Impact of Cochlear Dose on Hearing Preservation Following Stereotactic Radiosurgery in Treatment of Vestibular Schwannomas: A Multi-Center Study.

OBJECTIVE: Stereotactic radiosurgery (SRS) is a well-established treatment for vestibular schwannomas (VS). Hearing loss remains a main morbidity of VS and its treatments, including SRS. The effects of radiation parameters of SRS on hearing remain unknown. The goal of this study is to determine the effect of tumor volume, patient demographics, pretreatment hearing status, cochlear radiation dose, total tumor radiation dose, fractionation, and other radiotherapy parameters on hearing deterioration. METHODS: Multicenter retrospective analysis of 611 patients who underwent SRS for VS from 1990-2020 and had pre- and post-treatment audiograms. RESULTS: Pure tone averages (PTAs) increased and word recognition scores (WRSs) decreased in treated ears at 12-60 months while remaining stable in untreated ears. Higher baseline PTA, higher tumor radiation dose, higher maximum cochlear dose, and usage of single fraction resulted in higher post radiation PTA; WRS was only predicted by baseline WRS and age. Higher baseline PTA, single fraction treatment, higher tumor radiation dose, and higher maximum cochlear dose resulted in a faster deterioration in PTA. Below a maximum cochlear dose of 3 Gy, there were no statistically significant changes in PTA or WRS. CONCLUSIONS: Decline of hearing at one year in VS patients after SRS is directly related to maximum cochlear dose, single versus 3-fraction treatment, total tumor radiation dose, and baseline hearing level. The maximum safe cochlear dose for hearingtbrowd preservation at one year is 3 Gy, and the use of 3 fractions instead of one fraction was better at preserving hearing.

Image-guided LINAC radiosurgery in hypothalamic hamartomas.

Introduction: Hypothalamic hamartomas (HH) are developmental malformations that are associated with mild to severe drug-refractory epilepsy. Stereotactic radiosurgery (SRS) is an emerging non-invasive option for the treatment of small and medium-sized HH, providing good seizure outcomes without neurological complications. Here, we report our experience treating HH with frameless LINAC SRS. Materials and methods: We retrospectively collected clinical and neuroradiological data of ten subjects with HH-related epilepsy that underwent frameless image-guided SRS. Results: All patients underwent single-fraction SRS using a mean prescribed dose of 16.27 Gy (range 16-18 Gy). The median prescription isodose was 79% (range 65-81 Gy). The mean target volume was 0.64 cc (range 0.26-1.16 cc). Eight patients experienced complete or near complete seizure freedom (Engel class I and II). Five patients achieved complete seizure control within 4 to 18 months after the treatment. Four patients achieved Engel class II outcome, with stable results. One patient had a reduction of seizure burden superior to 50% (Engel class III). One patient had no benefit at all (Engel class IV) and refused further treatments. Overall, at the last follow-up, three patients experience class I, five class II, one class III and one class IV outcome. No neurological complications were reported. Conclusions: Frameless LINAC SRS provides good seizure and long-term neuropsychosocial outcome, without the risks of neurological complications inherently associated with microsurgical resection.

Image-Guided Stereotactic Radiosurgery for the Treatment of Spasticity and Pain: A Preliminary Experience.

Background Spasticity is a major health problem worldwide. Response to current medical and rehabilitation treatments is often poor. Surgical treatment is available only for a very limited number of patients. Aim We recently reported the application of stereotactic radiosurgery as a treatment option for spasticity and related pain. This paper describes a larger experience using image-guided stereotactic radiosurgery targeting the cervical or lumbar spinal roots to relieve spasticity and pain in four patients. Methods All the patients had refractory spasticity and related pain, one patient had additional paroxystic neuralgic pain. The cause of spasticity and pain was a traumatic brain and/or spinal cord injury, brain and/or spinal cord surgery, and stroke. Symptoms affected the right superior limb in one patient, and the inferior limbs in three patients (unilaterally in two, bilaterally in one). According to the symptoms, one patient was treated at the cervical level (C7 right sensory root) and three patients at lumbar level (right L4, left S1, and L2 roots bilaterally). The target was selected on constructive interference in steady-state (CISS) MR, focusing the irradiation on the postganglionic sensory segment of the cervical root or the intra-foraminal dorsolateral sensory portion of the lumbar roots. Appropriate spasticity and pain scales were used to assess the patient's status after the treatment. Results The treatments were tolerated well. Marked symptomatic relief was found in all the treated patients. Improvements in spasticity and pain scales were observed up to the latest follow-up. After 2 years, the mean reduction of the visual analog scale (VAS) and Modified Ashworth Scale (MAS) was 64.3% and 43.7%, respectively, while the median reduction of MAS score was 50%. Conclusions Except for a previous case report, this is the first study describing a novel noninvasive technique based on image-guided radiosurgery to treat severe spasticity and pain due to brain and spinal cord injury. This novel technique appears to be safe and effective and deserves to be studied further.

