Natural Course of Cerebral Cavernous Malformations in Children: A Five-Year Follow-Up Study.

BACKGROUND AND PURPOSE: The purpose of this study was to investigate the natural course of cerebral cavernous malformations (CCM) in the pediatric population, with special emphasis on the risk of first and recurrent bleeding over a 5-year period. METHODS: Our institutional database was screened for patients with CCM treated between 2003 and 2020. Patients ≤18 years of age with complete magnetic resonance imaging data set, clinical baseline characteristics, and ≥1 follow-up examination were included. Surgically treated individuals were censored after CCM removal. We assessed the impact of various parameters on first or recurrent intracerebral hemorrhage (ICH) at diagnosis using univariate and multivariate logistic regression adjusted for age and sex. Kaplan-Meier and Cox regression analyses were performed to determine the cumulative 5-year risk for (re)hemorrhage. RESULTS: One hundred twenty-nine pediatric patients with CCM were analyzed. Univariate logistic regression identified brain stem CCM (odds ratio, 3.15 [95% CI, 1.15-8.63]; P=0.026) and familial history of CCM (odds ratio, 2.47 [95% CI, 1.04-5.86]; P=0.041) as statistically significant predictors of ICH at diagnosis. Multivariate logistic regression confirmed this correlation (odds ratio, 3.62 [95% CI, 1.18-8.99]; P=0.022 and odds ratio, 2.53 [95% CI, 1.07-5.98]; P=0.035, respectively). Cox regression analysis identified ICH as mode of presentation (hazard ratio, 14.01 [95% CI, 1.80-110.39]; P=0.012) as an independent predictor for rehemorrhage during the 5-year follow-up. The cumulative 5-year risk of (re)bleeding was 15.9% (95% CI, 10.2%-23.6%) for the entire cohort, 30.2% (20.2%-42.3%) for pediatric patients with ICH at diagnosis, and 29.5% (95% CI, 13.9%-51.1%) for children with brain stem CCM. CONCLUSIONS: Pediatric patients with brain stem CCM and familial history of CCM have a higher risk of ICH as mode of presentation. During untreated 5-year follow-up, they revealed a similar risk of (re)hemorrhage compared to adult patients. The probability of (re)bleeding increases over time, especially in cases with ICH at presentation or brain stem localization.

Mortality in Patients with Brainstem Cavernous Malformations.

OBJECTIVE: Brainstem cavernous malformations (BSCM)-associated mortality has been reported up to 20% in patients managed conservatively, whereas postoperative mortality rates range from 0 to 1.9%. Our aim was to analyze the actual risk and causes of BSCM-associated mortality in patients managed conservatively and surgically based on our own patient cohort and a systematic literature review. METHODS: Observational, retrospective single-center study encompassing all patients with BSCM that presented to our institution between 2006 and 2018. In addition, a systematic review was performed on all studies encompassing patients with BSCM managed conservatively and surgically. RESULTS: Of 118 patients, 54 were treated conservatively (961.0 person years follow-up in total). No BSCM-associated mortality was observed in our conservatively as well as surgically managed patient cohort. Our systematic literature review and analysis revealed an overall BSCM-associated mortality rate of 2.3% (95% CI: 1.6-3.3) in 22 studies comprising 1,251 patients managed conservatively and of 1.3% (95% CI: 0.9-1.7) in 99 studies comprising 3,275 patients with BSCM treated surgically. CONCLUSION: The BSCM-associated mortality rate in patients managed conservatively is almost as low as in patients treated surgically and much lower than in frequently cited reports, most probably due to the good selection nowadays in regard to surgery.

Surgical Treatment of Cavernous Malformations Involving the Midbrain: A Single-Center Case Series of 34 Patients.

BACKGROUND: Cavernous malformations (CMs) involving the midbrain are more challenging for surgical treatment than are CMs at other sites because of the surrounding critical structures and deep location. However, specific features and treatment strategies have not been well illustrated. OBJECTIVE: To evaluate the long-term durability of surgical treatment of midbrain CMs (MBCMs) as well as surgical outcomes and complications. METHODS: A retrospective study was conducted in 34 patients who underwent microsurgical resection of MBCMs between 1995 and 2015. Demographics, lesion characteristics, surgical approaches, surgical outcomes, and complications were analyzed. RESULTS: A total of 34 adult patients with a mean age of 38.6 years were assessed. All patients presented with a history of hemorrhage. Lesion locations included the midbrain (n = 27), midbrain and thalamus (n = 2), and pontomesencephalic junction (n = 5). Mean lesion size was 1.7 cm; average clinical follow-up was 5.6 years. Mean modified Rankin Scale (mRS) scores on admission, at discharge, and at last follow-up were 2.0, 2.7, and 1.7, respectively. Postoperatively, 19 patients (55.9%) showed new or worsened neurologic deficits. Multivariate analysis showed that admission mRS score (≥3) was an independent predictor of poor functional outcome (odds ratio, 50.832; 95% confidence interval, 2.967-901.283; P = 0.007). No rehemorrhage or recurrence case was found during the follow-up period. CONCLUSIONS: Although surgery for MBCMs is associated with significant perioperative morbidity and mortality, most patients show favorable outcomes. Higher preoperative mRS score is an independent predictor of poor functional outcome.

