Association of Left Atrial Stiffness With Risk of Cryptogenic Ischemic Stroke in Young Adults.

Background: Incidence of cryptogenic ischemic stroke (CIS) in young adults is increasing. Early left atrial (LA) myopathy might be 1 of the underlying mechanisms, but this has only been scarcely explored. Objectives: The purpose of this study was to assess the association between increased LA stiffness and CIS in young adults. Methods: In the multicenter SECRETO (Searching for Explanations for Cryptogenic Stroke in the Young: Revealing the Etiology, Triggers, and Outcome) study, LA function was analyzed by speckle tracking echocardiography in 150 CIS patients (aged 18-49 years) and 150 age- and sex-matched controls. Minimum and maximum LA volumes, LA reservoir and contractile strain were measured. LA stiffness was calculated by the ratio: mitral peak E-wave velocity divided by mitral annular e' velocity (E/e')/LA reservoir strain and considered increased if ≥0.22. Increased LA volumes, LA stiffness, and/or reduced LA strain indicated LA myopathy. Logistic regression was used to determine the relation between LA stiffness and CIS and the clinical variables associated with LA stiffness. Results: Increased LA stiffness was found in 36% of patients and in 18% of controls (P < 0.001). Increased LA stiffness was associated with a 2.4-fold (95% CI: 1.1-5.3) higher risk of CIS after adjustment for age, sex, comorbidities, and echocardiographic confounders (P = 0.03). In patients, obesity, pre-CIS antihypertensive treatment, older age, and lower LA contractile strain were all related to increased LA stiffness (all P < 0.05). Conclusions: LA myopathy with increased LA stiffness and impaired LA mechanics more than doubles the risk of CIS in patients under the age of 50 years. This provides new insights into the link between LA dysfunction and CIS at young ages. (Searching for Explanations for Cryptogenic Stroke in the Young: Revealing the Etiology, Triggers, and Outcome [SECRETO]; NCT01934725).

Association between heavy alcohol consumption and cryptogenic ischaemic stroke in young adults: a case-control study.

BACKGROUND: The underlying risk factors for young-onset cryptogenic ischaemic stroke (CIS) remain unclear. This multicentre study aimed to explore the association between heavy alcohol consumption and CIS with subgroup analyses stratified by sex and age. METHODS: Altogether, 540 patients aged 18-49 years (median age 41; 47.2% women) with a recent CIS and 540 sex-matched and age-matched stroke-free controls were included. Heavy alcohol consumption was defined as >7 (women) and >14 (men) units per week or at least an average of two times per month ≥5 (women) and ≥7 (men) units per instance (binge drinking). A conditional logistic regression adjusting for age, sex, education, hypertension, cardiovascular diseases, diabetes, hypercholesterolaemia, current smoking, obesity, diet and physical inactivity was used to assess the independent association between alcohol consumption and CIS. RESULTS: Patients were twice as more often heavy alcohol users compared with controls (13.7% vs 6.7%, p<0.001), were more likely to have hypertension and they were more often current smokers, overweight and physically inactive. In the entire study population, heavy alcohol consumption was independently associated with CIS (adjusted OR 2.11; 95% CI 1.22 to 3.63). In sex-specific analysis, heavy alcohol consumption was associated with CIS in men (2.72; 95% CI 1.25 to 5.92), but not in women (1.56; 95% CI 0.71 to 3.41). When exploring the association with binge drinking alone, a significant association was shown in the entire cohort (2.43; 95% CI 1.31 to 4.53) and in men (3.36; 95% CI 1.44 to 7.84), but not in women. CONCLUSIONS: Heavy alcohol consumption, particularly binge drinking, appears to be an independent risk factor in young men with CIS.

Thrombolysis treatment protected impairment of functional ability, quality of life and fatigue seven years after stroke.

