Influence of Pregnancy on Hemorrhage Risk in Women With Cerebral and Spinal Cavernous Malformations.

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.

Cavernous Malformation Hemorrhagic Presentation at Diagnosis Associated with Low 25-Hydroxy-Vitamin D Level.

BACKGROUND: Cavernous malformations (CM) are angiographically occult vascular malformations that may be incidental or present with intracerebral or spinal hemorrhage, seizures, or nonhemorrhagic focal neurologic deficit (FND). Recently in vitro data have suggested vitamin D may play a role in stabilizing CCM2 endothelial cells. Little is known about the effect of vitamin D in human CM disease. METHODS: Beginning in 2015, consecutive patients at our institution with radiologically confirmed CM were recruited to participate in a prospective clinical registry as well as 25-hydroxy-vitamin D study. A structured interview, survey, and examination were performed at baseline. Medical records and magnetic resonance imaging studies were reviewed and data collected included comorbid conditions, medication use, and location of CM. Standard definition of clinical hemorrhage, FND, and seizures was used. Univariate and multivariate logistic regression models were used, and OR, 95% CIs, and likelihood-ratio p values were calculated to determine the influence of the 25-hydroxy-vitamin D level on clinical presentation with hemorrhage. RESULTS: Of 213 patients enrolled in the clinical registry between January 2015 and October 2018, 70 participated in the vitamin D study (median age: 38.3 years; 51.4% female). Of the 70 participants, 30 (42.9%) presented with hemorrhage. 25-Hydroxy-vitamin D levels were performed within 1 year of symptoms in 64.1% of patients. Patients presenting with hemorrhage had a lower 25-hydroxy-vitamin D level compared to those presenting with seizure without hemorrhage, FND, or as an incidental finding (median 25.5 ng/mL; range 11-59 hemorrhage vs. median 31.0; range 14-60, no hemorrhage; p = 0.04). After adjusting for age, month of blood draw, and body mass index, 25-hydroxy-vitamin D remained a significant predictor of hemorrhagic presentation. Brainstem location also predicted hemorrhage at presentation. CONCLUSION: Low 25-hydroxy-vitamin D level was more common in patients with CM presenting with hemorrhage. This study supports the potential role of modifiable factor in the initial clinical presentation of CM. Further study is needed to determine the role of vitamin D on prospective hemorrhage risk and whether supplementation may be beneficial.

The Influence of Physical Activity on Cavernous Malformation Hemorrhage.

BACKGROUND AND AIM: Cavernous malformations are low-flow vascular malformations of the central nervous system. Brainstem location and prior hemorrhage increase future hemorrhage risk. We sought to determine the influence of physical activity on hemorrhage risk. METHODS: Consecutive patients with radiologically confirmed cavernous malformations participated in a prospective registry with structured, baseline interviews, surveys, and examinations. Patients were asked about unusual events prior to initial clinical presentation. Medical records and MRIs were reviewed. Patients were surveyed about their physical activity after receiving their diagnosis. Annual follow-up surveys to patients ascertained new hemorrhages. Follow-up terminated at last follow-up, hemorrhage, surgery, or death. Univariate analysis assessed the risk of physical activities on prospective hemorrhage. RESULTS: Of 195 patients, 117 (60%) were female. Median diagnosis age was 41 years. After diagnosis, 103 (52.8%) patients returned the physical activity survey (cerebral n = 100; spine n = 3). Over 539.4 patient years, 23 had a prospective hemorrhage. Five patients were removed from analysis because they had less than 6 weeks of physical-activity exposure before censor. The remaining 98 had no difference in prospective hemorrhage risk than those patients participating greater than or equal to 3 times monthly in walking, running, greater than 20-pound or less than 20-pound weight lifting, or noncontact sports. Few (n = 5) reported contact-sport participation, scuba diving (n = 2), or high-altitude climbing (n = 1) greater than 3 times monthly. CONCLUSIONS: Aerobic activity and noncontact sports do not increase hemorrhage risk in cerebral cavernous malformation; patients should not be restricted. Less is known about contact sports, high-altitude climbing, scuba diving, and those with spinal-cord cavernous malformation.

Distinguishing mimics from true hemorrhagic cavernous malformations.

Cavernous malformations (CM) are angiographically occult vascular malformations. CM appear as discrete, small lesions with mixed-signal characteristics on T2 reflecting the underlying pathology. However, the appearance is not pathognomonic. Distinguishing true CM from hemorrhagic tumors can be difficult. We report 5 cases of tumors mimicking CMs. We compared clinical, initial radiologic features, and MRI evolution between 5 tumor mimics and 51 true hemorrhagic, sporadic, brain CM. Compared to true CM, mimic patients were older (47.0 vs. 38.3 years; p = 0.076) and more likely to have a history of primary neoplasm (60% vs 12%; p = 0.0267). Radiologically, the CM mimics demonstrated a higher likelihood of lesion enhancement on the initial diagnostic MRI (60% vs. 16.7%%; p = 0.0609). On follow-up MRI (<1 year after baseline), CM mimics typically had persistent edema (100.0% vs. 6.25%, p = 0.0003) and demonstrated mixed density on ADC (100% vs. 32.1%; p = 0.0199) as well as increased likelihood of enhancement (100% vs 25.8, p = 0.0852). CM mimics were less likely to evolve to Type 2 or 3 lesions (25.0% vs. 84.4%, p = 0.0278). Clinical and radiologic factors may distinguish tumor metastases from true hemorrhagic CM. CM mimics should be suspected in older patients with a history of neoplasm and contrast enhancement on initial MRI. A repeat MRI within 90 days post-initial hemorrhage should be considered to confirm CM diagnosis. Persistent edema without rebleed, lesion enhancement, mixed signal on apparent diffusion co-efficient, and persistence of a Type 1 lesion should raise suspicion of a metastatic tumor.

