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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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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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Ajay Niranjan, Ahmed Kashkoush, Hideyuki Kano, Edward A. Monaco III, John C. Flickinger and L. Dade Lunsford

OBJECTIVE

Seizures are the second-most common presenting symptom in patients with lobar arteriovenous malformations (AVMs). However, few studies have assessed the long-term effect of stereotactic radiosurgery (SRS) on seizure control. The authors of this study assess the outcome of SRS for these patients to identify prognostic factors associated with seizure control.

METHODS

Patients with AVM who presented with a history of seizure and underwent SRS at the authors’ institution between 1987 and 2012 were retrospectively assessed. The total cohort included 155 patients with a mean follow-up of 86 months (range 6–295 months). Primary outcomes assessed were seizure frequency, antiepileptic drug regimen, and seizure freedom for 6 months prior to last follow-up.

RESULTS

Seizure-free status was achieved in 108 patients (70%), with an additional 23 patients (15%) reporting improved seizure frequency as compared to their pre-SRS status. The median time to seizure-free status was estimated to be 12 months (95% CI 0–27 months) as evaluated via Kaplan-Meier survival analysis. The mean seizure frequency prior to SRS was 14.2 (95% CI 5.4–23.1) episodes per year. Although not all patients tried, the proportion of patients successfully weaned off all antiepileptic drugs was 18% (28/155 patients). On multivariate logistic regression, focal impaired awareness seizure type (also known as complex partial seizures) and superficial venous drainage were significantly associated with a decreased odds ratio for seizure-free status at last follow-up (OR 0.37 [95% CI 0.15–0.92] for focal impaired awareness seizures; OR 0.36 [95% CI 0.16–0.81] for superficial venous drainage). The effects of superficial venous drainage on seizure outcome were nonsignificant when excluding patients with < 2 years of follow-up. AVM obliteration did not correlate with long-term seizure freedom (p = 0.202, chi-square test).

CONCLUSIONS

This study suggests that SRS improves long-term seizure control and increases the likelihood of being medication free, independently of AVM obliteration. Patients with focal impaired awareness seizures were less likely to obtain long-term seizure relief.

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Diogo Cordeiro, Zhiyuan Xu, Gautam U. Mehta, Dale Ding, Mary Lee Vance, Hideyuki Kano, Nathaniel Sisterson, Huai-che Yang, Douglas Kondziolka, L. Dade Lunsford, David Mathieu, Gene H. Barnett, Veronica Chiang, John Lee, Penny Sneed, Yan-Hua Su, Cheng-chia Lee, Michal Krsek, Roman Liscak, Ahmed M. Nabeel, Amr El-Shehaby, Khaled Abdel Karim, Wael A. Reda, Nuria Martinez-Moreno, Roberto Martinez-Alvarez, Kevin Blas, Inga Grills, Kuei C. Lee, Mikulas Kosak, Christopher P. Cifarelli, Gennadiy A. Katsevman and Jason P. Sheehan

OBJECTIVE

Recurrent or residual adenomas are frequently treated with Gamma Knife radiosurgery (GKRS). The most common complication after GKRS for pituitary adenomas is hypopituitarism. In the current study, the authors detail the timing and types of hypopituitarism in a multicenter, international cohort of pituitary adenoma patients treated with GKRS.

METHODS

Seventeen institutions pooled clinical data obtained from pituitary adenoma patients who were treated with GKRS from 1988 to 2016. Patients who had undergone prior radiotherapy were excluded. A total of 1023 patients met the study inclusion criteria. The treated lesions included 410 nonfunctioning pituitary adenomas (NFPAs), 262 cases of Cushing’s disease (CD), and 251 cases of acromegaly. The median follow-up was 51 months (range 6–246 months). Statistical analysis was performed using a Cox proportional hazards model to evaluate factors associated with the development of new-onset hypopituitarism.

RESULTS

At last follow-up, 248 patients had developed new pituitary hormone deficiency (86 with NFPA, 66 with CD, and 96 with acromegaly). Among these patients, 150 (60.5%) had single and 98 (39.5%) had multiple hormone deficiencies. New hormonal changes included 82 cortisol (21.6%), 135 thyrotropin (35.6%), 92 gonadotropin (24.3%), 59 growth hormone (15.6%), and 11 vasopressin (2.9%) deficiencies. The actuarial 1-year, 3-year, 5-year, 7-year, and 10-year rates of hypopituitarism were 7.8%, 16.2%, 22.4%, 27.5%, and 31.3%, respectively. The median time to hypopituitarism onset was 39 months.

In univariate analyses, an increased rate of new-onset hypopituitarism was significantly associated with a lower isodose line (p = 0.006, HR = 8.695), whole sellar targeting (p = 0.033, HR = 1.452), and treatment of a functional pituitary adenoma as compared with an NFPA (p = 0.008, HR = 1.510). In multivariate analyses, only a lower isodose line was found to be an independent predictor of new-onset hypopituitarism (p = 0.001, HR = 1.38).

