Untreated Brain Arteriovenous Malformations Research Articles

Age-Dependent Hemorrhage Risk and Obliteration Benefit After Radiosurgery for Brain Arteriovenous Malformation

Because patients with untreated brain arteriovenous malformations (BAVMs) are at variable risks of cerebral hemorrhage and associated mortality and morbidity, it is essential to identify patient populations who benefit most from prophylactic interventions. This study aimed to examine age-dependent differences in the therapeutic effect of stereotactic radiosurgery (SRS) on BAVMs. This retrospective observational study enrolled patients with BAVMs who underwent SRS at our institution between 1990 and 2017. The primary outcome was post-SRS hemorrhage, and the secondary outcomes included nidus obliteration, post-SRS early signal changes, and mortality. To investigate age-related differences in outcomes after SRS, we performed age-stratified analyses using the Kaplan-Meier analysis and weighted logistic regression with the inverse probability of censoring weighting (IPCW). To address significant differences in patient baseline characteristics, we also performed inverse probability of treatment weighting (IPTW) adjusted for possible confounders to investigate age-related differences in outcomes after SRS. A total of 735 patients with 738 BAVMs were stratified by age. Age-stratified analysis using a weighted logistic regression model with IPCW showed a direct correlation between patient age and post-SRS hemorrhage (odds ratio [OR], 95% confidence interval [CI], and P value: 2.20, 1.34-3.63, and .002 at 18 months; 1.86, 1.17-2.93, and .008 at 36 months; and 1.61, 1.05-2.48, and .030 at 54 months, respectively). The age-stratified analysis also showed an inverse relationship between age and obliteration over the first 42 months after SRS (OR, 95% CI, and P value: 0.05, 0.02-0.12, and <.001 at 6 months; 0.55, 0.44-0.70, and <.001 at 24 months; and 0.76, 0.63-0.91, and .002 at 42 months, respectively). These results were also confirmed with the IPTW analyses. Our analysis demonstrated that patients' age at SRS is significantly associated with hemorrhage and the nidus obliteration rate after treatment. In particular, younger patients are more likely to exhibit reduced cerebral hemorrhages and achieve earlier nidus obliteration compared with older patients.

Living with a Brain AVM: A Quality of Life Assessment.

Brain arteriovenous malformations (AVM) are uncommon vascular lesions with the risk of hemorrhage, epileptic seizures, neurological deficits, and headache. Comparing the risks of the natural history and that of preventive treatment, a recent study has found observation more beneficial than treatment for unruptured AVMs. This study, however, did not consider the long-term impact of carrying a brain AVM on everyday activities. In this study we analyzed the Quality Of Life (QOL) of patients with untreated AVMs, a measure increasingly used in clinical trials to asses this kind of impact. We enrolled 36 patients with unruptured, untreated brain AVM from our hospital database and measured their QOL retrospectively using the EQ-5D-5L questionnaire. As a control group we used the results of the Research Report, a nationwide study based on the quality of life of 5534 healthy Hungarians in 2002. Due to the low number of cases, statistical analysis could not be made. Headache proved to be the most common AVM-related sign in our cohort (40%, n=17), with a female predominance; neurological deficit was detected in 33% (n=14), while epileptic seizures occurred in 26% (n=11), more commonly affecting male subjects. Anxiety and discomfort seemed to be the most prevalent influencing factors on QOL, especially in the youngest age group (18-34years). Female subjects showed a greater dependence than men in all age groups, though males had a more significant impairment in their usual activities. Older patients were affected more significantly in their self-care and usual activities compared with the younger population. Untreated AVMs have a significant negative impact on patients carrying unruptured brain AVMs, as proved by QOL assessment. Beside neurological deficits, this impact should also be considered in the therapeutic decision.

Incidence of Spontaneous Obliteration in Untreated Brain Arteriovenous Malformations.

