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Martin H. Weiss, Gabriel Zada, John D. Carmichael and William T. Couldwell

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Monica Mureb, Danielle Golub, Carolina Benjamin, Jason Gurewitz, Ben A. Strickland, Gabriel Zada, Eric Chang, Dušan Urgošík, Roman Liščák, Ronald E. Warnick, Herwin Speckter, Skyler Eastman, Anthony M. Kaufmann, Samir Patel, Caleb E. Feliciano, Carlos H. Carbini, David Mathieu, William Leduc, DCS, Sean J. Nagel, Yusuke S. Hori, Yi-Chieh Hung, Akiyoshi Ogino, Andrew Faramand, Hideyuki Kano, L. Dade Lunsford, Jason Sheehan and Douglas Kondziolka

OBJECTIVE

Trigeminal neuralgia (TN) is a chronic pain condition that is difficult to control with conservative management. Furthermore, disabling medication-related side effects are common. This study examined how stereotactic radiosurgery (SRS) affects pain outcomes and medication dependence based on the latency period between diagnosis and radiosurgery.

METHODS

The authors conducted a retrospective analysis of patients with type I TN at 12 Gamma Knife treatment centers. SRS was the primary surgical intervention in all patients. Patient demographics, disease characteristics, treatment plans, medication histories, and outcomes were reviewed.

RESULTS

Overall, 404 patients were included. The mean patient age at SRS was 70 years, and 60% of the population was female. The most common indication for SRS was pain refractory to medications (81%). The median maximum radiation dose was 80 Gy (range 50–95 Gy), and the mean follow-up duration was 32 months. The mean number of medications between baseline (pre-SRS) and the last follow-up decreased from 1.98 to 0.90 (p < 0.0001), respectively, and this significant reduction was observed across all medication categories. Patients who received SRS within 4 years of their initial diagnosis achieved significantly faster pain relief than those who underwent treatment after 4 years (median 21 vs 30 days, p = 0.041). The 90-day pain relief rate for those who received SRS ≤ 4 years after their diagnosis was 83.8% compared with 73.7% in patients who received SRS > 4 years after their diagnosis. The maximum radiation dose was the strongest predictor of a durable pain response (OR 1.091, p = 0.003). Early intervention (OR 1.785, p = 0.007) and higher maximum radiation dose (OR 1.150, p < 0.0001) were also significant predictors of being pain free (a Barrow Neurological Institute pain intensity score of I–IIIA) at the last follow-up visit. New sensory symptoms of any kind were seen in 98 patients (24.3%) after SRS. Higher maximum radiation dose trended toward predicting new sensory deficits but was nonsignificant (p = 0.075).

CONCLUSIONS

TN patients managed with SRS within 4 years of diagnosis experienced a shorter interval to pain relief with low risk. SRS also yielded significant decreases in adjunct medication utilization. Radiosurgery should be considered earlier in the course of treatment for TN.

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Rebecca M. Burke, Ching-Jen Chen, Dale Ding, Thomas J. Buell, Jennifer D. Sokolowski, Cheng-Chia Lee, Hideyuki Kano, Kathryn N. Kearns, Shih-Wei Tzeng, Huai-che Yang, Paul P. Huang, Douglas Kondziolka, Natasha Ironside, David Mathieu, Christian Iorio-Morin, Inga S. Grills, Caleb Feliciano, Gene H. Barnett, Robert M. Starke, L. Dade Lunsford and Jason P. Sheehan

OBJECTIVE

Stereotactic radiosurgery (SRS) is a treatment option for pediatric brain arteriovenous malformations (AVMs), and early obliteration could encourage SRS utilization for a subset of particularly radiosensitive lesions. The objective of this study was to determine predictors of early obliteration after SRS for pediatric AVMs.

METHODS

The authors performed a retrospective review of the International Radiosurgery Research Foundation AVM database. Obliterated pediatric AVMs were sorted into early (obliteration ≤ 24 months after SRS) and late (obliteration > 24 months after SRS) responders. Predictors of early obliteration were identified, and the outcomes of each group were compared.

