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Gamma Knife Radiosurgery for Patients with Multiple Intracranial Meningiomas
Original Article
Gamma Knife Radiosurgery for Patients with Multiple Intracranial Meningiomas Wei Chen, Xiaoyu Wang, Fujun Liu, Jing Chen
OBJECTIVE: The aim of this study was to evaluate the safety and efficacy of Gamma Knife radiosurgery (GKRS) in patients with multiple intracranial meningiomas (MIMs).
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METHODS: The authors performed a retrospective analysis of 42 consecutive patients (7 men and 35 women) with MIMs who underwent GKRS. The median age of the patients at the time of GKRS was 57.5 years (range, 27e77 years). A total of 115 tumors among 42 patients were identified through imaging or postoperative histopathologic examination, of which 90 were treated with GKRS.
peritumor edema, and >2 tumors treated by GKRS are predictors of unfavorable outcome after GKRS.
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RESULTS: Follow-up imaging studies were available for 75 tumors in 36 patients (83.3%), with a mean follow-up period of 45.0 months (range, 6.6e90.4 months); 41 patients (97.6%) received clinical follow-up for 16.7 to 106.7 months (average, 57.1 months). Local tumor control was achieved in 68 tumors (90.7%) at the last follow-up. On univariate analysis, surgical resection before GKRS more than once (P [ 0.048) and high World Health Organization (WHO) classification (grades II and III) (P [ 0.001) were associated with tumor progression. Patients with worsening clinical manifestation showed correlation with peritumor edema (P < 0.001) and had >2 lesions treated by GKRS (P < 0.001) on univariate analysis.
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CONCLUSIONS: GKRS is a safe and effective treatment for MIMs. Variables including surgical resection before GKRS more than once, high grade WHO classification,
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Key words Gamma Knife radiosurgery - Multiple intracranial meningiomas - Stereotactic radiosurgery -
Abbreviations and Acronyms CI: Confidence interval GKRS: Gamma Knife radiosurgery MIMs: Multiple intracranial meningiomas MR: Magnetic resonance OR: Odds ratio SRS: Stereotactic radiosurgery WHO: World Health Organization
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INTRODUCTION
M
ultiple intracranial meningiomas (MIMs) are rare tumors defined by the presence of at least 2 meningiomas that appear simultaneously or not, at different intracranial sites.1,2 They are estimated to account for about 1% of all meningiomas. The most common intracranial primary tumors represent approximately 36.4% of all central nervous system tumors3 before,4,5 and up to 10% of meningiomas after, the advent of computed tomography and magnetic resonance imaging (MRI).6,7 The clinical manifestations of MIMs are mainly dependent on the location of tumor involvement. Most commonly, patients present with headache, dizziness, weakness or numbness of extremities, and other central cranial nerve deficits that show no difference from solitary meningioma. Standard treatment or a consensus on special treatment for MIMs has not been proposed, and reasonable management needs to be established. To date, surgical resection is the mainstay treatment modality for this disease.8,9 Total resection contributes to a high likelihood of local tumor control, and with the development of imaging and microsurgery techniques, the outcome has greatly improved. However, the surgical operation of MIMs is still challenging for neurosurgeons because of the number and locations of tumors, such as the brainstem or eloquent areas. In this situation, it is necessary to explore another approach in the management of MIMs.
Department of Neurosurgery, West China Hospital of Sichuan University, Chengdu, Sichuan Province, People’s Republic of China To whom correspondence should be addressed: Jing Chen, M.D. [E-mail: [email protected]] Citation: World Neurosurg. (2019) 128:e495-e500. https://doi.org/10.1016/j.wneu.2019.04.184 Journal homepage: www.journals.elsevier.com/world-neurosurgery Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2019 Elsevier Inc. All rights reserved.
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ORIGINAL ARTICLE WEI CHEN ET AL.
GAMMA KNIFE RADIOSURGERY FOR MULTIPLE INTRACRANIAL MENINGIOMAS
Gamma Knife radiosurgery (GKRS) is widely accepted as an effective treatment option for a variety of brain disorders, including brain neoplasms, vascular tumors, and functional disorders.10 During the past decades, studies were performed to establish the safety and effectiveness of GKRS for solitary meningiomas.10-16 However, there are limited data regarding the treatment of MIMs by GKRS, and the available evidence includes only limited cases.15,17-19 In the present study we describe the clinical and imaging outcomes in 42 patients treated with GKRS for MIMs, and we discuss the role of GKRS as a primary or adjuvant approach in the management of MIMs. MATERIALS AND METHODS Patient Population Between January 2009 and December 2016, 42 consecutive patients with MIMs who underwent GKRS at the Gamma Knife Center of West China Hospital, Sichuan University, were enrolled. The diagnoses of MIMs were based on histopathologic assessment or MR images according to the definition.1,2 Exclusion criteria included 1) patients who accepted whole brain radiation therapy before GKRS, 2) lack of cooperation for evaluation or loss to follow-up, and 3) diagnoses of neurofibromatosis type 2. Gamma Knife Radiosurgical Technique The treatment strategy was explained in detail to each patient, and written informed consent was obtained from all patients before GKRS. After consent had been obtained, the procedure was performed on a Leksell Gamma Knife model C (Elekta Instruments AB, Stockholm, Sweden), and the frame was installed on the patient’s head with the aid of a local anesthetic agent. Gadolinium-enhanced slice thickness of 3-mm MR images of T1weighted sequences were obtained for pretreatment localization and treatment planning. We used the Leksell Gamma Plan (version 9.0, Elekta AB) for GKRS treatment planning. Follow-Up and Assessment Strategy Periodic follow-up was carried out for patients in the