Neuro-ophthalmologic outcomes of standard versus hypo-fractionated stereotactic radiotherapy of AVPM.

BACKGROUND: Most anterior visual pathway meningiomas (AVPM) are benign and slow-growing, but these tumors may affect visual functions, including visual acuity (VA) and visual field (VF). Due to location, most are treated non-surgically by fractionated stereotactic radiotherapy (FSRT), aiming to prevent tumor progression and visual functions deterioration. Unfortunately, FSRT in itself may affect visual functions. The current preferred treatment regimen (in terms of safety and effectiveness) is undetermined. While most cases are treated with conventional fractionation (cFSRT)-50.4-54 Gy in 28-30 fractions of 1.8-2 Gy, advances in technology have allowed shortening of total treatment length to hypofractionation (hSRT)-25-27 Gy in 3-5 fractions of 5-9 Gy. Our aim was to evaluate the association of radiotherapy regimen for treating AVPM (cFSRT vs. hSRT) with visual function outcomes (VA, VF) at the last neuro-ophthalmologic evaluation. METHODS: We conducted a retrospective cohort study of AVPM cases treated at Sheba Medical Center during 2004-2015. We compared cFSRT and hSRT regimens regarding visual function (VA, VF) outcomes at the last neuro-ophthalmologic evaluation. VA was determined by the logarithm of the minimum angle of resolution (LogMAR). VF was determined by the mean deviation (MD). A clinically relevant change in VA was defined as 0.2 LogMAR. RESULTS: 48 patients (13 receiving hSRT, 35 receiving cFSRT) were included, with a median follow-up of 55 months. No significant difference was evident regarding LogMAR or MD of involved eyes at the last evaluation. Six (17%) patients in the cFSRT group experienced clinically relevant VA deterioration in the involved eye, compared with six (46%) in hSRT (p = 0.06). CONCLUSION: Our findings, using comprehensive and meticulous investigation of visual outcomes, suggest that hSRT may be associated with higher risk for VA and VF deterioration in AVPM especially in ONSM. We recommend the use of cFSRT for ONSM.

Radiation-induced vascular malformations in the brain, mimicking tumor in MRI-based treatment response assessment maps (TRAMs).

•Of 310 brain tumors patients recruited, histology of 99 lesions was available.•Of those, 5 were histologically confirmed as radiation-induced malformations.•TRAMs cannot differentiate active tumor from vascular malformation.

[FRACTIONATED STEREOTACTIC RADIOSURGERY: A GAME CHANGER FOR NEUROSURGERY].

The article by Dr. Cohen-Inbar published in this issue of Harefuah is a timely review that brings to the general medical community the recent important developments in the field of radiosurgery--the evolution of multi-session radiosurgery [or "FSR", standing for Fractionated Stereotactic Radiation]. Radiosurgery and FSR continue to have a tremendous impact on modern neurosurgery. Sharing sub-millimetric accuracy in radiation delivery made possible by real-time-imaging positioning, frameless single and multisession radiosurgery have become two faces of a therapeutic technique with wide application in the field of intracranial pathology. Blending dose fractionation with delivery precision, FSR is a hybrid tool that can be implemented safely and effectively for practically any intra-cranial pathology without restrictions of volume or location. Dr. Cohen Inbar reviews the available data regarding doses, fractionation schemes, and results for the different pathologies in which FSR is being increasingly applied. FSR, as single-dose radiosurgery since the late 1980s, has changed the practice of neurosurgery. Radical microsorgical tumor removal at any cost in demanding intracranial locations has been replaced by upfront conservative volume-reduction surgery, leaving the more complicated part of those tumors to safer elimination by precise irradiation in single or multiple sessions. In Israel, further to the first unit operative since 1993 at the Sheba Medical Center, 3 new active LINAC based treatment sites have been added in recent years, with facilities either planned or under construction in the remaining major medical centers with neurosurgical and radiotherapy resources. They are evidence of the central role this modality has captured in the management of intracranial pathology.

Predicting and reducing cranioplasty infections by clinical, radiographic and operative parameters - A historical cohort study.

