Caring for Patients With Diabetes in Stroke Neurology.

Diabetes is a heterogeneous disease that affects 9% of the world's population (11% in the United States). The consequences of diabetes for the brain are severe; it nearly doubles a person's risk of stroke and is a major contributor to risk for cerebral small vessel disease and dementia. These effects on the brain are in addition to peripheral neuropathy, retinopathy, nephropathy, and coronary heart disease. In this article, we explain the treatments that can prevent or mitigate its harmful effects and propose a role for neurologists and other neurology clinicians in managing patients during routine care.

Protecting the Brain, From the Heart: Safely Mitigating the Consequences of Thrombosis in Intracerebral Hemorrhage Survivors With Atrial Fibrillation.

Optimal antithrombotic management after intracerebral hemorrhage remains one of the central unresolved issues for patients who survive, especially for those patients with atrial fibrillation. Given the observational nature of the studies regarding anticoagulation resumption after intracerebral hemorrhage, there is uncertainty regarding resumption of oral anticoagulation therapy and its timing. There is limited high-quality evidence to guide clinical practice, leading to significant practice variation and uncertainty for patients and providers. Here, we aim to provide the key elements to guide clinicians in their individual decision: whether or not to start or resume anticoagulation in patients with a history of intracerebral hemorrhage.

Central vs site outcome adjudication in the IRIS trial.

BACKGROUND: Central adjudication of outcome events is the standard in clinical trial research. We examine the benefit of central adjudication in the Insulin Resistance Intervention after Stroke (IRIS) trial and show how the benefit is influenced by outcome definition and features of the adjudicated events. METHODS: IRIS tested pioglitazone for prevention of stroke and myocardial infarction in patients with a recent transient ischemic attack or ischemic stroke. We compared the hazard ratios for study outcomes classified by site and central adjudication. We repeated the analysis for an updated stroke definition. RESULTS: The hazard ratios for the primary outcome were identical (0.76) and statistically significant regardless of adjudicator. The hazard ratios for stroke alone were nearly identical with site and central adjudication, but only reached significance with site adjudication (HR, 0.80; p = 0.049 vs. HR, 0.82; p = 0.09). Using the updated stroke definition, all hazard ratios were lower than with the original IRIS definition and statistically significant regardless of adjudication method. Agreement was higher when stroke type was certain, subtype was large vessel or cardioembolic, signs or symptoms lasted > 24 h, imaging showed a stroke, and when NIHSS was ≥3. DISCUSSION: Central stroke adjudication caused the hazard ratio for a main secondary outcome in IRIS (stroke alone) to be higher and lose statistical significant compared with site review. The estimate of treatment effects were larger with the updated stroke definition. There may be benefit of central adjudication for events with specific features, such as shorter symptom duration or normal brain imaging.

Intracerebral Hemorrhage Outcomes in the Very Elderly.

BACKGROUND: There is a paucity of outcomes data in patients over 80 years presenting with intracerebral hemorrhage (ICH). The primary aim of our study is to describe outcomes in this patient population. METHOD: Retrospective study of patients admitted with primary ICH from January 2012 to July 2018. Data were obtained from the Rush University Get With The Guidelines database; only patients 80 or above were included. RESULTS: A total of 1713 patients were screened and 220 patients met inclusion criteria. About 68.2% were female and mean age was 85.6 years old. Median ICH score on admission was 2 (IQR 1-3). Location of ICH included: deep (48.2%), lobar (40%), and cerebellum (9.5%). ICH etiologies included hypertensive (51.8%), cerebral amyloid angiopathy (26.8%), coagulopathy (5.9%), and the remaining were undetermined. CT angiograms were performed in 34.5% (n = 76) of patients; of these patients one arteriovenous malformation was identified. Patients underwent the following procedures: external ventricular drains (8.6%), decompression (3.6%), and ventriculoperitoneal shunts (1.8%). Tracheostomy and percutaneous gastrostomy placement were performed in 8.2%. About 4.5% had seizures and 1.5% were treated for status epilepticus. Disposition at hospital discharge included: subacute nursing facility ([SNF] 24.1%), acute rehabilitation (23.2%), hospice (18.2%), death (18.2%), home (11.8%), long-term acute care facility ([LTAC] 3.6%), and unknown (1%). Patients with an ICH score ≥2 on admission had a roughly 6 times higher chance of experiencing an unfavorable outcome (LTAC, SNF, or death), when compared to patients with lower ICH score. CONCLUSIONS: This study shows that a significant proportion (35%) of ICH patients ≥80 years old have a good outcome, with discharge to home or to rehabilitation. Our data suggest that older patients with ICH presenting with supratentorial hemorrhages (volume < 30 cc) without intraventricular extension can have good outcomes despite their age.

