Stereotactic radiosurgery for arteriovenous malformations of the basal ganglia and thalamus: an international multicenter study.

OBJECTIVE: Arteriovenous malformations (AVMs) of the basal ganglia (BG) and thalamus are associated with elevated risks of both hemorrhage if left untreated and neurological morbidity after resection. Therefore, stereotactic radiosurgery (SRS) has become a mainstay in the management of these lesions, although its safety and efficacy remain incompletely understood. The aim of this retrospective multicenter cohort study was to evaluate the outcomes of SRS for BG and thalamic AVMs and determine predictors of successful endpoints and adverse radiation effects. METHODS: The authors retrospectively reviewed data on patients with BG or thalamic AVMs who had undergone SRS at eight institutions participating in the International Gamma Knife Research Foundation (IGKRF) from 1987 to 2014. Favorable outcome was defined as AVM obliteration, no post-SRS hemorrhage, and no permanently symptomatic radiation-induced changes (RICs). Multivariable models were developed to identify independent predictors of outcome. RESULTS: The study cohort comprised 363 patients with BG or thalamic AVMs. The mean AVM volume and SRS margin dose were 3.8 cm3 and 20.7 Gy, respectively. The mean follow-up duration was 86.5 months. Favorable outcome was achieved in 58.5% of patients, including obliteration in 64.8%, with rates of post-SRS hemorrhage and permanent RIC in 11.3% and 5.6% of patients, respectively. Independent predictors of favorable outcome were no prior AVM embolization (p = 0.011), a higher margin dose (p = 0.008), and fewer isocenters (p = 0.044). CONCLUSIONS: SRS is the preferred intervention for the majority of BG and thalamic AVMs. Patients with morphologically compact AVMs that have not been previously embolized are more likely to have a favorable outcome, which may be related to the use of a higher margin dose.

Down-Regulated Expression of Magnesium Transporter Genes Following a High Magnesium Diet Attenuates Sciatic Nerve Crush Injury.

BACKGROUND: Magnesium supplementation has potential for use in nerve regeneration. The expression of some magnesium transporter genes is reflective of the intracellular magnesium levels. OBJECTIVE: To assess the expression of various magnesium transporter genes as they relate to neurological alterations in a sciatic nerve injury model. METHODS: Sciatic nerve injury was induced in rats, which were then fed either basal or high magnesium diets. Magnesium concentrations and 5 magnesium transporter genes (SLC41A1, MAGT1, CNNM2, TRPM6, and TRPM7) were measured in the tissue samples. RESULTS: The high magnesium diet attenuated cytoskeletal loss in a dose-dependent manner in isolated nerve explants. The high magnesium diet augmented nerve regeneration and led to the restoration of nerve structure, increased S-100, and neurofilaments. This increased regeneration was consistent with the improvement of neurobehavioral and electrophysiological assessment. The denervated muscle morphology was restored with the high magnesium diet, and that was also highly correlated with the increased expression of desmin and acetylcholine receptors in denervated muscle. The plasma magnesium levels were significantly elevated after the animals consumed a high magnesium diet and were reciprocally related to the down-regulation of CNNM2, MagT1, and SCL41A1 in the blood monocytes, nerves, and muscle tissues of the nerve crush injury model. CONCLUSION: The increased plasma magnesium levels after consuming a high magnesium diet were highly correlated with the down-regulation of magnesium transporter genes in monocytes, nerves, and muscle tissues after sciatic nerve crush injury. The study findings suggest that there are beneficial effects of administering magnesium after a nerve injury.

Late administration of high-frequency electrical stimulation increases nerve regeneration without aggravating neuropathic pain in a nerve crush injury.