Cranioplasty is a relatively straightforward and common procedure, yet it carries a substantial rate of infection that causes major morbidity and mortality. The authors' objective was to assess the effect of various variables on the risk of developing post-cranioplasty infections, and to enable the prediction and reduction of its incidence, contributing to an improved patient-selection. The medical records, microbiologic cultures, imaging studies and operative reports of patients who have undergone cranioplasty between the years 2008-2014 at Sheba Medical Center, a tertiary care teaching hospital in Tel-Hashomer, Israel, were reviewed and evaluated for potential predictive factors of infection. Cox regression was applied for uni- as well as multi-variate analyses, and a Kaplan-Meier curve and Log-Rank test were used to describe the association between neurological deficit prior to operation and occurrence of infection. Eighty-eight patients who had undergone cranioplasties using autologous as well as various artificial materials were included in the study. The overall rate of infection was 13.6%; median time to infection was 30.5 days (interquartile range: 17.35-43.5). Pre-operative degree of neurological disability was the strongest predictor for infection in both uni- and multi-variate analyses (Hazard ratio [HR]=18.9, 95% confidence interval [CI]: 1.9-187 p=0.014). Patients admitted due to trauma (HR=7.04 CI: 0.9-54.6, p=0.062) and autologous graft material (HR=2.88, 95% CI: 0.92-9.09, p=0.07) were associated with a trend toward a higher risk for infection. In conclusion, careful patient selection is a key concept in avoiding harmful post-cranioplasty infections. Modified Rankin Score yields a well-established tool that predicts the risk of infection.

Delayed contrast extravasation MRI: a new paradigm in neuro-oncology.

BACKGROUND: Conventional magnetic resonance imaging (MRI) is unable to differentiate tumor/nontumor enhancing tissues. We have applied delayed-contrast MRI for calculating high resolution treatment response assessment maps (TRAMs) clearly differentiating tumor/nontumor tissues in brain tumor patients. METHODS: One hundred and fifty patients with primary/metastatic tumors were recruited and scanned by delayed-contrast MRI and perfusion MRI. Of those, 47 patients underwent resection during their participation in the study. Region of interest/threshold analysis was performed on the TRAMs and on relative cerebral blood volume maps, and correlation with histology was studied. Relative cerebral blood volume was also assessed by the study neuroradiologist. RESULTS: Histological validation confirmed that regions of contrast agent clearance in the TRAMs >1 h post contrast injection represent active tumor, while regions of contrast accumulation represent nontumor tissues with 100% sensitivity and 92% positive predictive value to active tumor. Significant correlation was found between tumor burden in the TRAMs and histology in a subgroup of lesions resected en bloc (r(2) = 0.90, P < .0001). Relative cerebral blood volume yielded sensitivity/positive predictive values of 51%/96% and there was no correlation with tumor burden. The feasibility of applying the TRAMs for differentiating progression from treatment effects, depicting tumor within hemorrhages, and detecting residual tumor postsurgery is demonstrated. CONCLUSIONS: The TRAMs present a novel model-independent approach providing efficient separation between tumor/nontumor tissues by adding a short MRI scan >1 h post contrast injection. The methodology uses robust acquisition sequences, providing high resolution and easy to interpret maps with minimal sensitivity to susceptibility artifacts. The presented results provide histological validation of the TRAMs and demonstrate their potential contribution to the management of brain tumor patients.

Delayed contrast extravasation MRI for depicting tumor and non-tumoral tissues in primary and metastatic brain tumors.

