Cause Of Intracranial Hemorrhage Research Articles

NOTCH4 gene polymorphisms as potential risk factors for brain arteriovenous malformation development and hemorrhagic presentation.

OBJECTIVE Arteriovenous malformations (AVMs) of the brain are a frequent and important cause of intracranial hemorrhage in young adults. Little is known about the molecular-genetic pathomechanisms underlying AVM development. Genes of the NOTCH family control the normal development of vessels and proper arteriovenous specification. Transgenic mice with constitutive expression of active NOTCH4 frequently develop AVMs. Here, the authors report a genetic association study investigating possible associations between NOTCH4 gene polymorphisms and formation and clinical presentation of AVMs. METHODS After PCR amplification and direct DNA sequencing or restriction digests, 10 single-nucleotide polymorphisms (SNPs) of the NOTCH4 gene were used for genotyping 153 AVM patients and 192 healthy controls (i.e., blood donors). Pertinent clinical data were available for 129 patients. Uni- and multivariate single-marker and explorative haplotype analyses were performed to identify potential genetic risk factors for AVM development and for hemorrhagic or epileptic presentation. RESULTS Eleven calculated haplotypes consisting of 3-4 SNPs (most of which were located in the epidermal growth factor-like domain of the NOTCH4 gene) were observed significantly more often among AVM patients than among controls. Univariate analysis indicated that rs443198_TT and rs915895_AA genotypes both were significantly associated with hemorrhage and that an rs1109771_GG genotype was associated with epilepsy. The association between rs443198_TT and AVM bleeding remained significant in the multivariate regression analysis. CONCLUSIONS The authors' results suggest NOTCH4 SNPs as possible genetic risk factors for the development and clinical presentation of AVMs and a role of NOTCH4 in the pathogenesis of this disease.

Abstract WMP118: A Radio-clinical Scale to Predict Long-term Outcome After Brain Arteriovenous Malformation Rupture: The Ruptured AVM Prognostic Score

Background and Purpose: Brain arteriovenous malformations (BAVMs) are a leading cause of intracranial hemorrhage in young adults. Contrary to subarachnoid hemorrhage, there is no validated scale dedicated to stratifying patients with BAVM rupture. We aimed to design a new BAVM prognostic score. Methods: Records of 135 patients with 139 BAVM rupture events consecutively admitted to a tertiary care center during 11 years were reviewed. Independent predictors of long-term poor outcome (modified Rankin scale (mRS) > 3) more than one year after admission were identified. A risk stratification scale was developed and compared to the intracerebral hemorrhage (ICH) score to predict poor outcome and delta mRS (difference between follow-up and baseline pre-hemorrhage mRS). Results: Multivariate logistic regression followed by stepwise analysis determined that consciousness level (odd ratio [OR] 6.5, 95% confidence interval (CI) [3.09-13.7], P < 10-3), hematoma volume (OR 1.84, 95% CI [1.21-2.8], P = 0.005) and intraventricular hemorrhage (OR 7.46, 95% CI [2.66-21], P-value < 10-3) were independently associated with 1-year poor outcome. A 12-scale simplified score for ruptured BAVM prognostication was constructed combining consciousness level, hematoma volume and intraventricular hemorrhage . This new score was a stronger predictor of poor outcome (P=0.009) and delta mRS 3 (P=0.01) than ICH score. Conclusion: We propose a new admission score (the Ruptured AVM Prognostic Score [RAPS]) dedicated to stratifying the risk of poor long-term outcome after BAVM rupture. This easy to use score may serve both to improve communication between healthcare providers and consistency in clinical research.

Abstract 50: Evaluation of Candidate Polymorphisms for Association With Brain Arteriovenous Malformations and Intracranial Hemorrhage in Hereditary Hemorrhagic Telangiectasia

