Publications by authors named "Jukka Putaala"

170 Publications

Left Atrial Appendage Occlusion versus Novel Oral Anticoagulation for Stroke Prevention in Atrial Fibrillation: Rationale and Design of the Multicenter Randomized Occlusion-AF Trial.

Am Heart J 2021 Sep 16. Epub 2021 Sep 16.

Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark. Electronic address:

Background: The prevalence of atrial fibrillation (AF) is increasing globally, which is a major clinical and public health concern due to the five-fold increased risk of stroke. Oral anticoagulation with novel oral anticoagulants (NOACs) is the current primary option for stroke prevention in patients with AF, although it increases the risk of major bleeding. Patients with prior ischemic cerebrovascular events are at particularly high risk of both recurrent ischemic events and major bleeding. Left atrial appendage occlusion (LAAO) provides an alternative option for stroke prevention in high-risk patients, however, with currently limited evidence. Thus, randomized trials comparing LAAO to NOACs are needed.

Objective: The Occlusion-AF trial is designed to assess whether LAAO is non-inferior to NOAC therapy for reduction of the combined endpoint of stroke, systemic embolism, major bleeding (Bleeding Academic Research Consortium ≥ 3) and all-cause mortality in patients with AF and a recent ischemic stroke or transient ischemic attack (TIA).

Methods And Analysis: Investigator-initiated multicenter, multinational, randomized open-label non-inferiority trial with blinded outcome evaluation (PROBE design). Patients with documented AF, and an ischemic stroke or TIA within 6 months will be eligible for enrollment. Major exclusion criteria are modified Rankin Scale > 3 at enrollment, glomerular filtration rate < 15 ml/min, and life-expectancy less than 2 years. A total of 750 patients will be randomized 1:1 to receive either a NOAC or LAAO using the Amplatzer Amulet (Abbott, MN, USA) or Watchman FLX (Boston Scientific, MN, USA) with subsequent life-long aspirin 75 mg daily. Follow-up will be based on in-office and telephone follow-up in combination with long-term follow-up (10 years) through national hospital discharge registries in the individual Nordic countries. The primary outcome will be a composite endpoint of stroke, systemic embolism, major bleeding (BARC ≥ 3) and all-cause mortality at 2-year follow-up.

Conclusion: The Occlusion-AF trial is designed to compare LAAO to NOAC therapy for secondary stroke prevention in AF patients with a high risk of recurrent thromboembolic events, i.e. with previous ischemic stroke or TIA, and otherwise eligible for anticoagulation. The results are expected to contribute significantly to the understanding of the effects of LAAO compared to the standard contemporary pharmacological treatment in these patients.
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http://dx.doi.org/10.1016/j.ahj.2021.08.020DOI Listing
September 2021

Declining mortality of cerebral venous sinus thrombosis with thrombocytopenia after SARS-CoV-2 vaccination.

Eur J Neurol 2021 Sep 18. Epub 2021 Sep 18.

Department of Neurology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands.

Background: High mortality rates have been reported in patients with cerebral venous sinus thrombosis (CVST) due to vaccine-induced immune thrombotic thrombocytopenia (VITT) after vaccination with adenoviral vector SARS-CoV-2 vaccines. The aim of this study was to evaluate whether mortality of patients with CVST-VITT has decreased over time.

Methods: We used the EudraVigilance database of the European Medicines Agency to identify cases of CVST with concomitant thrombocytopenia occurring within 28 days of SARS-CoV-2 vaccination. Vaccines were grouped based on vaccine type (adenoviral or mRNA). Cases with CVST onset until 28 March were compared to cases after 28 March 2021, which was the day when the first scientific paper on VITT was published.

Results: We identified 270 cases of CVST with thrombocytopenia, of which 266 (99%) occurred after adenoviral vector SARS-CoV-2 vaccination (ChAdOx1 nCoV-19 n=243, Ad26.COV2.S n=23). Reported mortality among adenoviral cases with onset up to 28 March 2021 was 47/99 (47%, 95%CI 37-58%) compared to 36/167 (22%, 95%CI 16-29%) in cases with onset after 28 March (p=<0.001). None of the 4 cases of CVST with thrombocytopenia occurring after mRNA vaccination died.

Conclusion: Reported mortality of CVST with thrombocytopenia after vaccination with adenoviral vector-based SARS-CoV-2 vaccines has significantly decreased over time, which may indicate a beneficial effect of earlier recognition and/or improved treatment on outcome after VITT.
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http://dx.doi.org/10.1111/ene.15113DOI Listing
September 2021

Adherence to oral anticoagulation in ischemic stroke patients with atrial fibrillation.

Ann Med 2021 12;53(1):1613-1620

Department of Neurology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.

Background: Non-vitamin K antagonist oral anticoagulants (NOAC) have superior safety and comparable efficacy profile compared to vitamin-K antagonists (VKAs), with more convenient dosing schemes. However, issues with adherence to the NOACs remain unsolved.

Aims: We sought to investigate the adherence to oral anticoagulation (OAC) and baseline factors associated with poor adherence after ischaemic stroke in patients with atrial fibrillation (AF).

Methods: We recruited hospitalised patients (2013-2019) from two prospective stroke registries in Larissa and Helsinki University Hospitals and invited survived patients to participate in a telephone interview. We assessed adherence with the Adherence to Refills and Medications Scale (ARMS) and defined poor adherence as a score of over 17. In addition to demographics, individual comorbidities, and stroke features, we assessed the association of CHADS-VASc and SAMe-TTR scores with poor adherence.

Results: Among 396 patients (median age 75.0 years, interquartile range [IQR] 70-80; 57% men; median time from ischaemic stroke to interview 21 months [IQR 12-33]; median ARMS score 17 [IQR 17-19]), 56% of warfarin users and 44% of NOAC users reported poor adherence. In the multivariable regression model adjusted for site, sex, and age, poor adherence was independently associated with tertiary education, absence of heart failure, smoking history, use of VKA prior to index stroke, and prior ischaemic stroke. CHADS-VASc and SAMe-TTR scores were not associated with poor adherence.

Conclusions: Adherence was poor in half of AF patients who survived an ischaemic stroke. Independent patient-related factors, rather than composite scores, were associated with poor adherence in these patients.KEY MESSAGESAdherence was poor in half of the atrial fibrillation patients who survived an ischaemic stroke.Independent patient-related factors rather than composite scores were associated with poor adherence.The findings support the importance of recognising adherence support as a crucial part of holistic patient care recommended by recent AF guideline.
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http://dx.doi.org/10.1080/07853890.2021.1968031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8439221PMC
December 2021

Genome-wide association study identifies first locus associated with susceptibility to cerebral venous thrombosis.

Ann Neurol 2021 Aug 30. Epub 2021 Aug 30.

Department of Molecular and Translational Medicine, Division of Biology and Genetics, University of Brescia, Italy.

Objective: Cerebral venous thrombosis (CVT) is an uncommon form of stroke affecting mostly young individuals. Although genetic factors are thought to play a role in this cerebrovascular condition, its genetic etiology is not well understood.

Methods: Genome-wide association study performed to identify genetic variants influencing susceptibility to CVT. A two-stage genome-wide study was undertaken in 882 Europeans diagnosed with CVT and 1205 ethnicity-matched control subjects divided into discovery and independent replication datasets.

