Stereotactic Radiosurgery for Benign Cavernous Sinus Meningiomas: A Multicentre Study and Review of the Literature.

Cavernous sinus meningiomas (CSMs) remain a surgical challenge due to the intimate involvement of their contained nerves and blood vessels. Stereotactic radiosurgery (SRS) is a safe and effective minimally invasive alternative for the treatment of small- to medium-sized CSMs. Objective: To assess the medium- to long-term outcomes of SRS for CSMs with respect to tumour growth, prevention of further neurological deterioration and improvement of existing neurological deficits. This multicentric study included data from 15 European institutions. We performed a retrospective observational analysis of 1222 consecutive patients harbouring 1272 benign CSMs. All were treated with Gamma Knife stereotactic radiosurgery (SRS). Clinical and imaging data were retrieved from each centre and entered into a common database. All tumours with imaging follow-up of less than 24 months were excluded. Detailed results from 945 meningiomas (86%) were then analysed. Clinical neurological outcomes were available for 1042 patients (85%). Median imaging follow-up was 67 months (mean 73.4, range 24-233). Median tumour volume was 6.2 cc (+/-7), and the median marginal dose was 14 Gy (+/-3). The post-treatment tumour volume decreased in 549 (58.1%), remained stable in 336 (35.6%) and increased in only 60 lesions (6.3%), yielding a local tumour control rate of 93.7%. Only 27 (2.8%) of the 60 enlarging tumours required further treatment. Five- and ten-year actuarial progression-free survival (PFS) rates were 96.7% and 90.1%, respectively. Tumour control rates were higher for women than men (p = 0.0031), and also for solitary sporadic meningiomas (p = 0.0201). There was no statistically significant difference in outcome for imaging-defined meningiomas when compared with histologically proven WHO Grade-I meningiomas (p = 0.1212). Median clinical follow up was 61 months (mean 64, range 6-233). Permanent morbidity occurred in 5.9% of cases at last follow-up. Stereotactic radiosurgery is a safe and effective method for treating benign CSM in the medium term to long term.

Evolution of gamma knife capsulotomy for intractable obsessive-compulsive disorder.

For more than half a century, stereotactic neurosurgical procedures have been available to treat patients with severe, debilitating symptoms of obsessive-compulsive disorder (OCD) that have proven refractory to extensive, appropriate pharmacological, and psychological treatment. Although reliable predictors of outcome remain elusive, the establishment of narrower selection criteria for neurosurgical candidacy, together with a better understanding of the functional neuroanatomy implicated in OCD, has resulted in improved clinical efficacy for an array of ablative and non-ablative intervention techniques targeting the cingulum, internal capsule, and other limbic regions. It was against this backdrop that gamma knife capsulotomy (GKC) for OCD was developed. In this paper, we review the history of this stereotactic radiosurgical procedure, from its inception to recent advances. We perform a systematic review of the existing literature and also provide a narrative account of the evolution of the procedure, detailing how the procedure has changed over time, and has been shaped by forces of evidence and innovation. As the procedure has evolved and adverse events have decreased considerably, favorable response rates have remained attainable for approximately one-half to two-thirds of individuals treated at experienced centers. A reduction in obsessive-compulsive symptom severity may result not only from direct modulation of OCD neural pathways but also from enhanced efficacy of pharmacological and psychological therapies working in a synergistic fashion with GKC. Possible complications include frontal lobe edema and even the rare formation of delayed radionecrotic cysts. These adverse events have become much less common with new radiation dose and targeting strategies. Detailed neuropsychological assessments from recent studies suggest that cognitive function is not impaired, and in some domains may even improve following treatment. We conclude this review with discussions covering topics essential for further progress of this therapy, including suggestions for future trial design given the unique features of GKC therapy, considerations for optimizing stereotactic targeting and dose planning using biophysical models, and the use of advanced imaging techniques to understand circuitry and predict response. GKC, and in particular its modern variant, gamma ventral capsulotomy, continues to be a reliable treatment option for selected cases of otherwise highly refractory OCD.

