The influence of diabetes and hyperglycemia on clinical course after intracerebral hemorrhage.
Passero Stefano,Ciacci Giuseppe,Ulivelli Monica
OBJECTIVE:To determine whether diabetes and admission hyperglycemia in nondiabetic patients influence outcome and the occurrence of cerebral and medical complications after intracerebral hemorrhage (ICH). METHODS:The study sample included 764 patients with ICH. The effects of diabetes and admission hyperglycemia were examined in relation to 30-day and 3-month mortality using Cox regression models controlling for potential confounders. The analysis was conducted for the entire sample of patients and repeated in comatose and noncomatose patients. RESULTS:Among comatose patients, neither diabetes nor admission hyperglycemia contributed significant predictive information, as nearly all patients died. In noncomatose patients, diabetes was an independent predictor of 30-day (odds ratio [OR] 1.31; 95% CI 1.08 to 1.58) and 3-month (OR 1.30; 95% CI 1.08 to 1.56) mortality and was associated with a greater incidence of infectious (OR 1.24; 95% CI 1.03 to 1.49) and cerebral (OR 1.42; 95% CI 1.10 to 1.83) complications. Among nondiabetic patients with Glasgow Coma Scale score of >8, hyperglycemia was an independent predictor of 30-day (OR 1.29; 95% CI 1.05 to 1.58) and 3-month (OR 1.27; 95% CI 1.05 to 1.53) mortality and was associated with a greater incidence of cerebral complications (OR 1.47; 95% CI 1.12 to 2.94). CONCLUSIONS:Both diabetes and admission hyperglycemia in nondiabetic patients are predictors of poor outcome after supratentorial ICH. This may be related to the greater incidence of cerebral and infectious complications in diabetic patients and of cerebral complications in hyperglycemic nondiabetic patients.
Occult infarct with acute hemorrhagic stroke in juvenile diabetic ketoacidosis.
Lin Jainn-Jim,Lin Kuang-Lin,Wang Huei-Shyong,Wong Alex Mun-Ching,Hsia Shao-Hsuan
Brain & development
Diabetes ketoacidosis (DKA) is one of the common complications of type I insulin-dependent diabetes mellitus. Neurological deterioration during an episode of DKA is usually assumed to be caused by cerebral edema and cerebral vascular accidents. However, hemorrhagic stroke is a very rare complication of juvenile DKA. We describe a girl who had newly diagnosed insulin-dependent diabetes mellitus with juvenile DKA developed intracerebral hemorrhage.
Suppressing Interferon-γ Stimulates Microglial Responses and Repair of Microbleeds in the Diabetic Brain.
Taylor Stephanie,Mehina Eslam,White Emily,Reeson Patrick,Yongblah Kevin,Doyle Kristian P,Brown Craig E
The Journal of neuroscience : the official journal of the Society for Neuroscience
Microcirculatory damage is a common complication for those with vascular risk factors, such as diabetes. To resolve vascular insults, the brain's immune cells (microglia) must rapidly envelop the site of injury. Currently, it is unknown whether Type 1 diabetes, a condition associated with chronic immune system dysfunction, alters microglial responses to damage and what mechanisms are responsible. Using two-photon microscopy in adult male mice, we show that microglial envelopment of laser-induced cerebral microbleeds is diminished in a hyperglycemic mouse model of Type 1 diabetes, which could not be fully rescued with chronic insulin treatment. Microglia were important for vessel repair because reduced microglial accumulation in diabetic mice or near-complete depletion in healthy controls was associated with greater secondary leakage of the damaged vessel. Broadly suppressing inflammation with dexamethasone in diabetic mice but not healthy controls, significantly enhanced microglial responses to microbleeds and attenuated secondary vessel leakage. These enhancements were associated with changes in IFN-γ signaling because dexamethasone suppressed abnormally high levels of IFN-γ protein levels in brain and blood serum of diabetic mice. Further, blocking IFN-γ in diabetic mice with neutralizing antibodies restored normal microglial chemotaxic responses and purinoceptor gene expression, as well as mitigated secondary leakage. These results suggest that abnormal IFN-γ signaling disrupts microglial function in the diabetic brain, and that immunotherapies targeting IFN-γ can stimulate microglial repair of damaged vessels. Although Type 1 diabetes is an established risk factor for vascular complications, such as microbleeds, and is known to hinder wound healing in the body, no study has examined how diabetes impacts the brain's innate immune reparative response (involving cells called microglia) to vascular injury. Here we show that microglial responses to brain microbleeds were diminished in diabetic animals, which also exacerbated secondary leakage from damaged vessels. These impairments were related to abnormally high levels of the proinflammatory cytokine IFN-γ because reducing IFN-γ with immunosuppressant drugs or blocking antibodies helped restore normal microglial responses and repair of damaged vessels. These data highlight the use of IFN-γ modulating therapeutics to enhance vascular repair in at-risk populations.