Results: In the overall case-control cohort, we identified highly significant associations with 37 SNPs within 9q34.2 region. The strongest association was with rs8176645 (combined P = 9.15 × 10 ; OR = 2.01, 95%CI: 1.76-2.31). The discovery set findings were validated across an independent European cohort. Genetic risk score for this 9q34.2 region increases CVT risk by a pooled estimate OR = 2.65 (95%CI: 2.21-3.20, P = 2.00 × 10 ). SNPs within this region were in strong linkage disequilibrium (LD) with coding regions of the ABO gene. ABO blood group was determined using allele combination of SNPs rs8176746 and rs8176645. Blood groups A, B or AB, were at 2.85 times (95%CI: 2.32-3.52, P = 2.00 × 10 ) increased risk of CVT compared with individuals with blood group-O.

Interpretation: We present the first chromosomal region to robustly associate with a genetic susceptibility to CVT. This region more than doubles the likelihood of CVT, a risk greater than any previously identified thrombophilia genetic risk marker. That the identified variant is in strong LD with the coding region of the ABO gene with differences in blood group prevalence provides important new insights into the pathophysiology of CVT. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/ana.26205DOI Listing
August 2021

Cerebral small-vessel disease is associated with the severity of diabetic retinopathy in type 1 diabetes.

BMJ Open Diabetes Res Care 2021 Aug;9(1)

Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland.

Introduction: Cerebral small-vessel disease is common in neurologically asymptomatic individuals with type 1 diabetes. The retinal vasculature is thought to mirror the brain's vasculature, but data on this association are limited in type 1 diabetes. Our aim was to study associations between diabetic retinopathy severity and cerebral small-vessel disease in type 1 diabetes.

Research Design And Methods: For this cross-sectional study, we enrolled 189 participants with type 1 diabetes (median age 40 (33-45) years; 53% female; diabetes duration 21.6 (18.2-30.7) years) and 29 healthy age-matched and sex-matched controls as part of the Finnish Diabetic Nephropathy Study. Participants underwent a clinical investigation, brain MRI, and fundus imaging. Signs of cerebral small-vessel disease in brain MRIs were analyzed in relation to diabetic retinopathy severity (Early Treatment Diabetic Retinopathy Study (ETDRS) score).

Results: In type 1 diabetes, participants with cerebral small-vessel disease had higher ETDRS scores (35 (20-61) vs 20 (20-35), p=0.022) and a higher prevalence of proliferative diabetic retinopathy than those without cerebral small-vessel disease (25% vs 9%, p=0.002). In adjusted analysis, proliferative diabetic retinopathy was associated with cerebral small-vessel disease (OR 2.57 (95% CI 1.04 to 6.35)). Median ETDRS score (35 (20-65) vs 20 (20-35), p=0.024) and proliferative diabetic retinopathy prevalence were higher (29% vs 13%, p=0.002) in participants with versus without cerebral microbleeds. ETDRS scores increased by number of cerebral microbleeds (p=0.001), both ETDRS score (OR 1.05 (95% CI 1.02 to 1.09)) and proliferative diabetic retinopathy (8.52 (95% CI 1.91 to 37.94)) were associated with >2 cerebral microbleeds in separate multivariable analysis. We observed no association with white matter hyperintensities or lacunar infarcts.

Conclusions: Presence of cerebral small-vessel disease on brain MRI, particularly cerebral microbleeds, is associated with the severity of diabetic retinopathy.
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http://dx.doi.org/10.1136/bmjdrc-2021-002274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8386215PMC
August 2021

A Randomized, Sham-Controlled Trial of Repetitive Transcranial Magnetic Stimulation Targeting M1 and S2 in Central Poststroke Pain: A Pilot Trial.

Neuromodulation 2021 Aug 9. Epub 2021 Aug 9.

Department of Anaesthesiology, Intensive Care and Pain Medicine, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.

Objectives: Central poststroke pain (CPSP), a neuropathic pain condition, is difficult to treat. Repetitive transcranial magnetic stimulation (rTMS) targeted to the primary motor cortex (M1) can alleviate the condition, but not all patients respond. We aimed to assess a promising alternative rTMS target, the secondary somatosensory cortex (S2), for CPSP treatment.

Materials And Methods: This prospective, randomized, double-blind, Sham-controlled three-arm crossover trial assessed navigated rTMS (nrTMS) targeted to M1 and S2 (10 sessions, 5050 pulses per session at 10 Hz). Participants were evaluated for pain, depression, anxiety, health-related quality of life, upper limb function, and three plasticity-related gene polymorphisms including Dopamine D2 Receptor (DRD2). We monitored pain intensity and interference before and during stimulations, and at one month. A conditioned pain modulation test was performed using the cold pressor test. This assessed the efficacy of the descending inhibitory system, which may transmit TMS effects in pain control.

Results: We prescreened 73 patients, screened 29, and included 21, of whom 17 completed the trial. NrTMS targeted to S2 resulted in long-term (from baseline to one-month follow-up) pain intensity reduction of ≥30% in 18% (3/17) of participants. All stimulations showed a short-term effect on pain (17-20% pain relief), with no difference between M1, S2, or Sham stimulations, indicating a strong placebo effect. Only nrTMS targeted to S2 resulted in a significant long-term pain intensity reduction (15% pain relief). The cold pressor test reduced CPSP pain intensity significantly (p = 0.001), indicating functioning descending inhibitory controls. The homozygous DRD2 T/T genotype is associated with the M1 stimulation response.

Conclusions: S2 is a promising nrTMS target in the treatment of CPSP. The DRD2 T/T genotype might be a biomarker for M1 nrTMS response, but this needs confirmation from a larger study.
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http://dx.doi.org/10.1111/ner.13496DOI Listing
August 2021

Should Tenecteplase be Given in Clinical Practice for Acute Ischemic Stroke Thrombolysis?

Stroke 2021 Aug 28;52(9):3075-3080. Epub 2021 Jul 28.

Department of Neurology, Helsinki University Hospital and University of Helsinki, Finland (J.P., M.K.).

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http://dx.doi.org/10.1161/STROKEAHA.121.034244DOI Listing
August 2021

Post-SARS-CoV-2-vaccination cerebral venous sinus thrombosis: an analysis of cases notified to the European Medicines Agency.

Eur J Neurol 2021 Jul 22. Epub 2021 Jul 22.

Department of Neurosciences and Mental Health, Neurology Service, Hospital de Santa Maria/CHULN, University of Lisbon, Lisbon, Portugal.

Background And Purpose: Cerebral venous sinus thrombosis (CVST) has been described after vaccination against SARS-CoV-2. The clinical characteristics of 213 post-vaccination CVST cases notified to the European Medicines Agency are reported.

Methods: Data on adverse drug reactions after SARS-CoV-2 vaccination notified until 8 April 2021 under the Medical Dictionary for Regulatory Activities Term 'Central nervous system vascular disorders' were obtained from the EudraVigilance database. Post-vaccination CVST was compared with 100 European patients with CVST from before the COVID-19 pandemic derived from the International CVST Consortium.