Gamma Ventral Capsulotomy in Intractable Obsessive-Compulsive Disorder.

BACKGROUND: Despite the development of effective pharmacologic and cognitive behavioral treatments for obsessive-compulsive disorder (OCD), some patients continue to be treatment-refractory and severely impaired. Fiber tracts connecting orbitofrontal and dorsal anterior cingulate cortex with subcortical nuclei have been the target of neurosurgical lesions as well as deep brain stimulation in these patients. We report on the safety and efficacy of ventral gamma capsulotomy for patients with intractable OCD. METHODS: Fifty-five patients with severely disabling, treatment-refractory OCD received bilateral lesions in the ventral portion of the anterior limb of the internal capsule over a 20-year period using the Leksell Gamma Knife. The patients were prospectively followed over 3 years with psychiatric, neurologic, and neuropsychological assessments of safety and efficacy, as well as structural neuroimaging. RESULTS: Thirty-one of 55 patients (56%) had an improvement in the primary efficacy measure, the Yale-Brown Obsessive Compulsive Scale, of ≥35% over the 3-year follow-up period. Patients had significant improvements in depression, anxiety, quality of life, and global functioning. Patients tolerated the procedure well without significant acute adverse events. Five patients (9%) developed transient edema that required short courses of dexamethasone. Three patients (5%) developed cysts at long-term follow-up, 1 of whom developed radionecrosis resulting in an ongoing minimally conscious state. CONCLUSIONS: Gamma Knife ventral capsulotomy is an effective radiosurgical procedure for many treatment-refractory OCD patients. A minority of patients developed cysts at long-term follow-up, 1 of whom had permanent neurological sequelae.

Neuraxial blocks and spinal haematoma: Review of 166 cases published 1994 - 2015. Part 2: diagnosis, treatment, and outcome.

BACKGROUND: Bleeding into the vertebral canal causing a spinal haematoma (SH) is a rare but serious complication to central neuraxial blocks (CNB). Of all serious complications to CNBs, neurological injury associated with SH has the worst prognosis. Around the turn of the millennium, the first guidelines aiming to reduce the risk of this complication were published. These guidelines are based on known risk factors for SH, rather than evidence from randomized, controlled trials (RCTs). RCTs, and hence meta-analysis of RCTs, are not appropriate for identifying rare events. Analysing data from a significant number of published case reports of rare complications may reveal risk factors and patterns undetectable in reports on occasional cases, and can thereby help to improve management of CNBs. The aims of the present review were to analyse case reports of SH after CNBs published between 1994 and 2015 with regard to diagnosis, treatment, and outcome of SH after CNB. METHODS: MEDLINE and EMBASE were utilized to find case reports published in English, German, or Scandinavian languages between 1994 and end of 2015, using appropriate search terms. Reference lists were also scrutinized for case reports. We documented initial and worst symptoms and signs of SH, diagnostic methods, treatment, and outcome of the SH. We calculated occurrences in per cent using the number of informative reports as denominator. RESULTS: One hundred and sixty-six case reports on spinal hematomas after CNB published during the years between 1994 and 2015 were identified. Eighty per cent of the patients had severe neurological symptoms (paresis or paralysis). When compared over time, outcomes have improved significantly. Among patients subjected to surgical evacuation of the hematoma, outcomes were best if surgery was performed within 12hours from the first sign of motor dysfunction. However, even patients operated after more than 24hours had relatively favourable outcomes. Whereas the outcomes after surgical evacuation of the epidural haematomas were quite satisfactory, only one of the operations for subdural haematoma (SSDH) resulted in a favourable outcome. CONCLUSIONS AND IMPLICATIONS: Suspicion of a spinal hematoma calls for the consultation of an orthopaedic or neurological surgeon without delay. MRI is the recommended diagnostic tool. Surgical evacuation within 12h from the first sign of motor dysfunction seems to lead to the best outcome, although many patients operated as late as after more than 24hours did regain full motor function. Despite the poor prognosis after surgical evacuation of SSDH, the outcomes after post-CNB spinal haematoma in general have improved significantly over time.