Spontaneous obliteration (SpO) of untreated arteriovenous malformations (AVMs) is rare with fewer than 100 cases reported. The incidence and predisposing factors of SpO remain unclear, impeding our understanding of lesion progression in untreated patients. To determine the incidence rate and predisposing factors of SpO in a North American cohort. AVMs were retrospectively evaluated at our institution for over 25 yr. Untreated AVMs were divided into 2 groups: SpO-AVMs and non-SpO-AVMs. All statistical results were based on univariate analyses. Incidence was generated from counts of SpO over the untreated interval in patient years from birth until obliteration, treatment, or last follow-up. One hundred fifty-four patients had untreated AVMs; SpO was observed in 4. Average ages were 49.0±23.6 and 48.7±20.4 yr in the SpO-AVM and non-SpO-AVM group, respectively (P=.98). Average AVM sizes were 2.0±1.8 cm (SpO-AVMs) and 3.7±2.6 cm (non-SpO-AVMs, P=.25). All SpO-AVMs and 40 (27.0%) non-SpO-AVMs had a ruptured presentation (P=.006). A single draining vein was observed in all SpO-AVMs and 39 (32.8%) non-SpO-AVMs (P=.01). Deep venous drainage was not observed in any SpO-AVMs, but in 81 (57.9%) non-SpO-AVMs (P=.04). Mean follow-up time was 37.0±42.6 and 75.6±161.7 mo in SpO-AVM and non-SpO-AVMs patients, respectively. Of the 2 SpO-AVM patients with postobliteration follow-up, 1 experienced recanalization. From a 672-patient cohort, the incidence of SpO over 28 961 patient years was 0.014%. SpO-AVMs have an annual incidence rate of approximately 0.014% and tend to present with rupture, a single draining vein, and superficial venous drainage. Expectation of SpO for untreated AVMs is not justified, and patients should anticipate life-long hemorrhagic risk for untreated AVMs.

The factors associated with hemorrhagic presentation in children with untreated brain arteriovenous malformation: a meta-analysis.

OBJECTIVE Rupture of arteriovenous malformations (AVMs) would result in high mortality and prevalence of disability in pediatric patients. Decisions regarding the treatment of AVMs need to weigh the risk of rupture over the course of their natural history against the possibility of creating a lesion during treatment. Multiple factors have been proposed to predict hemorrhagic presentation of pediatric patients with AVMs. The aim of this meta-analysis was to evaluate the predictors of hemorrhagic presentation in pediatric patients with AVMs. METHODS The authors searched the PubMed and EMBASE databases. Studies reporting the predictors of hemorrhagic presentation in children with untreated brain AVMs were included. The predictive ability of identified predictors was assessed by odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS A higher risk of hemorrhagic presentation was found in AVMs with smaller size (< 3 cm, OR 2.97, 95% CI 1.94–4.54, p < 0.00001), deep venous drainage (OR 2.28, 95% CI 1.55–3.36, p < 0.0001), a single draining vein (OR 2.23, 95% CI 1.27–3.92, p = 0.005), a single feeder (OR 3.72, 95% CI 1.31–10.62, p = 0.01), a deep location (OR 1.82, 95% CI 1.22–2.72, p = 0.004), an infratentorial location (OR 2.25, 95% CI 1.19–4.26, p = 0.01), and diffuse morphology (OR 8.94, 95% CI 3.01–26.55, p < 0.0001). In addition, the AVMs with draining vein ectasia (OR 0.35, 95% CI 0.13–0.97, p = 0.04) and high Spetzler-Martin (SM) grade (OR 0.53, 95% CI 0.36–0.78, p = 0.001) had a lower risk of hemorrhagic presentation in pediatric patients. CONCLUSIONS Smaller AVMs, deep venous drainage, a single draining vein, a single feeder, deep/infratentorial location, diffuse morphology, and high SM grade were identified as positive predictors for hemorrhagic presentation. Particularly, patients with diffuse AVMs have a higher risk of hemorrhagic presentation than other factors and may need active treatments. However, factors such as age, sex, draining vein stenosis, and associated aneurysms were not associated with hemorrhagic presentation. ABBREVIATIONS AVM = arteriovenous malformation; CI = confidence interval; NOS = Newcastle-Ottawa Scale; OR = odds ratio; SM = Spetzler-Martin.

