Association of Acute Incidental Cerebral Microinfarcts With Subsequent Ischemic Stroke in Patients With Cancer: A Population-Based Study.

BACKGROUND AND OBJECTIVES: Incidental diffuse-weighted imaging (DWI)-positive subcortical and cortical lesions, or acute incidental cerebral microinfarcts (CMIs), are a common type of brain ischemia, which can be detected on magnetic resonance DWI for approximately 2 weeks after occurrence. Acute incidental CMI was found to be more common in patients with cancer. Whether acute incidental CMI predicts future ischemic stroke is still unknown. We aimed to examine the association between acute incidental CMI in patients with cancer and subsequent ischemic stroke or transient ischemic attack (TIA). METHODS: This is a retrospective cohort study. We used Clalit Health Services records, representing over half of the Israeli population, to identify adults with lung, breast, pancreatic, or colon cancer who underwent brain MRI between January 2014 and April 2020. We included patients who underwent scan between 1 year before cancer diagnosis and 1 year after diagnosis. Primary outcome was ischemic stroke or TIA using International Classification of Diseases, Ninth Revision codes. Secondary outcomes were intracranial hemorrhage (ICH) and mortality. Records were followed from first MRI until primary outcome, death, or end of follow-up (January 2023). Cox proportional hazards models were used to calculate hazard ratio (HR) for patients with and without acute incidental CMI, as a time-dependent covariate. RESULTS: The study cohort included 1,618 patients with cancer, among whom, 59 (3.6%) had acute incidental CMI on at least 1 brain MRI. The median (interquartile range) time from acute incidental CMI to stroke or TIA was 26 days (14-84). On multivariable analysis, patients with acute incidental CMI had a higher stroke or TIA risk (HR 2.97, 95% CI 1.08-8.18, p = 0.035) compared with their non-CMI counterparts. Acute incidental CMIs were also associated with mortality after multivariable analysis (HR 2.76, 95% CI 2.06-3.71, p < 0.001); no association with ICH was found. DISCUSSION: Acute incidental CMI on brain MRI in patients with active cancer is associated with an increased risk of near-future ischemic stroke or TIA and mortality. This finding might suggest that randomly detected acute incidental CMI in patients with cancer may guide primary cerebrovascular risk prevention and etiologic workup.

Impact of demographic and clinical factors on in-hospital delays in acute ischemic stroke treatment.

BACKGROUND: Delays in reperfusion treatment, both intravenous thrombolysis (IVT) and endovascular treatment (EVT), adversely affect outcomes in patients with acute ischemic stroke (AIS). To alleviate these delays, it is essential to comprehend how patients' baseline and stroke characteristics impact in-hospital reperfusion delays. While demographic and socioeconomic factors affect stroke outcomes, their impact on in-hospital delays remains unclear. METHOD: This is retrospective analysis at a tertiary stroke center, encompassing AIS patients receiving IVT and / or EVT between 2019 and 2022 (re-canalization cohort). Outcomes of interest were time intervals of admission to CT and admission to recanalization. Univariable analyses explored age, gender, baseline functional status, socioeconomic status (SES), ethnicity, vascular risk factors, and stroke characteristics. Subsequently, multivariable logistic regression analyses were performed. RESULTS: Altogether, 313 patients treated with IVT and 293 with EVT were included in the re-canalization cohort. No demographic variables were found to be associated with stroke treatment time intervals. Following multivariable analysis, stroke severity (low NIHSS, p < 0.01), arrival to the hospital by other means than ambulance (p < 0.01), and atypical stroke symptoms (p < 0.01), were associated with in-hospital delays, both in the EVT and the IVT groups. CONCLUSION: Our findings indicate that patients with a more severe ischemic stroke, typical stroke symptoms, and arrival by ambulance have shorter stroke treatment time intervals. These results emphasize that, in atypical cases, even a lower suspicion of stroke should promote urgent workup for stroke diagnosis. Our findings do not indicate any influence of demographic or SES on in-hospital reperfusion delays.

Efficacy and safety of Apixaban in the treatment of cerebral venous sinus thrombosis: a multi-center study.

