Stereotactic radiosurgery (SRS) for patients with brainstem cerebral cavernous malformations (CCMs): An International, Multicentric Study

Stereotactic radiosurgery (SRS) for patients with brainstem cerebral cavernous malformations (CCMs): An International, Multicentric Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Stereotactic radiosurgery (SRS) for patients with brainstem cerebral cavernous malformations (CCMs): An International, Multicentric Study Sam Dayawansa, Chloe Dumot, Georgios Mantziaris, Zhiyuan Xu, Stylianos Pikis, and 31 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3949128/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 29 Oct, 2024 Read the published version in Scientific Reports → Version 1 posted 11 You are reading this latest preprint version Abstract Introduction: Brainstem cerebral cavernous malformations (CCM) are clinically more aggressive compared to superficial CCMs. Due to their location, resection can be challenging, making stereotactic radiosurgery (SRS) an attractive alternative for symptomatic patient. Method: Brainstem CCM patients (n=170) were treated with Gamma Knife SRS at 11 radiosurgical centers. Hemorrhagic risk reduction, risk factors of post-SRS hemorrhage, and clinical outcomes were retrospectively analyzed. Results: Most patients had a single (165/170 patients) brainstem CCMs treated; the majority of CCMs (165/181) presented with bleeding. Single-session SRS decreased the risk of repeat hemorrhage in patients with hemorrhagic brainstem CCM (HR: 0.17, p<0.001) using recurrent multivariate analysis. The annual hemorrhage rate decreased from 14.8 per 100 CCM-years before SRS to 2.3 after treatment. Using univariate Cox-analysis, the probability of a new hemorrhages after SRS was reduced for patient older than 35 years (HR= 0.21, p=0.002) and increased with a margin dose >13Gy (HR= 2.57, p=0.044). Adverse radiation effect (ARE) occurred in 9 patients (5.3%) and was symptomatic in four (2.4%). At a median follow-up of 3.4 years (Inter-quartile range: 5.4), 13 patients (8.0%) had a worsened clinical status, with the treated CCM being the cause in 5.6% (10) of the patients. Conclusion: Single-session SRS decreased the risk of repeat hemorrhage in patients with hemorrhagic brainstem CCM and conveyed this benefit with a low risk of advrse radiation effects (ARE) and worsening clinical status. Health sciences/Diseases Health sciences/Neurology Physical sciences/Physics cerebral cavernous malformation hemorrhagic Stereotactic radiosurgery brainstem Figures Figure 1 Introduction Brainstem cerebral cavernous malformations (CCMs) represent 18% of CCM’s. 1 Unlike superficial lesion, brainstem CCMs are more prone to hemorrhage and are thought to be more aggressive in their natural history course. 2 The risk of repeat hemorrhage is estimated to be as high as 30.8% at 5 years for patients with brainstem CCMs presenting with intracerebral hemorrhage or focal neurological deficit compared to 18.4% in other location. 3 Microsurgical resection is the preferred option to treat symptomatic or hemorrhagic CCM. However, the risk of surgery in this location is high with a mortality rate of 1.5% and a long-term morbidity of 16%, 1 while in other cases some lesions are not amenable to surgery. 4 Stereotactic radiosurgery (SRS) can be an alternative treatment option for brainstem CCM patients. 5–7 However, SRS’s role for such patients remains inadequately defined due to the lack of radiological endpoints and uncertainty about the extent to which CCM hemorrhage is reduced.Our intention with this retrospective, multicentric study is to better define the benefits and risks of treating brainstem CCM patients using Gamma Knife radiosurgery, and better define the role of SRS in the management of brainstem CCM patients. 8 Methods Study population and participant inclusion/exclusion criteria This study follows the guidelines set forth by the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE). 9 All methods were carried out in accordance with relevant guidelines, regulations and experimental protocols were approved university of Virginia licensing committee. Also, when necessary, the informed consent was obtained from all subjects and/or their legal guardian(s). Eleven hospital from 9 countries participated through the International Radiosurgery Research Foundation (IRRF). Each center obtained individual IRB approval for sharing de-identified data. Internal consistency from each cohort was checked and any missing data or discrepancies were resolved by request to the centers. The centers contributed data on patients treated with SRS between 1995 and 2021. This is a focused analysis of patients with brainstem CCMs treated with single-session SRS. Patients lacking follow-up after SRS were excluded. Patients with prior resection had residual cavernous malformations that were treated with SRS. SRS technique The Leksell Gamma-Knife (Elekta AB) available at each participating with the Leksell G head frame (Elekta AB) center were used to deliver the prescribed radiation dose in a single fraction. Stereotactic, high-resolution brain magnetic resonance imaging (MRI) and/or computed tomography (CT) scanning were used for planning. Study endpoints and follow-up The difference between symptomatic intracerebral hemorrhage (ICH) rates prior to and after SRS was the primary endpoint; the occurrence and evolution of neurological deficit, and the development of adverse radiation effects (ARE) were secondary outcomes. Hemorrhage was defined by new/worsening neurological symptoms and evidence of new bleeding on MRI or CT. 8 Nonhemorrhagic focal neurological deficit (FND) was defined as a new or worsening focal neurological deficit attributable to the anatomic location of the lesion in the absence of radiological hemorrhage. 8,10 Neurological symptoms at last follow-up were classified as improved, stable, or worsened. A worsening clinical condition was defined as the occurrence of new, permanent symptoms and/or worsening of at least one neurological symptom. Neither epilepsy nor headache were taken into account to define neurological status. ARE were defined as new or worsening perilesional T2 hyperintensity post-SRS or cyst development. Follow-up was performed according to local protocols, usually every 6 months after SRS for 2 years and annually thereafter. The Zabramski stage was defined per CCM before SRS and at last imaging follow-up. 11 In the case of neurological deterioration, the patients underwent radiographic studies at the time of the diagnosis of new neurological symptoms to evaluate for associated imaging changes. Volumetric changes were categorized based on pre-specified cutoff points: increase with enlargement by more than 20%, decrease with volumetric reduction exceeding 20% of baseline volume, and stable otherwise. 12 Statistical analysis The statistical analysis was performed using R language in R Studio. 13,14 No data were imputed. A p-value <0.05 was considered statistically significant. The analyses were performed per patient or per cavernoma depending on the parameter. Continuous variables were descriptively summarized using medians with interquartile ranges (IQR), and categorical factors were reported using percentages. Normality of continuous variables was assessed graphically and with the use of the Shapiro-Wilk test. The reasoning and methodology behind the calculation of annual hemorrhage rates (AHR) and the statistical models chosen for the identification of risk factors for outcome measures has been previously described. 12 In brief, three pre-SRS AHR were calculated (from birth to SRS with all hemorrhages, from diagnosis to SRS with all hemorrhages, from diagnosis to SRS with first hemorrhage excluded if it led to diagnosis).The post-SRS AHR was calculated by dividing the cumulative number of hemorrhages by the cumulative number of contributed years of follow-up by each lesion. Each lesion contributed risk time from the date of SRS to the date of last follow-up, death or new procedure for CCM. To assess the treatment effect, we compared the pre-SRS AHR with the overall and first 2-year post-SRS AHR using the methodology described by Sahai et al. 15 Univariate and multivariate recurrent event analysis for overall hemorrhage was performed with the Prentice, William and Peterson Gap-Time model (PWP-GT), using the third method for AHR calculation. 6 Statistically significant factors and clinically relevant ones with a p-value less than 0.20 were included in the multivariate analysis. A Cox regression model was performed to identify risk factors associated with post-SRS hemorrhage 16 , and Kaplan-Meier curves for first hemorrhage after SRS were plotted. Logistic regression was performed to evaluate risk factors of ARE. Optimal cut-off points for continuous variable were calculated with the Youden index. Results Demographics The study included 170 patients [female: 100 (58.8%)] with a median age of 37.3 (IQR: 27.5) years at diagnosis. One patient (0.6%) was diagnosed with a CCM2 mutation. The initial presentation was hemorrhage in 132 patients (77.6%), FND in 28 (16.5%), and seizure in 3 (1.8%). Seven patients (4.1%) were asymptomatic at the time of diagnosis. Prior to SRS, 85 (50.0%) patients had a cranial nerve deficit, 50 (29.4%) a motor deficit, and 49 (28.8%) a sensory deficit. Table 1 Among the 170 patients, three were treated for two brainstem CCM, one patient for three CCM, and one patient for 5 CCM. Overall, 181 CCM were treated by SRS. The median time from diagnosis to SRS was 0.9 years (IQR: 4.3). Prior surgical resection occurred in 13 (7.2%) of CCM with a median delay from surgical resection to SRS of 3.2 years (IQR:5.6). A DVA was associated in 26 (14.4%) of the CCM and the CCM was adjacent to an ependymal surface in 42 (23.2%) cases. Table 2 The CCM were treated with a median margin dose of 12.0Gy (IQR:2.0) at a 50% (IQR:10) isodose line for a median volume of 0.4 cm3 (IQR:0.9). Table 2 Prior to SRS, 26 (14.4%) CCM never experiences a defined acute and/or subacute hemorrhage, 103 (56.9%) CCM bled one time, 37 (20.4%) CCM bled two times, 12 (6.6%) CCM bled three times, 1 (0.6%) four times, and 2 (1.1%) five times. Hemorrhage analysis Among CCMs with hemorrhage prior to SRS (n=155), the pre-SRS AHR varied based on the methodology used; 3.6 per 100 CCM-years (follow-up from birth: 6309.9 years; 227 hemorrhages), 42.0 per 100 CCM-years (follow-up from diagnosis: 540.5 years; 227 hemorrhages), and 14.8 per 100 CCM-years (follow-up from diagnosis: 540.5 years; 80 hemorrhages after the exclusion of hemorrhages leading to CCM diagnosis). The overall post-SRS AHR was 2.3 per 100 CCM-years (follow-up post SRS: 736.8 years; 17 hemorrhages) and specificallyin the first 2 years 2.8 per 100 CCM-years (follow-up post SRS: 288.3years; 9 hemorrhages) and after the two first years 1.8 per 100 CCM-years (follow-up post SRS: 449.1 years; 8 hemorrhages). There was a statistically significant reduction in hemorrhage rate post-SRS (-6.4 per 100 CCM-years, 95% CI:3.87-11.13, p<0.0001). Using recurrent analysis, SRS was associated with a reduction of hemorrhage risk (HR= 0.17, 95% CI= 0.09-0.34, p<0.001) in multivariate analysis. Table 3 After SRS, among all the CCM (n=181), new hemorrhages occurred in 19 CCM (10.5%) with 18 (9.9%) CCMs having bled one time and one (0.6%) CCM twice. Three CCM (3/26, 11.5%) without hemorrhage prior SRS, bled after SRS. The median delay from SRS to the first bleeding post-SRS was 3.2 (IQR:6.1) years. In one case, the DVA associated with the CCM was occluded and was considered the reason for the bleeding. Using univariate Cox-analysis, the probability of a new hemorrhages after SRS was reduced for patient older than 35 years old (HR= 0.21, 95% CI= 0.08-0.56, p=0.002) and increased with margin doses >13Gy (HR= 2.57, 95% CI=1.03-6.45, p=0.044. The number of hemorrhages prior to SRS was not associated with a risk modification of new bleeding after SRS. Table 4 The probability of new hemorrhage after SRS was 4% (95% CI= 0.8-7.2), 11.2% (95% CI= 4.6-17.3) and 20.8% (95% CI= 