Introduction: Brain arteriovenous malformations (AVM) are an important cause of intracranial hemorrhage (ICH) in young adults. Most are sporadic, but also occur in inherited diseases such as hereditary hemorrhagic telangiectasia (HHT). ICH presentation of brain AVM in both sporadic and HHT cases is a marker of high ICH risk. In order to investigate whether the same genetic modifiers influence sporadic and HHT brain AVM, we evaluated candidate genetic polymorphisms reported as associated with sporadic brain AVM, with ICH presentation or ICH during clinical course, in HHT patients. Methods: We genotyped 8 polymorphisms ( APOE E2/3/4 [rs7412, rs429358], ANGPTL rs116724, EPHB4 rs314308, IL6 -174G>C [rs1800795], IL1B -31T>C [rs1143627], ITGB8 rs10486391, TNF -238G>A[rs361525]) in 753 Caucasian HHT patients enrolled by the Brian Vascular Malformation Consortium (BVMC). Genotypes were collapsed into risk allele carriers vs. other for analysis, as published for sporadic AVM. APOE E2/3/4 haplotypes were assigned based on genotypes of the 2 APOE polymorphisms. Association of genotype with phenotype was evaluated by multivariable logistic regression adjusted for age, gender and accounting for family clustering. We used a nominal significance threshold of p=0.05, requiring the same direction of effect as in sporadic brain AVM (odds ratio for risk genotype [OR]>1). Results: Among 753 HHT patients, 155 (21%) had brain AVM, of whom 26 (17%) presented with ICH. Two additional brain AVM patients had ICH during follow-up. None of the 7 variants (6 single nucleotide polymorphisms and APOE haplotype) were significantly associated with brain AVM (OR=0.6-1.3), with ICH presentation of brain AVM (OR=0.4-1.9), or with any brain AVM ICH in HHT patients (OR=0.5-2.1). Conclusions: Common genetic variants previously reported to be associated with sporadic brain AVM were not associated with brain AVM nor with ICH in the BVMC HHT cohort, suggesting different genetic modifiers may influence sporadic and HHT brain AVM. However, the number of ICH cases in the cohort is small, so the confidence intervals are wide and we cannot rule out clinically important associations. The BVMC is enrolling additional HHT patients to expand the cohort and increase power for association analyses.

Anesthetic concern during cesarean delivery in patient with ruptured cerebral arteriovenous malformation

Vascular malformations of the brain are a rare cause of intracranial hemorrhage during pregnancy. The presentation of arteriovenous malformations during pregnancy is usually a result of hemorrhage following rupture. Once hemorrhage occurs, it accounts for 5–12% of all the maternal deaths and remains the third most common nonobstetric cause of maternal morbidity. Successful anesthetic management during cesarean delivery requires close monitoring to address both the varying maternal and fetal needs. The fundamental aims are to maintain oxygenation and stable systemic, cerebral, and placental hemodynamics and to avoid increase in intracranial pressure.

Vascular Integrity in the Pathogenesis of Brain Arteriovenous Malformation.

Brain arteriovenous malformation (bAVM) is an important cause of intracranial hemorrhage (ICH), particularly in the young population. ICH is the first clinical symptom in about 50 % of bAVM patients. The vessels in bAVM are fragile and prone to rupture, causing bleeding into the brain. About 30 % of unruptured and non-hemorrhagic bAVMs demonstrate microscopic evidence of hemosiderin in the vascular wall. In bAVM mouse models, vascular mural cell coverage is reduced in the AVM lesion, accompanied by vascular leakage and microhemorrhage. In this review, we discuss possible signaling pathways involved in abnormal vascular development in bAVM.

Outcome after intracranial haemorrhage from dural arteriovenous fistulae; a systematic review and case-series

Dural arteriovenous fistulae (DAVFs) are a rare cause of intracranial haemorrhage. We aimed to investigate outcome of patients with intracranial haemorrhage from a DAVF. We performed a systematic literature search for studies reporting outcome after intracranial haemorrhage caused by a DAVF. We used predefined selection criteria and assessed the quality of the studies. In addition, we studied outcome in all patients with DAVF who had presented with intracranial haemorrhage at two university centers in the Netherlands, between January 2007 and April 2012. We calculated case fatality and proportions of patients with poor outcome (defined as modified Rankin Scale ≥ 3 or Glasgow Outcome Scale ≤ 3) during follow-up. We investigated mean age, sex, mid-year of study and percentage of patients with parenchymal haemorrhage as determinants of case fatality and poor outcome. The literature search yielded 16 studies, all but two retrospective and all hospital-based. Combined with our cohort of 29 patients the total number of patients with DAVF-related intracranial haemorrhage was 326 (58 % intracerebral haemorrhage). At a median follow-up of 12 months case fatality was 4.7 % (95 % CI 2.5–7.5; 17 cohorts) and the proportion of patients with poor outcome 8.3 % (95 % CI 3.1–15.7; nine cohorts). We found no effect of mean age, sex, mid-year of the cohorts and percentage of patients with parenchymal haemorrhage on either outcome. Hospital based case-series suggest a relatively low risk of death and poor outcome in patients with intracranial haemorrhage due to rupture of a DAVF. These risks may be underestimated because of bias.Electronic supplementary materialThe online version of this article (doi:10.1007/s00415-015-7898-x) contains supplementary material, which is available to authorized users.