OBJECTIVES: We studied quality of life, functional outcome, depression, and fatigue of ischemic stroke patients treated with or without thrombolysis seven years post-stroke. MATERIALS AND METHODS: A total of 204 ischemic stroke patients treated with or without thrombolysis during 2013-2015. After seven years the 136 survivors were assessed with telephone interview, which included questions about subjective quality of life (European Quality of Life-5 Dimensions), depression, fatigue with Fatigue Severity Scale, functional ability assessed with Barthel Index and Modified Rankin Scale, living conditions, need of care, and medical aids. RESULTS: At admission patients with thrombolysis had higher National Institutes of Health Stroke Scale scores compared with those not treated with thrombolysis. At seven years post-stroke, 99% of alive patients answered the questionnaires. There were no group differences concerning functional outcome, quality of life, depression, fatigue, or insomnia. The Barthel Index was normal in both groups. The quality of life was good in both groups without group differences in any domains. Of all patients, 68% reported no problems in usual activities, and 61% were without pain. Anxiety or depression were experienced by 19% of all stroke patients, while fatigue was present in 32% of cases. CONCLUSIONS: Seven years post-stroke the quality of life was good and functional outcome remained in good level in both study groups. One third experienced fatigue, while every fifth experienced depression. The thrombolysis treatment seems to protect from decreased quality of life, fatigue, and decreased mobility, self-care, and usual activities despite more severe stroke.

24-hour ambulatory blood pressure and cryptogenic ischemic stroke in young adults.

BACKGROUND: In young patients, up to 40% of ischemic strokes remain cryptogenic despite modern-day diagnostic work-up. There are limited data on blood pressure (BP) behavior in these patients. Thus, we aimed to compare ambulatory blood pressure (ABP) profiles between young patients with a recent cryptogenic ischemic stroke (CIS) and stroke-free controls. PATIENTS AND METHODS: In this substudy of the international multicenter case-control study SECRETO (NCT01934725), 24-hour ambulatory blood pressure monitoring (ABPM) was performed in consecutive 18-49-year-old CIS patients and stroke-free controls. The inclusion criteria were met by 132 patients (median age, 41.9 years; 56.1% males) and 106 controls (41.9 years; 56.6% males). We assessed not only 24-hour, daytime, and nighttime ABP but also hypertension phenotypes and nocturnal dipping status. RESULTS: 24-hour and daytime ABP were higher among controls. After adjusting for relevant confounders, a non-dipping pattern of diastolic blood pressure (DBP) was associated with CIS in the entire sample (odds ratio, 3.85; 95% confidence interval, 1.20-12.42), in participants without antihypertensives (4.86; 1.07-22.02), and in participants without a patent foramen ovale (PFO) (7.37; 1.47-36.81). After excluding patients in the first tertile of the delay between the stroke and ABPM, a non-dipping pattern of DBP was not associated with CIS, but a non-dipping pattern of both systolic BP and DBP was (4.85; 1.37-17.10). In participants with a PFO and in those without hypertension by any definition, no associations between non-dipping patterns of BP and CIS emerged. CONCLUSIONS: Non-dipping patterns of BP were associated with CIS in the absence of a PFO but not in the absence of hypertension. This may reflect differing pathophysiology underlying CIS in patients with versus without a PFO. Due to limitations of the study, results regarding absolute ABP levels should be interpreted with caution.Key MessagesNocturnal non-dipping patterns of blood pressure were associated with cryptogenic ischemic stroke except in participants with a patent foramen ovale and in those without hypertension by any definition, which may indicate differing pathophysiology underlying cryptogenic ischemic stroke in patients with and without a patent foramen ovale.It might be reasonable to include ambulatory blood pressure monitoring in the diagnostic work-up for young patients with ischemic stroke to detect not only the absolute ambulatory blood pressure levels but also their blood pressure behavior.

Nocturnal hypoxemia and central apneas increase mortality, but not recurrent ischemic events after ischemic stroke.

