Hemorrhagic Outcome of Brainstem Cavernous Malformations following Radiosurgery: Dose-Response Relationship.

INTRODUCTION: This study aimed to assess the impact of gamma knife radiosurgery on brainstem cavernous malformations (CMs). METHODS: A total of 85 patients (35 females; median age 41.0 years) who underwent gamma knife radiosurgery for brainstem CMs at our institute between 2006 and 2015 were enrolled in a prospective clinical observation trial. Risk factors for hemorrhagic outcomes were evaluated, and outcomes were compared across different margin doses. RESULTS: The pre-radiosurgery annual hemorrhage rate (AHR) was 32.3% (44 hemorrhages during 136.2 patient-years). The median planning target volume was 1.292 cc. The median margin and maximum doses were 15.0 and 29.2 Gy, respectively, with a median isodose line of 50.0%. The post-radiosurgery AHR was 2.7% (21 hemorrhages during 769.9 patient-years), with a rate of 5.5% within the first 2 years and 2.0% thereafter. The post-radiosurgery AHR for patients with margin doses of ≤13.0 Gy (n = 15), 14.0-15.0 Gy (n = 50), and ≥16.0 Gy (n = 20) was 5.4, 2.7, and 0.6%, respectively. Correspondingly, transient adverse radiation effects were observed in 6.7 (1/15), 10.0 (5/50), and 30.0% (6/20) of cases, respectively. An increased margin dose per 1 Gy (hazard ratio: 0.530, 95% CI: 0.341-0.826, p = 0.005) was identified as an independent protective factor against post-radiosurgery hemorrhage. Margin doses of ≥16.0 Gy were associated with improved hemorrhagic outcomes (hazard ratio: 0.343, 95% confidence interval [CI]: 0.157-0.749, p = 0.007), but an increased risk of adverse radiation effects (odds ratio: 3.006, 95% CI: 1.041-8.677, p = 0.042). CONCLUSION: The AHR of brainstem CMs decreased following radiosurgery, and our study revealed a significant dose-response relationship. Margin doses of 14-15 Gy were recommended. Further studies are required to validate our findings.

Radiosurgery effects and adverse effects in symptomatic eloquent brain-located Cavernomas.

In this study, the dose schedule efficacy, safety and late adverse effects of stereotactic radiosurgery (SRS) were evaluated for patients with symptomatic cavernomas who were not eligible for surgery and treated with SRS. Between January 2013 and December 2018, 53 patients with cavernomas were treated using SRS with the CyberKnife® system. Patients' diseases were deeply located or were in subcortical functional brain regions. In addition to bleeding, 23 (43.4%) patients had epilepsy, 12 (22.6%) had neurologic symptoms and 16 patients (30.2%) had severe headaches. The median volume was 741 (range, 421-1351) mm3, and the median dose was 15 (range, 14-16) Gy in one fraction. After treatment, six (50%) of 12 patients with neurologic deficits still had deficits. Rebleeding after treatment developed in only two (3.8%) patients. The drug was completely stopped in 14 (60.9%) out of 23 patients who received epilepsy treatment, and the dose of levetiracetam decreased from 2000 mg to 1000 mg in four (17.3%) of nine patients. Radiologically, complete response (CR) was observed in 13 (24.5%) patients, and partial responses (PR) were observed in 32 (60.2%) patients. Clinical response of CR was observed in 30 (56.6%) patients, PR was observed in 16 (30.2%), stable disease (SD) was observed in three (5.7%) and four (7.5%) patients progressed. In conclusion, SRS applied in the appropriate dose schedule may be an effective and reliable method in terms of symptom control and prevention of rebleeding, especially in patients with inoperable cavernomas.

Management of pediatric cerebral cavernous malformations with gamma knife radiosurgery: a report of 46 cases.

