Markers of early vascular aging are not associated with cryptogenic ischemic stroke in the young: A case-control study.

BACKGROUND AND PURPOSE: We aimed to assess the association between covert atherosclerosis, arterial stiffness, and early-onset cryptogenic ischemic stroke (CIS) in a prospective case-control study. METHODS: We enrolled 123 young CIS patients (median age 41 years; 42% women) and 123 age- and sex-matched controls. Carotid intima-media thickness (CIMT), Augmentation Index (AIx), central pulse wave velocity (PWV), and subendocardial viability ratio (SEVR) were compared between patients and controls. Conditional logistic regression was used adjusting for age, systolic blood pressure, diastolic blood pressure, current smoking, total cholesterol/high-density lipoprotein cholesterol (Total-C/HDL-C) ratio, and glycated albumin to assess the independent association between CIMT, arterial stiffness and CIS. RESULTS: Patients with higher CIMT and PWV were older, more often men and they had more frequently well-documented risk factors, lower HDL and higher Total-C/HDL-C ratio compared to other tertiles. In univariate comparisons, we found no differences between patients and controls regarding CIMT, AIx, or PWV. In the entire cohort, patients had a significantly lower SEVR compared to controls (146.3%, interquartile range [IQR] 125.7-170.3 vs. 158.0%, IQR 141.3-181.0, P=0.010). SEVR was lower also in women compared to their controls (132.0%, IQR 119.4-156.1 vs. 158.7%, IQR 142.0-182.8, P=0.001) but no significant difference appeared between male patients and male controls. However, after adjusting for comorbidities and laboratory values these significant differences were lost (odds ratio [OR] 1.52, 95% confidence interval [CI] 0.47-4.91) in the entire cohort and OR 3.89, 95% CI 0.30-50.80 in women). CONCLUSIONS: Higher CIMT and PWV were associated to higher age, male sex, and several well-documented cardiovascular risk factors. However, in this study we could not prove that either covert atherosclerosis or arterial stiffness contribute to pathogenesis of early-onset CIS.

Glycemic control is not related to cerebral small vessel disease in neurologically asymptomatic individuals with type 1 diabetes.

AIMS: To determine if medium- and long-term blood glucose control as well as glycemic variability, which are known to be strong predictors of vascular complications, are associated with underlying cerebral small vessel disease (cSVD) in neurologically asymptomatic individuals with type 1 diabetes. METHODS: A total of 189 individuals (47.1% men; median age 40.0, IQR 33.0-45.2 years) with type 1 diabetes (median diabetes duration of 21.7, IQR 18.3-30.7 years) were enrolled in a cross-sectional retrospective study, as part of the Finnish Diabetic Nephropathy (FinnDiane) Study. Glycated hemoglobin (HbA1c) values were collected over the course of ten years before the visit including a clinical examination, biochemical sampling, and brain magnetic resonance imaging. Markers of glycemic control, measured during the visit, included HbA1c, fructosamine, and glycated albumin. RESULTS: Signs of cSVD were present in 66 (34.9%) individuals. Medium- and long-term glucose control and glycemic variability did not differ in individuals with signs of cSVD compared to those without. Further, no difference in any of the blood glucose variables and cSVD stratified for cerebral microbleeds (CMBs) or white matter hyperintensities were detected. Neither were numbers of CMBs associated with the studied glucose variables. Additionally, after dividing the studied variables into quartiles, no association with cSVD was observed. CONCLUSIONS: We observed no association between glycemic control and cSVD in neurologically asymptomatic individuals with type 1 diabetes. This finding was unexpected considering the large number of signs of cerebrovascular pathology in these people after two decades of chronic hyperglycemia and warrants further studies searching for underlying factors of cSVD.

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

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.

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

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.

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

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 HbA1c. 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.

Comparison of Manual Cross-Sectional Measurements and Automatic Volumetry of the Corpus Callosum, and Their Clinical Impact: A Study on Type 1 Diabetes and Healthy Controls.