Background: Information regarding the safety and efficacy of specific direct oral anticoagulants (DOAC) in the treatment of cerebral sinus and venous thrombosis (CSVT) is scarce. Apixaban is one of the most frequently prescribed DOACs. Therefore, we aimed to compare the safety and efficacy of Apixaban with those of vitamin k antagonists (VKA) in patients with CSVT. Methods: Prospective CSVT databases from seven academic medical centers were retrospectively analyzed. Patients treated with Apixaban were compared to those treated with VKA. Data on demographics, clinical presentations, risk factors, radiological and outcome parameters were studied. Results: Overall, 403 patients were included in the analysis. Of them, 48 (12%) were treated with Apixaban, and 355 (88%) were treated with VKA. Rates of coagulopathies were significantly higher in the VKA-treated patients but no other differences between the groups were found in baseline characteristics and underlying etiology. No significant differences were found between groups in efficacy or safety parameters including the rates of recanalization, favorable outcomes, one-year mortality, seizures, intracranial hemorrhage or CSVT recurrences. Conclusion: Our data suggests that Apixaban may be safe and effective for patients with CSVT. These results should be tested in prospective randomized clinical studies.

Complex left appendage morphology is associated with Embolic Stroke of Undetermined Source.

INTRODUCTION: Variations in the left atrial appendage (LAA) morphology are associated with different embolic risk in patients with atrial fibrillation (AF). Data are scarce regarding the association between LAA morphology and Embolic stroke of undetermined source (ESUS). PATIENTS AND METHODS: Using cardiac computed tomography (CCT) scans, LAA morphology was categorized as either chicken wing (CW), cactus, windsock, or cauliflower. Furthermore, we examined the presence of large secondary lobes arising from the main lobe, considering their existence as indicative of a complex LAA morphology. LAA morphologies were compared between ESUS (n = 134) and AF patients (n = 120); and between ESUS patients with (n = 24) and without (n = 110) subsequent AF diagnosis during long-term follow-up. RESULTS: ESUS patients had a significantly higher prevalence of cauliflower morphology compared to AF group (52% vs 34%, respectively, p = 0.01); however, no significant difference was found between the groups when categorizing LAA morphology to either CW or non-CW. ESUS patients had significantly higher prevalence of large secondary lobes compared with AF patients (50% vs 29%, respectively, p = 0.001). When comparing ESUS patients with and without AF diagnosis during follow-up (20-48 months of follow-up, median 31 months), there were no significant differences in the prevalence of the "classical" morphologies, but large secondary lobes were significantly more prevalent among those without subsequent AF diagnosis. CONCLUSION: ESUS patients have a high prevalence of complex LAA morphology, which might be associated with an increased risk for thrombus formation even in the absence of AF.

Impact of dementia status on intravenous thrombolysis and endovascular treatment for acute ischemic stroke: Retrospective study.

INTRODUCTION: Individuals with dementia are underrepresented in interventional studies for acute ischemic stroke (AIS). This research gap creates a bias against their treatment in clinical practice. Our goal was to compare the safety and efficacy of intravenous-thrombolysis (t-PA) and endovascular treatment (EVT) in individuals with or without pre-AIS dementia. METHOD: A retrospective study of AIS patients receiving t-PA or EVT between 2019 and 2022. Patients were classified as dementia on a case-by-case review of baseline assessment. Additional variables included demographic, vascular risk factors, AIS severity and treatment. Outcomes of interest were intracerebral hemorrhage, mortality in 90-days, and the difference in modified rankin scale (mRS) before AIS and in 90-days follow-up. Outcomes were compared across non-matched groups and following propensity-score matching. RESULTS: Altogether, 628 patients were included, of which 68 had pre-AIS dementia. Compared to non-dementia group, dementia group were older, had a higher rate of vascular risk factors, higher pre-stroke mRS and higher baseline NIHSS. Individuals with dementia had higher rates of mortality (25% vs.11%,p < 0.01) on non-matched comparison. All cohort and restricted t-PA EVT matched analysis showed no difference in any outcome. Regression analysis confirmed that AIS severity at presentation and its treatment, not dementia, were the chief contributors to patients' outcomes. DISCUSSION: Our results indicate that pre-AIS dementia does not impact the efficacy or safety of EVT or t-PA for AIS. We thus call for more inclusive research on stroke therapy with regards to baseline cognitive status. Such studies are urgently required to inform stroke guidelines and enhance care.

Lung cancer is associated with acute ongoing cerebral ischemia: A population-based study.

