Flemming, Kelly D.

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.

Introduction: Small case series have suggested that cerebral amyloid angiopathy (CAA) and reversible cerebral vasoconstriction syndrome (RCVS) are the most common causes of non-traumatic convexal SAH (cSAH). Our objective was to describe the spectrum of clinical and imaging features in a large series of non-traumatic cSAH patients. Methods: A retrospective observational study of consecutive patients with non-traumatic cSAH was performed. The Mayo Clinic Medical Records Linkage system was used to identify all patients evaluated at Mayo Clinic in Rochester with potential non-traumatic cSAH between January 1, 1996 and October 1, 2014. Clinical and radiologic data were abstracted from the comprehensive medical record. Results: We identified 88 patients [median age, 64 years (range: 25-85)] with non-traumatic cSAH. The most common causes were reversible cerebral vasoconstriction syndrome (26, 29.5%), cerebral amyloid angiopathy (23, 26.1%), indeterminate (14, 15.9%), and endocarditis (9, 10.2%). Other causes include posterior reversible encephalopathy syndrome, cerebral vein thrombosis, vasculitis, carotid occlusive disease, thrombosed developmental venous anomaly, and hyperperfusion syndrome after carotid revascularization. CAA patients commonly presented at an older age than RCVS patients (75 years vs 51 years, p<0.0001). The most common clinical presentation for CAA was sensorimotor dysfunction while thunderclap headache was the most common presentation of RCVS. Thirteen patients (14.7%) had recurrent cSAH and twelve patients (13.6%) had a subsequent intracerebral hemorrhage over a median follow up of 16 months. The risk was high among CAA patients, with subsequent lobar ICH occurring in 43.5% of cases, superficial siderosis in 95%, and recurrent cSAH in 39.1%, compared to 3.8%, 28.5% and 7.7% respectively in RCVS. Conclusions: Our study demonstrates the clinical diversity of cSAH. Older age, sensorimotor dysfunctions suggest CAA as the underlying cause. Younger age and thunderclap headache predict RCVS. Various other causes also need to be considered in the differential diagnosis. CAA patients have high rates of subsequent lobar ICH, development of superficial siderosis, and recurrent cSAH.

Introduction: Patients with intracerebral cavernous malformations (ICMs) may present with or later develop seizures. There are limited data regarding the clinical demographics of these patients, predictors of medically treatable versus medically refractory seizures, and long term seizure outcome. Objective: We aimed to characterize the clinical and radiographic features of supratentorial ICMs that present with seizures and describe their response to medical treatment. Methods: Patients with supratentorial ICMs were identified from a radiographic database for cases seen between 1989 and 1999. Clinical and radiographic information was abstracted and prospective follow up was obtained. Medically refractory seizures were defined as patients who were not seizure-free at last follow up, or who underwent surgery for refractory seizures. Results: A total of 206 patients were identified with a radiographic diagnosis of supratentorial ICM, 103 (50%) of whom presented with seizures and 7 (3%) who later developed seizures. Compared to those with seizures, patients without seizures were more likely to have a subcortical supratentorial ICM and to be on an antithrombotic agent. Intracerebral hemorrhage (ICH) at diagnosis did not predict presentation with seizure at diagnosis. Among the 59 patients treated with antiepileptics only, 16 (27%) were seizure-free at last follow up, 7 of whom no longer required medication and 8 of whom were controlled on a single agent. In the remainder of patients who were not seizure-free, seizure frequency was reduced in 37%, unchanged in 12%, increased in 5%, and unknown in 19%. Of the total 110 patients with seizures, 46 (42%) underwent at least one surgical removal of an ICM for medically refractory seizures. Conclusions: To date this study is one of the largest cohorts of ICM patients with seizures. Seizure is a common presentation in patients with cortical supratentorial ICMs. The presence of ICH at ICM diagnosis is not related to an increased occurrence of seizures at presentation. One-fourth of patients treated with antiepileptics alone eventually become seizure-free, almost half of which do not require medication at follow-up, suggesting that some non-surgical patients may not require life-long antiepileptic therapy.