BACKGROUND: The aim of the study was to investigate whether findings in cardiorespiratory polygraphy had an association with stroke mortality or ischemic event recurrence after ischemic stroke. METHODS: We prospectively studied 204 ischemic stroke patients who underwent cardiorespiratory polygraphy within the first 48 h after the symptom onset. We followed all these patients for a median of 6.2 years. We evaluated mortality, time of survival, causes of death and new ischemic events. RESULTS: Of 204 ischemic stroke patients, 43 died and 48 had a new ischemic event during the follow-up. The lowest arterial oxyhemoglobin saturation (min SaO2) (P = 0.007) was lower, the percentage of time spent below arterial oxyhemoglobin saturation less than 90% (T90) (P = 0.005) was higher, and central apnea index per hour (CAI/h) (P = 0.04) was higher among the deceased. Male gender, older age, diabetes mellitus, elevated modified Rankin scale (mRS) score, lower Glasgow Coma Scale (GCS) score and CAI/h independently predicted higher mortality. Peripheral arterial disease (PAD) and higher National Institutes of Health Stroke Scale (NIHSS) score were independent predictors for a recurrent ischemic event. Among those having respiratory event index (REI) at least 30, older age and lower GCS score independently predicted higher mortality. Only 21 stroke patients initiated continuous positive airway pressure (CPAP) treatment; of those, only one had a new ischemic event. CONCLUSIONS: The non-survivors had more severe nocturnal hypoxemia and more central apneas than survivors. Among patients with REI at least 30/h, increased CAI predicted higher mortality, but not independently. CLINICAL TRIAL REGISTRATION: URL:http://www. CLINICALTRIALS: gov. Unique identifier: NCT01861275.

Obesity and the Risk of Cryptogenic Ischemic Stroke in Young Adults.

OBJECTIVES: We examined the association between obesity and early-onset cryptogenic ischemic stroke (CIS) and whether fat distribution or sex altered this association. MATERIALS AND METHODS: This prospective, multi-center, case-control study included 345 patients, aged 18-49 years, with first-ever, acute CIS. The control group included 345 age- and sex-matched stroke-free individuals. We measured height, weight, waist circumference, and hip circumference. Obesity metrics analyzed included body mass index (BMI), waist-to-hip ratio (WHR), waist-to-stature ratio (WSR), and a body shape index (ABSI). Models were adjusted for age, level of education, vascular risk factors, and migraine with aura. RESULTS: After adjusting for demographics, vascular risk factors, and migraine with aura, the highest tertile of WHR was associated with CIS (OR for highest versus lowest WHR tertile 2.81, 95%CI 1.43-5.51; P=0.003). In sex-specific analyses, WHR tertiles were not associated with CIS. However, using WHO WHR cutoff values (>0.85 for women, >0.90 for men), abdominally obese women were at increased risk of CIS (OR 2.09, 95%CI 1.02-4.27; P=0.045). After adjusting for confounders, WC, BMI, WSR, or ABSI were not associated with CIS. CONCLUSIONS: Abdominal obesity measured with WHR was an independent risk factor for CIS in young adults after rigorous adjustment for concomitant risk factors.

Long-term survival after primary intracerebral hemorrhage: A population-based case-control study spanning a quarter of a century.

BACKGROUND AND PURPOSE: The aim of this study was to determine the differences in life expectancy and causes of death after primary intracerebral hemorrhage (ICH) relative to general population controls. METHODS: In a population-based setting, 963 patients from Northern Ostrobothnia who had their first-ever ICH between 1993 and 2008 were compared with a cohort of 2884 sex- and age-matched controls in terms of dates and causes of death as extracted from the Causes of Death Register kept by Statistics Finland and valid up to the end of 2017. RESULTS: Of our 963 patients, 781 died during the follow-up time (mortality 81.1%). Cerebrovascular disease was the most common cause of death for these patients, 37.3% compared with 8.2% amongst the controls. The most common reasons for cerebrovascular mortality in the ICH patients were late sequelae of ICH in 12.8% (controls 0%) and new bleeding in 10.6% (controls 1.0%). The long-term survivors had a smaller ICH volume (median 12 ml) than those patients who died within 3 months (median 39 ml). The mortality rate of ICH patients during a follow-up between 12 and 24 years was still higher than that of their controls (hazard ratio 2.08, 95% confidence interval 1.58-2.74, p < 0.001). CONCLUSIONS: Very long-term ICH survivors have a constant excess mortality relative to controls even 10 years after the index event. A significantly larger proportion of patients died of cerebrovascular causes and fewer because of cancer relative to the controls.

Increased mortality after post-stroke epilepsy following primary intracerebral hemorrhage.