The Spectrum of Nontraumatic Convexity Subarachnoid Hemorrhage.

BACKGROUND: Nontraumatic convexity subarachnoid hemorrhage (cSAH) is a nonaneurysmal variant that is associated with diverse etiologies. METHODS: With IRB approval, we retrospectively reviewed consecutive nontraumatic cSAH from July 1, 2006 to July 1, 2016. Data were abstracted on demographics, medical history, neuroimaging, etiology, and clinical presentation. RESULTS: We identified 94 cases of cSAH. The cases were classified according to the following etiologies: reversible cerebral vasoconstriction syndrome (RCVS) 17 (18%), cerebral amyloid angiopathy (CAA) 15 (16%), posterior reversible encephalopathy syndrome 16 (17%), cerebral venous thrombosis 10 (11%), large artery occlusion 7 (7%), endocarditis 6 (6%), and cryptogenic 25 (27%). Early rebleeding occurred in 9 (10%) patients. Time from initial imaging to CT rebleeding was 40 hours (range, 5-74). CAA was associated with the highest mean age at 75.8 and RCVS the lowest at 47.6 years (P< .0001). Among patients with RCVS, initial vascular imaging was negative in 6 (35%), and repeat imaging documented vasoconstriction at a mean delay of 5 days (range, 3-16). CONCLUSION: There were significant differences among the subgroups in cSAH, with CAA presenting as older men with transient neurological deficits, and RCVS presenting as younger women with thunderclap headache. Rebleeding was seen in 10% of cSAH patients. One-third of RCVS patients with cSAH required repeat vascular imaging to diagnose vasoconstriction.

In Vitro Studies on Degradation of Gamma-L-Glutamyl-L-Cysteine and Gamma-L-Glutamyl-D-Cysteine in Blood: Implications for Treatment of Stroke.

Treatment for ischemic stroke involves a thrombolytic agent to re-establish blood flow in the brain. However, delayed reperfusion may cause injury to brain capillaries. Previous studies indicate that the antioxidant gamma-L-glutamyl-L-cysteine (γ-Glu-Cys) contributes to reducing reperfusion injury to the cerebral vasculature in rats, when administered intravascularly. To determine the stability of γ-Glu-Cys in blood, the peptide was incubated in rat serum in vitro, and its degradation was quantified by high-pressure liquid chromatography. The half-time (t1/2) for degradation of γ-Glu-Cys was 11 ± 1 minute (mean ± SD, n = 3). A similar pattern of degradation was observed when γ-Glu-Cys was incubated in the presence of human plasma (t1/2 = 17 ± 8 minutes, n = 3). In a second series of experiments, degradation of an analog (γ-Glu-D-Cys) was tested in rat serum and found to be more stable than the native molecule. The initial velocity for degradation of γ-Glu-D-Cys (0.12 ± 0.02 mM/min; mean ± SD, n = 3) was significantly (P = 0.006) less than that of γ-Glu-Cys (0.22 ± 0.03 mM/min; mean ± SD, n = 3). Furthermore, an in vitro assay indicated that the analog has as an oxidative capacity that equals that of the original peptide in the presence of rat serum and human plasma. Finally, both peptides were found to be similarly effective in preventing lysis of intact cells using in vitro assays. These studies show that γ-Glu-Cys remains intact in blood for several minutes, and the analog γ-Glu-D-Cys may be a more stable, but similarly effective antioxidant.

Addressing disparities in the global epidemiology of stroke.

Stroke is the second leading cause of death and the third leading cause of disability worldwide. Though the burden of stroke worldwide seems to have declined in the past three decades, much of this effect reflects decreases in high-income countries (HICs). By contrast, the burden of stroke has grown rapidly in low-income and middle-income countries (LMICs), where epidemiological, socioeconomic and demographic shifts have increased the incidence of stroke and other non-communicable diseases. Furthermore, even in HICs, disparities in stroke epidemiology exist along racial, ethnic, socioeconomic and geographical lines. In this Review, we highlight the under-acknowledged disparities in the burden of stroke. We emphasize the shifting global landscape of stroke risk factors, critical gaps in stroke service delivery, and the need for a more granular analysis of the burden of stroke within and between LMICs and HICs to guide context-appropriate capacity-building. Finally, we review strategies for addressing key inequalities in stroke epidemiology, including improvements in epidemiological surveillance and context-specific research efforts in under-resourced regions, development of the global workforce of stroke care providers, expansion of access to preventive and treatment services through mobile and telehealth platforms, and scaling up of evidence-based strategies and policies that target local, national, regional and global stroke disparities.