Introduction: Obstructive sleep apnea (OSA) is an independent risk factor for ischemic stroke; however the causal mechanisms are unknown. Understanding etiology of stroke in OSA patients may: (1) aid in ascertaining how OSA exerts its influence in increasing stroke risk, and (2) facilitate tailoring recurrent stroke prevention management strategies in OSA patients. Our study compares stroke subtypes in OSA cases versus controls without significant sleep disordered breathing. Hypothesis: We hypothesized cardioembolic (CE) strokes would occur more frequently in OSA cases than in controls. Methods: Consecutive patients were identified who underwent polysomnography (PSG) at Mayo Clinic and suffered an ischemic stroke within one year after PSG. Patients with an apnea-hypopnea index (AHI) ≤ 10 were classified as controls; AHI > 10 classified as OSA cases. Mechanism of stroke was determined using (1) the Causative Classification System for Ischemic Stroke (CCS) and (2) the phenotype definitions used in the Trial of Org 10172 in Acute Stroke Treatment (TOAST). Information on cardiovascular risk factors, neuroimaging, and echocardiography data were collected on each patient. Results: In 53 total subjects, CE strokes were more common among OSA cases (72% vs 33%, p=0.01). Large artery atherosclerosis and small vessel occlusion strokes were more common in controls. Atrial fibrillation (AF) was more frequent in OSA patients (59% vs 24%, p=0.01). Frequency of CE stroke increased with OSA severity. The association between OSA and CE stroke remained significant after controlling for AF (p=0.03, OR 4.5). Echocardiogram data revealed CE stroke risk factors were more frequent in OSA cases (84% vs 52% p=0.02). There were no significant differences between groups for left ventricular ejection fraction, left atrial volume index, or right ventricular systolic pressure. Conclusions: The results demonstrate a strong association between OSA and CE stroke. In OSA patients presenting with cryptogenic stroke, high clinical suspicion for cardioembolism is warranted. This may lead to consideration of further studies (eg, transesophageal echocardiography, Holter monitoring, or extended cardiac monitoring) to identify cardioembolic risk factors such as paroxysmal AF.

Background: Cavernous malformations (CM) are low flow vascular malformations of the central nervous system. Brainstem location and prior hemorrhage increase the risk for future hemorrhage. Little is known about the influence of physical activity on increasing the risk of hemorrhage. Methods: Consecutive patients with radiologically confirmed CM were recruited to participate in a prospective registry beginning in 2015. A structured interview, survey, and examination were performed at baseline. Patients were asked if anything unusual occurred in the days leading to initial clinical presentation. Medical records and magnetic resonance imaging (MRI) studies were reviewed. Patients were surveyed about their involvement in select physical activity after the diagnosis of CM was made. Follow up surveys were sent annually to patients to ascertain new clinical hemorrhages. Follow up was censored at last follow up, hemorrhage, surgery, or death. Univariate analysis was performed to assess whether involvement in select physical activities increased the risk of prospective hemorrhage. Results: Of 195 patients, 117 (60 %) were female and the average age at diagnosis was 41 years (31-56 years). One hundred and three (52.8%) patients returned the survey about physical activity after diagnosis (cerebral n=100; spine n=3). Twenty-three patients had a prospective hemorrhage over 539.4 patient years. Five of these patients were removed from the analysis because they had less than 6 weeks of physical activity exposure before censor. Of 98 remaining patients, there was no difference in prospective hemorrhage risk in those patients participating 3 or more times monthly in walking, running, lifting more than 20 pound weights, lifting less than 20 pound weights, or participating in non-contact sports. Very few patients reported participation in contact sports (n=5), scuba diving (n=2) or high altitude climbing (n=1) more than 3 times monthly. Conclusion: Aerobic activity and non-contact sports do not increase the risk of hemorrhage in patients with cerebral CM and patients should not be restricted. Less information is known about contact sports, high altitude climbing or scuba diving and those with spinal cord CM.

Introduction: Cortical superficial siderosis (cSS) refers to deposition of blood breakdown products along the cerebral cortex, causing characteristic staining patterns seen with iron-sensitive MRI techniques. Cortical superficial siderosis is a relatively rare disorder, but has been linked to cerebral amyloid angiopathy and Alzheimer’s disease. The objective of this study was to determine the frequency and natural history of cSS in the general elderly population. Methods: MRI scans from the Mayo Clinic Study of Aging (MCSA), an ongoing population-based study of elderly residents in Olmsted County, Minnesota, were reviewed by neuroradiologists. Participants with cSS were identified based on linear pattern of hypointensity on gradient recalled echo imaging consistent with cSS. Exclusion criteria were: 1) MRI findings not consistent with cSS or 2) alternative explanation for MRI findings (such as aneurysmal subarachnoid hemorrhage, intracranial surgery, or trauma). Additional data abstracted included extent of cSS, presence of cerebral microbleeds, and clinical outcome. Results: Eleven out of 1,441 participants had MRI scans showing cSS (0.8%). When stratified by age, the frequency was 0.4% in those 50 to 70 years old and 1.1% in those over 70 years old. Six participants had only focal involvement of cSS (restricted to three or fewer sulci) and five had disseminated involvement (affecting more than three sulci). Microbleeds were seen in four of five (80%) participants with disseminated cSS, but none with focal cSS. Five participants (2 focal, 3 disseminated cSS) had follow up MRI scans, with an average follow up of 25 months. There was no further hemorrhage in those with focal cSS. However, all three participants with disseminated cSS experienced additional hemorrhage: one with new microbleeds, one with new microbleeds and lobar hemorrhage, and one with sulcal subarachnoid hemorrhage and lobar hemorrhage. Conclusion: Although rare, cSS may be encountered in the general elderly population. Extent of involvement of cSS and concomitant microbleeds may be important risk factors for progression of disease and intracerebral hemorrhage. The clinical significance of focal cSS occurring in the absence of microbleeds requires further investigation.

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.