Contemporary radiosurgery of cerebral cavernous malformations: Part 2. Treatment outcome for hemispheric lesions

OBJECTIVEThe role of radiosurgery (RS) in treating superficial cavernous malformations (CMs) is insufficiently studied in part because of the disappointing results of early experimental attempts as compared to the mostly safe and effective microsurgery. Nonetheless, because of lesion- or treatment-specific factors, a therapeutic alternative may be required. In this study, the authors aimed to assess the safety of RS in treating superficial CMs and to analyze its long-term effect on hemorrhage rates and epilepsy control.METHODSThe authors conducted a retrospective analysis of 96 patients with 109 CMs located in the cerebral or cerebellar hemispheres and treated with RS between 1995 and 2014. A median of 15 Gy (range 10–25 Gy) was given to the 50% prescription isodose level, lesion volume was 604 mm3 (4–8300 mm3), and the prescription isodose volume was 638.5 mm3 (4–9500 mm3). Outcomes were compared to those of 206 deep-seated lesions reported on in another study. Ninety-five patients had available follow-up, which was a median of 7 years (1–21 years). Median patient age was 42 years (0.5–77) at presentation and 45 (3–80) at treatment. Seventy-one CMs presented with symptomatic hemorrhage, and 52 caused seizures.RESULTSIn the nonhemorrhagic group (37 lesions), one bleed occurred during the follow-up period, for an annual bleed rate of 0.4% per lesion. The lifetime annual bleed rate of CMs having a single hemorrhage prior to treatment was 2.5%. The rebleed rate in the single-bleed group decreased from 1.8% within the first 2 years after RS to 0.7% thereafter. The pretreatment rebleed rate for lesions having multiple bleeds prior to RS was 14.15%, which fell to 3.85% for the first 2 years after RS and declined to 1.3% thereafter. Multivariate analysis showed younger age, deep lesion location, and multiple pretreatment hemorrhages as significant predictors of posttreatment hemorrhage.Pretreatment hemorrhages led to permanent deficits in 41.4% of the cases with a single bleed and in 46.1% of cases with multiple bleeds. Only mild (modified Rankin Scale score 1) and a low rate of permanent neurological deficits were caused either by posttreatment hemorrhages (4.3%) or by radiation (2%).The rate of improvement in epilepsy was 84.9% after RS in patients with at least one seizure prior to treatment, not depending on the presence of hemorrhage or the time interval between presentation and treatment. Favorable outcome occurred in 81% of patients whose seizures were not controlled with antiepileptic medication prior to RS.CONCLUSIONSRadiosurgery for superficial CMs is safe and appears to be effective, offering a real treatment alternative to surgery for selected patients. Given their relatively benign natural history, superficial CMs require further study to verify the long-term benefit of RS over the lesions’ natural history.

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Contemporary radiosurgery of cerebral cavernous malformations: Part 1. Treatment outcome for critically located hemorrhagic lesions

Journal of Neurosurgery ◽

10.3171/2017.5.jns17776 ◽

2019 ◽

Vol 130 (6) ◽

pp. 1817-1825 ◽

Cited By ~ 4

Author(s):

Gábor Nagy ◽

Wendy Burkitt ◽

Stuart S. Stokes ◽

Debapriya Bhattacharyya ◽

John Yianni ◽

...

Keyword(s):