7.7-32.0) at 2, 5, and 10 years, respectively. Figure 1 Imaging outcomes The median follow-up imaging was 3.4 years (IQR=5.1) after SRS. At last follow-up, the CCM volume was decreased in 77/179 (43.0%), stable in 99/179 (55.3%) and increased in 3/179 (1.7%). The pre-SRS Zabramski score was 1 in 49/178 (27.5%), 2 in 108/178 (60.7%), 3 in 18/178 (10.1%) and 4 in 3/ 178 (1.7%). After SRS, the Zabramski score was unchanged in 100/146 (68.5%) CCM. Table 5 Adverse Radiation effects AREs occurred in 9 CCM and 9 patients (5.3%). ARE was symptomatic in four cases (2.2%). One (0.6%) patient developed a cyst that required stereotactic aspiration and thalamotomy for the associated tremor. T2 hyperintensities occurred in 8 (4.7%) patients. They were managed conservatively in 6 and with a transient course of corticosteroids in two. No factors were associated with the occurrence of ARE using logistic analysis. Table 6 Clinical outcomes per patient New neurological deficits occurred in 27 (15.9%) patients, with 12 (7.1%) being permanent. The cause was new post-SRS hemorrhage in 11 (6.5%) (8 (4.4%) transient deficit and 3 (1.7%) permanent deficit), ARE in 2 (1.2%) (one (0.6%) transient and one (0.6%) permanent deficit). Two (2.1%) patients (with transient deficit) presented with ARE and a new hemorrhage. In three (1.8%) patients (with permanent deficit), the symptoms were linked to the CCM despite the lack of evidence of hemorrhage or ARE on imaging. Four (2.4%) patients developed new neurologic symptom unrelated to the CCM (one (0.6%) permanent and three (1.8%) transient); two (2.1%) patients (with permanent deficit) had hemorrhage from other CCMs. In three (1.8%) patients (with 2 (1.2%) permanent deficit and one (0.6%) transient), the reason for the new deficit is unknown; one (0.6%) patient had a worsening of his clinical presentation (dysesthesia and hypoesthesia in one hand) without clear radiologic explanation. Overall, with all events considered, 69 patients (42.3%) demonstrated improvement, 81 (49.7%) exhibited stability, and 13 (8.0%) had a worsening of their clinical neurological status at a median follow-up of 3.4 years (IQR: 5.4). Among the 13 patient with worsening of their clinical neurological status, 10 (5.6%) were potentially associated with the treated CCM (new hemorrhage, ARE, unknown). The data of previous symptom evolution were missing for 7 patients. No patient died during the follow-up period. Additional treatment Two patients had repeat SRS, and three had an open neurosurgical procedure with a median delay of 7.5 years (IQR=4.8) from initial SRS. Discussion One-hundred and seventy patients with 181 CCM were included in this study. The majority had experienced at least one hemorrhagic event (85.6% of the CCM) prior to treatment. Patients with brainstem CCMS are more likely to present with hemorrhage relative to superficial lesions, as observed in previous report 2 . There was a statistically significant reduction in AHR following SRS (-6.4 per 100 CCM-years, 95% CI=3.87-11.13, p<0.0001) and risk of bleeding (HR: 0.17 (95% CI= 0.09-0.34), p13Gy were more likely to bleed after SRS (HR: 2.57 (95% CI= (1.03-6.45), p=0.044), a recent observation. This result replicated one previous study which included part of this population with hemorrhagic CCMs irrespective of their location 12 . One potential explanation is that high radiation doses induce overexpression of VEGF, leading to neovascularization and subsequent bleeding. 17 The risk factor of new hemorrhages after SRS was reduced for patient older than 35 years old (HR: 0.21, p=0.014). The impact of age on hemorrhage risk is controversial; In a recent meta-analysis, age was not significantly associated with hemorrhage risk. 18 These differences could be linked to the differences in the population included in each study. Increasing age is also associated with less VEGF expression. 19 These observations and the role of VEGF need further investigation. ARE occurred in 5.3% (9) of patients, with only 2.2% of them having associated symptoms. At last follow-up, 10 (5.6%) patients had worse clinical status due to the CCM- or treatment-related complications. In an earlier study, SRS was responsible for a high rate of neurological and ARE complication. 20 Improvement in technique, such as lowering the prescription dose, avoiding targeting the hemosiderin rim and using high-resolution MRI, might be responsible for the lower complication rate describe in our study and recent reports. 21–23 Brainstem CCMs patients should be managed with either active surveillance, SRS or resective surgery. Based on the existing literature, all 3 modalities of treatment are reasonable and should be considered for patients. Active surveillance, although seemingly harmless, carries a high risk of hemorrhage; recent evidence shows a 23% risk of hemorrhage in the natural course of brainstem CCMs 24 . Microsurgical resection, even in experienced hands, carries moderate to severe risk of periprocedural morbidity and mortality, along with a probability of incomplete resection. 25,26 The current guidelines recommended SRS after a second hemorrhage, in case of surgically inaccessible lesion. 27 As repeat hemorrhage is associated with higher risk of neurological deficit compared to a single event, SRS could potentially be offered after a first hemorrhage for inaccessible lesion. 28 Further works to define which patients have higher risk of rebleeding could help to improve outcomes in this pathology. 29 Limitations Even though the multi-centric design can partially mitigate the effect of individual center biases, its retrospective nature makes it subject to selection bias and institutional treatment practices. Patients had their images with various MRI sequences and/or CT scans over a long time. This could have introduced bias in the evaluation of hemorrhage and ARE. However, our scrutiny would have mitigated its effect. The low number of patient limited the analysis of risk factors associated with new hemorrhage after SRS or ARE. Conclusion Single-session SRS appreciably decreases the risk of repeat hemorrhage in patients with hemorrhagic brainstem CCM. Prescription doses ≤13 Gy could reduce SRS-related complications and the risk of repeat hemorrhage. The rate of permanent complication linked to the treated CCM is 5.6% after SRS. Abbreviations AHR: Annual hemorrhage rate, CT: Computed tomography, CCM: Cerebral cavernous malformations, CI: Confidence interval, DVA: Developmental venous anomaly, FND: Focal neurological deficit, HR: Hazard ratio, ICH: Intracerebral hemorrhage, MRI: Magnetic resonance imaging, OR: Odd ratio, SRS: Stereotactic radiosurgery Declarations Conflict of Interest : None Disclosure of Funding : None Acknowledgement : Dr Dumot gratefully acknowledges receipt of a grant for mobility from the “Hospices civils de Lyon”, France, from the “Institut Servier”, France, from the “Societe française of Neurochirurgie (SFNC)”, France, from the “Fondation Planiol”, France and from the “Phillip foundation” Data availability The datasets used and analyzed during the current study available from the corresponding author on reasonable request. References Gross BA, Batjer HH, Awad IA, Bendok BR, Du R. Brainstem cavernous malformations: 1390 surgical cases from the literature. 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J Neurosurg . 2020;134(3):917-928. doi:10.3171/2019.12.JNS192856 Tables Table 1: Demographic characteristics of the 170 included patients Demographics Number (%) Age at diagnosis (years), median (IQR) 37.3 (27.5) Age at SRS (years), median (IQR) 40.8 (28.2) Sex Male 70 (41.2%) Female 100 (58.8%) Genetic mutation identified 1 (0.6%) Initial presentation Incidental* 7 (4.1%) Seizure* 3 (1.8%) Hemorrhage 132 (77.6%) Focal Neurological deficit* 28 (16.5%) Clinical symptoms pre-SRS None 11 (6.5%) Motor deficit 50 (29.4%) Sensory deficit 49 (28.8%) Cerebellar symptom 15 (8.8%) Cranial nerve deficit 85 (50.0%) Seizure 6 (3.5%) Headaches 16 (9.4%) Others † 21 (12.4%) IQR: Interquartile range, SRS: Stereotactic radiosurgery *Not associated with acute or subacute hemorrhage; the patients had a hemorrhage later after diagnosis. †speech disorder, memory loss, unspecified gait trouble, unspecified vertigo. Table 2: Clinical, radiological and treatment characteristics of 181 CCM Clinical and radiological data per CCM Number (%) Previous surgery 13 (7.2%) Location adjacent to ependymal plane 42 (23.2%) Associated developmental venous anomaly 26 (14.4%) Number of pre-SRS hemorrhages 0 26 (14.4%) 1 103 (56.9%) 2 37 (20.4%) 3 12 (6.6%) 4 1 (0.6%) 5 2 (1.1%) Median (IQR) time from diagnosis to SRS, years 0.9 (4.3) Zabramski Classification 1 49 (27.5%) 2 108 (60.7%) 3 18 (10.1%) 4 3 (1.7%) Unknown 3 Dosimetric parameter per CCM, median (IQR) Target volume cm 3 , median (IQR) 0.4 (0.9) Margin dose Gy, median (IQR) 12.0 (2.0) Isocenter, median (IQR) 4.0 (5.0) Isodose line %, median (IQR) 50.0 (10.0) CCM: cerebral cavernous malformation, IQR: Interquartile range, SRS: Stereotactic radiosurgery Table 3: Annual hemorrhage rate per 100 CCM-years for patient with hemorrhagic CCM prior to SRS Annual hemorrhage rate per 100 CCM-years Pre-SRS Post-SRS <2y post-SRS ≥ 2y post-SRS Overall Overall cohort (n=155) From birth 3.4 2.8 1.8 2.3 From diagnosis with 1 st hemorrhage included 42.0 From diagnosis with 1 st hemorrhage excluded* 14.8 Single hemorrhage before SRS (n=103) From birth 2.53 1.6 1.4 1.5 From diagnosis with 1 st hemorrhage included 46.8 From diagnosis with 1 st hemorrhage excluded* 3.6 Multiple hemorrhages before SRS (n=52) From birth 5.6 6.1 2.5 3.8 From diagnosis with 1 st hemorrhage included 38.7 From diagnosis with 1 st hemorrhage excluded* 22.5 *except when the diagnosis was before the first hemorrhage (n=21 cases for overall series and single bleed patients). CCM: Cerebral cavernous malformations, SRS: Stereotactic radiosurgery Table 4: Risk factors associated to hemorrhage Recurrent event analysis using the Prentice Williams and Peterson-Gap time model for risk factors associated with hemorrhage in 155 brainstem CCM. Factor Univariate analysis Multivariate anlysis p HR (95%CI) p HR (95%CI) Gender female 0.18 1.42 (0.86-2.35) 0.38 1.25 (0.76-2.05) Developemental venous anomaly 0.35 1.32 (0.74-2.35) Prior surgery 0.22 1.43 (0.81-2.52) SRS <0.001 0.16 (0.08-0.32) 35 0.002 0.21 (0.08-0.56) Volume >0.3cc 0.36 1.61 (0.58-4.50) Margin >13Gy 0.044 2.57 (1.03-6.45) Hemorrhage before SRS 0 1 hemorrhages before SRS 0.74 0.79 (0.20-3.11) ≥ 2 hemorrhages before SRS 0.35 (0.50-6.98) CI:Confidence interval, HR:Hazard ratio, Sterotactic radiosurgery *No multivariate analysis was performed due to the low number of events Table 5: Outcomes after SRS in 414 CCM Outcomes per 414 CCM Adverse radiation effect 46 (11.1%) New hemorrhage after SRS 41 (9.90%) 1 34 (8.21%) 2 5 (1.2%) 3 2 (0.5%) CCM volume at last FU Decreased 171 (41.5%) Stable 232 (56.3%) Increased 9 (2.2%) Unknown 2 Zabramski post SRS 1 30 (7.9%) 2 271 (71.5%) 3 63 (16.6%) 4 15 (4.0%) Unknown 35 Zabramski evolution before and after SRS Unchanged 288 (76.2) PreSRS=1 to post SRS 2 26 (6.9%) PreSRS=1 to post SRS 3 7 (1.9%) PreSRS=1 to post SRS 4 7 (1.9%) PreSRS=2 to post SRS 1 6 (1.6%) PreSRS=2 to post SRS 3 36 (15.9%) PreSRS=2 to post SRS 4 7 (1.9%) PreSRS=3 to post SRS 2 1 (0.3%) Unknown 36 Outcomes for 381 patients New patient with seizure post SRS 3 (0.8%) Seizure control at last FU Seizure free (Engel I) 46 (57.5%) Rare seizure (Engel II) 11 (13.75%) Significant improvement (Engel III) 8 (10%) No improvement (Engel IV A+B) 12 (15%) Worse (Engel IV C) 3 (3.75%) Discontinuation of seizure medication 14 (17.5%) Symptom evolution among patient Neurologic improvement 119 (32.1%) Neurologic stability 83 (22.4%) Neurological worsening 20 (5.4%) No symptom prior SRS and no new symptom 149 (40.3%) Missing data 10 New neurological deficit after SRS* Transient 40 (10.5%) Permanent 20 (5.2%) Deficit due to ARE 19 (5.0%) Deficit due to a new hemorrhage of treated CCM 22 (5.8%) New neurological deficit from other reason 19 (5.0%) Death (1.6%) *Headaches and seizures were