study. The first clinical follow-up examination was performed 3 months after treatment, and subsequent follow-up examinations were made every 3 months during the first year and every 6 months thereafter. Each patient’s history and physical examination findings were recorded and compared with those documented before GKRS. Radiologic follow-up was undertaken by contrast-enhanced MRI. The first radiologic follow-up examination was performed 6 months after the initial treatment; subsequent follow-up examinations were conducted every 6 months during the second year and every year thereafter. For clinical assessment, changes in clinical manifestation (symptoms and/or signs) were based on results of the physical examination and patients’ self-assessment. We defined >50% improvement as clinical improvement. For radiologic assessment, follow-up MR images were compared with preoperative GKRS images. Tumors were measured in the maximum transverse, anteroposterior, and vertical dimensions. Half of the product of these 3 diameters was used as a surrogate for tumor volume. The tumor volume response was classified as follows: shrinkage (>20% decrease in tumor volume), stable (0%e20% change in
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tumor volume), and tumor progression (>20% increase in tumor volume) at the last follow-up examination.20 Local control was defined as shrinkage or stabilization of the treated tumor. Statistical Analysis Local tumor control was calculated from the day of GKRS with the Kaplan-Meier method, and a log-rank (Mantel-Cox) test was performed to compare 2-group variables. Variables were tested categorically and included sex (male vs. female), age (cutoff value of 57 years), previous surgery (<2 times vs. 2 times), edema (yes vs. no), WHO) classification (grade I vs. grades II and III), number of GKRS during hospitalization (<2 times vs. 2 times), prescribed dose (cutoff value of 13 Gy), number of total tumors (2 lesions vs. 3 lesions), number of tumors treated by GKRS (<2 lesions vs. 2lesions), pre-GKRS volume (cutoff value of 0.87 cm3), and post-GKRS volume (cutoff value of 0.87 cm3). P 0.05 was considered statistically significant. All statistical analysis was performed with standard available statistical software (SPSS, version 25.0; SPSS Inc., New York, USA). RESULTS The patient population (total 42) consisted of 7 men (16.7%) and 35 women (83.3%), with a median age of 57.5 years (range, 27e77 years). A total of 115 tumors among these patients were identified, of which 90 were irradiated by GKRS. Most patients (59.5%, n ¼ 25) underwent microsurgery resection (between 1 and 3 operations each) before GKRS. GKRS was applied as an upfront treatment in all patients’ 80/90 tumors (88.9%) and as an adjunctive treatment approach in 8 patients’ 10/90 tumors (11.1%). In 1 patient, tumor volume exceeded 10 cm3 and in another 5 patients the tumors were scattered in brain, and the GKRS procedure was divided into 2 sessions (the time between 2 sessions was 2 days). The most common location for the tumors was parasagittal (46.7%, n ¼ 42), followed by cerebral or cerebellar convexity (28.9%, n ¼ 26). The mean tumor volumes before and after GKRS were 1.76 2.10 cm3 (range, 0.24e11.76 cm3) and 1.48 1.63 cm3 (range, 0e14.78 cm3), respectively. The median prescription dose was 13.0 Gy (range, 8.0e16.0 Gy), and the median isodose line was 50.0% (range, 45.0%e50.0%). Tables 1 and 2 summarize the characteristics of the patients in this study. Radiologic Outcomes In total, 6/42 patients (14.3%) were excluded in the final radiologic analysis: 3/42 patients (7.1%) for insufficient follow-up (the period between GKRS and the last follow-up <6 months), 2/42 patients (4.8%) for refusal to undergo radiologic examination, and 1/42 patient (2.4%) because of death, probably related to meningioma, a high WHO grade tumor during follow-up (her data were incomplete). Therefore, 36 patients’ 75 tumors (83.3%) with a mean follow-up period of 45.0 months (range, 6.6e90.4 months) were included in our final radiologic analysis. Follow-up MR images demonstrated that overall tumor local control was achieved in 36/42 patients’ (85.7%) 68/90 tumors (90.7%) at the last follow-up (Figure 1). Twenty-five tumors (33.3%) in 17 patients were smaller at the time of GKRS, and 43/90 tumors (57.3%) in 23 patients were unchanged. Tumor progression was observed in 6 patients’ 7/90 tumors (9.3%) after GKRS. It
WORLD NEUROSURGERY, https://doi.org/10.1016/j.wneu.2019.04.184
ORIGINAL ARTICLE WEI CHEN ET AL.
GAMMA KNIFE RADIOSURGERY FOR MULTIPLE INTRACRANIAL MENINGIOMAS
Table 1. Demographic, Clinical, and Tumor Characteristics of Patients with Multiple Intracranial Meningiomas
Table 2. Gamma Knife Radiosurgery Treatment Characteristics of Patients with Multiple Intracranial Meningiomas
Characteristic
Factor
Total
Number
% or Range
42
Number of GKRS During Hospitalization
Sex Male Female Age (years), median (range)
7
Value (% or Range)
16.7%
35
83.3%
57.5
27e77
Number of surgeries before GKRS
1
36 (85.7%)
2
6 (14.3%)
Number of tumors treated by GKRS 1
10 (23.8%)
2
21 (50.0%)
0
17
40.5%
3
9 (21.4%)
1
19
45.2%
4
0 (0.0%)
2
5
11.9%
5
1 (2.4%)
3
1
2.4%
6
1 (2.4%)
Edema
Changes of tumors
Yes
11
26.2%
Shrinkage
No
31
73.8%
Stable
4 (9.5%)
Progression
5 (11.9%)
1
10
23.8%
2
21
50.0%
Mean pre-GKRS volume (cm3) 3
Number of tumors
23 (54.8%)
Parameters of GKRS 1.76 2.10 1.48 1.63
3
9
21.4%
Mean post-GKRS volume (cm )
4
2
4.8%
Median prescribed dose (Gy)
13.0 (8.0e16.0)
Median isodose line (%)
50.0 (42.0e55.0)
Parasagittal
42
46.7%
Convexity
26
28.9%
Location
Posterior fossa
6
6.7%
Olfactory groove
5
5.6%
Sphenoid wing
4
4.4%
Cerebellopontine angle
3
3.3%
Middle cranial fossa
2
2.2%
Lateral ventricle
2
2.2%
Grade I
17
40.5%
Grade II
2
4.8%
Grade III
1
2.4%
Clinical Outcomes The most common clinical presentations before GKRS included headache (n ¼ 21), followed by vertigo (n ¼ 6) and paralysis (n¼5). (Table 3) The mean clinical follow-up period was 57.1 months. An improvement in symptoms was observed in 12 patients (29.3%) and occurred at a mean follow-up time of 4.6 months (range, 0.3e12.0 months) after GKRS. Twenty-one patients (51.2%) still experienced their original symptoms, and 8 patients (19.5%) experienced transient headache and dizziness.