INTRODUCTION: Pediatric cerebral cavernous malformations (CCMs) are commonly treated vascular anomalies with different clinical characteristics than their adult counterparts. Outcomes of Gamma Knife Radiosurgery (GKRS) for pediatric CCMs have not explicitly been reported. This paper reports our experience in managing pediatric CCMs with GKRS. METHODS: We retrospectively reviewed the clinical features, GKRS parameters, and clinical and radiological outcomes of 46 children with 64 CCMs. RESULTS: A total of 46 children, including 19 girls and 27 boys, with a median age of 16 years (3-17 years), were enrolled in the study. The median age at first CCM diagnosis was 13 years (range, 2-17 years). Twenty-two patients (47.8%) had more than one neurological symptom at the time of diagnosis, and the most common presenting symptom was seizure (28.3%). The most common location was supratentorial superficial (53.1%), and 17.4% of patients had multiple CCMs. A developmental venous anomaly was detected in 5 patients (10.9%). During a total of 52.4 retrospective patient-years in patients with > 1 hemorrhage episode, the calculated annual hemorrhage rate was 40.1%. The median post-GKRS follow-up was 79 months (range, 19-175 months), with an overall 306.2 prospective patient years. The annual hemorrhage rate (AHR) during the first 2 years after GKRS and after the initial 2 years was 1.11% and 0.46%, respectively. Regarding clinical factors and GKRS parameters, univariate analysis revealed a significant association with post-GKRS AHR and volume (p = 0.023) only. Patients with pre-GKRS seizures showed favorable seizure control (Engel class I and II) in 8 children (61.5%). There was no mortality in our series. CONCLUSION: Low AHR following GKRS with no radiation-induced toxicity makes GKRS a therapeutic alternative for pediatric CCMs.

Stereotactic radiosurgery for cerebral cavernous malformation: comparison of hemorrhage rates before and after stereotactic radiosurgery.

OBJECTIVE: Cerebral cavernous malformation (CM) is an angiographically occult vascular pathology. Although microsurgery is the gold standard treatment to control the symptoms of CM, resection carries high risk in some situations, especially eloquent areas. The objective was to evaluate annual hemorrhage rates (AHRs) before and after stereotactic radiosurgery (SRS) treatment of cerebral CM in different locations. METHODS: A total of 195 patients (119 women and 76 men) with CM treated at the Gazi University Gamma Knife Center between April 2005 and June 2017 were analyzed. The mean ± SD follow-up period was 67.4 ± 31.1 months (range 12 days to 170 months). AHR before SRS, AHR after SRS, morbidity associated with radiation, seizure control rate after SRS, lesion volume, coexistence with developmental venous anomaly, and SRS treatment parameters were analyzed, with evaluation of radiological data and clinical charts performed retrospectively. The seizure control rate was assessed using the Engel outcome scale. RESULTS: The AHR before SRS was 15.3%. Application of SRS to these patients significantly reduced the AHR rates to 2.6% during the first 2 years after treatment and to 1.4% thereafter. Favorable seizure control (Engel class I and II) after radiosurgery was achieved in 23 patients (88.5%) with epilepsy. Radiation-related temporary complications occurred in 15.4% of patients, and permanent morbidity occurred in 4.6%. CONCLUSIONS: SRS is a safe and effective treatment modality for reducing the hemorrhage risk of CM. The authors suggest that SRS should be considered for the treatment of patients with CM, high surgical risks, and hemorrhage history, instead of a using a wait-and-see policy.

Outcome of intracerebral cavernoma treated by Gamma Knife radiosurgery based on a double-blind assessment of treatment indication.

