- Email: [email protected]
Long-Term Outcome of Gamma Knife Radiosurgery for Symptomatic Brainstem Cavernous Malformation
Original Article
Long-Term Outcome of Gamma Knife Radiosurgery for Symptomatic Brainstem Cavernous Malformation Kawngwoo Park, Jin Wook Kim, Hyun-Tai Chung, Sun Ha Paek, Dong Gyu Kim
OBJECTIVE: We sought to analyze the long-term outcome of Gamma Knife radiosurgery (GKS) for symptomatic brainstem cavernous malformation (s-BSCM).
-
METHODS: Forty-five patients (14 males, 31 females) were treated with GKS for s-BSCM from January 1998 to December 2011. All patients were followed up for >5 years, and their clinical data were analyzed retrospectively. All patients had a history of symptomatic bleeding once or more before GKS. These hemorrhages caused neurologic deficits including cranial nerve deficits, hemiparesis, hemisensory deficits, spasticity, or chorea. The mean target volume of s-BSCM was 1.82 cm3, and the median prescribed marginal dose of radiation was 13 Gy. The mean clinical and imaging follow-up period was 9.31 years (range 5.1e19.4 years).
monitor patients closely to determine their subsequent treatment.
-
RESULTS: The 45 patients had 69 hemorrhagic events before GKS. During the follow-up period after GKS, 35 patients had no hemorrhagic event, 6 patients had 1 episode of symptomatic hemorrhage, and 4 patients had 2 episodes. The calculated annual hemorrhage rate was 40.06% at preGKS, 3.3% at 2 years after GKS, 1.48% at 5 years after GKS, and 4.64% at >5 years after GKS. In this study of 45 patients, symptomatic radiation-induced complications developed in only 1 patient (2.2%). No patients had died at the last follow-up.
-
CONCLUSIONS: GKS for s-BSCM is a safe and effective alternative to surgical resection for reducing the rate of recurrent hemorrhage. Because the annual hemorrhage rate increases >5 years after GKS, clinicians should
-
Key words Brainstem - Cavernous malformation - Gamma Knife radiosurgery - Symptomatic hemorrhage -
Abbreviations and Acronyms AHR: Annual hemorrhage rate BSCM: Brainstem cavernous malformation CM: Cavernous malformation GKS: Gamma Knife radiosurgery
INTRODUCTION
A
lthough brainstem cavernous malformation (BSCM) is rare,1,2 intracranial hemorrhage caused by BSCMs is sometimes life threatening. Although a wait-and-see strategy is commonly adopted because the annual hemorrhage rate (AHR) of asymptomatic cavernous malformations (CM) is low at 0.25%e0.7%/person-year,2,3 symptomatic BSCMs (s-BSCM) should be treated differently due to frequent rebleeding and high morbidity by hemorrhage.4-6 The current treatment for s-BSCMs is microsurgical resection7,8; however, this is more risky for surgical morbidity and mortality in the case of intraparenchymal BSCMs. In a previous report published in 2002, we showed that AHR of intracranial CMs could be reduced from 35.5% to 1.5% after Gamma Knife radiosurgery (GKS) with a mean follow-up period of 38.3 months (range 21e67 months).9 Recently, several reports showed that GKS has played an important role in treating deeply seated BSCMs, which are considered to have a high complication rate.10-13 In meta-analysis of radiosurgery for BSCMs, radiosurgery has shown that the AHR can be lowered from 4%e121.8% to 4.3%e12.5% and further down to 0%e3.6% after 2 years of radiosurgery.14 Although several reports have confirmed that GKS is safe and effective in treating BSCMs,10,11,13,15 there is lack of clinical results with long-term follow-up of >2 years. The purpose of this study was to investigate the AHR and radiation-induced complications in
MRI: Magnetic resonance imaging s-BSCM: Symptomatic brainstem cavernous malformation Department of Neurosurgery, Seoul National University Hospital, Seoul, Republic of Korea To whom correspondence should be addressed: Jin Wook Kim, M.D. [E-mail: [email protected]] Citation: World Neurosurg. (2018). https://doi.org/10.1016/j.wneu.2018.05.164 Journal homepage: www.WORLDNEUROSURGERY.org Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2018 Elsevier Inc. All rights reserved.
WORLD NEUROSURGERY -: e1-e6, - 2018
www.WORLDNEUROSURGERY.org
e1
ORIGINAL ARTICLE KAWNGWOO PARK ET AL.
BRAINSTEM CAVERNOUS MALFORMATION BY GKS
patients with s-BSCM who had at least 5 years of follow-up after GKS. MATERIALS AND METHODS
Table 1. Patient Characteristics in 45 Patients with at Least 5 Years of Follow-Up After Gamma Knife Surgery (GKS) for Brainstem Cavernous Malformations Characteristic
Patient Population A total of 87 patients underwent GKS for s-BSCMs in a single institution between January 1998 and December 2011. For the purpose of the current study, we selectively included consecutive patients who were followed for at least 5 years after GKS. The study was conducted in 45 patients with available clinical data and adequate radiologic images. The mean age in these patients was 36.6 years (range 3e67 years), and the predominant sex was female (68.9%). The locations of s-BSCMs were in the pons for 21 patients (46.7%), midbrain for 16 patients (35.5%), and medulla for 8 patients (17.8%). All patients were s-BSCM patients who experienced 1 hemorrhages before GKS. Before they underwent GKS, hemorrhage had occurred once in 26 CMs (57.8%), twice in 15 patients (33.3%), three times in 3 patients (6.7%), and 4 times in 1 patient (2.2%) (Table 1). In this study, episodes of hemorrhage were identified on the basis of the occurrence of newly developed neurologic symptoms associated with magnetic resonance imaging (MRI) findings of recently developed hemorrhage. All patients except 1 were treated with GKS after neurologic stabilization from the hemorrhagic event. Before treatment, neurologic symptoms occurred in 38 (84.4%) of 45 patients. Seven patients had improved neurologic symptoms before GKS. Of these patients, 29 of them (64.4%) had cranial nerve deficits, 8 of them (17.8%) had hemiparesis, 18 of them (40.0%) had hemisensory deficits, 1 of them (2.2%) had spasticity, and 2 of them (4.4%) had chorea. Gamma Knife Radiosurgery Stereotactic radiosurgery was performed using the Leksell Gamma Knife model B (Elekta AB, Stockholm, Sweden) until 2002, model C (Elekta AB) until 2009, and model Perfexion (Elekta AB) thereafter. The target volume was delineated on the T1-weighted gadolinium-enhanced transverse MRI except the hemosiderin rim. The mean target volume was 1.88 cm3 (range 0.1e13.5 cm3). The determination of GKS dose was related to the volume of the BSCMs, up to 16 Gy of marginal dose in the small lesion. Otherwise, the dose was reduced. The mean marginal dose was 13.0 Gy (range 9e16 Gy), and the mean maximum dose was 25.7 Gy (range 12e32 Gy). The number of isocenters ranged from 2 to 23 (mean 8.0), and the isodose line was 50%e80% (mean 50.0%) (Table 2). All patients were treated with single-session GKS. The mean delay between the last hemorrhage and GKS was 2.74 months (range 0.1e15.1 months). Follow-Up and Statistics After GKS, all patients underwent MRI studies and clinical evaluation at 3 months, 6 months, 1 year, and then annually. All of 45 patients were available for study with more than 5 years of followup period after GKS for s-BSCMs. The mean follow-up period was 9.31 years (range 5.1e19.4 years). We carefully monitored any clues suggesting hemorrhage including new foci of high signal intensity on T1-weighted MRI, volume expansion of irradiated lesions, and edematous changes revealed on T2-weighted MRI. The AHR was
e2
www.SCIENCEDIRECT.com
Number (%)
Age (mean SD) (years, range)
36.6 16.6 (3e67)
Female-to-male ratio (% female)
31/14 (68.9%)
Location Midbrain
16 (35.5%)
Pons
21 (46.7%)
Medulla
8 (17.8%)
Number of pre-GKS hemorrhagic events 1
26 (57.8%)
2
15 (33.3%)
3
3 (6.7%)
4
1 (2.2%)
Patients with neurologic deficit before GKS Present
38 (84.4%)
Absent
7 (15.6%)
Surgical resection before GKS
3 (6.7%)
SD, standard deviation.