Subarachnoid and parenchymal haemorrhages as a complication of severe diabetic ketoacidosis in a preadolescent with new onset type 1 diabetes.
Finn Bryan P,Power Claire,McSweeney Niamh,Breen Dorothy,Wyse Gerald,O'Connell Susan M
Diabetic ketoacidosis (DKA) is one of the most common causes of morbidity and mortality in new onset type 1 diabetes mellitus (T1DM). Children have a higher rate of neurological complications from DKA when compared to adults. The differential for sudden focal neurological deterioration in the setting of DKA is cerebral oedema followed by ischaemic and haemorrhagic stroke. Spontaneous intracranial haemorrhages can present with non-specific features frequently, for example, impaired consciousness, even when biochemical parameters are improving in the setting of DKA. We report the case of a girl with new onset T1D who presented in severe DKA and subsequently developed intracerebral parenchymal and subarachnoid haemorrhages. Our patient is unique in that no focal neurological or neuropsychological deficits have been found at 1-year follow up, compared to the literature which suggests poor outcomes. Our case contrasts with these previous cases as none of the other case reports demonstrated subarachnoid haemorrhages with survival.
The Relationship between Neutrophil-to-Lymphocyte Ratio and Intracerebral Hemorrhage in Type 2 Diabetes Mellitus.
Luo Peng,Li Rui,Yu Siyuan,Xu Tingting,Yue Shufan,Ji Yongli,Chen Xin,Xie Haiting
Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association
INTRODUCTION:Chronic systematic inflammation has been suggested to be associated with the occurrence and development of cardiovascular events. Low-grade systematic inflammation persists in type 2 diabetes mellitus (T2DM) patients. In addition, the risk of cerebral hemorrhage in these patients is increased compared with non-diabetic patients. Neutrophil-to-lymphocyte ratio (NLR) is the ratio derived by dividing the neutrophil count with the lymphocyte count from a peripheral blood sample. This study aimed to explore the relation between NLR and cerebral hemorrhage, and to prove that NLR is an independent risk factor of cerebral hemorrhage in T2DM patients. METHODS:In total, 429 cases of T2DM patients were included. The patients were divided into two groups depending on the presence of cerebral hemorrhage: the cerebral hemorrhage group (n = 87) and the control group (n = 342). Based on clinical and laboratory data of diabetes diagnosis, this article investigates the relationship between NLR and the risk of cerebral hemorrhage. RESULTS:Increase in NLR was positively correlated with the incidence of cerebral hemorrhage in T2DM patients and might serve as an independent risk factor of cerebral hemorrhage in T2DM patients (OR: 4.451, 95% CI: 2.582-7.672). NLR >2.58 might be useful in predicting the threshold value of cerebral hemorrhage risk in newly diagnosed T2DM patients (area under the curve: .72, 95% CI: .659-.780, P < .001) CONCLUSION: As an indicator of the degree of systematic inflammation, NLR is an independent risk factor of cerebral hemorrhage in T2DM patients.
Increased Spontaneous Central Bleeding and Cognition Impairment in APP/PS1 Mice with Poorly Controlled Diabetes Mellitus.