Non-conventional Ultra-High Dose Rate (FLASH) Microbeam Radiotherapy Provides Superior Normal Tissue Sparing in Rat Lung Compared to Non-conventional Ultra-High Dose Rate (FLASH) Radiotherapy.

Conventional radiotherapy is a widely used non-invasive form of treatment for many types of cancer. However, due to a low threshold in the lung for radiation-induced normal tissue damage, it is of less utility in treating lung cancer. For this reason, surgery is the preferred treatment for lung cancer, which has the detriment of being highly invasive. Non-conventional ultra-high dose rate (FLASH) radiotherapy is currently of great interest in the radiotherapy community due to demonstrations of reduced normal tissue toxicity in lung and other anatomy. This study investigates the effects of FLASH microbeam radiotherapy, which in addition to ultra-high dose rate incorporates a spatial segmentation of the radiation field, on the normal lung tissue of rats. With a focus on fibrotic damage, this work demonstrates that FLASH microbeam radiotherapy provides an order of magnitude increase in normal tissue radio-resistance compared to FLASH radiotherapy. This result suggests FLASH microbeam radiotherapy holds promise for much improved non-invasive control of lung cancer.

Stereotactic Dorsolateral Irradiation of Spinal Nerve Roots: A Novel Technique for the Treatment of Spasticity and Pain.

Selective dorsal rhizotomy is an established surgical treatment to improve the neurological and functional status of children with spastic cerebral palsy and adults with spasticity and pain caused by a variety of brain and spinal injuries. This procedure requires a dorsolumbar laminectomy to expose the appropriate dorsal rootlets, which are sectioned according to the presence of sustained electromiographic discharges. Image-guided robotic radiosurgery targeting the intracisternal sensory root of the trigeminal nerve has been described as a safe and effective non-invasive treatment for trigeminal neuralgia, a paroxystic pain disorder which often responds poorly to medical therapy. Image-guided radiosurgery requires no frame placement and can treat brain or spinal targets with submillimetric precision. This technique can be used to treat cervical or lumbar dorsal roots. A 44-year-old patient with von Hippel-Lindau disease developed severe spastic tetraparesis following multiple brain and spinal procedures. Spasticity and related pain mostly affected the right leg, with sustained electromiographic discharges originating from the right L4 nerve root. Response to medical therapy with baclofen and cannabinoids was poor. Due to geographical and logistical issues, the patient declined the placement of an intrathecal baclofen pump. Considering the poor general condition of the patient and his decision to avoid invasive procedures, a novel treatment option was offered to provide relief from spasticity and pain: stereotactic image-guided irradiation delivered to the sensory root. The patient underwent a right intraforaminal dorsolateral L4 root stereotactic irradiation with a delivered dose of 45 Gy prescribed to the 82% isodose. The treatment was well tolerated, without side effects. Resolution of spasticity and related pain in the right leg was found six months after the procedure. A marked reduction of spasticity and pain was also evident in the contralateral leg. These improvements have been stable over the last 18 months. So far, two additional patients underwent stereotactic dorsolateral spinal root irradiation (one delivered to a cervical, the other to a lumbar), with similar positive outcomes. These preliminary results suggest that spinal root stereotactic image-guided irradiation, a novel treatment option in the neurosurgical armamentarium, is a safe and effective procedure and deserves further investigation.

ZAP-X: A Novel Radiosurgical Device for the Treatment of Trigeminal Neuralgia.