OBJECTIVES: This study aimed to determine whether post-stroke epilepsy (PSE) predicts mortality, and to describe the most prominent causes of death (COD) in a long-term follow-up after primary intracerebral hemorrhage (ICH). METHODS: We followed 3-month survivors of a population-based cohort of primary ICH patients in Northern Ostrobothnia, Finland, for a median of 8.8 years. Mortality and CODs were compared between those who developed PSE and those who did not. PSE was defined according to the ILAE guidelines. CODs were extracted from death certificates (Statistics Finland). RESULTS: Of 961 patients, 611 survived for 3 months. 409 (66.9%) had died by the end of the follow-up. Pneumonia was the only COD that was significantly more common among the patients with PSE (56% vs. 37% of deaths). In the multivariable models, PSE (hazard ratio [HR] 1.41, 95% confidence interval [CI] 1.06-1.87), age (HR 1.07, 95% CI 1.06-1.08), male sex (HR 1.35, 95% CI 1.09-1.67), dependency at 3 months (HR 1.52, 95% CI 1.24-1.88), non-subcortical ICH location (subcortical location HR 0.78, 95% CI 0.61-0.99), diabetes (HR 1.43, 95% CI 1.07-1.90) and cancer (HR 1.45, 95% CI 1.06-1.98) predicted death in the long-term follow-up. CONCLUSION: PSE independently predicted higher late morality of ICH in our cohort. Pneumonia-related deaths were more common among the patients with PSE.

Association between Migraine and Cryptogenic Ischemic Stroke in Young Adults.

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.

Unattended sleep study in screening for sleep apnea in the acute phase of ischemic stroke.

OBJECTIVES: We aimed to compare the feasibility of automatically and manually scored cardiorespiratory polygraphy results for sleep apnea screening in the acute phase of ischemic stroke. METHODS: Prospective study included 204 ischemic stroke patients, who underwent nocturnal unattended portable monitoring with three-channel device during 48 h after onset of stroke symptoms. Sleep apnea diagnosis was determined as a respiratory event index (REI) ≥5/hour. RESULTS: The mean age of the patients was 67.7 years and 62.7% were males. Automatic scoring identified sleep apnea in 148/72.5% and manual scoring in 186/91.2% of patients, showing moderate agreement (Kappa value 0.407). Of the cohort, 39 (19.1%) patients fulfilled the criteria for diagnosis of central sleep apnea (CSA) (>50% of events central) and 165 (80.9%) had obstructive sleep apnea (OSA). Automatic scoring identified poorly the type of events, and missed 18.6% of recordings. Oxygen desaturation 4% index (ODI4), interclass correlation coefficient (ICC) value 0.993, (95% CI 0.990-0.994), lowest saturation (ICC value 0.989, 95% CI 0.985-0.991) and percent of time spent <90% (ICC value 0.987, 95% CI 0.982-0.990) showed excellent agreement. Interclass correlation value for REI was 0.869 (95% CI 0.828 to 0.901) and ICC value 0.848 (95% CI 0.800 to 0.885) for obstructive apnea index, both indicating good agreement. Automatic scoring underestimated the severity of sleep apnea. CONCLUSIONS: Both automatically and manually scored results recognized sleep apnea, albeit manual scoring identified more sleep apnea. Sleep apnea diagnosis agreement was moderate. Underestimation of the severity of sleep apnea by automatic scoring may result in undertreatment of sleep apnea. CLINICAL TRIAL REGISTRATION: URL:http://www.clinicaltrials.cov. Unique identifier: NCT01861275.

Comparison of optic disc evaluation methods in neurology emergency patients.

BACKGROUND: The optic disc examination is critical for the diagnostics of several acute neurological disorders. However, dilation of the pupil is not recommended for neurological patients, which complicates ophthalmoscopy. AIMS OF THE STUDY: Present pilot study compared a portable fundus camera to an ophthalmoscope in fundus examinations of neurological emergency patients. To our knowledge, this is the first comparative study of the subject. The fundus photographs were later reviewed with an ophthalmologist. METHODS: The study included 60 adults, volunteer neurological emergency patients with either headache, cerebrovascular disorder, or acute confusional state (delirium). Patients' non-mydriatic fundus examination was conducted with an ophthalmoscope and a Smartscope Pro fundus camera. RESULTS: Fundus photography succeeded in 56 (93%), partially succeeded in 2 (3%), and failed in 2 (3%) cases compared with ophthalmoscopy that succeeded in 35 (58%), partially succeeded in 14 (23%), and failed in 11 (18%) cases (P < .0005). The researcher and the ophthalmologist agreed in the findings in 54 out of 58 cases (93%). In six cases (7%), the researcher had failed to detect a non-critical ophthalmic finding. CONCLUSIONS: The neurological fundus examination by fundus camera seems to be superior to regular ophthalmoscopy in defining the critical optic disc findings in emergency patients.