Ramos-Rodriguez Juan José,Infante-Garcia Carmen,Galindo-Gonzalez Lucia,Garcia-Molina Yaiza,Lechuga-Sancho Alfonso,Garcia-Alloza Mónica
Alzheimer's disease (AD) and vascular dementia (VaD) are the most common causes of dementia, and borderlines are blurred in many cases. Aging remains the main risk factor to suffer dementia; however, epidemiological studies reveal that diabetes may also predispose to suffer AD. In order to further study this relationship, we have induced hypoinsulinemic diabetes to APPswe/PS1dE9 (APP/PS1) mice, a classical model of AD. APP/PS1 mice received streptozotocin (STZ) ip at 18 weeks of age, when AD pathology is not yet established in this animal model. Cognition was evaluated at 26 weeks of age in the Morris water maze and the new object discrimination tests. We observed that STZ-induced episodic and working memory impairment was significantly worsened in APP/PS1 mice. Postmortem assessment included brain atrophy, amyloid-beta and tau pathology, spontaneous bleeding, and increased central inflammation. Interestingly, in APP/PS1-STZ diabetic mice, we detected a shift in Aβ soluble/insoluble levels, towards more toxic soluble species. Phospho-tau levels were also increased in APP/PS1-STZ mice, accompanied by an exacerbated inflammatory process, both in the close proximity to senile plaque (SP) and in SP-free areas. The presence of hemorrhages was significantly higher in APP/PS1-STZ mice, and although pericytes and endothelium were only partially affected, it remains possible that blood-brain barrier alterations underlie observed pathological features. Our data support the implication of the diabetic process in AD and VaD, and it is feasible that improving metabolic control could delay observed central pathology.
Association between diabetes mellitus and incidence of intracerebral haemorrhage and case fatality rates: A retrospective population-based cohort study.
Boulanger Marion,Al-Shahi Salman Rustam,Kerssens Jan,Wild Sarah H,
Diabetes, obesity & metabolism
We investigated the associations between diabetes (type 1, type 2 or no diabetes) and intracerebral haemorrhage (ICH) incidence as well as case fatality after ICH, in a retrospective cohort study of people aged 40 to 89 years in Scotland during the period 2004 to 2013, using linkage of population-based records of diagnosed diabetes, hospital discharges and deaths. We calculated ICH incidence and 30-day case fatality after hospital admission for ICH, along with their relative risks (RR) and 95% confidence intervals (CIs), among people with type 1 or type 2 diabetes compared to people without diabetes, adjusting for age, sex and socio-economic status (SES). There were 77, 1275 and 9778 incident ICH events and the case-fatality rate was 44% (95% CI 33, 57), 38% (95% CI 35, 41) and 36% (95% CI 35, 37) in people with type 1, type 2 and without diabetes, respectively. In comparison with absence of diabetes, type 1 diabetes was associated with a higher incidence of ICH (1.74, 95% CI 1.38-2.21) and higher case fatality after ICH (1.35, 95% CI 1.01-1.70), after adjustment for age, sex and SES. The small increases in ICH incidence (1.06, 95% CI 0.99-1.12) and case-fatality (1.04, 95% CI 0.96-1.13) in people with type 2 diabetes compared with people without diabetes were not statistically significant.
Prestroke glycemic status is associated with the functional outcome in spontaneous intracerebral hemorrhage.
Zhang Guanghui,Wu Fangrong,Xu Yan,Feng Jinzhou,Cai Zenglin,Xu Bingchao,Zhou Xinyu,He Mingli
Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology
Admission hyperglycemia is thought to be related to poor neurological function and high mortality in patients with spontaneous intracerebral hemorrhage (sICH). However, it is not known whether prestroke glycemic status affects functional outcome of sICH. The study was aimed to disclose the association between prestroke glycemic status and outcome in patients with sICH. The study included 288 patients with sICH. Prestroke glycemic status was represented by hemoglobin A1c (HbA1c) values measured the next day after admission. Correlations between HbA1c and age, hematoma volume, NIHSS, and mRS were analyzed using Spearman's correlation analysis. Patients were categorized into two groups according to hematoma volume (≤25 mL or >25 mL), mRS values (≤2 or >2), or hematoma location (lobar hematoma or deep hematoma). Logistic regression analyses were used to determine the relative independent risk factors for hematoma volume, hematoma location, and mRS values. In patients with sICH, HbA1c was significantly correlated with hematoma volume, NIHSS, and mRS. High HbA1c levels were independently associated with large hematoma volume, deep ICH, and poor outcome. When patients were stratified by history of diabetes, the predictive effect of HbA1c on outcomes was only observed in patients with diabetes. Admission glucose was also related to hematoma volume, but failed to predict outcome. Although both admission glucose and HbA1c independently predicted hematoma volume in patients with sICH, HbA1c alone could serve as a better predictor of poor outcome in diabetic patients after sICH.
