Brainstem Cerebral Cavernous Malformations Research Articles

Stereotactic radiosurgery (SRS) for patients with brainstem cerebral cavernous malformations (CCMs): an international, multicentric study

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. 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. 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 > 13 Gy (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. 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.

Improving tractography in brainstem cavernoma patients by distortion correction

IntroductionThe resection of brainstem cerebral cavernous malformations (CCM) harbors the risk of damaging the corticospinal tract (CST) and other major tracts. Hence, visualization of eloquent fiber tracts supports pre- and intraoperative planning. However, diffusion tensor imaging fiber tracking at brainstem level suffers from distortion due to field inhomogeneities and eddy currents by steep diffusion gradients. Research questionThis study aims to analyze the effect of distortion correction for CST tractography in brainstem CCM patients. Material and methods25 patients who underwent resection of brainstem CCM were enrolled, 24 suffered from hemorrhage. We performed an anatomically based tractography of the CST with a mean minimal fractional anisotropy of 0.22 ± 0.04 before and after cranial distortion correction (CDC). Accuracy was measured by anatomical plausibility and aberrant fibers. ResultsCDC led to a more precise CST tractography, further approximating its assumed anatomical localization in all cases. CDC resulted in a significantly more ventral location of the CST of 1.5 ± 0.6 mm (6.1 ± 2.7 mm before CDC vs. 4.6 ± 2.1 mm after CDC; p < .0001) as measured by the distance to the basilar artery and of 1.7 ± 0.6 mm (8.9 ± 2.7 mm vs. 7.2 ± 2.1 mm; p < .0001) in relation to the clivus. Aberrant fibers were reduced by CDC in 44% of cases. We found a mean difference in CST volume of 0.6 ± 0.8 ccm. We could not detect motor deficits after resection of irregular fibers. Discussion and conclusionCDC effectively corrects tractography for distortion at brainstem level, especially in patients suffering from brainstem CCM, further approximating its actual anatomical localization.

Association Between Beta-Blocker or Statin Drug Use and the Risk of Hemorrhage From Cerebral Cavernous Malformations.

Background:We aimed to determine the association between beta-blocker or statin drug use and the future risk of symptomatic intracranial hemorrhage or persistent/progressive focal neurological deficit from cerebral cavernous malformations (CCM).Methods:The population-based Scottish Audit of Intracranial Vascular Malformations prospectively identified adults resident in Scotland first diagnosed with CCM during 1999 to 2003 or 2006 to 2010. We compared the association between beta-blocker or statin drug use after first presentation and the occurrence of new intracranial hemorrhage or persistent/progressive focal neurological deficit due to CCM for up to 15 years of prospective follow-up. We confirmed proportional hazards and used survival analysis with multivariable adjustment for age, intracranial hemorrhage at CCM presentation, and brain stem CCM location.Results:Sixty-three (21%) of 300 adults used beta-blockers (27/63 [43%] used propranolol), and 73 (24%) used statin drugs over 3634 person-years of follow-up. At baseline, the only statistically significant imbalances in prespecified potential confounders were age by statin use and intracranial hemorrhage at presentation by beta-blocker use. Beta-blocker use was associated with a lower risk of new intracranial hemorrhage or persistent/progressive focal neurological deficit (adjusted hazard ratio, 0.09 [95% CI, 0.01–0.66]; P=0.018). Statin use was associated with a nonsignificant lower risk of intracranial hemorrhage or persistent/progressive focal neurological deficit (adjusted hazard ratio, 0.37 [95% CI, 0.01–1.07]; P=0.067).Conclusions:Beta-blocker, but not statin, use was associated with a lower risk of intracranial hemorrhage or persistent/progressive focal neurological deficit in patients with CCM.

Overview of cerebral cavernous malformations: comparison of treatment approaches

ObjectivesThe comparison of treatment efficacy for cerebral cavernous malformations (CCMs) has not yet been well researched.DesignPubMed, Cochrane Library, Science Direct, ISI Web of Science, Embase and additional sources were searched...