Stroke Volume Predicts Nocturnal Hypoxemia in the Acute Ischemic Stroke after Intravenous Thrombolysis.

The Goal: The aim of the study was to investigate whether stroke volume or the presence of ischemic stroke lesion on follow-up computed tomography 1 day after admission had association with sleep apnea among ischemic stroke patients undergoing thrombolysis. MATERIALS AND METHODS: We prospectively recruited 110 consecutive ischemic stroke patients and performed computed tomography on admission and after 24 hours after intravenous thrombolysis. Stroke volume was measured from post-thrombolysis computed tomography scans. Unattended cardiorespiratory polygraphy with a 3-channel device was performed during 48 hours after admission. FINDINGS: Of 110 ischemic stroke patients treated with thrombolysis 65.5% were men. Mean age was 65.8 years and body mass index 27.5 kg/m2. The mean Epworth sleepiness scale score was 4.7. Eight patients (12.7%) with visible acute stroke after thrombolysis and none in the other group had hemorrhage as complication (P ˂ .001). Sleep apnea, determined as a respiratory event index greater than or equal to 5/hour, was diagnosed in 96.4% patients. Respiratory event index greater than 15/h was found in 72.8% of patients. Both mean baseline oxygen desaturation index (23.9 versus 16.5, P = .028) and obstructive apneas/hour (6.2 versus 2.7, P = .007) were higher in visible stroke group. Stroke volume (mean 15.9 mL) correlated with proportion of time spent below saturation less than 90%, P = .025. CONCLUSIONS: Acute ischemic stroke patients treated with thrombolysis with visible stroke were more likely to have nocturnal hypoxemia than patients with not visible strokes. Stroke volume correlated with time spent below saturation of 90%.

The Evolution of Sleep Apnea Six Months After Acute Ischemic Stroke and Thrombolysis.

STUDY OBJECTIVES: Our goal was to investigate the evolution of prevalence, severity, and type of sleep apnea among patients who had an ischemic stroke, with or without treatment with thrombolysis after 6 months. METHODS: We prospectively studied 204 patients who had an ischemic stroke (110 in the thrombolysis and 94 in the non-thrombolysis group). After follow-up, 177 patients were eligible for a final analysis (98 in the thrombolysis group and 79 in the non-thrombolysis group). An unattended sleep study with a three-channel portable device was performed both on admission and after the 6-month follow-up. RESULTS: The patients receiving thrombolysis were younger than those in the non-thrombolysis group (mean 65.5 versus 69.6 years P = .039). Sleep apnea, defined as a respiratory event index (REI) ≥ 5 events/h, was diagnosed in 92.7% patients, 93.9% versus 91.1% (P = .488) in the thrombolysis and non-thrombolysis groups, respectively. The prevalence remained unchanged during follow-up. Mild sleep apnea progressed to moderate or severe sleep apnea in 69.2% of the patients. Globally, mean central apneas per hour increased by 2.2% (P = .002), whereas obstructive apneas declined by 1.7% (P = .014). The mean change of oxygen desaturation index was -6.1% (P < .001) in the thrombolysis group, -1.8% (P = .327) in the non-thrombolysis group, and 4.2% (P = .001) in the whole group. In the non-thrombolysis group, the risk for new sleep apnea incidence increased by 6.1-fold (P = .024) at follow-up when compared to the thrombolysis group. CONCLUSIONS: Sleep apnea prevalence remained high in patients who had an ischemic stroke at 6 months post-stroke. The risk for developing sleep apnea after stroke was significantly lower among patients undergoing thrombolysis. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Title: Ischaemic Stroke and Sleep Apnea in Northern Part of Finland; Identifier: NCT01861275; URL: https://clinicaltrials.gov/ct2/show/NCT01861275.