Optimal Timing for Resumption of Anticoagulation After Intracranial Hemorrhage in Patients With Mechanical Heart Valves.

BACKGROUND: Anticoagulation in patients with intracranial hemorrhage (ICH) and mechanical heart valves is often held for risk of ICH expansion; however, there exists a competing risk of acute ischemic stroke (AIS). Optimal timing to resume anticoagulation remains uncertain. METHODS AND RESULTS: We retrospectively studied patients with ICH and mechanical heart valves from 2000 to 2018. The primary outcome was a composite end point of symptomatic hematoma expansion or new ICH, AIS, and intracardiac thrombus up to 30 days post-ICH. The exposure was timing of reinitiation of anticoagulation classified as early (resumed up to 7 days after ICH), late (≥7 and up to 30 days after ICH), and never if not resumed or resumed after 30 days post-ICH. We included 184 patients with ICH and mechanical heart valves (65 anticoagulated early, 100 late, 19 not resumed by day 30 post-ICH). Twelve patients had AIS, 16 new ICH, and 6 intracardiac thromboses. The mean time from ICH to anticoagulation was 12.7 days. Composite outcomes occurred in 12 patients resumed early (18.5%), 14 resumed late (14.0%), and 4 never resumed (21.1%). There was no increased hazard of the composite outcome (hazard ratio [HR], 1.1 [95% CI, 0.2-6.0]), AIS, or worsening or new ICH among patients resumed early versus late. There was no difference in the composite among patients never resumed versus resumed. Patients who never resumed anticoagulation had significantly more severe ICH (median Glasgow Coma Scale: 10.6, 13.9, and 13.9 among those who resumed never, early, and late, respectively; P=0.0001), higher in-hospital mortality (56.5%, 0%, and 0%, respectively; P<0.0001), and an elevated 30-day AIS risk (HR, 15.9 [95% CI, 1.9-129.7], P=0.0098). CONCLUSIONS: In this study of patients with ICH and mechanical heart valves, there was no difference in 30-day thrombotic and hemorrhagic brain-related outcomes when anticoagulation was resumed within 7 versus 7 to 30 days after ICH. Withholding anticoagulation >30 days was associated with severe baseline ICH, higher in-hospital case fatality, and elevated AIS risk.

Impaired mobility and MRI markers of vascular brain injury: Atherosclerosis Risk in Communities and UK Biobank studies.

Background: Vascular brain injury (VBI) may be an under-recognised contributor to mobility impairment. We examined associations between MRI VBI biomarkers and impaired mobility. Methods: We separately analysed Atherosclerosis Risk in Communities (ARIC) and UK Biobank (UKB) study cohorts. Inclusion criteria were no prevalent clinical stroke, and available brain MRI and balance and gait data. MRI VBI biomarkers were (ARIC: ventricular and white matter hyperintensity (WMH) volumes, non-lacunar and lacunar infarctions, microhaemorrhage; UKB: ventricular, brain and WMH volumes, fractional anisotropy (FA), mean diffusivity (MD), intracellular and isotropic free water volume fractions). Quantitative biomarkers were categorised into tertiles. Mobility impairment outcomes were imbalance and slow walk in ARIC and recent fall and slow walk in UKB. Adjusted multivariable logistic regression analyses were performed. Results: We included 1626 ARIC (mean age 76.2 years; 23.4% imbalance, 25.0% slow walk) and 40 098 UKB (mean age 55 years; 15.8% falls, 2.8% slow walk) participants. In ARIC, imbalance associated with four of five VBI measures (all p values<0.05), most strongly with WMH (adjusted OR, aOR 1.64; 95% CI 1.18 to 2.29). Slow walk associated with four of five VBI measures, most strongly with WMH (aOR 2.32; 95% CI 1.66 to 3.24). In UKB, falls associated with all VBI measures except WMH, most strongly with FA (aOR 1.16; 95% CI 1.08 to 1.24). Slow walking associated with WMH, FA and MD, most strongly with FA (aOR 1.57; 95% CI 1.32 to 1.87). Conclusions: VBI is associated with mobility impairment in community-dwelling, clinically stroke-free cohorts. Consequences of VBI may extend beyond clinically apparent stroke to include mobility.