Surgery for cerebral cavernous malformations: a systematic review and meta-analysis.

We sought to quantify the risks of neurosurgical excision of cerebral cavernous malformations (CCMs) in a systematic review of cohort studies. We updated our previous systematic review by searching OVID Medline, OVID EMBASE, and the Cochrane Library from 1 January 2013 to 30 April 2019. The primary outcome was a composite of death attributed to CCM or surgery, non-fatal symptomatic intracerebral haemorrhage (ICH), or new or worsened persistent non-haemorrhagic focal neurological deficit (FND). We included 70 cohorts, 67 reporting surgery alone, and three compared surgery to conservative management. A total of 5,089 patients (median age 36years, 52% female) underwent surgery (total follow-up 19,404 patient-years). The annual rate of the composite outcome was 4.2% (95% CI 2.9 to 5.7; 46 cohorts; I2 = 93%), which was higher in cohorts reporting exclusively brainstem CCM (6.0%, 95% CI 4.1-8.3; 25 cohorts, I2 = 92%) versus predominantly supratentorial CCM (2.4%, 95% CI 1.3-3.8, 21 cohorts, I2 = 86%, phet = 0.001). The annual rate of the composite outcome was higher in cohorts with > 95% presenting with ICH (6.1%, 95% CI 4.2-8.4; 23 cohorts, I2 = 93%) versus others (2.3%, 95% CI 1.2-3.7; 23 cohorts, I2 = 83%, phet = 0.001). The incidence of the composite outcome did not change over time in cohorts of exclusively brainstem CCM (p = 0.7) or predominantly supratentorial CCM (p = 0.5). The risk of death, ICH, or FND after CCM excision is ~ 4%. This risk is higher for brainstem CCM and CCM that have caused ICH but has not changed over time. This systematic review was registered (PROSPERO CRD42019131246).

Surgical Management of Brain Cavernous Malformations.

Surgical removal of accessible lesions is the only direct therapeutic approach for cerebral cavernous malformations (CCMs). The approach should be carefully evaluated according to clinical, anatomical, and neuroradiological assessment in order to both select the patient and avoid complications. In selected cases, a quantitative anatomical study with a preoperative simulation of surgery could be used to plan the operation. Neuronavigation, ultrasound, and neurophysiologic monitoring are generally required respectively to locate the CCMs and to avoid critical areas. The chapter describes all the possible surgical approaches for supratentorial, infratentorial, deep seated and brain stem CCMs. In any case before performing surgery, the physicians should always consider the benign nature of the lesions and the absolute necessity to avoid not only neurological deficits, but also a neuropsychological impairment that could affect the quality of life of the patients.

Could propranolol be beneficial in adult cerebral cavernous malformations?

Surgery is the only therapeutic option for cerebral cavernous malformations (CCM) and is proposed, whenever possible, after haemorrhagic events, neurological symptoms, or epilepsy, radiosurgery being a controversial alternative in some cases. However, there is no treatment for non-accessible lesions, such as brainstem CCM, multiple CCM, or those located in functional areas. Propranolol, a non-selective beta-blocker used as first-line treatment for infantile haemangiomas, has proved spectacularly effective in a few cases of adult patients with CCM. We herein review the histological, in vitro data and clinical findings that support the idea of propranolol as a potential treatment for CCM. Since one retrospective study has not been conclusive, we support the idea that prospective trials are necessary.

Surgical Approaches for Symptomatic Cerebral Cavernous Malformations of the Thalamus and Brainstem.