calculated by dividing the total number of hemorrhages in all patients by the total number of patient-years for which they were observed. The AHR was compared before and after GKS using the chisquare test. We also analyzed for variables that might affect the rate of rebleeding of s-BSCM, such as location, sex, age at presentation, mass size, and irradiated marginal dose, using Cox regression analysis. The statistical analysis was performed using SPSS (version 22.0; IBM Corporation, Armonk, New York, USA), and the level of statistical significance was set at P < 0.05. RESULT Pre-GKS Hemorrhage Rate We calculated the pre-GKS hemorrhage rate in 45 patients who experienced at least 2 bleeding episodes. The pre-GKS observation period extended from the time of the patient’s first symptomatic image-documented hemorrhage to the time of GKS. A total of 59.9 patient-years were recorded. There were 69 hemorrhagic events during this period. The date of the first hemorrhage is the date of diagnosis. Therefore the first hemorrhage was not taken into account in the number of events. After exclusion of the first hemorrhage, the calculated AHR was 40.06% (95% confidence interval, 37.86e42.26) (24 events in 59.9 patient-years). PostLGamma Knife Surgery Hemorrhage Rate The observation period following GKS was defined as the time from treatment until the most recent clinical follow-up. Thus the mean follow-up period after GKS was 9.31 years (range 5.1e19.4 years),
WORLD NEUROSURGERY, https://doi.org/10.1016/j.wneu.2018.05.164
ORIGINAL ARTICLE KAWNGWOO PARK ET AL.
BRAINSTEM CAVERNOUS MALFORMATION BY GKS
Table 2. Gamma Knife Surgery Parameters for Patients with Brainstem Cavernous Malformation Parameter
Mean (Range)
Target volume (cm3)
1.8 (0.1e13.5)
Margin dose (Gy)
13.0 (9e16)
Max dose (Gy)
25.7 (18e32)
Isodose level
50.0 (50e80)
Number of shots
8.0 (2e23)
with an overall observation period of 418.9 person-years. None of the patients died during the follow-up. Fourteen hemorrhagic events in 10 patients were documented during this period. Of these hemorrhages, 3 events occurred in 3 patients during the first 2 years after GKS, from which the AHR of 3.33% was calculated (3 hemorrhages/ 90 person-years). And the AHR at 5 years after GKS was calculated to be 1.48% (two hemorrhages/135 person-years) on the basis of 2 events in 2 patients. After >5 years of follow-up, 9 hemorrhages in 5 patients were identified during 193.9 person-years, giving the AHR of 4.64% (95% confidence interval 2.01e7.27). Of the 5 patients who had the hemorrhagic event after 5 years of GKS, 4 patients had 2 events and 1 patient underwent 1 event during the follow-up period. However, this increase was not statistically significant. Statistical analysis revealed that the risk of BSCM hemorrhages was significantly reduced in the initial 2 years after GKS (P < 0.01), as shown in Figure 1. One representative case is shown in Figure 2.
Predictable Factor Associated with Rebleeding Although clinical factors such as age at presentation, sex, mass size, locations, and GKS dose could influence hemorrhage, we could not identify any correlation between the postulated risk factors and the incidence of rebleeding. Univariate analysis using the Cox regression proportional-hazard model did not reveal significant associations between rebleeding after GKS and any factor including age at presentation (P ¼ 0.55), sex (O ¼ 0.44), GKS dose (P ¼ 0.31), and mass size (P ¼ 0.97). When we compared the AHRs for marginal dose <13 Gy and >14 Gy by calculating the 95% confidence interval, there was no significant difference.
Figure 1. Annual hemorrhage rate following Gamma Knife radiosurgery.
WORLD NEUROSURGERY -: e1-e6, - 2018
Clinical Outcomes and Radiation-Induced Complication Of the 38 patients with pre-GKS neurologic symptoms, 25 of them (65.8%) had improved symptoms after GKS for BSCM. In 12 patients, there was no improvement in their neurologic deficits even after GKS and the symptoms of 1 patient deteriorated because of edema after GKS (Table 3). No patients died during the last follow-up period. The patient who had worsened neurologic symptoms after GKS recovered after steroid treatment for 1 month. The volume of the BSCMs before and after the treatment was measured on MRI using the GammaPlan treatment planning software (version 11, Elekta AB, Stockholm, Sweden). We defined a significant mass reduction or increment as change in the total volume of >20% from the baseline. In all patients, follow-up MRI was available. Mass shrinkage occurred in 32 patients (71.1%), and it was stationary in 13 patients (28.9%). No patient showed a mass increment in the latest follow-up images (Table 3). DISCUSSION BSCM is known to be associated with higher rates of bleeding and permanent neurologic deficits than other CMs because of its critical location.16,17 Additionally, recent meta-analysis reported higher rates of rebleeding in s-BSCM than in other CMs.18 In a meta-analysis of 1620 patients with CMs by Horne et al,18 an estimated 5-year rebleeding rate of s-BSCM was 30.8% and the risk of developing a recurrent hemorrhage or new neurologic deficit was reported as 50.7%. Although the rebleeding rate by natural course of BSCMs is low and the incidence of significant morbidity is reported to be 8%,19 s-BSCMs should be considered critical disorders that warrant aggressive treatment, even if conservative treatment with close observation is another therapeutic alternative. Furthermore, the natural history of s-BSCMs is considered completely different from asymptomatic lesions, as frequent hemorrhages or neurologic deteriorations occur after the first event.19,20 On the basis of this information, several reports have suggested the need for active treatment rather than a wait-and-see strategy.13,21-23 Although the optimal treatment strategy for s-BSCMs remains controversial, surgical resection is still considered the first treatment option for BSCMs because of improvement in microsurgery and other advances, such as intraoperative neuronavigation, intraoperative neuromonitoring, and postoperative care techniques. However, surgical resection of BSCMs often carries appreciable morbidity and mortality including hemiparesis, paresthesia, and cranial nerve dysfunction. Because of this high rate of treatment-related complications, GKS has arisen as an alternative to surgical resection for BSCMs. Its use to treat BSCMs over the past decade has demonstrated that GKS is an effective treatment option for patients with BSCMs, especially symptomatic brainstem intraparenchymal CMs.11,13,14 Several researchers have reported a significant reduction in AHR after GKS for patients with BSCMs.10-13,24,25 They demonstrated that AHR continued to decline in the first 2 years after GKS and thereafter (Table 4). Our results are consistent with those previously reported. The notable feature of our study is that we reported long-term follow-up of the patient with s-BSCM after GKS. Our results show that the AHR by s-BSCMs decreased from 40.06% pre-GKS to 3.33% 2 years and 1.48% 5 years after GKS,
www.WORLDNEUROSURGERY.org
e3
ORIGINAL ARTICLE KAWNGWOO PARK ET AL.