Background and purpose: Degenerative change of the corpus callosum might serve as a clinically useful surrogate marker for net pathological cerebral impact of diabetes type 1. We compared manual and automatic measurements of the corpus callosum, as well as differences in callosal cross-sectional area between subjects with type 1 diabetes and healthy controls. Materials and methods: This is a cross-sectional study on 188 neurologically asymptomatic participants with type 1 diabetes and 30 healthy age- and sex-matched control subjects, recruited as part of the Finnish Diabetic Nephropathy Study. All participants underwent clinical work-up and brain MRI. Callosal area was manually measured and callosal volume quantified with FreeSurfer. The measures were normalized using manually measured mid-sagittal intracranial area and volumetric intracranial volume, respectively. Results: Manual and automatic measurements correlated well (callosal area vs. volume: ρ = 0.83, p < 0.001 and mid-sagittal area vs. intracranial volume: ρ = 0.82, p < 0.001). We found no significant differences in the callosal measures between cases and controls. In type 1 diabetes, the lowest quartile of normalized callosal area was associated with higher insulin doses (p = 0.029) and reduced insulin sensitivity (p = 0.033). In addition, participants with more than two cerebral microbleeds had smaller callosal area (p = 0.002). Conclusion: Manually measured callosal area and automatically segmented are interchangeable. The association seen between callosal size with cerebral microbleeds and insulin resistance is indicative of small vessel disease pathology in diabetes type 1.

The role of blood pressure in risk of ischemic and hemorrhagic stroke in type 1 diabetes.

BACKGROUND: Hypertension is one of the strongest risk factors for stroke in the general population, while systolic blood pressure has been shown to independently increase the risk of stroke in type 1 diabetes. The aim of this study was to elucidate the association between different blood pressure variables and risk of stroke in type 1 diabetes, and to explore potential nonlinearity of this relationship. METHODS: We included 4105 individuals with type 1 diabetes without stroke at baseline, participating in the nationwide Finnish Diabetic Nephropathy Study. Mean age at baseline was 37.4 ± 11.9 years, median duration of diabetes 20.9 (interquartile range 11.5-30.4) years, and 52% were men. Office systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured. Based on these pulse pressure (PP) and mean arterial pressure (MAP) were calculated. Strokes were classified based on medical and autopsy records, as well as neuroimaging. Cox proportional hazard models were performed to study how the different blood pressure variables affected the risk of stroke and its subtypes. RESULTS: During median follow-up time of 11.9 (9.21-13.9) years, 202 (5%) individuals suffered an incident stroke; 145 (72%) were ischemic and 57 (28%) hemorrhagic. SBP, DBP, PP, and MAP all independently increased the risk of any stroke. SBP, PP, and MAP increased the risk of ischemic stroke, while SBP, DBP, and MAP increased the risk of hemorrhagic stroke. SBP was strongly associated with stroke with a hazard ratio of 1.20 (1.11-1.29)/10 mmHg. When variables were modeled using restricted cubic splines, the risk of stroke increased linearly for SBP, MAP, and PP, and non-linearly for DBP. CONCLUSIONS: The different blood pressure variables are all independently associated with increased risk of stroke in individuals with type 1 diabetes. The risk of stroke, ischemic stroke, and hemorrhagic stroke increases linearly at blood pressure levels less than the current recommended treatment guidelines.

Clinical and MRI Features of Cerebral Small-Vessel Disease in Type 1 Diabetes.

OBJECTIVE: To assess the prevalence of cerebral small-vessel disease (SVD) in subjects with type 1 diabetes compared with healthy control subjects and to characterize the diabetes-related factors associated with SVD. RESEARCH DESIGN AND METHODS: This substudy was cross-sectional in design and included 191 participants with type 1 diabetes and median age 40.0 years (interquartile range 33.0-45.1) and 30 healthy age- and sex-matched control subjects. All participants underwent clinical investigation and brain MRIs, assessed for cerebral SVD. RESULTS: Cerebral SVD was more common in participants with type 1 diabetes than in healthy control subjects: any marker 35% vs. 10% (P = 0.005), cerebral microbleeds (CMBs) 24% vs. 3.3% (P = 0.008), white matter hyperintensities 17% vs. 6.7% (P = 0.182), and lacunes 2.1% vs. 0% (P = 1.000). Presence of CMBs was independently associated with systolic blood pressure (odds ratio 1.03 [95% CI 1.00-1.05], P = 0.035). CONCLUSIONS: Cerebral SVD, CMBs in particular, is more common in young people with type 1 diabetes compared with healthy control subjects.