WHO classification, n ¼ 20
Image follow-up, mean (range)
45.0
6.6e90.4
Clinical follow-up, mean (range)
57.1
16.7e106.7
GKRS, Gamma Knife radiosurgery; WHO, World Health Organization.
is worth mentioning that 2 patients’ pathologic diagnoses were WHO grade II atypical, and 1 patient had WHO grade III anaplastic meningioma. Among them, 1 patient with tumor progression underwent additional surgical resection, 1 patient underwent repeated radiosurgery 26 months after initial GKRS, and another patient was lost to follow up.
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Figure 1. Kaplan-Meier curve showing overall tumor control rate from the time of Gamma Knife radiosurgery for 42 patients with multiple intracranial meningiomas.
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GAMMA KNIFE RADIOSURGERY FOR MULTIPLE INTRACRANIAL MENINGIOMAS
and III) (P ¼ 0.001) were associated with tumor progression. Patients with worsening clinical manifestation showed correlation with peritumor edema (P < 0.001) and had >2 tumors treated by GKRS (P < 0.001) on univariate analysis. No statistically significant variable was identified in the multivariate analysis.
Table 3. Clinical Manifestations in Patients with Multiple Intracranial Meningiomas* Number of Cases After GKRS Number of Cases Symptoms at the Time of and Signs GKRS Exacerbation Stabilization Improvement Headache
21
4*
11
6
None
9
1*
8
0
Vertigo
6
2*
4
0
Paralysis
5
0
1
4
Seizure
4
0
1
3
Olfactory loss
3
0
3
0
Nausea and vomiting
2
1
0
1
Visual loss
1
0
0
1
Hearing loss
1
0
1
0
DISCUSSION
*One patient can harbor several symptoms or signs.
No patient experienced permanent neurologic impairments or radiation-induced complications after GKRS. Prognostic Factors The results for the variables analyzed for overall tumor local control and clinical manifestation are presented in Table 4. On univariate analysis, surgical resection before GKRS more than once (P ¼ 0.048) and high WHO classification (grades II
In the present cohort, our findings showed that overall local control was achieved in 90.7% of tumors in patients with MIMs during the follow-up period. In a large cohort study, Santacroce et al21 reported the local tumor control rate was 92.5% with a median imaging follow-up of 63 months. Similarly, a previous study by Bledsoe et al13 revealed that tumor control was 99% at 3 years and 92% at 7 years after radiosurgery. A related article reported an overall tumor control rate in patients with meningiomas of 91%.11 More recently, Patibandla et al14 published their post hoc analysis of stereotactic radiosurgery (SRS) for WHO grade I posterior fossa meningiomas in 120 patients. The overall tumor control rate was 89.2%; for patients treated with a margin dose 16 Gy, the progression-free survival rate during 2 to 10 years after SRS was 100%. With special regard to MIMs, a study by Samblas et al15 demonstrated 3-year and 5-year overall survival rates for all patients of 95% and 90%, respectively, and the mean gross tumor volume decreased from 4.17 cm3 to 3.23 cm3 after SRS (P ¼ 0.057) during the median follow-up time of 5.8 years (range, 1e13.6 years). In addition, a study by Liu et al18 on GKRS for meningiomas in patients with neurofibromatosis type 2 revealed that in a total of 125 meningiomas were identified among 12 patients, the 5-year local control rate for meningiomas was 92%. Similarly, another study by Birckhead et al19 suggested that the 5-year and 10-year rates of local control were both 96%
Table 4. Univariable Analysis of Prognostic Factors for Local Tumor Control and Clinical Manifestation in Patients with Multiple Intracranial Meningiomas Tumor Control Factor
Clinical Manifestation
OR (95% CI)
P Value
OR (95% CI)
P Value
Sex (M vs. F)
1.40 (0.79e2.48)
0.227
1.21 (0.16e8.99)
0.814
Age (>57 years)
0.78 (0.40e1.51)
0.333
0.78 (0.41e1.48)
0.653
Previous surgery (2 times)
1.87 (0.83e4.17)
0.048
1.46 (0.84e2.52)
0.278
Edema (no vs. yes)
1.59 (0.70e3.61)
0.116
7.27 (1.16e45.64)
<9.001
WHO classification (grade I vs. grades II & III)
1.67 (0.82e3.41)
0.001
1.75 (0.92e3.32)
0.005
Number of GKRS during hospitalization (2 times)
1.93 (0.87e4.31)
0.105
1.17 (0.77e1.78)
0.796
Prescribed dose (>13 Gy)
1.03 (0.70e1.52)
0.975
1.21 (0.80e1.83)
0.143
Number of total tumors (3 lesions)
1.31 (0.56e3.04)
0.604
0.97 (0.53e1.77)
0.557
Number of tumors treated by GKRS (2 lesions)
1.29 (0.19e8.81)
0.376
0.35 (0.11e1.45)
<0.001
Pre-GKRS volume (<0.87 cm3)
0.38 (0.24e0.60)
0.077
0.97 (0.45e2.11)
0.659
3
0.38 (0.24e0.60)
0.082
1.00 (0.41e2.42)
0.615
Post-GKRS volume (<0.87 cm )
OR, odds ratio; CI, confidence interval; WHO, World Health Organization; GKRS, Gamma Knife radiosurgery.