Pediatric cerebral arteriovenous malformations

Pial arteriovenous malformations (AVMs) of the brain are vascular abnormalities located in the subpial space that consist of direct communications from artery to vein via intervening nidus. AVMs are the most common intracranial pathology and frequent cause of intracranial hemorrhage in children. Moreover, the epidemiology and clinical findings particular to chil- dren with AVMs can be ascribed to the distinct angioarchitecture of pediatric AVMs. However, the natural history and treatment of pediatric AVMs is relatively unknown. In this article, we review current knowledge of pediatric pial AVMs.

Novel use of 4D-CTA in imaging of intranidal aneurysms in an acutely ruptured arteriovenous malformation: is this the way forward?

Ruptured arteriovenous malformation (AVM) is a frequent cause of intracranial hemorrhage. The presence of associated aneurysms, especially intranidal aneurysms, is considered to increase the risk of re-hemorrhage. We present two...

Early sodium and fluid intake and severe intraventricular hemorrhage in extremely low birth weight infants.

Hypernatremic dehydration is an important cause of intracranial hemorrhage. A possible association of intraventricular hemorrhage (IVH) with hypernatremia and/or high sodium intake has been suggested in preterm infants. To investigate the associations of early fluid and sodium intake or serum sodium concentrations with severe intraventricular hemorrhage (IVH) in extremely low birth weight (ELBW) infants, we reviewed the medical records of 169 inborn ELBW infants. Daily fluid and sodium intake, urine output, weight loss and serum sodium concentration during the first 4 days of life were obtained. Patients were divided into the severe IVH (grade 3/4) and the control (no or grade 1/2 IVH) group. The maximum serum sodium concentration and the incidence of hypernatremia did not differ between the two groups. Related to the fluid balance and sodium intake, the risk for severe IVH was strongly associated with total fluid and sodium intake during the initial four days of life. With respect to the fluids other than transfusion, severe IVH can be discriminated only by sodium intake but not by fluid intake. Large randomized controlled trials are required to clarify the causal relationship between the early sodium intake and severe IVH in ELBW infants.

The surgical treatment of wounds on a bacteriological basis.

We studied 24 patients with autopsy-proven cerebral amyloid angiopathy. Eight patients were demented or had some other medical problem and died of pneumonia or systemic disease. Sixteen patients died of...

Congenital cerebral cavernous malformations in an infant: A case report

Abusive head trauma is a leading cause of infant death, but other causes of intracranial hemorrhage must be systematically excluded. Here we present a case of multiple hemorrhagic cavernous malformations that was initially thought to be indicative of abusive head trauma. Using a clinical decision-making framework, we provide insight into child abuse diagnostics.

Isolated right carotidynia: CT, MRI, FDG-PET and contrast-enhanced ultrasound carotid examination findings

Isolated right carotidynia: CT, MRI, FDG-PET and contrast-enhanced ultrasound carotid examination findings

Cerebral amyloid angiopathy (CAA), an often missed cause of intracranial bleeding

Cerebral amyloid angiopathy (CAA), an often missed cause of intracranial bleeding

Subdural haematoma as a rare complication of cochlear implantation: case report and literature review

To report a case of subdural haematoma occurring as an extremely rare and life-threatening complication of cochlear implantation, and to explore the causative association between intracranial haemorrhage and cochlear implantation surgical techniques. This association has not previously been reviewed in depth. A three-year-old boy was diagnosed with a large subdural haematoma, one week after cochlear implantation. After emergency evacuation of the haematoma, the patient made an excellent recovery and was discharged from hospital without any neurological deficit. Mechanisms of injury are discussed and the literature reviewed, focusing on the possible causes of intracranial haemorrhage identified after cochlear implantation. Notably, bone drilling had been used in all reported cases, and the probable causative injury had always occurred after such drilling. The issue of bone drilling during cochlear implantation is raised, and alternative methods of implant housing suggested, in order to avoid intracranial haemorrhage.

