Association of hemorrhage-to-treatment time with outcomes in patients with brainstem cavernous malformations: a nationwide cohort study.

BACKGROUND: Brainstem cavernous malformations (BSCMs) often present with haemorrhage, but the optimal timing for microsurgical intervention remains unclear. This study aims to explore how intervention timing relates to neurological outcomes in haemorrhagic BSCM patients undergoing microsurgery, offering insights for clinical decisions. METHODS: A total of 293 consecutive patients diagnosed with BSCMs, who underwent microsurgery were identified between March 2011 and January 2023 at two comprehensive centres in China, with a postoperative follow-up duration exceeding 6 months. Utilizing logistic regression models with restricted cubic splines, distinct time groups were identified. Subsequently, matching weight analysis compared these groups in terms of outcomes, new haemorrhage rates, cranial nerve deficits, and perioperative complications. The primary outcome was an unfavourable outcome, which was defined as a mRS score greater than 2 at the latest follow-up. RESULTS: Among the 293 patients, 48.5% were female, median age was (39.9±14.3) years, and median haemorrhage-to-treatment time was 42 days. Patients were categorized into acute (≤21 days), subacute (22-42 days), and delay (>42 days) intervention groups. After matching, 186 patients were analyzed. Adjusted analysis showed lower unfavourable outcome rates for acute [adjusted odds ratio (OR), 0.73; 95% CI, 0.65-0.82; P<0.001] and subacute (adjusted OR, 0.83; 95% CI, 0.72-0.95; P=0.007) groups compared to the delay group. Subacute intervention led to fewer cranial nerve deficits (adjusted OR, 0.76; 95% CI, 0.66-0.88, P<0.001). New haemorrhage incidence didn't significantly differ among groups. CONCLUSIONS: For haemorrhagic BSCMs patients, delayed microsurgical intervention that exceeded 42 days after a prior haemorrhage were associated with an increased risk of unfavourable neurological outcomes.

[Brain Stem and Para-Brain Stem Lesions].

Surgeries for brainstem lesions and adjacent areas needs meticulous manipulation in the profoundly deep surgical field. Moreover, it is associated with a high risk of complications pertinent to resection. The opportunity for a surgeon to amass extensive surgical experience in these lesions is limited. Additionally, the reduced tissue mobility in the brainstem, compared to other lesions, makes selecting the optimal surgical approach critical. Preoperative simulation is pivotal in surmounting these challenges. However, the limitations of preoperative simulations should be recognized in accurately depicting diminutive vessels and cranial nerves around the brainstem. Incorporating intraoperative anatomical observations and data from intraoperative monitoring into a surgical strategy is imperative. Here, we present three cases in which we believe preoperative simulation was effective; a cavernous hemangioma of the brainstem, trochlear schwannoma, and diffuse midline glioma in the pons.

Antithrombotic Therapy in Cerebral Cavernous Malformations: A Systematic Review, Meta-Analysis, and Network Meta-Analysis.

BACKGROUND: Cerebral cavernous malformations are complex vascular anomalies in the central nervous system associated with a risk of intracranial hemorrhage. Traditional guidelines have been cautious about the use of antithrombotic therapy in this patient group, citing concerns about potential bleeding risk. However, recent research posits that antithrombotic therapy may actually be beneficial. This study aims to clarify the association between antithrombotic therapy, including antiplatelet and anticoagulant medications, and the risk of intracranial hemorrhage in patients with cerebral cavernous malformations. METHODS AND RESULTS: A comprehensive literature search was conducted in PubMed, Web of Science, and Scopus databases, following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Nine single-center, nonrandomized cohort studies involving 2709 patients were included. Outcomes were analyzed using random-effects model, and a network meta-analysis was conducted for further insight. Of the 2709 patients studied, 388 were on antithrombotic therapy. Patients on antithrombotic therapy had a lower risk of presenting with intracranial hemorrhage (odds ratio [OR], 0.56 [95% CI, 0.45-0.7]; P<0.0001). In addition, the use of antithrombotic therapy was associated with lower risk of intracranial hemorrhage from a cerebral cavernous malformation on follow-up (OR, 0.21 [95% CI, 0.13-0.35]; P<0.0001). A network meta-analysis revealed a nonsignificant OR of 0.73 (95% CI, 0.23-2.56) when antiplatelet therapy was compared with anticoagulant therapy. CONCLUSIONS: Our study explores the potential benefits of antithrombotic therapy in cerebral cavernous malformations. Although the analysis suggests a possible role for antithrombotic agents, it is critical to note that the evidence remains preliminary. Fundamental biases in study design, such as ascertainment and assignment bias, limit the weight of our conclusions. Therefore, our findings should be considered hypothesis-generating and not definitive for clinical practice change.