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in patients with neurofibromatosis type 2-associated MIMs. It is important to note that small tumors were included in that study, and those tumors contributed to a relatively high tumor control rate. These findings along with our results suggest that tumor control rates for both WHO grade I meningiomas and MIMs are relatively high. The optimal prescribed dose for MIMs needs to be established because of the rarity of these tumors and the lack of prospective randomized studies. In the present study, the prescribed doses for the tumors ranged from 12 Gy to 15 Gy at the mean 50% isodose line (range, 45%e50%), depending on the size and location of the lesion. The mean tumor margin dose was 14 Gy (range, 10e16 Gy) in the study by Birckhead et al19 Similarly, Santacroce et al21 reported a median dose to tumor margin of 14 Gy in their study. In addition, a detailed analysis by Patibandla et al14 revealed that different margin doses yielded different tumor control rates, as reported above. The authors suggested that doses of 13 to 16 Gy seemed to afford reasonable tumor control and neurologic preservation for the majority of posterior fossa meningiomas patients. We have noted that less favorable control was observed in tumors with atypical histologic characteristics. Thus, without these 3 patients, the rate of tumor control would be much higher. However, this must be taken into account because it indicates that GKRS alone might yield less favorable outcomes when atypical and anaplastic meningiomas are treated. In our present series, the results revealed that improvement of clinical symptoms occurred in 12 patients (29.3%) after GKRS, 21 patients (51.2%) still retained their original symptoms signs, and 8 patients (19.5%) experienced transient headache and dizziness. No patient experienced permanent neurologic impairments or radiation-induced complications after GKRS. This finding was similar to most of those in the earlier published studies.11,14,15 Samblas et al15 reported, regarding the clinical examination, that clinical symptoms improved in 36% of patients and remained stable in 45% of the patients, and only 7 patients (9.6%) had late complications at their institution. There was no treatment-related mortality in their study population. Patibandla et al14 found that post-SRS improvement in neurologic symptoms occurred in 23.3% (28 patients), whereas symptoms were stable in 70.8% (85 patients) and worsened in 5.8% (7 patients). Kondziolka et al11 added data from 290 patients with meningioma; that of 234 patients who had symptoms before GKRS 62 (26%) improved, 126 (54%) had no change in symptoms, 46 (20%) gradually worsened, and 32 of 34 (94%) asymptomatic patients remained asymptomatic. These results along with our data indicate that GKRS can achieve good tumor control while resulting in a low morbidity rate. The patients tolerated the procedure well without additional morbidity, and therefore patients are able to return to their normal lifestyle almost immediately. Furthermore, we investigated the potential variables that could influence the outcome. We found a statistically significant relationship between surgical resection before GKRS more than once, high grade WHO classification, peritumor edema, >2 tumors treated by GKRS, and unfavorable outcomes after GKRS using univariate analysis. In a retrospective study, Sheehan et al22 found
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that new peritumoral edema occurred or preexisting edema worsened in 40% of treated meningiomas after treatment, and the median time to onset of peak edema was 36 months after SRS. They further determined that factors including initial tumor volume >10 cm3, absence of prior resection, and higher margin dose were significantly associated with increased risk of new or progressive edema after SRS. This finding was confirmed by Jang et al12 and Kan et al.23 Studies based on the investigation of the natural history of MIMs have indicated that not all patients with MIMs require treatment.6,24-26 As for those who need to be treated, surgical removal is the mainstay modality of therapy currently.8,9 However, the tendency of multiplicity, recurrence after removal, and separated spread of the tumors means that this method may not be ideal because of cumulative damage to nerves. Compared with surgery, GKRS offers noninvasive local treatment, improves clinical symptoms with low morbidity, and can be used to treat multiple, widely separated tumors in a single session with minimal toxicity and low cost. Therefore, GKRS represents a noninvasive approach that may provide a valuable option for treating patients with MIMs. Our study has several limitations. First of all, it is limited by its retrospective nature and small sample size. In addition, the available radiologic follow-up period is relatively short (mean imaging follow-up time <5 years). Inasmuch as meningioma grows slowly and can be progressive in the long term,14 evaluation of outcome could be confounded in the setting of short-term follow-up. Another limitation to this research is that the patient group had some important heterogeneous characteristics, such as history of radiation exposure and differing treatment strategies. We attempted to address these by performing subgroup analyses to obtain more representative data, but obviously those results are limited by even smaller sample sizes. Larger prospective studies with long-term follow-up are required to obtain this information in the future. Considering that MIMs are rare, our findings are valuable for providing evidences of GKRS as a treatment option for patients with MIMs. CONCLUSIONS In summary, the current results of this clinical experience suggest that GKRS is a safe and effective treatment approach for MIMs. These results support a potential role for GKRS as a primary or adjunctive therapy modality in the treatment of patients with MIMs. Surgical resection before GKRS more than once, high grade WHO classification, peritumor edema, and number of tumors are predictive factors of unfavorable outcomes after GKRS and could be potential therapeutic targets to improve the outcomes. Larger studies with longer follow-up periods are warranted to verify these results and define optimal radiosurgical strategies. ACKNOWLEDGMENTS The authors thank the colleagues in their department who participated in this study or helped their work during data acquisition. Special thanks to Wen Jiang and Jing Chen for their professional editorial assistance.
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8. Linsler S, Keller C, Urbschat S, Ketter R, Oertel J. Prognosis of meningiomas in the early 1970s and today. Clin Neurol Neurosurg. 2016;149:98-103. 9. Rogers L, Barani I, Chamberlain M, et al. Meningiomas: Knowledge base, treatment outcomes, and uncertainties. A RANO review. J Neurosurg. 2015;122:4-23. 10. Koga T, Shin M, Saito N. Role of gamma knife radiosurgery in neurosurgery: Past and future perspectives. Neurol Med Chir (Tokyo). 2010;50: 737-748. 11. Kondziolka D, Patel AD, Kano H, Flickinger JC, Lunsford LD. Long-term outcomes after gamma
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18. Liu A, Kuhn EN, Lucas JT Jr, Laxton AW, Tatter SB, Chan MD. Gamma knife radiosurgery for meningiomas in patients with neurofibromatosis type 2. J Neurosurg. 2015;122:536-542. 19. Birckhead B, Sio TT, Pollock BE, Link MJ, Laack NN. Gamma Knife radiosurgery for neurofibromatosis type 2-associated meningiomas: A 22-year patient series. J Neuro Oncol. 2016;130: 553-560. 20. Jo KI, Im YS, Kong DS, et al. Multisession gamma knife surgery for benign orbital tumors. J Neurosurg. 2012;117:102-107.
21. Santacroce A, Walier M, Regis J, et al. Long-term tumor control of benign intracranial meningiomas after radiosurgery in a series of 4565 patients. Neurosurgery. 2012;70:32-39. discussion 39. 22. Sheehan JP, Lee CC, Xu Z, Przybylowski CJ, Melmer PD, Schlesinger D. Edema following gamma knife radiosurgery for parasagittal and parafalcine meningiomas. J Neurosurg. 2015;123: 1287-1293. 23. Kan P, Liu JK, Wendland MM, Shrieve D, Jensen RL. Peritumoral edema after stereotactic radiosurgery for intracranial meningiomas and molecular factors that predict its development. J Neuro Oncol. 2007;83:33-38. 24. Wong RH, Wong AK, Vick N, Farhat HI. Natural history of multiple meningiomas. Surg Neurol Int. 2013;4:71. 25. Olivero WC, Lister JR, Elwood PW. The natural history and growth rate of asymptomatic meningiomas: A review of 60 patients. J Neurosurg. 1995; 83:222-224. 26. Nakamura M, Roser F, Michel J, Jacobs C, Samii M. The natural history of incidental meningiomas. Neurosurgery. 2003;53:62-70. discussion 70-71. Conflict of interest statement: The authors declare that the article content was composed in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Received 12 March 2019; accepted 22 April 2019 Citation: World Neurosurg. (2019) 128:e495-e500. https://doi.org/10.1016/j.wneu.2019.04.184 Journal homepage: www.journals.elsevier.com/worldneurosurgery Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2019 Elsevier Inc. All rights reserved.