Introduction The treatment of trigeminal neuralgia (TN) is one of the most demanding of all radiosurgery procedures, requiring accurate delivery and sharp dose fall off. ZAP-X®, a new, innovative frameless radiosurgical device, maybe an attractive platform for the treatment of TN and other functional brain disorders. Here, we compared the dosimetry of ZAP-X plans for a single patient to that generated by a well-established dedicated radiosurgery device, the CyberKnife. Methods Radiosurgery plans that delineated the cranial nerve from a single patient's fused computed tomography and magnetic resonance imaging (CT-MR) data set were planned on both the ZAP-X and CyberKnife, with the latter serving as a validated benchmark. The same target and treatment planning constraints were applied. Plans were evaluated by a physician with experience treating TN and a medical physicist. The ZAP-X treatment plan used two isocenters delivered through 4-mm collimators based on a non-isocentric plan that delivered 29,441 MU through 81 beams. The CyberKnife plans used a 5-mm collimator for a non-isocentric plan that delivered 17,880 MU through 88 beams. Results Based on visual inspection, the isodose volumes covered by ZAP-X and CyberKnife were similar at the prescription isodose (70% and 80%, respectively, with a maximum dose (Dmax) of 7500 cGy. The conformality index was better for the CyberKnife as compared to ZAP-X. However, the irradiated volumes were smaller at the 50%, 20%, and 10% isodoses for ZAP-X (0.12 cc, 0.57 cc, and 1.69 for ZAP-X; 0.18 cc, 0.91 cc, and 3.41 cc for CyberKnife). In particular, the 20% and 10% isodose volumes were much smaller for ZAP-X, especially on the axial and sagittal planes. Conclusions ZAP-X treatment planning for TN compares favorably with equivalent planning on CyberKnife. The brain volumes containing the 20% and 10% isodoses are smaller using ZAP-X, thus relatively sparing critical structures close to the target, including the Gasserian ganglion and brainstem. This feature could be of clinical relevance by potentially reducing treatment-related complications.

Factors affecting outcome in frameless non-isocentric stereotactic radiosurgery for trigeminal neuralgia: a multicentric cohort study.

BACKGROUND: Stereotactic radiosurgery (SRS) is an effective treatment for trigeminal neuralgia (TN). Nevertheless, a proportion of patients will experience recurrence and treatment-related sensory disturbances. In order to evaluate the predictors of efficacy and safety of image-guided non-isocentric radiosurgery, we analyzed the impact of trigeminal nerve volume and the nerve dose/volume relationship, together with relevant clinical characteristics. METHODS: Two-hundred and ninety-six procedures were performed on 262 patients at three centers. In 17 patients the TN was secondary to multiple sclerosis (MS). Trigeminal pain and sensory disturbances were classified according to the Barrow Neurological Institute (BNI) scale. Pain-free-intervals were investigated using Kaplan Meier analyses. Univariate and multivariate Cox regression analyses were performed to identify predictors. RESULTS: The median follow-up period was 38 months, median maximal dose 72.4 Gy, median target nerve volume 25 mm3, and median prescription dose 60 Gy. Pain control rate (BNI I-III) at 6, 12, 24, 36, 48, and 60 months were 96.8, 90.9, 84.2, 81.4, 74.2, and 71.2%, respectively. Overall, 18% of patients developed sensory disturbances. Patients with volume ≥ 30 mm3 were more likely to maintain pain relief (p = 0.031), and low integral dose (< 1.4 mJ) tended to be associated with more pain recurrence than intermediate (1.4-2.7 mJ) or high integral dose (> 2.7 mJ; low vs. intermediate: log-rank test, χ2 = 5.02, p = 0.019; low vs. high: log-rank test, χ2 = 6.026, p = 0.014). MS, integral dose, and mean dose were the factors associated with pain recurrence, while re-irradiation and MS were predictors for sensory disturbance in the multivariate analysis. CONCLUSIONS: The dose to nerve volume ratio is predictive of pain recurrence in TN, and re-irradiation has a major impact on the development of sensory disturbances after non-isocentric SRS. Interestingly, the integral dose may differ significantly in treatments using apparently similar dose and volume constraints.

Understanding High-Dose, Ultra-High Dose Rate, and Spatially Fractionated Radiation Therapy.

The National Cancer Institute's Radiation Research Program, in collaboration with the Radiosurgery Society, hosted a workshop called Understanding High-Dose, Ultra-High Dose Rate and Spatially Fractionated Radiotherapy on August 20 and 21, 2018 to bring together experts in experimental and clinical experience in these and related fields. Critically, the overall aims were to understand the biological underpinning of these emerging techniques and the technical/physical parameters that must be further defined to drive clinical practice through innovative biologically based clinical trials.