BACKGROUND: The benefit and the risk profile of Gamma Knife radiosurgery (GKRS) for intracerebral cavernoma remains incompletely defined in part due to the natural history of low incidence of bleeding and spontaneous regression of this vascular malformation. In this study, we retrieved cases from a prospectively collected database to assess the outcome of intracerebral cavernoma treated with GKRS using a double blinded review process for treatment. METHODS: From 2003 to 2018, there were 94 cases of cavernoma treated by GKRS in the doubly blinded assessments by two experienced neurological and approved for GKRS treatment. All the patients received GKRS with margin dose of 11-12 (Gray) Gy and afterwards were assessed for neurological outcome, radiologic response, and quality of life. RESULTS: The median age of the patients was 48 (15-85) years with median follow up of 77 (26-180) months post SRS. The mean target volume was 1.93 ± 3.45 cc. In those who has pre-SRS epilepsy, 7 of 16 (43.7%) achieved seizure freedom (Engel I/II) and 9 of 16 (56.3%) achieved decreased seizures (Engel III) after SRS. Rebleeding occurred in 2 cases (2.1%) at 13 and 52 months post SRS. The radiologic assessment demonstrated 20 (21.3%) cases of decreased cavernoma volume, 69 (73.4%) were stable, and 5 (7.3%) increased size. Eighty-seven of 94 (92.5%) cases at the last follow up achieve improvement in their quality of life, but 7 cases (7.4%) showed a deterioration. In statistical analysis, the effective seizure control class (Engel I/II) was highly correlated with patient harboring a single lesion (p < 0.05) and deep seated location of the cavernoma (p < 0.01). New neurological deficits were highly correlated with decreased mental (p < 0.001) and physical (p < 0.05) components of quality of life testing, KPS (p < 0.001), deep seated location (p < 0.01), and increased nidus volume (p < 0.05). Quality of life deterioration either in physical component (p < 0.01), mental component (p < 0.01), and KPS (p < 0.05) was highly correlated with increased cavernoma volume. CONCLUSION: Low margin dose GKRS for intracerebral cavernoma offers reasonable seizure control and improved quality of life while conferring a low risk of treatment complications including adverse radiation effect.

Gamma Knife radiosurgery for cerebral cavernous malformation.

This is a retrospective study examining the efficacy and safety of Gamma Knife radiosurgery (GKS) in treating patients with cerebral cavernous malformations (CCMs). Between 1993 and 2018, 261 patients with 331 symptomatic CCMs were treated by GKS. The median age was 39.9 years and females were predominant (54%). The median volume of CCMs was 3.1 mL. The median margin dose was 11.9 Gy treat to a median isodose level of 59%. Median clinical and imaging follow-up times were 69 and 61 months, respectively. After the initial hemorrhage that led to CCM diagnosis, 136 hemorrhages occurred in the period prior to GKS (annual incidence = 23.6%). After GKS, 15 symptomatic hemorrhages occurred within the first 2 years of follow-up (annual incidence = 3.22%), and 37 symptomatic hemorrhages occurred after the first 2 years of follow-up (annual incidence = 3.16%). Symptomatic radiation-induced complication was encountered in 8 patients (3.1%). Mortality related to GKS occurred in 1 patient (0.4%). In conclusion, GKS decreased the risk of hemorrhage in CCM patients presenting with symptomatic hemorrhage. GKS is a viable alternative treatment option for patients with surgically-inaccessible CCMs or significant medical comorbidities.

Stereotactic radiosurgery for cerebral cavernous malformations: A systematic review.

OBJECTIVE: The efficacy of stereotactic radiosurgery (SRS) for the treatment of cerebral cavernous malformations (CCMs) is uncertain, so we set out to quantify clinical outcomes after SRS for CCM and compare them to microsurgical excision or conservative management. METHODS: We searched Ovid Medline and Ovid EMBASE from inception until June 1, 2018, for peer-reviewed publications describing clinical outcomes after SRS for ≥10 people with CCM in cohorts with or without a comparison group treated with neurosurgical excision or conservative management. Two reviewers independently extracted data from the included studies to quantify cohort characteristics and the incidence of the primary outcome (death attributable to CCM or its treatment) and secondary outcomes (incident nonfatal symptomatic intracerebral hemorrhage [ICH] and incident nonhemorrhagic persistent focal neurologic deficit [FND]). We assessed whether comparative studies showed a dramatic association (meaning the conventionally calculated probability comparing 2 differently managed patient groups from the same population was <0.01 with a rate ratio greater than 10). RESULTS: We included 30 cohort studies involving a total of 1,576 patients undergoing SRS for CCM. Four nonrandomized studies compared SRS to other treatment strategies, but did not demonstrate dramatic associations. During a median follow-up of 48 (interquartile range 35-62) months after SRS, the annual incidences (95% confidence interval) of outcomes were death 0.18% (0.10-0.31), ICH 2.40% (2.05-2.80), FND 0.71% (0.53-0.96), and the composite of death, ICH, or FND 3.63% (3.17-4.16). Outcomes did not differ by CCM location or type of SRS. CONCLUSION: After SRS for CCM, the annual incidences of death, ICH, and FND are <5% and seem comparable to outcomes without SRS. A randomized trial of SRS for CCM is needed.