RESULTS

The overall study cohort was composed of 345 pediatric patients with obliterated AVMs. The early and late obliteration cohorts were made up of 95 (28%) and 250 (72%) patients, respectively. Independent predictors of early obliteration were female sex, a single SRS treatment, a higher margin dose, a higher isodose line, a deep AVM location, and a smaller AVM volume. The crude rate of post-SRS hemorrhage was 50% lower in the early (3.2%) than in the late (6.4%) obliteration cohorts, but this difference was not statistically significant (p = 0.248). The other outcomes of the early versus late obliteration cohorts were similar, with respect to symptomatic radiation-induced changes (RICs), cyst formation, and tumor formation.

CONCLUSIONS

Approximately one-quarter of pediatric AVMs that become obliterated after SRS will achieve this radiological endpoint within 24 months of initial SRS. The authors identified multiple factors associated with early obliteration, which may aid in prognostication and management. The overall risks of delayed hemorrhage, RICs, cyst formation, and tumor formation were not statistically different in patients with early versus late obliteration.

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Michael M. McDowell, Nitin Agarwal, Gordon Mao, Stephen Johnson, Hideyuki Kano, L. Dade Lunsford and Stephanie Greene

OBJECTIVE

The study of pediatric arteriovenous malformations (pAVMs) is complicated by the rarity of the entity. Treatment choice has often been affected by the availability of different modalities and the experience of the providers present. The University of Pittsburgh experience of multimodality treatment of pAVMs is presented.

METHODS

The authors conducted a retrospective cohort study examining 212 patients with pAVM presenting to the University of Pittsburgh between 1988 and 2018, during which patients had access to surgical, endovascular, and radiosurgical options. Univariate analysis was performed comparing good and poor outcomes. A poor outcome was defined as a modified Rankin Scale (mRS) score of ≥ 3. Multivariate analysis via logistic regression was performed on appropriate variables with a p value of ≤ 0.2. Seventy-five percent of the cohort had at least 3 years of follow-up.

RESULTS

Five patients (2.4%) did not receive any intervention, 131 (61.8%) had GKRS alone, 14 (6.6%) had craniotomies alone, and 2 (0.9%) had embolization alone. Twenty-two (10.4%) had embolization and Gamma Knife radiosurgery (GKRS); 20 (9.4%) had craniotomies and GKRS; 8 (3.8%) had embolization and craniotomies; and 10 (4.7%) had embolization, craniotomies, and GKRS. Thirty-one patients (14.6%) were found to have poor outcome on follow-up. The multivariate analysis performed in patients with poor outcomes was notable for associations with no treatment (OR 18.9, p = 0.02), hemorrhage requiring craniotomy for decompression alone (OR 6, p = 0.03), preoperative mRS score (OR 2.1, p = 0.004), and Spetzler-Martin score (OR 1.8, p = 0.0005). The mean follow-up was 79.7 ± 62.1 months. The confirmed radiographic obliteration rate was 79.4% and there were 5 recurrences found on average 9.5 years after treatment.

CONCLUSIONS

High rates of long-term functional independence (mRS score of ≤ 2) can be achieved with comprehensive multimodality treatment of pAVMs. At this center there was no difference in outcome based on treatment choice when accounting for factors such as Spetzler-Martin grade and presenting morbidity. Recurrences are rare but frequently occur years after treatment, emphasizing the need for long-term screening after obliteration.

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Gregory Neil Bowden, Jong Oh Kim, Andrew Faramand, Kevin Fallon, John Flickinger and L. Dade Lunsford

OBJECTIVE

The use of Gamma Knife stereotactic radiosurgery (GKSRS) for the treatment of extensive intracranial metastases has been expanding due to its superior dosimetry and efficacy. However, there remains a dearth of data regarding the dose parameters in actual clinical scenarios. The authors endeavored to calculate the radiation dose to the brain when treating ≥ 15 brain metastases with GKSRS.

METHODS

This retrospective analysis reviewed dosage characteristics for patients requiring single-session GKSRS for the treatment of ≥ 15 brain metastases. Forty-two patients met the inclusion criteria between 2008 and 2017. The median number of tumors at the initial GKSRS procedure was 20 (range 15–39 tumors), accounting for 865 tumors in this study. The median aggregate tumor volume was 3.1 cm3 (range 0.13–13.26 cm3), and the median marginal dose was 16 Gy (range 14–19 Gy).