ObjectiveSurgical resection of thalamic and brainstem cerebral cavernous malformations (CCMs) is associated with significant operative morbidity, but it may be outweighed, in some cases, by the neurological damage from recurrent hemorrhage in these eloquent areas. The goals of this retrospective cohort study are to describe the technical nuances of surgical approaches and determine the postoperative outcomes for CCMs of the thalamus and brainstem.Materials and MethodsWe reviewed an institutional database of patients harboring thalamic or brainstem CCMs, who underwent surgical resection from 2010 to 2014. The baseline and follow-up neuroimaging and clinical findings of each patient and the operative details of each case were evaluated.ResultsA total of eight patients, including two with thalamic and six with brainstem CCMs, were included in the study cohort. All patients had progressive neurological deterioration from recurrent CCM hemorrhage, and the median modified Rankin Scale (mRS) at presentation was 3. The median CCM maximum diameter and volume were 1.7 cm and 1.8 cm3, respectively. The thalamic CCMs were resected using the anterior transcallosal transchoroidal and supracerebellar infratentorial approaches each in one case (13%). The brainstem CCMs were resected using the retrosigmoid and suboccipital trans-cerebellomedullary fissure approaches each in three cases (38%). After a median follow-up of 11.5 months, all patients were neurologically stable or improved, with a median mRS of 2. The rate of functional independence (mRS 0-2) was 63%.ConclusionMicroneurosurgical techniques and approaches can be safely and effectively employed for the management of thalamic and brainstem CCMs in appropriately selected patients.

Solitary Sporadic Cerebral Cavernous Malformations: Risk Factors of First or Recurrent Symptomatic Hemorrhage and Associated Functional Impairment

To quantify the risk of a first or recurrent hemorrhage and the associated functional impairment in patients with sporadic solitary cerebral cavernous malformations (CCMs) and to investigate the potential risk factors. We undertook an observational study (n=199) of consecutive patients with the diagnosis of a single, sporadic CCM using clinical and magnetic resonance imaging follow-up to identify prospective hemorrhage events and associated functional impairment. We calculated the annual hemorrhage risk rates, calculated cumulative risks, and performed uni- and multivariate analysis to assess outcome predictors. There were 199 adults identified, and 712.5 person years of follow-up were analyzed. Overall annual rates of hemorrhage were 6.03%, 11.95%, and 1.03% in the complete cohort, in those presenting with previous hemorrhage, and in those without, respectively. The 5-year risk of hemorrhage was higher in those presenting with previous hemorrhage than those without (40.9%; 95% confidence interval [CI], 31.78-50.73 vs. 8.6%; 95% CI, 3.97-16.95; P < 0.0001) and in those with a brainstem CCM compared with nonbrainstem CCM (51.6%; 95% CI, 37.61-65.46 vs. 17.1%; 95% CI, 4.55-32.04; P < 0.0001). In the multivariate analysis, previous hemorrhage (odds ratio, 7.18; 95% CI, 1.8-28.11; P= 0.005), age less than 45 years (odds ratio, 2.61; 95% CI, 1.03-6.61; P= 0.042), and brainstem location (odds ratio, 7.44; 95% CI, 2.09-26.50; P= 0.002) increased the risk of hemorrhage. Of the patients, 30% showed a moderate or severe disability associated with a CCM hemorrhage (5-year risk of severe hemorrhage, 8.9%; 95% CI, 5.50-13.99). This study provides an estimate of symptomatic hemorrhage risk and the associated disability in patients with sporadic solitary CCM and an investigation of risk factors.

Abstract 193: Cerebral Cavernous Malformation Location and Mode of Presentation Predict the Risk of Hemorrhage During Their Untreated Clinical Course: Individual Patient Data Meta-Analysis

