Management Of Cerebral Cavernous Malformations Research Articles

Clinical outcomes following stereotactic radiosurgery for cerebral cavernous malformations of the basal ganglia and thalamus.

There are few reports of outcomes following stereotactic radiosurgery (SRS) for the management of cerebral cavernous malformations (CCMs) of the basal ganglia or thalamus. Therefore, the authors aimed to clarify these outcomes. Centers participating in the International Radiosurgery Research Foundation were queried for CCM cases managed with SRS from October 2001 to February 2021. The primary outcome of interest was hemorrhage-free survival (HFS) with a secondary outcome of symptomatic adverse radiation events (AREs). Assessment of the association of prognostic factors with HFS was conducted via Kaplan-Meier analysis and log-rank test. Chi-square tests were conducted to assess potential factors associated with the incidence of AREs. Seventy-three patients were identified. The median patient age was 43.5 years (range 4.4-79.5 years). Fifty-nine (80.8%) patients had hemorrhage prior to SRS. The median treatment volume was 0.9 cm3 (range 0.07-10.1 cm3) with a median margin prescription dose (MPD) of 12 Gy (range 10-20 Gy). One-, 3-, 5-, and 10-year HFS were 93.0%, 89.9%, 89.9%, and 83.0%, respectively, with one hemorrhage-related death approximately 1 year after SRS and nearly 60% and 30% of patients having improvement or stability of symptoms, respectively. There was no correlation between lesion size or MPD and HFS. Seven (9.6%) patients experienced AREs (MPDs > 12 Gy in all cases). Lesion size > 1.0 cm3 was correlated with the incidence of an ARE (p = 0.019). Forty-two (93.3%) of 45 patients treated with an MPD ≤ 12 Gy experienced neither hemorrhage nor AREs following SRS versus 17 (60.7%) of 28 patients treated with an MPD > 12 Gy (p = 0.0006). SRS is a reasonable treatment strategy and confers clinical stability or improvement and hemorrhage avoidance in patients harboring CCMs of the basal ganglia or thalamus. An MPD of approximately 12 Gy is recommended for the management of CCM.

Approach Selection Strategies for Repeat Resection of Brain Cavernous Malformations: Cohort Study.

Neurosurgical management of cerebral cavernous malformations (CMs) often benefits from using skull base approaches. Although many CMs are cured by resection, residual or recurrent disease may require repeat resection. To review approach selection strategies for reoperation of CMs to aid decision-making for repeat procedures. In this retrospective cohort study, a prospectively maintained single-surgeon registry was queried for patients with CMs who underwent repeat resection from January 1, 1997, to April 30, 2021. Of 854 consecutive patients, 68 (8%) underwent 2 operations; 40 had accessible data on both. In most reoperations (33/40 [83%]), the index approach was repeated. In most reoperations using the index approach (29/33 [88%]), that approach was deemed ideal (no equivalent or superior alternative), whereas in some (4/33 [12%]), the alternative approach was deemed unsafe because of conformation of the tract. Among patients with reoperations using an alternative approach (7/40 [18%]), 2 with index transsylvian approaches underwent bifrontal transcallosal approaches, 2 with index presigmoid approaches underwent extended retrosigmoid revisions, and 3 with index supracerebellar-infratentorial approaches underwent alternative supracerebellar-infratentorial trajectory revisions. Among patients with reoperations with an alternative approach considered or selected (11/40 [28%]), 8 of 11 patients had a different surgeon for the index resection than for the repeat resection. The extended retrosigmoid-based approaches were used most often for reoperations. Repeat resection of recurrent or residual CMs is a challenging neurosurgical niche at the intersection of cerebrovascular and skull base disciplines. Suboptimal index approaches may limit surgical options for repeat resection.

