The endoscopic endonasal approach is not superior to the microscopic transcranial approach for anterior skull base meningiomas—a meta-analysis

Object In the past decade, the endonasal transsphenoidal approach (eTSA) has become an alternative to the microsurgical transcranial approach (mTCA) for tuberculum sellae meningiomas (TSMs) and olfactory groove meningiomas (OGMs). The aim of this meta-analysis was to evaluate which approach offered the best surgical outcomes. Methods A systematic review of the literature from 2004 and meta-analysis were conducted in accordance with the PRISMA guidelines. Pooled incidence was calculated for gross total resection (GTR), visual improvement, cerebrospinal fluid (CSF) leak, intraoperative arterial injury, and mortality, comparing eTSA and mTCA, with p-interaction values. Results Of 1684 studies, 64 case series were included in the meta-analysis. Using the fixed-effects model, the GTR rate was significantly higher among mTCA patients for OGM (eTSA: 70.9% vs. mTCA: 88.5%, p-interaction < 0.01), but not significantly higher for TSM (eTSA: 83.0% vs. mTCA: 85.8%, p-interaction = 0.34). Despite considerable heterogeneity, visual improvement was higher for eTSA than mTCA for TSM (p-interaction < 0.01), but not for OGM (p-interaction = 0.33). CSF leak was significantly higher among eTSA patients for both OGM (eTSA: 25.1% vs. mTCA: 10.5%, p-interaction < 0.01) and TSM (eTSA: 19.3%, vs. mTCA: 5.81%, p-interaction < 0.01). Intraoperative arterial injury was higher among eTSA (4.89%) than mTCA patients (1.86%) for TSM (p-interaction = 0.03), but not for OGM resection (p-interaction = 0.10). Mortality was not significantly different between eTSA and mTCA patients for both TSM (p-interaction = 0.14) and OGM resection (p-interaction = 0.88). Random-effect models yielded similar results. Conclusion In this meta-analysis, eTSA was not shown to be superior to mTCA for resection of both OGMs and TSMs. Electronic supplementary material The online version of this article (10.1007/s00701-017-3390-y) contains supplementary material, which is available to authorized users.

Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00701-017-3390-y) contains supplementary material, which is available to authorized users.

Introduction
The mainstay of treatment for tuberculum sellae meningiomas (TSMs) and olfactory groove meningiomas (OGMs) is surgery. Goals of surgery include obtaining tissue for histopathological diagnosis and relieving pressure caused by the tumor on neighboring structures such as the olfactory nerves, anterior cerebral arteries, optic nerves, and pituitary gland. At the same time, these structures are very susceptible to manipulation, and damage to these structures can lead to great morbidity [51].
Traditionally, TSMs and OGMs are resected using a microscopic transcranial approach (mTCA). Various approaches have been described, including interhemispheric, pterional, bifrontal, and subfrontal mTCA [1, 2, 5-7, 9, 47, 51, 56, 64, 70]. In the last decade, however, as a result of the evolution of endoscopic surgery for pituitary adenomas, these meningiomas have been increasingly resected using an endonasal endoscopic transsphenoidal approach (eTSA), as first described by Jho et al. in 2004 [38]. Although the endoscopic approach is generally viewed as less invasive, with some studies suggesting that eTSA caused fewer postoperative changes on magnetic resonance imaging (MRI) compared to mTCA possibly indicating less manipulation [22], it has been suggested that eTSA results in higher rates of CSF leaks and potentially different outcomes (e.g., less GTR) [18,42]. However, a direct comparison between eTSA and mTCA is currently lacking. Therefore, the aim of this systematic review and meta-analysis was to evaluate which approach (eTSA vs. mTCA) offers the best surgical outcomes.

Search strategy and paper selection
To identify studies reporting on outcomes of surgically treated TSMs and OGMs, a systematic review of the literature was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement [54]. Both PubMed and Embase databases were searched on September 12, 2016. Because the outcomes of endoscopic surgery were first described in 2004 and microscopic resection has seen a continuous improvement, only articles published in 2004 or later were included [26,38]. The search strategy was drawn up using the keywords Bmeningioma,^Btuberculum sellae,^Bolfactory groove,^a nd synonyms (Supplementary Table 1). Duplicates were removed using Endnote X7. 5.
Two authors (IM and TO) independently screened the titles and abstracts of the articles for papers reporting surgical outcomes of resected OGMs and TSMs. After full-text screening, articles that reported outcomes of surgically treated OGMs and TSMs were included. Case reports, commentaries, congress abstracts, reviews, animal studies, studies describing an endoscopically assisted approach, studies reporting on the use of a keyhole approach, studies in pediatric patients (< 18 years old), re-operations, and cadaveric studies were excluded. Only literature in English and Dutch was reviewed. Discrepancies in selection were sorted out by discussion, and a senior author (MB) was consulted if the discrepancy could not be solved by discussion.

Data extraction
The following study characteristics were extracted from the full text of the selected studies: study design, number of patients, follow-up duration, study geographic location, percentage of WHO II and III meningiomas, percentage of males in the study population, mean age of the study population, and surgery type (transcranial or endoscopic endonasal). The following outcomes were extracted: number of patients with GTR (defined as Simpson grade I or II), number of patients with preoperative visual problems, number of patients with improved vision post-surgery, postoperative cerebrospinal fluid (CSF) leakage, number of intraoperative arterial injury, and all-cause mortality (within 30 days after resection). Furthermore, perioperative blood loss, hospital length of stay, and operation length were extracted. Study quality was assessed with the adjusted Newcastle Ottawa Scale (NOS) [80]. If the study in question was a case series, comparability was ignored.