BRAINSTEM CAVERNOUS MALFORMATION BY GKS
Figure 2. A 48-year-old man, with no prior history of comorbidities, presented with acute onset of headache associated with a left hemiparesis and gait disturbance. Brain magnetic resonance imaging (MRI) showed a cavernous malformation of 13.5 cm3 located in the midbrain (A). Gamma Knife surgery (GKS) was performed with a marginal radiation dose of 13 Gy
and the decrease remained significant up to 5 years after GKS. However, the AHR increased again to 4.64% at >5 years of GKS, which implies that additional treatment (e.g., repeat radiosurgery) might be considered. Although we did not show a statistically significant increase in >5 years of AHR, the frequency of rebleeding seemed to be slightly increased compared with 5 years before GKS. More specifically, rebleeding occurred in 5 patients with 9 rebleeding events, of which 4 patients had 2 rebleeding episodes each. Conclusively, whether this increase in rebleeding was due to treatment failure or recurrence of BSCM was unknown. However, several reports in the literature indicated that results after long-term observation of radiosurgery for BSCMs did not show consistency with these increase. Kida et al29 reported 63 BSCMs at mean follow-up of 55 months and only 2 bleeds after 5 years of GKS. Monaco et al24 reported that only 3 bleeds were observed in 68 BSCM patients with a mean follow-up of 5.2 years. Frischer et al27 also showed a low AHR of 0.61% (1 hemorrhage/163 person-years) over a long-term follow-up of median 5.2 years in 38 patients who were diagnosed with BSCM and underwent radiosurgery. In contrast, Fuetsch et al26 reported a median follow-up of 7.1 years for 14 patients with AHR of 4.8% (4 hemorrhages/82.8 person-years). Although Fuetsch’s study was limited in a relatively small number of patients and treatment with LINAC-based radiosurgery, it is reasonable that AHR may be around 5% after long-term follow-up after radiosurgery. Reports of the histopathology of CM after radiosurgery indicate that most vessels were obliterated by fibrinoid necrosis, endothelial cell destruction, and marked fibrosis in the connective tissue stroma.24,30 In this regard, it is possible that the AHR increases again at >5 years after the GKS because of recanalization. Shrinkage of the lesion after GKS was observed in 71.1% of the patients, though it is not clear whether this change was really induced by radiation or absorption of hemorrhage. The majority of patients (65.8%) showed neurologic improvement at the last follow-up, and none showed worsening after GKS. Therefore the overall outcome after GKS in our study was favorable and compatible with that reported elsewhere (see Table 4). The strengths of our study include the long-term follow-up (median 111.7 months) after GKS for BSCMs. Although the AHR at >5
e4
www.SCIENCEDIRECT.com
to the 50% isodose line. After GKS, the patient’s neurologic symptoms disappeared completely. Serial T1-weighted MRI with contrast media demonstrated that the BSCM remained controlled at 3 months (B), 13 months (C), 25 months (D), and 119 months (E) after GKS.
years rises to 4.64%, these figures remain notably lower than the AHR of CMs, which is 18.7%.31 Interestingly, the precise longterm outcomes of CMs, especially BSCMs, are largely unknown including the latent risk of hemorrhage, adverse effects, and delayed neurologic events. Our results showed that AHR is still low even 5 years after GKS for BSCMs, although given that the AHR increased again to 4.64% at >5 years after GKS, long-term survivors of BSCMs might require careful follow-up with close monitoring. Although the optimal marginal radiation dose for BSCMs is still unclear, Lee et al12 and Kim et al25 suggested that a marginal dose as low as 11 Gy was sufficient to reduce the radiation-related complications of BSCMs. This dose was effective in the reduction of the AHR to 2.4%3.8% at 2 years after GKS and in improving neurologic symptoms, while the rate of radiationinduced complications was 2.32%.12,25 Liu et al11 also reported similar clinical results with a low marginal dose of 11.9 Gy. However, the mean marginal dose in our study was 13.0 Gy, and there was no difference in comparing and analyzing >13 Gy. To sum up, a therapeutic radiation dose for s-BSCMs seems to be sufficient to 11e13 Gy without radiation toxicity.
Table 3. Clinical Outcomes After Gamma Knife Surgery for Brainstem Cavernous Malformation Variable
Number of Patients (%)
Neurologic deficit (n ¼ 38) Improved
25 (65.8%)
Sustained
12 (31.6%)
Worsen
1 (2.6%)
Radiologic finding (n ¼ 45) Decrease
32 (71.1%)
Stable
13 (28.9%)
Increase
0
WORLD NEUROSURGERY, https://doi.org/10.1016/j.wneu.2018.05.164
ORIGINAL ARTICLE KAWNGWOO PARK ET AL.
BRAINSTEM CAVERNOUS MALFORMATION BY GKS
Table 4. Literature Summary of Main Studies on Brainstem Cavernous Malformation Treated with Stereotactic Radiosurgery Number of Patients
Mean Marginal Dose, Gy
Mean Follow-Up Months
Pre-GKS AHR, %
Post-GKS AHR, % (Before 2 Years / After 2 Years)
Complication Rate, %
Mortality Rate, %
Monaco et al. 201024
68
15.8
62.4
32.4
8.2 / 1.4
1.5
0
Lee et al. 201212
49
11
40.6
31.3
4.3 / 3.6
2.0
0
Fuetsch et al. 2012
14
13.9*
85.2*
12.5
4.8y
25
0
Park et al. 201313
20
13
38.9
39.5
8.2 / 0
5.0
0
39
13
43
33.6
8.1 / 2.4
0
0
Series
26
Kim et al. 201425 Frischer et al. 2014
38
12*
62.4*
47.6
2.6 / 0.6
—
0
Liu et al. 201611
43
11.9
36
28.0
3.9 / 1.9
2.3
0
Ucuncu Kefeli et al. 201728
81
11.8
50
55.7
0.87y
0
0
Present study
45
13
111.7
40.1
3.3 / 1.5 / 4.6y
2.2
0
27
GKS, Gamma Knife radiosurgery; AHR, annual hemorrhage rate. *Median values. y5 years after GKS.
Indubitably, GKS treatment for BSCMs shows good clinical outcomes compared with the results of surgical resection for BSCMs.32-34 Although complete removal of BSCMs may be possible through surgical resection, there is always the risk of surgical morbidity and mortality. A retrospective study of 1390 surgical cases from the literature showed that the rates of early postoperative morbidity and long-term worsening were 45% and 15%, respectively.35 However, most analyses of GKS report <5% of complication rates and 0% of mortality rates. Furthermore, not all patients can be treated surgically and some patients can only be operated on selectively including those with acute extraparenchymal hemorrhage, exophytic lesion, or mass effect caused by hemorrhages.7,8 Considering that surgical resection of BSCMs remains difficult, GKS could be contemplated as an easier and more accessible treatment options for the clinician. Our study has some limitations. First, it was not a prospective trial. Therefore selection bias could not be ruled out in this study. Second, we did not have information regarding the number of untreated patients and natural history of BSCMs, so we could not determine whether the CMs existed from birth or arose de novo. Third, selection bias might be present because of excluding patients with a follow-up of <5 years. Moreover, the pre-GKS period was necessarily shorter, which biases the results toward higher AHR at pre-GKS. Nonetheless, our study demonstrates the efficacy of relatively low-dose GKS by reporting the clinical course of s-BSCM patients who have been treated for >5 years previously. A
REFERENCES 1. Cantore G, Missori P, Santoro A. Cavernous angiomas of the brain stem. Intra-axial anatomical pitfalls and surgical strategies. Surg Neurol. 1999; 52:84-93. 2. Del Curling O Jr, Kelly DL Jr, Elster AD, Craven TE. An analysis of the natural history of cavernous angiomas. J Neurosurg. 1991;75:702-708.
prospective randomized series study with larger population should be performed to define the role of GKS in the management of BSCMs. CONCLUSION Although the optimal treatment strategy for s-BSCMs remains unclear, it seems apparent that GKS is safe and effective as a treatment modality of s-BSCMs. Our study demonstrated that the ARH remains low even 5 years after GKS and no radiation-induced toxicity was observed. Although there was no statistically significant increase, the AHR increases again from 1.48% to 4.64% in patients >5 years after GKS for s-BSCMs, which suggests that long-term survivors after GKS might require careful follow-up with close monitoring. Per these results, GKS might be a therapeutic alternative to surgical resection for s-BSCMs. Further prospective study is necessary to identify the natural history of s-BSCMs and optimal marginal radiation dose. ACKNOWLEDGMENTS The authors express special thanks of gratitude to Professor Jin Wook Kim and Professor Chang Suk Suh as the principal of Seoul National University Hospital, who provided the golden opportunity to work on this wonderful project. They also helped us with research and learning many new things. We are sincerely thankful.