Grades of brain arteriovenous malformations and risk of hemorrhage and death.

ObjectiveTo assess the relationship of the grade of unruptured and untreated Brain Arteriovenous Malformations (AVMs), with the risk of subsequent stroke and death during follow‐up.MethodsThis prospective study was drawn from a cohort of adult patients with unruptured AVMs, who participated in the conservative treatment arm (medical management only for headache or seizures) of the randomized clinical trial of unruptured brain AVMs (ARUBA study). The grade of AVMs (Spetzler–Martin scale) was dichotomized into categories: AVMs of grades I and II were considered low grade; AVMs of grades III and IV were considered high grade. There were no grade V AVM patients in ARUBA. The primary outcome was symptomatic stroke (hemorrhagic or ischemic – documented by imaging) or death.ResultsThe conservative treatment group had 123 patients (“as treated” analysis). 71 (57.7%) had lesions characterized for this analysis as low‐grade lesions and 52 (42.2%) as high grade. From the total of 10 (8.13%) primary outcomes, three occurred (4.22%) in low‐grade AVMs and seven (13.46%) in high‐grade AVMs (P = 0.0942).InterpretationStatistical analysis of the cohort of patients with unruptured and untreated AVMs from ARUBA study showed that the graduation categories (Spetzler–Martin grades) were not associated with the outcome of subsequent stroke or death.

Critical review of brain AVM surgery, surgical results and natural history in 2017.

An understanding of the present standing of surgery, surgical results and the role in altering the future morbidity and mortality of untreated brain arteriovenous malformations (bAVMs) is appropriate considering the myriad alternative management pathways (including radiosurgery, embolization or some combination of treatments), varying risks and selection biases that have contributed to confusion regarding management. The purpose of this review is to clarify the link between the incidence of adverse outcomes that are reported from a management pathway of either surgery or no intervention with the projected risks of surgery or no intervention. A critical review of the literature was performed on the outcomes of surgery and non-intervention for bAVM. An analysis of the biases and how these may have influenced the outcomes was included to attempt to identify reasonable estimates of risks. In the absence of treatment, the cumulative risk of future hemorrhage is approximately 16% and 29% at 10 and 20years after diagnosis of bAVM without hemorrhage and 35% and 45% at 10 and 20years when presenting with hemorrhage (annualized, this risk would be approximately 1.8% for unruptured bAVMs and 4.7% for 8years for bAVMs presenting with hemorrhage followed by the unruptured bAVM rate). The cumulative outcome of these hemorrhages depends upon whether the patient remains untreated and is allowed to have a further hemorrhage or is treated at this time. Overall, approximately 42% will develop a new permanent neurological deficit or death from a hemorrhagic event. The presence of an associated proximal intracranial aneurysm (APIA) and restriction of venous outflow may increase the risk for subsequent hemorrhage. Other risks for increased risk of hemorrhage (age, pregnancy, female) were examined, and their purported association with hemorrhage is difficult to support. Both the Spetzler-Martin grading system (and its compaction into the Spetzler-Ponce tiers) and Lawton-Young supplementary grading system are excellent in predicting the risk of surgery. The 8-year risk of unfavorable outcome from surgery (complication leading to a permanent new neurological deficit with a modified Rankin Scale score of greater than one, residual bAVM or recurrence) is dependent on bAVM size, the presence of deep venous drainage (DVD) and location in critical brain (eloquent location). For patients with bAVMs who have neither a DVD nor eloquent location, the 8-year risk for an unfavorable outcome increases with size (increasing from 1cm to 6cm) from 1% to 9%. For patients with bAVM who have either a DVD or eloquent location (but not both), the 8-year risk for an unfavorable outcome increases with the size (increasing from 1cm to 6cm) from 4% to 35%. For patients with bAVM who have both a DVD and eloquent location, the 8-year risk for unfavorable outcome increases with size (increasing from 1cm to 3cm) from 12% to 38%. Patients with a Spetzler-Ponce A bAVM expecting a good quality of life for the next 8years are likely to do better with surgery in expert centers than remaining untreated. Ongoing research is urgently required on the outcome of management pathways for bAVM.