Results: In all, 213 CVST cases were identified: 187 after AstraZeneca/Oxford (ChAdOx1 nCov-19) vaccination and 26 after a messenger RNA (mRNA) vaccination (25 with Pfizer/BioNTech, BNT162b2, and one with Moderna, mRNA-1273). Thrombocytopenia was reported in 107/187 CVST cases (57%, 95% confidence interval [CI] 50%-64%) in the ChAdOx1 nCov-19 group, in none in the mRNA vaccine group (0%, 95% CI 0%-13%) and in 7/100 (7%, 95% CI 3%-14%) in the pre-COVID-19 group. In the ChAdOx1 nCov-19 group, 39 (21%) reported COVID-19 polymerase chain reaction tests were performed within 30 days of CVST symptom onset, and all were negative. Of the 117 patients with a reported outcome in the ChAdOx1 nCov-19 group, 44 (38%, 95% CI 29%-47%) had died, compared to 2/10 (20%, 95% CI 6%-51%) in the mRNA vaccine group and 3/100 (3%, 95% CI 1%-8%) in the pre-COVID-19 group. Mortality amongst patients with thrombocytopenia in the ChAdOx1 nCov-19 group was 49% (95% CI 39%-60%).

Conclusions: Cerebral venous sinus thrombosis occurring after ChAdOx1 nCov-19 vaccination has a clinical profile distinct from CVST unrelated to vaccination. Only CVST after ChAdOx1 nCov-19 vaccination was associated with thrombocytopenia.
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http://dx.doi.org/10.1111/ene.15029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8444640PMC
July 2021

Endothelial Dysfunction is Associated With Early-Onset Cryptogenic Ischemic Stroke in Men and With Increasing Age.

J Am Heart Assoc 2021 Jul 6;10(14):e020838. Epub 2021 Jul 6.

Department of Neurology Helsinki University Hospital and Clinical NeurosciencesUniversity of Helsinki Finland.

Background The aim of this study was to assess the association between endothelial function and early-onset cryptogenic ischemic stroke (CIS), with subgroup analyses stratified by sex and age groups. Methods and Results We prospectively enrolled 136 consecutive patients aged 18 to 49 years (median age, 41 years; 44% women) with a recent CIS and 136 age- and sex-matched (±5 years) stroke-free controls. Endothelial function was measured with an EndoPAT 2000 device and analyzed as tertiles of natural logarithm of reactive hyperemia index with lower values reflecting dysfunction. We used conditional logistic regression adjusting for age, education, hypertension, diabetes mellitus, dyslipidemia, current smoking, heavy drinking, obesity, and diet score to assess the independent association between endothelial function and CIS. Patients in the lowest tertile of natural logarithm of reactive hyperemia index were more often men and they more frequently had a history of dyslipidemia; they were also more often obese, had a lower diet score, and lower high-density lipoprotein cholesterol. In the entire cohort, we found no association in patients with endothelial function and CIS compared with stroke-free controls. In sex- and age-specific analyses, endothelial dysfunction was associated with CIS in men (adjusted odds ratio [OR], 3.50 for lowest versus highest natural logarithm of reactive hyperemia index tertile; 95% CI, 1.22-10.07) and in patients ≥41 years (OR, 5.78; 95% CI, 1.52-21.95). These associations remained significant when dyslipidemia was replaced with the ratio of total to high-density lipoprotein cholesterol. Conclusions Endothelial dysfunction appears to be an independent player in early-onset CIS in men and patients approaching middle age.
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http://dx.doi.org/10.1161/JAHA.121.020838DOI Listing
July 2021

Frequency of Thrombocytopenia and Platelet Factor 4/Heparin Antibodies in Patients With Cerebral Venous Sinus Thrombosis Prior to the COVID-19 Pandemic.

JAMA 2021 07;326(4):332-338

Department of Neurology, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.

Importance: Cases of cerebral venous sinus thrombosis in combination with thrombocytopenia have recently been reported within 4 to 28 days of vaccination with the ChAdOx1 nCov-19 (AstraZeneca/Oxford) and Ad.26.COV2.S (Janssen/Johnson & Johnson) COVID-19 vaccines. An immune-mediated response associated with platelet factor 4/heparin antibodies has been proposed as the underlying pathomechanism.

Objective: To determine the frequencies of admission thrombocytopenia, heparin-induced thrombocytopenia, and presence of platelet factor 4/heparin antibodies in patients diagnosed with cerebral venous sinus thrombosis prior to the COVID-19 pandemic.

Design, Setting, And Participants: This was a descriptive analysis of a retrospective sample of consecutive patients diagnosed with cerebral venous sinus thrombosis between January 1987 and March 2018 from 7 hospitals participating in the International Cerebral Venous Sinus Thrombosis Consortium from Finland, the Netherlands, Switzerland, Sweden, Mexico, Iran, and Costa Rica. Of 952 patients, 865 with available baseline platelet count were included. In a subset of 93 patients, frozen plasma samples collected during a previous study between September 2009 and February 2016 were analyzed for the presence of platelet factor 4/heparin antibodies.

Exposures: Diagnosis of cerebral venous sinus thrombosis.

Main Outcomes And Measures: Frequencies of admission thrombocytopenia (platelet count <150 ×103/μL), heparin-induced thrombocytopenia (as diagnosed by the treating physician), and platelet factor 4/heparin IgG antibodies (optical density >0.4, in a subset of patients with previously collected plasma samples).

Results: Of 865 patients (median age, 40 years [interquartile range, 29-53 years], 70% women), 73 (8.4%; 95% CI, 6.8%-10.5%) had thrombocytopenia, which was mild (100-149 ×103/μL) in 52 (6.0%), moderate (50-99 ×103/μL) in 17 (2.0%), and severe (<50 ×103/μL) in 4 (0.5%). Heparin-induced thrombocytopenia with platelet factor 4/heparin antibodies was diagnosed in a single patient (0.1%; 95% CI, <0.1%-0.7%). Of the convenience sample of 93 patients with cerebral venous sinus thrombosis included in the laboratory analysis, 8 (9%) had thrombocytopenia, and none (95% CI, 0%-4%) had platelet factor 4/heparin antibodies.

Conclusions And Relevance: In patients with cerebral venous sinus thrombosis prior to the COVID-19 pandemic, baseline thrombocytopenia was uncommon, and heparin-induced thrombocytopenia and platelet factor 4/heparin antibodies were rare. These findings may inform investigations of the possible association between the ChAdOx1 nCoV-19 and Ad26.COV2.S COVID-19 vaccines and cerebral venous sinus thrombosis with thrombocytopenia.
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http://dx.doi.org/10.1001/jama.2021.9889DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8317004PMC
July 2021

Initiation of antidepressants in young adults after ischemic stroke: a registry-based follow-up study.

J Neurol 2021 Jun 24. Epub 2021 Jun 24.

Department of Neurology, Helsinki University Hospital and University of Helsinki, Haartmaninkatu 4, 00029, Helsinki, Finland.

Objective: Data on post-stroke use of antidepressants in young individuals are scarce. We examined pattern and factors associated with initiating post-stroke antidepressants (PSAD) after ischemic stroke (IS) in young adults.