BACKGROUND AND OBJECTIVES: Cerebral microinfarcts (CMIs) are the most common type of brain ischemia; however, they are extremely rare in the general population. CMIs can be detected by magnetic resonance diffusion-weighted imaging (MRI-DWI) only for a very short period of approximately 2 weeks after their formation and are associated with an increased stroke risk and cognitive impairment. We aimed to examine CMI detection rate in patients with lung cancer (LC), which is strongly associated with ischemic stroke risk relative to other cancer types. METHODS: We used the Clalit Health Services record (representing more than 5 million patients) to identify adults with LC and breast, pancreatic, or colon cancer (non-lung cancer, NLC) who underwent brain magnetic resonance diffusion (MRI) scan within 5 years following cancer diagnosis. All brain MRI scans were reviewed, and CMIs were documented, as well as cardiovascular risk factors. RESULTS: Our cohort contained a total of 2056 MRI scans of LC patients and 1598 of NLC patients. A total of 143 CMI were found in 73/2056 (3.5%) MRI scans of LC group compared to a total of 29 CMI in 22/1598 (1.4%) MRI scans of NLC (p < 0.01). Cancer type (e.g. LC vs NLC) was the only associated factor with CMI incidence on multivariate analysis. After calculating accumulated risk, we found an incidence of 2.5 CMI per year in LC patients and 0.5 in NLC. DISCUSSION: CMIs are common findings in cancer patients, especially in LC patients and therefore might serve as a marker for occult brain ischemia, cognitive decline, and cancer-related stroke (CRS) risk.

Clinicoradiologic Criteria for the Diagnosis of Stroke-like Episodes in MELAS.

Background and Objectives: Stroke-like episodes (SLEs) in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome are often misdiagnosed as acute ischemic stroke (AIS). We aimed to determine unique clinical and neuroimaging features for SLEs and formulate diagnostic criteria. Methods: We retrospectively identified patients with MELAS admitted for SLEs between January 2012 and December 2021. Clinical features and imaging findings were compared with a cohort of patients who presented with AIS and similar lesion topography. A set of criteria was formulated and then tested by a blinded rater to evaluate diagnostic performance. Results: Eleven MELAS patients with 17 SLE and 21 AISs were included. Patients with SLEs were younger (median 45 [37-60] vs 77 [68-82] years, p < 0.01) and had a lower body mass index (18 ± 2.6 vs 29 ± 4, p < 0.01), more commonly reported hearing loss (91% vs 5%, p < 0.01), and more commonly presented with headache and/or seizures (41% vs 0%, p < 0.01). The earliest neuroimaging test performed at presentation was uniformly a noncontrast CT. Two main patterns of lesion topography with a stereotypical spatiotemporal evolution were identified-an anterior pattern (7/21, 41%) starting at the temporal operculum and spreading to the peripheral frontal cortex and a posterior pattern (10/21, 59%) starting at the cuneus/precuneus and spreading to the lateral occipital and parietal cortex. Other distinguishing features for SLEs vs AIS were cerebellar atrophy (91% vs 19%, p < 0.01), previous cortical lesions with typical SLE distribution (46% vs 9%, p = 0.03), acute lesion tissue hyperemia and venous engorgement on CT angiography (CTA) (45% vs 0%, p < 0.01), and no large vessel occlusion on CTA (0% vs 100%, p < 0.01). Based on these clinicoradiologic features, a set of diagnostic criteria were constructed for possible SLE (sensitivity 100%, specificity 81%, AUC 0.905) and probable SLE (sensitivity 88%, specificity 95%, AUC 0.917). Discussion: Clinicoradiologic criteria based on simple anamnesis and a CT scan at presentation can accurately diagnose SLE and lead to early administration of appropriate therapy. Classification of Evidence: This study provides Class III evidence that an algorithm using clinical and imaging features can differentiate stroke-like episodes due to MELAS from acute ischemic strokes.

Intracranial stenting for large vessel intracranial atherosclerotic disease: Retrospective study.

BACKGROUND: Intracranial atherosclerotic disease (ICAD) is a common cause for stroke and can be defined as symptomatic (stroke) or asymptomatic. Current guidelines recommend against intracranial stenting (ICS) for patients with ICAD; treatment of patients who failed the best medical therapy is still debatable. METHODS: We introduce a preliminary retrospective analysis of our tertiary stroke center during 2018-2022 of patients that were treated with ICS either in acute phase or elective (eICS). Study endpoints were stroke, functional outcome (modified Rankin Score [mRS] at 3 months), and serious adverse events. RESULTS: Thirty-three stents were implanted, 21 in acute group and 12 in the eICS group. Most patients (75%) were treated with a new generation self-expandible stent. One patient had peri-procedural stroke and four patients had transient ischemic event or stroke during follow-up. There were eight cases of death (all acute group patients, seven of which occurred in the posterior circulation). Fifteen patients (62%) had favorable clinical outcomes (mRS 0-2 for pre-stroke), of which 10/10 (100%) in the eICS, the other two eICS patients had pre-morbid mRS 3 with no clinical change. CONCLUSIONS: The evolution of new devices for ICS and the accumulating interventional experience might open a new era. As no other effective alternative treatment options exist for preventing recurrent stroke, stenting is still common practice in many tertiary centers either urgently or as elective procedure for refractory cases.