Prevalence of sleep apnea at the acute phase of ischemic stroke with or without thrombolysis.

OBJECTIVE: The aim of the study was to compare the prevalence, type, and severity of sleep apnea during the acute phase of ischemic stroke among patients either receiving or not receiving thrombolysis. METHODS: We recruited 246 consecutive adult ischemic stroke patients. Patients underwent cardiorespiratory sleep study with portable three-channel device during the first 48 h after the symptom onset of ischemic stroke. RESULTS: We enrolled 110 (65.5% male) stroke patients in the thrombolysis group and 94 (59.6% male) in the nonthrombolysis group. In the thrombolysis group, the median National Institutes of Health Stroke Scale (NIHSS) score was higher (5.5) compared to the nonthrombolysis group (2.0) (p < 0.001). There was a lower incidence of lacunar (17.3% vs 36.2%, p = 0.002) and cerebellar (2.7% vs 16.0%, p < 0.001) strokes and a higher frequency of middle cerebral artery syndrome (60.9% vs 33.0%, p < 0.001) in the thrombolysis group compared to the nonthrombolysis group. Sleep apnea defined as an apnea-hypopnea index (AHI) ≥ 5/h was diagnosed in 186 (91.2%) patients, its prevalence being higher in the thrombolysis (96.4%) compared to the nonthrombolysis (85.1%) group (p = 0.007). The mean baseline AHI was 33.7/h in the thrombolysis group compared to 26.8/h in the nonthrombolysis group (p = 0.017). CONCLUSION: Sleep apnea was present in the vast majority of ischemic stroke patients. The stroke patients treated with thrombolysis were more likely to have sleep apnea, to have elevated NIHSS score at admission, and to be younger. Sleep apnea was more severe among those receiving thrombolysis as compared to those who were not. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.cov. Unique identifier: NCT01861275.

Poststroke epilepsy in long-term survivors of primary intracerebral hemorrhage.

OBJECTIVE: To identify the incidence and predisposing factors for development of poststroke epilepsy (PSE) after primary intracerebral hemorrhage (PICH) during a long-term follow-up. METHODS: We performed a retrospective study of patients who had had their first-ever PICH between January 1993 and January 2008 in Northern Ostrobothnia, Finland, and who survived for at least 3 months. These patients were followed up for PSE. The associations between PSE occurrence and sex, age, Glasgow Coma Scale (GCS) score on admission, hematoma location and volume, early seizures, and other possible risk factors for PSE were assessed using the Cox proportional hazards regression model. RESULTS: Of the 615 PICH patients who survived for longer than 3 months, 83 (13.5%) developed PSE. The risk of new-onset PSE was highest during the first year after PICH with cumulative incidence of 6.8%. In univariable analysis, the risk factors for PSE were early seizures, subcortical hematoma location, larger hematoma volume, hematoma evacuation, and a lower GCS score on admission, whereas patients with infratentorial hematoma location or hypertension were less likely to develop PSE (all variables p < 0.05). In multivariable analysis, we found subcortical location (hazard ratio [HR] 2.27, 95% confidence interval [CI] 1.35-3.81, p < 0.01) and early seizures (HR 3.63, 95% CI 1.99-6.64, p < 0.01) to be independent risk factors, but patients with hypertension had a lower risk of PSE (HR 0.54, 0.35-0.84, p < 0.01). CONCLUSIONS: Subcortical hematoma location and early seizures increased the risk of PSE after PICH in long-term survivors, while hypertension seemed to reduce the risk.

Searching for Explanations for Cryptogenic Stroke in the Young: Revealing the Triggers, Causes, and Outcome (SECRETO): Rationale and design.