WORLD NEUROSURGERY, https://doi.org/10.1016/j.wneu.2019.04.184
Gamma Knife Radiosurgery for Patients with Multiple Intracranial Meningiomas Wei Chen, Xiaoyu Wang, Fujun Liu, Jing Chen
OBJECTIVE: The aim of this study was to evaluate the safety and efficacy of Gamma Knife radiosurgery (GKRS) in patients with multiple intracranial meningiomas (MIMs).
-
METHODS: The authors performed a retrospective analysis of 42 consecutive patients (7 men and 35 women) with MIMs who underwent GKRS. The median age of the patients at the time of GKRS was 57.5 years (range, 27e77 years). A total of 115 tumors among 42 patients were identified through imaging or postoperative histopathologic examination, of which 90 were treated with GKRS.
peritumor edema, and >2 tumors treated by GKRS are predictors of unfavorable outcome after GKRS.
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RESULTS: Follow-up imaging studies were available for 75 tumors in 36 patients (83.3%), with a mean follow-up period of 45.0 months (range, 6.6e90.4 months); 41 patients (97.6%) received clinical follow-up for 16.7 to 106.7 months (average, 57.1 months). Local tumor control was achieved in 68 tumors (90.7%) at the last follow-up. On univariate analysis, surgical resection before GKRS more than once (P [ 0.048) and high World Health Organization (WHO) classification (grades II and III) (P [ 0.001) were associated with tumor progression. Patients with worsening clinical manifestation showed correlation with peritumor edema (P < 0.001) and had >2 lesions treated by GKRS (P < 0.001) on univariate analysis.
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CONCLUSIONS: GKRS is a safe and effective treatment for MIMs. Variables including surgical resection before GKRS more than once, high grade WHO classification,
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Key words Gamma Knife radiosurgery - Multiple intracranial meningiomas - Stereotactic radiosurgery -
Abbreviations and Acronyms CI: Confidence interval GKRS: Gamma Knife radiosurgery MIMs: Multiple intracranial meningiomas MR: Magnetic resonance OR: Odds ratio SRS: Stereotactic radiosurgery WHO: World Health Organization
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INTRODUCTION
M
ultiple intracranial meningiomas (MIMs) are rare tumors defined by the presence of at least 2 meningiomas that appear simultaneously or not, at different intracranial sites.1,2 They are estimated to account for about 1% of all meningiomas. The most common intracranial primary tumors represent approximately 36.4% of all central nervous system tumors3 before,4,5 and up to 10% of meningiomas after, the advent of computed tomography and magnetic resonance imaging (MRI).6,7 The clinical manifestations of MIMs are mainly dependent on the location of tumor involvement. Most commonly, patients present with headache, dizziness, weakness or numbness of extremities, and other central cranial nerve deficits that show no difference from solitary meningioma. Standard treatment or a consensus on special treatment for MIMs has not been proposed, and reasonable management needs to be established. To date, surgical resection is the mainstay treatment modality for this disease.8,9 Total resection contributes to a high likelihood of local tumor control, and with the development of imaging and microsurgery techniques, the outcome has greatly improved. However, the surgical operation of MIMs is still challenging for neurosurgeons because of the number and locations of tumors, such as the brainstem or eloquent areas. In this situation, it is necessary to explore another approach in the management of MIMs.
Department of Neurosurgery, West China Hospital of Sichuan University, Chengdu, Sichuan Province, People’s Republic of China To whom correspondence should be addressed: Jing Chen, M.D. [E-mail: [email protected]] Citation: World Neurosurg. (2019) 128:e495-e500. https://doi.org/10.1016/j.wneu.2019.04.184 Journal homepage: www.journals.elsevier.com/world-neurosurgery Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2019 Elsevier Inc. All rights reserved.
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GAMMA KNIFE RADIOSURGERY FOR MULTIPLE INTRACRANIAL MENINGIOMAS
Gamma Knife radiosurgery (GKRS) is widely accepted as an effective treatment option for a variety of brain disorders, including brain neoplasms, vascular tumors, and functional disorders.10 During the past decades, studies were performed to establish the safety and effectiveness of GKRS for solitary meningiomas.10-16 However, there are limited data regarding the treatment of MIMs by GKRS, and the available evidence includes only limited cases.15,17-19 In the present study we describe the clinical and imaging outcomes in 42 patients treated with GKRS for MIMs, and we discuss the role of GKRS as a primary or adjuvant approach in the management of MIMs. MATERIALS AND METHODS Patient Population Between January 2009 and December 2016, 42 consecutive patients with MIMs who underwent GKRS at the Gamma Knife Center of West China Hospital, Sichuan University, were enrolled. The diagnoses of MIMs were based on histopathologic assessment or MR images according to the definition.1,2 Exclusion criteria included 1) patients who accepted whole brain radiation therapy before GKRS, 2) lack of cooperation for evaluation or loss to follow-up, and 3) diagnoses of neurofibromatosis type 2. Gamma Knife Radiosurgical Technique The treatment strategy was explained in detail to each patient, and written informed consent was obtained from all patients before GKRS. After consent had been obtained, the procedure was performed on a Leksell Gamma Knife model C (Elekta Instruments AB, Stockholm, Sweden), and the frame was installed on the patient’s head with the aid of a local anesthetic agent. Gadolinium-enhanced slice thickness of 3-mm MR images of T1weighted sequences were obtained for pretreatment localization and treatment planning. We used the Leksell Gamma Plan (version 9.0, Elekta AB) for GKRS treatment planning. Follow-Up and Assessment Strategy Periodic follow-up was carried out for patients in the study. The first clinical follow-up examination was performed 3 