[RADIOSURGERY OF INTRACEREBRAL CAVERNOMAS--CURRENT INTERNATIONAL TRENDS]. / AZ INTRACEREBRALIS CAVERNOMÁK SUGÁRSEBÉSZETE--HOL TART MA A VILÁG?

Although still a controversial management option, radio-surgery of intracranial cavernomas has become increasingly popular world-wide during the last decade. Microsurgery is a safe and effective treatment for symptomatic hemispheric cavernomas. However, the indication for microsurgical resection of deep eloquent cavernomas is relatively limited even in experienced hands. The importance of radiosurgery has recently been appreciated in parallel with increasing positive experiences both in terms of effectiveness and safety, especially for cases high risk for surgical resection, in the brainstem, thalamus and basal ganglia. While radiosurgery was earlier indicated mainly for surgically inaccessible lesions that had bled multiple times, a more proactive policy has recently become more accepted. In our opinion preventive treatment with the low morbidity radiosurgery serves the patients' interest especially for deep eloquent lesions that had bled not more than once, due to the cumulative morbidity of repeated hemorrhages. Despite our increasing knowledge on natural history, there is currently no available treatment algorithm for cavernomas. Arguments for all three treatment modalities (observation, microsurgery and radiosurgery) are established, but their indication criteria are yet to be defined. It is time to organize a prospective population based data collection in Hungary, which appears to be the most realistic way to clarify indication criteria.

[RADIOSURGERY OF INTRACEREBRAL CAVERNOMAS--CURRENT HUNGARIAN PRACTICE]. / AZ INTRACEREBRALIS CAVERNOMÁK SUGÁRSEBESZETE--HOL TART MAGYARORSZÁG?

BACKGROUND AND PURPOSE: Radiosurgery is an increasingly popular treatment option especially for deep eloquent intracerebral cavernomas that are often too risky for surgical removal, but their re-bleed carries significant risk for persisting neurological deficit. Gamma-radiation based radiosurgery has been being available since 2007 in Hungary in Debrecen. Our aim is to summarize our experience accumulated during the first five years of treatment and to compare it to the international experience. PATIENT SELECTION AND METHODS: We retrospectively analyzed 51 cavernomas in 45 patients treated between 2008 and 2012 in terms of localization, natural history, and the effect of radiosurgery on re-bleed risk and epilepsy, and its side effects. RESULTS: We treated 26.5% deep eloquent (brainstem, thalamic/basal ganglia) and 72.5% superficial hemispheric cavernomas. The median presentation age was 25 years (13-60) for deep, and 45 years (6-67) for superficial cavernomas. They were treated median of 1 year after presentation. 64.5% of deep cavernomas bled before treatment, the annual risk of first hemorrhage was 2%/lesion, re-bleed risk 21.7%, with 44% persisting morbidity. 13.5% of superficial cavernomas bled prior to treatment, the risk of first bleed was 0.3%, there was no re-bleed, and 35% caused epilepsy. We used GammaART-6000TM rotating gamma system for treatment, marginal dose was 14 Gy (10-16), and treatment volume 1.38-1.53 cm3. Re-bleed risk of deep eloquent lesions fell to 4% during the first two years after treatment and to 0% thereafter, and no hemorrhage occurred from superficial lesions after treatment. Persisting morbidity in deep lesions came from adverse radiation effect in 7% and from re-bleed in 7%, and there was no persisting side effect in superficial cavernomas. 87.5% of cases of epilepsy resistant to medical therapy improved. Radiological regression was found in 37.5% and progression in 2% after treatment. CONCLUSIONS: Radiosurgery of cavernomas is safe and effective. Early preventive treatment for deep cavernomas carrying high surgical risk is justified. Moreover, for superficial lesions that are surgically easily accessible radiosurgery also appears to be an attractive alternative.