Prognosis and Its Predictors After Incident Stroke in Patients With Type 1 Diabetes.

OBJECTIVE: Although patients with type 1 diabetes have a poor prognosis after a stroke, predictors of survival after an incident stroke in these patients are poorly studied. RESEARCH DESIGN AND METHODS: In this observational study, a total of 144 patients of 4,083 with type 1 diabetes from the Finnish Diabetic Nephropathy (FinnDiane) Study suffered an incident stroke in 1997-2010, and were followed for a mean 3.4 ± 3.1 years after the stroke. Information was recorded on hard cardiovascular events and death as a result of cardiovascular or diabetes-related cause, collectively referred to as vascular composite end point. Information was collected from medical records, death certificates, and the National Care Register of Health Care. Predictors at the time of the incident stroke were studied for the end points. RESULTS: During follow-up, 104 (72%) patients suffered a vascular composite end point. Of these, 33 (32%) had a recurrent stroke, 33 (32%) a hard cardiovascular event, and 76 (53%) died of cardiovascular or diabetes-related causes, with an overall 1-year survival of 76% and 5-year survival of 58%. The predictors of a vascular composite end point were hemorrhagic stroke subtype (hazard ratio 2.03 [95% CI 1.29-3.19]), as well as chronic kidney disease stage 2 (2.48 [1.17-5.24]), stage 3 (3.04 [1.54-6.04]), stage 4 (3.95 [1.72-9.04]), and stage 5 (6.71 [3.14-14.34]). All-cause mortality increased with deteriorating kidney function. CONCLUSIONS: Patients with type 1 diabetes with an incident stroke have a poor cardiovascular prognosis and a high risk of all-cause mortality. In particular, hemorrhagic stroke subtype and progression of diabetic kidney disease conveys worse outcome.

Different risk factor profiles for ischemic and hemorrhagic stroke in type 1 diabetes mellitus.

BACKGROUND AND PURPOSE: Despite the fact that patients with type 1 diabetes mellitus have a markedly increased risk of experiencing a stroke, independent risk factors for stroke and its subtypes in these patients have remained unclear. METHODS: A total of 4083 patients with type 1 diabetes mellitus from the Finnish Diabetic Nephropathy (FinnDiane) Study, without a history of stroke at baseline, were included. Strokes were classified based on medical files and brain imaging. At baseline, mean age was 37.4±11.8 years, duration of diabetes mellitus was 20.0 (11.0-30.0) years, and 51% were men. During 9.0±2.7 years (36 680 patient-years) of follow-up, 105 patients experienced an ischemic stroke and 44 a hemorrhagic stroke. Cox proportional hazards analyses were performed to determine independent risk factors. RESULTS: Independent risk factors for ischemic stroke were duration of diabetes mellitus, presence of diabetic nephropathy, higher hemoglobin A1c, higher systolic blood pressure, insulin resistance, and history of smoking, whereas sex, lipids, high-sensitivity C-reactive protein, and the metabolic syndrome were not associated with an increased risk. Diabetic nephropathy, severe diabetic retinopathy, higher systolic blood pressure, and lower body mass index were independently associated with hemorrhagic stroke. CONCLUSIONS: The risk factor profile for ischemic stroke seems partly different from that of hemorrhagic stroke in patients with type 1 diabetes mellitus.

Incidence of stroke according to presence of diabetic nephropathy and severe diabetic retinopathy in patients with type 1 diabetes.