Recombinant adiponectin peptide promotes neuronal survival after intracerebral haemorrhage by suppressing mitochondrial and ATF4-CHOP apoptosis pathways in diabetic mice via Smad3 signalling inhibition.
Wu Xun,Luo Jianing,Liu Haixiao,Cui Wenxing,Guo Wei,Zhao Lei,Guo Hao,Bai Hao,Guo Kang,Feng Dayun,Qu Yan
OBJECTIVE:Low levels of adiponectin (APN), a biomarker of diabetes mellitus, have been implicated in the poor outcome of intracerebral haemorrhage (ICH). Herein, we aimed to demonstrate the neuroprotective effects of a blood-brain barrier-permeable APN peptide (APNp) on ICH injury in diabetic mice and explore the underlying mechanisms. MATERIALS AND METHODS:Recombinant APNp was administrated intraperitoneally to mice with collagenase-induced ICH. Neurological deficits, brain water content and neural apoptosis were assessed. Western blotting, immunofluorescence staining, quantitative RT-PCR and transmission electron microscopy were used to determine the signalling pathways affected by APNp. RESULTS:Adiponectin peptide significantly alleviated neural apoptosis, neurological deficits and brain oedema following ICH in diabetic mice. Mechanistically, APNp promoted the restoration of peroxisome proliferator-activated receptor gamma coactivator (PGC)-1α related mitochondrial function and suppressed activating transcription factor 4 (ATF4)-CCAAT-enhancer-binding protein homologous protein (CHOP)-induced neural apoptosis. Furthermore, Smad3 signalling was found to play a regulatory role in this process by transcriptionally regulating the expression of PGC-1α and ATF4. APNp significantly suppressed the elevated phosphorylation and nuclear translocation of Smad3 after ICH in diabetic mice, while the protective effects of APNp on mitochondrial and ATF4-CHOP apoptosis pathways were counteracted when Smad3 was activated by exogenous transforming growth factor (TGF)-β1 treatment. CONCLUSIONS:Our study provided the first evidence that APNp promoted neural survival following ICH injury in the diabetic setting and revealed a novel mechanism by which APNp suppressed mitochondrial and ATF4-CHOP apoptosis pathways in a Smad3 dependent manner.
Role for HIF-1α and Downstream Pathways in Regulating Neuronal Injury after Intracerebral Hemorrhage in Diabetes.
Yu Zhen,Tang Ling,Chen Lifen,Li Jinfang,Wu Wanfu,Hu Changlin
Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology
BACKGROUND/AIMS:HIF-1α is accumulated in the cellular nucleus and cytoplasm under conditions of oxygen deprivation and engaged in pathophysiologic changes of homeostasis by modulating the expression of several target genes. As an endogenous signaling protein, HIF-1α contributes to in neuroprotection, erythropoiesis, and apoptosis modulation. The purpose of this study was to examine the role played by HIF-1α in regulating neurological injury evoked by intracerebral hemorrhage (ICH) through its downstream product, namely vascular endothelial growth factor (VEGF). In particular, we examined the effects of diabetic hyperglycemia on HIF-1α response in the processing of ICH. METHODS:ELISA was used to measure HIF-1α and VEGF; and Western Blot analysis to examine the protein expression of VEGFR-2 and Caspase-3. Neurological Severity Score and brain water content were used to indicate neurological function and brain edema. RESULTS:HIF-1α and VEGF were significantly increased in the brain after induction of ICH in non-diabetic control rats and diabetic rats; however, the amplified levels of HIF-1α and VEGF were attenuated in diabetic rats (P<0.05 vs. non-diabetic rats) as compared with non-diabetic rats. Also, the protein expression of VEGF receptor subtype 2 was significantly less in the brain of diabetic rats (P<0.05 vs. non-diabetic rats). Further, cerebral infusion of HIF-1 activator stabilized VEGF levels, attenuated Caspase-3 and improved neurological deficits induced by ICH and the effects are smaller in diabetic animals. CONCLUSION:HIF-1α activated by ICH likely plays a beneficial role via VEGF mechanisms and response of HIF-1α is largely impaired in diabetes. This has pharmacological implications to target specific HIF-1α and VEGF pathway for neuronal dysfunction and vulnerability related to ICH.