not taken into account for this classification ARE: Adverse radiation effect, CCM: cerebral cavernous malformations, FU: Follow-up, SRS: Stereotactic radiiosurgery Table 6: Logistic regression for the risk factor associated with an adverse radiation effect occurrence (413 CCM). Factor Univariate analysis Multivariate anlysis p OR (95%CI) p OR (95%CI) Gender female 0.52 0.82(0.44-1.51) DVA 0.25 1.63 (0.67-3.57) Age >65 0.42 0.43 (0.02-2.17) Volume >0.7cc <0.001 6.72 (3.20-15.9) 13Gy <0.001 6.39 (3.23-13.6) <0.001 5.17 (2.55-11.2) Location brainstem vs others 0.005 0.32 (0.13-0.67) 0.050 0.43 (0.18-0.96) Multiple hemorrhages pre SRS 0.71 1.15 (0.53-2.29) CI: Confidence Interval, DVA: Developmental venous anomaly, OR: Odd-ratio, SRS: Stereotactic radiosurgery Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 29 Oct, 2024 Read the published version in Scientific Reports → Version 1 posted Editorial decision: Revision requested 09 Aug, 2024 Reviews received at journal 05 Aug, 2024 Reviewers agreed at journal 29 Jul, 2024 Reviews received at journal 13 May, 2024 Reviewers agreed at journal 12 May, 2024 Reviewers agreed at journal 17 Mar, 2024 Reviewers invited by journal 12 Mar, 2024 Editor assigned by journal 12 Mar, 2024 Editor invited by journal 08 Mar, 2024 Submission checks completed at journal 08 Mar, 2024 First submitted to journal 11 Feb, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3949128","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":278298063,"identity":"cc066b03-9089-4ddb-9a37-1169100b06e0","order_by":0,"name":"Sam Dayawansa","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA4ElEQVRIiWNgGAWjYDADfmbmA0BKQoZ4LZLtbQkgLTzEazE4c8YARBPWIt9+Ok3i5446eYYbOZ9f3aix4GFgP3x0A37Dc7dJ9p45bNg4I3ebdc4xoMN40tJu4NXCkLvtBm/bAcZmidxtxjlsQC0SPGZ4tcj3v912829bnX2bRM4z45x/RGhhuJG77TZvG3NiD88Z5se5bURoMbjxdvtv2bbDyTPY28yYc/skeNgI+UW+P3ez4du2Otv9h5kff875VifHz374GH6HIQE2CTBJrHIQYP5AiupRMApGwSgYOQAA0CtKi0B88FMAAAAASUVORK5CYII=","orcid":"","institution":"University of Virginia","correspondingAuthor":true,"prefix":"","firstName":"Sam","middleName":"","lastName":"Dayawansa","suffix":""},{"id":278298064,"identity":"ef7f42d2-8c1d-4562-a182-99d745b361c3","order_by":1,"name":"Chloe Dumot","email":"","orcid":"","institution":"University of Virginia","correspondingAuthor":false,"prefix":"","firstName":"Chloe","middleName":"","lastName":"Dumot","suffix":""},{"id":278298065,"identity":"7f2c18d4-7b16-4117-82c1-d0cec1a69e62","order_by":2,"name":"Georgios Mantziaris","email":"","orcid":"","institution":"University of Virginia","correspondingAuthor":false,"prefix":"","firstName":"Georgios","middleName":"","lastName":"Mantziaris","suffix":""},{"id":278298066,"identity":"eed4331d-f38d-4b1f-983f-ec8e2147411f","order_by":3,"name":"Zhiyuan Xu","email":"","orcid":"","institution":"University of Virginia","correspondingAuthor":false,"prefix":"","firstName":"Zhiyuan","middleName":"","lastName":"Xu","suffix":""},{"id":278298067,"identity":"ea5064be-f240-4576-aea7-0241ebb9bb9f","order_by":4,"name":"Stylianos Pikis","email":"","orcid":"","institution":"University of Virginia","correspondingAuthor":false,"prefix":"","firstName":"Stylianos","middleName":"","lastName":"Pikis","suffix":""},{"id":278298068,"identity":"53c4f20e-bad0-4e1f-ac1d-92f758fc50a2","order_by":5,"name":"Selcuk Peker","email":"","orcid":"","institution":"Koc University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Selcuk","middleName":"","lastName":"Peker","suffix":""},{"id":278298069,"identity":"45284a10-a6d7-49e4-af2e-2ee0466becdb","order_by":6,"name":"Yavuz Samanci","email":"","orcid":"","institution":"Koc University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Yavuz","middleName":"","lastName":"Samanci","suffix":""},{"id":278298070,"identity":"00d2be5f-9769-449b-9713-222cfb00f5d8","order_by":7,"name":"Gokce D Ardor","email":"","orcid":"","institution":"Koc University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Gokce","middleName":"D","lastName":"Ardor","suffix":""},{"id":278298072,"identity":"34f3c5ab-112d-47d3-9efc-35b0bcb32c88","order_by":8,"name":"Ahmed M. 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Bowden","email":"","orcid":"","institution":"University of Alberta","correspondingAuthor":false,"prefix":"","firstName":"Greg","middleName":"N.","lastName":"Bowden","suffix":""},{"id":278298106,"identity":"e30ab245-86ee-4d2e-9ca5-f43ad99a1435","order_by":34,"name":"Samir Patel","email":"","orcid":"","institution":"University of Alberta","correspondingAuthor":false,"prefix":"","firstName":"Samir","middleName":"","lastName":"Patel","suffix":""},{"id":278298107,"identity":"c2db8de5-fe24-4c9f-86b9-0f69d107c018","order_by":35,"name":"jason sheehan","email":"","orcid":"","institution":"University of Virginia","correspondingAuthor":false,"prefix":"","firstName":"jason","middleName":"","lastName":"sheehan","suffix":""}],"badges":[],"createdAt":"2024-02-11 18:37:37","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3949128/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3949128/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41598-024-77140-z","type":"published","date":"2024-10-29T16:20:21+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":52541687,"identity":"1103aeef-804d-4e38-9100-a1811c9123ed","added_by":"auto","created_at":"2024-03-12 17:33:53","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":145045,"visible":true,"origin":"","legend":"\u003cp\u003eProbability of new hemorrhage after SRS\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3949128/v1/90714b3d15e3668c96a246a5.jpg"},{"id":68207090,"identity":"23ba741a-274a-4b2f-a2b6-8ad67e18e47a","added_by":"auto","created_at":"2024-11-04 16:34:53","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1066270,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3949128/v1/c2c379d5-af52-449c-9388-4f94f621bc1b.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Stereotactic radiosurgery (SRS) for patients with brainstem cerebral cavernous malformations (CCMs): An International, Multicentric Study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eBrainstem cerebral cavernous malformations (CCMs) represent 18% of CCM’s.\u003csup\u003e1\u003c/sup\u003e Unlike superficial lesion, brainstem CCMs are more prone to hemorrhage and are thought to be more aggressive in their natural history course.\u003csup\u003e2\u003c/sup\u003e The risk of repeat hemorrhage is estimated to be as high as 30.8% at 5 years for patients with brainstem CCMs presenting with intracerebral hemorrhage or focal neurological deficit compared to 18.4% in other location.\u003csup\u003e3\u003c/sup\u003e Microsurgical resection is the preferred option to treat symptomatic or hemorrhagic CCM. However, the risk of surgery in this location is high with a mortality rate of 1.5% and a long-term morbidity of 16%,\u003csup\u003e1\u003c/sup\u003e while in other cases some lesions are not amenable to surgery.\u003csup\u003e4\u003c/sup\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eStereotactic radiosurgery (SRS) can be an alternative treatment option for brainstem CCM patients.\u0026nbsp;\u003csup\u003e5–7\u003c/sup\u003e\u0026nbsp; However, SRS’s role for such patients remains inadequately defined due to the lack of radiological endpoints and uncertainty about the extent to which CCM hemorrhage is reduced.Our intention with this retrospective, multicentric study is to better define the benefits and risks of treating brainstem CCM patients using Gamma Knife radiosurgery, and better define the role of SRS in the management of brainstem CCM patients.\u003csup\u003e8\u003c/sup\u003e\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003eStudy population and participant inclusion/exclusion criteria\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study follows the guidelines set forth by the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE).\u003csup\u003e9\u0026nbsp;\u003c/sup\u003e\u003cstrong\u003eAll methods were carried out in accordance with relevant guidelines, regulations\u0026nbsp;and experimental protocols were approved university of Virginia licensing committee. Also, when necessary, the informed consent was obtained from all subjects and/or their legal guardian(s).\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEleven hospital from 9 countries participated through the International Radiosurgery Research Foundation (IRRF). Each center obtained individual IRB approval for sharing de-identified data. Internal consistency from each cohort was checked and any missing data or discrepancies were resolved by request to the centers. The centers contributed data on patients treated with SRS between 1995 and 2021. This is a focused analysis of patients with brainstem CCMs treated with single-session SRS. Patients lacking follow-up after SRS were excluded. Patients with prior resection had residual cavernous malformations that were treated with SRS.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSRS technique\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe Leksell Gamma-Knife (Elekta AB) available at each participating with the Leksell G head frame (Elekta AB) center were used to deliver the prescribed radiation dose in a single fraction. Stereotactic, high-resolution brain magnetic resonance imaging (MRI) and/or computed tomography (CT) scanning were used for planning.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy endpoints and follow-up\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe difference between symptomatic intracerebral hemorrhage (ICH) rates prior to and after SRS was the primary endpoint; the occurrence and evolution of neurological deficit, and the development of adverse radiation effects (ARE) were secondary outcomes. Hemorrhage was defined by new/worsening neurological symptoms and evidence of new bleeding on MRI or CT.\u003csup\u003e8\u003c/sup\u003e Nonhemorrhagic focal neurological deficit (FND) was defined as a new or worsening focal neurological deficit attributable to the anatomic location of the lesion in the absence of radiological hemorrhage.\u003csup\u003e8,10\u003c/sup\u003e Neurological symptoms at last follow-up were classified as improved, stable, or worsened. A worsening clinical condition was defined as the occurrence of new, permanent symptoms and/or worsening of at least one neurological symptom. Neither epilepsy nor headache were taken into account to define neurological status. ARE were defined as new or worsening perilesional T2 hyperintensity post-SRS or cyst development.\u003c/p\u003e\n\u003cp\u003eFollow-up was performed according to local protocols, usually every 6 months after SRS for 2 years and annually thereafter. The Zabramski stage was defined per CCM before SRS and at last imaging follow-up.\u003csup\u003e11\u003c/sup\u003e In the case of neurological deterioration, the patients underwent radiographic studies at the time of the diagnosis of new neurological symptoms to evaluate for associated imaging changes. Volumetric changes were categorized based on pre-specified cutoff points: increase with enlargement by more than 20%, decrease with volumetric reduction exceeding 20% of baseline volume, and stable otherwise.\u003csup\u003e12\u003c/sup\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe statistical analysis was performed using R language in R Studio.\u003csup\u003e13,14\u003c/sup\u003e No data were imputed. A p-value \u0026lt;0.05 was considered statistically significant. The analyses were performed per patient or per cavernoma depending on the parameter.\u003c/p\u003e\n\u003cp\u003eContinuous variables were descriptively summarized using medians with interquartile ranges (IQR), and categorical factors were reported using percentages. Normality of continuous variables was assessed graphically and with the use of the Shapiro-Wilk test.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe reasoning and methodology behind the calculation of annual hemorrhage rates (AHR) and the statistical models chosen for the identification of risk factors for outcome measures has been previously described.