Microsurgical Resection of Giant Radio-Induced Cavernous Malformation: 2- Dimensional Video.

Radioinduced cavernous malformations (RICMs) are low-flow, angiographically occult vascular lesions. Giant radioinduced cavernous malformations (GRICMs) are a subtype of RICMs that are characterized by their large size. GRICMs are defined as RICMs that are larger than 3 cm in diameter.1 They are uncommon conditions accounting for 0.1% to 0.5% among patients who have received radiation therapy for head and neck cancer or brain tumors.2,3 The risk of developing GRICMs increases with the dose of radiation received and the length of time since radiation exposure.4 Other factors that may increase the risk of developing GRICMs include age, genetic predisposition, and underlying medical conditions.5 Due to the relatively low incidence of GRICMs and the limited number of studies on this condition, there are limited data about the management of this condition. This case report describes a 12-year-old female who was previously treated for a pilocytic astrocytoma in 2012. After undergoing stereotactic biopsy and whole-brain radiotherapy (50 gray in 28 sections), she was diagnosed with a radioinduced cavernous malformation in 2016 during follow-up imaging. The RICM was managed conservatively with imaging follow-up, which showed no increase in size between 2016 and 2019. However, in 2020, the patient experienced a seizure episode associated with left-sided hemiplegia. Further investigation with cranial magnetic resonance imaging and digital subtraction angiography showed a mixed-intensity image and surrounded by a low signal intensity rim on T2-weighted images, representing hemosiderin in the right central lobe, with intense perilesional edema, with no enhancement. Given the size and location of the mass, the patient underwent microsurgical resection of the RICM (Video 1). The surgery was successful, and the lesion was successfully resected. This case highlights the importance of careful monitoring for RICMs in patients who have received radiation therapy, as well as the potential for these lesions to cause significant symptoms and disability. The case also demonstrates that surgical intervention may be necessary in some cases to manage RICMs and that microsurgical resection can be an effective treatment option. The patient gave informed consent for surgery and video recording.

Quantitative image signature and machine learning-based prediction of outcomes in cerebral cavernous malformations.

PURPOSE: There is increasing interest in novel prognostic tools and predictive biomarkers to help identify, with more certainty, cerebral cavernous malformations (CCM) susceptible of bleeding if left untreated. We developed explainable quantitative-based machine learning models from magnetic resonance imaging (MRI) in a large CCM cohort to demonstrate the value of artificial intelligence and radiomics in complementing natural history studies for hemorrhage and functional outcome prediction. MATERIALS AND METHODS: One-hundred-eighty-one patients from a prospectively registered cohort of 366 adults with CCM were included. Fluid attenuated inversion recovery (FLAIR) T2-weighted brain images were preprocessed, and CCM and surrounding edema were segmented before radiomic feature computation. Minority class oversampling, dimensionality reduction and feature selection methods were applied. With prospective hemorrhage as primary outcome, machine learning models were built, cross-validated, and compared using clinico-radiologic, radiomic, and combined features. SHapley Additive exPlanations (SHAP) was used for interpretation to determine the radiomic features with most contribution to hemorrhage prediction. RESULTS: The highest performances in hemorrhage predictions on the test set were combining radiomic and clinico-radiological features with an area under the curve (AUC) of 83% using linear regression and selected features, and an F1 score of 61% and 85% sensitivity using K-nearest neighbors with principal component analysis (PCA). Multilayer perceptron had the best performance predicting modified Rankin Scale ≥ 2 with an AUC of 74% using PCA derived features. For interpretation of the selected radiomic signature XGBoost model, Shapley additive explanations highlighted 6 radiomic features contributing the most to hemorrhage prediction. CONCLUSION: Quantitative image-based modeling using machine learning has the potential to highlight novel imaging biomarkers that predict hemorrhagic and functional outcomes, ensuring more precise and personalized care for CCM patients.