OBJECTIVE: Type 1 diabetes is associated with a markedly increased risk of stroke, but only a few studies on the incidence of stroke in type 1 diabetes exist. Therefore, we assessed the incidence of stroke in patients with type 1 diabetes and studied the impact of diabetic nephropathy (DN) and severe diabetic retinopathy (SDR) on this risk. RESEARCH DESIGN AND METHODS: We studied 4,083 patients with type 1 diabetes from the Finnish Diabetic Nephropathy Study. Mean age was 37.4 ± 11.8 years, duration of diabetes was 21.6 ± 12.1 years, and 52% were men. Strokes were identified from medical records, death certificates, and the National Hospital Discharge Register and classified based on medical files and brain images. RESULTS: During 36,680 person-years of follow-up, 149 (4%) patients suffered an incident stroke (105 infarctions and 44 hemorrhages). Of the infarctions, 58 (55%) were lacunar. The incidence of stroke, cerebral infarction, and cerebral hemorrhage was 406 (95% CI 344-477), 286 (234-347), and 120 (87-161) per 100,000 person-years, respectively. In an adjusted analysis, microalbuminuria increased the risk of stroke with a hazard ratio (HR) of 3.2 (1.9-5.6), macroalbuminuria 4.9 (2.9-8.2), and end-stage renal disease 7.5 (4.2-13.3), and SDR increased the risk with an HR of 3.0 (1.9-4.5). The risk of cerebral infarction, cerebral hemorrhage, and lacunar infarction increased in a similar manner. The proportion of lacunar versus nonlacunar infarction did not change across DN groups. CONCLUSIONS: The presence of SDR and DN, independently, increases the risk of stroke, cerebral infarction, and cerebral hemorrhage in patients with type 1 diabetes.

Subarachnoid hemorrhage in type 1 diabetes: a prospective cohort study of 4,083 patients with diabetes.

OBJECTIVE: To estimate for the first time the incidence of subarachnoid hemorrhage (SAH) in type 1 diabetes. RESEARCH DESIGN AND METHODS: Using the nationwide Finnish Diabetic Nephropathy (FinnDiane) Study cohort of 4,083 patients with type 1 diabetes (mean age of 37.4 ± 11.8 years at enrollment), we analyzed the incidence of first-ever SAH events. RESULTS: During the follow-up time of 36,680 person-years (median 9.4 years), 15 patients with type 1 diabetes experienced an aneurysmal or nonaneurysmal SAH, and thus the crude incidence of SAH was 40.9 (95% CI 22.9-67.4) per 100,000 person-years. One patient had a verified aneurysmal SAH, and four patients died suddenly of an SAH, which was most likely caused by an aneurysm. SAHs in 10 out of 15 patients were classified as nonaneurysmal SAH, and thus the crude incidence of nonaneurysmal SAH was 27.3 (13.1-50.1) per 100,000 person-years. None of the nonaneurysmal SAHs were fatal. In univariate analysis, current smokers had a hazard ratio of 4.82 (95% CI 1.31-17.81) for nonaneurysmal SAH. CONCLUSIONS: The incidence of nonaneurysmal SAH is high among patients with type 1 diabetes. Our findings suggest that nonaneurysmal SAH is a distinct new microvascular complication in type 1 diabetes.

Stroke mimics and intravenous thrombolysis.

STUDY OBJECTIVE: The necessity for rapid administration of intravenous thrombolysis in patients with acute ischemic stroke may lead to treatment of patients with conditions mimicking stroke. We analyze stroke patients treated with intravenous thrombolysis in our center to characterize cases classified as stroke mimics. METHODS: We identified and reviewed all cases with a diagnosis other than ischemic stroke in our large-scale single-center stroke thrombolysis registry. We compared these stroke mimics with patients with neuroimaging-negative and neuroimaging-positive ischemic stroke results. RESULTS: Among 985 consecutive intravenous thrombolysis-treated patients, we found 14 stroke mimics (1.4%; 95% confidence interval 0.8% to 2.4%), 694 (70.5%) patients with neuroimaging-positive ischemic stroke results, and 275 (27.9%) patients with neuroimaging-negative ischemic stroke results. Stroke mimics were younger than patients with neuroimaging-negative or -positive ischemic stroke results. Compared with patients with neuroimaging-positive ischemic stroke results, stroke mimics had less severe symptoms at baseline and better 3-month outcome. No differences appeared in medical history or clinical features between stroke mimics and patients with neuroimaging-negative ischemic stroke results. None of the stroke mimics developed symptomatic intracerebral hemorrhage compared with 63 (9.1%) among patients with neuroimaging-positive ischemic stroke results and 6 (2.2%) among patients with neuroimaging-negative ischemic stroke results. CONCLUSION: Stroke mimics were infrequent among intravenous thrombolysis-treated stroke patients in this cohort, and their treatment did not lead to harmful complications.