The current standard of care for newly diagnosed glioblastoma multiforme (GBM) is resection followed by radiotherapy with concomitant and adjuvant temozolomide. Recent studies suggest that nearly half of the patients with early radiological deterioration post treatment do not suffer from tumor recurrence but from pseudoprogression. Similarly, a significant number of patients with brain metastases suffer from radiation necrosis following radiation treatments. Conventional MRI is currently unable to differentiate tumor progression from treatment-induced effects. The ability to clearly differentiate tumor from non-tumoral tissues is crucial for appropriate patient management. Ten patients with primary brain tumors and 10 patients with brain metastases were scanned by delayed contrast extravasation MRI prior to surgery. Enhancement subtraction maps calculated from high resolution MR images acquired up to 75 min after contrast administration were used for obtaining stereotactic biopsies. Histological assessment was then compared with the pre-surgical calculated maps. In addition, the application of our maps for prediction of progression was studied in a small cohort of 13 newly diagnosed GBM patients undergoing standard chemoradiation and followed up to 19.7 months post therapy. The maps showed two primary enhancement populations: the slow population where contrast clearance from the tissue was slower than contrast accumulation and the fast population where clearance was faster than accumulation. Comparison with histology confirmed the fast population to consist of morphologically active tumor and the slow population to consist of non-tumoral tissues. Our maps demonstrated significant correlation with perfusion-weighted MR data acquired simultaneously, although contradicting examples were shown. Preliminary results suggest that early changes in the fast volumes may serve as a predictor for time to progression. These preliminary results suggest that our high resolution MRI-based delayed enhancement subtraction maps may be applied for clear depiction of tumor and non-tumoral tissues in patients with primary brain tumors and patients with brain metastases.

Visual outcome in meningiomas around anterior visual pathways treated with linear accelerator fractionated stereotactic radiotherapy.

PURPOSE: Meningiomas threatening the anterior visual pathways (AVPs) and not amenable for surgery are currently treated with multisession stereotactic radiotherapy. Stereotactic radiotherapy is available with a number of devices. The most ubiquitous include the gamma knife, CyberKnife, tomotherapy, and isocentric linear accelerator systems. The purpose of our study was to describe a case series of AVP meningiomas treated with linear accelerator fractionated stereotactic radiotherapy (FSRT) using the multiple, noncoplanar, dynamic conformal rotation paradigm and to compare the success and complication rates with those reported for other techniques. PATIENTS AND METHODS: We included all patients with AVP meningiomas followed up at our neuro-ophthalmology unit for a minimum of 12 months after FSRT. We compared the details of the neuro-ophthalmologic examinations and tumor size before and after FSRT and at the end of follow-up. RESULTS: Of 87 patients with AVP meningiomas, 17 had been referred for FSRT. Of the 17 patients, 16 completed >12 months of follow-up (mean 39). Of the 16 patients, 11 had undergone surgery before FSRT and 5 had undergone FSRT as first-line management. Tumor control was achieved in 14 of the 16 patients, with three meningiomas shrinking in size after RT. Two meningiomas progressed, one in an area that was outside the radiation field. The visual function had improved in 6 or stabilized in 8 of the 16 patients (88%) and worsened in 2 (12%). CONCLUSIONS: Linear accelerator fractionated RT using the multiple noncoplanar dynamic rotation conformal paradigm can be offered to patients with meningiomas that threaten the anterior visual pathways as an adjunct to surgery or as first-line treatment, with results comparable to those reported for other stereotactic RT techniques.

Cavernous sinus meningiomas: a large LINAC radiosurgery series.

One hundred and seventeen patients with cavernous sinus meningiomas had LINAC radiosurgery at our institution in the period 1993-2007. Six cases were lost and 9 had less than 1 year follow up. The remaining 102 patients were prospectively followed up at 1 y intervals with clinical, neuro-ophthalmological and MRI examinations. Patients' age ranged between 31 and 86 years (mean 57). Seventy percent were females. The mean tumor volume was 7 cc. Thirty-three patients had previous microsurgery. Tumors were defined with high resolution MRI obtained 1-2 days before treatment and fused to stereotactic CT. Treatment was mostly delivered through a minimultileaf collimator and multiple dynamic arcs. The minimal dose to the tumor margin was 12-17.5 Gy (mean 13.5) encompassed by the 80% isodose shell. Radiation dose to the optic apparatus was kept below 10 Gy. Follow up ranged from 12 to 180 months (mean 67 months). Tumor control (lack of growth) was 98% (58% of the tumors reduced their volumes). Sixty-four patients presented with cranial nerve deficit. Thirty-nine percent improved or resolved following radiosurgery. Cranial neuropathy had significantly higher resolution rates when radiosurgery was performed early (<1 year) after its appearance (53% as opposed to 26%) even in patients with deficits post surgery. Complications were seen in five patients (1 with deafferentation pain, 1 with facial hypesthesia, 1 with visual loss and 2 with partial VI neuropathy). Radiosurgery had a high control rate for meningiomas of the cavernous sinus with few and mild complications. Cranial neuropathy can be solved by treatment, particularly those of recent onset.

