Flemming, Kelly D.

Importance Annual rates of first intracranial hemorrhage (ICH) from unruptured brain arteriovenous malformations (AVMs) are often quoted as 2% to 4% in clinical practice. Precise estimates and risk factors are unavailable to inform treatment decisions. Objective To provide estimates of rates and risk factors for first ICH in a large cohort study of unruptured brain AVMs. Design, Setting, and Participants The Multicenter Arteriovenous Malformation Research Study (MARS) included data from 9 cohorts, each contributing 100 or more unruptured brain AVMs. The study was conducted from 2017 to 2023 with retrospective and prospective data collection for existing cohorts and/or new recruitment. This was an international study (2 population-based and 7 referral-based cohorts) that included participants diagnosed with an unruptured brain AVM. Exposures Demographic, clinical, and angiographic characteristics. Main Outcome and Measure The primary outcome was time to first ICH after diagnosis of unruptured brain AVM. Data were collected using standardized definitions; missing data were imputed. Cox regression analysis was performed, censoring at first brain AVM treatment, death, or last visit, and allowing baseline hazards to vary by cohort. Results A total of 3225 individuals were eligible for participation in this study. After 195 exclusions, 3030 participants (median [IQR] age, 38 [25-50] years; 1524 female [50.3%]) were included. Among 2989 participants with unruptured brain AVMs, 1333 (45%) presented with seizure. The median (IQR) maximal brain AVM diameter was 3.1 (2.2-4.4) cm, 248 of 2466 AVMs (10%) had exclusively deep venous drainage, 297 of 2690 (11%) were in supratentorial deep or cerebellar locations, and 457 of 2440 (19%) had associated arterial aneurysms. First ICH occurred in 159 participants over 11 339 person-years of follow-up for an ICH rate of 1.40 (95% CI, 1.20-1.64) per 100 person-years. Significant independent risk factors included (1) increasing age category at diagnosis (hazard ratio [HR], 0.87; 95% CI, 0.53-1.41 for those aged 20 to 39 years; HR, 1.23; 95% CI, 0.74-2.04 for those aged 40 to 59 years; and HR, 2.01; 95% CI, 1.14-3.57 for those aged 60 years vs younger than 20 years; P = .008), (2) presence of associated aneurysms (HR, 1.66; 95% CI, 1.06-2.59; P = .03), and (3) cerebellar or supratentorial deep location (HR, 1.87; 95% CI, 1.16-3.00; P = .01). Conclusions and Relevance The annual ICH rate from unruptured brain AVM was lower than that commonly cited in clinical practice. Increasing age, associated arterial aneurysms, and cerebellar or supratentorial deep brain AVM location were associated with risk of first ICH. These results may be used to counsel patients about the natural history of unruptured brain AVMs.

BACKGROUND AND OBJECTIVES: Brainstem cavernous malformations (BSCM) can result in spontaneous intracerebral hemorrhage (ICH), often resulting in significant morbidity. We aimed to assess the functional outcome and identify predictors of functional neurological outcome after single and multiple symptomatic hemorrhages. METHODS: As part of an international multicenter collaboration, institutional databases from 3 different tertiary referral centers included BSCM patients with complete baseline characteristics, MRI Data set, ≥1 ICH, and ≥1 follow-up examination followed at our institutions between 2003 and 2023. Functional neurological outcome was obtained using the modified Rankin Scale at diagnosis, before and after each ICH, and last follow-up. Patients were excluded after surgical removal of the lesion and/or loss of follow-up. RESULTS: A total of 383 patients (41.47 ± 15.51 age; 220 [57.4%] female) were included and followed for an average of 63.16 ± 85.75 months. Functional neurological outcome deteriorated in 47.2% ( P = .010) after the second ICH and in 46.5% ( P = .007) after the third ICH. Moreover, the functional neurological status was impaired in 22.3% ( P < .001) of patients at last available follow-up compared with the time of BSCM diagnosis. CONCLUSION: In our study, we observed that the chance of full recovery might decrease with each ICH. We observed a significantly associated neurological deterioration after each ICH compared with initial ICH.