Towards a neurocognitive profile in familial cerebral cavernous malformations.

BACKGROUND: Familial cerebral cavernous malformations (FCCM) is a rare autosomal dominant disease, characterized by vascular malformations that can lead to macro and microhemorrhages. The neurocognitive impact of FCCM is still underrecognized. METHODS: We report the clinical, neurocognitive, imaging and genetic data of a three generation family with FCCM. RESULTS: A 63-year-old man (proband) had progressive memory impairment since the last year. Neurologic exam was unremarkable. Brain MRI showed multiple large cavernomas (mainly in the pons, left temporal, and right temporo-parietal) and scattered microhemorrhages. Neuropsychological assessment mainly revealed left frontal and right temporo-parietal dysfunction. A 41-year-old daughter, presented with headache, vertigo and memory complaints in the last 2 years. Neurological examination revealed left central facial paralysis. Brain MRI showed two small right parietal and internal capsule cavernomas, as well as microhemorrhages. Neuropsychological assessment showed moderate temporal neocortical left dysfunction. A 34-year-old daughter had recurrent headache and memory complaints, with unremarkable neurological exam. Brain MRI revealed two large cavernomas (left fronto-orbitary and inferior temporal), with few microhemorrhages. Neuropsychological assessment was normal. A granddaughter had mild headaches and a small right cerebellar cavernoma, without microhemorrhages. Neuropsychological assessment showed mild temporal neocortical left dysfunction. A nonsense variant, c.55C > T; p.R19* generating a premature stop codon in CCM2 gene shared by all affected family members was identified. CONCLUSIONS: Neuropsychological evaluation showed that memory complaints and cognitive impairment could be an important unrecognized finding in FCCM. Its pathophysiological mechanisms are still unknown but the role of recurrent microhemorrhages could provide an interesting hypothesis.

Return to Play in Collision Sport After Hemorrhages of a Cerebral Cavernoma.

ABSTRACT: Discovering a cerebral vascular malformation in an athlete should lead to evaluating hemorrhagic risk, notably in contact sports. Cavernous angioma is one of the most frequent pathologies in this context. It can be identified by a hemorrhage, the onset of an epileptic seizure, or, increasingly so, incidentally, while performing a medical examination for another reason. Whether sports practice is a risk factor for hemorrhage is unclear in available literature. When treatment is needed, surgery remains the gold standard. Currently, little data are available on the possibility of resuming contact sports after craniotomy. We report the case of a rugby player who underwent surgery for intracerebral cavernoma. We provide details on how the player was finally cleared to resume rugby practice and on the therapeutic management of this lesion.

Zabramski classification in predicting the occurrence of symptomatic intracerebral hemorrhage in sporadic cerebral cavernous malformations.

OBJECTIVE: The authors aimed to investigate the evolutionary characteristics of the Zabramski classification of cerebral cavernous malformations (CCMs) and the value of the Zabramski classification in predicting clinical outcome in patients with sporadic CCM. METHODS: This retrospective study consecutively included cases of sporadic CCM that had been untreated from January 2001 through December 2021. Baseline and follow-up patient information was recorded. The evolution of the Zabramski classification of a sporadic CCM was defined as the initial lesion type changing into another type for the first time on MRI follow-up. The primary outcome was the occurrence of a hemorrhage event, which was defined as a symptomatic event with radiological evidence of overt intracerebral hemorrhage. RESULTS: Among the 255 included cases, 55 (21.6%) were classified as type I CCM, 129 (50.6%) as type II CCM, and 71 (27.8%) as type III CCM, based on initial MRI. During a mean follow-up of 58.8 ± 33.6 months, 51 (20.0%) patients had lesion classification transformation, whereas 204 (80.0%) patients maintained their initial type. Among the 51 transformed lesions, 29 (56.9%) were type I, 11 (21.6%) were type II, and 11 (21.6%) were type III. Based on all follow-up imaging, of the initial 55 type I lesions, 26 (47.3%) remained type I and 27 (49.1%) regressed to type III because of hematoma absorption; 91.5% of type II and 84.5% of type III lesions maintained their initial type during MRI follow-up. The classification change rate of type I lesions was statistically significantly higher than those of type II and III lesions. After a total follow-up of 1157.7 patient-years, new clinical hemorrhage events occurred in 40 (15.7%) patients. The annual cumulative incidence rate for symptomatic hemorrhage in all patients was 3.4 (95% CI 2.5-4.7) per 100 person-years. Kaplan-Meier survival analysis showed that the annual cumulative incidence rate for symptomatic hemorrhage of type I CCM (15.3 per 100 patient-years) was significantly higher than those of type II (0.6 per 100 patient-years) and type III (2.3 per 100 patient-years). CONCLUSIONS: This study suggests that the Zabramski classification is helpful in estimating clinical outcome and can assist with surgical decision-making in patients with sporadic CCM.