RESULTS

The median of the mean brain dose was 2.58 Gy (range 0.95–3.67 Gy), and 79% of patients had a dose < 3 Gy. The 12-Gy dose volume was a median of 12.45 cm3, which was equivalent to 0.9% of the brain volume. The median percentages of brain receiving 5 Gy and 3 Gy were 6.7% and 20.4%, respectively. There was no correlation between the number of metastases and the mean dose to the brain (p = 0.8). A greater tumor volume was significantly associated with an increased mean brain dose (p < 0.001). The median of the mean dose to the bilateral hippocampi was 2.3 Gy. Sixteen patients had supplementary GKSRS, resulting in an additional mean dose of 1.4 Gy (range 0.2–3.8 Gy) to the brain.

CONCLUSIONS

GKSRS is a viable means of managing extensive brain metastases. This procedure provides a relatively low dose of radiation to the brain, especially when compared with traditional whole-brain radiation protocols.

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Yi-Chieh Hung, Cheng-Chia Lee, Huai-che Yang, Nasser Mohammed, Kathryn N. Kearns, Shi-Bin Sun, David Mathieu, Charles J. Touchette, Ahmet F. Atik, Inga S. Grills, Bryan Squires, Dale Ding, Brian J. Williams, Mehran B. Yusuf, Shiao Y. Woo, Roman Liscak, Jaromir Hanuska, Jay C. Shiao, Douglas Kondziolka, L. Dade Lunsford, Zhiyuan Xu and Jason P. Sheehan

OBJECTIVE

Central neurocytomas (CNs) are uncommon intraventricular tumors, and their rarity renders the risk-to-benefit profile of stereotactic radiosurgery (SRS) unknown. The aim of this multicenter, retrospective cohort study was to evaluate the outcomes of SRS for CNs and identify predictive factors.

METHODS

The authors retrospectively analyzed a cohort of patients with CNs treated with SRS at 10 centers between 1994 and 2018. Tumor recurrences were classified as local or distant. Adverse radiation effects (AREs) and the need for a CSF shunt were also evaluated.

RESULTS

The study cohort comprised 60 patients (median age 30 years), 92% of whom had undergone prior resection or biopsy and 8% received their diagnosis based on imaging alone. The median tumor volume and margin dose were 5.9 cm3 and 13 Gy, respectively. After a median clinical follow-up of 61 months, post-SRS tumor recurrence occurred in 8 patients (13%). The 5- and 10-year local tumor control rates were 93% and 87%, respectively. The 5- and 10-year progression-free survival rates were 89% and 80%, respectively. AREs were observed in 4 patients (7%), but only 1 was symptomatic (2%). Two patients underwent post-SRS tumor resection (3%). Prior radiotherapy was a predictor of distant tumor recurrence (p = 0.044). Larger tumor volume was associated with pre-SRS shunt surgery (p = 0.022).

CONCLUSIONS

Treatment of appropriately selected CNs with SRS achieves good tumor control rates with a reasonable complication profile. Distant tumor recurrence and dissemination were observed in a small proportion of patients, which underscores the importance of close post-SRS surveillance of CN patients. Patients with larger CNs are more likely to require shunt surgery before SRS.

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Adomas Bunevicius, Hideyuki Kano, Cheng-Chia Lee, Michal Krsek, Ahmed M. Nabeel, Amr El-Shehaby, Khaled Abdel Karim, Nuria Martinez-Moreno, David Mathieu, John Y. K. Lee, Inga Grills, Douglas Kondziolka, Roberto Martinez-Alvarez, Wael A. Reda, Roman Liscak, Yan-Hua Su, L. Dade Lunsford, Mary Lee Vance and Jason P. Sheehan

OBJECTIVE

The optimal time to perform stereotactic radiosurgery after incomplete resection of adrenocorticotropic hormone (ACTH)–producing pituitary adenoma in patients with Cushing’s disease (CD) remains unclear. In patients with persistent CD after resection of ACTH-producing pituitary adenoma, the authors evaluated the association of the interval between resection and Gamma Knife radiosurgery (GKRS) with outcomes.