3. Robinson JR, Awad IA, Little JR. Natural history of the cavernous angioma. J Neurosurg. 1991;75: 709-714. 4. Wang Z, Wang L, Zhu XD, Wu Q, Shi LF, Wang YJ, et al. [Brainstem cavernous malformation and its surgical treatment]. J Zhejiang Univ Med Sci. 2015;44:371-375. 5. Acerbi F, La Corte E, D’Incerti L, Ferroli P. Are there effective alternatives to surgery for the
WORLD NEUROSURGERY -: e1-e6, - 2018
treatment of symptomatic brainstem cavernous malformation? World Neurosurg. 2015;83:313-316. 6. Woodley-Cook J, Noel de Tilly L, MacDonald L. Brainstem cavernous malformation. BMJ Case Rep. 2013:2013. 7. Ding D, Starke RM, Crowley RW, Liu KC. Surgical approaches for symptomatic cerebral cavernous malformations of the thalamus and brainstem. J Cerebrovasc Endovasc Neurosurg. 2017;19:19-35.
www.WORLDNEUROSURGERY.org
e5
ORIGINAL ARTICLE KAWNGWOO PARK ET AL.
BRAINSTEM CAVERNOUS MALFORMATION BY GKS
8. Abla AA, Turner JD, Mitha AP, Lekovic G, Spetzler RF. Surgical approaches to brainstem cavernous malformations. Neurosurg Focus. 2010; 29:E8.
19. Kupersmith MJ, Kalish H, Epstein F, Yu G, Berenstein A, Woo H, et al. Natural history of brainstem cavernous malformations. Neurosurgery. 2001;48:47-53.
9. Kim DG, Choe WJ, Paek SH, Chung HT, Kim IH, Han DH. Radiosurgery of intracranial cavernous malformations. Acta Neurochir. 2002;144:869-878.
20. Ziyal IM, Ozgen T. Natural history of brainstem cavernous malformations. Neurosurgery. 2001;49: 1023-1024.
30. Gewirtz RJ, Steinberg GK, Crowley R, Levy RP. Pathological changes in surgically resected angiographically occult vascular malformations after radiation. Neurosurgery. 1998;42:738-742.
10. Aboukais R, Estrade L, Devos P, Blond S, Lejeune JP, Reyns N. Gamma Knife radiosurgery of brainstem cavernous malformations. Stereotact Funct Neurosurg. 2016;94:397-403.
21. Walcott BP, Choudhri O, Lawton MT. Brainstem cavernous malformations: natural history versus surgical management. J Clin Neurosci. 2016;32: 164-165.
31. Li D, Hao SY, Jia GJ, Wu Z, Zhang LW, Zhang JT. Hemorrhage risks and functional outcomes of untreated brainstem cavernous malformations. J Neurosurg. 2014;121:32-41.
11. Liu HB, Wang Y, Yang S, Gong FL, Xu YY, Wang W. Gamma Knife radiosurgery for brainstem cavernous malformations. Clin Neurol Neurosurg. 2016;151:55-60.
22. Xie MG, Li D, Guo FZ, Zhang LW, Zhang JT, Wu Z, et al. Brainstem cavernous malformations: surgical indications based on natural history and surgical outcomes. World Neurosurg. 2018;110: 55-63.
32. Garcia RM, Ivan ME, Lawton MT. Brainstem cavernous malformations: surgical results in 104 patients and a proposed grading system to predict neurological outcomes. Neurosurgery. 2015;76: 265-277.
23. Kida Y, Hasegawa T, Iwai Y, Shuto T, Satoh M, Kondoh T, et al. Radiosurgery for symptomatic cavernous malformations: a multi-institutional retrospective study in Japan. Surg Neurol Int. 2015; 6(Suppl 5):S249-S257.
33. Bradac O, Majovsky M, de Lacy P, Benes V. Surgery of brainstem cavernous malformations. Acta neurochirurgica. 2013;155:2079-2083.
12. Lee CC, Pan DH, Chung WY, Liu KD, Yang HC, Wu HM, et al. Brainstem cavernous malformations: the role of Gamma Knife surgery. J Neurosurg. 2012;117(Suppl):164-169. 13. Park SH, Hwang SK. Gamma Knife radiosurgery for symptomatic brainstem intra-axial cavernous malformations. World Neurosurg. 2013;80:e261-266. 14. Lu XY, Sun H, Xu JG, Li QY. Stereotactic radiosurgery of brainstem cavernous malformations: a systematic review and meta-analysis. J Neurosurg. 2014;120:982-987. 15. Lee SH, Choi HJ, Shin HS, Choi SK, Oh IH, Lim YJ. Gamma Knife radiosurgery for brainstem cavernous malformations: should a patient wait for the rebleed? Acta Neurochir. 2014;156:1937-1946. 16. Porter PJ, Willinsky RA, Harper W, Wallace MC. Cerebral cavernous malformations: natural history and prognosis after clinical deterioration with or without hemorrhage. J Neurosurg. 1997;87:190-197.
24. Monaco EA, Khan AA, Niranjan A, Kano H, Grandhi R, Kondziolka D, et al. Stereotactic radiosurgery for the treatment of symptomatic brainstem cavernous malformations. Neurosurg Focus. 2010;29:E11. 25. Kim BS, Yeon JY, Kim JS, Hong SC, Lee JI. Gamma Knife radiosurgery of the symptomatic brain stem cavernous angioma with low marginal dose. Clin Neurol Neurosurg. 2014;126:110-114. 26. Fuetsch M, El Majdoub F, Hoevels M, Muller RP, Sturm V, Maarouf M. Stereotactic LINAC radiosurgery for the treatment of brainstem cavernomas. Strahlenther Onkol. 2012;188:311-316.
17. Fritschi JA, Reulen HJ, Spetzler RF, Zabramski JM. Cavernous malformations of the brain stem. A review of 139 cases. Acta Neurochir. 1994;130:35-46.
27. Frischer JM, Gatterbauer B, Holzer S, Stavrou I, Gruber A, Novak K, et al. Microsurgery and radiosurgery for brainstem cavernomas: effective and complementary treatment options. World Neurosurg. 2014;81:520-528.
18. Horne MA, Flemming KD, Su IC, Stapf C, Jeon JP, Li D, et al. Clinical course of untreated cerebral cavernous malformations: a meta-analysis of individual patient data. Lancet Neurol. 2016;15: 166-173.
28. Ucuncu Kefeli A, Sengoz M, Peker S. Gamma knife radiosurgery for hemorrhagic brainstem cavernomas. Turk Neurosurg. 2017. https://doi.org/ 10.5137/1019-5149.JTN.21690-17.1. [Epub ahead of print].
e6
www.SCIENCEDIRECT.com
29. Kida Y. Radiosurgery for cavernous malformations in basal ganglia, thalamus and brainstem. Prog Neurol Surg. 2009;22:31-37.
34. Abla AA, Lekovic GP, Turner JD, de Oliveira JG, Porter R, Spetzler RF. Advances in the treatment and outcome of brainstem cavernous malformation surgery: a single-center case series of 300 surgically treated patients. Neurosurgery. 2011;68: 403-414. 35. Gross BA, Batjer HH, Awad IA, Bendok BR, Du R. Brainstem cavernous malformations: 1390 surgical cases from the literature. World Neurosurg. 2013;80: 89-93.
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 31 January 2018; accepted 23 May 2018 Citation: World Neurosurg. (2018). https://doi.org/10.1016/j.wneu.2018.05.164 Journal homepage: www.WORLDNEUROSURGERY.org Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2018 Elsevier Inc. All rights reserved.