INTRODUCTION: Cerebral cavernous malformations (CCM) are the second commonest incidental finding on brain MRI and may cause symptomatic intracranial hemorrhage (ICH). However, the risk and predictors of ICH from CCM remain uncertain. HYPOTHESIS: Presentation with ICH or non-hemorrhagic focal neurological deficit (FND) attributable to CCM, brainstem CCM location, female sex, increasing age and multiple CCM predict ICH occurrence during follow-up without CCM treatment. METHODS: Three hospital-based cohorts and two cohorts from a population-based study provided individual patient data on clinical course from CCM diagnosis until either first CCM treatment or last available follow-up. We used survival analysis of each cohort to estimate the 5-year risk of symptomatic ICH or new FND, multivariable Cox regression to identify baseline predictors of outcome, and random-effects models to pool estimates in meta-analysis. RESULTS: Among 988 adults who experienced 62 ICHs during 3,232 person-years of follow-up, clinical presentation with ICH or FND (hazard ratio [HR] 7.4, 95% confidence interval [CI] 2.9-19.2) and brainstem CCM location (HR 5.7, 95% CI 3.2-10.3) were associated with a higher risk of a first ICH within five years of CCM diagnosis, but age, sex and CCM multiplicity were not. The 5-year estimated risk of ICH during untreated follow-up was 2.4% (95% CI 1.0-3.8) for 566 adults without ICH/FND from CCM outside the brainstem, 5.5% (95% CI 0-12.9) for 51 adults without ICH/FND from brainstem CCM, 10.6% (95% CI 5.1-16.1) for 198 adults with ICH/FND from CCM outside the brainstem, and 25.7% (95% CI 18.3-33.1) for 173 adults with ICH/FND from brainstem CCM. In secondary analyses of first ICH or FND, event rates increased but predictors remained unchanged. CONCLUSION: Mode of clinical presentation and CCM location are independently associated with ICH or FND within five years of CCM diagnosis, which can inform decisions about CCM treatment.

Treatment of cerebral cavernous malformations: a systematic review and meta-regression analysis

ObjectiveThe reported effects of treating cerebral cavernous malformations (CCMs) by neurosurgical excision or stereotactic radiosurgery are imprecise and vary between studies.MethodsWe searched Ovid Medline, EMBASE and The Cochrane Library for...

Cavernomas of the human brainstem: 3-dimensional reconstruction from histological slides using computerized techniques.

Cerebral cavernous malformations (CCMs) are described as vascular lesions consisting of endothelial-lined dilated vessels embedded in a connective tissue sheath without intervening parenchyma between them. Their anatomical connections with the normal blood vessels are still enigmatic and the fine three-dimensional (3-D) organization of these vascular lesions remains to be established. Two stacks of serial histological slices, obtained from two brainstem CCM lesions (from the necropsy of a CCM2 male patient), were stained using Masson's trichrome method and then digitized. Stacks of regions of interest underwent quasi-automatic processing: 1) propagative registering using blockmatching algorithms and Brain Visa programs; 2) 3-D segmentation using Aphelion; 3) display with Anatomist or ImageVis3D. These first histological 3-D reconstructions show the external limits of the caverns defined as the external limit of their collagen sheath. These pictures not only reveal the gross spatial organization of the lesions, but due to their high resolution (4 μm) and with the help of simple anaglyphic 3-D rendering, they also allow the visualization of connections between caverns and very small blood vessels.

Evaluation of linear accelerator (LINAC)-based stereotactic radiosurgery (SRS) for cerebral cavernous malformations: a 15-year single-center experience

BACKGROUND AND OBJECTIVESSurgery is the principal treatment for safely accessible hemorrhagic and symptomatic cavernous malformations. Nevertheless, the role of linear accelerator (LINAC)-based stereotactic radiosurgery (SRS) in the management of high-risk, symptomatic cavernoma lesions warrants further refinement. In this study, we evaluate the use of LINAC-based SRS for cerebral cavernous malformations (CMs) and report our 15-year single-center experience.DESIGN AND SETTINGSA retrospective study from the Department of Radiation Oncology and the Department of Neurosurgery at Gulhane Military Medical Academy and Medical Faculty, Ankara from April 1998 to June 2013.PATIENTS AND METHODSFifty-two patients (22 females and 30 males) with cerebral CM referred to our department underwent high-precision single-dose SRS using a LINAC with 6-MV photons. All patients had at least 1 bleeding episode prior to radiosurgery along with related symptoms. Median dose prescribed to the 85% to 95% isodose line encompassing the target volume was 15 Gy (range, 10–20).RESULTSOut of the total 52 patients, follow-up data were available for 47 patients (90.4%). Median age was 35 years (range, 19–63). Median follow-up time was 5.17 years (range, 0.08–9.5) after SRS. Three hemorrhages were identified in the post-SRS period. Statistically significant decrease was observed in the annual hemorrhage rate after radiosurgical treatment (pre-SRS 39% vs post-SRS 1.21, P<.0001). Overall, there were no radiosurgery-related complications resulting in mortality.CONCLUSIONLINAC-based SRS may be considered as a treatment option for high-risk, symptomatic cerebral CM of selected patients with prior bleeding from lesions located at surgically inaccessible or eloquent brain areas.