Long-term natural history of incidentally discovered cavernous malformations in a single-center cohort.

OBJECT: The aim of this study was to determine the prospective hemorrhage rate in a group of retrospectively identified patients in whom symptoms had an unclear relationship to an intracerebral cavernous malformation (ICM) or the malformation itself was an incidental finding. METHODS: Patients with incidentally discovered ICMs diagnosed between 1989 and 1999 were identified from a previously published cohort. Those with ICMs having an unclear relationship with existing symptoms were also eligible for analysis. Updated clinical and radiographic data pertaining to symptomatic intracerebral hemorrhage related to the ICM or new seizures were obtained through medical chart review and mail survey. In select patients, phone calls were made and death certificates were obtained when possible. The prospective hemorrhage rate was calculated as the number of prospective hemorrhages divided by the number of patient-years of follow-up. RESULTS: There were 1311 patient-years of follow-up among the 107 patients (49.5% male; mean age at diagnosis 52 years) eligible for this study. Forty-four patients died in the follow-up period, and the cause of death could be determined in 34 (77%). Two patients had a prospective hemorrhage, which was definitively related to the ICM in only one. Thus, the definitive prospective bleed rate was 0.08% per patient-year. No new seizures developed in any of the patients during the follow-up period. CONCLUSIONS: The risk of prospective hemorrhage in patients presenting asymptomatically with ICM is very low. This information can be useful in managing such patients and may be most applicable to those with a single ICM.

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

OBJECTIVE: The reported effects of treating cerebral cavernous malformations (CCMs) by neurosurgical excision or stereotactic radiosurgery are imprecise and vary between studies. METHODS: We searched Ovid Medline, EMBASE and The Cochrane Library for peer-reviewed publications of cohort studies describing outcomes of treating 20 or more patients with CCM with at least 80% completeness of follow-up. Two reviewers extracted data to quantify the incidence of a composite outcome (death, non-fatal intracranial haemorrhage, or new/worse persistent focal neurological deficit) after CCM treatment. We explored associations between summary measures of study characteristics and outcome using Poisson meta-regression analyses. RESULTS: We included 63 cohorts, involving 3424 patients. The incidence of the composite outcome was 6.6 (95% CI 5.7 to 7.5) per 100 person-years after neurosurgical excision (median follow-up 3.3 years) and 5.4 (95% CI 4.5 to 6.4) after stereotactic radiosurgery (median follow-up 4.1 years). After neurosurgical excision the incidence of the composite outcome increased with every per cent point increase in patients with brainstem CCM (rate ratio (RR) 1.03, 95% CI 1.01 to 1.05), and decreased with each more recent study midyear (RR 0.91, 95% CI 0.85 to 0.98) and each per cent point increase in patients presenting with haemorrhage (RR 0.98, 95% CI 0.96 to 1.00). We did not find significant associations in studies of stereotactic radiosurgery. CONCLUSIONS: The reported risks of CCM treatment (and the lower risks of neurosurgical excision over time, from recently bled CCMs, and for CCMs outside the brainstem) compare favourably with the risks of recurrent haemorrhage from CCM. Long-term effects, especially important for stereotactic radiosurgery, are unknown.

A single institution series of cavernomas of the brainstem.

We retrospectively analyzed a series of patients with brainstem cavernomas of the medulla, pons, or midbrain to attempt to define the natural history, indications for surgery, and outcome after surgical resection. Between 1993 and 2008, 52 patients with cavernomas of the brainstem presented to our institute and were managed either surgically or conservatively. Twenty-three patients underwent surgical excision using standard skull base approaches. Outcomes were correlated to the number of preoperative hemorrhages, location of the cavernoma, timing of surgery in relation to the hemorrhage and the preoperative neurological status. Nine patients improved after surgery, 12 deteriorated and two died. In the conservatively managed group, 15 patients had a good outcome, 11 deteriorated and one died. Multiple hemorrhages, poor preoperative neurological status and surgery during the acute phase were predictive of the surgical outcome. Excision of brainstem cavernomas should be considered in patients with symptomatic hemorrhages whose lesions approach the pial surface. Patients with minimal stable neurologic deficits without recurrent bleeds should be managed conservatively.

Stereotactic radiosurgery for deep-seated cavernous malformations: a move toward more active, early intervention. Clinical article.