Cyberknife Radiosurgery for Trigeminal Neuralgia.

Introduction Image-guided robotic radiosurgery is an emerging minimally-invasive treatment option for trigeminal neuralgia (TN). Our group has treated 560 cases up to date, and report here the clinical outcomes of 387 treatments with three years follow-up. This study represents the largest single-center experience on CyberKnife radiosurgery for the treatment of TN so far reported. Methods CyberKnife radiosurgery treatment was offered to patients with drug-resistant TN, after the failure of other treatments or refusal of invasive procedures. A second treatment was offered to patients with a poor response after the first treatment or with recurrent pain. Treatment protocol required the non-isocentric delivery of 60 Gy prescribed to the 80% isodose to a 6 mm retrogasserian segment of the affected trigeminal nerve. Retreatments typically received 45 Gy, again prescribed to the 80% isodose. The final plan was developed accordingly to individual anatomy and dose distribution over the trigeminal nerve, gasserian ganglion, and brainstem. Clinical outcomes such as pain control and hypoesthesia/numbness have been evaluated after 6, 12, 24, and 36 months.  Results Our group has treated 527 patients with Cyberknife radiosurgery at Centro Diagnostico Italiano (CDI), Milan, Italy, during the last decade. A minimum follow-up of six months was available on 496 patients. These patients received 560 treatments: 435 patients (87.7%) had a single treatment, 60 patients (12.1%) had two treatments, and one patient (0.2%) had five treatments (two on the right side, three on the left side). Twenty four patients had multiple sclerosis (4.8%). Four hundred and forty-three patients (84%) received the treatment without previous procedures, while 84 patients (16%) underwent radiosurgery after the failure of other treatments. A neurovascular conflict was identified in 59% of the patients. Three hundred and forty-three patients (receiving a total of 387 treatments) had a minimum of 36 months follow up. Pain relief rate at 6, 12, 18, 24, 30 and 36 months was respectively 92, 87, 87, 82, 78 and 76%. Forty-four patients out of 343 (12.8%) required a second treatment during the observed period. At 36 months post-treatment, 21 patients (6,1%) reported the presence of bothering facial hypoesthesia. Eighteen patients out of 21 (85.7%) developed this complication after a repeated treatment.  Conclusions Frameless image-guided robotic radiosurgery in experienced hands is a safe and effective procedure for the treatment of TN, providing excellent pain control rates in the absence of major neurological complications. Repeated treatments due to recurrent pain are associated with restored pain control but at the price of a higher rate of sensory complications.

A Wireless Neuroprosthesis for Patients with Drug-refractory Epilepsy: A Proof-of-Concept Study.

Objective Acute or protracted cortical recording may be necessary for patients with drug-refractory epilepsy to identify the ictogenic regions before undergoing resection. Currently, these invasive recording techniques present certain limitations, one of which is the need for cables connecting the recording electrodes placed in the intracranial space with external devices displaying the recorded electrocorticographic signals. This equates to a direct connection between the sterile intracranial space with the non-sterile environment. Due to the increasing likelihood of infections with time, subdural grids are typically removed a few days after implantation, a limiting factor in localizing the epileptogenic zone if seizures are not frequent enough to be captured within this time-frame. Furthermore, patients are bound to stay in the hospital, connected by the wires to the recording device, thus increasing substantially the treatment costs. To address some of the current shortcomings of invasive monitoring, we developed a neuroprosthesis made of a subdural silicone grid connected to a wireless transmitter allowing prolonged electrocorticografic recording and direct cortical stimulation. This device consists of a silicone grid with 128-platinum/iridium contacts, connected to an implantable case providing wireless recording and stimulation. The case also houses a wirelessly rechargeable battery for chronic long-term implants. We report the results of the first human proof-of-concept trial for wireless transmission of electrocorticographic recordings using a device suited for long-term implantation in three patients with drug-refractory epilepsy.  Methods Three patients with medically refractory epilepsy underwent the temporary intraoperative placement of the subdural grid connected to the wireless device for recording and transmission of electrocorticographic signals for a duration of five minutes before the conventional recording electrodes were placed or the ictal foci were resected. Results Wireless transmission of brain signals was successfully achieved. The wireless electrocorticographic signal was judged of excellent quality by a blinded neurophysiologist. Conclusions This preliminary experience reports the first successful placement of a wireless electrocorticographic recording device in humans. Long-term placement for prolonged wireless electrocorticographic recording in epilepsy patients will be the next step.