Experimental analysis of radiation dose distribution in radiosurgery. II. Dose fall-off outside the target volume.

INTRODUCTION: The role of radiation dose delivered to surrounding tissues outside target is often minimized in radiosurgery. We study histopathological effects of dose fall-offs outside the target using an experimental model of trigeminal nerve irradiation in the rat. MATERIAL AND METHODS: Sixteen rats were irradiated with a Gamma Knife at the right trigeminal nerve using a 90-Gy dose and 4 different gradients of dose fall-off; the brainstem at the trigeminal nerve root entry was histologically analyzed 3 months after irradiation. RESULTS: Four specific histopathological reactions were found as a consequence of the irradiation. All these reactions were significantly related to the gradient of dose fall-off. CONCLUSIONS: Different dose distributions outside the target could produce various histological effects in the irradiated tissue that could influence the outcome of radiosurgical treatment. A more rapid fall-off of dose (higher selectivity) is associated with less risk of histological changes in tissues surrounding the target.

Experimental analysis of radiation dose distribution in radiosurgery: I. Dose hot spot inside target volume.

INTRODUCTION: Radiosurgery is currently performed with different systems of focused radiation providing different dose heterogeneities within the target volume. Here, we aimed to study histological consequences of different dose distributions inside the target area in an experimental model of Gamma Knife irradiation in the rat striatum. MATERIAL AND METHODS: Twelve rats were irradiated by Gamma Knife at the same volume in the right striatum; the same margin dose of 45 Gy was prescribed for all rats. Three different dose distributions inside the target volume were applied. Brain sections at the level of the target area were histologically analyzed 3 months after irradiation. RESULTS: Of the 7 histopathological reactions found as a consequence of the irradiation, 6 of them were significantly related to the gradient of dose heterogeneity within the target volume. CONCLUSIONS: Dose distribution inside the target volume could influence the histological effects of radiosurgical irradiation on tissue included in the target. A high dose in the target volume is more likely to lead to the desired radiobiological result.

Irradiation of cochlear structures during vestibular schwannoma radiosurgery and associated hearing outcome.

OBJECT: The purpose of this study was to measure the dose of radiation delivered to the cochlea during a Gamma knife surgery (GKS) procedure for treatment of patients with vestibular schwannomas (VSs), and to analyze the relationship between cochlear irradiation and the hearing outcome of these patients. METHODS: Eighty-two patients with VSs were treated with GKS using a marginal dose of 12 Gy. No patient had neurofibromatosis Type 2 disease, and all had a Gardner-Robertson hearing class of I to IV before treatment, and a radiological and audiological follow-up of at least 1-year after GKS. The dosimetric data of the volume of the cochlea were retrospectively analyzed and were correlated with the auditory outcome of patients. RESULTS: The mean radiation dose delivered to the cochlear volume ranged from 1.30 to 10.00 Gy (median 4.15 Gy). The cochlea received significantly higher radiation doses in patients with worsening of hearing after GKS. A highly significant association between the cochlear and the intracanalicular dose of radiation delivered during GKS was found. CONCLUSIONS: During GKS for VSs, relatively high doses of radiation can be delivered to the cochlea. Worsening of hearing after GKS can be the consequence of either radiation injury to the cochlea or the irradiation dose delivered into the auditory canal, or both.

Effect of beam channel plugging on the outcome of gamma knife radiosurgery for trigeminal neuralgia.