Hemorrhagic Outcome of Brainstem Cavernous Malformations following Radiosurgery: Dose-Response Relationship.

INTRODUCTION: This study aimed to assess the impact of gamma knife radiosurgery on brainstem cavernous malformations (CMs). METHODS: A total of 85 patients (35 females; median age 41.0 years) who underwent gamma knife radiosurgery for brainstem CMs at our institute between 2006 and 2015 were enrolled in a prospective clinical observation trial. Risk factors for hemorrhagic outcomes were evaluated, and outcomes were compared across different margin doses. RESULTS: The pre-radiosurgery annual hemorrhage rate (AHR) was 32.3% (44 hemorrhages during 136.2 patient-years). The median planning target volume was 1.292 cc. The median margin and maximum doses were 15.0 and 29.2 Gy, respectively, with a median isodose line of 50.0%. The post-radiosurgery AHR was 2.7% (21 hemorrhages during 769.9 patient-years), with a rate of 5.5% within the first 2 years and 2.0% thereafter. The post-radiosurgery AHR for patients with margin doses of ≤13.0 Gy (n = 15), 14.0-15.0 Gy (n = 50), and ≥16.0 Gy (n = 20) was 5.4, 2.7, and 0.6%, respectively. Correspondingly, transient adverse radiation effects were observed in 6.7 (1/15), 10.0 (5/50), and 30.0% (6/20) of cases, respectively. An increased margin dose per 1 Gy (hazard ratio: 0.530, 95% CI: 0.341-0.826, p = 0.005) was identified as an independent protective factor against post-radiosurgery hemorrhage. Margin doses of ≥16.0 Gy were associated with improved hemorrhagic outcomes (hazard ratio: 0.343, 95% confidence interval [CI]: 0.157-0.749, p = 0.007), but an increased risk of adverse radiation effects (odds ratio: 3.006, 95% CI: 1.041-8.677, p = 0.042). CONCLUSION: The AHR of brainstem CMs decreased following radiosurgery, and our study revealed a significant dose-response relationship. Margin doses of 14-15 Gy were recommended. Further studies are required to validate our findings.

Trial Readiness of Cavernous Malformations With Symptomatic Hemorrhage, Part I: Event Rates and Clinical Outcome.

BACKGROUND: Cerebral cavernous malformation with symptomatic hemorrhage (SH) are targets for novel therapies. A multisite trial-readiness project (https://www.clinicaltrials.gov; Unique identifier: NCT03652181) aimed to identify clinical, imaging, and functional changes in these patients. METHODS: We enrolled adult cerebral cavernous malformation patients from 5 high-volume centers with SH within the prior year and no planned surgery. In addition to clinical and imaging review, we assessed baseline, 1- and 2-year National Institutes of Health Stroke Scale, modified Rankin Scale, European Quality of Life 5D-3 L, and patient-reported outcome-measurement information system, Version 2.0. SH and asymptomatic change rates were adjudicated. Changes in functional scores were assessed as a marker for hemorrhage. RESULTS: One hundred twenty-three, 102, and 69 patients completed baseline, 1- and 2-year clinical assessments, respectively. There were 21 SH during 178.3 patient years of follow-up (11.8% per patient year). At baseline, 62.6% and 95.1% of patients had a modified Rankin Scale score of 1 and National Institutes of Health Stroke Scale score of 0 to 4, respectively, which improved to 75.4% (P=0.03) and 100% (P=0.06) at 2 years. At baseline, 74.8% had at least one abnormal patient-reported outcome-measurement information system, Version 2.0 domain compared with 61.2% at 2 years (P=0.004). The most common abnormal European Quality of Life 5D-3 L domains were pain (48.7%), anxiety (41.5%), and participation in usual activities (41.4%). Patients with prospective SH were more likely than those without SH to display functional decline in sleep, fatigue, and social function patient-reported outcome-measurement information system, Version 2.0 domains at 2 years. Other score changes did not differ significantly between groups at 2 years. The sensitivity of scores as an SH marker remained poor at the time interval assessed. CONCLUSIONS: We report SH rate, functional, and patient-reported outcomes in trial-eligible cerebral cavernous malformation with SH patients. Functional outcomes and patient-reported outcomes generally improved over 2 years. No score change was highly sensitive or specific for SH and could not be used as a primary end point in a trial.

