Absence Of Vascular Occlusion Research Articles

Progressive Lacunar Strokes: A Predictive Score

Background and PurposeProgressive lacunar syndromes (PLS) occur in up to 20-30% of patients with lacunar strokes, increasing the risk of long term dependency. Our aim is to develop a predictive score to identify patients at high risk of presenting PLS. MethodsWe derived a risk score for PLS in a cohort of consecutive patients (n=187) presenting with one of the five classic lacunar syndromes (LS) and absence of vascular occlusion, perfusion deficit or symptomatic stenosis. A risk score was developed using the coefficients from the logistic regression model, and receiver operating characteristic (ROC) analysis was conducted to assess the prognostic value of the risk score. Sensitivity, specificity and accuracy were estimated for each total point score. ResultsOut of 187 patients included in our sample, 52 (27.8%) presented PLS. Previous history of diabetes mellitus (1 point), diastolic blood pressure at admission (2 points), clinical deficits consistent with a pure motor syndrome (1 point) and asymptomatic intracranial atheromatosis or stenosis in non-symptomatic territory (1 point) were independent predictors for PLS. The estimated area under the ROC curve for this model was 0.77 (95% CI,0.68 - 0.84). ConclusionThis score could be a useful tool in routine clinical practice to predict the occurrence of PLS, allowing the identification of those patients with LS who are at high risk of long term dependency due to early neurological worsening, and who would benefit the most from an intensive treatment.

Elimination of the fibrinogen integrin αMβ2-binding motif improves renal pathology in mice with sickle cell anemia

AbstractSickle cell anemia (SCA) is caused by a point mutation in the β-globin gene that leads to devastating downstream consequences including chronic hemolytic anemia, episodic vascular occlusion, and cumulative organ damage resulting in death. SCA patients show coagulation activation and inflammation even in the absence of vascular occlusion. The coagulation factor fibrinogen is not only central to hemostasis but also plays important roles in pathologic inflammatory processes, in part by engaging neutrophils/macrophages through the αMβ2 integrin receptor. To determine whether fibrin(ogen)-mediated inflammation is a driver of SCA-associated pathologies, hematopoietic stem cells from Berkeley sickle mice were transplanted into homozygous Fibγ390-396A mice that express normal levels of a mutant form of fibrin(ogen) that does not engage αMβ2. Fibγ390-396A mice with SCA displayed an impressive reduction of reactive oxygen species (ROS) in white blood cells (WBCs), decreased circulating inflammatory cytokines/chemokines, and significantly improved SCA-associated glomerular pathology highlighted by reduced glomerulosclerosis, inflammatory cell infiltration, ischemic lesions, mesangial thickening, mesangial hypercellularity, and glomerular enlargement. In addition, Fibγ390-396A mice with SCA had improved glomerular protective responses and podocyte/mesangial transcriptional signatures that resulted in reduced albuminuria. Interestingly, the fibrinogen γ390-396A mutation had a negligible effect on cardiac, lung, and liver functions and pathologies in the context of SCA over a year-long observation period. Taken together, our data support that fibrinogen significantly contributes to WBC-driven inflammation and ROS production, which is a key driver of SCA-associated glomerulopathy, and may represent a novel therapeutic target against irreversible kidney damage in SCA.

Diminished Renal Pathology in a Mouse Model of Sickle Cell Anemia in Which Fibrinogen Binding to Mac-1 Is Inhibited