BACKGROUND AND OBJECTIVES: This study aimed to evaluate predictors of hypertrophic olivary degeneration (HOD) in patients with brainstem cerebral cavernous malformations (CCMs) and to examine its association with functional outcomes. METHODS: A cohort of 120 patients with brainstem CCM was analyzed using prospectively collected registry data and retrospective chart reviews. Demographic, clinical, radiological, and surgical data were evaluated. Predictors of HOD and poor functional outcomes were identified through univariate and multivariate analyses. RESULTS: The cohort included 54 females (45.0%), with a mean age at diagnosis of 43.8 years (SD = 16.5). Symptomatic hemorrhage was present in 70.8% of patients at diagnosis, and 28.3% underwent surgical intervention. Radiographic HOD was observed in 20% of patients (n = 24), with 87% of cases involving lesions within the Guillain–Mollaret triangle (GMT). Larger lesion size (odds ratio [OR] = 1.09, 95% CI: 1.01-1.19, P = .027), pontine location (OR = 19.81, P = .006), and GMT involvement (OR = 25.24, P < .001) were significantly associated with HOD. Repeated symptomatic hemorrhage and surgery, including the extent of resection, did not predict the development of HOD. Patients with HOD had worse functional outcomes at last follow-up ( P = .012), with GMT involvement remaining the sole independent predictor of mRS ≥3 (OR = 3.44, P = .040). CONCLUSION: HOD reflects trans-synaptic degeneration within the GMT and is strongly associated with lesion location and size. It serves as a radiological marker of cumulative damage to the brainstem. Preoperative imaging and risk stratification focusing on GMT involvement are critical for guiding management and counseling patients with brainstem CCM.

Features of new bleeding on conventional imaging in cerebral cavernous malformations (CCMs) often disappear after several weeks, yet the risk of rebleeding persists long thereafter. Increases in mean lesional quantitative susceptibility mapping (QSM) ≥ 6% on MRI during 1 year of prospective surveillance have been associated with new symptomatic hemorrhage (SH) during that period. The authors hypothesized that QSM at a single time point reflects features of hemorrhage in the prior year or potential bleeding in the subsequent year. Twenty-eight features were extracted from 265 QSM acquisitions in 120 patients enrolled in a prospective trial readiness project, and machine learning methods examined associations with SH and biomarker bleed (QSM increase ≥ 6%) in prior and subsequent years. QSM features including sum variance, variance, and correlation had lower average values in lesions with SH in the prior year (p < 0.05, false discovery rate corrected). A support-vector machine classifier recurrently selected sum average, mean lesional QSM, sphericity, and margin sharpness features to distinguish biomarker bleeds in the prior year (area under the curve = 0.61, 95% CI 0.52–0.70; p = 0.02). No QSM features were associated with a subsequent bleed. These results provide proof of concept that machine learning may derive features of QSM reflecting prior hemorrhagic activity, meriting further investigation. Clinical trial registration no.: NCT03652181 ( ClinicalTrials.gov )

BACKGROUND AND OBJECTIVES: This study aimed to investigate the clinical presentation, natural history, and long-term outcome of sporadic cerebral cavernous malformations (CCMs) based on initial Zabramski classification. METHODS: A prospective cohort of 285 patients with sporadic CCMs was analyzed. Patients were classified into Zabramski Types I-IV based on diagnostic MRI. Clinical presentation, lesion size, location, and developmental venous anomaly presence were recorded. Prospective symptomatic hemorrhage (SH) (censored at first hemorrhage, surgery, or last follow-up) and functional outcomes were assessed using Kaplan-Meier and Cox regression analyses. Functional outcomes were measured with the modified Rankin Scale (mRS) at baseline, annually, and at the last follow-up. RESULTS: The cohort included 58.9% women and 41.1% men, with a mean age at diagnosis of 44.5 years. Zabramski Types I-IV (n = 113, 125, 40, and 7, respectively) differed significantly in clinical presentation ( P < .001). Type I lesions were symptomatic in 97.3%, Types II and III in 34.4% and 22.5%, respectively, while all Type IV lesions were asymptomatic. Type I lesions had the highest annual hemorrhage rate (13.9% per year) and a 5-year cumulative risk of 50.6%. Types II and III had lower rates (2.9% and 1.8%), whereas no hemorrhages occurred in Type IV lesions. At baseline, 70.8% of Type I patients had mRS ≥2, which decreased to 35.4% at the last follow-up. Type III lesions had favorable outcomes, with 7.5% of patients having mRS ≥2 at the last follow-up. Type IV lesions remained asymptomatic throughout. Severe SH significantly increased the odds of poor outcomes (mRS ≥3; P < .001), whereas Zabramski type was not predictive of outcomes after adjustment. CONCLUSION: Zabramski classification aids in stratifying hemorrhage risk and guiding management in CCMs. Severe SH is a critical determinant of functional outcomes, underscoring the need for comprehensive risk assessments and individualized patient care strategies.

