Flemming, Kelly D

A Carotid web (CaW) is defined as a focal shelf-like projection of non-atheromatous, fibrous tissue along the posterior wall of the carotid bulb. CaW are rare and commonly overlooked lesions increasingly recognized as a cause of stroke in otherwise healthy patients. Intravascular imaging modalities such as intravascular ultrasound and optical coherence tomography (OCT) have been proposed as an adjunct to digital subtraction angiography for the evaluation of CaW. However, the use of OCT in CaW has yet to be described. This report investigated the utility of OCT as an adjunct imaging modality in the evaluation of CaW morphology in a young patient with recurrent ischemic strokes.

Background: Patients with cerebral or spinal cavernous malformations (CM) and a primary headache disorder are often limited in medication options due to concern for bleeding risk. Methods: From a prospective cohort of CM patients (2015–2020), demographics, mode of clinical presentation, and radiographic data were collected. Follow up of patients was performed with electronic medical record review, in person visits and/or written surveys. Select medication use was ascertained from the time of the CM diagnosis to a censor date of first prospective symptomatic hemorrhage, complete surgical excision of sporadic form CM, or death. The influence of non-aspirin NSAID (NA-NSAID), triptan, or OnabotulinumtoxinA on prospective hemorrhage risk was assessed. Results: As of August 20, 2020, 329 patients with spinal or cerebral CM (58% female; 20.1% familial; 42.2% initial presentation due to hemorrhage; 27.4% brainstem) were included. During a follow-up of 1799.9 patient years, 92 prospective hemorrhages occurred. Use of NA-NSAIDs, triptans, and OnabotulinumtoxinA after the diagnosis of CM was unassociated with an increased risk of prospective hemorrhage. Conclusions: Use of triptans and NA-NSAIDs, does not precipitate CM hemorrhage. Similarly, we did not find that OnabotulinumtoxinA precipitated CM hemorrhage in a limited number of patients at doses <200 units per session.

BACKGROUND Little is known about whether coronavirus disease 2019 (COVID-19) influences cavernous malformation (CM) formation or hemorrhage risk. OBSERVATIONS The authors present the case of a 31-year-old patient who developed a hemorrhagic, de novo CM in the setting of a developmental venous anomaly within 3 months of COVID-19 respiratory disease. The authors speculate that COVID-19 disease stimulated formation of the CM through TLR4 inflammatory pathways and subsequently led to the hemorrhagic presentation because of hypercoagulability related to the disease. LESSONS This case raises the possibility that COVID-19 may be a risk factor for de novo development of CMs in predisposed patients.

Background and Purpose: Brain cavernous angiomas with symptomatic hemorrhage (CASH) have a high risk of neurological disability from recurrent bleeding. Systematic assessment of baseline features and multisite validation of novel magnetic resonance imaging biomarkers are needed to optimize clinical trial design aimed at novel pharmacotherapies in CASH. Methods: This prospective, multicenter, observational cohort study included adults with unresected, adjudicated brain CASH within the prior year. Six US sites screened and enrolled patients starting August 2018. Baseline demographics, clinical and imaging features, functional status (modified Rankin Scale and National Institutes of Health Stroke Scale), and patient quality of life outcomes (Patient-Reported Outcomes Measurement Information System-29 and EuroQol-5D) were summarized using descriptive statistics. Patient-Reported Outcomes Measurement Information System-29 scores were standardized against a reference population (mean 50, SD 10), and one-sample t test was performed for each domain. A subgroup underwent harmonized magnetic resonance imaging assessment of lesional iron content with quantitative susceptibility mapping and vascular permeability with dynamic contrast-enhanced quantitative perfusion. Results: As of May 2020, 849 patients were screened and 110 CASH cases enrolled (13% prevalence of trial eligible cases). The average age at consent was 46±16 years, 53% were female, 41% were familial, and 43% were brainstem lesions. At enrollment, ≥90% of the cohort had independent functional outcome (modified Rankin Scale score ≤2 and National Institutes of Health Stroke Scale score <5). However, perceived health problems affecting quality of life were reported in >30% of patients (EuroQol-5D). Patients had significantly worse Patient-Reported Outcomes Measurement Information System-29 scores for anxiety ( P =0.007), but better depression ( P =0.002) and social satisfaction scores ( P =0.012) compared with the general reference population. Mean baseline quantitative susceptibility mapping and permeability of CASH lesion were 0.45±0.17 ppm and 0.39±0.31 mL/100 g per minute, respectively, which were similar to historical CASH cases and consistent across sites. Conclusions: These baseline features will aid investigators in patient stratification and determining the most appropriate outcome measures for clinical trials of emerging pharmacotherapies in CASH.