WORLD NEUROSURGERY, https://doi.org/10.1016/j.wneu.2018.05.164
Long-Term Outcome of Gamma Knife Radiosurgery for Symptomatic Brainstem Cavernous Malformation Kawngwoo Park, Jin Wook Kim, Hyun-Tai Chung, Sun Ha Paek, Dong Gyu Kim
OBJECTIVE: We sought to analyze the long-term outcome of Gamma Knife radiosurgery (GKS) for symptomatic brainstem cavernous malformation (s-BSCM).
-
METHODS: Forty-five patients (14 males, 31 females) were treated with GKS for s-BSCM from January 1998 to December 2011. All patients were followed up for >5 years, and their clinical data were analyzed retrospectively. All patients had a history of symptomatic bleeding once or more before GKS. These hemorrhages caused neurologic deficits including cranial nerve deficits, hemiparesis, hemisensory deficits, spasticity, or chorea. The mean target volume of s-BSCM was 1.82 cm3, and the median prescribed marginal dose of radiation was 13 Gy. The mean clinical and imaging follow-up period was 9.31 years (range 5.1e19.4 years).
monitor patients closely to determine their subsequent treatment.
-
RESULTS: The 45 patients had 69 hemorrhagic events before GKS. During the follow-up period after GKS, 35 patients had no hemorrhagic event, 6 patients had 1 episode of symptomatic hemorrhage, and 4 patients had 2 episodes. The calculated annual hemorrhage rate was 40.06% at preGKS, 3.3% at 2 years after GKS, 1.48% at 5 years after GKS, and 4.64% at >5 years after GKS. In this study of 45 patients, symptomatic radiation-induced complications developed in only 1 patient (2.2%). No patients had died at the last follow-up.
-
CONCLUSIONS: GKS for s-BSCM is a safe and effective alternative to surgical resection for reducing the rate of recurrent hemorrhage. Because the annual hemorrhage rate increases >5 years after GKS, clinicians should
-
Key words Brainstem - Cavernous malformation - Gamma Knife radiosurgery - Symptomatic hemorrhage -
Abbreviations and Acronyms AHR: Annual hemorrhage rate BSCM: Brainstem cavernous malformation CM: Cavernous malformation GKS: Gamma Knife radiosurgery
INTRODUCTION
A
lthough brainstem cavernous malformation (BSCM) is rare,1,2 intracranial hemorrhage caused by BSCMs is sometimes life threatening. Although a wait-and-see strategy is commonly adopted because the annual hemorrhage rate (AHR) of asymptomatic cavernous malformations (CM) is low at 0.25%e0.7%/person-year,2,3 symptomatic BSCMs (s-BSCM) should be treated differently due to frequent rebleeding and high morbidity by hemorrhage.4-6 The current treatment for s-BSCMs is microsurgical resection7,8; however, this is more risky for surgical morbidity and mortality in the case of intraparenchymal BSCMs. In a previous report published in 2002, we showed that AHR of intracranial CMs could be reduced from 35.5% to 1.5% after Gamma Knife radiosurgery (GKS) with a mean follow-up period of 38.3 months (range 21e67 months).9 Recently, several reports showed that GKS has played an important role in treating deeply seated BSCMs, which are considered to have a high complication rate.10-13 In meta-analysis of radiosurgery for BSCMs, radiosurgery has shown that the AHR can be lowered from 4%e121.8% to 4.3%e12.5% and further down to 0%e3.6% after 2 years of radiosurgery.14 Although several reports have confirmed that GKS is safe and effective in treating BSCMs,10,11,13,15 there is lack of clinical results with long-term follow-up of >2 years. The purpose of this study was to investigate the AHR and radiation-induced complications in
MRI: Magnetic resonance imaging s-BSCM: Symptomatic brainstem cavernous malformation Department of Neurosurgery, Seoul National University Hospital, Seoul, Republic of Korea To whom correspondence should be addressed: Jin Wook Kim, M.D. [E-mail: [email protected]] Citation: World Neurosurg. (2018). https://doi.org/10.1016/j.wneu.2018.05.164 Journal homepage: www.WORLDNEUROSURGERY.org Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2018 Elsevier Inc. All rights reserved.
WORLD NEUROSURGERY -: e1-e6, - 2018
www.WORLDNEUROSURGERY.org
e1
ORIGINAL ARTICLE KAWNGWOO PARK ET AL.
BRAINSTEM CAVERNOUS MALFORMATION BY GKS
patients with s-BSCM who had at least 5 years of follow-up after GKS. MATERIALS AND METHODS
Table 1. Patient Characteristics in 45 Patients with at Least 5 Years of Follow-Up After Gamma Knife Surgery (GKS) for Brainstem Cavernous Malformations Characteristic
Patient Population A total of 87 patients underwent GKS for s-BSCMs in a single institution between January 1998 and December 2011. For the purpose of the current study, we selectively included consecutive patients who were followed for at least 5 years after GKS. The study was conducted in 45 patients with available clinical data and adequate radiologic images. The mean age in these patients was 36.6 years (range 3e67 years), and the predominant sex was female (68.9%). The locations of s-BSCMs were in the pons for 21 patients (46.7%), midbrain for 16 patients (35.5%), and medulla for 8 patients (17.8%). All patients were s-BSCM patients who experienced 1 hemorrhages before GKS. Before they underwent GKS, hemorrhage had occurred once in 26 CMs (57.8%), twice in 15 patients (33.3%), three times in 3 patients (6.7%), and 4 times in 1 patient (2.2%) (Table 1). In this study, episodes of hemorrhage were identified on the basis of the occurrence of newly developed neurologic symptoms associated with magnetic resonance imaging (MRI) findings of recently developed hemorrhage. All patients except 1 were treated with GKS after neurologic stabilization from the hemorrhagic event. Before treatment, neurologic symptoms occurred in 38 (84.4%) of 45 patients. Seven patients had improved neurologic symptoms before GKS. Of these patients, 29 of them (64.4%) had cranial nerve deficits, 8 of them (17.8%) had hemiparesis, 18 of them (40.0%) had hemisensory deficits, 1 of them (2.2%) had spasticity, and 2 of them (4.4%) had chorea. Gamma Knife Radiosurgery Stereotactic radiosurgery was performed using the Leksell Gamma Knife model B (Elekta AB, Stockholm, Sweden) until 2002, model C (Elekta AB) until 2009, and model Perfexion (Elekta AB) thereafter. The target volume was delineated on the T1-weighted gadolinium-enhanced transverse MRI except the hemosiderin rim. The mean target volume was 1.88 cm3 (range 0.1e13.5 cm3). The determination of GKS dose was related to the volume of the BSCMs, up to 16 Gy of marginal dose in the small lesion. Otherwise, the dose was reduced. The mean marginal dose was 13.0 Gy (range 9e16 Gy), and the mean maximum dose was 25.7 Gy (range 12e32 Gy). The number of isocenters ranged from 2 to 23 (mean 8.0), and the isodose line was 50%e80% (mean 50.0%) (Table 2). All patients were treated with single-session GKS. The mean delay between the last hemorrhage and GKS was 2.74 months (range 0.1e15.1 months). Follow-Up and Statistics After GKS, all patients underwent MRI studies and clinical evaluation at 3 months, 6 months, 1 year, and then annually. All of 45 patients were available for study with more than 5 years of followup period after GKS for s-BSCMs. The mean follow-up period was 9.31 years (range 5.1e19.4 years). We carefully monitored any clues suggesting hemorrhage including new foci of high signal intensity on T1-weighted MRI, volume expansion of irradiated lesions, and edematous changes revealed on T2-weighted MRI. The AHR was
e2
www.SCIENCEDIRECT.com
Number (%)
Age (mean SD) (years, range)
36.6 16.6 (3e67)
Female-to-male ratio (% female)
31/14 (68.9%)
Location Midbrain
16 (35.5%)
Pons
21 (46.7%)
Medulla
8 (17.8%)
Number of pre-GKS hemorrhagic events 1
26 (57.8%)
2
15 (33.3%)
3
3 (6.7%)
4
1 (2.2%)
Patients with neurologic deficit before GKS Present
38 (84.4%)
Absent
7 (15.6%)
Surgical resection before GKS
3 (6.7%)
SD, standard deviation.