Sickle cell anemia (SCA) is caused by a point mutation in the beta-globin gene. SCA has potentially devastating consequences including chronic hemolytic anemia, episodic vascular occlusion, inflammation and oxidative stress, and cumulative multi-organ damage resulting in early mortality. In fact, with reduction of childhood mortality due to early diagnosis and infection prophylaxis, end-organ damage is the major cause of death in SCA. SCA patients show hyper coagulative state in the absence of vascular occlusion. Recently, our group has shown that reduction of circulating major clotting factor, thrombin, in SCA mice significantly improves survival, reduces inflammation, results in reduced multi-organ damage and prolongs survival (Arumugam 2015). However, the mechanism(s) by which thrombin contributes to the pathophysiology of SCA remains undefined. While fibrinogen functions primarily to occlude blood vessels after cleavage by thrombin into fibrin, and thereby prevents excessive bleeding, it also plays an important role in the pathologic inflammatory disease processes through mitogenic, chemotactic, and immune-regulatory activities by interacting with neutrophils/ macrophages via the Mac-1 receptor. To test the hypothesis that leukocyte engagement of fibrinogen via Mac-1 and secondary inflammation are drivers of SCA-associated organ pathologies, hematopoietic stem cells (HSC) from the well-characterized humanized murine model of SCA, Berkeley sickle mice (HbS or SS) were transplanted into the Fibγ390-396A mice, the later expressing a mutant fibrinogen γ-chain which does not interact with Mac-1 (named as F1M SS). Fibγ390-396 mutation has no effect on clotting functions, supports platelet adhesion, and does not cause spontaneous hemorrhagic events in mice during development or adulthood (Flick 2004). As a control, normal fibrinogen expressing mice were also transplanted with HSC from sickle mice (named as F1WT SS). One year after HSC transplant, the F1M SS and F1WT SS mice were analyzed for blood parameters, reactive oxygen species (ROS), inflammatory cytokines, and organ functions and pathologies. We found that genetically imposed inhibition of fibrinogen binding to Mac-1 resulted in mild reduction (not statistically significant) of neutrophil, monocyte, and platelet counts. There was no significant difference in RBC parameters between F1WT SS and F1M SS mice. However, we found an impressive reduction in WBC ROS and decreased circulating inflammatory cytokines, IL-6 (79.1 ± 19.5 vs. 303.5 ± 73.9, P < 0.001), KC (132.7 ± 19.4 vs. 200.7 ± 33.6, P=0.04) and TNF-α (25.9 ± 2.8 vs. 37.7 ± 3.9, P=0.02) in F1M SS mice compared to F1WT SS mice. We also found significant improvement in SCA-associated glomerular pathologies such as reduced glomerulosclerosis, inflammatory cell infiltration, ischemic lesions, mesangial thickening, mesangial hyper cellularity and glomerular enlargement; associated with reduced albuminuria (123.3 ± 19.5 vs. 322.1 ± 91.4, P=0.03) in F1M SS mice compared to F1WT SS mice. However, tubular pathologies and urine osmolality were not improved in F1M SS mice. RNA-Seq analyses of glomerular preparation revealed improved glomerular protective responses and diminished loss of podocyte/mesangial cell signatures in F1M SS mice compared to F1WT SS mice. Interestingly, unlike the pan-organ improvement with thrombin reduction (Arumugam, 2015), fibrinogen binding to Mac-1 had minimal to no effect on cardiac, lung, and liver functions and pathologies. Taken together, our data support that fibrinogen significantly contributes to the WBC-driven inflammation and ROS production, and represents a key driver of SCA-associated glomerulopathy, and may provide a novel therapeutic target against irreversible kidney damage in SCA. DisclosuresMullins:Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees. Malik:CSL Behring: Patents & Royalties.

Long-Term Azathioprine Use and the Development of Non-Cirrhotic Portal Hypertension