PURPOSE: We studied the influence of using plugs for brainstem protection during gamma knife radiosurgery (GKR) of trigeminal neuralgia (TN), with special emphasis on irradiation doses delivered to the trigeminal nerve, pain outcomes, and incidence of trigeminal dysfunction. METHODS AND MATERIALS: A GKR procedure for TN using an anterior cisternal target and a maximum dose of 90 Gy was performed in 109 patients. For 49 patients, customized beam channel blocking (plugs) were used to reduce the dose delivered to the brainstem. We measured the mean and integrated radiation doses delivered to the trigeminal nerve and the clinical course of patients treated with and without plugs. RESULTS: We found that blocking increases the length of trigeminal nerve exposed to high-dose radiation, resulting in a significantly higher mean dose to the trigeminal nerve. Significantly more of the patients with blocking achieved excellent pain outcomes (84% vs. 62%), but with higher incidences of moderate and bothersome trigeminal nerve dysfunction (37% mild/10% bothersome with plugs vs. 30% mild/2% bothersome without). CONCLUSIONS: The use of plugs to protect the brainstem during GKR treatment for TN increases the dose of irradiation delivered to the intracisternal trigeminal nerve root and is associated with an important increase in the incidence of trigeminal nerve dysfunction. Therefore, beam channel blocking should be avoided for 90 Gy-GKR of TN.

Stereotactic targeting of the ventrointermediate nucleus of the thalamus by direct visualization with high-field MRI.

OBJECTIVE: To evaluate the ability of high-field MRI to consistently produce high-resolution, anatomical images of the thalamic ventrointermediate nucleus (Vim) suitable for stereotactic targeting. METHODS: MR images of the thalamus of patients treated for essential tremor were acquired prior to treatment using a 3-tesla MR system. Similar images were acquired in 6 volunteers using, for comparison, both a 1.5-tesla and a 3.0-tesla system. RESULTS: The thalamic Vim was clearly and consistently delineated on the 3-tesla images. These images were successfully used for target localization in essential tremor patients. In the volunteers data, images acquired using the 1.5-tesla system were inferior to those acquired using the 3-tesla system, lacking the ability to consistently provide reliably defined borders of the Vim. CONCLUSION: 3-Tesla MRI can provide high-quality depiction of the Vim, potentially enabling accurate treatment planning by direct visualization and definition of the targeted Vim.

Role of intracanalicular volumetric and dosimetric parameters on hearing preservation after vestibular schwannoma radiosurgery.

PURPOSE: To analyze the relationship between hearing preservation after gamma knife radiosurgery (GKR) for vestibular schwannoma (VS) and some volumetric and dosimetric parameters of the intracanalicular components of VS. METHODS AND MATERIALS: This study included 82 patients with a VS treated by GKR; all patients had no NF2 disease, a Gardner-Robertson hearing class 1-4 before treatment, a marginal dose of 12 Gy, and a radiologic and audiologic follow-up > or =1 year post-GKR. The volume of both the entire tumor and the intracanalicular part of the tumor and the mean and integrated dose of these two volumes were correlated to the auditory outcomes of patients. RESULTS: At last hearing follow-up, 52 patients had no hearing worsening, and 30 patients had an increase of > or =1 class on Gardner-Robertson classification. We found that hearing preservation after GKR is significantly correlated with the intracanalicular tumor volume, as well as with the integrated dose delivered to the intracanalicular tumor volume. CONCLUSIONS: Some volumetric and dosimetric parameters of the intracanalicular part of the tumor influence hearing preservation after GKR of VS. Consequently, we advise the direct treatment of patients with preserved functional hearing and a VS including a small intracanalicular volume.

Moyamoya disease--diagnosis and treatment: indirect cerebral revascularization at the Sheba Medical Center.

Moyamoya disease is a cerebral vasculopathy characterized mainly by progressive narrowing of the major intracranial vessels. While more common and having a familial predilection in the Far East, it can also develop in association with some common hereditary diseases and can be acquired after environmental exposure. In the young its manifestations are the result of cerebral ischemia. Adults usually suffer from repeated incidents of intracerebral hemorrhage. Surgical revascularization of ischemic cerebral territories plays a major role in their treatment. We review the literature and present our series of three adult and five pediatric patients; these patients were diagnosed at our institution and treated with indirect revascularization techniques.

Pretreatment prediction of brain tumors' response to radiation therapy using high b-value diffusion-weighted MRI.