Methods: Helsinki Young Stroke Registry includes patients aged 15-49 years with first-ever IS, 1994-2007. Data on prescriptions, hospitalizations and death came from nationwide registers. We defined time of initiating PSAD as time of the first filled prescription for antidepressants within 1 year from IS. We assessed factors associated with initiating PSAD with multivariable Cox regression models, allowing for time-varying effects when appropriate.

Results: We followed 888 patients, of which 206 (23.2%) initiated PSAD. Higher hazard of starting PSAD within the first 100 days appeared among patients with mild versus no limb paresis 2.53 (95% confidence interval 1.48-4.31) and during later follow-up among those with silent infarcts (2.04; 1.27-3.28), prior use of antidepressants (2.09; 1.26-3.46) and moderate versus mild stroke (2.06; 1.18-3.58). The relative difference in the hazard rate for moderate-severe limb paresis persisted both within the first 100 days (3.84, 2.12-6.97) and during later follow-up (4.54; 2.51-8.23). The hazard rate was higher throughout the follow-up among smokers (1.48; 1.11-1.97) as well as lower (1.78; 1.25-2.54) and upper white-collar workers (2.00; 1.24-3.23) compared to blue-collar workers.

Conclusion: One-fourth of young adults started PSADs within 1 year from IS. We identified several specific clinical characteristics associated with PSAD initiation, highlighting their utility in assessing the risk of post-stroke depression during follow-up.
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http://dx.doi.org/10.1007/s00415-021-10678-4DOI Listing
June 2021

Right atrium and cryptogenic ischaemic stroke in the young: a case-control study.

Open Heart 2021 May;8(1)

Department of Clinical Physiology and Nuclear Medicine, HUS Medical Imaging Center, Helsinki, Finland.

Background: Recent studies suggest left atrial (LA) dysfunction in cryptogenic stroke. We studied the dynamics of right atrium (RA) and right atrial appendage (RAA) in young adults with cryptogenic stroke. We hypothesised that bi-atrial dysfunction and blood stagnation might contribute to thrombosis formation in patients with patent foramen ovale (PFO), as deep venous thrombosis is detected only in the minority of patients.

Methods: Thirty patients (aged 18-49) with a first-ever cryptogenic stroke and 30 age-matched and sex-matched stroke-free controls underwent cardiac magnetic resonance (CMR) imaging. An approach to estimate the RAA volume was developed, using crista terminalis and pectinate muscles as anatomical landmarks. Atrial expansion indices were calculated as (maximal volume - minimal volume) ×100%/minimal volume. Total pulmonary to systemic blood flow ratio (Qp/Qs) was based on phase contrast CMR. Right-to-left shunt (RLS) was evaluated with transoesophageal echocardiography in 29 patients and transcranial Doppler in 30 controls, moderate-to-severe RLS considered as clinically significant.

Results: We found that RA and RAA volumes were similar between patients and controls. Also, RA expansion index was similar, but RAA (95.6%±21.6% vs 108.7%±25.8%, p=0.026) and LA (126.2%±28% vs 144.9%±36.3%, p=0.023) expansion indices were lower in patients compared with controls. Seven (24%) of 29 patients had an RLS compared with 1 (3%) of 30 controls (p=0.012). Among 59 study subjects, RLS was associated with lower RA (81.9%±15.9% vs 98.5%±29.5%, p=0.030), RAA (84.7%±18% vs 105.6%±24.1%, p=0.022), LA (109.8%±18.6% vs 140.1%±33.7%, p=0.017) and LAA (median 102.9% (IQR 65.6%-121.7%) vs 229.1% (151.8%-337.5%], p=0.002) expansion indices and lower Qp/Qs ratio (0.91±0.06 vs 0.98±0.07, p=0.027).

Conclusions: This study suggests bi-atrial dysfunction in young adults with cryptogenic stroke, associated with moderate-to-severe RLS. Dysfunction of the atria and atrial appendages may be an additional mechanism for PFO-related stroke.

Trial Registration Number: NCT01934725.
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http://dx.doi.org/10.1136/openhrt-2021-001596DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8137166PMC
May 2021

Editorial: Current Challenges in Cardioembolic Stroke.

Front Neurol 2021 27;12:688371. Epub 2021 Apr 27.

Department of Neurology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.

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http://dx.doi.org/10.3389/fneur.2021.688371DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8112548PMC
April 2021

Coagulopathy and its effect on treatment and mortality in patients with traumatic intracranial hemorrhage.

Acta Neurochir (Wien) 2021 05 23;163(5):1391-1401. Epub 2021 Mar 23.

Department of Neurology, Helsinki University Hospital and University of Helsinki, Haartmaninkatu 4, 00290, Helsinki, Finland.

Background: The role of coagulopathy in patients with traumatic brain injury has remained elusive. In the present study, we aim to assess the prevalence of coagulopathy in patients with traumatic intracranial hemorrhage, their clinical features, and the effect of coagulopathy on treatment and mortality.

Methods: An observational, retrospective single-center cohort of consecutive patients with traumatic intracranial hemorrhage treated at Helsinki University Hospital between 01 January and 31 December 2010. We compared clinical and radiological parameters in patients with and without coagulopathy defined as drug- or disease-induced, i.e., antiplatelet or anticoagulant medication at a therapeutic dose, thrombocytopenia (platelet count < 100 E9/L), international normalized ratio > 1.2, or thromboplastin time < 60%. Primary outcome was 30-day all-cause mortality. Logistic regression analysis allowed to assess for factors associated with coagulopathy and mortality.

Results: Of our 505 patients (median age 61 years, 65.5% male), 206 (40.8%) had coagulopathy. Compared to non-coagulopathy patients, coagulopathy patients had larger hemorrhage volumes (mean 140.0 mL vs. 98.4 mL, p < 0.001) and higher 30-day mortality (18.9% vs. 9.7%, p = 0.003). In multivariable analysis, older age, lower admission Glasgow Coma Scale score, larger hemorrhage volume, and conservative treatment were independently associated with mortality. Surgical treatment was associated with lower mortality in both patients with and without coagulopathy.

Conclusions: Coagulopathy was more frequent in patients with traumatic intracranial hemorrhage presenting larger hemorrhage volumes compared to non-coagulopathy patients but was not independently associated with higher 30-day mortality. Hematoma evacuation, in turn, was associated with lower mortality irrespective of coagulopathy.
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http://dx.doi.org/10.1007/s00701-021-04808-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8053656PMC
May 2021

Carotid intima-media thickness and arterial stiffness in relation to cerebral small vessel disease in neurologically asymptomatic individuals with type 1 diabetes.

Acta Diabetol 2021 Jul 20;58(7):929-937. Epub 2021 Mar 20.

Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland.

Aims: To determine if arterial functional and structural changes are associated with underlying cerebral small vessel disease in neurologically asymptomatic individuals with type 1 diabetes.

Methods: We enrolled 186 individuals (47.8% men; median age 40.0, IQR 33.0-45.0 years) with type 1 diabetes (median diabetes duration of 21.6, IQR 18.2-30.3 years), and 30 age- and sex-matched healthy controls, as part of the Finnish Diabetic Nephropathy (FinnDiane) Study. All individuals underwent a biochemical work-up, brain magnetic resonance imaging (MRI), ultrasound of the common carotid arteries and arterial tonometry. Arterial structural and functional parameters were assessed by carotid intima-media thickness (CIMT), pulse wave velocity and augmentation index.