OBJECT: The role of radiosurgery in the treatment of cavernous malformations (CMs) remains controversial. It is frequently recommended only for inoperable lesions that have bled at least twice. Rehemorrhage can carry a substantial risk of morbidity, however. The authors reviewed their practice of treating deep-seated inoperable CMs to assess the complication rate of radiosurgery, the impact that radiosurgery might have on rebleeding, and whether a more active, earlier intervention is justified in managing this condition. METHODS: The authors performed a retrospective analysis of 113 patients with 79 brainstem and 39 thalamic/basal ganglia CMs treated with Gamma Knife surgery. Lesions were stratified into 2 groups: those that might be lower risk with no more than 1 symptomatic bleed before radiosurgical treatment and those deemed high risk with multiple symptomatic hemorrhages before treatment. RESULTS: Forty-one CMs had multiple symptomatic hemorrhages before radiosurgery with a first-ever bleed rate of 2.9% per lesion per year, a rebleed rate of 30.5% per lesion per year, and a median time of 1.5 years between the first and second bleeds. In this group the rebleed rate decreased to 15% for the first 2 years after radiosurgery and declined further to 2.4% thereafter. Pretreatment multiple bleeds led to persistent deficits in 72% of the patients. Seventy-seven CMs had no more than 1 symptomatic bleed before radiosurgery, making for a lifetime bleed rate of 2.2% per lesion per year. The short period between the presenting bleed and treatment (median 1 year) makes the natural history in this group uncertain. The rate of hemorrhage in the first 2 years after treatment was 5.1%, and 1.3% thereafter. Pretreatment hemorrhages resulted in permanent deficits in 43% of the patients in this group, a rate significantly lower than in the multiple-bleeds group (p < 0.001). Posttreatment hemorrhages led to persistent deficits in only 7.3% of the patients. Permanent adverse radiation effects were rare (7.3%) and minor in both groups. CONCLUSIONS: Stereotactic radiosurgery is a safe management strategy for CMs in eloquent sites with the marked advantage of reducing rebleed risks in patients with repeated pretreatment hemorrhages. The benefit in treating CMs with a single bleed is less clear. Note, however, that repeated hemorrhage carries a significant risk of increased morbidity far in excess of any radiosurgery-related morbidity, and the authors assert that this finding justifies the early active management of deep-seated CMs.

Surgical management of brain cavernomas in children.

BACKGROUND: Cavernous hemangiomas are benign vascular hamartomas caused by developmental malformations of the vascular bed. They can be found in 0.3-0.7% of the population, whereas one fourth of these lesions occur in children. METHODS: In the present study, we report on 16 cases of cavernomas surgically treated in our institute. From each patient's file, the age, sex, lesion location, symptoms and follow-up were analyzed. RESULTS: The most commonly presenting symptom was epilepsy. Radiological signs of acute hemorrhage were observed in 3 cases. Three children had multiple cavernomas. The parietal lobe was the most common site of occurrence, whereas only 2 cavernomas were infratentorial. There was no operative mortality. Postoperatively, there was no additional neurological deficit, and all patients gradually improved. In a case of pontine cavernoma, there was a need for reoperation due to rebleeding. CONCLUSION: With the improvement of microsurgical techniques and modern neuroimaging, nearly all cavernomas can be safely removed. Total resection is associated with patients' clinical improvement and seizure control.

Cavernous malformations of the central nervous system in the pediatric age group.

OBJECTIVE: The main clinico-diagnostic features, risk factors and associated diseases of cavernous malformations (CMs), also called cavernous angiomas or cavernomas, of the central nervous system (CNS) in children are described, and the most relevant differences compared to the affected adult population are pointed out, focusing on the management of pediatric patients harboring cranial and spinal CMs. MATERIALS: This was a retrospective study of a series of 42 children symptomatic for CMs of the cranial and spinal compartments (35 supratentorial brain lesions, 5 infratentorial and 2 in the spinal region) operated on between 1975 and 2005, with a clinical follow-up ranging from 12 to 192 months. The results were compared with those found in the most recent literature dealing with pediatric CMs of the CNS. RESULTS: Surgical treatment produced excellent or good results in 69% of our 42 children. Unchanged neurological deficits were observed in 23.8% of cases, while morbidity from surgical procedures was 7.14%. Mortality was absent in this series. These surgical results are comparable with those found in the literature, where morbidity and mortality rates from surgery are 8.8 and 1.13%, respectively, and are mostly associated with procedures for the excision of deep, critically located cavernomas. CONCLUSION: CMs represent the most common CNS vascular lesion in children, although their incidence is 4 times lower than that of the adult population. The natural history of pediatric CMs throughout the neuraxis seems to be more aggressive than in adult patients; these lesions have higher rates of growth and hemorrhage, larger dimensions and often atypical radiological pictures at diagnosis. Beside the familial form of the disease, which is more often associated with multiple lesions and an earlier age of clinical presentation, the major risk factor for CMs in children seems to be radiotherapy for CNS tumors. Furthermore, a greater number of CMs coexistent with mixed angiomatous lesions have been reported in children than in adults. Surgical results are related to the preoperative neurological status of the children; symptomatic patients who are operated on early, before they develop severe neurological deficits or long-standing seizures, may achieve the best clinical outcome. Radiosurgery does not seem to be advisable in children as an alternative treatment for deep CMs or those causing epilepsy.