Leksell Stereotactic Radiosurgery for Cavernous Malformations.

Cavernous malformations (CM) represent a distinct subgroup of brain vascular malformations that are characterized by small sinusoidal vascular channels with hyaline degeneration and old blood pigments. Because of the increasing availability of magnetic resonance imaging (MRI) they are detected much more frequently in the present era. CM may be solitary or found in the context of a familial variant that results in an increasing number of CM developing as the patient ages. Because of the variable risk of subacute bleeding, their management options have been controversial. The annual risk of an incidentally detected CM bleeding is <0.5% each year. Leksell radiosurgery is used for a subgroup of patients who have repeatedly bled. In general, CM best considered for stereotactic radiosurgery are deep seated and do not pre-sent to a pial or ependymal surface where microsurgical corridors for removal are feasible. When radiosurgery is used for patients at high risk for both re-bleeding as well as microsurgical resection, the risk of bleeding can be reduced from as high as 33% each year to <0.5% each year after a 2-year latency interval. The target lies within the hemosiderin rim detected during the MRI that is part of planning. Marginal doses are significantly less than those used for angiographically visible arteriovenous malformations.

Stereotactic radiosurgery for hypervascular intracranial tumors.

OBJECTIVE: To evaluate the safety and efficacy of SRS treatment of central neurocytomas (CNCs), cavernous sinus hemangiomas (CSHs), and glomus tumors (GTs); and to compare upfront stereotactic radiosurgery (SRS) and adjuvant SRS in the treatment of these hypervascular tumors. METHODS: This was a retrospective review of consecutive CNCs, CSHs, and GTs treated with SRS between 1993 and 2017. Tumor response was categorized based on volumetric analysis on magnetic resonance imaging: (1) tumor regression [> 10% decrease in tumor volume (TV)]; (2) stable tumor (≤ 10% change in TV); or (3) tumor progression (> 10% increase in TV). RESULTS: Sixty hypervascular tumors (CNC: 28; CSH: 16; GT: 16) underwent SRS between 1993 and 2017. Margin doses were 13 Gy, 12 Gy, and 14 Gy for CNCs, CSHs, and GTs, respectively. Tumor regression was observed in 54 tumors (90%) with initial SRS after a median follow-up of 82 months. Relative reductions in TVs for CNCs were 38%, 52%, and 73% at 12, 24, and 48 months, respectively. Relative reductions in TVs for CSHs were 51%, 68%, and 88% at 12, 24, and 48 months, respectively. Relative reductions in TVs for GTs were 22%, 31%, and 47% at 12, 24, and 48 months, respectively. Upfront SRS was performed in 26 patients (43%). No difference in relative TV reductions were found between upfront and adjuvant SRS. Adverse radiation effects were observed in five patients. No mortality was encountered. CONCLUSION: SRS for hypervascular tumors is associated with high rates of tumor regression with low risk of complications. No significant difference in rates of relative TV reduction were found between upfront and adjuvant SRS. Hence, upfront SRS may be considered in select patients.

Long-Term Outcome of Gamma Knife Radiosurgery for Brain Cavernoma: Factors Associated with Subsequent De Novo Cavernoma Formation.

BACKGROUND: We aimed to evaluate the factors associated with de novo brain cavernoma formations after patients underwent gamma knife radiosurgery (GKRS) and confirmed whether developmental venous anomaly (DVA) presented with a cavernoma and whether the cavernoma was included in the GKRS target location. METHODS: From January 2003 to December 2008, 95 patients underwent radiosurgery for brain cavernoma at our institution. Of these, 15 with multiple cavernomas related to familial cavernoma or with a history of surgical treatment for cavernoma were excluded. A total of 80 patients (44 men and 36 women; average age, 39.4 years) with sporadic cavernoma were retrospectively analyzed by considering the patient characteristics, including sex, age, target volume, radiation dose, clinical symptoms, cavernoma location, radiosurgery complications, and morphology of DVA. RESULTS: The average target volume, mean radiation dose, and mean target percentage were 1019.2 mm3, 13.7 Gy, and 51.1%, respectively. Nineteen patients showed cavernomas associated with DVA; of these, de novo cavernoma formations were noticed in 4 patients at a median of 49.5 months after undergoing GKRS. All de novo cavernomas were related to the presence of DVA and were located near the brainstem or cerebral peduncle. De novo cavernomas occurred when DVAs were not included in the GKRS-target location. CONCLUSIONS: All de novo cavernomas were located near the brainstem or cerebral peduncle, and they occurred in the presence of DVAs. The presence of DVA in the radiosurgery target location might be potentially an important factor associated with de novo cavernoma formation.