BACKGROUND: Worldwide, about 1.3 million annual ischaemic strokes (IS) occur in adults aged <50 years. Of these early-onset strokes, up to 50% can be regarded as cryptogenic or associated with conditions with poorly documented causality like patent foramen ovale and coagulopathies. KEY HYPOTHESES/AIMS: (1) Investigate transient triggers and clinical/sub-clinical chronic risk factors associated with cryptogenic IS in the young; (2) use cardiac imaging methods exceeding state-of-the-art to reveal novel sources for embolism; (3) search for covert thrombosis and haemostasis abnormalities; (4) discover new disease pathways using next-generation sequencing and RNA gene expression studies; (5) determine patient prognosis by use of phenotypic and genetic data; and (6) adapt systems medicine approach to investigate complex risk-factor interactions. DESIGN: Searching for Explanations for Cryptogenic Stroke in the Young: Revealing the Etiology, Triggers, and Outcome (SECRETO; NCT01934725) is a prospective multi-centre case-control study enrolling patients aged 18-49 years hospitalised due to first-ever imaging-proven IS of undetermined etiology. Patients are examined according to a standardised protocol and followed up for 10 years. Patients are 1:1 age- and sex-matched to stroke-free controls. Key study elements include centralised reading of echocardiography, electrocardiography, and neurovascular imaging, as well as blood samples for genetic, gene-expression, thrombosis and haemostasis and biomarker analysis. We aim to have 600 patient-control pairs enrolled by the end of 2018. SUMMARY: SECRETO is aiming to establish novel mechanisms and prognosis of cryptogenic IS in the young and will provide new directions for therapy development for these patients. First results are anticipated in 2019.

Reversal strategies for vitamin K antagonists in acute intracerebral hemorrhage.

OBJECTIVE: There is little evidence to guide treatment strategies for intracerebral hemorrhage on vitamin K antagonists (VKA-ICH). Treatments utilized in clinical practice include fresh frozen plasma (FFP) and prothrombin complex concentrate (PCC). Our aim was to compare case fatality with different reversal strategies. METHODS: We pooled individual ICH patient data from 16 stroke registries in 9 countries (n = 10 282), of whom 1,797 (17%) were on VKA. After excluding 250 patients with international normalized ratio < 1.3 and/or missing data required for analysis, we compared all-cause 30-day case fatality using Cox regression. RESULTS: We included 1,547 patients treated with FFP (n = 377, 24%), PCC (n = 585, 38%), both (n = 131, 9%), or neither (n = 454, 29%). The crude case fatality and adjusted hazard ratio (HR) were highest with no reversal (61.7%, HR = 2.540, 95% confidence interval [CI] = 1.784-3.616, p < 0.001), followed by FFP alone (45.6%, HR = 1.344, 95% CI = 0.934-1.934, p = 0.112), then PCC alone (37.3%, HR = 1.445, 95% CI = 1.014-2.058, p = 0.041), compared to reversal with both FFP and PCC (27.8%, reference). Outcomes with PCC versus FFP were similar (HR = 1.075, 95% CI = 0.874-1.323, p = 0.492); 4-factor PCC (n = 441) was associated with higher case fatality compared to 3-factor PCC (n = 144, HR = 1.441, 95% CI = 1.041-1.995, p = 0.027). INTERPRETATION: The combination of FFP and PCC might be associated with the lowest case fatality in reversal of VKA-ICH, and FFP may be equivalent to PCC. Randomized controlled trials with functional outcomes are needed to establish the most effective treatment.

Improved survival of patients with warfarin-associated intracerebral haemorrhage: a retrospective longitudinal population-based study.

BACKGROUND: Warfarin-associated intracerebral haemorrhage carries poor outcome due to rapid haemorrhage growth. Reversal of warfarin anticoagulation with prothrombin complex concentrate has been implemented as an acute treatment option for these subjects. AIM: We investigated whether survival of subjects with warfarin-associated intracerebral haemorrhage had improved after implementation of reversal of warfarin anticoagulation with prothrombin complex concentrate. METHODS: We identified all subjects with warfarin-associated intracerebral haemorrhage during 1993-2008 among the population of Northern Ostrobothnia, Finland. From 2004 onwards, prothrombin complex concentrate was used in Oulu University Hospital, the only hospital treating intracerebral haemorrhage subjects in the region, to counteract the effect of warfarin in subjects with warfarin-associated intracerebral haemorrhage. We compared the outcomes of subjects admitted during 1993-2003 and 2004-2008 and those treated and not treated with prothrombin complex concentrate. We also explored the predictors for one-year survival of the warfarin-associated intracerebral haemorrhage subjects. RESULTS: We identified altogether 181 subjects who had intracerebral haemorrhage while on warfarin. One-year survival was significantly (P = 0·031) higher for the 60 subjects admitted during 2004-2008 (43·3%) than for the 121 admitted before 2004 (30·6%). In multivariable analysis, prothrombin complex concentrate treatment reduced one-year case fatality (hazard ratio 0·52, 95% confidence interval 0·29-0·93). Thromboembolic complications did not occur more frequently among those treated with prothrombin complex concentrate. CONCLUSION: The survival of warfarin-associated intracerebral haemorrhage subjects among the population of Northern Ostrobothnia has improved likely because of introduction of prothrombin complex concentrate.