Natural History ◽

Current Knowledge ◽

Neurological Deficits ◽

Temporary Increase ◽

Long Term Effects ◽

Cavernous Malformations ◽

Intention To Treat ◽

Study Results

OBJECTIVELong-term benefits of radiosurgery (RS) applying modern protocols to treat cavernous malformations (CMs) remain unclear as critics may consider the decrease in the rebleed rate generally observed 2 years after RS as a reflection of the lesion’s natural history. The authors adopted an early intention-to-treat attitude since rehemorrhage from deep-seated CMs ultimately leads to stepwise neurological deterioration. The safety of this early policy was previously demonstrated. Here, the authors revisit their current practice in a larger population with a longer follow-up time to assess the long-term effects of RS in the context of current knowledge on the natural history of CMs.METHODSThe authors conducted a retrospective analysis of 210 patients with 210 hemorrhagic CMs located in the brainstem, thalamus, or basal ganglia and treated with Gamma Knife RS between 1995 and 2014. Two hundred six patients had available follow-up, which was a median of 5.5 years (range 1–20 years). The median age was 37 years (0.5–77 years) at presentation and 43 (2–78) at treatment. One hundred twenty-seven CMs had bled once and 83 had had multiple hemorrhages prior to treatment.RESULTSThe lifetime annual bleed rate of CMs having a single hemorrhage prior to treatment was 2.4% per lesion. The hemorrhage rate stabilized at 1.1% after a temporary increase of 4.3% within the first 2 years after RS. The annual pretreatment hemorrhage rate was 2.8% for the lesions having multiple bleeds prior to RS with a pretreatment rebleed rate of 20.7% and with a modest gradual decrease within the first 5 years and remaining stable at 11.55% thereafter. The rebleed rate fell to 7.9% for the first 2 years after RS and declined further to 1.3% thereafter, which was significantly lower than the long-term pretreatment rebleed risk. The rate of hemorrhage-free survival remained 86.4% and 75.1% (1 patient each) at 20 years after RS in the single- and multiple-bleed groups, respectively.Pretreatment hemorrhages resulted in permanent deficits in 48.8% of the cases with a single bleed and in 77.1% of the cases with multiple bleeds. Both the rate and severity of deficits were significantly lower in the first group. Only mild and a low rate of permanent neurological deficits were caused either by posttreatment hemorrhages (7.4%) or by radiation (7.2%). The rate of persistent morbidity in the single-bleed group remained significantly lower at the end of the study than pretreatment morbidity in the multiple-bleed group (OR 2.9, 95% CI 1.6–5.3). Lesion-specific mortality was < 1%.CONCLUSIONSThe hemorrhage rate of CMs after RS remained low after the first 2 years during the longer follow-up period. The benefit of early treatment appears to be confirmed by the study results as repeated hemorrhages carry the risk of significantly higher cumulative morbidity than the morbidity associated with RS.

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Natural history and treatment options of radiation-induced brain cavernomas: a systematic review

Neurosurgical Review ◽

10.1007/s10143-021-01598-y ◽

2021 ◽

Author(s):

Gildas Patet ◽

Andrea Bartoli ◽

Torstein R. Meling

Keyword(s):

Systematic Review ◽

Natural History ◽

Radiation Treatment ◽

Neurological Deficits ◽

Cochrane Library ◽

Average Dose ◽

Cavernous Malformations ◽

Radiation Induced ◽

The Mean

AbstractRadiation-induced cavernous malformations (RICMs) are delayed complications of brain irradiation during childhood. Its natural history is largely unknown and its incidence may be underestimated as RCIMS tend to develop several years following radiation. No clear consensus exists regarding the long-term follow-up or treatment. A systematic review of Embase, Cochrane Library, PubMed, Google Scholar, and Web of Science databases, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, was performed. Based on our inclusion/exclusion criteria, 12 articles were included, totaling 113 children with RICMs, 86 were treated conservatively, and 27 with microsurgery. We were unable to precisely define the incidence and natural history from this data. The mean age at radiation treatment was 7.3 years, with a slight male predominance (54%) and an average dose of 50.0 Gy. The mean time to detection of RICM was 9.2 years after radiation. RICM often developed at distance from the primary lesion, more specifically frontal (35%) and temporal lobe (34%). On average, 2.6 RICMs were discovered per child. Sixty-seven percent were asymptomatic. Twenty-one percent presented signs of hemorrhage. Clinical outcome was favorable in all children except in 2. Follow-up data were lacking in most of the studies. RICM is most often asymptomatic but probably an underestimated complication of cerebral irradiation in the pediatric population. Based on the radiological development of RICMs, many authors suggest a follow-up of at least 15 years. Studies suggest observation for asymptomatic lesions, while surgery is reserved for symptomatic growth, hemorrhage, or focal neurological deficits.