months after treatment, and subsequent follow-up examinations were made every 3 months during the first year and every 6 months thereafter. Each patient’s history and physical examination findings were recorded and compared with those documented before GKRS. Radiologic follow-up was undertaken by contrast-enhanced MRI. The first radiologic follow-up examination was performed 6 months after the initial treatment; subsequent follow-up examinations were conducted every 6 months during the second year and every year thereafter. For clinical assessment, changes in clinical manifestation (symptoms and/or signs) were based on results of the physical examination and patients’ self-assessment. We defined >50% improvement as clinical improvement. For radiologic assessment, follow-up MR images were compared with preoperative GKRS images. Tumors were measured in the maximum transverse, anteroposterior, and vertical dimensions. Half of the product of these 3 diameters was used as a surrogate for tumor volume. The tumor volume response was classified as follows: shrinkage (>20% decrease in tumor volume), stable (0%e20% change in
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tumor volume), and tumor progression (>20% increase in tumor volume) at the last follow-up examination.20 Local control was defined as shrinkage or stabilization of the treated tumor. Statistical Analysis Local tumor control was calculated from the day of GKRS with the Kaplan-Meier method, and a log-rank (Mantel-Cox) test was performed to compare 2-group variables. Variables were tested categorically and included sex (male vs. female), age (cutoff value of 57 years), previous surgery (<2 times vs. 2 times), edema (yes vs. no), WHO) classification (grade I vs. grades II and III), number of GKRS during hospitalization (<2 times vs. 2 times), prescribed dose (cutoff value of 13 Gy), number of total tumors (2 lesions vs. 3 lesions), number of tumors treated by GKRS (<2 lesions vs. 2lesions), pre-GKRS volume (cutoff value of 0.87 cm3), and post-GKRS volume (cutoff value of 0.87 cm3). P 0.05 was considered statistically significant. All statistical analysis was performed with standard available statistical software (SPSS, version 25.0; SPSS Inc., New York, USA). RESULTS The patient population (total 42) consisted of 7 men (16.7%) and 35 women (83.3%), with a median age of 57.5 years (range, 27e77 years). A total of 115 tumors among these patients were identified, of which 90 were irradiated by GKRS. Most patients (59.5%, n ¼ 25) underwent microsurgery resection (between 1 and 3 operations each) before GKRS. GKRS was applied as an upfront treatment in all patients’ 80/90 tumors (88.9%) and as an adjunctive treatment approach in 8 patients’ 10/90 tumors (11.1%). In 1 patient, tumor volume exceeded 10 cm3 and in another 5 patients the tumors were scattered in brain, and the GKRS procedure was divided into 2 sessions (the time between 2 sessions was 2 days). The most common location for the tumors was parasagittal (46.7%, n ¼ 42), followed by cerebral or cerebellar convexity (28.9%, n ¼ 26). The mean tumor volumes before and after GKRS were 1.76 2.10 cm3 (range, 0.24e11.76 cm3) and 1.48 1.63 cm3 (range, 0e14.78 cm3), respectively. The median prescription dose was 13.0 Gy (range, 8.0e16.0 Gy), and the median isodose line was 50.0% (range, 45.0%e50.0%). Tables 1 and 2 summarize the characteristics of the patients in this study. Radiologic Outcomes In total, 6/42 patients (14.3%) were excluded in the final radiologic analysis: 3/42 patients (7.1%) for insufficient follow-up (the period between GKRS and the last follow-up <6 months), 2/42 patients (4.8%) for refusal to undergo radiologic examination, and 1/42 patient (2.4%) because of death, probably related to meningioma, a high WHO grade tumor during follow-up (her data were incomplete). Therefore, 36 patients’ 75 tumors (83.3%) with a mean follow-up period of 45.0 months (range, 6.6e90.4 months) were included in our final radiologic analysis. Follow-up MR images demonstrated that overall tumor local control was achieved in 36/42 patients’ (85.7%) 68/90 tumors (90.7%) at the last follow-up (Figure 1). Twenty-five tumors (33.3%) in 17 patients were smaller at the time of GKRS, and 43/90 tumors (57.3%) in 23 patients were unchanged. Tumor progression was observed in 6 patients’ 7/90 tumors (9.3%) after GKRS. It
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GAMMA KNIFE RADIOSURGERY FOR MULTIPLE INTRACRANIAL MENINGIOMAS
Table 1. Demographic, Clinical, and Tumor Characteristics of Patients with Multiple Intracranial Meningiomas
Table 2. Gamma Knife Radiosurgery Treatment Characteristics of Patients with Multiple Intracranial Meningiomas
Characteristic
Factor
Total
Number
% or Range
42
Number of GKRS During Hospitalization
Sex Male Female Age (years), median (range)
7
Value (% or Range)
16.7%
35
83.3%
57.5
27e77
Number of surgeries before GKRS
1
36 (85.7%)
2
6 (14.3%)
Number of tumors treated by GKRS 1
10 (23.8%)
2
21 (50.0%)
0
17
40.5%
3
9 (21.4%)
1
19
45.2%
4
0 (0.0%)
2
5
11.9%
5
1 (2.4%)
3
1
2.4%
6
1 (2.4%)
Edema
Changes of tumors
Yes
11
26.2%
Shrinkage
No
31
73.8%
Stable
4 (9.5%)
Progression
5 (11.9%)
1
10
23.8%
2
21
50.0%
Mean pre-GKRS volume (cm3) 3
Number of tumors
23 (54.8%)
Parameters of GKRS 1.76 2.10 1.48 1.63
3
9
21.4%
Mean post-GKRS volume (cm )
4
2
4.8%
Median prescribed dose (Gy)
13.0 (8.0e16.0)
Median isodose line (%)
50.0 (42.0e55.0)
Parasagittal
42
46.7%
Convexity
26
28.9%
Location
Posterior fossa
6
6.7%
Olfactory groove
5
5.6%
Sphenoid wing
4
4.4%
Cerebellopontine angle
3
3.3%
Middle cranial fossa
2
2.2%
Lateral ventricle
2
2.2%
Grade I
17
40.5%
Grade II
2
4.8%
Grade III
1
2.4%
Clinical Outcomes The most common clinical presentations before GKRS included headache (n ¼ 21), followed by vertigo (n ¼ 6) and paralysis (n¼5). (Table 3) The mean clinical follow-up period was 57.1 months. An improvement in symptoms was observed in 12 patients (29.3%) and occurred at a mean follow-up time of 4.6 months (range, 0.3e12.0 months) after GKRS. Twenty-one patients (51.2%) still experienced their original symptoms, and 8 patients (19.5%) experienced transient headache and dizziness.