The role of the concept of biologically effective dose (BED) in treatment planning in radiosurgery.

Radiosurgery (RS) treatment times vary, even for the same prescription dose, due to variations in the collimator size, the number of iso-centres/beams/arcs used and the time gap between each of these exposures. The biologically effective dose (BED) concept, incorporating fast and slow components of repair, was used to show the likely influence of these variables for Gamma Knife patients with Vestibular Schwannomas. Two patients plans were selected, treated with the Model B Gamma Knife, these representing the widest range of treatment variables; iso-centre numbers 3 and 13, overall treatment times 25.4 and 129.6 min, prescription dose 14 Gy. These were compared with 3 cases treated with the Perfexion(®) Gamma Knife. The iso-centre number varied between 11 and 18, treatment time 35.7 - 74.4 min, prescription dose 13 Gy. In the longer Model B Gamma Knife treatment plan the 14 Gy iso-dose was best matched by the 58 Gy2.47 iso-BED line, although higher and lower BED values were associated with regions on the prescription iso-dose. The equivalent value for the shorter treatment was 85 Gy2.47. BED volume histograms showed that a BED of 85 Gy2.47 only covered ∼65% of the target in the plan with the longer overall treatment time. The corresponding BED values for the 3 cases, treated with the Perfexion(®) Gamma Knife, were 59.5, 68.5 and 71.5 Gy2.47. In conclusion BED calculations, taking account of the repair of sublethal damage, may indicate the importance of reporting overall time to reflect the biological effectiveness of the total physical dose applied.

Stereotactic radiosurgery in the treatment of brain metastases: the current evidence.

Chemotherapy has made substantial progress in the therapy of systemic cancer, but the pharmacological efficacy is insufficient in the treatment of brain metastases. Fractionated whole brain radiotherapy (WBRT) has been a standard treatment of brain metastases, but provides limited local tumor control and often unsatisfactory clinical results. Stereotactic radiosurgery using Gamma Knife, Linac or Cyberknife has overcome several of these limitations, which has influenced recent treatment recommendations. This present review summarizes the current literature of single session radiosurgery concerning survival and quality of life, specific responses, tumor volumes and numbers, about potential treatment combinations and radioresistant metastases. Gamma Knife and Linac based radiosurgery provide consistent results with a reproducible local tumor control in both single and multiple brain metastases. Ideally minimum doses of ≥18Gy are applied. Reported local control rates were 90-94% for breast cancer metastases and 81-98% for brain metastases of lung cancer. Local tumor control rates after radiosurgery of otherwise radioresistant brain metastases were 73-90% for melanoma and 83-96% for renal cell cancer. Currently, there is a tendency to treat a larger number of brain metastases in a single radiosurgical session, since numerous studies document high local tumor control after radiosurgical treatment of >3 brain metastases. New remote brain metastases are reported in 33-42% after WBRT and in 39-52% after radiosurgery, but while WBRT is generally applied only once, radiosurgery can be used repeatedly for remote recurrences or new metastases after WBRT. Larger metastases (>8-10cc) should be removed surgically, but for smaller metastases Gamma Knife radiosurgery appears to be equally effective as surgical tumor resection (level I evidence). Radiosurgery avoids the impairments in cognition and quality of life that can be a consequence of WBRT (level I evidence). High local efficacy, preservation of cerebral functions, short hospitalization and the option to continue a systemic chemotherapy are factors in favor of a minimally invasive approach with stereotactic radiosurgery.

Standardization of terminology in stereotactic radiosurgery: Report from the Standardization Committee of the International Leksell Gamma Knife Society: special topic.