Results: Cerebral microbleeds (CMBs) were present in 23.7% and white matter hyperintensities (WMHs) in 16.7% of individuals with type 1 diabetes. Those with type 1 diabetes and CMBs had higher median (IQR) CIMT 583 (525 - 663) μm than those without 556 (502 - 607) μm, p = 0.016). Higher CIMT was associated with the presence of CMBs (p = 0.046) independent of age, eGFR, ApoB, systolic blood pressure, albuminuria, history of retinal photocoagulation and HbA. Arterial stiffness and CIMT were increased in individuals with type 1 diabetes and WMHs compared to those without; however, these results were not independent of cardiovascular risk factors.

Conclusions: Structural, but not functional, arterial changes are associated with underlying CMBs in asymptomatic individuals with type 1 diabetes.
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http://dx.doi.org/10.1007/s00592-021-01678-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8187193PMC
July 2021

Mutations in a Neurovascular Disease Causing Stroke, Cognitive Impairment, and Tremor.

Neurol Genet 2021 Feb 21;7(1):e548. Epub 2021 Jan 21.

Department of Clinical Sciences Lund, Neurology (A.I., E.K., A.G.L., A.P.), Lund University; Section of Neurology (A.I., E.K., A.G.L., A.P.), Skåne University Hospital, Lund; Department of Clinical Genetics and Pathology (E.E., S.S.), Laboratory Medicine, Region Skåne; Department of Clinical Sciences Lund (E.E.), Division of Pathology, Lund University; Bioinformatics Core Facility (K.T.), Sahlgrenska Academy at University of Gothenburg, Sweden; Neurology (N.M.-M., J.P.), University of Helsinki, and Helsinki University Hospital, Finland; Department of Imaging and Function (C.H.), Skånes University Hospital, Lund; and Department of Clinical Sciences, Diagnostic Radiology (C.H.), Lund University, Sweden.

Objective: To describe a possible novel genetic mechanism for cerebral small vessel disease (cSVD) and stroke.

Methods: We studied a Swedish kindred with ischemic stroke and intracerebral hemorrhage, tremor, dysautonomia, and mild cognitive decline. Members were examined clinically, radiologically, and by histopathology. Genetic workup included whole-exome sequencing (WES) and whole-genome sequencing (WGS) and intrafamilial cosegregation analyses.

Results: Fifteen family members were examined clinically. Twelve affected individuals had white matter hyperintensities and 1 or more of (1) stroke episodes, (2) clinically silent lacunar ischemic lesions, and (3) cognitive dysfunction. All affected individuals had tremor and/or atactic gait disturbance. Mild symmetric basal ganglia calcifications were seen in 3 affected members. Postmortem examination of 1 affected member showed pathologic alterations in both small and large arteries the brain. Skin biopsies of 3 affected members showed extracellular amorphous deposits within the subepidermal zone, which may represent degenerated arterioles. WES or WGS did not reveal any potentially disease-causing variants in known genes for cSVDs or idiopathic basal ganglia calcification, but identified 1 heterozygous variant, NM_004672.4 c.322G>A p.(Asp108Asn), that cosegregated with the disease in this large family. MAP3K6 has known functions in angiogenesis and affects vascular endothelial growth factor expression, which may be implicated in cerebrovascular disease.

Conclusions: Our data strongly suggest the variant to be causative for this novel disease phenotype, but the absence of functional data and the present lack of additional families with this disease and mutations still limit the formal evidence for the variant's pathogenicity.
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http://dx.doi.org/10.1212/NXG.0000000000000548DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7958314PMC
February 2021

The impact of parental risk factors on the risk of stroke in type 1 diabetes.

Acta Diabetol 2021 Jul 15;58(7):911-917. Epub 2021 Mar 15.

Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum Helsinki, Helsinki, Finland.

Background: Individuals with type 1 diabetes have a markedly increased risk of stroke. In the general population, genetic predisposition has been linked to increased risk of stroke, but this has not been assessed in type 1 diabetes. Our aim was, therefore, to study how parental risk factors affect the risk of stroke in individuals with type 1 diabetes.

Methods: This study represents an observational follow-up of 4011 individuals from the Finnish Diabetic Nephropathy Study, mean age at baseline 37.6 ± 11.9 years. All strokes during follow-up were verified from medical records or death certificates. The strokes were classified as either ischemic or hemorrhagic. All individuals filled out questionnaires concerning their parents' medical history of hypertension, diabetes, stroke, and/or myocardial infarction.

Results: During a median follow-up of 12.4 (10.9-14.2) years, 188 individuals (4.6%) were diagnosed with their first ever stroke; 134 were ischemic and 54 hemorrhagic. In Cox regression analysis, a history of maternal stroke increased the risk of hemorrhagic stroke, hazard ratio 2.86 (95% confidence interval 1.27-6.44, p = 0.011) after adjustment for sex, age, BMI, retinal photocoagulation, and diabetic kidney disease. There was, however, no association between maternal stroke and ischemic stroke. No other associations between parental risk factors and ischemic or hemorrhagic stroke were observed.

Conclusion: A history of maternal stroke increases the risk of hemorrhagic stroke in individuals with type 1 diabetes. Other parental risk factors seem to have limited impact on the risk of stroke.
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http://dx.doi.org/10.1007/s00592-021-01694-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8187180PMC
July 2021

Timing of initiation of oral anticoagulants in patients with acute ischemic stroke and atrial fibrillation comparing posterior and anterior circulation strokes.

Eur Stroke J 2020 Dec 22;5(4):374-383. Epub 2020 Jul 22.

Internal Medicine, San Giuseppe Hospital, Empoli, Italy.

Introduction: The aim of this study in patients with acute posterior ischaemic stroke (PS) and atrial fibrillation (AF) was to evaluate (1) the risks of recurrent ischaemic event and severe bleeding and (2) these risks in relation with oral anticoagulant therapy (OAT) and its timing.

Materials And Methods: Patients with PS were prospectively included; the outcome events of these patients were compared with those of patients with anterior stroke (AS) which were taken from previous registries. The primary outcome was the composite of stroke recurrence, transient ischaemic attack, symptomatic systemic embolism, symptomatic cerebral bleeding and major extracranial bleeding occurring within 90 days from acute stroke.

Results: A total of 2470 patients were available for the analysis: 473 (19.1%) with PS and 1997 (80.9%) with AS. Over 90 days, 213 (8.6%) primary outcome events were recorded: 175 (8.7%) in patients with AS and 38 (8.0%) in those with PS. In patients who initiated OAT within 2 days, the primary outcome occurred in 5 out of 95 patients (5.3%) with PS compared to 21 out of 373 patients (4.3%) with AS (OR 1.07; 95% CI 0.39-2.94). In patients who initiated OAT between days 3 and 7, the primary outcome occurred in 3 out of 103 patients (2.9%) with PS compared to 26 out of 490 patients (5.3%) with AS (OR 0.54; 95% CI 0.16-1.80).

Discussion: our findings suggest that, when deciding the time to initiate oral anticoagulation, the location of stroke, either anterior or posterior, does not predict the risk of outcome events.