Predictive value of C-reactive protein for the outcome after primary intracerebral hemorrhage.

OBJECT: Primary intracerebral hemorrhage (ICH) carries high morbidity and mortality rates. Several factors have been suggested as predicting the outcome. The value of C-reactive protein (CRP) levels in predicting a poor outcome is unclear, and findings have been contradictory. In their population-based cohort, the authors tested whether, independent of confounding factors, elevated CRP levels on admission (< 24 hours after ictus) are associated with an unfavorable outcome. METHODS: The authors identified all patients who suffered primary ICH between 1993 and 2008 among the population of Northern Ostrobothnia, Finland, and from the laboratory records they extracted the CRP values at admission. Independent predictors of an unfavorable outcome (moderate disability or worse according to the Glasgow Outcome Scale at 3 months) were tested by unconditional logistic regression in a model including all the well-established confounding factors and CRP on admission. RESULTS: Of 961 patients, 807 (84%) had CRP values available within 24 hours of admission, and multivariable analysis showed elevated CRP at that point to be associated with an unfavorable outcome (OR 1.41 per 10 mg/L [95% CI 1.09-1.81], p < 0.01), together with diabetes mellitus (OR 1.99 [95% CI 1.09-3.64], p < 0.05), age (1.06 per year [95% CI 1.04-1.08], p < 0.001), low Glasgow Coma Scale score (0.75 per unit [95% CI 0.67-0.84], p < 0.001), hematoma size (1.05 per ml [95% CI 1.03-1.07], p < 0.001), and the presence of an intraventricular hemorrhage (2.70 [95% CI 1.66-4.38], p < 0.001). Subcortical location predicted a favorable outcome (0.33 [95% CI 0.20-0.54], p < 0.001). CONCLUSIONS: Elevated CRP on admission is an independent predictor of an unfavorable outcome and is only slightly associated with the clinical and radiological severity of the bleeding.

Immediate, early and late seizures after primary intracerebral hemorrhage.

BACKGROUND: Seizures after primary intracerebral hemorrhage (PICH) are significant and treatable complications, but the factors predicting immediate, early and late seizures are poorly known. We investigated characteristics and outcome with special reference to occurrence and timing of a first seizure among consecutive subjects with PICH. METHODS: A population-based study was conducted in Northern Ostrobothnia, Finland, in 1993-2008 that included all patients with a first-ever primary ICH without any prior diagnosis of epilepsy. Immediate (<24h after admission), early (1-14 days) and late (>2 weeks) seizures were considered separately. RESULTS: Out of a total of 935 ICH patients, 51 had immediate, 21 early and 58 late seizures. The patients with seizures were significantly younger than the others and more often had a subcortical hematoma location (p<0.05). Lifestyle factors did not differ between the groups. The risk factors for immediate seizures in multivariable analysis were a low Glasgow coma scale score (GCS) on admission, subcortical location and age inversely (p<0.01). The only independent risk factor for early seizures was subcortical location (p<0.001), whereas subcortical location (p<0.001), age inversely (p<0.01) and hematoma evacuation (p<0.05) independently predicted late seizures. Immediate and early seizures predicted infectious complications (p<0.05). CONCLUSIONS: Patients with subcortical hematoma and of younger age are at risk for immediate seizures after primary ICH irrespective of hematoma size. Patients with immediate and early seizures more often had infectious complications. Surgery increases the risk of a late seizure after ICH.