CyberKnife® Radiosurgery as First-line Treatment for Catastrophic Epilepsy Caused by Hypothalamic Hamartoma.

Hypothalamic hamartomas (HH) are deep-seated lesions often associated with catastrophic epilepsy (an epileptic syndrome characterized by severe, drug-refractory seizures eventually leading to mental retardation and death). Radical microsurgical resection is not feasible for lesions located within the wall of the third ventricle inside the hypothalamus. Frame-based stereotactic radiosurgery has been reported as an effective treatment modality for small- to medium-size intrahypothalamic hamartomas, providing excellent seizure outcomes without lasting complications. This report describes the use of frameless image-guided robotic radiosurgery (CyberKnife® Radiosurgery System) as a first-line treatment in two children with catastrophic epilepsy induced by HH. Both patients experienced multiple-daily complex partial and gelastic seizures, as well as almost daily generalized seizures. The prescribed dose was 16 Gy (to the 65% isodose for case I; to the 70% isodose for case II). Lesional volume was 11.5 cc (case I) and 8.9 cc (case II). A steady reduction of the seizure frequency and severity was achieved after the treatment, starting about three months after the treatment. The generalized seizures disappeared within one year, while complete resolution of the gelastic seizures required up to 18 months. No seizure recurrence and no radiation-induced side effects or complications were witnessed over a follow-up period of ten years and eight months (case I) and nine years and seven months (case II) since the treatment. CyberKnife radiosurgery proved to be a safe and effective non-invasive first-line treatment in these two children with catastrophic epilepsy caused by HH.

Micro-imaging of Brain Cancer Radiation Therapy Using Phase-contrast Computed Tomography.

PURPOSE: Experimental neuroimaging provides a wide range of methods for the visualization of brain anatomic morphology down to subcellular detail. Still, each technique-specific detection mechanism presents compromises among the achievable field-of-view size, spatial resolution, and nervous tissue sensitivity, leading to partial sample coverage, unresolved morphologic structures, or sparse labeling of neuronal populations and often also to obligatory sample dissection or other sample invasive manipulations. X-ray phase-contrast imaging computed tomography (PCI-CT) is an experimental imaging method that simultaneously provides micrometric spatial resolution, high soft-tissue sensitivity, and ex vivo full organ rodent brain coverage without any need for sample dissection, staining or labeling, or contrast agent injection. In the present study, we explored the benefits and limitations of PCI-CT use for in vitro imaging of normal and cancerous brain neuromorphology after in vivo treatment with synchrotron-generated x-ray microbeam radiation therapy (MRT), a spatially fractionated experimental high-dose radiosurgery. The goals were visualization of the MRT effects on nervous tissue and a qualitative comparison of the results to the histologic and high-field magnetic resonance imaging findings. METHODS AND MATERIALS: MRT was administered in vivo to the brain of both healthy and cancer-bearing rats. At 45 days after treatment, the brain was dissected out and imaged ex vivo using propagation-based PCI-CT. RESULTS: PCI-CT visualizes the brain anatomy and microvasculature in 3 dimensions and distinguishes cancerous tissue morphology, necrosis, and intratumor accumulation of iron and calcium deposits. Moreover, PCI-CT detects the effects of MRT throughout the treatment target areas (eg, the formation of micrometer-thick radiation-induced tissue ablation). The observed neurostructures were confirmed by histologic and immunohistochemistry examination and related to the micro-magnetic resonance imaging data. CONCLUSIONS: PCI-CT enabled a unique 3D neuroimaging approach for ex vivo studies on small animal models in that it concurrently delivers high-resolution insight of local brain tissue morphology in both normal and cancerous micro-milieu, localizes radiosurgical damage, and highlights the deep microvasculature. This method could assist experimental small animal neurology studies in the postmortem evaluation of neuropathology or treatment effects.

A novel neural prosthesis providing long-term electrocorticography recording and cortical stimulation for epilepsy and brain-computer interface.