Surgical treatment of symptomatic cerebral cavernous malformations in eloquent brain regions

Despite the increased risk of hemorrhage and deteriorating neurological function of once-bled cerebral cavernous malformations (CM), the management of eloquently located CMs remains controversial. All eloquently located CMs (n = 45) surgically treated between 03/2006 and 04/2011 in our department were consecutively evaluated. Eloquence was characterized according to Spetzler and Martin's definition. The following locations were approached: brainstem, n = 16; sensorimotor, n = 8; visual pathway, n = 7; cerebellum (deep nuclei and peduncles), n = 7; basal ganglia, n = 4, and language, n = 3. Follow-up data was available for 41 patients (91%) with a median interval of 14months. Outcomes were evaluated according to the Glasgow outcome and the modified Rankin scale. Immediately after surgery, 47% (n = 21) had a new deficit. At follow-up, 80% (n = 36) recovered to at least preoperative status or were better than before surgery, 9% (n = 4) exhibited a slight, and 7% (n = 3) had a moderate neurological impairment. Only two cases (4%) with a new permanent severe deficit were observed, both related to dorsal brainstem surgery. The outcome after the surgery of otherwise located brainstem CMs was as beneficial as that for non-brainstem CMs. Patients with initially poor neurological performance fared worse than oligosymptomatic patients. Despite the high postoperative transient morbidity, the majority improved profoundly during follow-ups. Compared with natural history, surgical treatment should be considered for all eloquent symptomatic CMs. Dorsal brainstem location and poor preoperative neurological status are associated with an increased postoperative morbidity.

Stereotactic LINAC radiosurgery for the treatment of brainstem cavernomas

The management of deep-seated cerebral cavernous malformations (CCMs) is still controversial. Although surgery remains the treatment of choice in patients with recurrent hemorrhage, patients with CCMs located in the brainstem are in many cases not eligible for resection due to high procedure-related morbidity and mortality. We evaluated the long-term outcome of LINAC radiosurgery (LINAC-RS) for the treatment of brainstem CCMs. Between December 1992 and March 2008, 14 patients (6 men, 8 women) harboring brainstem CCMs underwent LINAC-RS. Pretreatment neuroimaging showed no associated developmental venous angiomas (DVAs) in any of our patients. Prior to treatment, all patients suffered at least from one symptomatic hemorrhage (median 1.8, range 1–3). A median follow-up of 7.1 years (range 2.0–16.8 years) could be obtained in 12 patients. We applied a median tumor surface dose of 13.9 Gy (range 11–18 Gy; median tumor volume 1.6 ml, range 0.4–4.3 ml). Following LINAC-RS, neurological outcome improved in 4 (33.3%) and remained unchanged in 8 patients (66.7%). Rebleeding with subsequent transient neurological status deterioration occurred in 4 patients (33.3%), leading to additional surgical resection in 2 patients (16.7%). The corresponding annual hemorrhage rate was 4.8% (4/82.8 patient–years). Adverse radiation effects (ARE, defined by perilesional hyperintensity on T2-weighted MR images) were revealed in 3 patients (25%), leading to transient neurological deficits in 2 patients (16.7%). There were no procedure-related complications leading to either permanent morbidity or mortality. Our results support the role of LINAC-RS as an efficient and safe treatment to significantly reduce the annual hemorrhage rate in patients suffering from brainstem CCMs not eligible to microsurgery. Compared with radiosurgery for arteriovenous malformations (AVMs), the intervention-related morbidity is higher.