BACKGROUND: High-frequency transcutaneous neuromuscular electrical nerve stimulation (TENS) is currently used for the administration of electrical current in denervated muscle to alleviate muscle atrophy and enhance motor function; however, the time window (i.e. either immediate or delayed) for achieving benefit is still undetermined. In this study, we conducted an intervention of sciatic nerve crush injury using high-frequency TENS at different time points to assess the effect of motor and sensory functional recovery. RESULTS: Animals with left sciatic nerve crush injury received TENS treatment starting immediately after injury or 1 week later at a high frequency(100 Hz) or at a low frequency (2 Hz) as a control. In SFI gait analysis, either immediate or late admission of high-frequency electrical stimulation exerted significant improvement compared to either immediate or late administration of low-frequency electrical stimulation. In an assessment of allodynia, immediate high frequency electrical stimulation caused a significantly decreased pain threshold compared to late high-frequency or low-frequency stimulation at immediate or late time points. Immunohistochemistry staining and western blot analysis of S-100 and NF-200 demonstrated that both immediate and late high frequency electrical stimulation showed a similar effect; however the effect was superior to that achieved with low frequency stimulation. Immediate high frequency electrical stimulation resulted in significant expression of TNF-α and synaptophysin in the dorsal root ganglion, somatosensory cortex, and hippocampus compared to late electrical stimulation, and this trend paralleled the observed effect on somatosensory evoked potential. The CatWalk gait analysis also showed that immediate electrical stimulation led to a significantly high regularity index. In primary dorsal root ganglion cells culture, high-frequency electrical stimulation also exerted a significant increase in expression of TNF-α, synaptophysin, and NGF in accordance with the in vivo results. CONCLUSION: Immediate or late transcutaneous high-frequency electrical stimulation exhibited the potential to stimulate the motor nerve regeneration. However, immediate electrical stimulation had a predilection to develop neuropathic pain. A delay in TENS initiation appears to be a reasonable approach for nerve repair and provides the appropriate time profile for its clinical application.

Stereotactic radiosurgery for deep intracranial arteriovenous malformations, part 2: Basal ganglia and thalamus arteriovenous malformations.

The aim of this review is to critically analyze the outcomes following stereotactic radiosurgery (SRS) for arteriovenous malformations (AVM) of the basal ganglia and thalamus. The management of these deep-seated lesions continues to challenge neurosurgeons. Basal ganglia and thalamic AVM show a higher risk of hemorrhage, and an associated devastating morbidity and mortality, as compared to AVM in more superficial locations. Any of the currently available treatment modalities may fail or result in iatrogenic neurologic deterioration. Recent evidence from A Randomized Trial of Unruptured Brain AVM (ARUBA) further deters aggressive approaches that carry a significant risk of treatment-related adverse events. Microsurgical resection, endovascular embolization and SRS all play a role in the treatment of AVM. SRS is an effective therapeutic option for AVM of the thalamus and basal ganglia that are deemed high risk for resection. SRS offers acceptable obliteration rates, with generally lower risks of hemorrhage occurring during the latency period compared to the AVM natural history. Considering that incompletely obliterated lesions still harbor the potential for rupture, additional treatments such as repeat SRS and microsurgical resection should be considered when complete obliteration is not achieved by an initial SRS procedure. Patients with AVM of the basal ganglia and thalamus require continued clinical and radiologic observation and follow-up after SRS, even after angiographic obliteration has been confirmed.

Intracranial inertial cavitation threshold and thermal ablation lesion creation using MRI-guided 220-kHz focused ultrasound surgery: preclinical investigation.