Clinical score for early diagnosis and treatment of stroke-like episodes in MELAS syndrome.

BACKGROUND AND OBJECTIVES: Stroke-like episodes (SLEs) in patients with MELAS syndrome are often initially misdiagnosed as acute ischemic stroke (AIS), resulting in treatment delay. We aimed to determine clinical features that may distinguish SLEs from AISs and explore the benefit of early L-arginine treatment on patient outcomes. METHODS: We looked retrospectively for MELAS patients admitted between January 2005 and January 2022 and compared them to an AIS cohort with similar lesion topography. MELAS patients who received L-arginine within 40 days of their first SLE were defined as the early treatment group and the remaining as late or no treatment group. RESULTS: Twenty-three SLEs in 10 MELAS patients and 21 AISs were included. SLE patients had significantly different features: they were younger, more commonly reported hearing loss, lower body mass index, had more commonly a combination of headache and/or seizures at presentation, serum lactate was higher, and hemiparesis was less common. An SLE Early Clinical Score (SLEECS) was constructed by designating one point to each above features. SLEECS ≥ 4 had 80% sensitivity and 100% specificity for SLE diagnosis. Compared to late or no treatment, early treatment group patients (n = 5) had less recurrent SLEs (total 2 vs. 11), less seizures (14% vs. 25%, p = 0.048), lower degree of disability at first and last follow-up (modified ranking scale, mRS 2 ± 0.7 vs. 4.2 ± 1, p = 0.005; 2 ± 0.7 vs. 5.8 ± 0.5, p < 0.001, respectively), and a lower mortality (0% vs. 80% p = 0.048). CONCLUSIONS: The SLEECS model may aid in the early diagnosis and treatment of SLEs and lead to improved clinical outcomes.

Effect of time delay in inter-hospital transfer on outcomes of endovascular treatment of acute ischemic stroke.

Background: Endovascular treatment (EVT) with mechanical thrombectomy is the standard of care for large vessel occlusion (LVO) in acute ischemic stroke (AIS). The most common approach today is to perform EVT in a comprehensive stroke center (CSC) and transfer relevant patients for EVT from a primary stroke center (PSC). Rapid and efficient treatment of LVO is a key factor in achieving a good clinical outcome. Methods: We present our retrospective cohort of patients who underwent EVT between 2018 and 2021, including direct admissions and patients transferred from PSC. Primary endpoints were time intervals (door-to-puncture, onset-to-puncture, door-to-door) and favorable outcome (mRS ≤ 2) at 90 days. Secondary outcomes were successful recanalization, mortality rate, and symptomatic intracranial hemorrhage (sICH). Additional analysis was performed for transferred patients not treated with EVT; endpoints were time intervals, favorable outcomes, and reason for exclusion of EVT. Results: Among a total of 405 patients, 272 were admitted directly to our EVT center and 133 were transferred; there was no significant difference between groups in the occluded vascular territory, baseline NIHSS, wake-up strokes, or thrombolysis rate. Directly admitted patients had a shorter door-to-puncture time than transferred patients (190 min vs. 293 min, p < 0.001). The median door-to-door shift time was 204 min. We found no significant difference in functional independence, successful recanalization rates, or sICH rates. The most common reason to exclude transferred patients from EVT was clinical or angiographic improvement (55.6% of patients). Conclusion: Our results show that transferring patients to the EVT center does not affect clinical outcomes, despite the expected delay in EVT. Reassessment of patients upon arrival at the CSC is crucial, and patient selection should be done based on both time and tissue window.

Cardiac CT for intra-cardiac thrombus detection in embolic stroke of undetermined source (ESUS).