\u003csup\u003e12\u003c/sup\u003e\u0026nbsp; In brief, three pre-SRS AHR were calculated (from birth to SRS with all hemorrhages, from diagnosis to SRS with all hemorrhages, from diagnosis to SRS with first hemorrhage excluded if it led to diagnosis).The post-SRS AHR was calculated by dividing the cumulative number of hemorrhages by the cumulative number of contributed years of follow-up by each lesion. Each lesion contributed risk time from the date of SRS to the date of last follow-up, death or new procedure for CCM. To assess the treatment effect, we compared the pre-SRS AHR with the overall and first 2-year post-SRS AHR using the methodology described by Sahai et al.\u003csup\u003e15\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eUnivariate and multivariate recurrent event analysis for overall hemorrhage was performed with the Prentice, William and Peterson Gap-Time model (PWP-GT), using the third method for AHR calculation.\u003csup\u003e6\u003c/sup\u003e Statistically significant factors and clinically relevant ones with a p-value less than 0.20 were included in the multivariate analysis. A Cox regression model was performed to identify risk factors associated with post-SRS hemorrhage\u003csup\u003e16\u003c/sup\u003e, and Kaplan-Meier curves for first hemorrhage after SRS were plotted. Logistic regression was performed to evaluate risk factors of ARE. Optimal cut-off points for continuous variable were calculated with the Youden index.\u0026nbsp;\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eDemographics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study included 170 patients [female: 100 (58.8%)] with a median age of 37.3 (IQR: 27.5) years at diagnosis. One patient (0.6%) was diagnosed with a CCM2 mutation. The initial presentation was hemorrhage in 132 patients (77.6%), FND in 28 (16.5%), and seizure in 3 (1.8%). Seven patients (4.1%) were asymptomatic at the time of diagnosis. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePrior to SRS, 85 (50.0%) patients had a cranial nerve deficit, 50 (29.4%) a motor deficit, and 49 (28.8%) a sensory deficit. \u003cstrong\u003eTable 1\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAmong the 170 patients, three were treated for two brainstem CCM, one patient for three CCM, and one patient for 5 CCM. Overall, 181 CCM were treated by SRS. The median time from diagnosis to SRS was 0.9 years (IQR: 4.3). Prior surgical resection occurred in 13 (7.2%) of CCM with a median delay from surgical resection to SRS of 3.2 years (IQR:5.6). A DVA was associated in 26 (14.4%) of the CCM and the CCM was adjacent to an ependymal surface in 42 (23.2%) cases.\u0026nbsp;\u003cstrong\u003eTable 2\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe CCM were treated with a median margin dose of 12.0Gy (IQR:2.0) at a 50% (IQR:10) isodose line for a median volume of 0.4 cm3 (IQR:0.9).\u0026nbsp;\u003cstrong\u003eTable 2\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePrior to SRS, 26 (14.4%) CCM never experiences a defined acute and/or subacute hemorrhage, 103 (56.9%) CCM bled one time, 37 (20.4%) CCM bled two times, 12 (6.6%) CCM bled three times, 1 (0.6%) four times, and 2 (1.1%) five times.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHemorrhage analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAmong CCMs with hemorrhage prior to SRS (n=155), the pre-SRS AHR varied based on the methodology used; 3.6 per 100 CCM-years (follow-up from birth: 6309.9 years; 227 hemorrhages), 42.0 per 100 CCM-years (follow-up from diagnosis: 540.5 years; 227 hemorrhages), and 14.8 per 100 CCM-years (follow-up from diagnosis: 540.5 years; 80 hemorrhages after the exclusion of hemorrhages leading to CCM diagnosis).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe overall post-SRS AHR was 2.3 per 100 CCM-years (follow-up post SRS: 736.8 years; 17 hemorrhages) and specificallyin the first 2 years 2.8 per 100 CCM-years (follow-up post SRS: 288.3years; 9 hemorrhages) and after the two first years 1.8 per 100 CCM-years (follow-up post SRS: 449.1 years; 8 hemorrhages). There was a statistically significant reduction in hemorrhage rate post-SRS (-6.4 per 100 CCM-years, 95% CI:3.87-11.13, p\u0026lt;0.0001). Using recurrent analysis, SRS was associated with a reduction of hemorrhage risk (HR= 0.17, 95% CI= 0.09-0.34, p\u0026lt;0.001) in multivariate analysis.\u003cstrong\u003e\u0026nbsp;Table 3\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAfter SRS, among all the CCM (n=181), new hemorrhages occurred in 19 CCM (10.5%) with \u0026nbsp;18 (9.9%) CCMs having bled one time and one (0.6%) CCM twice. Three CCM (3/26, 11.5%) without hemorrhage prior SRS, bled after SRS. The median delay from SRS to the first bleeding post-SRS was 3.2 (IQR:6.1) years. In one case, the DVA associated with the CCM was occluded and was considered the reason for the bleeding.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eUsing univariate Cox-analysis, the probability of a new hemorrhages after SRS was reduced for patient older than 35 years old (HR= 0.21, 95% CI= 0.08-0.56, p=0.002) and increased with margin doses \u0026gt;13Gy (HR= 2.57, 95% CI=1.03-6.45, p=0.044. The number of hemorrhages prior to SRS was not associated with a risk modification of new bleeding after SRS. \u003cstrong\u003eTable 4\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe probability of new hemorrhage after SRS was 4% (95% CI= 0.8-7.2), 11.2% (95% CI= 4.6-17.3) and 20.8% (95% CI= 7.7-32.0) at 2, 5, and 10 years, respectively. \u003cstrong\u003eFigure 1\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eImaging outcomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe median follow-up imaging was 3.4 years (IQR=5.1) after SRS. At last follow-up, the CCM volume was decreased in 77/179 (43.0%), stable in 99/179 (55.3%) and increased in 3/179 (1.7%).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe pre-SRS Zabramski score was 1 in 49/178 (27.5%), 2 in 108/178 (60.7%), 3 in 18/178 (10.1%) and 4 in 3/ 178 (1.7%). After SRS, the Zabramski score was unchanged in 100/146 (68.5%) CCM. \u003cstrong\u003eTable 5\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAdverse Radiation effects\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAREs occurred in 9 CCM and 9 patients (5.3%). \u0026nbsp;ARE was symptomatic in four cases (2.2%). One (0.6%) patient developed a cyst that required stereotactic aspiration and thalamotomy for the associated tremor. \u0026nbsp; T2 hyperintensities occurred in 8 (4.7%) patients. \u0026nbsp;They were managed conservatively in 6 and with a transient course of corticosteroids in two. No factors were associated with the occurrence of ARE using logistic analysis. \u003cstrong\u003eTable 6\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical outcomes per patient\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNew neurological deficits occurred in 27 (15.9%) patients, with 12 (7.1%) being permanent. The cause was new post-SRS hemorrhage in 11 (6.5%) (8 (4.4%) transient deficit and 3 (1.7%) permanent deficit), ARE in 2 (1.2%) (one (0.6%) transient and one (0.6%) permanent deficit). Two (2.1%) patients (with transient deficit) presented with ARE and a new hemorrhage. In three (1.8%) patients (with permanent deficit), the symptoms were linked to the CCM despite the lack of evidence of hemorrhage or ARE on imaging. Four (2.4%) patients developed new neurologic symptom unrelated to the CCM (one (0.6%) permanent and three (1.8%) transient); two (2.1%) patients (with permanent deficit) had hemorrhage from other CCMs. In three (1.8%) patients (with 2 (1.2%) permanent deficit and one (0.6%) transient), the reason for the new deficit is unknown; one (0.6%) patient had a worsening of his clinical presentation (dysesthesia and hypoesthesia in one hand) without clear radiologic explanation.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOverall, with all events considered, 69 patients (42.3%) demonstrated improvement, 81 (49.7%) exhibited stability, and 13 (8.0%) had a worsening of their clinical neurological status at a median follow-up of 3.4 years (IQR: 5.4). Among the 13 patient with worsening of their clinical neurological status, 10 (5.6%) were potentially associated with the treated CCM (new hemorrhage, ARE, unknown). The data of previous symptom evolution were missing for 7 patients. No patient died during the follow-up period.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAdditional treatment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTwo patients had repeat SRS, and three had an open neurosurgical procedure with a median delay of 7.5 years (IQR=4.8) from initial SRS.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eOne-hundred and seventy patients with 181 CCM were included in this study. The majority had experienced at least one hemorrhagic event (85.6% of the CCM) prior to treatment. Patients with brainstem CCMS are more likely to present with hemorrhage relative to superficial lesions, as observed in previous report\u003csup\u003e2\u003c/sup\u003e. There was a statistically significant reduction in AHR following SRS (-6.4 per 100 CCM-years, 95% CI=3.87-11.13, p\u0026lt;0.0001) and risk of bleeding (HR: 0.17 (95% CI= 0.09-0.34), p\u0026lt;0.001) when using recurrent event analysis. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn univariate Cox analysis, patients treated with a margin dose \u0026gt;13Gy were more likely to bleed after SRS (HR: 2.57 (95% CI=\u0026nbsp;(1.03-6.45), p=0.044), a recent observation. This result replicated one previous study which included part of this population with hemorrhagic CCMs irrespective of their location\u003csup\u003e12\u003c/sup\u003e. One potential explanation is that high radiation doses induce overexpression of VEGF, leading to neovascularization and subsequent bleeding.\u003csup\u003e17\u003c/sup\u003e The risk factor of new hemorrhages after SRS was reduced for patient older than 35 years old (HR: 0.21, p=0.014). \u0026nbsp;The impact of age on hemorrhage risk is controversial; In a recent meta-analysis, age was not significantly associated with hemorrhage risk.\u003csup\u003e18\u003c/sup\u003e These differences could be linked to the differences in the population included in each study. Increasing age is also associated with less VEGF expression.\u003csup\u003e19\u003c/sup\u003e These observations and the role of VEGF need further investigation.\u003c/p\u003e\n\u003cp\u003eARE occurred in 5.3% (9) of patients, with only 2.2% of them having associated symptoms. At last follow-up,\u0026nbsp;10 (5.6%) patients had worse clinical status due to the CCM- or treatment-related complications. In an earlier study, SRS was responsible for a high rate of neurological and ARE complication.\u003csup\u003e20\u003c/sup\u003e Improvement in technique, such as lowering the prescription dose, avoiding targeting the hemosiderin rim and using high-resolution MRI, might be responsible for the lower complication rate describe in our study and recent reports.\u003csup\u003e21–23\u003c/sup\u003e \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eBrainstem CCMs patients should be managed with either active surveillance, SRS or resective surgery. Based on the existing literature, all 3 modalities of treatment are reasonable and should be considered for patients. Active surveillance, although seemingly harmless, carries a high risk of hemorrhage; recent evidence shows a 23% \u0026nbsp;risk of hemorrhage in the natural course of brainstem CCMs\u003csup\u003e24\u003c/sup\u003e. \u0026nbsp; Microsurgical resection, even in experienced hands, carries moderate to severe risk of periprocedural morbidity and mortality, along with a probability of incomplete resection.\u003csup\u003e25,26\u003c/sup\u003eThe current guidelines recommended SRS after a second hemorrhage, in case of surgically inaccessible lesion.\u003csup\u003e27\u003c/sup\u003e As repeat hemorrhage is associated with higher risk of neurological deficit compared to a single event, SRS could potentially be offered after a first hemorrhage for inaccessible lesion.