OBJECTIVE: Wireless technology is a novel tool for the transmission of cortical signals. Wireless electrocorticography (ECoG) aims to improve the safety and diagnostic gain of procedures requiring invasive localization of seizure foci and also to provide long-term recording of brain activity for brain-computer interfaces (BCIs). However, no wireless devices aimed at these clinical applications are currently available. The authors present the application of a fully implantable and externally rechargeable neural prosthesis providing wireless ECoG recording and direct cortical stimulation (DCS). Prolonged wireless ECoG monitoring was tested in nonhuman primates by using a custom-made device (the ECoG implantable wireless 16-electrode [ECOGIW-16E] device) containing a 16-contact subdural grid. This is a preliminary step toward large-scale, long-term wireless ECoG recording in humans. METHODS: The authors implanted the ECOGIW-16E device over the left sensorimotor cortex of a nonhuman primate (Macaca fascicularis), recording ECoG signals over a time span of 6 months. Daily electrode impedances were measured, aiming to maintain the impedance values below a threshold of 100 KΩ. Brain mapping was obtained through wireless cortical stimulation at fixed intervals (1, 3, and 6 months). After 6 months, the device was removed. The authors analyzed cortical tissues by using conventional histological and immunohistological investigation to assess whether there was evidence of damage after the long-term implantation of the grid. RESULTS: The implant was well tolerated; no neurological or behavioral consequences were reported in the monkey, which resumed his normal activities within a few hours of the procedure. The signal quality of wireless ECoG remained excellent over the 6-month observation period. Impedance values remained well below the threshold value; the average impedance per contact remains approximately 40 KΩ. Wireless cortical stimulation induced movements of the upper and lower limbs, and elicited fine movements of the digits as well. After the monkey was euthanized, the grid was found to be encapsulated by a newly formed dural sheet. The grid removal was performed easily, and no direct adhesions of the grid to the cortex were found. Conventional histological studies showed no cortical damage in the brain region covered by the grid, except for a single microscopic spot of cortical necrosis (not visible to the naked eye) in a region that had undergone repeated procedures of electrical stimulation. Immunohistological studies of the cortex underlying the grid showed a mild inflammatory process. CONCLUSIONS: This preliminary experience in a nonhuman primate shows that a wireless neuroprosthesis, with related long-term ECoG recording (up to 6 months) and multiple DCSs, was tolerated without sequelae. The authors predict that epilepsy surgery could realize great benefit from this novel prosthesis, providing an extended time span for ECoG recording.

Staged Image-guided Robotic Radiosurgery and Deferred Chemotherapy to Treat a Malignant Glioma During and After Pregnancy.

A 26-year-old pregnant woman with a fast-growing malignant deep-seated brain glioma was offered a therapeutic abortion to allow subsequent surgical resection. This option was refused by the mother, but the fast tumor growth placed the life of both mother and child at risk. A staged CyberKnife radiosurgery treatment was then planned, aiming to provide at least temporary tumor growth control and allow a safe delivery while keeping the doses received by the fetus well below the allowed doses. Growth control and the safe delivery of a healthy child were achieved after this first treatment. An intensive chemotherapy program based on the combination of Avastin, irinotecan, and Temodal was then started. Recurring tumor growth was treated with a second CyberKnife procedure while continuing the above chemotherapy protocol. At 43 months after the second CyberKnife procedure, the tumor had disappeared on magnetic resonance imaging. Neither mother nor child showed the neurological sequelae. Staged radiosurgery and deferred chemotherapy proved to be a safe and effective treatment to allow the delivery of a healthy child and the long-term control of an aggressive brain glioma.

Synchrotron-generated microbeams induce hippocampal transections in rats.

Synchrotron-generated microplanar beams (microbeams) provide the most stereo-selective irradiation modality known today. This novel irradiation modality has been shown to control seizures originating from eloquent cortex causing no neurological deficit in experimental animals. To test the hypothesis that application of microbeams in the hippocampus, the most common source of refractory seizures, is safe and does not induce severe side effects, we used microbeams to induce transections to the hippocampus of healthy rats. An array of parallel microbeams carrying an incident dose of 600 Gy was delivered to the rat hippocampus. Immunohistochemistry of phosphorylated γ-H2AX showed cell death along the microbeam irradiation paths in rats 48 hours after irradiation. No evident behavioral or neurological deficits were observed during the 3-month period of observation. MR imaging showed no signs of radio-induced edema or radionecrosis 3 months after irradiation. Histological analysis showed a very well preserved hippocampal cytoarchitecture and confirmed the presence of clear-cut microscopic transections across the hippocampus. These data support the use of synchrotron-generated microbeams as a novel tool to slice the hippocampus of living rats in a minimally invasive way, providing (i) a novel experimental model to study hippocampal function and (ii) a new treatment tool for patients affected by refractory epilepsy induced by mesial temporal sclerosis.