Introduction: Non-cirrhotic portal hypertension (NCPH) is caused by intra- and extrahepatic etiologies. NCPH presents with signs of portal hypertension, especially variceal bleeding and splenomegaly. Extrahepatic portal vein thrombosis, nonalcoholic steatohepatitis, and primary sclerosing cholangitis are the most prevalent causes in the Western world. In rare cases, immunosuppressive drugs, particularly azathioprine (AZA), 6-mercaptopurine, and 6-thioguanine (TG), have been implicated in nodular regenerative hyperplasia, an idiopathic form of NCPH. Here we describe a case of NCPH with obstructive portal venopathy possibly induced by long-term AZA use. Case: A 44-year-old male with type I diabetes and Crohn's Disease was referred to our hepatology clinic for management of presumed cirrhosis. At the age of 40, after 20 years on AZA, EGD demonstrated grade II esophageal varices. Ultrasound revealed increased liver echogenicity and marked heterogeneity, as well as portal vein dilatation and splenomegaly. Beta-blocker therapy was initiated and AZA was discontinued. Adalimumab was started but was switched to vedolizumab one year later due to coccidioidomycosis infection. Labs were significant for thrombocytopenia, leukopenia, and microcytic anemia. MRI on presentation to our facility demonstrated splenomegaly and patent portal veins but no signs of cirrhosis. Ultrasound-guided liver biopsy demonstrated dense portal fibrosis and focal obliteration of portal vein branches. Portal vein branches were absent from portal tracts, and outlet venules were dilated (Figure 1). There was no evidence for clinical, radiologic, or histological cirrhosis or fatty liver disease.2250 Figure 1. Absence of portal veins from portal tracts with dilatations of the outlet venules (“herniated” portal veins, arrows), consistent with obstructive portal venopathy (A. H&E stain x200; B. Trichrome stain x100).Discussion: While the pathogenesis of AZA-induced NCPH remains uncertain, there is evidence that glutathione depletion, which is toxic to sinusoidal endothelial cells, leads to veno-occlusive disease. Whether occlusive venopathy is attributable to 6-TG toxicity alone remains unclear. Portal fibrosis and obstructive venopathy on histology in the absence of vascular occlusion on imaging suggest that portal hypertension in our patient was heralded by intrahepatic changes. Damage to endothelium by 6-TG represents one possible mechanism; however, it is just as feasible that an autoimmune process led to NCPH in this patient. We thus propose further research into possible associations between AZA and NCPH.

Radiological features of IgG4-related disease in the head, neck, and brain

Immunoglobulin (Ig) G4-related disease is a recently designated benign clinical entity histopathologically characterized by sclerosing inflammation and infiltration of numerous IgG4+ plasma cells that affects multiple organs. The purpose of this study is to characterize the imaging findings of patients with histopathologically proven IgG4-related disease in the head, neck, and brain. A total of 17 patients (15 males, 2 females; mean age, 66.1 ± 7.4years) with histopathologically proven IgG4-related disease in the head, neck, and brain were identified in two hospitals between January 2004 and December 2010. Imaging findings were retrospectively reviewed, with particular attention to the location and number of lesions, internal architecture, enhancement patterns, presence of vascular occlusion or compression, and changes in adjacent bones. The lesions, presented as either enlarged gland(s), or focal, localized nodules/masses, were distributed in the lacrimal gland (n = 7), the parotid gland (n = 14), the submandibular gland (n = 10), the pituitary gland (n = 2), skull base dura mater (n = 2), and the pterygopalatine fossa (n = 3). All lesions were well-defined and iso- to hypointense on T2-weighted magnetic resonance images and showed homogeneous enhancement. No lesion showed vascular occlusion or compression. Bones adjacent to the lesions showed remodeling (erosion or sclerosis) without signs of destruction (n = 6). Four patients had lesions involving multiple areas which extended along the trigeminal nerve, accompanied by expansion of neural foramina along their courses, with no signs of bone destruction. Sites of predilection for IgG4-related disease in the head, neck, and brain include the lacrimal, salivary, and pituitary glands. Recognition of the typical radiological features of IgG4-related disease, such as well-defined lesion borders, T2 hypointensity, homogeneous and gradual enhancement pattern, absence of vascular occlusion or compression, and presence of bone remodeling without destruction, may be of help in the diagnosis of this benign clinical entity.

Editorial Comment

The authors describe their method of laparoscopic nephron-sparing surgery in the absence of vascular occlusion. The method has been successfully applied in a small series of patients and might provide an alternative technique for this challenging operation.