Trial Readiness of Cavernous Malformations With Symptomatic Hemorrhage, Part II: Biomarkers and Trial Modeling.

BACKGROUND: Quantitative susceptibility mapping (QSM) and dynamic contrast-enhanced quantitative perfusion (DCEQP) magnetic resonance imaging sequences assessing iron deposition and vascular permeability were previously correlated with new hemorrhage in cerebral cavernous malformations. We assessed their prospective changes in a multisite trial-readiness project. METHODS: Patients with cavernous malformation and symptomatic hemorrhage (SH) in the prior year, without prior or planned lesion resection or irradiation were enrolled. Mean QSM and DCEQP of the SH lesion were acquired at baseline and at 1- and 2-year follow-ups. Sensitivity and specificity of biomarker changes were analyzed in relation to predefined criteria for recurrent SH or asymptomatic change. Sample size calculations for hypothesized therapeutic effects were conducted. RESULTS: We logged 143 QSM and 130 DCEQP paired annual assessments. Annual QSM change was greater in cases with SH than in cases without SH (P=0.019). Annual QSM increase by ≥6% occurred in 7 of 7 cases (100%) with recurrent SH and in 7 of 10 cases (70%) with asymptomatic change during the same epoch and 3.82× more frequently than clinical events. DCEQP change had lower sensitivity for SH and asymptomatic change than QSM change and greater variance. A trial with the smallest sample size would detect a 30% difference in QSM annual change during 2 years of follow-up in 34 or 42 subjects (1 and 2 tailed, respectively); power, 0.8, α=0.05. CONCLUSIONS: Assessment of QSM change is feasible and sensitive to recurrent bleeding in cavernous malformations. Evaluation of an intervention on QSM percent change may be used as a time-averaged difference between 2 arms using a repeated measures analysis. DCEQP change is associated with lesser sensitivity and higher variability than QSM. These results are the basis of an application for certification by the US Food and Drug Administration of QSM as a biomarker of drug effect on bleeding in cavernous malformations. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03652181.

Bleeding risk evaluation in cerebral cavernous malformation, the role of medications, and hemorrhagic factors: a case-control study.

OBJECTIVE: Cerebral cavernous malformations (CCMs) are vascular lesions with an overall risk of rupture from 2% to 6% per year, which is associated with significant morbidity and mortality. The diagnostic incidence is increasing, so it is of paramount importance to stratify patients based on their risk of rupture. Data in the literature seem to suggest that specific medications, particularly antithrombotic and cardiovascular agents, are associated with a reduced risk of bleeding. However, the effect of the patient coagulative status on the cumulative bleeding risk remains unclear. The aim of this study was to assess the impact of different radiological, clinical, and pharmacological factors on the bleeding risk of CCMs and to assess the predictive power of an already validated scale for general bleeding risk, the HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly, drugs/alcohol concomitantly). METHOD: This was a multicenter retrospective observational study. The authors collected imaging, clinical status, and therapy data on patients with bleeding and nonbleeding CCMs. Univariate analysis and subsequent multivariate logistic regression were performed between the considered variables and bleeding or nonbleeding status to identify potential independent predictors of bleeding. RESULTS: The authors collected data on 257 patients (46.7% male, 25.3% with bleeding CCMs). Compared with patients with nonbleeding lesions, those with bleeding CCMs were younger, less frequently had hypertension, and less frequently required antiplatelet drugs and beta-blockers (all p < 0.05). Bleeding lesions, however, had significantly higher median volumes (1050 mm3 vs 523 mm3 , p < 0.001). On multivariate analyses, after adjusting for age, history of hypertension and diabetes, and use of antiplatelet drugs or beta-blockers, lesion volume ≥ 300 mm3 was the only significant predictor of bleeding (adjusted OR 3.11, 95% CI 1.09-8.86). When the diagnostic accuracy of different volume thresholds was explored, volume ≥ 300 mm3 showed a limited sensitivity (36.7%, 95% CI 24.6%-50.0%), but a high specificity 78.2% (95% CI 71.3%-84.2%), with an area under the curve of 0.57 (95% CI 0.51-0.64). CONCLUSIONS: This study supports previous findings that the CCM volume is the only factor influencing the bleeding risk. Antithrombotic agents and propranolol seem to have a protective role against the bleeding events. A high HAS-BLED score was not associated with an increased bleeding risk. Further studies are needed to confirm these results.