Image-Guided Robotic Radiosurgery for Trigeminal Neuralgia.

BACKGROUND: Frameless, non-isocentric irradiation of an extended segment of the trigeminal nerve introduces new concepts in stereotactic radiosurgery for medically resistant trigeminal neuralgia (TN). OBJECTIVE: To report the results of the largest single-center experience about image-guided robotic radiosurgery for TN. METHODS: A cohort of 138 patients treated with CyberKnife® (Accuray Incorporated, Sunnyvale, California) radiosurgery with a minimum follow-up of 36 mo were recruited. Pain relief, medications, sensory disturbances, rate and time of pain recurrence were prospectively analyzed. RESULTS: Median follow-up was 52.4 mo; median dose 75 Gy; median target length 5.7-mm; median target volume 40 mm³; median prescription dose 60 Gy (80% isodose line). Actuarial pain control rate (Barrow Neurological Institute [BNI] class I-IIIa) at 6, 12, 24, and 36 mo were 93.5%, 85.8%, 79.7%, and 76%, respectively. Overall, 33 patients (24%) required a second treatment. Overall, 18.1% developed sensory disturbances after 16.4 ± 8.7 mo. One patient (0.7%) developed BNI grade IV dysfunction; 6 (4.3%) developed BNI grade III (somewhat bothersome) hypoesthesia after retreatment; BNI grade II (not bothersome) hypoesthesia was reported by 18 patients (11 after retreatment). Shorter nerve length (<6 mm vs 6 mm), smaller nerve volume (<30 mm3 vs >30 mm3), and lower prescription dose (<58 vs >58 Gy) were associated with treatment failure (P = .01, P = .02, P = .03, respectively). Re-irradiation independently predicted sensory disturbance (P < .001). CONCLUSION: Targeting a 6-mm segment of the trigeminal nerve with a prescribed dose of 60 Gy appears safe and effective. Persistent pain control was achieved in most patients with acceptable risk of sensory complications, which were typically found after re-irradiation.

Rat sensorimotor cortex tolerance to parallel transections induced by synchrotron-generated X-ray microbeams.

Microbeam radiation therapy is a novel preclinical technique, which uses synchrotron-generated X-rays for the treatment of brain tumours and drug-resistant epilepsies. In order to safely translate this approach to humans, a more in-depth knowledge of the long-term radiobiology of microbeams in healthy tissues is required. We report here the result of the characterization of the rat sensorimotor cortex tolerance to microradiosurgical parallel transections. Healthy adult male Wistar rats underwent irradiation with arrays of parallel microbeams. Beam thickness, spacing and incident dose were 100 or 600 µm, 400 or 1200 µm and 360 or 150 Gy, respectively. Motor performance was carried over a 3-month period. Three months after irradiation rats were sacrificed to evaluate the effects of irradiation on brain tissues by histology and immunohistochemistry. Microbeam irradiation of sensorimotor cortex did not affect weight gain and motor performance. No gross signs of paralysis or paresis were also observed. The cortical architecture was not altered, despite the presence of cell death along the irradiation path. Reactive gliosis was evident in the microbeam path of rats irradiated with 150 Gy, whereas no increase was observed in rats irradiated with 360 Gy.

Inverse treatment planning for spinal robotic radiosurgery: an international multi-institutional benchmark trial.