CONCLUSIONS

Hypopituitarism remains the most common unintended effect of GKRS for a pituitary adenoma. Treating the target volume at an isodose line of 50% or greater and avoiding whole-sellar radiosurgery, unless necessary, will likely mitigate the risk of post-GKRS hypopituitarism. Follow-up of these patients is required to detect and treat latent endocrinopathies.

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Amitabh Gupta, Zhiyuan Xu, Hideyuki Kano, Nathaniel Sisterson, Yan-Hua Su, Michal Krsek, Ahmed M. Nabeel, Amr El-Shehaby, Khaled A. Karim, Nuria Martínez-Moreno, David Mathieu, Brendan J. McShane, Roberto Martínez-Álvarez, Wael A. Reda, Roman Liscak, Cheng-Chia Lee, L. Dade Lunsford and Jason P. Sheehan

OBJECTIVE

Gamma Knife radiosurgery (GKS) is typically used after failed resection in patients with Cushing’s disease (CD) and acromegaly. Little is known about the upfront role of GKS for patients with CD and acromegaly. In this study, the authors examine the outcome of upfront GKS for patients with these functioning adenomas.

METHODS

An international group of 7 Gamma Knife centers sent pooled data from 46 patients (21 with CD and 25 with acromegaly) undergoing upfront GKS to the coordinating center of the study for analysis. Diagnosis was established on the basis of clinical, endocrine, and radiological studies. All patients were treated on a common radiosurgical platform and longitudinally followed for tumor control, endocrine remission, and hypopituitarism. Patients received a tumor median margin dose of 25 Gy (range 12–40.0 Gy) at a median isodose of 50%.

RESULTS

The median endocrine follow-up was 69.5 months (range 9–246 months). Endocrine remission was achieved in 51% of the entire cohort, with 28% remission in acromegaly and 81% remission for those with CD at the 5-year interval. Patients with CD achieved remission earlier as compared to those with acromegaly (p = 0.0005). In patients post-GKS, the pituitary adenoma remained stable (39%) or reduced (61%) in size. Hypopituitarism occurred in 9 patients (19.6%), and 1 (2.2%) developed third cranial nerve (CN III) palsy. Eight patients needed further intervention, including repeat GKS in 6 and transsphenoidal surgery in 2.

CONCLUSIONS

Upfront GKS resulted in good tumor control as well as a low rate of adverse radiation effects in the whole group. Patients with CD achieved a faster and far better remission rate after upfront GKS in comparison to patients with acromegaly. GKS can be considered as an upfront treatment in carefully selected patients with CD who are unwilling or unable to undergo resection, but it has a more limited role in acromegaly.

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Kyung-Jae Park, Hideyuki Kano, Aditya Iyer, Xiaomin Liu, Daniel A. Tonetti, Craig Lehocky, Andrew Faramand, Ajay Niranjan, John C. Flickinger, Douglas Kondziolka and L. Dade Lunsford

OBJECTIVE

The authors of this study evaluate the long-term outcomes of stereotactic radiosurgery (SRS) for cavernous sinus meningioma (CSM).

METHODS

The authors retrospectively assessed treatment outcomes 5–18 years after SRS in 200 patients with CSM. The median patient age was 57 years (range 22–83 years). In total, 120 (60%) patients underwent Gamma Knife SRS as primary management, 46 (23%) for residual tumors, and 34 (17%) for recurrent tumors after one or more surgical procedures. The median tumor target volume was 7.5 cm3 (range 0.1–37.3 cm3), and the median margin dose was 13.0 Gy (range 10–20 Gy).

RESULTS

Tumor volume regressed in 121 (61%) patients, was unchanged in 49 (25%), and increased over time in 30 (15%) during a median imaging follow-up of 101 months. Actuarial tumor control rates at the 5-, 10-, and 15-year follow-ups were 92%, 84%, and 75%, respectively. Of the 120 patients who had undergone SRS as a primary treatment (primary SRS), tumor progression was observed in 14 (11.7%) patients at a median of 48.9 months (range 4.8–120.0 months) after SRS, and actuarial tumor control rates were 98%, 93%, 85%, and 85% at the 1-, 5-, 10-, and 15-year follow-ups post-SRS. A history of tumor progression after microsurgery was an independent predictor of an unfavorable response to radiosurgery (p = 0.009, HR = 4.161, 95% CI 1.438–12.045). Forty-four (26%) of 170 patients who had presented with at least one cranial nerve (CN) deficit improved after SRS. Development of new CN deficits after initial microsurgical resection was an unfavorable factor for improvement after SRS (p = 0.014, HR = 0.169, 95% CI 0.041–0.702). Fifteen (7.5%) patients experienced permanent CN deficits without evidence of tumor progression at a median onset of 9 months (range 2.3–85 months) after SRS. Patients with larger tumor volumes (≥ 10 cm3) were more likely to develop permanent CN complications (p = 0.046, HR = 3.629, 95% CI 1.026–12.838). Three patients (1.5%) developed delayed pituitary dysfunction after SRS.

CONCLUSIONS

This long-term study showed that Gamma Knife radiosurgery provided long-term tumor control for most patients with CSM. Patients who underwent SRS for progressive tumors after prior microsurgery had a greater chance of tumor growth than the patients without prior surgery or those with residual tumor treated after microsurgery.