calculated by dividing the total number of hemorrhages in all patients by the total number of patient-years for which they were observed. The AHR was compared before and after GKS using the chisquare test. We also analyzed for variables that might affect the rate of rebleeding of s-BSCM, such as location, sex, age at presentation, mass size, and irradiated marginal dose, using Cox regression analysis. The statistical analysis was performed using SPSS (version 22.0; IBM Corporation, Armonk, New York, USA), and the level of statistical significance was set at P < 0.05. RESULT Pre-GKS Hemorrhage Rate We calculated the pre-GKS hemorrhage rate in 45 patients who experienced at least 2 bleeding episodes. The pre-GKS observation period extended from the time of the patient’s first symptomatic image-documented hemorrhage to the time of GKS. A total of 59.9 patient-years were recorded. There were 69 hemorrhagic events during this period. The date of the first hemorrhage is the date of diagnosis. Therefore the first hemorrhage was not taken into account in the number of events. After exclusion of the first hemorrhage, the calculated AHR was 40.06% (95% confidence interval, 37.86e42.26) (24 events in 59.9 patient-years). PostLGamma Knife Surgery Hemorrhage Rate The observation period following GKS was defined as the time from treatment until the most recent clinical follow-up. Thus the mean follow-up period after GKS was 9.31 years (range 5.1e19.4 years),
WORLD NEUROSURGERY, https://doi.org/10.1016/j.wneu.2018.05.164
ORIGINAL ARTICLE KAWNGWOO PARK ET AL.
BRAINSTEM CAVERNOUS MALFORMATION BY GKS
Table 2. Gamma Knife Surgery Parameters for Patients with Brainstem Cavernous Malformation Parameter
Mean (Range)
Target volume (cm3)
1.8 (0.1e13.5)
Margin dose (Gy)
13.0 (9e16)
Max dose (Gy)
25.7 (18e32)
Isodose level
50.0 (50e80)
Number of shots
8.0 (2e23)
with an overall observation period of 418.9 person-years. None of the patients died during the follow-up. Fourteen hemorrhagic events in 10 patients were documented during this period. Of these hemorrhages, 3 events occurred in 3 patients during the first 2 years after GKS, from which the AHR of 3.33% was calculated (3 hemorrhages/ 90 person-years). And the AHR at 5 years after GKS was calculated to be 1.48% (two hemorrhages/135 person-years) on the basis of 2 events in 2 patients. After >5 years of follow-up, 9 hemorrhages in 5 patients were identified during 193.9 person-years, giving the AHR of 4.64% (95% confidence interval 2.01e7.27). Of the 5 patients who had the hemorrhagic event after 5 years of GKS, 4 patients had 2 events and 1 patient underwent 1 event during the follow-up period. However, this increase was not statistically significant. Statistical analysis revealed that the risk of BSCM hemorrhages was significantly reduced in the initial 2 years after GKS (P < 0.01), as shown in Figure 1. One representative case is shown in Figure 2.
Predictable Factor Associated with Rebleeding Although clinical factors such as age at presentation, sex, mass size, locations, and GKS dose could influence hemorrhage, we could not identify any correlation between the postulated risk factors and the incidence of rebleeding. Univariate analysis using the Cox regression proportional-hazard model did not reveal significant associations between rebleeding after GKS and any factor including age at presentation (P ¼ 0.55), sex (O ¼ 0.44), GKS dose (P ¼ 0.31), and mass size (P ¼ 0.97). When we compared the AHRs for marginal dose <13 Gy and >14 Gy by calculating the 95% confidence interval, there was no significant difference.
Figure 1. Annual hemorrhage rate following Gamma Knife radiosurgery.
WORLD NEUROSURGERY -: e1-e6, - 2018
Clinical Outcomes and Radiation-Induced Complication Of the 38 patients with pre-GKS neurologic symptoms, 25 of them (65.8%) had improved symptoms after GKS for BSCM. In 12 patients, there was no improvement in their neurologic deficits even after GKS and the symptoms of 1 patient deteriorated because of edema after GKS (Table 3). No patients died during the last follow-up period. The patient who had worsened neurologic symptoms after GKS recovered after steroid treatment for 1 month. The volume of the BSCMs before and after the treatment was measured on MRI using the GammaPlan treatment planning software (version 11, Elekta AB, Stockholm, Sweden). We defined a significant mass reduction or increment as change in the total volume of >20% from the baseline. In all patients, follow-up MRI was available. Mass shrinkage occurred in 32 patients (71.1%), and it was stationary in 13 patients (28.9%). No patient showed a mass increment in the latest follow-up images (Table 3). DISCUSSION BSCM is known to be associated with higher rates of bleeding and permanent neurologic deficits than other CMs because of its critical location.16,17 Additionally, recent meta-analysis reported higher rates of rebleeding in s-BSCM than in other CMs.18 In a meta-analysis of 1620 patients with CMs by Horne et al,18 an estimated 5-year rebleeding rate of s-BSCM was 30.8% and the risk of developing a recurrent hemorrhage or new neurologic deficit was reported as 50.7%. Although the rebleeding rate by natural course of BSCMs is low and the incidence of significant morbidity is reported to be 8%,19 s-BSCMs should be considered critical disorders that warrant aggressive treatment, even if conservative treatment with close observation is another therapeutic alternative. Furthermore, the natural history of s-BSCMs is considered completely different from asymptomatic lesions, as frequent hemorrhages or neurologic deteriorations occur after the first event.19,20 On the basis of this information, several reports have suggested the need for active treatment rather than a wait-and-see strategy.13,21-23 Although the optimal treatment strategy for s-BSCMs remains controversial, surgical resection is still considered the first treatment option for BSCMs because of improvement in microsurgery and other advances, such as intraoperative neuronavigation, intraoperative neuromonitoring, and postoperative care techniques. However, surgical resection of BSCMs often carries appreciable morbidity and mortality including hemiparesis, paresthesia, and cranial nerve dysfunction. Because of this high rate of treatment-related complications, GKS has arisen as an alternative to surgical resection for BSCMs. Its use to treat BSCMs over the past decade has demonstrated that GKS is an effective treatment option for patients with BSCMs, especially symptomatic brainstem intraparenchymal CMs.11,13,14 Several researchers have reported a significant reduction in AHR after GKS for patients with BSCMs.10-13,24,25 They demonstrated that AHR continued to decline in the first 2 years after GKS and thereafter (Table 4). Our results are consistent with those previously reported. The notable feature of our study is that we reported long-term follow-up of the patient with s-BSCM after GKS. Our results show that the AHR by s-BSCMs decreased from 40.06% pre-GKS to 3.33% 2 years and 1.48% 5 years after GKS,
www.WORLDNEUROSURGERY.org
e3
ORIGINAL ARTICLE KAWNGWOO PARK ET AL.