Multimodal endovascular treatment of a vertebrovertebral fistula presenting with subarachnoid hemorrhage and hydrocephalus

Vertebrovertebral fistulae are rare vascular malformations that uncommonly can rupture to present clinically as intracranial subarachnoid hemorrhage. We report a 69-year-old man presenting following spontaneous apoplectic collapse. Initial workup revealed diffuse, intracranial subarachnoid hemorrhage, intraventricular hemorrhage and hydrocephalus. However, the etiology was not apparent on CT angiography of the head. Catheter-based angiography was performed, demonstrating a single-hole, high-flow vertebrovertebral fistula, arising from the V2 segment and decompressing into both cervical and skull base venous structures. Definitive treatment consisted of endovascular fistula obliteration with a combination of coil and liquid embolic material. The patient made a full neurological recovery. High cervical and skull base fistulae are rare causes of intracranial hemorrhage; endovascular treatment is effective at disconnection of the arteriovenous shunt.

Bilateral ophthalmic-ethmoidal dural arteriovenous fistula presenting with intracranial hemorrhage: a rare entity

Dural arteriovenous fistulas (DAVFs) are rare lesions. The most common locations of DAVFs are cavernous, sigmoid and transverse sinuses. Anterior cranial fossa is one of the less frequent placement for DAVFs and the risk of hemorrhage in this region is increased. Reported hemorrhage risks have been ranged from 62 to 91 %, and an aggressive clinical course is more likely than a benign clinical course. A 47-year-old man was admitted to our emergency room with headache and the computed tomography revealed frontal hemorrhage. Neurological examination was normal. We applied cerebral angiography in our interventional neurology department and an anterior cranial fossa DAVFs, supplied by bilateral ophthalmic-ethmoidal arteries, was determined. DAVFs are a rare cause of intracranial hemorrhages and in the literature anterior cranial fossa DAVFs have been reported scarcely, so that we aimed to present this rare entity.

Neonatal alloimmune thrombocytopenia: pathogenesis, diagnosis and management

Neonatal alloimmune thrombocytopenia, (NAIT) is caused by maternal antibodies raised against alloantigens carried on fetal platelets. Although many cases are mild, NAIT is a significant cause of morbidity and mortality in newborns and is the most common cause of intracranial haemorrhage in full-term infants. In this report, we review the pathogenesis, clinical presentation, laboratory diagnosis and prenatal and post-natal management of NAIT and highlight areas of controversy that deserve the attention of clinical and laboratory investigators.

Prevalence and Clinical Significance of Low Avidity HPA-1a Antibodies in Women Exposed to HPA-1a During Pregnancy