OBJECT: In biological tissues, it is known that the creation of gas bubbles (cavitation) during ultrasound exposure is more likely to occur at lower rather than higher frequencies. Upon collapsing, such bubbles can induce hemorrhage. Thus, acoustic inertial cavitation secondary to a 220-kHz MRI-guided focused ultrasound (MRgFUS) surgery is a serious safety issue, and animal studies are mandatory for laying the groundwork for the use of low-frequency systems in future clinical trials. The authors investigate here the in vivo potential thresholds of MRgFUS-induced inertial cavitation and MRgFUS-induced thermal coagulation using MRI, acoustic spectroscopy, and histology. METHODS: Ten female piglets that had undergone a craniectomy were sonicated using a 220-kHz transcranial MRgFUS system over an acoustic energy range of 5600-14,000 J. For each piglet, a long-duration sonication (40-second duration) was performed on the right thalamus, and a short sonication (20-second duration) was performed on the left thalamus. An acoustic power range of 140-300 W was used for long-duration sonications and 300-700 W for short-duration sonications. Signals collected by 2 passive cavitation detectors were stored in memory during each sonication, and any subsequent cavitation activity was integrated within the bandwidth of the detectors. Real-time 2D MR thermometry was performed during the sonications. T1-weighted, T2-weighted, gradient-recalled echo, and diffusion-weighted imaging MRI was performed after treatment to assess the lesions. The piglets were killed immediately after the last series of posttreatment MR images were obtained. Their brains were harvested, and histological examinations were then performed to further evaluate the lesions. RESULTS: Two types of lesions were induced: thermal ablation lesions, as evidenced by an acute ischemic infarction on MRI and histology, and hemorrhagic lesions, associated with inertial cavitation. Passive cavitation signals exhibited 3 main patterns identified as follows: no cavitation, stable cavitation, and inertial cavitation. Low-power and longer sonications induced only thermal lesions, with a peak temperature threshold for lesioning of 53°C. Hemorrhagic lesions occurred only with high-power and shorter sonications. The sizes of the hemorrhages measured on macroscopic histological examinations correlated with the intensity of the cavitation activity (R2 = 0.74). The acoustic cavitation activity detected by the passive cavitation detectors exhibited a threshold of 0.09 V·Hz for the occurrence of hemorrhages. CONCLUSIONS: This work demonstrates that 220-kHz ultrasound is capable of inducing a thermal lesion in the brain of living swines without hemorrhage. Although the same acoustic energy can induce either a hemorrhage or a thermal lesion, it seems that low-power, long-duration sonication is less likely to cause hemorrhage and may be safer. Although further study is needed to decrease the likelihood of ischemic infarction associated with the 220-kHz ultrasound, the threshold established in this work may allow for the detection and prevention of deleterious cavitations.

A magnetic resonance imaging, histological, and dose modeling comparison of focused ultrasound, radiofrequency, and Gamma Knife radiosurgery lesions in swine thalamus.

OBJECT: The purpose of this study was to use MRI and histology to compare stereotactic lesioning modalities in a large brain model of thalamotomy. METHODS: A unilateral thalamotomy was performed in piglets utilizing one of 3 stereotactic lesioning modalities: focused ultrasound (FUS), radiofrequency, and radiosurgery. Standard clinical lesioning parameters were used for each treatment; and clinical, MRI, and histological assessments were made at early (< 72 hours), subacute (1 week), and later (1-3 months) time intervals. RESULTS: Histological and MRI assessment showed similar development for FUS and radiofrequency lesions. T2-weighted MRI revealed 3 concentric lesional zones at 48 hours with resolution of perilesional edema by 1 week. Acute ischemic infarction with macrophage infiltration was most prominent at 72 hours, with subsequent resolution of the inflammatory reaction and coalescence of the necrotic zone. There was no apparent difference in ischemic penumbra or "sharpness" between FUS or radiofrequency lesions. The radiosurgery lesions presented differently, with latent effects, less circumscribed lesions at 3 months, and apparent histological changes seen in white matter beyond the thalamic target. Additionally, thermal and radiation lesioning gradients were compared with modeling by dose to examine the theoretical penumbra. CONCLUSIONS: In swine thalamus, FUS and radiosurgery lesions evolve similarly as determined by MRI, histological examination, and theoretical modeling. Radiosurgery produces lesions with more delayed effects and seemed to result in changes in the white matter beyond the thalamic target.

Gamma Knife surgery for basal ganglia and thalamic arteriovenous malformations.