OBJECTIVE Symptomatic nonsaccular vertebrobasilar aneurysms (NSVBAs) are associated with high rates of aneurysm-related death. Anecdotal evidence suggests that brainstem infarction may be a harbinger of aneurysm rupture. The authors aimed to investigate the association between brainstem infarction and subsequent NSVBA rupture. METHODS The clinical records and radiographic imaging studies of patients presenting to the authors’ institution between 1996 and 2019 for evaluation and management of an NSVBA were retrospectively reviewed to determine the effect of perforating artery infarction on the natural history of NSVBAs. Kaplan-Meier curves for patients with and patients without perforator infarction were constructed, and predictors of aneurysm rupture were identified using a multivariate Cox proportional hazards model. RESULTS There were 98 patients with 591.3 person-years of follow-up who met the inclusion criteria for analysis. There were 20 patients who experienced perforator infarction during follow-up. Ten patients (10.2%) experienced aneurysm rupture during follow-up and 26 patients (26.5%) died due to aneurysm-related complications, with annual rates of rupture and aneurysm-related death of 1.7% and 4.4%, respectively. Five patients with a perforator infarction later experienced aneurysm rupture, with a median time between infarction and rupture of 3 months (range 0–35 months). On multivariate analysis, the presence of intraaneurysmal thrombus (risk ratio [RR] 4.01, 95% confidence interval [CI] 1.12–14.44, p = 0.033) and perforator infarction (RR 6.37, 95% CI 1.07–37.95, p = 0.042) were independently associated with risk of aneurysm rupture. CONCLUSIONS NSVBAs continue to be extremely challenging clinical entities with a poor prognosis. These results suggest that brainstem infarction due to perforating artery occlusion may be a harbinger of near-term aneurysm rupture.

Background and Purpose: Pregnancy as a hemorrhage risk factor in women with cavernous malformations (CMs) is controversial. We describe prospective hemorrhage risk in women who become pregnant after an established CM diagnosis. Methods: Beginning in 2015, we recruited consecutive patients with radiologically confirmed CM of the brain or spinal cord to participate in a prospective registry. Participants underwent a baseline and annual medical record review, imaging review, and annual surveys to ascertain pregnancies, deliveries, and neurological complications. We collected prospective hemorrhage data on reproductive age women. We calculated prospective hemorrhage rates on childbearing age patients based on the number of hemorrhages occurring post-CM diagnosis during pregnancy and nonpregnancy, divided by the years of follow-up and censored at last follow-up, age 46, or surgery in sporadic-form CM. The hemorrhage rates were compared and the 95% CI presented with a P value of <0.05. Results: Of 160 women, 90 presented with CM under the age of 46 (average age 31.6 years; 25.6% familial form; 46.7% with hemorrhage; 24.4% brain stem location). These 90 patients had 136 pregnancies before CM diagnosis; 36 pregnancies occurred at or after the diagnosis of CM. Four patients had a hemorrhage while pregnant or postpartum leading to the first CM diagnosis. During 402.6 years of follow-up while not pregnant, 42 hemorrhages occurred prospectively yielding a 10.4% per year (95% CI, 7.5–14.0) risk of hemorrhage while not pregnant. No hemorrhages occurred during 32 prospective pregnancies (26 live births including 1 twinset and 7 nonviable fetuses) after CM diagnosis during 26.9 years of pregnancy time yielding a rate of 0% per year (95% CI, 0–13.6). We found no statistical difference in the rates of hemorrhage during pregnant and nonpregnant time ( P =0.09). No hemorrhage occurred during delivery. Conclusions: Our prospective data suggest that pregnancy does not increase the risk of hemorrhage in women with a known brain or spinal cord CM and that vaginal delivery is safe in appropriate candidates.

Abstract BACKGROUND Cerebral cavernous angioma (CA) is a capillary microangiopathy predisposing more than a million Americans to premature risk of brain hemorrhage. CA with recent symptomatic hemorrhage (SH), most likely to re-bleed with serious clinical sequelae, is the primary focus of therapeutic development. Signaling aberrations in CA include proliferative dysangiogenesis, blood-brain barrier hyperpermeability, inflammatory/immune processes, and anticoagulant vascular domain. Plasma levels of molecules reflecting these mechanisms and measures of vascular permeability and iron deposition on magnetic resonance imaging are biomarkers that have been correlated with CA hemorrhage. OBJECTIVE To optimize these biomarkers to accurately diagnose cavernous angioma with symptomatic hemorrhage (CASH), prognosticate the risk of future SH, and monitor cases after a bleed and in response to therapy. METHODS Additional candidate biomarkers, emerging from ongoing mechanistic and differential transcriptome studies, would further enhance the sensitivity and specificity of diagnosis and prediction of CASH. Integrative combinations of levels of plasma proteins and characteristic micro-ribonucleic acids may further strengthen biomarker associations. We will deploy advanced statistical and machine learning approaches for the integration of novel candidate biomarkers, rejecting noncorrelated candidates, and determining the best clustering and weighing of combined biomarker contributions. EXPECTED OUTCOMES With the expertise of leading CA researchers, this project anticipates the development of future blood tests for the diagnosis and prediction of CASH to clinically advance towards precision medicine. DISCUSSION The project tests a novel integrational approach of biomarker development in a mechanistically defined cerebrovascular disease with a relevant context of use, with an approach applicable to other neurological diseases with similar pathobiologic features.