AbstractAbstract 266Neonatal alloimmune thrombocytopenia (NAIT) is caused by maternal antibodies specific for fetal platelet antigens and is the most common cause of intracranial hemorrhage in full term infants. The antigen HPA-1a, carried on beta 3 integrin (GPIIIa), is the most common trigger for NAIT and the 2% of women who are HPA-1a-negative are at risk to produce such antibodies. Most HPA-1a antibodies causing NAIT can be easily detected but it is not rare for an HPA-1a negative mother who lacks detectable antibodies to give birth to an infant with thrombocytopenia. Several recent reports suggest that low avidity HPA-1a antibodies not detected by conventional serologic methods are responsible for some of these cases (Socher 2009, Bakchoul 2011).To examine this question, we retroactively analyzed a cohort of 3478 suspected NAIT cases referred for laboratory diagnosis. Among 677 HPA-1a-negative mothers, we identified 61 in whom HPA-1a-specific antibodies were not detected by conventional methods. Surface plasmon resonance (SPR) analysis enables ligand-receptor interaction to be studied in real time without washing the target. Using this approach, we studied reactions of IgG from the 61 archived serum samples against purified GPIIb/IIIa isolated from group O platelets and identified 18 samples that reacted preferentially with the HPA-1a-positive version of the integrin in comparison with HPA-1a-negative integrin. Information defining clinical status was obtained on 13 of these cases by follow-up communication. Seven cases had been referred because of neonatal thrombocytopenia. Platelet nadirs ranged from 8,000/ul to 141,000/ul (median 38,000/ul). Five of the 7 infants had bleeding and were given maternal platelet transfusions and/or IVIgG. Normal platelet counts were achieved after 4 to 70 days (median 7 days). One infant had a normal platelet count, however IVIgG had been given to its mother throughout pregnancy. The remaining 5 cases were referred in mid-pregnancy because an HPA-1a-negative sister previously gave birth to an infant with NAIT. Four of these infants had normal platelets at birth; one had mild TP (platelets 125,000/ul). Only 3 of 12 mothers typed for HLA were positive for HLA-DRB3*0101, a marker found in >95% of women who make “conventional” HPA-1a antibodies during pregnancy (p < 0.001). The ability of human antibodies to cause destruction of human platelets in vivo can be studied in the NOD/SCID mouse, which lacks xenoantibodies normally found in other species (Newman 2007). Serum from 4 mothers was available in quantities sufficient for mouse studies; three of the four maternal sera caused accelerated destruction of HPA-1a-positive, but not HPA-1a-negative platelets.These findings indicate that low-avidity HPA-1a antibodies not detectable by conventional serologic methods are made by a subset of women exposed to the HPA-1a antigen during pregnancy and that some, but not all of these antibodies are capable of causing NAIT, which is usually mild, but can be severe. Women negative for HLA-DRB3*0101 may be especially prone to produce antibodies of this type. Maternal-fetal incompatibility for platelet antigens other than HPA-1a is very common and many apparent NAIT cases not involving HPA-1a go unresolved. The possibility that low avidity antibodies specific for antigens other than HPA-1a are responsible for some of these cases deserves study. Disclosures:No relevant conflicts of interest to declare.

Perlecan domain V is upregulated in human brain arteriovenous malformation and could mediate the vascular endothelial growth factor effect in lesional tissue

Brain arteriovenous malformation (BAVM), a rare but important cause of intracranial hemorrhage, has increased angiogenesis and inflammation as key components of the nidus of abnormal vessels and stroma that form the resected surgical specimen. Accordingly, both vascular endothelial growth factor (VEGF) and transforming growth factor-β have been implicated in the pathology of BAVM for their proangiogenic and vascular-regulating roles. The C-terminal fragment of the extracellular matrix component perlecan (domain V, DV) has been shown to be increased and through the α5β1 integrin, to increase VEGF levels in and around areas of cerebral ischemic injury, another proangiogenic condition. We aimed to determine whether the concentrations of DV, DV's proangiogenic receptor α5β1 integrin, or DV's antiangiogenic receptor α2β1 integrin are elevated in human BAVM tissue. DV levels were increased in BAVM compared with control brain tissue from epileptic resection, as was α5β1 integrin. In addition, α5β1 integrin was preferentially increased and localized to endothelial cells compared with α2β1 integrin. VEGF and transforming growth factor-β levels were also increased in BAVM compared with control tissue. Furthermore, increases in all components were strongly correlated. Excessive generation of proangiogenic DV in BAVM suggests that DV may participate in its pathology and may represent a future therapeutic target.

Vitamin K nutrition, metabolism, and requirements: current concepts and future research.

In 2001, the US Food and Nutrition Board concluded that there were insufficient data with which to establish a RDA for vitamin K, in large part because of a lack of robust endpoints that reflected adequacy of intake. Knowledge of the relative bioavailability of multiple vitamin K forms was also poor. Since then, stable isotope methodologies have been applied to the assessment of the bioavailability of the major dietary form of vitamin K in its free state and when incorporated into a plant matrix. There is a need for stable isotope studies with enhanced sensitivity to expand knowledge of the bioavailability, absorption, disposition, and metabolism of different molecular forms of vitamin K. Another area for future research stems from evidence that common polymorphisms or haplotypes in certain key genes implicated in vitamin K metabolism might affect nutritional requirements. Thus far, much of this evidence is indirect via effects on warfarin dose requirements. In terms of clinical endpoints, vitamin K deficiency in early infancy continues to be a leading cause of intracranial bleeding even in developed countries and the reasons for its higher prevalence in certain Asian countries has not been solved. There is universal consensus for the need for vitamin K prophylaxis in newborns, but the effectiveness of any vitamin K prophylactic regimen needs to be based on sound nutritional principles. In contrast, there is still a lack of suitable biomarkers or clinical endpoints that can be used to determine vitamin K requirements among adults.