BRAINSTEM CAVERNOUS MALFORMATION BY GKS
Figure 2. A 48-year-old man, with no prior history of comorbidities, presented with acute onset of headache associated with a left hemiparesis and gait disturbance. Brain magnetic resonance imaging (MRI) showed a cavernous malformation of 13.5 cm3 located in the midbrain (A). Gamma Knife surgery (GKS) was performed with a marginal radiation dose of 13 Gy
and the decrease remained significant up to 5 years after GKS. However, the AHR increased again to 4.64% at >5 years of GKS, which implies that additional treatment (e.g., repeat radiosurgery) might be considered. Although we did not show a statistically significant increase in >5 years of AHR, the frequency of rebleeding seemed to be slightly increased compared with 5 years before GKS. More specifically, rebleeding occurred in 5 patients with 9 rebleeding events, of which 4 patients had 2 rebleeding episodes each. Conclusively, whether this increase in rebleeding was due to treatment failure or recurrence of BSCM was unknown. However, several reports in the literature indicated that results after long-term observation of radiosurgery for BSCMs did not show consistency with these increase. Kida et al29 reported 63 BSCMs at mean follow-up of 55 months and only 2 bleeds after 5 years of GKS. Monaco et al24 reported that only 3 bleeds were observed in 68 BSCM patients with a mean follow-up of 5.2 years. Frischer et al27 also showed a low AHR of 0.61% (1 hemorrhage/163 person-years) over a long-term follow-up of median 5.2 years in 38 patients who were diagnosed with BSCM and underwent radiosurgery. In contrast, Fuetsch et al26 reported a median follow-up of 7.1 years for 14 patients with AHR of 4.8% (4 hemorrhages/82.8 person-years). Although Fuetsch’s study was limited in a relatively small number of patients and treatment with LINAC-based radiosurgery, it is reasonable that AHR may be around 5% after long-term follow-up after radiosurgery. Reports of the histopathology of CM after radiosurgery indicate that most vessels were obliterated by fibrinoid necrosis, endothelial cell destruction, and marked fibrosis in the connective tissue stroma.24,30 In this regard, it is possible that the AHR increases again at >5 years after the GKS because of recanalization. Shrinkage of the lesion after GKS was observed in 71.1% of the patients, though it is not clear whether this change was really induced by radiation or absorption of hemorrhage. The majority of patients (65.8%) showed neurologic improvement at the last follow-up, and none showed worsening after GKS. Therefore the overall outcome after GKS in our study was favorable and compatible with that reported elsewhere (see Table 4). The strengths of our study include the long-term follow-up (median 111.7 months) after GKS for BSCMs. Although the AHR at >5
e4
www.SCIENCEDIRECT.com
to the 50% isodose line. After GKS, the patient’s neurologic symptoms disappeared completely. Serial T1-weighted MRI with contrast media demonstrated that the BSCM remained controlled at 3 months (B), 13 months (C), 25 months (D), and 119 months (E) after GKS.
years rises to 4.64%, these figures remain notably lower than the AHR of CMs, which is 18.7%.31 Interestingly, the precise longterm outcomes of CMs, especially BSCMs, are largely unknown including the latent risk of hemorrhage, adverse effects, and delayed neurologic events. Our results showed that AHR is still low even 5 years after GKS for BSCMs, although given that the AHR increased again to 4.64% at >5 years after GKS, long-term survivors of BSCMs might require careful follow-up with close monitoring. Although the optimal marginal radiation dose for BSCMs is still unclear, Lee et al12 and Kim et al25 suggested that a marginal dose as low as 11 Gy was sufficient to reduce the radiation-related complications of BSCMs. This dose was effective in the reduction of the AHR to 2.4%3.8% at 2 years after GKS and in improving neurologic symptoms, while the rate of radiationinduced complications was 2.32%.12,25 Liu et al11 also reported similar clinical results with a low marginal dose of 11.9 Gy. However, the mean marginal dose in our study was 13.0 Gy, and there was no difference in comparing and analyzing >13 Gy. To sum up, a therapeutic radiation dose for s-BSCMs seems to be sufficient to 11e13 Gy without radiation toxicity.
Table 3. Clinical Outcomes After Gamma Knife Surgery for Brainstem Cavernous Malformation Variable
Number of Patients (%)
Neurologic deficit (n ¼ 38) Improved
25 (65.8%)
Sustained
12 (31.6%)
Worsen
1 (2.6%)
Radiologic finding (n ¼ 45) Decrease
32 (71.1%)
Stable
13 (28.9%)
Increase
0
WORLD NEUROSURGERY, https://doi.org/10.1016/j.wneu.2018.05.164
ORIGINAL ARTICLE KAWNGWOO PARK ET AL.
BRAINSTEM CAVERNOUS MALFORMATION BY GKS
Table 4. Literature Summary of Main Studies on Brainstem Cavernous Malformation Treated with Stereotactic Radiosurgery Number of Patients
Mean Marginal Dose, Gy
Mean Follow-Up Months
Pre-GKS AHR, %
Post-GKS AHR, % (Before 2 Years / After 2 Years)
Complication Rate, %
Mortality Rate, %
Monaco et al. 201024
68
15.8
62.4
32.4
8.2 / 1.4
1.5
0
Lee et al. 201212
49
11
40.6
31.3
4.3 / 3.6
2.0
0
Fuetsch et al. 2012
14
13.9*
85.2*
12.5
4.8y
25
0
Park et al. 201313
20
13
38.9
39.5
8.2 / 0
5.0
0
39
13
43
33.6
8.1 / 2.4
0
0
Series
26
Kim et al. 201425 Frischer et al. 2014
38
12*
62.4*
47.6
2.6 / 0.6
—
0
Liu et al. 201611
43
11.9
36
28.0
3.9 / 1.9
2.3
0
Ucuncu Kefeli et al. 201728
81
11.8
50
55.7
0.87y
0
0
Present study
45
13
111.7
40.1
3.3 / 1.5 / 4.6y
2.2
0
27
GKS, Gamma Knife radiosurgery; AHR, annual hemorrhage rate. *Median values. y5 years after GKS.
Indubitably, GKS treatment for BSCMs shows good clinical outcomes compared with the results of surgical resection for BSCMs.32-34 Although complete removal of BSCMs may be possible through surgical resection, there is always the risk of surgical morbidity and mortality. A retrospective study of 1390 surgical cases from the literature showed that the rates of early postoperative morbidity and long-term worsening were 45% and 15%, respectively.35 However, most analyses of GKS report <5% of complication rates and 0% of mortality rates. Furthermore, not all patients can be treated surgically and some patients can only be operated on selectively including those with acute extraparenchymal hemorrhage, exophytic lesion, or mass effect caused by hemorrhages.7,8 Considering that surgical resection of BSCMs remains difficult, GKS could be contemplated as an easier and more accessible treatment options for the clinician. Our study has some limitations. First, it was not a prospective trial. Therefore selection bias could not be ruled out in this study. Second, we did not have information regarding the number of untreated patients and natural history of BSCMs, so we could not determine whether the CMs existed from birth or arose de novo. Third, selection bias might be present because of excluding patients with a follow-up of <5 years. Moreover, the pre-GKS period was necessarily shorter, which biases the results toward higher AHR at pre-GKS. Nonetheless, our study demonstrates the efficacy of relatively low-dose GKS by reporting the clinical course of s-BSCM patients who have been treated for >5 years previously. A
REFERENCES 1. Cantore G, Missori P, Santoro A. Cavernous angiomas of the brain stem. Intra-axial anatomical pitfalls and surgical strategies. Surg Neurol. 1999; 52:84-93. 2. Del Curling O Jr, Kelly DL Jr, Elster AD, Craven TE. An analysis of the natural history of cavernous angiomas. J Neurosurg. 1991;75:702-708.
prospective randomized series study with larger population should be performed to define the role of GKS in the management of BSCMs. CONCLUSION Although the optimal treatment strategy for s-BSCMs remains unclear, it seems apparent that GKS is safe and effective as a treatment modality of s-BSCMs. Our study demonstrated that the ARH remains low even 5 years after GKS and no radiation-induced toxicity was observed. Although there was no statistically significant increase, the AHR increases again from 1.48% to 4.64% in patients >5 years after GKS for s-BSCMs, which suggests that long-term survivors after GKS might require careful follow-up with close monitoring. Per these results, GKS might be a therapeutic alternative to surgical resection for s-BSCMs. Further prospective study is necessary to identify the natural history of s-BSCMs and optimal marginal radiation dose. ACKNOWLEDGMENTS The authors express special thanks of gratitude to Professor Jin Wook Kim and Professor Chang Suk Suh as the principal of Seoul National University Hospital, who provided the golden opportunity to work on this wonderful project. They also helped us with research and learning many new things. We are sincerely thankful.