Predictors of Initial Presentation with Hemorrhage in Patients with Cavernous Malformations.

BACKGROUND: Cavernous malformations (CMs) are low-flow vascular malformations of the central nervous system which are incidental or present with hemorrhage, seizures, or focal neurologic deficit (FND). Little is known about the time course of symptoms and the predictors of initial hemorrhagic presentation. METHODS: Beginning in 2015, consecutive patients with radiologically confirmed CMs were recruited and completed a structured interview and written survey at baseline. Medical records and magnetic resonance imaging studies were reviewed. Data collected included the following: comorbid conditions, select medication use, and location of CMs. Logistic-regression models determined predictors of initial presentation with hemorrhage. RESULTS: Of 202 patients, 58.4% were women (average age at diagnosis, 43.7 ± 16.5 years). Of the patients, 37.1%, 6.5%, and 14.8% presented with hemorrhage, FND, and seizures, respectively. CM was an incidental finding in 40.6%. Most patients presenting with hemorrhage (66.7%) deteriorated over 2-30 days after symptom onset. Brainstem location correlated with a higher likelihood of initial presentation with hemorrhage. Aspirin use and nonsteroidal anti-inflammatory drug use were more common in patients with CMs who did not present with hemorrhage. The effect of estrogen and aspirin was stronger in the sporadic compared with the familial form of CMs. In women, estrogen use increased the likelihood of presenting with hemorrhage. CONCLUSIONS: This prospective cohort study confirms brainstem location increases the likelihood of presenting with hemorrhage, but also supports a potential role of select medications on the initial clinical presentation of CMs. Further data from combined cohorts may aid in determining whether the influence of medications is different in familial versus sporadic form CMs.

Affected health domains in patients with brainstem cavernous malformations.

BACKGROUND: Brainstem cavernous malformations (CM) carry high risks of hemorrhage and neurologic morbidity. While much is published on physical effects of brainstem CM, very little is known about these patients' quality of life. This study aimed to assess the quality of life PROMIS-29 health domains of brainstem CM patients and identify quality of life predictors. METHODS: This was a cross-sectional study of adult patients with at least one brainstem CM identified by advertising on the Angioma Alliance website and from our institutional CM registry. A web-based questionnaire was administered and included self-reported information about the patient, cavernous malformation, residual clinical symptoms, and treatment. In addition, patients filled out the PROMIS-29 (version 1.0). The PROMIS-29 has 7 health domains and is standardized against the general population. We defined impaired quality of life as at least one out of 7 abnormal domains and used a 1 standard deviation cutoff for abnormal. We verified clinical and radiographic data to self-reported data in 28.8% of patients. RESULTS: A total of 104 patients (mean age of 46.5 ± 11.5 years; 77.9% females) were recruited. Most (82.7%) reported at least one symptomatic hemorrhagic event and 36.5% reported at least 1 surgical procedure. At least one abnormal PROMIS domain was present in 64.4% of patients with fatigue (34.6%), anxiety (35.6%), social (28.2%), and physical (27.9%) domains being the most common. Among patients with a Rankin Score of 0-2, 55% had at least one abnormal domain. Gait difficulty, but not age, sex, or surgery predicted impaired quality of life. CONCLUSION: More than half of patients with brainstem CM have impaired quality of life. Fatigue, anxiety, and social function, in addition to physical dysfunction, are common; practitioners should be aware of these concerns. PROMIS-29 provides additional information than modified Rankin Score and should be considered in clinical trials and when assessing treatment outcomes until a disease-specific outcome tool is available.

Infratentorial Developmental Venous Abnormalities and Inflammation Increase Odds of Sporadic Cavernous Malformation.

GOAL: Sporadic brain cavernous malformations commonly correlate with developmental venous anomalies; however, developmental venous anomalies may exist without cavernous malformations. Infratentorial location and specific angioarchitectural features of the developmental venous anomaly increase the odds of a concomitant malformation. Animal data also suggest chronic inflammatory disease, oxidative stress, and angiogenesis promote cavernous malformation development. We sought to determine potential clinical and radiologic factors promoting development of sporadic cavernous malformations. METHODS: One hundred and forty-five patients with sporadic, nonradiation-induced brain cavernous malformations (63 with radiologic-apparent and 82 with radiologic-occult developmental venous anomalies) were compared to developmental venous anomaly controls without associated malformation. Data collection included demographic information, comorbidities, medications at diagnosis, and location of the developmental venous anomaly and/or malformation. Logistic regression with likelihood ratios, odds ratios and 95% confidence intervals were calculated comparing malformation cases with controls. A similar analysis compared malformations with radiologic-apparent anomalies to controls. RESULTS: Compared to controls, cases were more likely to have had a major infectious illness (10.3% versus 2.3%; P = .0003 and/or chronic inflammatory disease (31.7% versus 21.3%; P = .0184) prior to diagnostic magnetic resonance imaging. Infratentorial location was more common in cavernous malformation cases (31.7% versus 15.7% controls; P ≤ .0001) with similar findings in cavernous malformation with radiologic-apparent developmental venous anomalies versus controls. CONCLUSIONS: Infratentorial developmental venous anomalies location, major infectious illness, and chronic inflammatory disorders increase the odds of sporadic cavernous malformation formation. Inflammation may promote local thrombosis of developmental venous anomalies, trigger angiogenic response through increased vascular permeability, or promote cavernous malformation through Toll-like receptor 4.