Seizure outcome in medically treated patients with adult-onset epilepsy and cerebral cavernous malformation.

PURPOSE: We evaluated long-term seizure outcomes of antiseizure medications (ASMs) and risk factors for drug resistance in patients with adult-onset epilepsy associated with cerebral cavernous malformation (CCM). MATERIALS AND METHODS: This retrospective observational study included patients newly diagnosed with adult-onset focal epilepsy associated with CCM. Patients received individualized treatments with ASMs. All patients were followed-up for at least 2 years. The main outcome measure was terminal 2 year seizure freedom (2-YSF). RESULTS: Forty eight subjects (28 men and 20 women) were included. Thirty-one (64.6%) subjects achieved a terminal 2-YSF (range 2.0-17.0 years). After treatment with the first drug regimen, 31 (64.6%) subjects achieved 2-YSF, with 23 remaining seizure-free until final follow-up visit. Of the 23 subjects treated with the second drug regimen and the six treated with the third drug regimen, ten (43.5%) and one (16.7%), respectively, achieved a terminal 2-YSF. Stepwise logistic regression analyses showed that terminal 2-YSF was negatively associated with epileptiform discharge on EEG at the time of diagnosis (odds ratio = 0.214, p = 0.047) and tended to be associated with age ≥ 45 years at seizure onset (odds ratio = 4.260, p = 0.056). CONCLUSION: The present study found that 64.6% of CCM patients with adult-onset epilepsy achieved terminal 2-YSF after ASM initiation. Interictal epileptiform discharge on EEG at the time of diagnosis was associated with poor prognosis. Failure to achieve sustained seizure freedom after two ASMs may indicate the need for surgical treatment.

Radiation-Induced Cerebral Cavernous Malformations: A Single-Center Experience and Systematic Literature Review.

OBJECTIVE: Radiation was first demonstrated to be associated with cavernomagenesis in 1992. Since then, a growing body of literature has shown the unique course and presentation of radiation-induced cavernous malformations (RICMs). This study summarizes the literature on RICMs and presents a single-center experience. METHODS: A prospectively maintained single institution vascular malformation database was searched for all cases of intracranial cavernous malformation (January 1, 1997-December 31, 2021). For patients with a diagnosis of RICM, information on demographic characteristics, surgical treatments, radiation, and surgical outcomes was obtained and analyzed. A comprehensive literature search was conducted using PubMed, Embase, Cochrane, and Web of Science databases for all reported cases of RICM. RESULTS: A retrospective review of 1662 patients treated at a single institution yielded 10 patients with prior radiation treatment in the neck or head region and a subsequent diagnosis of intracranial RICM. The median (interquartile range) latency between radiation and presentation was 144 (108-192) months. Nine of 10 patients underwent surgery; symptoms improved for 5 patients, worsened for 3, and were stable for 1. The systematic literature review yielded 64 publications describing 248 patients with RICMs. Of the 248 literature review cases, 71 (28.6%) involved surgical resection. Of 39 patients with reported surgical outcomes, 32 (82%) experienced improvement. CONCLUSIONS: RICMs have a unique course and epidemiology. RICMs should be considered when patients with a history of radiation present with neurologic impairment. When RICMs are identified, symptomatic patients can be treated effectively with surgical excision and close follow-up.

Epilepsy associated with cerebral cavernous malformations managed with stereotactic radiosurgery: an international, multicenter study.