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Treatments and outcomes of untreated cerebral cavernous malformations in China: study protocol of a nationwide multicentre prospective cohort study

BMJ Open ◽

10.1136/bmjopen-2020-037957 ◽

2020 ◽

Vol 10 (10) ◽

pp. e037957

Author(s):

Fuxin Lin ◽

Qiu He ◽

Zhuyu Gao ◽

Lianghong Yu ◽

Dengliang Wang ◽

...

Keyword(s):

Informed Consent ◽

Natural History ◽

Study Protocol ◽

Treated Group ◽

Secondary Outcome ◽

Long Term Outcomes ◽

Cavernous Malformations ◽

Electronic Data Capture System

IntroductionThe treatment decision and long-term outcomes of previously untreated cerebral cavernous malformation (U-CCM) are still controversial. Therefore, we are conducting a nationwide multicentre prospective registry study in China to determine the natural history and effect of surgical treatment on long-term outcomes in Chinese people with U-CCM.Methods and analysisThis study was started on 1 January 2018 and is currently ongoing. It is a cohort follow-up study across a 5-year period. Patients will be followed up for at least 3 years after inception. Patients with U-CCM will be enrolled from 24 Grade III, level A hospitals distributed all over China. The cohort size is estimated to be 1200 patients. Patients are registered in surgically treated group and conservatively treated group. Clinical characteristics, radiology information and laboratory data are prospectively collected using an electronic case report form through an electronic data capture system. The primary outcome of this study is poor clinical outcome at the last follow-up (modified Rankin Scale score >2 lasting at least 1 year). The secondary outcome includes symptomatic haemorrhage, drug refractory epilepsy, focal neurological deficits, morbidity and all-cause mortality during follow-up. Univariate and multivariate regression analysis will be performed to determine the risk factors for poor outcomes in all patients, and to estimate the effect of surgery. Life tables, Kaplan-Meier estimates, log-rank test and proportional hazards Cox regression will be used to analyse the follow-up data of conservatively treated patients to determine the natural history of U-CCM. Initial presentation and location of U-CCM are prespecified subgroup factors.Ethics and disseminationThe study protocol and informed consent form have been reviewed and approved by the Research Ethical Committee of First Affiliated Hospital of Fujian Medical University (FAHFMU-2018-003).Written informed consent will be obtained from each adult participant or from the guardian of each paediatric participant. The final results will be published in peer-reviewed journals.Trial registration numberNCT03467295.

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Coexistence of intracranial and spinal cavernous malformations: a study of prevalence and natural history

Journal of Neurosurgery ◽

10.3171/jns.2006.104.3.376 ◽

2006 ◽

Vol 104 (3) ◽

pp. 376-381 ◽

Cited By ~ 47

Author(s):

Aaron A. Cohen-Gadol ◽

Jeffrey T. Jacob ◽

Diane A. Edwards ◽

William E. Krauss

Keyword(s):

Family History ◽

Natural History ◽

Mr Imaging ◽

Neurological Deficits ◽

Cavernous Malformations ◽

Recurrent Hemorrhage ◽

Long Term Follow Up ◽

History Of ◽

Clinically Significant

Object The purpose of this study was to examine the prevalence of intracranial cavernous malformations (CMs) in a large series of predominantly Caucasian patients with spinal cord CMs. The authors also studied the natural history of spinal CMs in patients who were treated nonoperatively. Methods The medical records of 67 consecutive patients (32 female and 35 male patients) in whom a spinal CM was diagnosed between 1994 and 2002 were reviewed. The patients’ mean age at presentation was 50 years (range 13–82 years). Twenty-five patients underwent resection of the lesion. Forty-two patients in whom the spinal CM was diagnosed using magnetic resonance (MR) imaging were followed expectantly. Thirty-three (49%) of 67 patients underwent both spinal and intracranial MR imaging. All available imaging studies were reviewed to determine the coexistence of an intracranial CM. Fourteen (42%) of the 33 patients with spinal CMs who underwent intracranial MR imaging harbored at least one cerebral CM in addition to the spinal lesion. Six (43%) of these 14 patients did not have a known family history of CM. Data obtained during the long-term follow-up period (mean 9.7 years, total of 319 patient-years) were available for 33 of the 42 patients with a spinal CM who did not undergo surgery. Five symptomatic lesional hemorrhages (neurological events), four of which were documented on neuroimaging studies, occurred during the follow-up period, for an overall event rate of 1.6% per patient per year. No patient experienced clinically significant neurological deficits due to recurrent hemorrhage. Conclusions As many as 40% of patients with a spinal CM may harbor a similar intracranial lesion, and approximately 40% of patients with coexisting spinal and intracranial CMs may have the nonfamilial (sporadic) form of the disease. Patients with symptomatic spinal CMs who are treated nonoperatively may have a small risk of clinically significant recurrent hemorrhage. The findings will aid in evaluation of surveillance images and in counseling of patients with spinal CMs, irrespective of family history.

