carotid artery stenting (CAS), respectively, in patients with asymptomatic carotid artery stenosis of ≥70% European Carotid Surgery Trial (ECST) criteria.

Methods: SPACE-2 is a randomized, controlled, multicenter, open study. A major secondary endpoint was the cumulative rate of any stroke (ischemic or hemorrhagic) or death from any cause within 30 days plus an ipsilateral ischemic stroke within one year of follow-up. Safety was assessed as the rate of any stroke and death from any cause within 30 days after CEA or CAS. Protocol changes had to be implemented. The results on the one-year period after treatment are reported.

Findings: It was planned to enroll 3550 patients. Due to low recruitment, the enrollment of patients was stopped prematurely after randomization of 513 patients in 36 centers to CEA (n = 203), CAS (n = 197), or BMT (n = 113). The one-year rate of the major secondary endpoint did not significantly differ between groups (CEA 2.5%, CAS 3.0%, BMT 0.9%; p = 0.530) as well as rates of any stroke (CEA 3.9%, CAS 4.1%, BMT 0.9%; p = 0.256) and all-cause mortality (CEA 2.5%, CAS 1.0%, BMT 3.5%; p = 0.304). About half of all strokes occurred in the peri-interventional period. Higher albeit statistically non-significant rates of restenosis occurred in the stenting group (CEA 2.0% vs. CAS 5.6%; p = 0.068) without evidence of increased stroke rates.

Interpretation: The low sample size of this prematurely stopped trial of 513 patients implies that its power is not sufficient to show that CEA or CAS is superior to a modern medical therapy (BMT) in the primary prevention of ischemic stroke in patients with an asymptomatic carotid stenosis up to one year after treatment. Also, no evidence for differences in safety between CAS and CEA during the first year after treatment could be derived. Follow-up will be performed up to five years. Data may be used for pooled analysis with ongoing trials.
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March 2019