OBJECTIVE: Stereotactic radiosurgery (SRS) has been proposed as an alternative to resection for epilepsy control in patients with cerebral cavernous malformations (CCM) located in critical areas. METHODS: This multicentric, retrospective study evaluated seizure control in patients with a solitary CCM and a history of at least one seizure prior to SRS. RESULTS: 109 patients (median age at diagnosis 28.9 years, interquartile range (IQR) 16.4 years] were included. Prior to SRS, 2 (1.8%) were seizure-free without medication, 35 (32.1%) were seizure-free with antiseizure medications (ASM), 17 (15.6%) experienced an improvement of at least 50% in seizure frequency/intensity with ASM, and 55 (50.5%) experienced an improvement of less than 50% in seizure frequency/intensity with ASM. At a median follow-up of 3.5 years post-SRS (IQR: 4.9), 52 (47.7%) patients were Engel class I, 13 (11.9%) class II, 17 (15.6%) class III, 22 (20.2%) class IVA or IVB and 5 (4.6%) class IVC. For the 72 patients who had seizures despite medication prior to SRS, a delay > 1.5 years between epilepsy presentation and SRS decreased the probability to become seizure-free, HR 0.25 (95% CI 0.09-0.66), p = 0.006. The probability of achieving Engel I at the last follow-up was 23.6 (95% CI 12.7-33.1) and 31.3% (95% CI 19.3-50.8) at 2 and 5 years respectively. 27 patients were considered as having drug-resistant epilepsy. At a median follow-up of 3.1 years (IQR: 4.7), 6 (22.2%) of them were Engel I, 3 (11.1%) Engel II, 7 (25.9%) Engel III, 8 (29.6%) Engel IVA or IVB and 3 (11.1%) Engel IVC. INTERPRETATION: 47.7% of patients managed with SRS for solitary CCM presenting with seizures achieved Engel class I at the last follow-up.

Campylobacter fetus seeding of a cavernous malformation resulting in brain abscess: case report and literature review.

Microbial seeding of a cerebral cavernous malformation is an extremely rare occurrence with only 3 cases reported in the literature thus far. Campylobacter fetus is an opportunistic pathogen that rarely causes neurological infection with only 3 cases of C. fetus cerebral abscesses and 38 cases of C. fetus meningitis reported in the literature. There have been no cases of cerebral cavernous malformation seeding by C. fetus reported to date. We report the first case of cerebral cavernous malformation seeding by C. fetus, a case occurring in a previously healthy 16-year-old female who presented with suspected left cerebellar cavernous malformation with subacute hemorrhage. She underwent a suboccipital craniectomy for the resection of the cavernous malformation with additional intraoperative findings suggestive of cerebral abscess. Following positive blood and CSF cultures and surgical pathology results, the patient was diagnosed with C. fetus meningoencephalitis with co-infected left cerebellar cavernous malformation. This is the fourth reported case of microbial seeding of a cerebral cavernous malformation, and to our knowledge, the first case of a C. fetus-infected cavernous malformation. Compared to previous reports, the clinical events of this case strongly support the presence of a preexisting lesion that was secondarily seeded versus de novo formation as a result of prior infection.

Are there differences in clinical presentation, radiologic findings, and outcomes in female patients with cavernous malformation?

BACKGROUND: Little data exist regarding sex differences in cavernous malformations (CM) patients. METHODS: From an ongoing, prospective registry of consenting adults with CM, we assessed the differences between male and female patients in regard to age at presentation, type of presentation, radiologic characteristics and prospective, symptomatic hemorrhage and or focal neurologic deficit (FND) risk and functional outcome. Cox proportional-hazard ratios and 95% confidence intervals with P values < 0.05 were considered significant in the outcome analysis. Familial form CM female patients were compared to sporadic form. RESULTS: As of 1/1/2023, our cohort comprised 386 people (58.0% female) after excluding radiation-induced CM. There were no demographic or clinical presentation differences between male and female patients. Radiological features did not differ between sexes, except that female, sporadic patients were more likely to have an associated developmental venous anomaly (DVA) (43.2% male vs. 56.2% female; p = 0.03). Overall, there was no difference in prospective symptomatic hemorrhage or functional outcome between sexes. Female sex was a predictor of symptomatic hemorrhage or FND in sporadic patients with ruptured CM (39.6% males versus 65.7% females; p = 0.02). The latter was not due to presence or absence of DVA. Familial CM females were more likely to have a spinal cord CM (15.2% familial female vs. 3.9% sporadic female; p = 0.001) and had a longer time to recurrent hemorrhage than sporadic female (2.2 years sporadic vs. 8.2 years familial; p = 0.0006). CONCLUSION: Minimal differences in clinical, radiologic, and outcomes were found in male versus female patients and familial versus sporadic females in the overall CM patient group. The finding that sporadic form female patients with history of prior hemorrhage had increased rates of prospective hemorrhage or FND compared to male patients raise the question whether to "lump" or "split" ruptured versus unruptured CM patients when analyzing risk factors for prospective hemorrhage in natural history studies.