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Supratentorial cerebral cavernous malformations: clinical, surgical, and genetic involvement

Neurosurgical FOCUS ◽

10.3171/foc.2006.21.1.10 ◽

2006 ◽

Vol 21 (1) ◽

pp. 1-7 ◽

Cited By ~ 25

Author(s):

Vincenzo Antonio D'Angelo ◽

Costanzo De Bonis ◽

Rosina Amoroso ◽

Alessandro Calì ◽

Leonardo D'Agruma ◽

...

Keyword(s):

Mutational Analysis ◽

Family Members ◽

Neurological Deficits ◽

Cerebral Cavernous Malformations ◽

Cavernous Malformations ◽

Psychological Burden ◽

Management Algorithm ◽

Screening Protocol

Object Although there is general agreement on the methods of treatment for symptomatic supratentorial cerebral cavernous malformations (CMs) located in noneloquent areas, some controversy exists regarding the management of cerebral CMs that are asymptomatic and/or located in eloquent or deep areas. Moreover, recent advances in genetic findings could influence both standard clinical management and the follow-up strategy in affected individuals. Thus, the objective of this study was to develop, based on the authors' experience and a literature review, a management algorithm to deal with supratentorial cerebral CMs. Methods The authors retrospectively reviewed the clinical data related to 118 patients who underwent surgery for symptomatic supratentorial cerebral CMs at their institution. Twenty-eight of 118 patients harbored multiple lesions, and nine of these 28 patients had a clinically positive familial history. Genetic investigations were performed in 89 patients (75%). Conclusions Surgery for supratentorial cerebral CMs in noneloquent locations is safe and curative. In cerebral CMs located in deep and eloquent areas and with symptoms including progressive neurological deficits, evidence of hemorrhage, and uncontrolled seizures, surgical treatment according to an integrated plan based on frameless stereotactic guidance and functional magnetic resonance imaging is recommended and results in acceptably low morbidity. The data support the need for long-term imaging follow up in all patients, careful preoperative vascular studies to detect associated venous anomalies, and the importance of genetic mutational analysis. The DNA screening protocol will change the care of family members of patients with familial forms of cerebral CMs, because affected asymptomatic family members may benefit by early detection of lesions. At the same time, the exclusion of family members who are not carriers of the mutation as members of the population at risk reduces the economic and psychological burden of clinical and instrumental monitoring.

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Cavernous Malformation of Brainstem, Thalamus, and Basal Ganglia

Neurosurgery ◽

10.1227/neu.0b013e318283c9c2 ◽

2012 ◽

Vol 72 (4) ◽

pp. 573-589 ◽

Cited By ~ 65

Author(s):

Paritosh Pandey ◽

Erick M. Westbroek ◽

Peter A. Gooderham ◽

Gary K. Steinberg

Keyword(s):