Exacerbation of Thromboinflammation by Hyperglycemia Precipitates Cerebral Infarct Growth and Hemorrhagic Transformation.
Desilles Jean-Philippe,Syvannarath Varouna,Ollivier Véronique,Journé Clément,Delbosc Sandrine,Ducroux Célina,Boisseau William,Louedec Liliane,Di Meglio Lucas,Loyau Stéphane,Jandrot-Perrus Martine,Potier Louis,Michel Jean-Baptiste,Mazighi Mikael,Ho-Tin-Noé Benoit
BACKGROUND AND PURPOSE:Admission hyperglycemia is associated with a poor outcome in acute ischemic stroke. How hyperglycemia impacts the pathophysiology of acute ischemic stroke remains largely unknown. We investigated how preexisting hyperglycemia increases ischemia/reperfusion cerebral injury. METHODS:Normoglycemic and streptozotocin-treated hyperglycemic rats were subjected to transient middle cerebral artery occlusion. Infarct growth and brain perfusion were assessed by magnetic resonance imaging. Markers of platelet, coagulation, and neutrophil activation were measured in brain homogenates and plasma. Downstream microvascular thromboinflammation (DMT) was investigated by intravital microscopy. RESULTS:Hyperglycemic rats had an increased infarct volume with an increased blood-brain barrier disruption and hemorrhagic transformation rate compared with normoglycemic rats. Magnetic resonance imaging scans revealed that hyperglycemia enhanced and accelerated lesion growth and was associated with hemorrhagic transformation originating from territories that were still not completely reperfused at 1 hour after middle cerebral artery recanalization. Intravital microscopy and analysis of brain homogenates showed that DMT began immediately after middle cerebral artery occlusion and was exacerbated by hyperglycemia. Measurement of plasma serotonin and matrix metalloproteinase-9 indicated that platelets and neutrophils were preactivated in hyperglycemic rats. Neutrophils from hyperglycemic diabetic patients showed increased adhesion to endothelial cells as compared with neutrophils from normoglycemic donors in flow chamber experiments. CONCLUSIONS:We show that hyperglycemia primes the thromboinflammatory cascade, thus, amplifying middle cerebral artery occlusion-induced DMT. DMT exacerbation in hyperglycemic rats impaired reperfusion and precipitated neurovascular damage, blood-brain barrier disruption, and hemorrhagic transformation. Our results designate DMT as a possible target for reduction of the deleterious impact of hyperglycemia in acute ischemic stroke.
Proliferative retinopathy in type 1 diabetes is associated with cerebral microbleeds, which is part of generalized microangiopathy.
Woerdeman Jorn,van Duinkerken Eelco,Wattjes Mike P,Barkhof Frederik,Snoek Frank J,Moll Annette C,Klein Martin,de Boer Michiel P,Ijzerman Richard G,Serné Erik H,Diamant Michaela
OBJECTIVE We investigated whether proliferative diabetic retinopathy in type 1 diabetic patients can be generalized to cerebral small vessel disease and whether it is associated with impaired peripheral microvascular function. RESEARCH DESIGN AND METHODS Thirty-three patients with proliferative diabetic retinopathy (PDR+), 34 patients without proliferative diabetic retinopathy, and 33 controls underwent magnetic resonance imaging to assess cerebral microangiopathy (cerebral microbleeds) and ischemic damage (white matter hyperintensities and lacunes). Peripheral microvascular function, i.e., skin capillary density and capillary recruitment, was assessed by capillary microscopy. RESULTS Cerebral microbleeds, but not ischemic damage, were more prevalent in PDR+ patients versus the other groups (P < 0.05). A trend was found across groups for the lowest baseline capillary density in PDR+ patients (P for trend = 0.05). In individuals with microbleeds, capillary recruitment was impaired compared with those without microbleeds (P = 0.04). CONCLUSIONS In PDR+ patients, cerebral microbleed prevalence was higher and seems part of generalized microangiopathy that may affect the skin and the brain.