OBJECT: Gamma Knife surgery (GKS) has emerged as the treatment of choice for small- to medium-sized cerebral arteriovenous malformations (AVMs) in deep locations. The present study aims to investigate the outcomes of GKS for AVMs in the basal ganglia and thalamus. METHODS: Between 1989 and 2007, 85 patients with AVMs in the basal ganglia and 97 in the thalamus underwent GKS and were followed up for more than 2 years. The nidus volumes ranged from 0.1 to 29.4 cm(3) (mean 3.4 cm(3)). The mean margin dose at the initial GKS was 21.3 Gy (range 10-28 Gy). Thirty-six patients underwent repeat GKS for residual AVMs at a median 4 years after initial GKS. The mean margin dose at repeat GKS was 21.1 Gy (range 7.5-27 Gy). RESULTS: Following a single GKS, total obliteration of the nidus was confirmed on angiograms in 91 patients (50%). In 12 patients (6.6%) a subtotal obliteration was achieved. No flow voids were observed on MR imaging in 14 patients (7.7%). Following single or repeat GKS, total obliteration was angiographically confirmed in 106 patients (58.2%) and subtotal obliteration in 8 patients (4.4%). No flow voids on MR imaging were observed in 18 patients (9.9%). The overall obliteration rates following one or multiple GKSs based on MR imaging or angiography was 68%. A small nidus volume, high margin dose, low number of isocenters, and no history of embolization were significantly associated with an increased rate of obliteration. Twenty-one patients experienced 25 episodes of hemorrhage in 850 risk-years following GKS, yielding an annual hemorrhage rate of 2.9%. Four patients died in this series: 2 due to complications of hemorrhage and 2 due to unrelated diseases. Permanent neurological deficits caused by radiation were noted in 9 patients (4.9%). CONCLUSIONS: Gamma Knife surgery offers a reasonable chance of obliterating basal ganglia and thalamic AVMs and does so with a low risk of complications. It is an optimal treatment option in patients for whom the anticipated risk of microsurgery is too high.

Successful treatment of cervical dystonia induced by basal ganglion venous angioma with gamma knife thalamotomy.

Stereotatic radiosurgery is typically not the first line of treatment for cervical dystonia. We present a patient with a rare cervical dystonia induced by a venous angioma in the right basal ganglion. The patient was successfully treated with a gamma knife thalamotomy after failed treatments of botulinum toxin injections and peripheral denervation.

Trans sodium crocetinate: functional neuroimaging studies in a hypoxic brain tumor.

OBJECT: Intratumoral hypoxia is believed to be exhibited in high-grade gliomas. Trans sodium crocetinate (TSC) has been shown to increase oxygen diffusion to hypoxic tissues. In this research, the authors use oxygen-sensitive PET studies to evaluate the extent of hypoxia in vivo in a glioblastoma model and the effect of TSC on the baseline oxygenation of the tumor. METHODS: The C6 glioma cells were stereotactically implanted in the right frontal region of rat brains. Formation of intracranial tumors was confirmed on MR imaging. Animals were injected with Copper(II) diacetyl-di(N4-methylthiosemicarbazone) (Cu-ATSM) and then either TSC or saline (6 rats each). Positron emission tomography imaging was performed, and relative uptake values were computed to determine oxygenation within the tumor and normal brain parenchyma. Additionally, TSC or saline was infused into the animals, and carbonic anhydrase 9 (CA9) and hypoxia-inducing factor-1α (HIF-1α) protein expression were measured 1 day afterward. RESULTS: On PET imaging, all glioblastoma tumors demonstrated a statistically significant decrease in uptake of Cu-ATSM compared with the contralateral cerebral hemisphere (p = 0.000002). The mean relative uptake value of the tumor was 3900 (range 2203-6836), and that of the contralateral brain tissue was 1017 (range 488-2304). The mean relative hypoxic tumor volume for the saline group and TSC group (6 rats each) was 1.01 ± 0.063 and 0.69 ± 0.062, respectively (mean ± SEM, p = 0.002). Infusion of TSC resulted in a 31% decrease in hypoxic volume. Immunoblot analysis revealed expression of HIF-1α and CA9 in all tumor specimens. CONCLUSIONS: Some glioblastomas exhibit hypoxia that is demonstrable on oxygen-specific PET imaging. It appears that TSC lessens intratumoral hypoxia on functional imaging. Further studies should explore relative hypoxia in glioblastoma and the potential therapeutic gains that can be achieved by lessening hypoxia during delivery of adjuvant treatment.

Trans-sodium crocetinate enhancing survival and glioma response on magnetic resonance imaging to radiation and temozolomide.