\u003csup\u003e28\u003c/sup\u003e Further works to define which patients have higher risk of rebleeding could help to improve outcomes in this pathology.\u003csup\u003e29\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLimitations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEven though the multi-centric design can partially mitigate the effect of individual center biases, its retrospective nature makes it subject to selection bias and institutional treatment practices. Patients had their images with various MRI sequences and/or CT scans over a long time. This could have introduced bias in the evaluation of hemorrhage and ARE. However, our scrutiny would have mitigated its effect. The low number of patient limited the analysis of risk factors associated with new hemorrhage after SRS or ARE.\u0026nbsp;\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eSingle-session SRS appreciably decreases the risk of repeat hemorrhage in patients with hemorrhagic brainstem CCM. Prescription doses \u0026le;13 Gy could reduce SRS-related complications and the risk of repeat hemorrhage. The rate of permanent complication linked to the treated CCM is 5.6% after SRS.\u0026nbsp;\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eAHR: Annual hemorrhage rate, CT: Computed tomography, CCM: Cerebral cavernous malformations, CI: Confidence interval, DVA: Developmental venous anomaly, FND: Focal neurological deficit, HR: Hazard ratio, ICH: Intracerebral hemorrhage, MRI: Magnetic resonance imaging, OR: Odd ratio, SRS: Stereotactic radiosurgery\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eConflict of Interest : None\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDisclosure of Funding : None\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgement :\u0026nbsp;\u003c/strong\u003eDr Dumot gratefully acknowledges receipt of a grant for mobility from the \u0026ldquo;Hospices civils de Lyon\u0026rdquo;, France, from the \u0026ldquo;Institut Servier\u0026rdquo;, France, from the \u0026ldquo;Societe fran\u0026ccedil;aise of Neurochirurgie (SFNC)\u0026rdquo;, France, from the \u0026ldquo;Fondation Planiol\u0026rdquo;, France and from the \u0026ldquo;Phillip foundation\u0026rdquo;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and analyzed during the current study available from the corresponding author on reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eGross BA, Batjer HH, Awad IA, Bendok BR, Du R. 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Published online September 9, 2022:1-10. doi:10.3171/2022.7.JNS22314\u003c/li\u003e\n\u003cli\u003eWalcott BP, Choudhri O, Lawton MT. Brainstem cavernous malformations: Natural history versus surgical management. \u003cem\u003eJ Clin Neurosci\u003c/em\u003e. 2016;32:164-165. doi:10.1016/j.jocn.2016.03.021\u003c/li\u003e\n\u003cli\u003eNiranjan A, Lunsford LD. Stereotactic radiosurgery guidelines for the management of patients with intracranial cavernous malformations. \u003cem\u003eProg Neurol Surg\u003c/em\u003e. 2013;27:166-175. doi:10.1159/000341792\u003c/li\u003e\n\u003cli\u003eLi D, Zheng JJ, Weng JC, et al. Neurological outcomes of untreated brainstem cavernous malformations in a prospective observational cohort and literature review. \u003cem\u003eStroke Vasc Neurol\u003c/em\u003e. 2021;6(4):501-510. doi:10.1136/svn-2020-000608\u003c/li\u003e\n\u003cli\u003eLi D, Wu ZY, Liu PP, et al. Natural history of brainstem cavernous malformations: prospective hemorrhage rate and adverse factors in a consecutive prospective cohort. \u003cem\u003eJ Neurosurg\u003c/em\u003e. 2020;134(3):917-928. doi:10.3171/2019.12.JNS192856\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1:\u003c/strong\u003e Demographic characteristics of the 170 included patients\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"576\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"70.48611111111111%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eDemographics\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.51388888888889%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eNumber (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"70.48611111111111%\" valign=\"top\"\u003e\n \u003cp\u003eAge at diagnosis (years), median (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.51388888888889%\" valign=\"top\"\u003e\n \u003cp\u003e37.3 (27.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"70.48611111111111%\" valign=\"top\"\u003e\n \u003cp\u003eAge at SRS (years), median (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.51388888888889%\" valign=\"top\"\u003e\n \u003cp\u003e40.8 (28.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"70.48611111111111%\" valign=\"top\"\u003e\n \u003cp\u003eSex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.51388888888889%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"70.48611111111111%\" valign=\"top\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.51388888888889%\" valign=\"top\"\u003e\n \u003cp\u003e70 (41.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"70.48611111111111%\" valign=\"top\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.51388888888889%\" valign=\"top\"\u003e\n \u003cp\u003e100 (58.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"70.48611111111111%\" valign=\"top\"\u003e\n \u003cp\u003eGenetic mutation identified\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.51388888888889%\" valign=\"top\"\u003e\n \u003cp\u003e1 (0.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"70.48611111111111%\" valign=\"top\"\u003e\n \u003cp\u003eInitial presentation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.51388888888889%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"70.48611111111111%\" valign=\"top\"\u003e\n \u003cp\u003eIncidental*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.51388888888889%\" valign=\"top\"\u003e\n \u003cp\u003e7 (4.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"70.48611111111111%\" valign=\"top\"\u003e\n \u003cp\u003eSeizure*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.51388888888889%\" valign=\"top\"\u003e\n \u003cp\u003e3 (1.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"70.48611111111111%\" valign=\"top\"\u003e\n \u003cp\u003eHemorrhage\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.51388888888889%\" valign=\"top\"\u003e\n \u003cp\u003e132 (77.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"70.48611111111111%\" valign=\"top\"\u003e\n \u003cp\u003eFocal Neurological deficit*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.51388888888889%\" valign=\"top\"\u003e\n \u003cp\u003e28 (16.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"70.48611111111111%\" valign=\"top\"\u003e\n \u003cp\u003eClinical symptoms pre-SRS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.51388888888889%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"70.48611111111111%\" valign=\"top\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.51388888888889%\" valign=\"top\"\u003e\n \u003cp\u003e11 (6.5%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"70.48611111111111%\" valign=\"top\"\u003e\n \u003cp\u003eMotor deficit\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.51388888888889%\" valign=\"top\"\u003e\n \u003cp\u003e50 (29.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"70.48611111111111%\" valign=\"top\"\u003e\n \u003cp\u003eSensory deficit\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.51388888888889%\" valign=\"top\"\u003e\n \u003cp\u003e49 (28.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"70.48611111111111%\" valign=\"top\"\u003e\n \u003cp\u003eCerebellar symptom\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.51388888888889%\" valign=\"top\"\u003e\n \u003cp\u003e15 (8.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"70.48611111111111%\" valign=\"top\"\u003e\n \u003cp\u003eCranial nerve deficit\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.51388888888889%\" valign=\"top\"\u003e\n \u003cp\u003e85 (50.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"70.48611111111111%\" valign=\"top\"\u003e\n \u003cp\u003eSeizure\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.51388888888889%\" valign=\"top\"\u003e\n \u003cp\u003e6 (3.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"70.48611111111111%\" valign=\"top\"\u003e\n \u003cp\u003eHeadaches\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.51388888888889%\" valign=\"top\"\u003e\n \u003cp\u003e16 (9.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"70.48611111111111%\" valign=\"top\"\u003e\n \u003cp\u003eOthers\u0026nbsp;\u0026dagger;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.51388888888889%\" valign=\"top\"\u003e\n \u003cp\u003e21 (12.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eIQR: Interquartile range, SRS: Stereotactic radiosurgery\u003c/p\u003e\n\u003cp\u003e*Not associated with acute or subacute hemorrhage; the patients had a hemorrhage later after diagnosis. \u0026dagger;speech disorder, memory loss, unspecified gait trouble, unspecified vertigo.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2:\u003c/strong\u003e Clinical, radiological and treatment characteristics of 181 CCM\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"624\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"59.13461538461539%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eClinical and radiological data per CCM\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"40.86538461538461%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eNumber (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"59.13461538461539%\" valign=\"top\"\u003e\n \u003cp\u003ePrevious surgery\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"40.86538461538461%\" valign=\"top\"\u003e\n \u003cp\u003e13 (7.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"59.13461538461539%\" valign=\"top\"\u003e\n \u003cp\u003eLocation adjacent to ependymal plane\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"40.86538461538461%\" valign=\"top\"\u003e\n \u003cp\u003e42 (23.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"59.13461538461539%\" valign=\"top\"\u003e\n \u003cp\u003eAssociated developmental venous anomaly\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"40.86538461538461%\" valign=\"top\"\u003e\n \u003cp\u003e26 (14.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"59.13461538461539%\" valign=\"top\"\u003e\n \u003cp\u003eNumber of pre-SRS hemorrhages\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"40.86538461538461%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"59.13461538461539%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"40.86538461538461%\" valign=\"top\"\u003e\n \u003cp\u003e26 (14.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"59.13461538461539%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"40.86538461538461%\" valign=\"top\"\u003e\n \u003cp\u003e103 (56.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"59.13461538461539%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"40.86538461538461%\" valign=\"top\"\u003e\n \u003cp\u003e37 (20.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"59.13461538461539%\" valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"40.86538461538461%\" valign=\"top\"\u003e\n \u003cp\u003e12 (6.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"59.13461538461539%\" valign=\"top\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"40.86538461538461%\" valign=\"top\"\u003e\n \u003cp\u003e1 (0.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"59.13461538461539%\" valign=\"top\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"40.86538461538461%\" valign=\"top\"\u003e\n \u003cp\u003e2 (1.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"59.13461538461539%\" valign=\"top\"\u003e\n \u003cp\u003eMedian (IQR) time from diagnosis to SRS, years\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"40.86538461538461%\" valign=\"top\"\u003e\n \u003cp\u003e0.9 (4.