Propranolol therapy for cerebral cavernous malformations

Cerebral cavernous malformations (CCMs) are vascular malformations characterized by the abnormal growth of vascular structures in the central nervous system. However, the precise mechanism(s) responsible for the development of CCM vascular abnormalities remain poorly understood. Although the mechanisms of action of propranolol in CCM have not yet been fully explored it is not commonly prescribed, it has been shown to be effective in children and appears to play a protective role in the prevention of CCM‑derived hemorrhage in adults. The present study performed <em>in vitro</em> and <em>ex vivo</em> assays in order to examine the effects of propranolol on endothelial cells (ECs). The percentage of CD14⁺/CD31⁺ cells and the levels of VEGF in the peripheral blood (PB) of a child patient with CCM, with recurrent seizures and hemorrhages, who was maintained under propranolol therapy, were also analyzed. In addition to the effects of propranolol on differentiated ECs, and the decrease angiogenic‑related features <em>in vitro</em> and <em>ex vivo</em>, it was observed that in the PB of this patient, propranolol administration decreased the percentage of circulating cells sharing monocytic and EC features (CD14⁺/CD31⁺ cells), as well as the VEGF levels; this was concomitant with a good prognosis and with the reversion of CCM lesions. A decrease in VEGF levels by propranolol may also be involved in the impairment of the recruitment of CD14⁺/CD31⁺ monocytes functioning as endothelial progenitor cells to sustain the vascular lesion. On the whole, the present study demonstrates that propranolol impairs angiogenesis <em>in vitro</em> and may thus be a useful tool for the clinical management of CCM. Moreover, the present study highlights the monitorization of the levels of CD14⁺/CD31⁺ monocytes and VEGF levels as a useful tool for predicting the clinical efficacy of propranolol in patients with CCM.

Surgical management of pediatric intracranial cerebral cavernous malformations: a 10-year single-center experience.

Cerebral cavernous malformations (CCMs) are low-flow vascular malformations made up of dilated vascular spaces without intervening parenchyma that can occur throughout the central nervous system. CCMs can occur sporadically or in familial forms. Presentation is diverse, ranging from incidental discovery of asymptomatic CCMs to drug-resistant epilepsy and hemorrhages. We describe the surgical management of CCMs in pediatric patients at Bambino Gesù Children's Hospital in Rome over the last 10 years. The cases have been stratified based on the clinical presentation and the relevant literature is discussed accordingly. We discuss the rationale and technique used in these cases based on their presentation, as well as the generally positive outcomes we achieved with early surgical management, use of intraoperative ultrasound (ioUS) and intraoperative neuromonitoring. Surgical management of pediatric CCMs is a safe and effective strategy, low rates of postoperative morbidity and partial resection were observed.

Cerebral cavernous malformation presenting in childhood: a single-centered surgical experience of 29 cases

ObjectivesCerebral cavernous malformations (CMs) are benign vascular hamartomas of central nervous system. Although they are mostly asymptomatic, they may occasionally result in life-threatening complications leading to surgical treatment. The main goal is to evaluate the surgical outcomes of operated pediatric cerebral CMs in our clinic and compare our results with the literature. Patients and MethodsThe data of 29 pediatric patients who were operated for cerebral CMs in our clinic between 2007 and 2016 were collected. ResultsOf 29 patients, 13 were girls and 16 were boys, and the mean age at operation was 11.4 years (range from 2 to 17 years). Main symptoms at presentation were seizures (15 patients, 51.7 %), headache (12 patients, 41.3 %), and focal neurological deficits (4 patients, 13.7 %). The frequency of hemorrhage in CMs was significantly higher in younger patients (p = 0.019). Total excision was achieved in all patients. The mean follow-up period was 27.3 months (range from 12 to 97 months). New neurological deficit following surgery occurred in 1 patient (3.4 %) who completely recovered after 3 months. After surgery, 1 patient (3.4 %) has become free of preoperative deficit; while the rest (27 patients) remained in preoperative neurological status. Of 15 patients presented with seizures preoperatively, 10 patients (66.6 %) were seizure free (Engel Class 1), 4 (26.6 %) were “almost seizure free” (Engel Class 2) and one (6.6 %) experienced “worthwhile improvement” (Engel Class 3) at the last follow up visit. There was no mortality in our series. ConclusionAlthough management of cerebral CMs in childhood is controversial, total resection ensures good clinical outcome and seizure control. In addition, age can be a predisposing factor for hemorrhage.

Synopsis of Guidelines for the Clinical Management of Cerebral Cavernous Malformations: Consensus Recommendations Based on Systematic Literature Review by the Angioma Alliance Scientific Advisory Board Clinical Experts Panel.