Morbidity after Hemorrhage in Children with Untreated Brain Arteriovenous Malformation

Background: Children with untreated brain arteriovenous malformations (bAVM) are at risk of encountering life-threatening hemorrhage very early in their lives. The primary aim of invasive treatment is to reduce unfavorable outcome associated with a bAVM rupture. A better understanding of the morbidity of bAVM hemorrhage might be helpful for weighing the risks of untreated bAVM and invasive treatment. Our aim was to assess the clinical outcome after bAVM rupture and identify features to predict severe hemorrhage in children. Methods: We identified all consecutive children admitted to our institution for bAVMs between July 2009 and December 2014. Clinical outcome after hemorrhagic presentation and subsequent hemorrhage was evaluated using the modified Rankin Scale (mRS) for children. The association of demographic characteristics and bAVM morphology with severe hemorrhage (mRS >3 or requiring emergency hematoma evacuation) was studied using univariate and multivariable regression analyses. A nomogram based on multivariable analysis was formulated to predict severe hemorrhage risk for individual patients. Results: A total of 134 patients were identified with a mean treatment-free follow-up period of 2.1 years. bAVM ruptured in 83 (62%) children: 82 had a hemorrhage at presentation and 6 of them experienced a recurrent hemorrhage during follow-up; 1 patient had other diagnostic symptoms but bled during follow-up. Among them, 49% (41/83) had a severe hemorrhage; emergency hematoma evacuation was required in 28% of them (23/83), and 24% (20/83) remained as disabled (mRS ≥3) at last follow-up. Forty-six percent (38/82) of children with hemorrhagic presentation were severely disabled (mRS >3). Forty-three percent (3/7) were severely disabled after subsequent hemorrhage. The annual rate of severe subsequent hemorrhage was 1% in the overall cohort and 3.3% in children with ruptured presentation. All the subsequent severe hemorrhage events occurred in children with severe hemorrhage history (7%, 3/41). Periventricular location, non-temporal lobe location, and long draining vein were predictors for severe hemorrhage in pediatric untreated bAVMs. A nomogram based on bAVM morphology was contracted to predict severe hemorrhage risk for individual patients, which was well calibrated and had a good discriminative ability (adjusted C-statistic, 0.72). Conclusions: Evaluating bAVM morbidity and morphology might be helpful for weighing the risks of untreated bAVM in pediatric patients.

Abstract TMP112: Subsequent Hemorrhage in Children With Untreated Brain Arteriovenous Malformation: Higher Risk With Unbalanced Inflow and Outflow Angioarchitecture