OBJECT: This report has been prepared to ensure more uniform reporting of Gamma Knife radiosurgery treatment parameters by identifying areas of controversy, confusion, or imprecision in terminology and recommending standards. METHODS: Several working group discussions supplemented by clarification via email allowed the elaboration of a series of provisional recommendations. These were also discussed in open session at the 16th International Leksell Gamma Knife Society Meeting in Sydney, Australia, in March 2012 and approved subject to certain revisions and the performance of an Internet vote for approval from the whole Society. This ballot was undertaken in September 2012. RESULTS: The recommendations in relation to volumes are that Gross Target Volume (GTV) should replace Target Volume (TV); Prescription Isodose Volume (PIV) should generally be used; the term Treated Target Volume (TTV) should replace TVPIV, GTV in PIV, and so forth; and the Volume of Accepted Tolerance Dose (VATD) should be used in place of irradiated volume. For dose prescription and measurement, the prescription dose should be supplemented by the Absorbed Dose, or DV% (for example, D95%), the maximum and minimum dose should be related to a specific tissue volume (for example, D2% or preferably D1 mm3), and the median dose (D50%) should be recorded routinely. The Integral Dose becomes the Total Absorbed Energy (TAE). In the assessment of planning quality, the use of the Target Coverage Ratio (TTV/ GTV), Paddick Conformity Index (PCI = TTV2/[GTV · PIV]), New Conformity Index (NCI = [GTV · PIV]/TTV2), Selectivity Index (TTV/PIV), Homogeneity Index (HI = [D2% ­D98%]/D50%), and Gradient Index (GI = PIV0.5/PIV) are reemphasized. In relation to the dose to Organs at Risk (OARs), the emphasis is on dose volume recording of the VATD or the dose/volume limit (for example, V10) in most cases, with the additional use of a Maximum Dose to a small volume (such as 1 mm3) and/or a Point Dose and Mean Point Dose in certain circumstances, particularly when referring to serial organs. The recommendations were accepted by the International Leksell Gamma Knife Society by a vote of 92% to 8%. CONCLUSIONS: An agreed-upon and uniform terminology and subsequent standardization of certain methods and procedures will advance the clinical science of stereotactic radiosurgery.

Ladislau Steiner, 1920-2013.

The authors commemorate the life and career of Dr. Ladislau Steiner, one of the world's most highly regarded neurosurgeons, from Stockholm and Charlottesville, Virginia, who has died at age 92. They review the events of Dr. Steiner's early life, including his early training in his native Romania, his escape with his family from East Berlin, and his postgraduate training in neurosurgery at the Karolinska Institute in Stockholm. Dr. Steiner's work in the development of microsurgery and his collaboration with Lars Leksell in the development of Gamma Knife radiosurgery are described. After his retirement from Karolinska, Dr. Steiner had a second career as head of the Lars Leksell Gamma Knife Center at the University of Virginia in Charlottesville. The authors recall their own long association with Dr. Steiner and celebrate his contributions to the field of neurosurgery.

Application of the concept of biologically effective dose (BED) to patients with Vestibular Schwannomas treated by radiosurgery.

In the application of stereotactic radiosurgery, using the Gamma Knife, there are large variations in the overall treatment time for the same prescription dose, given in a single treatment session, for different patients. This is due to not only changes in the activity of the Cobolt-60 sources, but also to variations in the number of iso-centers used, the collimator size for a particular iso-center, and the time gap between the different iso-centers. Although frequently viewed as a single dose treatment the concept of biologically effective dose (BED), incorporating concurrent fast and a slow components of repair of sublethal damage, would imply potential variations in BED because of the influence of these different variables associated with treatment. This was investigated in 26 patients, treated for Vestibular Schwannomas, using the Series B Gamma-Knife, between 1999 and 2005. The iso-center number varied between 2 and 13, and the overall treatment time from 25.4-129.58 min. The prescription doses varied from 10-14 Gy. To obtain physical dose and dose-rates from each iso-center, in a number of locations in the region of interest, a prototype version of the Leksell GammaPlan® was used. For an individual patient, BED values varied by up to 15% for a given physical iso-dose. This was due to variation in the dose prescription at different locations on that iso-dose. Between patients there was a decline in the range of BED values as the overall treatment time increased. This increased treatment time was partly a function of the slow decline in the activity of the sources with time but predominantly due to changes in the number of iso-centers used. Thus, variations in BED values did not correlate with prescription dose but was modified by the overall treatment time.

Radiobiological principles: their application to γ knife therapy.