BACKGROUND: Despite many publications about cerebral cavernous malformations (CCMs), controversy remains regarding diagnostic and management strategies. OBJECTIVE: To develop guidelines for CCM management. METHODS: The Angioma Alliance (www.angioma.org), the patient support group in the United States advocating on behalf of patients and research in CCM, convened a multidisciplinary writing group comprising expert CCM clinicians to help summarize the existing literature related to the clinical care of CCM, focusing on 5 topics: (1) epidemiology and natural history, (2) genetic testing and counseling, (3) diagnostic criteria and radiology standards, (4) neurosurgical considerations, and (5) neurological considerations. The group reviewed literature, rated evidence, developed recommendations, and established consensus, controversies, and knowledge gaps according to a prespecified protocol. RESULTS: Of 1270 publications published between January 1, 1983 and September 31, 2014, we selected 98 based on methodological criteria, and identified 38 additional recent or relevant publications. Topic authors used these publications to summarize current knowledge and arrive at 23 consensus management recommendations, which we rated by class (size of effect) and level (estimate of certainty) according to the American Heart Association/American Stroke Association criteria. No recommendation was level A (because of the absence of randomized controlled trials), 11 (48%) were level B, and 12 (52%) were level C. Recommendations were class I in 8 (35%), class II in 10 (43%), and class III in 5 (22%). CONCLUSION: Current evidence supports recommendations for the management of CCM, but their generally low levels and classes mandate further research to better inform clinical practice and update these recommendations. The complete recommendations document, including the criteria for selecting reference citations, a more detailed justification of the respective recommendations, and a summary of controversies and knowledge gaps, was similarly peer reviewed and is available on line www.angioma.org/CCMGuidelines.

Management of cerebral cavernous malformations: from diagnosis to treatment.

Cerebral cavernous malformations are the most common vascular malformations and can be found in many locations in the brain. If left untreated, cavernomas may lead to intracerebral hemorrhage, seizures, focal neurological deficits, or headaches. As they are angiographically occult, their diagnosis relies on various MR imaging techniques, which detect different characteristics of the lesions as well as aiding in planning the surgical treatment. The clinical presentation and the location of the lesion are the most important factors involved in determining the optimal course of treatment of cavernomas. We concisely review the literature and discuss the advantages and limitations of each of the three available methods of treatment—microsurgical resection, stereotactic radiosurgery, and conservative management—depending on the lesion characteristics.

Management of Cerebral Cavernous Malformations: Molecular Insight and Clinical Considerations