Basal Ganglia ◽

Neurological Deficits ◽

Term Outcome ◽

Cavernous Malformations ◽

Long Term Outcome ◽

Brain Malformations ◽

Hemorrhage Risk ◽

Clinical Records

Abstract BACKGROUND: Cavernous malformations (CMs) in deep locations account for 9% to 35% of brain malformations and are surgically challenging. OBJECTIVE: To study the clinical features and outcomes following surgery for deep CMs and the complication of hypertrophic olivary degeneration (HOD). METHODS: Clinical records, radiological findings, operative details, and complications of 176 patients with deep CMs were reviewed retrospectively. RESULTS: Of 176 patients with 179 CMs, 136 CMs were in the brainstem, 27 in the basal ganglia, and 16 in the thalamus. Cranial nerve deficits (51.1%), hemiparesis (40.9%), numbness (34.7%), and cerebellar symptoms (38.6%) presented most commonly. Hemorrhage presented in 172 patients (70 single, 102 multiple). The annual retrospective hemorrhage rate was 5.1% (assuming CMs are congenital with uniform hemorrhage risk throughout life); the rebleed rate was 31.5%/patient per year. Surgical approach depended on the proximity of the CM to the pial or ependymal surface. Postoperatively, 121 patients (68.8%) had no new neurological deficits. Follow-up occurred in 170 patients. Delayed postoperative HOD developed in 9/134 (6.7%) patients with brainstem CMs. HOD occurred predominantly following surgery for pontine CMs (9/10 patients). Three patients with HOD had palatal myoclonus, nystagmus, and oscillopsia, whereas 1 patient each had limb tremor and hemiballismus. At follow-up, 105 patients (61.8%) improved, 44 (25.9%) were unchanged, and 19 (11.2%) worsened neurologically. Good preoperative modified Rankin Score (98.2% vs 54.5%, P = .001) and single hemorrhage (89% vs 77.3%, P < .05) were predictive of good long-term outcome. CONCLUSION: Symptomatic deep CMs can be resected with acceptable morbidity and outcomes. Good preoperative modified Rankin Score and single hemorrhage are predictors of good long-term outcome.

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Spontaneous improvement in urological dysfunction in children with congenital spinal lipomas of the conus medullaris

Journal of Neurosurgery Pediatrics ◽

10.3171/2014.2.peds13519 ◽

2014 ◽

Vol 13 (5) ◽

pp. 536-540 ◽

Cited By ~ 1

Author(s):

Jetan H. Badhiwala ◽

Eric M. Thompson ◽

Armando J. Lorenzo ◽

Abhaya V. Kulkarni

Keyword(s):

Natural History ◽

Conus Medullaris ◽

Neurological Deficits ◽

Long Term Follow Up ◽

Lower Urinary Tract Function ◽

Tract Function ◽

History Of ◽

Spontaneous Improvement

Congenital spinal lipomas of the conus (SLCs) are among the most common closed neural tube defects. The treatment of SLC is an area of controversy because the true natural history of this condition is unknown. Here, the authors present two cases of SLC presenting in infancy with compromised lower urinary tract function, which was objectively confirmed by abnormal urodynamic studies. In both cases, there was spontaneous improvement in urodynamic parameters, with stable normal urinary function at the long-term follow-up. Although cases of spontaneous radiological regression of SLC have very infrequently been reported, they have not been associated with the reversal of already present neurological deficits. This report reinforces the need for further delineation of the true natural history of SLC and highlights the dynamic nature of associated neurological compromise over time.

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Cerebral Cavernous Malformations: Patient-Reported Outcome Validates Conservative Management

Cerebrovascular Diseases ◽

10.1159/000480125 ◽

2017 ◽

Vol 44 (5-6) ◽

pp. 313-319 ◽

Cited By ~ 3

Author(s):

Vitor Chehuen Bicalho ◽

Anke Bergmann ◽

Flávio Domingues ◽

João Thiago Frossard ◽

Jorge Paes Barreto Marcondes de Souza

Keyword(s):