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"59.13461538461539%\" valign=\"top\"\u003e\n \u003cp\u003eZabramski Classification\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"40.86538461538461%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"59.13461538461539%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"40.86538461538461%\" valign=\"top\"\u003e\n \u003cp\u003e49 (27.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"59.13461538461539%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"40.86538461538461%\" valign=\"top\"\u003e\n \u003cp\u003e108 (60.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"59.13461538461539%\" valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"40.86538461538461%\" valign=\"top\"\u003e\n \u003cp\u003e18 (10.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"59.13461538461539%\" valign=\"top\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"40.86538461538461%\" valign=\"top\"\u003e\n \u003cp\u003e3 (1.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"59.13461538461539%\" valign=\"top\"\u003e\n \u003cp\u003eUnknown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"40.86538461538461%\" valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eDosimetric parameter per CCM, median (IQR)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"59.13461538461539%\" valign=\"top\"\u003e\n \u003cp\u003eTarget volume cm\u003csup\u003e3\u003c/sup\u003e, median (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"40.86538461538461%\" valign=\"top\"\u003e\n \u003cp\u003e0.4 (0.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"59.13461538461539%\" valign=\"top\"\u003e\n \u003cp\u003eMargin dose Gy, median (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"40.86538461538461%\" valign=\"top\"\u003e\n \u003cp\u003e12.0 (2.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"59.13461538461539%\" valign=\"top\"\u003e\n \u003cp\u003eIsocenter, median (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"40.86538461538461%\" valign=\"top\"\u003e\n \u003cp\u003e4.0 (5.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"59.13461538461539%\" valign=\"top\"\u003e\n \u003cp\u003eIsodose line %, median (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"40.86538461538461%\" valign=\"top\"\u003e\n \u003cp\u003e50.0 (10.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eCCM: cerebral cavernous malformation, IQR: Interquartile range, SRS: Stereotactic radiosurgery\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3:\u003c/strong\u003e Annual hemorrhage rate per 100 CCM-years for patient with hemorrhagic CCM prior to SRS\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"671\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.56716417910448%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"63.43283582089552%\" colspan=\"4\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAnnual hemorrhage rate per 100 CCM-years\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.56716417910448%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.865671641791046%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ePre-SRS\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"46.56716417910448%\" colspan=\"3\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ePost-SRS\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;2y\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003epost-SRS\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026ge; 2y\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003epost-SRS\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eOverall\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"5\" valign=\"top\"\u003e\n \u003cp\u003eOverall cohort (n=155)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.56716417910448%\" valign=\"top\"\u003e\n \u003cp\u003eFrom birth\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.865671641791046%\"\u003e\n \u003cp\u003e3.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.522388059701493%\" rowspan=\"3\"\u003e\n \u003cp\u003e2.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.522388059701493%\" rowspan=\"3\"\u003e\n \u003cp\u003e1.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.522388059701493%\" rowspan=\"3\"\u003e\n \u003cp\u003e2.3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"68.43575418994413%\" valign=\"top\"\u003e\n \u003cp\u003eFrom diagnosis with 1\u003csup\u003est\u003c/sup\u003e hemorrhage included\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"31.564245810055866%\"\u003e\n \u003cp\u003e42.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"68.43575418994413%\" valign=\"top\"\u003e\n \u003cp\u003eFrom diagnosis with 1\u003csup\u003est\u003c/sup\u003e hemorrhage excluded*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"31.564245810055866%\"\u003e\n \u003cp\u003e14.8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"5\" valign=\"top\"\u003e\n \u003cp\u003eSingle hemorrhage before SRS (n=103)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.56716417910448%\" valign=\"top\"\u003e\n \u003cp\u003eFrom birth\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.865671641791046%\"\u003e\n \u003cp\u003e2.53\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.522388059701493%\" rowspan=\"3\"\u003e\n \u003cp\u003e1.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.522388059701493%\" rowspan=\"3\"\u003e\n \u003cp\u003e1.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.522388059701493%\" rowspan=\"3\"\u003e\n \u003cp\u003e1.5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"68.43575418994413%\" valign=\"top\"\u003e\n \u003cp\u003eFrom diagnosis with 1\u003csup\u003est\u003c/sup\u003e hemorrhage included\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"31.564245810055866%\"\u003e\n \u003cp\u003e46.8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"68.43575418994413%\" valign=\"top\"\u003e\n \u003cp\u003eFrom diagnosis with 1\u003csup\u003est\u003c/sup\u003e hemorrhage excluded*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"31.564245810055866%\"\u003e\n \u003cp\u003e3.6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"5\" valign=\"top\"\u003e\n \u003cp\u003eMultiple hemorrhages before SRS (n=52)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.56716417910448%\" valign=\"top\"\u003e\n \u003cp\u003eFrom birth\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.865671641791046%\"\u003e\n \u003cp\u003e5.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.522388059701493%\" rowspan=\"3\"\u003e\n \u003cp\u003e6.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.522388059701493%\" rowspan=\"3\"\u003e\n \u003cp\u003e2.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.522388059701493%\" rowspan=\"3\"\u003e\n \u003cp\u003e3.8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"68.43575418994413%\" valign=\"top\"\u003e\n \u003cp\u003eFrom diagnosis with 1\u003csup\u003est\u003c/sup\u003e hemorrhage included\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"31.564245810055866%\"\u003e\n \u003cp\u003e38.7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"68.43575418994413%\" valign=\"top\"\u003e\n \u003cp\u003eFrom diagnosis with 1\u003csup\u003est\u003c/sup\u003e hemorrhage excluded*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"31.564245810055866%\"\u003e\n \u003cp\u003e22.5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e*except when the diagnosis was before the first hemorrhage (n=21 cases for overall series and single bleed patients).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCCM: Cerebral cavernous malformations, SRS: Stereotactic radiosurgery\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable\u0026nbsp;4:\u003c/strong\u003e Risk factors associated to hemorrhage\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"681\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"5\" valign=\"top\"\u003e\n \u003cp\u003eRecurrent event analysis using the Prentice Williams and Peterson-Gap time model for risk factors associated with hemorrhage in 155 brainstem CCM.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"37.5366568914956%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eFactor\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.032258064516128%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eUnivariate analysis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.43108504398827%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eMultivariate anlysis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.647058823529413%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ep\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.705882352941178%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eHR (95%CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.529411764705884%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ep\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.11764705882353%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eHR (95%CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"37.59177679882526%\" valign=\"top\"\u003e\n \u003cp\u003eGender female\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.013215859030836%\" valign=\"top\"\u003e\n \u003cp\u003e0.18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.91483113069016%\" valign=\"top\"\u003e\n \u003cp\u003e1.42 (0.86-2.35)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.684287812041116%\" valign=\"top\"\u003e\n \u003cp\u003e0.38\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.79588839941263%\" valign=\"top\"\u003e\n \u003cp\u003e1.25 (0.76-2.05)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"37.59177679882526%\" valign=\"top\"\u003e\n \u003cp\u003eDevelopemental venous anomaly\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.013215859030836%\" valign=\"top\"\u003e\n \u003cp\u003e0.35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.91483113069016%\" valign=\"top\"\u003e\n \u003cp\u003e1.32 (0.74-2.35)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.684287812041116%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.79588839941263%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"37.59177679882526%\" valign=\"top\"\u003e\n \u003cp\u003ePrior surgery\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.013215859030836%\" valign=\"top\"\u003e\n \u003cp\u003e0.22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.91483113069016%\" valign=\"top\"\u003e\n \u003cp\u003e1.43 (0.81-2.52)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.684287812041116%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.79588839941263%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"37.59177679882526%\" valign=\"top\"\u003e\n \u003cp\u003eSRS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.013215859030836%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.91483113069016%\" valign=\"top\"\u003e\n \u003cp\u003e0.16 (0.08-0.32)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.684287812041116%\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.79588839941263%\"\u003e\n \u003cp\u003e0.17 (0.09-0.34)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"37.59177679882526%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.013215859030836%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.91483113069016%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.684287812041116%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.79588839941263%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"5\" valign=\"top\"\u003e\n \u003cp\u003eCox analysis for factor associated with new hemorrhage after SRS in 180 CCM*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"37.59177679882526%\" valign=\"top\"\u003e\n \u003cp\u003eGender female\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.013215859030836%\"\u003e\n \u003cp\u003e0.34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.91483113069016%\"\u003e\n \u003cp\u003e1.64 (0.59-4.59)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.684287812041116%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.79588839941263%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"37.59177679882526%\" valign=\"top\"\u003e\n \u003cp\u003eDevelopemental venous anomaly\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.013215859030836%\"\u003e\n \u003cp\u003e0.43\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.91483113069016%\"\u003e\n \u003cp\u003e1.56 (0.51-4.72)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.684287812041116%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.79588839941263%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"37.59177679882526%\" valign=\"top\"\u003e\n \u003cp\u003eAge at SRS \u0026gt;35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.013215859030836%\"\u003e\n \u003cp\u003e0.002\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.91483113069016%\"\u003e\n \u003cp\u003e0.21 (0.08-0.56)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.684287812041116%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.79588839941263%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"37.59177679882526%\" valign=\"top\"\u003e\n \u003cp\u003eVolume \u0026gt;0.3cc\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.013215859030836%\"\u003e\n \u003cp\u003e0.36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.91483113069016%\"\u003e\n \u003cp\u003e1.61 (0.58-4.50)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.684287812041116%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.79588839941263%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"37.59177679882526%\" valign=\"top\"\u003e\n \u003cp\u003eMargin \u0026gt;13Gy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.013215859030836%\"\u003e\n \u003cp\u003e0.044\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.91483113069016%\"\u003e\n \u003cp\u003e2.57 (1.03-6.45)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.684287812041116%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.79588839941263%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"37.59177679882526%\" valign=\"top\"\u003e\n \u003cp\u003eHemorrhage before SRS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.013215859030836%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.91483113069016%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.684287812041116%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.79588839941263%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"37.59177679882526%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.013215859030836%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.91483113069016%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.684287812041116%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.79588839941263%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"37.59177679882526%\" valign=\"top\"\u003e\n \u003cp\u003e1 hemorrhages before SRS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.013215859030836%\"\u003e\n \u003cp\u003e0.74\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.91483113069016%\"\u003e\n \u003cp\u003e0.79 (0.20-3.11)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.684287812041116%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.79588839941263%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"37.59177679882526%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u0026ge;\u0026nbsp;2 hemorrhages before SRS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.013215859030836%\"\u003e\n \u003cp\u003e0.35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.91483113069016%\"\u003e\n \u003col\u003e\n \u003cli\u003e(0.50-6.98)\u003c/li\u003e\n \u003c/ol\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.684287812041116%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.79588839941263%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eCI:Confidence interval, HR:Hazard ratio, Sterotactic radiosurgery\u003c/p\u003e\n\u003cp\u003e*No multivariate analysis was performed due to the low number of events\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 5:\u003c/strong\u003e Outcomes after SRS in 414 CCM\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"652\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eOutcomes per 414 CCM\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"60.88957055214724%\" valign=\"top\"\u003e\n \u003cp\u003eAdverse radiation effect\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"39.11042944785276%\" valign=\"top\"\u003e\n \u003cp\u003e46 (11.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"60.88957055214724%\" valign=\"top\"\u003e\n \u003cp\u003eNew hemorrhage after SRS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"39.11042944785276%\" valign=\"top\"\u003e\n \u003cp\u003e41 (9.90%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"60.88957055214724%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"39.11042944785276%\" valign=\"top\"\u003e\n \u003cp\u003e34 (8.21%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"60.88957055214724%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"39.11042944785276%\" valign=\"top\"\u003e\n \u003cp\u003e5 (1.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"60.88957055214724%\" valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"39.11042944785276%\" valign=\"top\"\u003e\n \u003cp\u003e2 (0.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"60.88957055214724%\" valign=\"top\"\u003e\n \u003cp\u003eCCM volume at last FU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"39.11042944785276%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"60.88957055214724%\" valign=\"top\"\u003e\n \u003cp\u003eDecreased\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"39.11042944785276%\" valign=\"top\"\u003e\n \u003cp\u003e171 (41.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"60.88957055214724%\" valign=\"top\"\u003e\n \u003cp\u003eStable\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"39.11042944785276%\" valign=\"top\"\u003e\n \u003cp\u003e232 (56.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"60.88957055214724%\" valign=\"top\"\u003e\n \u003cp\u003eIncreased\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"39.11042944785276%\" valign=\"top\"\u003e\n \u003cp\u003e9 (2.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"60.88957055214724%\" valign=\"top\"\u003e\n \u003cp\u003eUnknown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"39.11042944785276%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"60.88957055214724%\" valign=\"top\"\u003e\n \u003cp\u003eZabramski post SRS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"39.11042944785276%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"60.88957055214724%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"39.11042944785276%\" valign=\"top\"\u003e\n \u003cp\u003e30 (7.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"60.88957055214724%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"39.11042944785276%\" valign=\"top\"\u003e\n \u003cp\u003e271 (71.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"60.88957055214724%\" valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"39.11042944785276%\" valign=\"top\"\u003e\n \u003cp\u003e63 (16.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"60.88957055214724%\" valign=\"top\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"39.11042944785276%\" valign=\"top\"\u003e\n \u003cp\u003e15 (4.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"60.88957055214724%\" valign=\"top\"\u003e\n \u003cp\u003eUnknown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"39.11042944785276%\" valign=\"top\"\u003e\n \u003cp\u003e35\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"60.88957055214724%\" valign=\"top\"\u003e\n \u003cp\u003eZabramski evolution before and after SRS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"39.11042944785276%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"60.88957055214724%\" valign=\"top\"\u003e\n \u003cp\u003eUnchanged\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"39.11042944785276%\" valign=\"top\"\u003e\n \u003cp\u003e288 (76.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"60.88957055214724%\" valign=\"top\"\u003e\n \u003cp\u003ePreSRS=1 to post SRS 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"39.11042944785276%\" valign=\"top\"\u003e\n \u003cp\u003e26 (6.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"60.88957055214724%\" valign=\"top\"\u003e\n \u003cp\u003ePreSRS=1 to post SRS 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"39.11042944785276%\" valign=\"top\"\u003e\n \u003cp\u003e7 (1.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"60.88957055214724%\" valign=\"top\"\u003e\n \u003cp\u003ePreSRS=1 to post SRS 4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"39.11042944785276%\" valign=\"top\"\u003e\n \u003cp\u003e7 (1.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"60.88957055214724%\" valign=\"top\"\u003e\n \u003cp\u003ePreSRS=2 to post SRS 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"39.11042944785276%\" valign=\"top\"\u003e\n \u003cp\u003e6 (1.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"60.88957055214724%\" valign=\"top\"\u003e\n \u003cp\u003ePreSRS=2 to post SRS 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"39.11042944785276%\" valign=\"top\"\u003e\n \u003cp\u003e36 (15.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"60.88957055214724%\" valign=\"top\"\u003e\n \u003cp\u003ePreSRS=2 to post SRS 4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"39.11042944785276%\" valign=\"top\"\u003e\n \u003cp\u003e7 (1.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"60.88957055214724%\" valign=\"top\"\u003e\n \u003cp\u003ePreSRS=3 to post SRS 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"39.11042944785276%\" valign=\"top\"\u003e\n \u003cp\u003e1 (0.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"60.88957055214724%\" valign=\"top\"\u003e\n \u003cp\u003eUnknown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"39.11042944785276%\" valign=\"top\"\u003e\n \u003cp\u003e36\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eOutcomes for 381 patients\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"60.88957055214724%\" valign=\"top\"\u003e\n \u003cp\u003eNew patient with seizure post SRS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"39.11042944785276%\" valign=\"top\"\u003e\n \u003cp\u003e3 (0.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"60.88957055214724%\" valign=\"top\"\u003e\n \u003cp\u003eSeizure control at last FU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"39.11042944785276%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"60.88957055214724%\" valign=\"top\"\u003e\n \u003cp\u003eSeizure free (Engel I)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"39.11042944785276%\" valign=\"top\"\u003e\n \u003cp\u003e46 (57.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"60.88957055214724%\" valign=\"top\"\u003e\n \u003cp\u003eRare seizure (Engel II)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"39.11042944785276%\" valign=\"top\"\u003e\n \u003cp\u003e11 (13.75%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"60.88957055214724%\" valign=\"top\"\u003e\n \u003cp\u003eSignificant improvement (Engel III)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"39.11042944785276%\" valign=\"top\"\u003e\n \u003cp\u003e8 (10%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"60.88957055214724%\" valign=\"top\"\u003e\n \u003cp\u003eNo improvement (Engel IV A+B)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"39.11042944785276%\" valign=\"top\"\u003e\n \u003cp\u003e12 (15%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"60.88957055214724%\" valign=\"top\"\u003e\n \u003cp\u003eWorse (Engel IV C)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"39.11042944785276%\" valign=\"top\"\u003e\n \u003cp\u003e3 (3.75%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"60.88957055214724%\" valign=\"top\"\u003e\n \u003cp\u003eDiscontinuation of seizure medication\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"39.11042944785276%\" valign=\"top\"\u003e\n \u003cp\u003e14 (17.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"60.88957055214724%\" valign=\"top\"\u003e\n \u003cp\u003eSymptom evolution among patient\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"39.11042944785276%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"60.88957055214724%\" valign=\"top\"\u003e\n \u003cp\u003eNeurologic improvement\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"39.11042944785276%\" valign=\"top\"\u003e\n \u003cp\u003e119 (32.