Conclusions: Patients with PS or AS and AF appear to have similar risks of ischaemic or haemorrhagic events at 90 days with no difference concerning the timing of initiation of OAT.
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http://dx.doi.org/10.1177/2396987320937116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856592PMC
December 2020

Evidence of subtle left ventricular systolic dysfunction in cryptogenic stroke in the young.

Echocardiography 2021 02 23;38(2):271-279. Epub 2021 Jan 23.

HUS Medical Imaging Center, Clinical Physiology and Nuclear Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

Introduction: Ischemic stroke in young patients often remains cryptogenic, that is, no underlying reason can be found. Some of these strokes may originate in the heart. Left ventricular (LV) dynamic volumetry and strain analysis are relatively new and promising methods for evaluating LV function.

Methods: In this pilot study, we recruited 30 young (18-50 years) patients with cryptogenic ischemic stroke and 30 age- and sex-matched controls from the SECRETO study (NCT01934725). The LV systolic function was assessed by LV volumetry (ejection fraction, peak emptying rate, and time to peak emptying rate). The longitudinal systolic function was assessed by speckle tracking strain and strain rate imaging, and by tissue velocity imaging derived MAD (mitral annular displacement) and septal S'.

Results: Stroke patients had less vigorous global longitudinal strain (median -18.9, interquartile range 3.3), compared to healthy controls (median -20.0, interquartile range 2.8), P = .010. There was no statistically significant differences in septal S', MAD, global longitudinal strain rate, or dynamic volumetry-derived parameters between the two groups.

Conclusions: Young cryptogenic stroke patients have subtly altered systolic function compared to healthy controls, found merely with longitudinal strain analysis. This infers that the heart may play a role in the pathogenesis of cryptogenic ischemic stroke.
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http://dx.doi.org/10.1111/echo.14978DOI Listing
February 2021

Tenecteplase in wake-up ischemic stroke trial: Protocol for a randomized-controlled trial.

Int J Stroke 2021 Jan 14:1747493020984073. Epub 2021 Jan 14.

Department of Clinical Medicine, UiT The Arctic University of Norway, Tromsø, Norway.

Background: Patients with wake-up ischemic stroke who have evidence of salvageable tissue on advanced imaging can benefit from intravenous thrombolysis. It is not known whether patients who do not fulfil such imaging criteria might benefit from treatment, but studies indicate that treatment based on non-contrast CT criteria may be safe. Tenecteplase has shown promising results in patients with acute ischemic stroke. The aim of the Tenecteplase in Wake-up Ischemic Stroke Trial (TWIST) is to compare the effect of thrombolytic treatment with tenecteplase and standard care versus standard care alone in patients with wake-up ischemic stroke selected by non-contrast CT.

Methods/design: TWIST is an international, investigator-initiated, multi-centre, prospective, randomized-controlled, open-label, blinded end-point trial of tenecteplase ( = 300) versus standard care ( = 300) in patients who wake up with an acute ischemic stroke and can be treated within 4.5 h upon awakening. Seventy-seven centres in 10 countries (Denmark, Estonia, Finland, Latvia, Lithuania, New Zealand, Norway, Sweden, Switzerland, and the United Kingdom) participate. The primary outcome is the modified Rankin Scale on the ordinal scale (0-6) at three months.

Discussion: TWIST aims to determine the effect and safety of thrombolytic treatment with tenecteplase in patients with wake-up ischemic stroke selected by non-contrast CT.

Trial Registration: ClinicalTrials.gov NCT03181360. EudraCT Number 2014-000096-80.
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http://dx.doi.org/10.1177/1747493020984073DOI Listing
January 2021

The prevalence and Covariates of Stroke in Khyber Pakhtunkhwa; From a European Perspective.

Pak J Med Sci 2021 Jan-Feb;37(1):1-3

Jukka Putaala MD, PhD. Neurology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.

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http://dx.doi.org/10.12669/pjms.37.1.3815DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794126PMC
January 2021

Reply to "Migraine and Cryptogenic Ischemic Stroke".

Ann Neurol 2021 03 5;89(3):629. Epub 2021 Jan 5.

Department of Neurology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.

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http://dx.doi.org/10.1002/ana.25997DOI Listing
March 2021

MRI Characterization of Non-traumatic Intracerebral Hemorrhage in Young Adults.

Front Neurol 2020 29;11:558680. Epub 2020 Oct 29.

Department of Radiology, Medical Imaging Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

Non-traumatic intracerebral hemorrhage (ICH) in younger population is a relatively rare event but is associated with considerable mortality and poor functional outcome. Imaging plays a crucial role in determining the underlying cause and guide treatment of ICH. In up to 41% of patients in prior studies, the underlying cause remained elusive. However, the usage of MRI as part of diagnostic work-up was scanty. We aimed to analyze MRI findings of ICH in younger patients and assess specificity and sensitivity of MRI in detecting structural or local underlying causes of ICH. We included patients aged 15-49 years with first-ever ICH identified from a prospective hospital discharge registry, 2000-2010. All study patients underwent MRI within 3 months of ICH. Imaging data was analyzed by a senior neuroradiologist blinded to final clinical diagnosis. We calculated the diagnostic accuracy of MRI in detecting structural/local underlying causes. Of our 116 patients (median age, 39; 67% males), structural/local causes were the leading causes of ICH (50.0%), and of these, bleeding cavernomas (23.3%) were the most frequent followed by arteriovenous malformations (12.9%), cerebral venous thrombosis (CVT) (7.8%), brain tumors (5.2%), and moyamoya disease (0.9%). Lobar location of ICH was more prevalent in younger patients. MRI was highly sensitive (90.0%; 95% confidence interval, 79.5-96.2%) for detection of structural/local causes compared with angiographic imaging (55.6%; 95% CI, 40.0-70.4%), while MRI was less specific (87.3%; 95% CI, 75.5-94.7%) for structural/local causes, compared with angiographic imaging (97.4%; 95% CI, 86.5-99.9%). MRI was highly sensitive for the detection of structural and local causes underlying ICH in young adults. Thus, MRI should be considered in the diagnostic work-up of all young ICH patients to enable targeted secondary prevention.
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http://dx.doi.org/10.3389/fneur.2020.558680DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7658320PMC
October 2020

Association between Migraine and Cryptogenic Ischemic Stroke in Young Adults.

Ann Neurol 2021 02 12;89(2):242-253. Epub 2020 Nov 12.

Neurology, Helsinki University Hospital, and University of Helsinki, Helsinki, Finland.

Objective: To assess the association between migraine and cryptogenic ischemic stroke (CIS) in young adults, with subgroup analyses stratified by sex and presence of patent foramen ovale (PFO).

Methods: We prospectively enrolled 347 consecutive patients aged 18 to 49 years with a recent CIS and 347 age- and sex-matched (±5 years) stroke-free controls. Any migraine and migraine with (MA) and migraine without aura (MO) were identified by a screener, which we validated against a headache neurologist. We used conditional logistic regression adjusting for age, education, hypertension, diabetes, waist-to-hip ratio, physical inactivity, current smoking, heavy drinking, and oral estrogen use to assess independent association between migraine and CIS. The effect of PFO on the association between migraine and CIS was analyzed with logistic regression in a subgroup investigated with transcranial Doppler bubble screen.