3. Robinson JR, Awad IA, Little JR. Natural history of the cavernous angioma. J Neurosurg. 1991;75: 709-714. 4. Wang Z, Wang L, Zhu XD, Wu Q, Shi LF, Wang YJ, et al. [Brainstem cavernous malformation and its surgical treatment]. J Zhejiang Univ Med Sci. 2015;44:371-375. 5. Acerbi F, La Corte E, D’Incerti L, Ferroli P. Are there effective alternatives to surgery for the
WORLD NEUROSURGERY -: e1-e6, - 2018
treatment of symptomatic brainstem cavernous malformation? World Neurosurg. 2015;83:313-316. 6. Woodley-Cook J, Noel de Tilly L, MacDonald L. Brainstem cavernous malformation. BMJ Case Rep. 2013:2013. 7. Ding D, Starke RM, Crowley RW, Liu KC. Surgical approaches for symptomatic cerebral cavernous malformations of the thalamus and brainstem. J Cerebrovasc Endovasc Neurosurg. 2017;19:19-35.
www.WORLDNEUROSURGERY.org
e5
ORIGINAL ARTICLE KAWNGWOO PARK ET AL.
BRAINSTEM CAVERNOUS MALFORMATION BY GKS
8. Abla AA, Turner JD, Mitha AP, Lekovic G, Spetzler RF. Surgical approaches to brainstem cavernous malformations. Neurosurg Focus. 2010; 29:E8.
19. Kupersmith MJ, Kalish H, Epstein F, Yu G, Berenstein A, Woo H, et al. Natural history of brainstem cavernous malformations. Neurosurgery. 2001;48:47-53.
9. Kim DG, Choe WJ, Paek SH, Chung HT, Kim IH, Han DH. Radiosurgery of intracranial cavernous malformations. Acta Neurochir. 2002;144:869-878.
20. Ziyal IM, Ozgen T. Natural history of brainstem cavernous malformations. Neurosurgery. 2001;49: 1023-1024.
30. Gewirtz RJ, Steinberg GK, Crowley R, Levy RP. Pathological changes in surgically resected angiographically occult vascular malformations after radiation. Neurosurgery. 1998;42:738-742.
10. Aboukais R, Estrade L, Devos P, Blond S, Lejeune JP, Reyns N. Gamma Knife radiosurgery of brainstem cavernous malformations. Stereotact Funct Neurosurg. 2016;94:397-403.
21. Walcott BP, Choudhri O, Lawton MT. Brainstem cavernous malformations: natural history versus surgical management. J Clin Neurosci. 2016;32: 164-165.
31. Li D, Hao SY, Jia GJ, Wu Z, Zhang LW, Zhang JT. Hemorrhage risks and functional outcomes of untreated brainstem cavernous malformations. J Neurosurg. 2014;121:32-41.
11. Liu HB, Wang Y, Yang S, Gong FL, Xu YY, Wang W. Gamma Knife radiosurgery for brainstem cavernous malformations. Clin Neurol Neurosurg. 2016;151:55-60.
22. Xie MG, Li D, Guo FZ, Zhang LW, Zhang JT, Wu Z, et al. Brainstem cavernous malformations: surgical indications based on natural history and surgical outcomes. World Neurosurg. 2018;110: 55-63.
32. Garcia RM, Ivan ME, Lawton MT. Brainstem cavernous malformations: surgical results in 104 patients and a proposed grading system to predict neurological outcomes. Neurosurgery. 2015;76: 265-277.
23. Kida Y, Hasegawa T, Iwai Y, Shuto T, Satoh M, Kondoh T, et al. Radiosurgery for symptomatic cavernous malformations: a multi-institutional retrospective study in Japan. Surg Neurol Int. 2015; 6(Suppl 5):S249-S257.
33. Bradac O, Majovsky M, de Lacy P, Benes V. Surgery of brainstem cavernous malformations. Acta neurochirurgica. 2013;155:2079-2083.
12. Lee CC, Pan DH, Chung WY, Liu KD, Yang HC, Wu HM, et al. Brainstem cavernous malformations: the role of Gamma Knife surgery. J Neurosurg. 2012;117(Suppl):164-169. 13. Park SH, Hwang SK. Gamma Knife radiosurgery for symptomatic brainstem intra-axial cavernous malformations. World Neurosurg. 2013;80:e261-266. 14. Lu XY, Sun H, Xu JG, Li QY. Stereotactic radiosurgery of brainstem cavernous malformations: a systematic review and meta-analysis. J Neurosurg. 2014;120:982-987. 15. Lee SH, Choi HJ, Shin HS, Choi SK, Oh IH, Lim YJ. Gamma Knife radiosurgery for brainstem cavernous malformations: should a patient wait for the rebleed? Acta Neurochir. 2014;156:1937-1946. 16. Porter PJ, Willinsky RA, Harper W, Wallace MC. Cerebral cavernous malformations: natural history and prognosis after clinical deterioration with or without hemorrhage. J Neurosurg. 1997;87:190-197.
24. Monaco EA, Khan AA, Niranjan A, Kano H, Grandhi R, Kondziolka D, et al. Stereotactic radiosurgery for the treatment of symptomatic brainstem cavernous malformations. Neurosurg Focus. 2010;29:E11. 25. Kim BS, Yeon JY, Kim JS, Hong SC, Lee JI. Gamma Knife radiosurgery of the symptomatic brain stem cavernous angioma with low marginal dose. Clin Neurol Neurosurg. 2014;126:110-114. 26. Fuetsch M, El Majdoub F, Hoevels M, Muller RP, Sturm V, Maarouf M. Stereotactic LINAC radiosurgery for the treatment of brainstem cavernomas. Strahlenther Onkol. 2012;188:311-316.
17. Fritschi JA, Reulen HJ, Spetzler RF, Zabramski JM. Cavernous malformations of the brain stem. A review of 139 cases. Acta Neurochir. 1994;130:35-46.
27. Frischer JM, Gatterbauer B, Holzer S, Stavrou I, Gruber A, Novak K, et al. Microsurgery and radiosurgery for brainstem cavernomas: effective and complementary treatment options. World Neurosurg. 2014;81:520-528.
18. Horne MA, Flemming KD, Su IC, Stapf C, Jeon JP, Li D, et al. Clinical course of untreated cerebral cavernous malformations: a meta-analysis of individual patient data. Lancet Neurol. 2016;15: 166-173.
28. Ucuncu Kefeli A, Sengoz M, Peker S. Gamma knife radiosurgery for hemorrhagic brainstem cavernomas. Turk Neurosurg. 2017. https://doi.org/ 10.5137/1019-5149.JTN.21690-17.1. [Epub ahead of print].
e6
www.SCIENCEDIRECT.com
29. Kida Y. Radiosurgery for cavernous malformations in basal ganglia, thalamus and brainstem. Prog Neurol Surg. 2009;22:31-37.
34. Abla AA, Lekovic GP, Turner JD, de Oliveira JG, Porter R, Spetzler RF. Advances in the treatment and outcome of brainstem cavernous malformation surgery: a single-center case series of 300 surgically treated patients. Neurosurgery. 2011;68: 403-414. 35. Gross BA, Batjer HH, Awad IA, Bendok BR, Du R. Brainstem cavernous malformations: 1390 surgical cases from the literature. World Neurosurg. 2013;80: 89-93.
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 31 January 2018; accepted 23 May 2018 Citation: World Neurosurg. (2018). https://doi.org/10.1016/j.wneu.2018.05.164 Journal homepage: www.WORLDNEUROSURGERY.org Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2018 Elsevier Inc. All rights reserved.
WORLD NEUROSURGERY, https://doi.org/10.1016/j.wneu.2018.05.164