Untreated clinical course of cerebral cavernous malformations: a prospective, population-based cohort study

SummaryBackgroundCerebral cavernous malformations (CCMs) are prone to bleeding but the risk of intracranial haemorrhage and focal neurological deficits, and the factors that might predict their occurrence, are unclear. We aimed to quantify these risks and investigate whether they are affected by sex and CCM location.MethodsWe undertook a population-based study using multiple overlapping sources of case ascertainment (including a Scotland-wide collaboration of neurologists, neurosurgeons, stroke physicians, radiologists, and pathologists, as well as searches of registers of hospital discharges and death certificates) to identify definite CCM diagnoses first made in Scottish residents between 1999 and 2003, which study neuroradiologists independently validated. We used multiple sources of prospective follow-up both to identify outcome events (which were assessed by use of brain imaging, by investigators masked to potential predictive factors) and to assess adults' dependence. The primary outcome was a composite of intracranial haemorrhage or focal neurological deficits (not including epileptic seizure) that were definitely or possibly related to CCM.Findings139 adults had at least one definite CCM and 134 were alive at initial presentation. During 1177 person-years of follow-up (completeness 97%), for intracranial haemorrhage alone the 5-year risk of a first haemorrhage was lower than the risk of recurrent haemorrhage (2·4%, 95% CI 0·0–5·7 vs 29·5%, 4·1–55·0; p<0·0001). For the primary outcome, the 5-year risk of a first event was lower than the risk of recurrence (9·3%, 3·1–15·4 vs 42·4%, 26·8–58·0; p<0·0001). The annual risk of recurrence of the primary outcome declined from 19·8% (95% CI 6·1–33·4) in year 1 to 5·0% (0·0–14·8) in year 5 and was higher for women than men (p=0·01) but not for adults with brainstem CCMs versus CCMs in other locations (p=0·17).InterpretationThe risk of recurrent intracranial haemorrhage or focal neurological deficit from a CCM is greater than the risk of a first event, is greater for women than for men, and declines over 5 years. This information can be used in clinical practice, but further work is needed to quantify risks precisely in the long term and to understand why women are at greater risk of recurrence than men.FundingUK Medical Research Council, Chief Scientist Office of the Scottish Government, and UK Stroke Association.

The natural history of familial cerebral cavernomas: a retrospective MRI study of 40 patients.

Our objective was to determine the natural history and prognostic factors of familial forms of cerebral cavernous malformations (CCM). Cavernomas are one of the most common central nervous system vascular malformations. Familial CCM is increasingly diagnosed, but little is known about its natural history. In a national survey, we analysed clinical and MRI features of 173 patients from 57 unrelated French families. Of these 40 had undergone at least two clinical and MRI examinations. Occurrence of haemorrhage, new lesions, change in signal intensity and size of lesions have been studied by comparison between first and last MRI studies. The CCM were classified according to Zabramski et al. Mean follow-up was 3.2 years (range 0.5-6.5 years). We followed 232 cavernomas (mean 5.9 per patient, range 1-17). Serial MRI demonstrated changes in 28 patients (70%). Bleeding occurred in 21 lesions (9.1%) in 14 patients (35%). The haemorrhagic risk was 2.5% per lesion-year, higher in type I and brain-stem CCM. We saw 23 new lesions appear in 11 patients (27.5%), with an incidence of 0.2 lesions per patient year. Signal change was observed in 11 patients (27.5%), in 14 lesions (6%), while 9 lesions (3.9%) in 9 patients (22.5%) changed significantly in size.