Instruction: Children with brain arteriovenous malformations (bAVM) are at risk of life-threatening hemorrhage in their early lives. Our aim was to analyze various angiographic features of bAVM in conjunction with other morphological risk factors to predict the risk of subsequent hemorrhage during follow-up in children. Methods: We identified all consecutive children admitted to our institution for bAVMs between July 2009 and September 2015. Children with at least 1 month of treatment-free follow-up after diagnosis were included in further analysis. The effects of bAVM features on hemorrhagic presentation were studied. Annual rates of AVM rupture as well as several potential risk factors for subsequent hemorrhage were analyzed using Kaplan-Meier analyses and Cox proportional hazards regression models. Results: We identified 110 patients with a mean follow-up period of 2.1 years (range, 1 month-15.4 years). The average annual risk of hemorrhage from untreated AVMs was 4.3%. Risk factors predicting hemorrhagic presentation in multivariable analysis were no generalized venous ectasia, deep venous drainage, fast arteriovenous shunt, and deep location. No generalized venous ectasia in conjunction with fast arteriovenous shunt was predictive of subsequent hemorrhage (RR, 7.55; 95%CI, 1.96-29.06). The annual rupture risk was 11.1% in bAVMs without generalized venous ectasia but with fast arteriovenous shunt. Conclusions: bAVM angiographic features suggesting unbalanced inflow and outflow might be helpful to identify children at higher risk for hemorrhage. No generalized venous ectasia and fast artriovenous shunt might be associated with an increased risk for hemorrhagic presentation and subsequent hemorrhage in pediatric patients with untreated bAVM.

Subsequent haemorrhage in children with untreated brain arteriovenous malformation: Higher risk with unbalanced inflow and outflow angioarchitecture.

Children with brain arteriovenous malformations (bAVMs) are at risk of life-threatening haemorrhage in their early lives. Our aim was to analyse various angioarchitectural features of bAVM to predict the risk of subsequent haemorrhage during follow-up in children. We identified all consecutive children admitted to our institution for bAVMs between July 2009 and September 2015. Children with at least 1month of treatment-free follow-up after diagnosis were included in further analysis. Annual rates of AVM rupture as well as several potential risk factors for subsequent haemorrhage were analysed using Kaplan-Meier analyses and Cox proportional hazards regression models. We identified 110 paediatric patients with a mean follow-up period of 2.1years (range, 1month-15.4years). The average annual risk of haemorrhage from untreated AVMs was 4.3% in children. No generalised venous ectasia in conjunction with fast arteriovenous shunt was predictive of subsequent haemorrhage (RR, 7.55; 95% CI 1.96-29.06). The annual rupture risk was 11.1% in bAVMs without generalised venous ectasia but with fast arteriovenous shunt. bAVM angiographic features suggesting unbalanced inflow and outflow might be helpful to identify children at higher risk for future haemorrhage. • Haemorrhage risk stratification is important for children with untreated brain AVM. • Angiographic features suggesting unbalanced inflow and outflow predict paediatric brain AVM haemorrhage. • Identifying AVMs with high rupture risk help patient selection and tailoring treatment.

Periventricular Location as a Risk Factor for Hemorrhage and Severe Clinical Presentation in Pediatric Patients with Untreated Brain Arteriovenous Malformations.

The morphologic features of brain arteriovenous malformations differ between children and adults; therefore, our aim was to analyze various features of brain arteriovenous malformations to assess the risk of hemorrhage in children. We identified all consecutive children admitted to Beijing Tiantan Hospital for brain arteriovenous malformations between July 2009 and April 2014. The effects of demographic characteristics and brain arteriovenous malformation morphology on hemorrhage presentation, annual bleeding rates, postnatal hemorrhage, and immediate posthemorrhagic neurologic outcomes were studied by using univariate and multivariable regression analyses. A total of 108 pediatric brain arteriovenous malformation cases were identified, 66 (61.1%) of which presented with hemorrhage. Of these, 69.7% of ruptured brain arteriovenous malformations were in a periventricular location. Periventricular nidus location (OR, 3.443; 95% CI, 1.328-8.926; P = .011) and nidus size (OR, 0.965; 95% CI, 0.941-0.989; P = .005) were independent predictors of hemorrhagic presentation. The annual hemorrhage rates in children with periventricular brain arteriovenous malformations were higher at 6.88% (OR, 1.965; 95% CI, 1.155-3.341; P < .05). The hemorrhage-free survival rates were also lower for children with periventricular brain arteriovenous malformations (log-rank, P = .01). Periventricular location (hazard ratio, 1.917; 95% CI, 1.131-3.250; P = .016) and nidus size (hazard ratio, 0.983; 95% CI, 0.969-0.997; P = .015) were associated with hemorrhage after birth in pediatric brain arteriovenous malformations. An ordinal analysis showed lower immediate posthemorrhage mRS in patients with periventricular brain arteriovenous malformations (OR for greater disability, 2.71; 95% CI, 1.03-7.11; P = .043). Small periventricular brain arteriovenous malformations were associated with increased hemorrhage risk in pediatric patients. Cautious follow-up of children with untreated periventricular brain arteriovenous malformations is recommended because of a higher hemorrhage risk and potentially more severe neurologic outcomes.