METHODS

Pooled data from 10 institutions participating in the International Radiosurgery Research Foundation were used in this study.

RESULTS

Data from 255 patients with a mean follow-up of 65.59 ± 49.01 months (mean ± SD) were analyzed. Seventy-seven patients (30%) underwent GKRS within 3 months; 46 (18%) from 4 to 6 months; 34 (13%) from 7 to 12 months; and 98 (38%) at > 12 months after the resection. Actuarial endocrine remission rates were higher in patients who underwent GKRS ≤ 3 months than when treatment was > 3 months after the resection (78% and 65%, respectively; p = 0.017). Endocrine remission rates were lower in patients who underwent GKRS at > 12 months versus ≤ 12 months after the resection (57% vs 76%, respectively; p = 0.006). In multivariate Cox regression analyses adjusted for clinical and treatment characteristics, early GKRS was associated with increased probability of endocrine remission (hazard ratio [HR] 1.518, 95% CI 1.039–2.218; p = 0.031), whereas late GKRS (HR 0.641, 95% CI 0.448–0.919; p = 0.015) was associated with reduced probability of endocrine remission. The incidence of some degree of new pituitary deficiency (p = 0.922), new visual deficits (p = 0.740), and other cranial nerve deficits (p = 0.610) was not significantly related to time from resection to GKRS.

CONCLUSIONS

Early GKRS is associated with an improved endocrine remission rate, whereas later GKRS is associated with a lower rate of endocrine remission after pituitary adenoma resection. Early GKRS should be considered for patients with CD after incomplete pituitary adenoma resection.

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Ching-Jen Chen, Cheng-Chia Lee, Hideyuki Kano, Kathryn N. Kearns, Dale Ding, Shih-Wei Tzeng, Ahmet Atik, Krishna Joshi, Gene H. Barnett, Paul P. Huang, Douglas Kondziolka, David Mathieu, Christian Iorio-Morin, Inga S. Grills, Thomas J. Quinn, Zaid A. Siddiqui, Kim Marvin, Caleb Feliciano, Andrew Faramand, L. Dade Lunsford and Jason P. Sheehan

OBJECTIVE

Contrary to the better described obliteration- and hemorrhage-related data after stereotactic radiosurgery (SRS) of brain arteriovenous malformations (AVMs) in pediatric patients, estimates of the rarer complications, including cyst and tumor formation, are limited in the literature. The aim of the present study was to assess the long-term outcomes and risks of SRS for AVMs in pediatric patients (age < 18 years).

METHODS

The authors retrospectively analyzed the International Radiosurgery Research Foundation pediatric AVM database for the years 1987 to 2018. AVM obliteration, post-SRS hemorrhage, cyst formation, and tumor formation were assessed. Cumulative probabilities, adjusted for the competing risk of death, were calculated.

RESULTS

The study cohort comprised 539 pediatric AVM patients (mean follow-up 85.8 months). AVM obliteration was observed in 64.3% of patients, with cumulative probabilities of 63.6% (95% CI 58.8%–68.0%), 77.1% (95% CI 72.1%–81.3%), and 88.1% (95% CI 82.5%–92.0%) over 5, 10, and 15 years, respectively. Post-SRS hemorrhage was observed in 8.4% of patients, with cumulative probabilities of 4.9% (95% CI 3.1%–7.2%), 9.7% (95% CI 6.4%–13.7%), and 14.5% (95% CI 9.5%–20.5%) over 5, 10, and 15 years, respectively. Cyst formation was observed in 2.1% of patients, with cumulative probabilities of 5.5% (95% CI 2.3%–10.7%) and 6.9% (95% CI 3.1%–12.9%) over 10 and 15 years, respectively. Meningiomas were observed in 2 patients (0.4%) at 10 and 12 years after SRS, with a cumulative probability of 3.1% (95% CI 0.6%–9.7%) over 15 years.

CONCLUSIONS

AVM obliteration can be expected after SRS in the majority of the pediatric population, with a relatively low risk of hemorrhage during the latency period. Cyst and benign tumor formation after SRS can be observed in 7% and 3% of patients over 15 years, respectively. Longitudinal surveillance for delayed neoplasia is prudent despite its low incidence.