WHO classification, n ¼ 20
Image follow-up, mean (range)
45.0
6.6e90.4
Clinical follow-up, mean (range)
57.1
16.7e106.7
GKRS, Gamma Knife radiosurgery; WHO, World Health Organization.
is worth mentioning that 2 patients’ pathologic diagnoses were WHO grade II atypical, and 1 patient had WHO grade III anaplastic meningioma. Among them, 1 patient with tumor progression underwent additional surgical resection, 1 patient underwent repeated radiosurgery 26 months after initial GKRS, and another patient was lost to follow up.
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Figure 1. Kaplan-Meier curve showing overall tumor control rate from the time of Gamma Knife radiosurgery for 42 patients with multiple intracranial meningiomas.
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GAMMA KNIFE RADIOSURGERY FOR MULTIPLE INTRACRANIAL MENINGIOMAS
and III) (P ¼ 0.001) were associated with tumor progression. Patients with worsening clinical manifestation showed correlation with peritumor edema (P < 0.001) and had >2 tumors treated by GKRS (P < 0.001) on univariate analysis. No statistically significant variable was identified in the multivariate analysis.
Table 3. Clinical Manifestations in Patients with Multiple Intracranial Meningiomas* Number of Cases After GKRS Number of Cases Symptoms at the Time of and Signs GKRS Exacerbation Stabilization Improvement Headache
21
4*
11
6
None
9
1*
8
0
Vertigo
6
2*
4
0
Paralysis
5
0
1
4
Seizure
4
0
1
3
Olfactory loss
3
0
3
0
Nausea and vomiting
2
1
0
1
Visual loss
1
0
0
1
Hearing loss
1
0
1
0
DISCUSSION
*One patient can harbor several symptoms or signs.
No patient experienced permanent neurologic impairments or radiation-induced complications after GKRS. Prognostic Factors The results for the variables analyzed for overall tumor local control and clinical manifestation are presented in Table 4. On univariate analysis, surgical resection before GKRS more than once (P ¼ 0.048) and high WHO classification (grades II
In the present cohort, our findings showed that overall local control was achieved in 90.7% of tumors in patients with MIMs during the follow-up period. In a large cohort study, Santacroce et al21 reported the local tumor control rate was 92.5% with a median imaging follow-up of 63 months. Similarly, a previous study by Bledsoe et al13 revealed that tumor control was 99% at 3 years and 92% at 7 years after radiosurgery. A related article reported an overall tumor control rate in patients with meningiomas of 91%.11 More recently, Patibandla et al14 published their post hoc analysis of stereotactic radiosurgery (SRS) for WHO grade I posterior fossa meningiomas in 120 patients. The overall tumor control rate was 89.2%; for patients treated with a margin dose 16 Gy, the progression-free survival rate during 2 to 10 years after SRS was 100%. With special regard to MIMs, a study by Samblas et al15 demonstrated 3-year and 5-year overall survival rates for all patients of 95% and 90%, respectively, and the mean gross tumor volume decreased from 4.17 cm3 to 3.23 cm3 after SRS (P ¼ 0.057) during the median follow-up time of 5.8 years (range, 1e13.6 years). In addition, a study by Liu et al18 on GKRS for meningiomas in patients with neurofibromatosis type 2 revealed that in a total of 125 meningiomas were identified among 12 patients, the 5-year local control rate for meningiomas was 92%. Similarly, another study by Birckhead et al19 suggested that the 5-year and 10-year rates of local control were both 96%
Table 4. Univariable Analysis of Prognostic Factors for Local Tumor Control and Clinical Manifestation in Patients with Multiple Intracranial Meningiomas Tumor Control Factor
Clinical Manifestation
OR (95% CI)
P Value
OR (95% CI)
P Value
Sex (M vs. F)
1.40 (0.79e2.48)
0.227
1.21 (0.16e8.99)
0.814
Age (>57 years)
0.78 (0.40e1.51)
0.333
0.78 (0.41e1.48)
0.653
Previous surgery (2 times)
1.87 (0.83e4.17)
0.048
1.46 (0.84e2.52)
0.278
Edema (no vs. yes)
1.59 (0.70e3.61)
0.116
7.27 (1.16e45.64)
<9.001
WHO classification (grade I vs. grades II & III)
1.67 (0.82e3.41)
0.001
1.75 (0.92e3.32)
0.005
Number of GKRS during hospitalization (2 times)
1.93 (0.87e4.31)
0.105
1.17 (0.77e1.78)
0.796
Prescribed dose (>13 Gy)
1.03 (0.70e1.52)
0.975
1.21 (0.80e1.83)
0.143
Number of total tumors (3 lesions)
1.31 (0.56e3.04)
0.604
0.97 (0.53e1.77)
0.557
Number of tumors treated by GKRS (2 lesions)
1.29 (0.19e8.81)
0.376
0.35 (0.11e1.45)
<0.001
Pre-GKRS volume (<0.87 cm3)
0.38 (0.24e0.60)
0.077
0.97 (0.45e2.11)
0.659
3
0.38 (0.24e0.60)
0.082
1.00 (0.41e2.42)
0.615
Post-GKRS volume (<0.87 cm )
OR, odds ratio; CI, confidence interval; WHO, World Health Organization; GKRS, Gamma Knife radiosurgery.