Gamma Knife treatments are regarded as single dose exposures, however, in reality the total dose delivered is the addition of a variable number of individual smaller doses from the variable number of iso-centres or shots, selected to cover a lesion. The dose prescription, in terms of dose and dose rate, to different points on a given physical iso-surface, will vary according to location. In radiobiological terms this treatment pattern does not represent a single exposure, but a schedule with a variable number of different sized dose fractions given at different dose rates with multiple incompletes repair intervals (the time between shots). Using the concept of biologically effective dose (BED), incorporating a fast and a slow component of repair, the biological effectiveness of a 12-shot protocol was found to vary with the decay in the activity of the (60)Co sources and the time interval between shots. However, the largest effect was found when this standard protocol was compared with one involving only 2 shots. It should be recognised in individual Gamma Knife treatments that there are many variables which have the potential to influence the biological effective of the treatment and thus the importance of a single variable may be difficult to determine in isolation. Reports in the literature support the results of these simulated calculations into the factors likely to change the biologically effective dose with the use of the Gamma Knife.

Long-term tumor control of benign intracranial meningiomas after radiosurgery in a series of 4565 patients.

BACKGROUND: Radiosurgery is the main alternative to microsurgical resection for benign meningiomas. OBJECTIVE: To assess the long-term efficacy and safety of radiosurgery for meningiomas with respect to tumor growth and prevention of associated neurological deterioration. Medium- to long-term outcomes have been widely reported, but no large multicenter series with long-term follow-up have been published. METHODS: From 15 participating centers, we performed a retrospective observational analysis of 4565 consecutive patients harboring 5300 benign meningiomas. All were treated with Gamma Knife radiosurgery at least 5 years before assessment for this study. Clinical and imaging data were retrieved from each center and uniformly entered into a database by 1 author (A.S.). RESULTS: Median tumor volume was 4.8 cm³, and median dose to tumor margin was 14 Gy. All tumors with imaging follow-up < 24 months were excluded. Detailed results from 3768 meningiomas (71%) were analyzed. Median imaging follow-up was 63 months. The volume of treated tumors decreased in 2187 lesions (58%), remained unchanged in 1300 lesions (34.5%), and increased in 281 lesions (7.5%), giving a control rate of 92.5%. Only 84 (2.2%) enlarging tumors required further treatment. Five- and 10-year progression-free survival rates were 95.2% and 88.6%, respectively. Tumor control was higher for imaging defined tumors vs grade I meningiomas (P < .001), for female vs male patients (P < .001), for sporadic vs multiple meningiomas (P < .001), and for skull base vs convexity tumors (P < .001). Permanent morbidity rate was 6.6% at the last follow-up. CONCLUSION: Radiosurgery is a safe and effective method for treating benign meningiomas even in the medium to long term.

Thirty years' experience with Gamma Knife surgery for metastases to the brain.

OBJECT: The aim of this study was to analyze factors influencing survival time and patterns of distant recurrences after Gamma Knife surgery (GKS) for metastases to the brain. METHODS: Information was available for 1855 of 1921 patients who underwent GKS for single or multiple cerebral metastases at 4 different institutions during different time periods between 1975 and 2007. The total number of Gamma Knife treatments administered was 2448, an average of 1.32 treatments per patient. The median survival time was analyzed, related to patient and treatment parameters, and compared with published data following conventional fractionated whole-brain irradiation. RESULTS: Twenty-five patients survived for longer than 10 years after GKS, and 23 are still alive. Age and primary tumor control were strongly related to survival time. Patients with single metastases had a longer survival than those with multiple metastases, but there was no difference in survival between patients with single and multiple metastases who had controlled primary disease. There were no significant differences in median survival time between patients with 2, 3-4, 5-8, or >8 metastases. The 5-year survival rate was 6% for the whole patient population, and 9% for patients with controlled primary disease. New hematogenous spread was a more significant problem than micrometastases in patients with longer survival. CONCLUSIONS: Patient age and primary tumor control are more important factors in predicting median survival time than number of metastases to the brain. Long-term survivors are more common than previously assumed.