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Ezequiel Goldschmidt, Wendy Fellows-Mayle, Rachel Wolfe, Ajay Niranjan, John C. Flickinger, L. Dade Lunsford and Peter C. Gerszten

OBJECTIVE

Stereotactic radiosurgery (SRS) has been used to treat trigeminal neuralgia by targeting the cisternal segment of the trigeminal nerve, which in turn triggers changes in the gasserian ganglion. In the lumbar spine, the dorsal root ganglion (DRG) is responsible for transmitting pain sensitivity and is involved in the pathogenesis of peripheral neuropathic pain. Therefore, radiosurgery to the DRG might improve chronic peripheral pain. This study evaluated the clinical and histological effects of high-dose radiosurgery to the DRG in a rodent model.

METHODS

Eight Sprague-Dawley rats received either 40- or 80-Gy SRS to the fifth and sixth lumbar DRGs using the Leksell Gamma Knife Icon. Animals were euthanized 3 months after treatment, and the lumbar spine was dissected and taken for analysis. Simple histology was used to assess collagen deposition and inflammatory response. GFAP, Neu-N, substance P, and internexin were used as a measure of peripheral glial activation, neurogenesis, pain-specific neurotransmission, and neurotransmission in general, respectively. The integrity of the spinothalamic tract was assessed by means of the von Frey test.

RESULTS

The animals did not exhibit any signs of motor or sensory deficits during the experimentation period. Edema, fibrosis, and vascular sclerotic changes were present on the treated, but not the control, side. SRS reduced the expression of GFAP without affecting the expression of Neu-N, substance P, or internexin. The von Frey sensory perception elicited equivalent results for the control side and both radiosurgical doses.

CONCLUSIONS

SRS did not alter sensory or motor function but reduced the activation of satellite glial cells, a pathway for DRG-mediated pain perpetuation. Radiosurgery provoked changes equivalent to the effects of focal radiation on the trigeminal ganglion after SRS for trigeminal neuralgia, suggesting that radiosurgery could be successful in relieving radiculopathic pain.

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Stephen Johnson, Hideyuki Kano, Andrew Faramand, Ajay Niranjan, John C. Flickinger and L. Dade Lunsford

OBJECTIVE

Optimizing outcomes in the management of patients with vestibular schwannomas (VSs) requires consideration of the patient’s goals. Earlier recognition of VS by imaging has led to an evolution in management. Stereotactic radiosurgery (SRS) has emerged as a frequently used strategy designed to reduce management risks, obtain long-term tumor control, and preserve current neurological function. The authors analyzed features that impact hearing preservation rates in patients with serviceable hearing prior to SRS.

METHODS

The study included 307 patients who had serviceable hearing (Gardner-Robertson hearing scale [GR] grade 1 or 2, speech discrimination score ≥ 50%, pure tone average ≤ 50 dB) at the time of SRS. The authors evaluated parameters that included age, tumor volume, hearing status, disequilibrium, tinnitus, Koos class, sex, and tumor margin dose. The Pittsburgh Hearing Prediction Score (PHPS) was evaluated as a method to predict long-term hearing outcomes in these cases.

RESULTS

At a median of 7.6 years after SRS (range 1–23 years), tumor control was achieved in 95% of patients. The overall serviceable hearing preservation rate was 77.8% at 3 years, 68.8% at 5 years, and 51.8% at 10 years. The PHPS assigns a total of 5 points based on patient age (1 point if < 45 years, 2 points if 45–59 years, and 3 points if ≥ 60 years), tumor volume (0 points if < 1.2 cm3, 1 point if ≥ 1.2 cm3), and GR grade (0 points if grade 1 hearing, 1 point if grade 2 hearing) The serviceable hearing preservation rate was 92.3% at 10 years in patients whose score total was 1. In contrast, none of the patients whose PHPS was 5 maintained serviceable hearing at 10 years (p < 0.001).

CONCLUSIONS

SRS resulted in a high rate of long-term tumor control and cranial nerve preservation. The PHPS helped to predict long-term hearing preservation rates in patients who underwent SRS when they still had serviceable hearing. The best long-term hearing preservation rates were found in younger patients with smaller tumor volumes.