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in patients with neurofibromatosis type 2-associated MIMs. It is important to note that small tumors were included in that study, and those tumors contributed to a relatively high tumor control rate. These findings along with our results suggest that tumor control rates for both WHO grade I meningiomas and MIMs are relatively high. The optimal prescribed dose for MIMs needs to be established because of the rarity of these tumors and the lack of prospective randomized studies. In the present study, the prescribed doses for the tumors ranged from 12 Gy to 15 Gy at the mean 50% isodose line (range, 45%e50%), depending on the size and location of the lesion. The mean tumor margin dose was 14 Gy (range, 10e16 Gy) in the study by Birckhead et al19 Similarly, Santacroce et al21 reported a median dose to tumor margin of 14 Gy in their study. In addition, a detailed analysis by Patibandla et al14 revealed that different margin doses yielded different tumor control rates, as reported above. The authors suggested that doses of 13 to 16 Gy seemed to afford reasonable tumor control and neurologic preservation for the majority of posterior fossa meningiomas patients. We have noted that less favorable control was observed in tumors with atypical histologic characteristics. Thus, without these 3 patients, the rate of tumor control would be much higher. However, this must be taken into account because it indicates that GKRS alone might yield less favorable outcomes when atypical and anaplastic meningiomas are treated. In our present series, the results revealed that improvement of clinical symptoms occurred in 12 patients (29.3%) after GKRS, 21 patients (51.2%) still retained their original symptoms signs, and 8 patients (19.5%) experienced transient headache and dizziness. No patient experienced permanent neurologic impairments or radiation-induced complications after GKRS. This finding was similar to most of those in the earlier published studies.11,14,15 Samblas et al15 reported, regarding the clinical examination, that clinical symptoms improved in 36% of patients and remained stable in 45% of the patients, and only 7 patients (9.6%) had late complications at their institution. There was no treatment-related mortality in their study population. Patibandla et al14 found that post-SRS improvement in neurologic symptoms occurred in 23.3% (28 patients), whereas symptoms were stable in 70.8% (85 patients) and worsened in 5.8% (7 patients). Kondziolka et al11 added data from 290 patients with meningioma; that of 234 patients who had symptoms before GKRS 62 (26%) improved, 126 (54%) had no change in symptoms, 46 (20%) gradually worsened, and 32 of 34 (94%) asymptomatic patients remained asymptomatic. These results along with our data indicate that GKRS can achieve good tumor control while resulting in a low morbidity rate. The patients tolerated the procedure well without additional morbidity, and therefore patients are able to return to their normal lifestyle almost immediately. Furthermore, we investigated the potential variables that could influence the outcome. We found a statistically significant relationship between surgical resection before GKRS more than once, high grade WHO classification, peritumor edema, >2 tumors treated by GKRS, and unfavorable outcomes after GKRS using univariate analysis. In a retrospective study, Sheehan et al22 found
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that new peritumoral edema occurred or preexisting edema worsened in 40% of treated meningiomas after treatment, and the median time to onset of peak edema was 36 months after SRS. They further determined that factors including initial tumor volume >10 cm3, absence of prior resection, and higher margin dose were significantly associated with increased risk of new or progressive edema after SRS. This finding was confirmed by Jang et al12 and Kan et al.23 Studies based on the investigation of the natural history of MIMs have indicated that not all patients with MIMs require treatment.6,24-26 As for those who need to be treated, surgical removal is the mainstay modality of therapy currently.8,9 However, the tendency of multiplicity, recurrence after removal, and separated spread of the tumors means that this method may not be ideal because of cumulative damage to nerves. Compared with surgery, GKRS offers noninvasive local treatment, improves clinical symptoms with low morbidity, and can be used to treat multiple, widely separated tumors in a single session with minimal toxicity and low cost. Therefore, GKRS represents a noninvasive approach that may provide a valuable option for treating patients with MIMs. Our study has several limitations. First of all, it is limited by its retrospective nature and small sample size. In addition, the available radiologic follow-up period is relatively short (mean imaging follow-up time <5 years). Inasmuch as meningioma grows slowly and can be progressive in the long term,14 evaluation of outcome could be confounded in the setting of short-term follow-up. Another limitation to this research is that the patient group had some important heterogeneous characteristics, such as history of radiation exposure and differing treatment strategies. We attempted to address these by performing subgroup analyses to obtain more representative data, but obviously those results are limited by even smaller sample sizes. Larger prospective studies with long-term follow-up are required to obtain this information in the future. Considering that MIMs are rare, our findings are valuable for providing evidences of GKRS as a treatment option for patients with MIMs. CONCLUSIONS In summary, the current results of this clinical experience suggest that GKRS is a safe and effective treatment approach for MIMs. These results support a potential role for GKRS as a primary or adjunctive therapy modality in the treatment of patients with MIMs. Surgical resection before GKRS more than once, high grade WHO classification, peritumor edema, and number of tumors are predictive factors of unfavorable outcomes after GKRS and could be potential therapeutic targets to improve the outcomes. Larger studies with longer follow-up periods are warranted to verify these results and define optimal radiosurgical strategies. ACKNOWLEDGMENTS The authors thank the colleagues in their department who participated in this study or helped their work during data acquisition. Special thanks to Wen Jiang and Jing Chen for their professional editorial assistance.
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18. Liu A, Kuhn EN, Lucas JT Jr, Laxton AW, Tatter SB, Chan MD. Gamma knife radiosurgery for meningiomas in patients with neurofibromatosis type 2. J Neurosurg. 2015;122:536-542. 19. Birckhead B, Sio TT, Pollock BE, Link MJ, Laack NN. Gamma Knife radiosurgery for neurofibromatosis type 2-associated meningiomas: A 22-year patient series. J Neuro Oncol. 2016;130: 553-560. 20. Jo KI, Im YS, Kong DS, et al. Multisession gamma knife surgery for benign orbital tumors. J Neurosurg. 2012;117:102-107.
21. Santacroce A, Walier M, Regis J, et al. Long-term tumor control of benign intracranial meningiomas after radiosurgery in a series of 4565 patients. Neurosurgery. 2012;70:32-39. discussion 39. 22. Sheehan JP, Lee CC, Xu Z, Przybylowski CJ, Melmer PD, Schlesinger D. Edema following gamma knife radiosurgery for parasagittal and parafalcine meningiomas. J Neurosurg. 2015;123: 1287-1293. 23. Kan P, Liu JK, Wendland MM, Shrieve D, Jensen RL. Peritumoral edema after stereotactic radiosurgery for intracranial meningiomas and molecular factors that predict its development. J Neuro Oncol. 2007;83:33-38. 24. Wong RH, Wong AK, Vick N, Farhat HI. Natural history of multiple meningiomas. Surg Neurol Int. 2013;4:71. 25. Olivero WC, Lister JR, Elwood PW. The natural history and growth rate of asymptomatic meningiomas: A review of 60 patients. J Neurosurg. 1995; 83:222-224. 26. Nakamura M, Roser F, Michel J, Jacobs C, Samii M. The natural history of incidental meningiomas. Neurosurgery. 2003;53:62-70. discussion 70-71. Conflict of interest statement: The authors declare that the article content was composed in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Received 12 March 2019; accepted 22 April 2019 Citation: World Neurosurg. (2019) 128:e495-e500. https://doi.org/10.1016/j.wneu.2019.04.184 Journal homepage: www.journals.elsevier.com/worldneurosurgery Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2019 Elsevier Inc. All rights reserved.
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