Introduction: Embolic stroke of undetermined source (ESUS) is a common medical challenge regarding secondary prevention strategy. Cardiac imaging is the cornerstone of embolic stroke workup, in an effort to diagnose high risk cardio-embolic sources. Cardiac computed tomography angiography (CCTA) is an emerging imaging modality with high diagnostic performance for intra-cardiac thrombus detection. The yield of CCTA implementation in addition to standard care in ESUS workup is unknown. Thus, the aim of this study was to assess the utility of CCTA in detecting intra-cardiac thrombi in the routine ESUS workup. Patients and methods: This is a retrospective observational analysis of ESUS cases managed in vascular neurology unit between 2019 and 2021. Within this ESUS registry, consecutive patients undergoing CCTA were included and carefully analyzed. Results: During the study period 1066 Ischemic stroke (IS) cases were treated and evaluated. 266/1066 (25%) met ESUS criteria and 129/266 (48%) underwent CCTA. Intra-cardiac thrombus was detected by CCTA in 22/129 (17%; 95% CI, 11.5%-23.5%) patients: left ventricular thrombus (LVT) in 13 (10.1%) patients, left atrial appendage (LAA) thrombus in 8 (6.2%) patients, and left atrial (LA) thrombus in 1 (0.8%) patient. Only 5/22 (23%) of these thrombi were suspected, but could not be confirmed, in trans-thoracic echocardiogram (TTE). Among CCTA-undergoing patients, 27/129 (21%; 95% CI, 14%-28%) were found to have an indication (including pulmonary embolism) for commencing anticoagulation (AC) treatment, rather than anti-platelets. In favor of CCTA implementation, 22/266 (8.2%; 95% CI, 4.9%-11.5%) patients within the entire ESUS cohort were diagnosed with intra-cardiac thrombus, otherwise missed. Conclusion: CCTA improves the detection of intra-cardiac thrombi in addition to standard care in ESUS patients. The implementation of CCTA in routine ESUS workup can change secondary prevention strategy in a considerable proportion of patients.

Repeated lumbar puncture in search of oligoclonal bands - What is the yield?

BACKGROUND: Cerebrospinal fluid (CSF) oligoclonal bands (OCBs) are immunoglobulins that represent intrathecal synthesis during central nervous system infection or inflammation. As repeated lumbar puncture (LP) is usually not performed unless clinically indicated, there is very limited data on the natural history and course of OCBs status in the CSF, its relation to disease activity, duration of persistence, and the rate of either CSF conversion of OCBs or disappearance. METHODS: We retrospectively collected data from adult patients with various neurological syndromes who had repeated CSF samplings. OCBs were analyzed by agarose gel electrophoresis or by isoelectric focusing. RESULTS: During the years 2010-2020, we identified 48 patients with at least two CSF OCBs results in Rabin Medical Center. These included 11 patients with Multiple Sclerosis, ADEM and NMOSD (one patient each), 7 patients with unspecified demyelinating disease, 4 with optic neuropathy, 15 patients with unknown diagnosis. Overall, 6/48 (12.5%) patients had change in OCBs status between first and second LP's. Four (8.33%) patients changed OCBs from positive to negative, and two patients (4.2%) from negative to positive. There was no significant difference in demographic, disease category, CSF constituents or time interval to second LP between patients who changed their OCBs status to those who did not. CONCLUSION: Repeated LP for OCBs analysis in our cohort did not yield a practical benefit. The conversion rate of OCBs status was low (12.5%) and in most cases did not lead to a change in the final diagnosis or patient's clinical management.

Efficacy and safety of endovascular treatment in patients older than 90 with acute ischemic stroke: A retrospective cohort study.

Background: Endovascular treatment (EVT) for acute ischemic stroke (AIS) with large vessel occlusion (LVO) is the standard of care treatment today. Although elderly patients comprise the majority of stroke patients, octogenarians and non-agenarians are often poorly represented or even excluded in clinical trials. We looked at the safety and efficacy of EVT for AIS with LVO in patients over 90 (Non-agenarians), in comparison to patients aged 80-89 (Octogenarians) and to patients younger than 80 years (<80yrs). Methods: A retrospective analysis of patients who underwent EVT in a single stroke center during 2015-2019. Patients were divided into three subgroups based on their age: Non-agenarians, Octogenarians, and patients <80 yrs. The groups were compared based on baseline characteristics and stroke variables. In addition, we compared clinical and radiological outcomes including functional outcomes measured by the modified ranking scale (mRS) at day 90, symptomatic intracranial hemorrhage (sICH), and mortality. Results: Three hundred and forty seven patients were included, 20 (5.7%) of them were non-agenarians, 96 (27.7%) were octogenarians and 231 (66.6%) were <80 yrs. No statistically significant differences were found between groups regarding baseline characteristics, cardiovascular risk factors, stroke variables, or successful revascularization rates. Puncture to recanalization time intervals showed an age-related non-significant increase between the groups with a median time of 67.8, 51.6, and 40.2 min of the non-agenarian, octogenarian, and <80 yrs groups, respectively (p-value = 0.3). Favorable outcome (mRS 0-2) was 15% in non-agenarians vs. 13.54% in octogenarians (p-value = 1) and 40.2% in <80 yrs. sICH occurred among 5% of non-agenarians, compared to 4% among octogenarians (p-value = 1) and 2.6% in <80 yrs. The mortality rate at 3 months was significantly higher (55%) in non-agenarians compared to octogenarians (28%) (p-value = 0.03) and to <80 yrs (19.48%). Conclusion: EVT in nonagenarians demonstrated a high rate of successful revascularization, whilst also showing an increased rate of sICH when compared to octogenarians. Mortality rates showed an age-related correlation. Although further studies are needed to clarify the patient selection algorithm and identify sub-groups of elderly patients that could benefit from EVT, we showed that some patients do benefit from EVT therefore exclusion should not be based on age alone.