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"60.88957055214724%\" valign=\"top\"\u003e\n \u003cp\u003eNeurologic stability\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"39.11042944785276%\" valign=\"top\"\u003e\n \u003cp\u003e83 (22.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"60.88957055214724%\" valign=\"top\"\u003e\n \u003cp\u003eNeurological worsening\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"39.11042944785276%\" valign=\"top\"\u003e\n \u003cp\u003e20 (5.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"60.88957055214724%\" valign=\"top\"\u003e\n \u003cp\u003eNo symptom prior SRS and no new symptom\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"39.11042944785276%\" valign=\"top\"\u003e\n \u003cp\u003e149 (40.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"60.88957055214724%\" valign=\"top\"\u003e\n \u003cp\u003eMissing data\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"39.11042944785276%\" valign=\"top\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"60.88957055214724%\" valign=\"top\"\u003e\n \u003cp\u003eNew neurological deficit after SRS*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"39.11042944785276%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"60.88957055214724%\" valign=\"top\"\u003e\n \u003cp\u003eTransient\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"39.11042944785276%\" valign=\"top\"\u003e\n \u003cp\u003e40 (10.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"60.88957055214724%\" valign=\"top\"\u003e\n \u003cp\u003ePermanent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"39.11042944785276%\" valign=\"top\"\u003e\n \u003cp\u003e20 (5.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"60.88957055214724%\" valign=\"top\"\u003e\n \u003cp\u003eDeficit due to ARE\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"39.11042944785276%\" valign=\"top\"\u003e\n \u003cp\u003e19 (5.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"60.88957055214724%\" valign=\"top\"\u003e\n \u003cp\u003eDeficit due to a new hemorrhage of treated CCM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"39.11042944785276%\" valign=\"top\"\u003e\n \u003cp\u003e22 (5.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"60.88957055214724%\" valign=\"top\"\u003e\n \u003cp\u003eNew neurological deficit from other reason\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"39.11042944785276%\" valign=\"top\"\u003e\n \u003cp\u003e19 (5.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"60.88957055214724%\" valign=\"top\"\u003e\n \u003cp\u003eDeath\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"39.11042944785276%\" valign=\"top\"\u003e\n \u003cp\u003e(1.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e*Headaches and seizures were not taken into account for this classification\u003c/p\u003e\n\u003cp\u003eARE: Adverse radiation effect, CCM: cerebral cavernous malformations, FU: Follow-up, SRS: Stereotactic radiiosurgery\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 6:\u003c/strong\u003e Logistic regression for the risk factor associated with an adverse radiation effect occurrence (413 CCM).\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"690\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.801161103047896%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eFactor\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"34.25253991291727%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eUnivariate analysis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.94629898403483%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eMultivariate anlysis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.474137931034484%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ep\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.603448275862068%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eOR (95%CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.379310344827587%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ep\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.543103448275865%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eOR (95%CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.7536231884058%\" valign=\"top\"\u003e\n \u003cp\u003eGender female\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.768115942028986%\"\u003e\n \u003cp\u003e0.52\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.579710144927535%\"\u003e\n \u003cp\u003e0.82(0.44-1.51)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.014492753623188%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.884057971014492%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.7536231884058%\" valign=\"top\"\u003e\n \u003cp\u003eDVA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.768115942028986%\"\u003e\n \u003cp\u003e0.25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.579710144927535%\"\u003e\n \u003cp\u003e1.63 (0.67-3.57)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.014492753623188%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.884057971014492%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.7536231884058%\" valign=\"top\"\u003e\n \u003cp\u003eAge \u0026gt;65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.768115942028986%\"\u003e\n \u003cp\u003e0.42\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.579710144927535%\"\u003e\n \u003cp\u003e0.43 (0.02-2.17)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.014492753623188%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.884057971014492%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.7536231884058%\" valign=\"top\"\u003e\n \u003cp\u003eVolume \u0026gt;0.7cc\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.768115942028986%\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.579710144927535%\"\u003e\n \u003cp\u003e6.72 (3.20-15.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.014492753623188%\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.884057971014492%\"\u003e\n \u003cp\u003e5.19 (2.41-12.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.7536231884058%\" valign=\"top\"\u003e\n \u003cp\u003eMargin dose \u0026gt;13Gy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.768115942028986%\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.579710144927535%\"\u003e\n \u003cp\u003e6.39 (3.23-13.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.014492753623188%\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.884057971014492%\"\u003e\n \u003cp\u003e5.17 (2.55-11.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.7536231884058%\" valign=\"top\"\u003e\n \u003cp\u003eLocation brainstem vs others\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.768115942028986%\"\u003e\n \u003cp\u003e0.005\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.579710144927535%\"\u003e\n \u003cp\u003e0.32 (0.13-0.67)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.014492753623188%\"\u003e\n \u003cp\u003e0.050\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.884057971014492%\"\u003e\n \u003cp\u003e0.43 (0.18-0.96)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.7536231884058%\" valign=\"top\"\u003e\n \u003cp\u003eMultiple hemorrhages pre SRS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.768115942028986%\"\u003e\n \u003cp\u003e0.71\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.579710144927535%\"\u003e\n \u003cp\u003e1.15 (0.53-2.29)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.014492753623188%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.884057971014492%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eCI: Confidence Interval, DVA: Developmental venous anomaly, OR: Odd-ratio, SRS: Stereotactic radiosurgery\u0026nbsp;\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"cerebral cavernous malformation, hemorrhagic, Stereotactic radiosurgery, brainstem","lastPublishedDoi":"10.21203/rs.3.rs-3949128/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3949128/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eIntroduction: \u003c/strong\u003eBrainstem cerebral cavernous malformations (CCM) are clinically more aggressive compared to superficial CCMs. Due to their location, resection can be challenging, making stereotactic radiosurgery (SRS) an attractive alternative for symptomatic patient.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethod: \u003c/strong\u003eBrainstem CCM patients (n=170) were treated with Gamma Knife SRS at 11 radiosurgical centers. Hemorrhagic risk reduction, risk factors of post-SRS hemorrhage, and clinical outcomes were retrospectively analyzed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eMost patients had a single (165/170 patients) brainstem CCMs treated; the majority of CCMs (165/181) presented with bleeding. Single-session SRS decreased the risk of repeat hemorrhage in patients with hemorrhagic brainstem CCM (HR: 0.17, p\u0026lt;0.001) using recurrent multivariate analysis. The annual hemorrhage rate decreased from 14.8 per 100 CCM-years before SRS to 2.3 after treatment. Using univariate Cox-analysis, the probability of a new hemorrhages after SRS was reduced for patient older than 35 years (HR= 0.21, p=0.002) and increased with a margin dose \u0026gt;13Gy (HR= 2.57, p=0.044). Adverse radiation effect (ARE) occurred in 9 patients (5.3%) and was symptomatic in four (2.4%). At a median follow-up of 3.4 years (Inter-quartile range: 5.4), 13 patients (8.0%) had a worsened clinical status, with the treated CCM being the cause in 5.6% (10) of the patients.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion: \u003c/strong\u003eSingle-session SRS decreased the risk of repeat hemorrhage in patients with hemorrhagic brainstem CCM and conveyed this benefit with a low risk of advrse radiation effects (ARE) and worsening clinical status.\u003c/p\u003e","manuscriptTitle":"Stereotactic radiosurgery (SRS) for patients with brainstem cerebral cavernous malformations (CCMs): An International, Multicentric Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-03-12 17:33:48","doi":"10.21203/rs.3.rs-3949128/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-08-09T06:56:41+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-08-05T13:25:19+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"276341539047641060360144250237414170372","date":"2024-07-30T02:07:24+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-05-14T03:24:31+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"223161867606510399739551760381129908740","date":"2024-05-13T00:11:48+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"c7695b4f-6464-407a-89f0-80007b0689e1","date":"2024-03-17T08:59:40+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-03-12T08:49:46+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-03-12T08:39:50+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2024-03-08T13:08:58+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-03-08T13:07:44+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2024-02-11T18:32:15+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"f4f9b629-8093-465d-97c5-9ba6bb8319e4","owner":[],"postedDate":"March 12th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":29313015,"name":"Health sciences/Diseases"},{"id":29313016,"name":"Health sciences/Neurology"},{"id":29313017,"name":"Physical sciences/Physics"}],"tags":[],"updatedAt":"2024-11-04T16:27:25+00:00","versionOfRecord":{"articleIdentity":"rs-3949128","link":"https://doi.org/10.1038/s41598-024-77140-z","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2024-10-29 16:20:21","publishedOnDateReadable":"October 29th, 2024"},"versionCreatedAt":"2024-03-12 17:33:48","video":"","vorDoi":"10.1038/s41598-024-77140-z","vorDoiUrl":"https://doi.org/10.1038/s41598-024-77140-z","workflowStages":[]},"version":"v1","identity":"rs-3949128","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3949128","identity":"rs-3949128","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}