Introduction: Cavernous malformations (cavernomas) occur in 0.4% - 0.9% of the population. Clinical symptoms are mainly caused by recurrent hemorrhages and/or their progressive growth. The neurological deficit depends on their exact localization. Most common symptoms are epileptic seizures. Particularly, in deep seated lesions (brain stem, basal ganglia, etc.) a well elaborated preoperative imaging is critical in ordert to select the most favorable approach for every patient. Usually, cavernomas occur as single lesions, but in some individuals (10-20%) more than one cavernoma might be diagnosed. Particularly in these patients a treatment strategy is critically dependant on the understanding of the biology of multiple (and familial?) lesions. Aim: Therefore, our recent research aimed at (1) unshadowing the biological activity and ageressivenes of cavernomas (2) understanding their human genetics and (3) increasing the imaging quality of cavernomas and associated venous malfomations. Material and Methods: Endothelial cells were isolated and purified from the fresh operative specimens of sporadic CCMs with single lesions (CCM-ECs). The expression profile of VEGF and its receptors as well as CCM1-3 genes were detected by real-time PCR. Endothelial proliferation, migration, sprouting and tube formation were compared in the absence and the presence of angiogenic stimuli and after CCM1-3 siRNA in CCM-ECs and in different types of healthy endothelial cells. Furthermore, a strong correlation with VEGF related neoangiogenesis as well as the influence of a PTEN deficiency was studied. Patients with multiple lesions were evalutated for germ line mutations of the CCM1-3 genes. By using susceptibility weighted imaging (SWI) at 7T high field strength MRI both patients with single and multiple lesions were evaluated for cavernomas and associated venous malformations (VM). Results: A highly activated VEGF system was revealed in CCM-ECs. Accordingly, CCM-ECs exhibited marked growth potential under normal culture conditions and a significantly high proliferation activity in response to various angiogenic stimuli including hypoxia, fetal calf serum and VEGF treatment. Furthermore, a significantly higher mobility, spontaneous growth of sprouts and extensively branched tubes were exclusively detected in CCM-ECs. In comparison to healthy endothelia, CCM-ECs resisted apoptotic stimuli and showed distinct responses toward to activating angiogenesis after CCM1 silencing. Endothelila proliferation was conducted by the VEGF related pathways. PTEN deficiency in endothelial cavernoma cells seems to play a role particularly in patients suffering from multiple cavernomas. Tyrosin-kinase receptor inhibitors suppresses neoangiogenetic activity in CCM1 deficient endothelial cells in an animal model. In patients with multiple cavernomas, a germ line mutation of the CCM1-3 genes can be found in up to 80%. Patients with CCM1 mutations might additionally display a cutaneous nevus. In the patients harbouring single cavernomas, a solitary or multiple venous drainage was found in all lesions using susceptibility weighted imaging (SWI) at 7T high field strength MRI. A typical so called developmental anomaly (DVA) was found in 30% of the lesions. In the other cases, associated VM were depicted as well, although showing a different phenotype when compared with DVAs. Conclusion: Cavernomas are growing and active lesions similar to benign tumors with also similar underlying molecular growth mechanisms. The highly activated VEGF system and the distinct angiogenic characteristics of CCM-ECs may serve as an endothelia-pathomechanism synergistically acting together with genetic and other factors for the development of vascular lesions in the human brain. Particularly, the surgical resection of lesions with a CCM1-3 gene defects (familial cavernomas) should be evaluated very carefully. Ultra-high-field magnetic resonance imaging at 7T improves the detection of cavernomas. The improved depiction of small cavernomas might possibly help to clarify cryptogenic seizures, which represent 30% of all seizures. We believe, that the additional information gained will have an impact on treatment plans for deep seated lesions in the future. Furthermore, our data support previous assumptions of CCMs being notoriously associated with local venous malformation (VM and DVA) involving larger outflow vessels.

Seizure Outcome after Resection of Supratentorial Cavernous Malformations: A Study of 168 Patients

The optimal management of cerebral cavernous malformations (CCMs) with epileptic seizures is still a matter of debate. The aim of our study was to examine seizure outcome in the largest published series of surgically treated patients with epilepsy due to a supratentorial CCM, and to define predictors for good surgical outcome. We retrospectively studied 168 consecutive patients with a single supratentorial CCM and symptomatic epilepsy in a multicenter study. Pre- and postoperative clinical examinations, age at epilepsy onset, age at operation, type of symptoms due to the CCM (seizures, headache, hemorrhage, focal deficits), type and frequency of epileptic seizures, and the localization and size of the CCM were assessed. Seizure outcome was determined in the first, second, and third postoperative years. The CCM was completely resected in all patients. More than two thirds of the patients were classified as seizure free in the first 3 postoperative years. Predictors for good seizure outcome were age older than 30 years at the time of surgery, mesiotemporal CCM localization, CCM size <1.5 cm, and the absence of secondarily generalized seizures. No mortality occurred in our series, but only mild postoperative neurologic deficits in 12 (7%) patients. Considering the natural history of CCMs, the favorable neurologic and seizure outcome, surgical resection of CCMs should be considered in all patients with supratentorial CCMs and concomitant epilepsy, irrespective of the presence or absence of predictors for a favorable seizure outcome.

Management of Cavernous Malformations in the Pediatric Population

The management of cavernous malformations (CMs) in a child is similar in many ways to that of CMs in an adult. There are specific general principles that need to be considered when approaching these lesions in children, however. The long life span anticipated in the pediatric patient may favor an aggressive surgical approach for single, small asymptomatic cavernous malformations or for certain symptomatic lesions in eloquent locations. The observed history of a given malformation may be the best guide to determine its treatment. The authors discuss some of these principles and review their experience with a series of children who have presented for management of cerebral CM.