Diffusion-weighted magnetic resonance imaging (DWMRI) is sensitive to tissues' biophysical characteristics, including apparent diffusion coefficients (ADCs) and volume fractions of water in different populations. In this work, we evaluate the clinical efficacy of DWMRI and high diffusion-weighted magnetic resonance imaging (HDWMRI), acquired up to b = 4000 sec/mm(2) to amplify sensitivity to water diffusion properties, in pretreatment prediction of brain tumors' response to radiotherapy. Twelve patients with 20 brain lesions were studied. Six ring-enhancing lesions were excluded due to their distinct diffusion characteristics. Conventional and DWMRI were acquired on a 0.5-T MRI. Response to therapy was determined from relative changes in tumor volumes calculated from contrast-enhanced T1-weighted MRI, acquired before and a mean of 46 days after beginning therapy. ADCs and a diffusion index, R(D), reflecting tissue viability based on water diffusion were calculated from DWMRIs. Pretreatment values of ADC and R(D) were found to correlate significantly with later tumor response/nonresponse (r = 0.76, P <.002 and r = 0.77, P <.001). This correlation implies that tumors with low pretreatment diffusion values, indicating high viability, will respond better to radiotherapy than tumors with high diffusion values, indicating necrosis. These results demonstrate the feasibility of using DWMRI for pretreatment prediction of response to therapy in patients with brain tumors undergoing radiotherapy.

Early detection of response to radiation therapy in patients with brain malignancies using conventional and high b-value diffusion-weighted magnetic resonance imaging.

PURPOSE: To study the feasibility of using diffusion-weighted magnetic resonance imaging (DWMRI), which is sensitive to the diffusion of water molecules in tissues, for detection of early tumor response to radiation therapy; and to evaluate the additional information obtained from high DWMRI, which is more sensitive to low-mobility water molecules (such as intracellular or bound water), in increasing the sensitivity to response. PATIENTS AND METHODS: Standard MRI and DWMRI were acquired before and at regular intervals after initiating radiation therapy for 10 malignant brain lesions in eight patients. RESULTS: One week posttherapy, three of six responding lesions showed an increase in the conventional DWMRI parameters. Another three responding lesions showed no change. Four nonresponding lesions showed a decrease or no change. The early change in the diffusion parameters was enhanced by using high DWMRI. When high DWMRI was used, all responding lesions showed increase in the diffusion parameter and all nonresponding lesions showed no change or decrease. Response was determined by standard MRI 7 weeks posttherapy. The changes in the diffusion parameters measured 1 week after initiating treatment were correlated with later tumor response or no response (P <.006). This correlation was increased to P <.0006 when high DWMRI was used. CONCLUSION: The significant correlation between changes in diffusion parameters 1 week after initiating treatment and later tumor response or no response suggests the feasibility of using DWMRI for early, noninvasive prediction of tumor response. The ability to predict response may enable early termination of treatment in nonresponding patients, prevent additional toxicity, and allow for early changes in treatment.

Linear accelerator radiosurgery for meningiomas in and around the cavernous sinus.

OBJECTIVE: A retrospective study to evaluate the efficacy and side effects of linear accelerator radiosurgery in the treatment of cavernous sinus meningiomas. METHODS: Between 1993 and 2001, 42 patients with meningiomas involving the cavernous sinus underwent linear accelerator radiosurgery at our institution. A mean radiation dose of 14 Gy was delivered to the tumor margin. The median tumor volume was 8.2 cm3 (mean, 8.4 cm3). Median follow-up was 36 months (mean, 38 mo). RESULTS: Control of tumor growth was achieved in 97.5% of the patients. There was no mortality or permanent extraocular motor or pituitary dysfunction. Treatment-related complications included new trigeminal neuropathy in 4.7% and a new visual field defect in 2.8%. Two patients required shunt placement after developing hydrocephalus. One patient with symptomatic temporal lobe edema underwent partial excision of the tumor. Improvement of existing cranial neuropathies was noted in 29% of affected trigeminal nerves, in 22% of oculomotor nerves, and in 13% of Cranial Nerves IV and VI. CONCLUSION: This study indicates that linear accelerator radiosurgery can achieve a high control rate of meningiomas involving the cavernous sinus with no mortality and a low incidence of morbidity.