BACKGROUND AND OBJECTIVES: Despite many publications about cavernous malformations (CMs), controversy remains regarding diagnostic and management strategies. To update evidence-based guidelines for the clinical management of brain and spinal cord CMs. METHODS: The Alliance to Cure CMs, the patient support group in the United States advocating on behalf of patients and research in CM, convened a multidisciplinary writing group comprising expert CM clinicians to help summarize the existing literature related to the clinical care of CM, focusing on 5 topics: (1) epidemiology and natural history, (2) genetic testing and counseling, (3) diagnostic criteria and imaging standards, (4) neurosurgical considerations, and (5) neurological considerations. Building on prior evidence-based recommendations reflecting literature review through October 2014, the group conducted a systematic review of the more recent literature, identified references for mandatory citation, rated evidence, developed recommendations, and established consensus according to a prespecified protocol. Finally, the writing group outlined remaining knowledge gaps and controversies to guide future research. RESULTS: From 2672 publications published between October 1, 2014, and March 15, 2023, and meeting key word criteria, 234 were selected based on prearticulated criteria for mandatory consideration in evidence-based recommendations. Topic authors used these and other supporting references to summarize current knowledge and arrive at 53 management recommendations, with unanimous consensus based on a Delphi process. These were rated by class (strength of recommendation) and level (quality of evidence) per the American Heart Association/American Stroke Association criteria. Eighteen recommendations were class 1 (34%), class 2 in 31 (58%), and class 3 in 4 (8%). Three were level A (6%), 19 (36%) were level B, and 31 (58%) were level C. CONCLUSION: Current evidence supports prior and new recommendations for the management of CMs, but many reflect moderate classes and low levels, mandating further research to better inform clinical practice.

BACKGROUND The clinical and radiological evolution of large capillary telangiectasias is largely unknown. OBSERVATIONS A 30-year-old female presented with progressive ataxia and nystagmus. She was found to have a large, diffuse enhancing pontomedullary lesion with associated hypointensity on susceptibility-weighted imaging consistent with a large capillary telangiectasia. In addition, she had a second capillary telangiectasia in the right frontal lobe, hypertrophic olivary degeneration (HOD), and multiple susceptibility lesions throughout the brain. The patient’s condition continued to deteriorate and she became nonambulatory over 8 years, with right-sided hemiparesis and hemiataxia, nystagmus, palatal myoclonus, and a left abducens palsy. Over the follow-up period, serial MR images showed increased cavitation of the lesion and significant brainstem atrophy. LESSONS Capillary telangiectasias are generally small, benign lesions composed of dilated capillaries. However, when large (≥ 1 cm), they can be symptomatic. The authors present the case of a diffuse capillary telangiectasia of the pons with HOD and a progressively declining course due to brainstem atrophy and enlarging cavitation of the lesion. The radiological evolution of an aggressive capillary telangiectasia has not been previously reported. https://thejns.org/doi/10.3171/CASE24746

Introduction and Hypothesis: New bleeding in cerebral cavernous malformations (CCM) heralds increased risk of future hemorrhage for several years, yet conventional imaging only detects new bleeding that occurred in the prior weeks. A biomarker of hemorrhage could help identifying high risk lesions. An increase of mean lesional quantitative susceptibility mapping (QSM) ≥6% on MRI has been adjudicated as reflecting new bleeding in CCM during longitudinal follow-up. However, mean lesional QSM from a single acquisition could not diagnose or prognosticate a bleed. We hypothesize that machine learning (ML) may identify diagnostic and prognostic features of bleeding within QSM maps at a single point in time. Material and Methods: Two hundred and sixty-five QSM maps of CCM lesions were acquired in 120 patients enrolled in National Institute of Health (NIH) multisite trial readiness project (NCT03652181). Each map was classified (Yes/No) in association with symptomatic hemorrhage (SH) and/or biomarker event with QSM increase ≥6% in the prior (diagnostic association) and subsequent (prognostic association) year. Twenty-eight features were extracted including 14 texture, 5 first-order statistical, as well as 3 size, shape, and morphological. Five-fold cross-validation was conducted on a support-vector machine (SVM) with linear stepwise kernel for both diagnostic and prognostic associations. Performance of individual features and composite classifiers was evaluated using student t-test ( p <0.05) with Bonferroni-correction and receiver operating characteristic (ROC) analysis, area under the curve (AUC). Results: Lesions with SH in the prior year had lower average values for sum variance (AUC=0.79, p<0.001), variance (AUC=0.79, p<0.001), and correlation (AUC=0.71, p=0.004) as compared to lesions without SH. The SVM classification method tasked with distinguishing lesions with mean QSM increase ≥6% in the prior year included recurrent selection of sum average, mean, sphericity and margin sharpness, yielding an AUC of 0.61 (p=0.02). In the prognostic cohort, no individual feature nor any SVM classification model was able to distinguish cases with a subsequent clinical bleed or biomarker event. Conclusion: This proof-of-concept suggests that ML may assist in deriving features on QSM maps acquired at a single timepoint, which reflect prior hemorrhagic activity in CCM. Further investigation is planned in larger cohorts and in conjunction with clinical trials of bleeding in CCM.