Results: The screener performance was excellent (Cohen kappa > 0.75) in patients and controls. Compared with nonmigraineurs, any migraine (odds ratio [OR] = 2.48, 95% confidence interval [CI] = 1.63-3.76) and MA (OR = 3.50, 95% CI = 2.19-5.61) were associated with CIS, whereas MO was not. The association emerged in both women (OR = 2.97 for any migraine, 95% CI = 1.61-5.47; OR = 4.32 for MA, 95% CI = 2.16-8.65) and men (OR = 2.47 for any migraine, 95% CI = 1.32-4.61; OR = 3.61 for MA, 95% CI = 1.75-7.45). Specifically for MA, the association with CIS remained significant irrespective of PFO. MA prevalence increased with increasing magnitude of the right-to-left shunt in patients with PFO.

Interpretation: MA has a strong association with CIS in young patients, independent of vascular risk factors and presence of PFO. ANN NEUROL 2021;89:242-253.
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http://dx.doi.org/10.1002/ana.25937DOI Listing
February 2021

Prolonged ECG with a novel recorder utilizing electrode belt and mobile device in patients with recent embolic stroke of undetermined source: A pilot study.

Ann Noninvasive Electrocardiol 2020 11 27;25(6):e12802. Epub 2020 Sep 27.

Department of Internal Medicine, Päijät-Häme Central Hospital, Lahti, Finland.

Background: Paroxysmal atrial fibrillation (pAF) is a major risk factor for ischemic stroke, but challenging to detect with routine short-term monitoring methods. In this pilot study, we present a novel method for prolonged ECG and screening for pAF in patients with a recent embolic stroke of unknown source (ESUS).

Methods: Fifteen patients aged ≥ 50 years with a recent ESUS were assigned to wear an external electrode belt-based 1-lead ECG device (Beat2Phone) continuously for 2 weeks (wear time). The device was operated via a mobile phone application in nonhospital conditions. The primary outcome was patient adherence to monitoring. Secondary outcomes were incidence of new pAF, quality-wise comparison to Holter, and usability of the novel ECG monitoring method with Systems Usability Scale (SUS). We also performed a 24- to 48-hr comparison between simultaneous Beat2Phone ECG and a standard Holter in 6 patients.

Results: Wear time of Beat2Phone device was over 80% in 5 (33.3%) patients, 50%-80% in 7 (46.6%) patients, and less than 50% in 3 (20%) patients. We detected pAF ≥ 30 s in 1 patient (6.7%). In the simultaneous monitoring with Beat2Phone and Holter, there were a total of 817 (out of 1979) analyzable periods of sinus rhythm or premature atrial or ventricular beats (Cohen's Kappa coefficient 0.92 ± 0.02 between Beat2Phone and Holter), and no pAF events. Beat2Phone ECG showed remarkable SUS scores in user evaluations (average score: 81.4 out of 100 on SUS).

Conclusions: Beat2Phone device was easy to use among ESUS patients and in optimal conditions provided high-quality 1-lead ECG signal for diagnosing pAF.

Clinical Trial Registration: The study was not registered, as it was a nonrandomized single-arm pilot study.
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http://dx.doi.org/10.1111/anec.12802DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7679839PMC
November 2020

A score to predict one-year risk of recurrence after acute ischemic stroke.

Int J Stroke 2021 07 17;16(5):602-612. Epub 2020 Jun 17.

Stroke Center, Neurology Service, Lausanne University Hospital, Lausanne, Switzerland.

Background: An acute ischemic stroke carries a substantial risk of further recurrences. We aimed at developing and validating a prognostic tool to predict one-year stroke recurrence after acute ischemic stroke.

Methods: An integer score was derived by Cox regression analysis on a hospital-referred cohort of 3246 acute ischemic stroke patients from Switzerland, and tested for external validity in three similar independent cohorts from Athens ( = 2495), Milan ( = 1279), and Helsinki ( = 714) by means of calibration and discrimination.

Results: In the derivation cohort, the recurrence rate was 7% ( = 228/3246). We developed a nine-point score comprising: previous stroke or transient ischemic attack (1-point), stroke mechanism (small vessel disease and unknown mechanism: 0-points; rare stroke mechanism: 3-points; other mechanisms: 1-point), pre-stroke antiplatelets (1-point), active malignancy (2-points), chronic cerebrovascular lesions on imaging (1-point) and absence of early ischemic changes on first imaging (1-point). In the derivation cohort, the one-year risk of re-stroke was 3.0% (95%CI 1.9-4.1) in 932 (29%) patients with a score 0-1, 7.2% (6.1-8.3) in 2038 (63%) with a score 2-4, and 19.2% (14.6-23.9) in 276 (8%) with a score ≥ 5. The score calibrated well in the Athens (recurrences = 208/2495), but not in the Helsinki (recurrences = 15/714) or Milan (recurrences = 65/1279) cohorts. The AUC was 0.67 in the derivation cohort, and 0.56, 0.70, and 0.63 in the Athens, Helsinki, and Milan cohorts, respectively.

Conclusion: We developed a score to predict one-year stroke recurrence risk in patients with acute ischemic stroke. Since the score was not completely validated when applied to external datasets where it displayed poor to fair calibration and discrimination, additional efforts are required to ameliorate our accuracy for predicting stroke recurrence, by better refining this prognostic tool or developing new ones. Clinical and radiological markers of established cerebrovascular disease and stroke etiology were better predictors than the usual demographic vascular risk factors.
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http://dx.doi.org/10.1177/1747493020932787DOI Listing
July 2021

Left ventricular non-compaction as a potential source for cryptogenic ischemic stroke in the young: A case-control study.

PLoS One 2020 14;15(8):e0237228. Epub 2020 Aug 14.

Heart and Lung Center, Helsinki University Hospital and Helsinki University, Helsinki, Finland.

Background: Up to 50% of ischemic strokes in the young after thorough diagnostic work-up remain cryptogenic or associated with low-risk sources of cardioembolism such as patent foramen ovale (PFO). We studied with cardiac magnetic resonance (CMR) imaging, whether left ventricular (LV) non-compaction-a possible source for embolic stroke due to sluggish blood flow in deep intertrabecular recesses-is associated with cryptogenic strokes in the young.

Methods: Searching for Explanations for Cryptogenic Stroke in the Young: Revealing the Etiology, Triggers, and Outcome (SECRETO; NCT01934725) is an international prospective multicenter case-control study of young adults (aged 18-49 years) presenting with an imaging-positive first-ever ischemic stroke of undetermined etiology. In this pilot substudy, 30 cases and 30 age- and sex-matched stroke-free controls were examined with CMR. Transcranial Doppler (TCD) bubble test was performed to evaluate the presence and magnitude of right-to-left shunt (RLS).