Cerebral microbleeds, cognitive impairment, and MRI in patients with diabetes mellitus.
Zhou Hong,Yang Juan,Xie Peihan,Dong Yulan,You Yong,Liu Jincai
Clinica chimica acta; international journal of clinical chemistry
Cerebral microbleeds (CMBs), a typical imaging manifestation marker of sporadic cerebral small vessel disease, play a critical role in vascular cognitive impairment, which is often accompanied by diabetes mellitus (DM). Hence, CMBs may, in part, be responsible for the occurrence and development of cognitive impairment in patients with diabetes. Novel magnetic resonance imaging (MRI) sequences, such as susceptibility-weighted imaging and T2*-weighted gradient-echo, have the capability of noninvasively revealing CMBs in the brain. Moreover, a correlation between CMBs and cognitive impairment in patients with diabetes has been suggested in applications of functional MRI (fMRI). Since pathological changes in the brain occur prior to observable decline in cognitive function, neuroimaging may help predict the progression of cognitive impairment in diabetic patients. In this article, we review the detection of CMBs using MRI in diabetic patients exhibiting cognitive impairment. Future studies should emphasize the development and establishment of a novel MRI protocol, including fMRI, for diabetic patients with cognitive impairment to detect CMBs. A reliable MRI protocol would also be helpful in understanding the pathological mechanisms of cognitive impairment in this important patient population.
Reduced Intracerebral Hemorrhage and Perihematomal Edema Volumes in Diabetics on Sulfonylureas.
Irvine Hannah,Male Shailesh,Robertson Jetter,Bell Caitlin,Bentho Oladi,Streib Christopher
Background and Purpose- Sulfonylurea medications have been linked to reduced brain edema and improved outcome following ischemic stroke, but their effects on primary intracerebral hemorrhage (pICH) have not been thoroughly explored. Increasing ICH volume and perihematomal edema (PHE) volume are predictors of poor outcome in pICH. We investigated whether preexisting sulfonylurea use influenced ICH volume, PHE volume, and discharge disposition in patients with type 2 diabetes mellitus presenting with pICH. Methods- We performed a retrospective chart review of all diabetic patients presenting with pICH to 2 tertiary academic centers from 2006 to 2016. All patients with diabetes mellitus, pICH, admission computed tomography scan, and sulfonylurea use on admission were included in our study. For each case, 2-matched controls (admission date, age, hematoma location [deep versus lobar], use of antiplatelet, or anticoagulant) with diabetes mellitus and pICH were consecutively selected. ICH and PHE volumes were measured via region of interest analysis on admission computed tomography. To mitigate the influence of ICH volume on PHE, the PHE/ICH surface area ratio was calculated. Hospital discharge disposition was determined via chart abstraction. We used the Wilcoxon rank-sum test and Fisher exact test to compare cases and controls. Results- Of 317 patients screened, 21 sulfonylurea cases and 42-matched controls met criteria for study inclusion. Sulfonylurea cases had significantly lower admission ICH volumes (median, 4 mL; interquartile range [IQR], 2-30 versus median, 25 mL; IQR, 6-60; P=0.011), PHE volumes (median, 4 mL; IQR, 0.9-24 versus median, 17; IQR, 6-37; P=0.0095), and PHE/ICH surface area ratios (median, 0.28; IQR, 0.1-0.4 versus median, 0.43; IQR, 0.3-0.6; P=0.013) as compared with controls. Sulfonylureas were associated with improved discharge disposition ( P=0.0062). Conclusions- In patients with diabetes mellitus and pICH, sulfonylurea use predicted lower ICH and PHE volumes, lower relative PHE, and improved discharge disposition. Given the paucity of treatment options for pICH, further study of sulfonylureas is warranted.