The Leksell Gamma Knife Perfexion and comparisons with its predecessors.

OBJECTIVE: The objective of this study is to introduce a new radiosurgical device, the Leksell Gamma Knife Perfexion (Elekta Instruments AB, Stockholm, Sweden). Design and performance characteristics are compared with previous models of the gamma knife in a clinical setting. METHODS: Performance-related features in the design of the new radiosurgical system are described, and the ability to create complex shapes of isodose volumes even with a single isocenter is demonstrated. The concept of "dynamic shaping" of dose distribution is introduced as a means of decreasing the exposure to structures outside the target. Dose plans for the Leksell Gamma Knife Models B, 4C, and Perfexion have been created for target pathologies to illustrate how the software and hardware of the new radiosurgical system can increase treatment quality, decrease treatment time, and increase patient comfort. Radiation doses to critical organs in the rest of the human body are compared. RESULTS: The automated collimator arrangement in the Perfexion makes it possible to produce more complex treatment volumes than with previous models of the gamma knife. This results from the enhanced ability to shape isodose volumes, even for single isocenters. The collimator arrangement and the patient positioning system also allow shorter patient transit times, reducing unwanted radiation exposure during movement between isocenters. CONCLUSION: The Perfexion exceeds the capabilities of previous gamma knife models in terms of treatment efficiency, conformity, and radiation protection. These qualities enable treatment of larger target volumes, especially close to eloquent areas. Pathologies previously inaccessible in the head and neck are now treatable due to the increased volume of the radiation cavity.

The Leksell Gamma Knife Perfexion and comparisons with its predecessors.

OBJECTIVE: The objective of this study is to introduce a new radiosurgical device, the Leksell Gamma Knife Perfexion (Elekta Instruments AB, Stockholm, Sweden). Design and performance characteristics are compared with previous models of the gamma knife in a clinical setting. METHODS: Performance-related features in the design of the new radiosurgical system are described, and the ability to create complex shapes of isodose volumes even with a single isocenter is demonstrated. The concept of "dynamic shaping" of dose distribution is introduced as a means of decreasing the exposure to structures outside the target. Dose plans for the Leksell Gamma Knife Models B, 4C, and Perfexion have been created for target pathologies to illustrate how the software and hardware of the new radiosurgical system can increase treatment quality, decrease treatment time, and increase patient comfort. Radiation doses to critical organs in the rest of the human body are compared. RESULTS: The automated collimator arrangement in the Perfexion makes it possible to produce more complex treatment volumes than with previous models of the gamma knife. This results from the enhanced ability to shape isodose volumes, even for single isocenters. The collimator arrangement and the patient positioning system also allow shorter patient transit times, reducing unwanted radiation exposure during movement between isocenters. CONCLUSION: The Perfexion exceeds the capabilities of previous gamma knife models in terms of treatment efficiency, conformity, and radiation protection. These qualities enable treatment of larger target volumes, especially close to eloquent areas. Pathologies previously inaccessible in the head and neck are now treatable due to the increased volume of the radiation cavity.

Integration of gamma knife surgery in the management of cerebral metastases from melanoma.

The aim of this study was to investigate the effect of gamma knife surgery on the local control of cerebral metastases from melanoma and to assess survival. In 29 patients, 105 of 178 cerebral metastases were treated with gamma knife surgery. Only five patients had metastases confined to the brain. Of the 96 metastases with magnetic resonance imaging follow-up, 61.5% regressed by more than 50% of the pretreatment volume, 25% regressing by more than 90% and 13.5% completely. The median survival from gamma knife surgery was 5.7 months (longest survival, 38 months). In multivariate analyses, a larger number of lesions requiring treatment (P < 0.001), recursive partitioning analysis class (P = 0.009) and a long time interval from initial melanoma diagnosis to detection of cerebral metastases (P = 0.001) influenced survival. It can be concluded that gamma knife surgery is a useful adjunct in the management of cerebral metastases from melanoma and has a significant impact on local control. Its greatest potential may be achieved in conjunction with systemic chemotherapy, especially in the presence of extracerebral metastases.