OBJECT: Glioblastoma (GB) tumors typically exhibit regions of hypoxia. Hypoxic areas within the tumor can make tumor cells less sensitive to chemotherapy and radiation therapy. Trans-sodium crocetinate (TSC) has been shown to transiently increase oxygen to hypoxic brain tumors. The authors examined whether this improvement in intratumor oxygenation translates to a therapeutic advantage when delivering standard adjuvant treatment to GBs. METHODS: The authors used C6 glioma cells to create a hypoxic GB model. The C6 glioma cells were stereotactically injected into the rat brain to create a tumor. Fifteen days later, MR imaging was used to confirm the presence of a glioma. The animals were randomly assigned to 1 of 3 groups: 1) temozolomide alone (350 mg/m(2)/day for 5 days); 2) temozolomide and radiation therapy (8 Gy); or 3) TSC (100 microg/kg for 5 days), temozolomide, and radiation therapy. Animals were followed through survival studies, and tumor response was assessed on serial MR images obtained at 15-day intervals during a 2-month period. RESULTS: Mean survival (+/- SEM) of the temozolomide-alone and the temozolomide/radiotherapy groups was 23.2 +/- 0.9 and 29.4 +/- 4.4 days, respectively. Mean survival in the TSC/temozolomide/radiotherapy group was 39.8 +/- 6 days, a statistically significant improvement compared with either of the other groups (p < 0.05). Although tumor size was statistically equivalent in all groups at the time of treatment initiation, the addition of TSC to temozolomide and radiotherapy resulted in a statistically significant reduction in the MR imaging-documented mean tumor size at 30 days after tumor implantation. The mean tumor size in the TSC/temozolomide/radiotherapy group was 18.9 +/- 6.6 mm(2) compared with 42.1 +/- 2.7 mm(2) in the temozolomide-alone group (p = 0.047) and 35.8 +/- 5.1 mm(2) in the temozolomide/radiation group (p = 0.004). CONCLUSIONS: In a hypoxic GB model, TSC improves the radiological and clinical effectiveness of temozolomide and radiation therapy. Further investigation of this oxygen diffusion enhancer as a radiosensitizer for hypoxic brain tumors seems warranted.

Use of trans sodium crocetinate for sensitizing glioblastoma multiforme to radiation: laboratory investigation.

OBJECT: Adjuvant treatment with radiation (radiation therapy or radiosurgery) is a mainstay of treatment for patients harboring glioblastomas multiforme (GBM). Hypoxic regions within the tumor make cells less sensitive to radiation therapy. Trans sodium crocetinate (TSC) has been shown to increase oxygen diffusion in the brain and elevate the partial brain oxygen level. The goal of this study was to evaluate the radiosensitizing effects of TSC on GBM tumors. METHODS: A rat C6 glioma model was used, in which C6 glioma cells were stereotactically injected into the rat brain to create a tumor. Following creation of a right frontal tumor, animals were randomized into 1 of 4 groups: 1) TSC alone (animal treated with moderate-dose TSC only); 2) radiation (animals receiving 8 Gy of cranial radiation); 3) radiation and low-dose TSC (animals receiving 8 Gy of radiation and 50 microg/kg of TSC); or 4) radiation and moderate-dose TSC (animals receiving 8 Gy of radiation and 100 microg/kg of TSC). Animals were observed clinically for 60 days or until death. Magnetic resonance (MR) imaging was performed at 2-week intervals on each animal and quantitatively evaluated for tumor response. Immunohistochemical analysis was performed on all brain tumors. Survival differences were also evaluated using the Kaplan-Meier method. RESULTS: On MR imaging, a statistically significant reduction in tumor size was seen in the group receiving moderate-dose TSC and radiation treatment compared with the group receiving radiation treatment alone. The rate of tumor growth was significantly less for the combination of TSC and radiation treatment compared with either modality alone. Median survival times for the TSC-only and the radiation therapy-only groups were 15 and 30 days, respectively. The 60-day median survival times for the groups receiving a combination of either low- or moderate-dose TSC with radiation therapy were statistically improved compared with those for the other treatment groups. CONCLUSIONS: Use of TSC improves the extent of GBM tumor regression following radiation therapy and enhances survival. Radiosensitization of hypoxic tumors through increased oxygen diffusion may have clinical utility in patients with GBM tumors but must be explored in a clinical trial.