Bleeding Risk of Cerebral Cavernous Malformations in Patients on Statin and Antiplatelet Medication: A Cohort Study.

BACKGROUND: Statin medication has been identified as a potential therapeutic target for stabilizing cerebral cavernous malformations (CCMs). Although increasing evidence suggests that antiplatelet medication decreases the risk of CCM hemorrhage, data on statin medication in clinical studies are scarce. OBJECTIVE: To assess the risk of symptomatic CCM-related hemorrhage at presentation and during follow-up in patients on statin and antiplatelet medication. METHODS: A single-center database containing patients harboring CCMs was retrospectively analyzed over 41 years and interrogated for symptomatic hemorrhage at diagnosis, during follow-up, and statin and antiplatelet medication. RESULTS: In total, 212 of 933 CCMs (22.7%), harbored by 688 patients, presented with hemorrhage at diagnosis. Statin medication was not associated with a decreased risk of hemorrhage at diagnosis (odds ratio [OR] 0.63, CI 0.23-1.69, P = .355); antiplatelet medication (OR 0.26, CI 0.08-0.86, P = .028) and combined statin and antiplatelet medication (OR 0.19, CI 0.05-0.66; P = .009) showed a decreased risk. In the antiplatelet-only group, 2 (4.7%) of 43 CCMs developed follow-up hemorrhage during 137.1 lesion-years compared with 67 (9.5%) of 703 CCMs during 3228.1 lesion-years in the nonmedication group. No follow-up hemorrhages occurred in the statin and the combined statin and antiplatelet medication group. Antiplatelet medication was not associated with follow-up hemorrhage (hazard ratio [HR] 0.7, CI 0.16-3.05; P = .634). CONCLUSION: Antiplatelet medication alone and its combination with statins were associated with a lower risk of hemorrhage at CCM diagnosis. The risk reduction of combined statin and antiplatelet medication was greater than in patients receiving antiplatelet medication alone, indicating a possible synergistic effect. Antiplatelet medication alone was not associated with follow-up hemorrhage.

Pediatric Cerebral Cavernous Malformation: A Single-Centered Experience of 23 Cases.

AIM: To describe, and to evaluate the clinical and radiological characteristics of pediatric cavernous malformations (CMs) and the surgical approaches and their outcomes in a single center. MATERIAL AND METHODS: We retrospectively reviewed pediatric patients with CMs that were treated in our center between 2010 and 2020. Radiological, clinical, and demographic features, as well as treatment details were evaluated. RESULTS: Of 23 patients, 12 were male, and 11 were female. Two patients with multiple CMs had a family history. The most common symptoms were headaches (9/23, 39.1%) and seizures (9/23, 39.1%). Twenty patients had single lesions and three patients had multiple lesions. According to Zabramski classification, eight (34.7%) patients had type 1, 11 (47.8%) had type 2 and four (17.3%) had type 3 lesions. Thirteen patients had recurrent preoperative hemorrhages and nine had increased lesion size. Seven patients (30.4%) had coexisting deep venous anomalies in the CM vicinity. Twenty-one patients underwent microsurgical resection (5/23 simple lesionectomy, 16/23 lesionectomy + resection of the surrounding hemosiderin ring). All lesions were completely resected. No surgical mortalities or major complications occurred. CONCLUSION: Since pediatric CMs are more aggressive than adult CMs, they should not be underestimated. Microsurgical total resection should be the first treatment choice where possible. We concluded that early surgical treatment and resection of perilesional hemosiderin-stained tissue, when feasible, yield the most favorable results at long-term follow-up including seizure outcomes.