Stereotactic radiosurgery (SRS) is the accurate, conformal delivery of high-dose radiation to well-defined targets while minimizing normal structure doses via steep dose gradients. While inverse treatment planning (ITP) with computerized optimization algorithms are routine, many aspects of the planning process remain user-dependent. We performed an international, multi-institutional benchmark trial to study planning variability and to analyze preferable ITP practice for spinal robotic radiosurgery. 10 SRS treatment plans were generated for a complex-shaped spinal metastasis with 21 Gy in 3 fractions and tight constraints for spinal cord (V14Gy < 2 cc, V18Gy < 0.1 cc) and target (coverage > 95%). The resulting plans were rated on a scale from 1 to 4 (excellent-poor) in five categories (constraint compliance, optimization goals, low-dose regions, ITP complexity, and clinical acceptability) by a blinded review panel. Additionally, the plans were mathemati-cally rated based on plan indices (critical structure and target doses, conformity, monitor units, normal tissue complication probability, and treatment time) and compared to the human rankings. The treatment plans and the reviewers' rankings varied substantially among the participating centers. The average mean overall rank was 2.4 (1.2-4.0) and 8/10 plans were rated excellent in at least one category by at least one reviewer. The mathematical rankings agreed with the mean overall human rankings in 9/10 cases pointing toward the possibility for sole mathematical plan quality comparison. The final rankings revealed that a plan with a well-balanced trade-off among all planning objectives was preferred for treatment by most par-ticipants, reviewers, and the mathematical ranking system. Furthermore, this plan was generated with simple planning techniques. Our multi-institutional planning study found wide variability in ITP approaches for spinal robotic radiosurgery. The participants', reviewers', and mathematical match on preferable treatment plans and ITP techniques indicate that agreement on treatment planning and plan quality can be reached for spinal robotic radiosurgery.

Radiation dose to the fetus during CyberKnife radiosurgery for a brain tumor in pregnancy.

PURPOSE: Pregnancy during radiosurgery is extremely rare in clinical practice. We report fetal dose results during CyberKnife radiosurgery for a brain tumor in pregnancy. METHODS AND MATERIALS: A 26 year old pregnant woman with a rapidly growing deep-seated grade-III glioma was treated during the third trimester of gestation using CyberKnife. Ultrasound imaging was used to determine the position of the embryo prior to treatment. A dose of 1400 cGy was prescribed aiming to control tumor growth until delivery of the child. Prior to radiosurgery, the treatment was simulated on an anthropomorphic phantom. Radiation dose to the embryo was measured using a Farmer chamber and EBT3 films. RESULTS: Fetal doses of 4.4 cGy and 4.1 cGy were measured for the embryo's head and legs, lying at 56 cm and 72 cm from the isocenter, respectively, using the Farmer chamber situated at 8.5 cm depth beneath the phantom surface. Dose results of 4.4 cGy, 3.5 cGy and 2.0 cGy were measured with the films situated at depths of 6.5 cm, 9.5 cm and 14.5 cm, respectively. An average dose of 4.2 cGy to the fetus was derived from the above values. A corresponding dose of 3.2 cGy was also calculated based on results obtained using EBT3 films situated upon the patient skin. CONCLUSIONS: The measured fetal doses are below the threshold of 10 cGy for congenital malformations, mental and growth retardation effects. The radiogenic cancer risk to the live-born embryo was estimated less than 0.3% over the normal incidence. The treatment was administered successfully, allowing the patient to deliver a healthy child.

A novel wireless recording and stimulating multichannel epicortical grid for supplementing or enhancing the sensory-motor functions in monkey (Macaca fascicularis).

Artificial brain-machine interfaces (BMIs) represent a prospective step forward supporting or replacing faulty brain functions. So far, several obstacles, such as the energy supply, the portability and the biocompatibility, have been limiting their effective translation in advanced experimental or clinical applications. In this work, a novel 16 channel chronically implantable epicortical grid has been proposed. It provides wireless transmission of cortical recordings and stimulations, with induction current recharge. The grid has been chronically implanted in a non-human primate (Macaca fascicularis) and placed over the somato-motor cortex such that 13 electrodes recorded or stimulated the primary motor cortex and three the primary somatosensory cortex, in the deeply anaesthetized animal. Cortical sensory and motor recordings and stimulations have been performed within 3 months from the implant. In detail, by delivering motor cortex epicortical single spot stimulations (1-8 V, 1-10 Hz, 500 ms, biphasic waves), we analyzed the motor topographic precision, evidenced by tunable finger or arm movements of the anesthetized animal. The responses to light mechanical peripheral sensory stimuli (blocks of 100 stimuli, each single stimulus being <1 ms and interblock intervals of 1.5-4 s) have been analyzed. We found 150-250 ms delayed cortical responses from fast finger touches, often spread to nearby motor stations. We also evaluated the grid electrical stimulus interference with somatotopic natural tactile sensory processing showing no suppressing interference with sensory stimulus detection. In conclusion, we propose a chronically implantable epicortical grid which can accommodate most of current technological restrictions, representing an acceptable candidate for BMI experimental and clinical uses.