Physician adherence to societal guidelines following colonoscopy with polypectomy.

BACKGROUND: Colorectal cancer is a significant cause of mortality and morbidity in western countries. Polypectomy reduces the incidence and mortality of colorectal cancer. Following polypectomy, recommendations regarding the frequency and duration of surveillance rely mostly on features of the resected polyps and are summarized in various gastroenterological societal guidelines. In this study, we aimed to delineate the accuracy of current post-polypectomy surveillance recommendations and to check whether active intervention would lead to an improvement in accuracy and consistency with societal guidelines. METHODS: We prospectively collected polypectomy reports over a 3-month period in 2 tertiary medical centers. We then performed an intervention that included: 1) presentation of results from 1st phase; 2) re-affirming the guidelines in a departmental meeting; 3) addition of a dedicated reporting form for post-polypectomy surveillance recommendations in the patients' electronic medical file. Finally, we conducted a second prospective collection of post-polypectomy recommendations, over a second 3-month period. RESULTS: Prior to the intervention, 76% of the colonoscopies with polypectomy had a recommendation for surveillance, compared to 85% after the intervention (P=0.003). Prior to the intervention, 65% of patients received a recommendation consistent with societal guidelines, compared with 78% after the intervention (P=0.001). CONCLUSION: Intervention, including re-affirmation of the current guidelines and creation of a dedicated reporting platform, significantly increases the number of follow-up recommendations after polypectomy and their consistency with societal guidelines.

Association of Diabetes and Glycated Hemoglobin With the Risk of Intracerebral Hemorrhage: A Population-Based Cohort Study.

OBJECTIVE: To examine the association of diabetes and glycated hemoglobin (HbA1c) with the risk of intracerebral hemorrhage (ICH) in a large population-based cohort. RESEARCH DESIGN AND METHODS: The computerized database of the largest health care provider in Israel was used to identify adult members aged 40 years or older and alive at 1 January 2010 (297,486 with diabetes and 1,167,585 without diabetes). The cohort was followed until 31 December 2017 for incidence of ICH. Multivariable Cox proportional hazards regression models, adjusted for baseline disease risk score, were applied to estimate the hazard ratio (HR) of ICH. RESULTS: Overall 4,170 ICH cases occurred during 10,730,915 person-years of follow-up. Diabetes was independently associated with increased ICH risk, with hazard ratio (HR) 1.36 (95% CI 1.27-1.45), and increased with longer diabetes duration: 1.23 (1.12-1.35) and 1.44 (1.34-1.56) for diabetes duration ≤5 years and >5 years, respectively. The increased ICH risk associated with diabetes was more pronounced in patients ≤60 years old (P interaction <0.001). Among patients with diabetes, HbA1c had a nonlinear J-shaped relationship with ICH (P for nonlinearity = 0.0186). Compared to the fourth HbA1c decile, 6.5-6.7% (48-50 mmol/mol), the HR for ICH was 1.27 (1.01-1.59) and 2.19 (1.75-2.73) in the lowest HbA1c decile, ≤6.0% (≤42 mmol/mol), and highest HbA1c decile, >9.3% (>78 mmol/mol), respectively. CONCLUSIONS: Diabetes is associated with increased risk of ICH that is directly associated with diabetes duration. ICH and HbA1c appear to have a J-shaped relationship, suggesting that both poor control as well as extreme intensive diabetes control might be associated with increased risk.