Multimodal angiographic assessment of cerebral arteriovenous malformations: a pilot study

PurposeWe describe our protocol of three-dimensional (3D) Roadmap intracranial navigation and image fusion for analysis of the angioarchitecture and endovascular treatment of brain arteriovenous malformations (AVMs).MethodsWe performed superselective catheterization of...

Natural history of brain arteriovenous malformations: a systematic review.

The authors aimed to systematically review the literature to clarify the natural history of brain arteriovenous malformations (BAVMs). The authors searched PubMed for one or more of the following terms: natural history, brain arteriovenous malformations, cerebral arteriovenous malformations, and risk of rupture. They included studies that reported annual rates of hemorrhage and that included either 100 patients or 5 years of treatment-free follow-up. The incidence of BAVMs is 1.12-1.42 cases per 100,000 person-years; 38%-68% of new cases are first-ever hemorrhage. The overall annual rates of hemorrhage for patients with untreated BAVMs range from 2.10% to 4.12%. Consistently implicated in subsequent hemorrhage are initial hemorrhagic presentation, exclusively deep venous drainage, and deep and infrantentorial brain location. The risk for rupture seems to be increased by large nidus size and concurrent arterial aneurysms, although these factors have not been studied as thoroughly. Venous stenosis has not been implicated in increased risk for rupture. For patients with BAVMs, although the overall risk for hemorrhage seems to be 2.10%-4.12% per year, calculating an accurate risk profile for decision making involves clinical attention and accounting for specific features of the malformation.

Distinctive distribution of lymphocytes in unruptured and previously untreated brain arteriovenous malformation.

To test the hypothesis that lymphocyte infiltration in brain arteriovenous malformation (bAVM) is not associated with iron deposition (indicator of microhemorrhage). Sections of unruptured, previously untreated bAVM specimens (n=19) were stained immunohistochemically for T-lymphocytes (CD3+), B-lymphocytes (CD20+), plasma cells (CD138+) and macrophages (CD68+). Iron deposition was assessed by hematoxylin and eosin and Prussian blue stains. Superficial temporal arteries (STA) were used as control. Both T lymphocytes and macrophages were present in unruptured, previously untreated bAVM specimens, whereas few B cells and plasma cells were detected. Iron deposition was detected in 8 specimens (42%; 95% confidence interval =20-67%). The samples with iron deposition tended to have more macrophages than those without (666±313 vs 478±174 cells/mm2; P=0.11). T-cells were clustered on the luminal side of the endothelial surface, on the vessel-wall, and in the perivascular regions. There was no correlation between T lymphocyte load and iron deposition (P=0.88). No macrophages and lymphocytes were detected in STA controls. T-lymphocytes were present in bAVM specimens. Unlike macrophages, the load and location of T-lymphocytes were not associated with iron deposition, suggesting the possibility of an independent cell-mediated immunological mechanism in bAVM pathogenesis.