Vascular Malformations ◽

Patient Reported Outcome ◽

Neurological Deficits ◽

Cerebral Cavernous Malformations ◽

Cavernous Malformations ◽

Familial Form ◽

Sf 36 ◽

Patient Reported

Background: Cerebral cavernous malformations (CCM) are clusters of dilated sinusoidal channels lined by a single layer of endothelium. In contradistinction to arteriovenous malformations, these lesions do not have smooth muscle or elastin in their lining and they are angiographically occult, and the MRI is the most sensitive test for CCM detection. CCM are one of the most prevalent vascular malformations of the central nervous system, affecting about 0.4-0.6% of the general population. The main complication of this malformation is the risk of bleeding, which may cause neurological deficits that affect the quality of life (QoL) in patients. When symtomatic, they may be surgically treated for relieving the mass effect and seizures refractory to drug uses, hemorrhage and drug-refractory epilepsy. Patient-reported outcome (PRO) may be a strategy that can be used to evaluate QoL of CCM population and was used in a sample of non-operated patients. Methods: An observational, cross-sectional analysis to evaluate the PRO using the SF-36 and EuroQol 5 dimensions (EQ-5D) questionnaires of QoL added to functional metrics using the Karnofsky Performance Status (KPS) in 49 patients not submitted to intervention and with long-term follow-up. Results: During the 364 person-years of follow-up, there was an average of individual follow-up of 7.42 years. The mean age was 46.8 years (18-84) - 57% of them were female, 71% had superficial lesions, and 65% had the familial form. Comparisons of SF-36 dimensions with KPS graded <100 had a worse score only in terms of the pain (p = 0.04), vitality (p = 0.001), and general state of health (p = 0.03) domains. The domain mental health was worse in patients without surgical indication (p = 0.032). The functional capacity domain had the highest overall grading in the group. The EQ-5D dimensions of mobility (p = 0.03) and pain/discomfort (p = 0.001) were the ones with lower score compared to KPS <100. Conclusion: The study is the first to evaluate, with validated tools, the PRO of non-operated CCM patients and has demonstrated in a selected group of patients that it was possible to achieve long-term clinical stability, thereby maintaining QoL and functional neurological outcome.

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The natural history of cerebral cavernous malformations

Journal of Neurosurgery ◽

10.3171/jns.1995.83.5.0820 ◽

1995 ◽

Vol 83 (5) ◽

pp. 820-824 ◽

Cited By ~ 416

Author(s):

Douglas Kondziolka ◽

L. Dade Lunsford ◽

John R. W. Kestle

Keyword(s):

Natural History ◽

Management Strategies ◽

Operative Management ◽

Neurological Deficits ◽

Cavernous Malformations ◽

Content Type ◽

Increased Risk ◽

History Of ◽

Fine Print

✓ To determine the natural history of brain cavernous malformations, the authors entered patients referred to their center into a prospective registry between 1987 and 1993. All patients underwent magnetic resonance imaging, which showed the typical appearance of this lesion, and conservative management was recommended in all. Patients or their referring physicians were contacted for follow-up data. The purpose of the study was to define the rate of symptomatic hemorrhage and to determine the outcome in those patients who had suffered seizures. Follow-up data were available for 122 patients with a mean age at entry of 37 years (range 4–82 years). The malformation was located in the brainstem in 43 cases (35%), the basal ganglia/thalamus in 20 (17%), and a hemispheric area in 59 (48%). Fifty percent of patients had never had a symptomatic hemorrhage, 41% had one bleed, 7% had two, and 2% had three. Seizures were reported in 23% of patients and headaches in 15%. Lesions were solitary in 80% of patients and multiple in 20%. The retrospective annual hemorrhage rate (61 bleeds/4550.6 patient-years of life) was 1.3%. The mean prospective follow-up period was 34 months. There were nine bleeds during this time, six with new neurological deficits. In patients without a prior bleed, the prospective annual rate of hemorrhage was 0.6%. In contrast, patients with prior hemorrhage had an annual bleed rate of 4.5% (p = 0.028). Patient sex (p = 0.97) or the presence of seizures (p = 0.11), headaches (p = 0.06), or solitary versus multiple lesions (p = 0.15) were not significant predictors of later hemorrhage. There was no difference in the rate of bleeds between brain locations. Four patients with seizures became seizurefree and four patients without seizures later developed seizures; only one patient developed intractable seizures. Fourteen patients (11%) underwent surgery (two after hemorrhage, five with seizures, and seven with progressive deficits), and five had radiosurgery. No patient died in the follow-up period. This study indicates that conservative versus operative management strategies may need to be redefined, especially in patients who present with hemorrhage and who appear to have a significantly increased risk of subsequent rehemorrhage.

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