Cavernous Sinus Hemangioma: Rare Vascular Tumor of Cavernous Sinus.

Cavernous sinus hemangiomas (CSHs) are rare vascular tumors, which are infrequently encountered in everyday neurosurgical practice. Attempted resection of this lesion without preoperative planning carries a high risk for significant blood loss and cranial neuropathies. Radiation treatments can provide an alternative and safe treatment modality for these lesions. Therefore an increased awareness is warranted for their clinical suspicion. We reported on a patient who presented with visual deficits and a mass in the sellar, suprasellar, and middle fossa regions. Given the high suspicion for a CSH due to characteristic radiologic findings, a keyhole craniotomy approach was safely used for an open biopsy. The final pathology was consistent with a CSH, and the patient subsequently underwent radiation therapy without complications.

Significant Hemorrhage Rate Reduction after Gamma Knife Radiosurgery in Symptomatic Cavernous Malformations: Long-Term Outcome in 95 Case Series and Literature Review.

BACKGROUND: The natural history of cavernous malformations (CMs) has remained unclear. This lack of knowledge has made treatment decisions difficult. Indeed, the use of stereotactic radiosurgery is nowadays controversial. The purpose of this paper is to throw light on the effectiveness of Gamma Knife radiosurgery (GKRS) therapy. METHODS: The authors reviewed data collected from a prospectively maintained database. A total of 95 patients (57 female and 38 male) underwent GKRS for high-surgical-risk CMs. A total of 76 cavernomas were deeply located (64 lesions in the brainstem and 12 lesions in the thalamus). All of them were located in eloquent regions. The median malformation volume was 1,570 mm3. The median tumor margin dose was 11.87 Gy, and the mean tumor maximum dose was 19.56 Gy. RESULTS: Ninety-five cavernous CMs were managed from 1994 to 2014. All patients had experienced at least 1 symptomatic bleeding incident before treatment (only 1 hemorrhage event in 81%). The median length of follow-up review was 78 months. The pretreatment annual hemorrhage rate was 3.06% compared with 1.4% during the first 3-year latency interval, and 0.16% thereafter (p = 0.004). Four patients developed new location-dependent neurological deficits, and 3 patients had edema-related headache after radiosurgery. All of them presented full recovery. CONCLUSIONS: The best dosage range for preventing bleeding was identified as between 11 and 12 Gy in our series. Although the efficacy of radiosurgery in CMs remains impossible to quantify, a very significant reduction in the bleeding rate occurs after a 3-year latency interval. No permanent neurological morbidity is reported in our series. These results defend the safety of GKRS in surgical high-risk CM from the first bleeding event.

Management of Cerebral Radiation Necrosis: A Retrospective Study of 12 Patients.

BACKGROUND: Cerebral radiation necrosis (RN) is a severe complication of radiotherapy for cerebral pathologies. This study discusses the radiographic and pathological features of 12 patients with RN and investigates the management strategy. METHODS: Eleven patients with brain tumors, and one with cerebral cavernous angioma, treated by surgical resection or Gamma Knife alone before radiotherapy developed RN during follow-up. Surgical resection for the cerebral RN was performed in nine patients, and the other three patients received medical treatment. The clinical features, magnetic resonance imaging (MRI), surgical findings, and pathological sections are reviewed. RESULTS: The diagnosis of RN was confirmed by histological study in all the patients; those with surgical and medical treatment recovered. CONCLUSION: As a major complication of radiotherapy, from the clinical and neuroradiological points of view, RN may simulate tumor recurrence. Due to the increasing number of patients with RN who will need to be treated in future years, the definite diagnosis and appropriate treatment of RN remain critical.