Impaired peri-nidal cerebrovascular reserve in seizure patients with brain arteriovenous malformations

Epileptic seizures are a common presentation in patients with newly diagnosed brain arteriovenous malformations, but the pathophysiological mechanisms causing the seizures remain poorly understood. We used magnetic resonance imaging-based quantitative cerebrovascular reactivity mapping and conventional angiography to determine whether seizure-prone patients with brain arteriovenous malformations exhibit impaired cerebrovascular reserve or morphological angiographic features predictive of seizures. Twenty consecutive patients with untreated brain arteriovenous malformations were recruited (10 with and 10 without epileptic seizures) along with 12 age-matched healthy controls. Blood oxygen level-dependent MRI was performed while applying iso-oxic step changes in end-tidal partial pressure of CO(2) to obtain quantitative cerebrovascular reactivity measurements. The brain arteriovenous malformation morphology was evaluated by angiography, to determine to what extent limitations of arterial blood supply or the presence of restricted venous outflow and tissue congestion correlated with seizure susceptibility. Only patients with seizures exhibited impaired peri-nidal cerebrovascular reactivity by magnetic resonance imaging (0.11 ± 0.10 versus 0.25 ± 0.07, respectively; P < 0.001) and venous drainage patterns suggestive of tissue congestion on angiography. However, cerebrovascular reactivity changes were not of a magnitude suggestive of arterial steal, and were probably compatible with venous congestion in aetiology. Our findings demonstrate a strong association between impaired peri-nidal cerebrovascular reserve and epileptic seizure presentation in patients with brain arteriovenous malformation. The impaired cerebrovascular reserve may be associated with venous congestion. Quantitative measurements of cerebrovascular reactivity using blood oxygen level-dependent MRI appear to correlate with seizure susceptibility in patients with brain arteriovenous malformation.

Arteriovenous Malformations of the Brain

See related article, pages 878–885. Cerebral arteriovenous malformations (AVM) represent a heterogeneous entity, and a multitude of classifications for this rare disorder exists. Moreover, data on different treatment regimens are controversial.1 In this issue of Stroke , Lasjaunias et al2 present a group of vascular malformations which they consider a distinct entity separate from other brain AVM and classify them as cerebral proliferative angiopathy. Criteria for this classification were predefined almost 20 years ago and included angiomorphological, cross-sectional imaging and in one case also histopathological data. In a large patient cohort of >1400 patients 49 patients (3.4%) were found to meet these criteria. Clinical signs included seizures, headaches and nonhemorrhagic neurological deficits. Angiography demonstrated a diffuse nidus, stenosis of the proximal arteries in almost 40% and a transdural supply in almost 60% of the cases. This angiographic appearance was considered as …

ASSOCIATION OF TUMOR NECROSIS FACTOR-α–238G&gt;A AND APOLIPOPROTEIN E2 POLYMORPHISMS WITH INTRACRANIAL HEMORRHAGE AFTER BRAIN ARTERIOVENOUS MALFORMATION TREATMENT

We previously reported specific genotypes of polymorphisms in two genes, tumor necrosis factor-alpha (TNF-alpha-238G > A) and Apolipoprotein E (ApoE e2), as independent predictors of new intracranial hemorrhage (ICH) in the natural course of untreated brain arteriovenous malformations. We hypothesized that the risk of posttreatment ICH would also be greater in patients with brain arteriovenous malformations with these genotypes. Two hundred fifteen patients undergoing brain arteriovenous malformation treatment (embolization, arteriovenous malformation resection, radiosurgery, or any combination of these) were genotyped and followed longitudinally. Association of genotype with new symptomatic ICH after initiation of treatment was assessed using Cox proportional hazards adjusted for treatment type, demographics, and established ICH risk factors censored at the time of the last follow-up evaluation or death. The cohort was 48% male and 55% Caucasian, and 52% had an ICH before the initiation of treatment; the mean age +/- standard deviation was 36.6 +/- 17.2 years. Posttreatment ICH occurred in 34 (16%) patients with a median follow-up period of 1.9 years (interquartile range, 1.6 yr). After adjustment, the risk of posttreatment ICH was greater for TNF-alpha-238 AG genotype (hazard ratio [HR], 3.5; 95% confidence interval [CI], 1.3-9.8; P = 0.016) and ApoE e2 (HR, 3.2; 95% CI, 1.0-9.7; P = 0.042). Similar trends for the TNF-alpha-238 AG genotype were seen in surgery (HR, 4.2; 95% CI, 0.6-28.8; P = 0.14) and radiosurgery subsets (HR, 3.8; 95% CI, 0.7-19.4; P = 0.11). An effect of ApoE e2 was seen in radiosurgery subsets (HR, 10.9; 95% CI, 1.3-93.7; P = 0.030), but not in surgery subsets (HR, 1.4; 95% CI, 0.3-7.4; P = 0.67). Despite a variety of different mechanisms for posttreatment hemorrhage, these data suggest that the TNF-alpha and ApoE genotypes may contribute common phenotypes of enhanced vascular instability that increase the risk of hemorrhagic outcome.