Symptomatic brainstem cavernomas.

OBJECTIVE: The goal of this study was to analyze the natural history of symptomatic brainstem cavernomas (medulla, pons, or midbrain) and outcome after surgical resection. METHODS: We retrospectively analyzed clinical data of all patients who presented to our institution with symptomatic brainstem cavernomas between 1995 and 2007 (n = 44). RESULTS: After a first neurological event, the median event-free interval was 2 years, with an annual event rate of 42%. After a second neurological event (new neurological deficit or significant worsening of the previous deficit), the median event-free interval was only 5 months, with a monthly event rate of 8%. After an observation period of up to 8 years, all patients ultimately underwent surgery. In 95% of the patients, surgery successfully prevented further events during a median follow-up period of 11 months (1 month-7 years; P < 0.001). The postoperative event rate was 5% per year in the first 2 years and 0% thereafter. In the multivariate analysis, only the preoperative modified Rankin scale score was predictive of the surgical outcome (odds ratio, 36.7; P = 0.015). The conditions of 2 patients (5%) were clinically worse compared with their preoperative conditions during the 1-year follow-up period; in one of these patients, this was caused by recurrent events. There was no mortality. CONCLUSION: The event rate of symptomatic lesions seems to be high, particularly after recurrent events. Surgical morbidity can be low. Timely and complete surgical resection is recommended for symptomatic brainstem cavernomas to prevent patients' functional decline owing to recurrent events.

Gamma knife surgery of brain cavernous hemangiomas.

OBJECT: The authors conducted a study to record more detailed information about the natural course and factors predictive of outcome following gamma knife surgery (GKS) for cavernous hemangiomas. METHODS: One hundred twelve patients with brain cavernous hemangiomas underwent GKS between 1993 and 2000. The median prescription dose was 16 Gy. One hundred seven patients were followed for a median of 48 months (range 6-114 months). The rebleeding rate was 1.6%, which is not significantly different with that prior to radiosurgery (2%). An increase in volume was observed in 1.8% of cases and a decrease in 45%. Perilesional edema was detected in 27% of patients, which, together with the rebleeding, caused a transient morbidity rate of 20.5% and permanent morbidity rate of 4.5%. Before radiosurgery 39% of patients suffered from epilepsy and this improved in 45% of them. Two patients with brainstem cavernous hemangiomas died due to rebleeding. Rebleeding was more frequent in female middle-aged patients with a history of bleeding, a larger lesion volume, and a prescription dose below 13 Gy. Edema after GKS occurred more frequently in patients who had surgery, a larger lesion volume, and in those in whom the prescription dose was more than 13 Gy. CONCLUSIONS: Gamma knife surgery of cavernous hemangiomas can produce an acceptable rate of morbidity, which can be reduced by using a lower margin dose. Lesion regression was observed in many patients. Radiosurgery seems to remain a suitable treatment modality in carefully selected patients.

Surgical decision-making on cerebral cavernous malformations.

This study is an attempt to clarify surgical decision-making on cerebral cavernous malformations based on the data available in the literature. Using a mathematical model, we calculated the morbidity-free survival curves of the patients harboring cerebral cavernous malformations. Using these survival curves, we calculated the morbidity-free life expectancies of the patients at certain age undergoing either natural course or surgery. For superficially located lesions, permissible surgical risks were very small ranging from 0.4 to 2.8 percent of combined morbidity and mortality. The surgical gain of morbidity free life expectancy was also very small (0.0-1.1 years) irrespective of patient's age or eloquence of the location. For deep lesions, the permissible risk of surgery was very large, ranging from 64.1% for a 20-year-old and 31.4% for a 60-year-old patient. The gain of morbidity-free life expectancy was also large for younger patients (17-25 years for 20-year-old patients), but this gain rapidly decreased as the patient's age grew older, becoming 1.1 to 3.1 years for 60-year-old patients. Surgery seems to be justified for younger patients with deep lesions. There seems to be little indication for surgery of superficial lesions as far as the risk of bleeding is concerned.