Factors associated with impaired kidney function and its impact on long-term outcome in young ischemic stroke.

BACKGROUND AND PURPOSE: After ischemic stroke, kidney dysfunction is linked to poor outcomes in the elderly, but regarding young patients, data are lacking. METHODS: We investigated estimated glomerular filtration rate (eGFR) on admission according to the Modification of Diet in Renal Disease equation in 958 consecutive patients aged 15 to 49 years with their first-ever ischemic stroke. Logistic regression adjusted for demographics and stroke risk factors served to identify factors related to low (<60) and high (>120 mL/min/1.73 m(2)) eGFR. In the long-term follow-up (mean, 8.9±3.8 years) study, Cox proportional hazards analysis described the association between eGFR and the following end points: nonfatal/fatal ischemic stroke; composite vascular event of any stroke, myocardial infarction, revascularization/other arterial occlusive event, or vascular death; and death of any cause. RESULTS: Estimated GFR was normal in 809 (84.4%), low in 43 (4.5%), and high in 106 (11.1%) patients. Type 1 diabetes (OR, 18.84; 95% CI, 8.65 to 41.03), hypertension (4.29; 1.94 to 9.48), and cardiovascular disease (2.66; 1.19 to 5.96) were independently associated with low eGFR. Type 2 diabetes (3.82; 1.93 to 7.55), lower age (0.95 per year; 0.93 to 0.98), and male gender (1.74; 1.08 to 2.82) were associated with high eGFR. Both low (hazard ratio, 5.73; 95% CI, 3.54 to 9.25) and high eGFR (1.78; 1.01 to 3.14) were associated with long-term mortality when adjusted for age, gender, risk factors, stroke severity, and subtype. No independent association appeared between eGFR and vascular events. CONCLUSIONS: Despite their different associated risk factors in our young patient cohort, both low and high eGFR predicted long-term mortality after ischemic stroke.

Post-thrombolytic hyperglycemia and 3-month outcome in acute ischemic stroke.

BACKGROUND: Treating hyperglycemia in acute ischemic stroke may be beneficial, but knowledge on its prognostic value and optimal target glucose levels is scarce. We investigated the dynamics of glucose levels and the association of hyperglycemia with outcomes on admission and within 48 h after thrombolysis. METHODS: We included 851 consecutive patients with acute ischemic stroke treated with intravenous thrombolysis in the Helsinki University Central Hospital during 1998-2008. Outcome measures were unfavorable 3- month outcome (3-6 on the modified Rankin Scale), death, and symptomatic intracerebral hemorrhage (sICH) according to NINDS criteria. Hyperglycemia was defined as a blood glucose level of ≥8.0 mmol/l. Four groups were identified based on (a) admission and (b) peak glucose levels 48 h after thrombolysis: (1) persistent normoglycemia (baseline plus 48-hour normoglycemia), (2) baseline hyperglycemia (48-hour normoglycemia), (3) 48-hour hyperglycemia (baseline normoglycemia), and (4) persistent hyperglycemia (baseline plus 48-hour hyperglycemia). RESULTS: 480 (56.4%) of our patients (median age 70 years; onset-to-needle time 199 min; National Institutes of Health Stroke Scale score 9), had persistent normoglycemia, 59 (6.9%) had baseline hyperglycemia, 175 (20.6%) had 48-hour hyperglycemia, while persistent hyperglycemia appeared in 137 (16.1%) patients. Persistent and 48-hour hyperglycemia independently predicted unfavorable outcome [odds ratio (OR) = 2.33, 95% confidence interval (CI) = 1.41-3.86, and OR = 2.17, 95% CI = 1.30-3.38, respectively], death (OR = 6.63, 95% CI = 3.25-13.54, and OR = 3.13, 95% CI = 1.56-6.27, respectively), and sICH (OR = 3.02, 95% CI = 1.68-5.43, and OR = 1.89, 95% CI = 1.04-3.43, respectively), whereas baseline hyperglycemia did not. CONCLUSIONS: Hyperglycemia (≥8.0 mmol/l) during 48 h after intravenous thrombolysis of ischemic stroke is strongly associated with unfavorable outcome, sICH, and death.