Clinical Outcome After First and Recurrent Hemorrhage in Patients With Untreated Brain Arteriovenous Malformation

Clinical Outcome After First and Recurrent Hemorrhage in Patients With Untreated Brain Arteriovenous Malformation

Clinical Outcome After First and Recurrent Hemorrhage in Patients With Untreated Brain Arteriovenous Malformation

The morbidity from spontaneous hemorrhage of untreated brain arteriovenous malformations (AVM) is not well described. The 241 consecutive AVM patients (mean age 37+/-16 years, 52% women) from the prospective Columbia AVM Databank initially presenting with hemorrhage were evaluated using the Rankin Scale (RS) and the National Institute of Health Stroke Scale (NIHSS). From the 241 AVM patients, 29 (12%) had subsequent intracranial hemorrhage during follow-up. For further comparisons, 84 non-AVM patients with intracerebral hemorrhage from the Northern Manhattan Study (NOMAS) served as a control group. In 241 AVM patients presenting with hemorrhage the median RS was 2 and the median NIHSS was 1 (49% RS 0 to 1, 61% NIHSS <2). The median time between hemorrhage and clinical evaluation was 11 days (mean 219 days). Recurrent AVM hemorrhage during follow-up resulted in no significant increase in morbidity (median RS 2, P=0.004; median NIHSS 3, P=0.322; time between hemorrhage and study evaluation: median 55 days, mean 657 days). Among AVM-hemorrhage subtypes, parenchymatous AVM hemorrhage was associated with higher stroke morbidity (odds ratio, 2.9; 95% CI, 1.5 to 5.8 for NIHSS > or =2) than nonparenchymatous hemorrhages. Parenchymatous AVM hemorrhage had a significantly better outcome (median NIHSS 1) than non-AVM related hemorrhage (median NIHSS 12; P<0.0001). Hemorrhage, either at initial presentation or during follow-up of untreated AVM patients appears to carry a lower morbidity than intracranial hemorrhage from other causes. These findings support a careful weighing of risks from interventional treatment and natural history.

Brain Arteriovenous Malformations

Although intracranial hemorrhages,1 interest in brain arteriovenous malformations (BAVMs) is expanding from its origins as a neuropathologic curiosity to the treatment-oriented specialties of neurological surgery, interventional neuroradiology, radiosurgery/therapy, and clinical neurology, and is even emerging as a subject in neuroepidemiology. Recent insights from uncontrolled series: argue for some genetic derangements in the origin of some of the lesions2,3; have revised some issues of pathophysiology4–7; track the risk of hemorrhage over time8; suggest the risk for hemorrhage can be predicted by vascular factors discoverable by noninvasive or minimally invasive imaging9,10; indicate many initial hemorrhage syndromes are mild,11 more so than that caused by non-BAVM parenchymal or aneurysmal subarachnoid hemorrhages12; have reassessed the outcomes from intervention in a variety of forms after initial hemorrhage13–15; raise questions concerning the safety and …