Results: There were no significant differences in LV volumes, masses or systolic function between cases and controls; none of the participants had non-compaction cardiomyopathy. Semi-automated assessment of LV non-compaction was highly reproducible. Non-compacted LV mass (median 14.0 [interquartile range 12.6-16.0] g/m2 vs. 12.7 [10.4-16.6] g/m2, p = 0.045), the ratio of non-compacted to compacted LV mass (mean 25.6 ± 4.2% vs. 22.8 ± 6.0%, p = 0.015) and the percentage of non-compacted LV volume (mean 17.6 ± 2.9% vs. 15.7 ± 3.8%, p = 0.004) were higher in cases compared to controls. In a multivariate conditional logistic regression model including non-compacted LV volume, RLS and body mass index, the percentage of non-compacted LV volume (odds ratio [OR] 1.55, 95% confidence interval [CI] 1.10-2.18, p = 0.011) and the presence of RLS (OR 11.94, 95% CI 1.14-124.94, p = 0.038) were independently associated with cryptogenic ischemic stroke.

Conclusions: LV non-compaction is associated with a heightened risk of cryptogenic ischemic stroke in young adults, independent of concomitant RLS and in the absence of cardiomyopathy.

Clinical Trial Registration: SECRETO; NCT01934725. Registered 4th September 2013. https://clinicaltrials.gov/ct2/show/NCT01934725.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0237228PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7428175PMC
October 2020

Characteristics and Outcomes in Patients With COVID-19 and Acute Ischemic Stroke: The Global COVID-19 Stroke Registry.

Stroke 2020 09 9;51(9):e254-e258. Epub 2020 Jul 9.

Stroke Center, Neurology Service, Department of Clinical Neurosciences, Lausanne University Hospital, Switzerland (P.M., E.M., D. Strambo).

Recent case-series of small size implied a pathophysiological association between coronavirus disease 2019 (COVID-19) and severe large-vessel acute ischemic stroke. Given that severe strokes are typically associated with poor prognosis and can be very efficiently treated with recanalization techniques, confirmation of this putative association is urgently warranted in a large representative patient cohort to alert stroke clinicians, and inform pre- and in-hospital acute stroke patient pathways. We pooled all consecutive patients hospitalized with laboratory-confirmed COVID-19 and acute ischemic stroke in 28 sites from 16 countries. To assess whether stroke severity and outcomes (assessed at discharge or at the latest assessment for those patients still hospitalized) in patients with acute ischemic stroke are different between patients with COVID-19 and non-COVID-19, we performed 1:1 propensity score matching analyses of our COVID-19 patients with non-COVID-19 patients registered in the Acute Stroke Registry and Analysis of Lausanne Registry between 2003 and 2019. Between January 27, 2020, and May 19, 2020, 174 patients (median age 71.2 years; 37.9% females) with COVID-19 and acute ischemic stroke were hospitalized (median of 12 patients per site). The median National Institutes of Health Stroke Scale was 10 (interquartile range [IQR], 4-18). In the 1:1 matched sample of 336 patients with COVID-19 and non-COVID-19, the median National Institutes of Health Stroke Scale was higher in patients with COVID-19 (10 [IQR, 4-18] versus 6 [IQR, 3-14]), =0.03; (odds ratio, 1.69 [95% CI, 1.08-2.65] for higher National Institutes of Health Stroke Scale score). There were 48 (27.6%) deaths, of which 22 were attributed to COVID-19 and 26 to stroke. Among 96 survivors with available information about disability status, 49 (51%) had severe disability at discharge. In the propensity score-matched population (n=330), patients with COVID-19 had higher risk for severe disability (median mRS 4 [IQR, 2-6] versus 2 [IQR, 1-4], <0.001) and death (odds ratio, 4.3 [95% CI, 2.22-8.30]) compared with patients without COVID-19. Our findings suggest that COVID-19 associated ischemic strokes are more severe with worse functional outcome and higher mortality than non-COVID-19 ischemic strokes.
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http://dx.doi.org/10.1161/STROKEAHA.120.031208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7359900PMC
September 2020

Late seizures in cerebral venous thrombosis.

Neurology 2020 09 5;95(12):e1716-e1723. Epub 2020 Aug 5.

From the Department of Neurology (M.S.v.K., S.M.S., S.M.Z., J.M.C.), Amsterdam UMC, University of Amsterdam, the Netherlands; Department of Clinical Neuroscience (E.L., J.Z., P.R., T.T., K.J.), Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg; Department of Neurology (E.L., J.Z., P.R., T.T., K.J.), Sahlgrenska University Hospital, Gothenburg, Sweden; Department of Neurology (S.H., T.T., J.P.), Helsinki University Hospital and University of Helsinki, Finland; Department of Neurology (M.R.H., M.A.), Inselspital, Bern University Hospital and University of Bern, Switzerland; National Institute of Neurology and Neurosurgery Manuel Velasco Suarez (F.S., A.A.), Mexico City, Mexico; Sina Hospital (M.M., M.G.), Hamadan University of Medical Science, Iran; Department of Neurosciences and Mental Health (Neurology) (D.A.d.S., P.C., J.M.F.), Hospital de Santa Maria/CHULN; University of Lisbon (D.A.d.S., P.C., J.M.F.), Portugal; Manchester Centre for Clinical Neurosciences (S.A.-A., M.N.M.P.), Salford Royal NHS Foundation Trust, UK; Department of Neurology (E.E., N.Y.), Istanbul Faculty of Medicine, Istanbul University, Turkey; Neurosciences Department (M.A.B.), Hospital Dr. R.A. Calderón Guardia, CCSS, San José, Costa Rica; and Department of Biomedicine, Neuroscience and Advanced Diagnostics (V.A., P.A.), University of Palermo, Italy.

Objective: To examine the incidence, characteristics, treatment, and predictors of late seizures (LS) after cerebral venous thrombosis (CVT), we described these features in a registry of 1,127 patients with CVT.

Methods: We included consecutive adult patients from an international consortium of 12 hospital-based CVT registries. We excluded patients with a history of epilepsy or with <8 days of follow-up. We defined LS as seizures occurring >7 days after diagnosis of CVT. We used multivariable Cox regression to identify predictors of LS.

Results: We included 1,127 patients with CVT. During a median follow-up of 2.0 years (interquartile range [IQR] 1.0-6.3), 123 patients (11%) experienced ≥1 LS (incidence rate for first LS 30 per 1,000 person-years, 95% confidence interval [CI] 25-35). Median time to first LS was 5 months (IQR 1-16 months). Baseline predictors of LS included status epilepticus in the acute phase (hazard ratio [HR] 7.0, 95% CI 3.9-12.6), decompressive hemicraniectomy (HR 4.2, 95% CI 2.4-7.3), acute seizure(s) without status epilepticus (HR 4.1, 95% CI 2.5-6.5), subdural hematoma (HR 2.3, 95% CI 1.1-4.9), and intracerebral hemorrhage (HR 1.9, 95% CI 1.1-3.1). Eighty-five patients (70% of patients with LS) experienced a recurrent seizure during follow-up, despite the fact that 94% received antiepileptic drug treatment after the first LS.

Conclusion: During a median follow-up of 2 years, ≈1 in 10 patients with CVT had LS. Patients with baseline intracranial bleeding, patients with acute symptomatic seizures, and those who underwent decompressive hemicraniectomy were at increased risk of developing LS. The high recurrence risk of LS justifies epilepsy diagnosis after a first LS.
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http://dx.doi.org/10.1212/WNL.0000000000010576DOI Listing
September 2020
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