Global Hemispheric CT Hypoperfusion May Differentiate Headache With Associated Neurological Deficits and Lymphocytosis From Acute Stroke

Headache with associated neurological deficits and lymphocytosis (HaNDL) is characterized by temporary recurrent neurological deficits, moderate–severe headache, cerebrospinal fluid lymphocytosis, elevated protein, and increased opening pressure.1 Although CT and MRI should be normal, single photon emission CT may indicate focal hypoperfusion and electroencephalogram may reveal slowing or even epileptiform activity2 resolving once the patient is symptom-free (3 months). Catheter angiography also yields normal results but may trigger an acute neurological episode.3,4 Because HaNDL is a benign, self-limited syndrome, it is important to differentiate it from cerebrovascular disease to avoid unnecessary interventions such as catheter angiography and thrombolysis. We present a case initially thought to be acute stroke in which the patient was considered for thrombolysis. CT perfusion changes atypical for stroke made stroke diagnosis questionable and thrombolysis was withheld. A 31-year-old man with hypertension, dyslipidemia, and sleep apnea (treated with continuous positive airway pressure), but no history of prior migraine, was brought into our emergency department by ambulance with suspected acute ischemic stroke. He had become aphasic at work so his coworkers called 911. On examination, he was globally aphasic without focal weakness or obvious sensory changes aside from questionable mild right facial paresis (National Institutes of Health Stroke Scale score 6). A noncontrast CT and CT angiogram (CTA) were normal, but CT perfusion revealed a striking pattern of …

Prognostic Value of CT Angiography in Patients with Suspected Vertebrobasilar Ischemia

The outcome of vertebrobasilar ischemia depends on the clinical presentation and the presence or absence of vascular occlusion. The aim of our study was to analyze the CT angiography (CTA) predictors of outcome in patients with suspected vertebrobasilar ischemia. We studied patients with suspected acute vertebrobasilar ischemia between April 2002 and January 2006 and had CTA done within 24 hours of symptom onset. We reviewed the final diagnosis and 3-month follow-up and analyzed the clinical and CTA predictors of outcome. Of the 133 patients, 21(15%), 18 (13%), and 16 (12%) had occlusion of basilar artery (BA), vertebral artery (VA), and posterior cerebral artery (PCA) respectively. The final diagnosis was stroke in 98 (73.6%), transient ischemic attack (TIA) in 10 (7.5%), and nonischemic in 25 (18.8%). No vascular occlusion was seen on CTA in patients with TIA and nonischemic diagnosis. At 3-month follow-up, we found a mortality rate of 10.6% and good functional outcome in 71.4%. The predictors of death in the multivariable analysis were the presence of BA occlusion (odds ratio[OR] 6.7, 95% CI, 1.4-30.6) and baseline National Institutes of Health Stroke Scale (NIHSS) (OR 1.14, 95% CI, 1.06-1.2). When patients with basilar occlusion were excluded, the presence of VA occlusion (OR 6.5, 95% CI, 1.34-31.4), age (OR 1.09, 95% CI, 1.03-1.14), and baseline NIHSS (OR 1.1, 95% CI, 1.03-1.18) predicted poorer outcome. The presence or absence of a vascular occlusion is a critical factor for prognosis in suspected acute vertebrobasilar ischemia and is correlated with the location of occlusion.

Hyperacute MRI in Stroke Diagnosis and Management (II)

The rapid and accurate evaluation of acute ischemic stroke has advanced dramatically with the newly available MRI techniques: magnetic resonance angiography (MRA), diffusion-weighted imaging (DWI), and perfusion-weighted imaging (PWI). Each imaging modality provides unique and valuable information: MRA demonstrates the presence or absence of vascular occlusion in large- and medium-sized vessels; DWI discloses the location and extent of ischemic brain tissue that has already manifested energy failure; and PWI provides information about the perfusion status of the microvasculature. Prior studies have revealed clearly the …