Gamma Knife radiosurgery for hemangioma of the cavernous sinus.

OBJECTIVE Cavernous sinus hemangiomas (CSHs) are rare vascular tumors. A direct microsurgical approach usually results in massive hemorrhage and incomplete tumor resection. Although stereotactic radiosurgery (SRS) has emerged as a therapeutic alternative to microsurgery, outcome studies are few. Authors of the present study evaluated the role of SRS for CSH. METHODS An international multicenter study was conducted to review outcome data in 31 patients with CSH. Eleven patients had initial microsurgery before SRS, and the other 20 patients (64.5%) underwent Gamma Knife SRS as the primary management for their CSH. Median age at the time of radiosurgery was 47 years, and 77.4% of patients had cranial nerve dysfunction before SRS. Patients received a median tumor margin dose of 12.6 Gy (range 12-19 Gy) at a median isodose of 55%. RESULTS Tumor regression was confirmed by imaging in all 31 patients, and all patients had greater than 50% reduction in tumor volume at 6 months post-SRS. No patient had delayed tumor growth, new cranial neuropathy, visual function deterioration, adverse radiation effects, or hypopituitarism after SRS. Twenty-four patients had presented with cranial nerve disorders before SRS, and 6 (25%) of them had gradual improvement. Four (66.7%) of the 6 patients with orbital symptoms had symptomatic relief at the last follow-up. CONCLUSIONS Stereotactic radiosurgery was effective in reducing the volume of CSH and attaining long-term tumor control in all patients at a median of 40 months. The authors' experience suggests that SRS is a reasonable primary and adjuvant treatment modality for patients in whom a CSH is diagnosed.

Sensitivity of patients with familial cerebral cavernous malformations to therapeutic radiation.

Familial cerebral cavernous malformations are autosomal dominant conditions that can result in significant morbidity. A two-hit mechanism is accepted as likely responsible for formation of these malformations. We present two patients with this disease who received therapeutic radiation and developed very high numbers of malformations within the radiation ports, supporting radiation as an accelerator of lesion formation and suggesting implications for risks of radiation in this disease.

Primary central nervous system histiocytic sarcoma presenting as a postradiation sarcoma: case report and literature review.

Histiocytic sarcoma (HS) is a rare neoplasm that occurs most commonly in the intestinal tract, skin, soft tissue, and lymph node. The incidence of primary central nervous system (CNS) HS is even rarer, with a total of 6 cases reported in the literature. An etiologic link has not been identified for CNS HS, and the current case of primary CNS HS is unique in that an etiologic link to prior radiation therapy is identified, associated with complex cytogenetic abnormalities in the tumor. Although radiation-associated sarcomas can present as any number of different pathologic entities, this is the first reported case of a radiation-associated CNS HS. The pathologic and immunophenotypic characteristics of this case, with a nearly obscuring heavy inflammatory infiltrate and expression of monocytic/histiocytic markers (CD163, CD68, CD4, fascin), are characteristic of CNS HS. A discussion of the differential diagnosis and review of relevant literature are presented.

[Lacunar infarction in brain tumor patients: chronic stage complication after radiation therapy].

The authors reported two relatively young adults with lacunar infarction that took place many years after radiation therapy. The first case was that of a 41-year-old male presenting with a slight decrease in consciousness and right hemiparesis of sudden occurrence. MRI revealed a lacunar infarction in the left internal capsule. This patient had received radiation therapy and chemotherapy for a right basal ganglia germinoma when he was 24 years old. The tumor completely disappeared and he was able to return to work. The second case was a 24-year-old female presenting with dysesthesia in the right upper extremity and nausea of sudden occurrence. MRI disclosed a lacunar infarct in the right corona radiata. The patient had received radiation therapy for a suprasellar tumor when she was 11 years old. The tumor considerably decreased in size and the patient conducted normal social life thereafter. MRI showed a lacunar infarction in the right corona radiata. Review of the literature was made and the possibility of radiation therapy as a causative factor of the lacunar infarction in relatively young adults was discussed.