Spinal Epidural Hematoma as a Complication of Intravenous Thrombolysis in an Acute Ischemic Stroke Patient.

An 80-year-old white male suffered a stroke, fell to the floor, and suffered acute right hemiparesis and facial palsy. After an intravenous alteplase infusion 2.5 h later, the patient first complained of numbness in his right arm, then neck pain, followed by left leg numbness and slowly progressing paraparesis. MRI of the spine demonstrated an acute spinal dorsal epidural hematoma extending from the C6 to the T6 level; 12 h later, he underwent hematoma evacuation and laminectomy. Three months after surgery, the patient was paraplegic with moderate sensory loss below mamillary level. Acute ischemic stroke is often associated with a sudden fall, which, after thrombolysis, may result in unusual hemorrhagic complications.

The neuroprotective KDI domain of gamma 1-laminin is a universal and potent inhibitor of ionotropic glutamate receptors.

Previous work from this laboratory indicates that the KDI (Lys-Asp-Ile) domain of gamma 1-laminin promotes functional regeneration of adult rat spinal cord injuries and protects adult rat hippocampal neurons against massive neuronal death induced by intracerebral injection of the glutamate analogue kainic acid. In the present study, we used patch clamp recordings on cultured human embryonic neocortical neurons and HEK 293 cells expressing recombinant glutamate receptor subunits to study a putative interaction of the KDI with the glutamate system. We show that the KDI domain of gamma 1-laminin is a universal and potent inhibitor of AMPA, kainate, and NMDA subclasses of glutamate receptors, with a noncompetitive action on the AMPA receptor channel activity. Glutamate neurotoxicity plays a key role in both CNS trauma and neurodegenerative disorders, so this unexpected, novel function of the gamma 1-laminin-derived tripeptide may prove clinically valuable in treatment of CNS trauma and/or disease.

Soluble KDI domain of gamma1 laminin protects adult hippocampus from excitotoxicity of kainic acid.

Recent data indicate that the soluble KDI domain of gamma1 laminin promotes survival and neurite outgrowth of human central neurons in vitro (Liebkind et al.[2003] J Neurosci Res 73:637-643), and seems to neutralize both glia- and myelin-derived signals that hamper regeneration in the central nervous system (CNS) of adult mammals. We show that damage of adult rat neocortical and hippocampal areas by a stereotaxic injection of kainic acid (KA) is prevented by a preceding injection of the soluble KDI domain. In the presence of the KDI domain, both neocortical and hippocampal areas show extensive gliosis but have viable neurons and glial cells, which are absent and the areas fully destroyed after injection of KA alone. This result indicates that the KDI domain of the gamma1 laminin protects the CNS against excitotoxic insults and promotes survival of both neurons and glial cells. The KDI domain may thus be a potential drug to prevent CNS damage induced by neurodegenerative disorders, mechanical injury, or ischemia.

Regeneration of adult rat spinal cord is promoted by the soluble KDI domain of gamma1 laminin.

Regeneration in the central nervous system (CNS) of adult mammals is hampered by formation of a glial scar and by proteins released from the myelin sheaths of injured neuronal pathways. Our recent data indicate that the KDI (Lys-Asp-Ile) domain of gamma1 laminin neutralizes both glial- and myelin-derived inhibitory signals and promotes survival and neurite outgrowth of cultured human spinal cord neurons. We show that after complete transection of the adult rat spinal cord, animals receiving onsite infusion of the KDI domain via osmotic mini-pumps recover and are able to sustain their body weights and walk with their hindlimbs. Animals treated with placebo suffer from irreversible hindlimb paralysis. Microscopic and molecular analyses of the spinal cords indicate that the KDI domain reduces tissue damage at the lesion site and enables neurite outgrowth through the injured area to effect functional recovery of the initially paralyzed animals. That the KDI domain enhances regeneration of acute spinal cord injuries in the adult rat suggests that it may be used to promote regeneration of spinal cord injuries in humans.