Meta-analysis
Comprehensive meta-analysis (CMA) version 3 was used to calculate the separate overall incidence using the fixed-effect model with the inverse variance method and the random-effect model according to the method of DerSimonian and Laird [27] in the endonasal endoscopic and transcranial approach for the following variables: GTR, arterial injury, visual improvement, CSF leakage, and mortality. A resulting pinteraction value from the subgroup analysis comparing eTSA and mTCA was considered significant if <0.05. Study heterogeneity was assessed by calculating I-squared and Pvalues from the Cochrane Q test. Publication bias was assessed with Begg's tests and was corrected for by a trimand-fill method. Finally, a meta-regression was conducted on each of age, gender (dichotomized by male percentage below/ above the median category), and continent (North America as the reference) for eTSA and mTCA separately. For visual outcomes, only continent could be assessed as a source of heterogeneity as not all patients presented with visual problems and baseline characteristics from this subgroup were not available. A subgroup analysis for tumor size and grade was not possible because of great variance in reporting.

Random-effect models
For all the above-mentioned results, the random-effect models yielded similar results (Tables 3 and 4).

Blood loss, operating time, and length of stay in hospital
For blood loss, operating time, and length of hospital stay, a quantitative meta-analysis was not feasible because of the paucity of studies reporting them; hence, these few studies were systematically reviewed. In TSM, mean blood loss ranged from 448 to 970 ml in three studies describing mTCA compared to 200 to 617 ml for eTSA [21,30,41,47]. The mean operating time ranged from 375 to 444 min for eTSA in two studies and from 116 to 426 min for mTCA in four studies [21,23,41,47,69]. Hospital length of stay ranged from 6 to 21 days in one study in patients treated by an eTSA [23].
For OGM, blood loss was only reported in one case series in patients operated with an interhemispheric approach (mean: 570.9 ml, SD: 442) [47]. The mean hospital length of stay for eTSA ranged from 11 to 13.5 days in two studies [9,13] compared to 8.5 to 18 days for mTCA [7,22,24,78]. Of these studies, one described the mean length of stay in both approaches, with a mean length of stay of 11 days for eTSA compared to 8.5 days in mTCA (p = 0.54) [22]. Operating time ranged from 6 to 10 h in one study reporting outcomes from eTSA [24]. In a study examining patients with an interhemispheric approach, the mean operating time was 209 min (standard deviation: 103) [47].

Discussion
In this meta-analysis, eTSA was not shown to be superior to mTCA for resection of both OGMs and TSMs. Only in patients with preoperative visual deficits due to TSM, eTSA seems superior to mTCA, but with great hetereogeneity. In patients with TSM, eTSA resulted in higher rates of visual improvement, similar rates of GTR, and more CSF leaks and intraoperative arterial injury, while in patients with OGM, results of both techniques were similar for visual improvement and intraoperative arterial injury, but worse in patients operated with eTSA for GTR and CSF leaks. There seems to be no substantial difference in perioperative blood loss, operating time, or length of hospital stay between the two approaches. There was no substantial difference between incidence rates in the fixed-and random-effect models. This could be explained by a relative lack of difference between the study populations in the studies, which could have been implicated in the case of a difference between the models. However, mTCA was associated with considerable heterogeneity for outcomes visual improvement in TSMs and CSF leak for OGMs, which could reflect a relatively greater inter-study variability for these outcomes.
Although no significant difference was identified in GTR rate for TSM, mTCA resulted in higher GTR rates in OGM. As OGMs are located more anteriorly than TSM, an extended eTSA approach is needed for OGM, which requires more extensive drilling of the anterior skull base and a potential suboptimal view because of the angle of the scope. However, it should also be noted that GTR was not always the primary the goal of surgery (e.g., the goal could be preserving vision) [43,72]. Furthermore, many other factors seem to influence GTR rate. One factor may be the learning curve associated with eTSA, as seen with pituitary adenoma resection [10,14,46]. Also, tumor factors such as large size and vascular enhancement can significantly lower the GTR rate for eTSA, as seen in one study in TSM [43]. Furthermore, presence of a Bcortical cuff^(a layer of brain between the tumor capsule and cerebral vessels) on MRI was associated with more GTR in OGM [40].
For visual improvement, it remains to be determined whether eTSA is truly associated with more visual improvement than mTCA in TSM as correction for the heterogeneity among mTCA studies could not be done. Therefore, the difference witnessed may be insignificant as seen with OGM. Furthermore, as the variance in reporting of tumor size did not allow for it to be incorporated in a meta-regression, the TSMs in the eTSA group may be smaller compared to the mTCA group. However, regarding visual outcomes, one study looking at the mTCA approach suggests that visual outcomes are associated with age and duration of visual symptoms but not with actual tumor size [28]. For both OGM and TSM, eTSA was significantly associated with more CSF leakage. However, prophylactic lumbar drain placement varied greatly; in some studies, almost all patients were given a prophylactic preoperative lumbar drain, while in other studies none of the included patients were drained [8,24,30,35,40,44]. Also, the different studies used different reconstruction techniques (e.g., introduction of a vascularized flap and use of certain glues), although this caused no considerable heterogeneity among the studies [40,44,62]. Another factor in the postoperative CSF leakage rate may be the neurosurgeon's level experience. Although the difference was not significant, in a small number of patients, one group had two leaks in their first group of patients (n = 8) compared to none in the latter group (n = 12) [40]. Also, use of a vascularized flap for reconstruction of the skull base seems to bring the CSF leakage rate down considerably [40,43,62]. Still, this rate is considerably higher than the overall incidence calculated for mTCA. Further improvement with more sophisticated reconstruction techniques following eTSA may bring the rate of CSF leakage down to those reported for mTCA.
MTCA for TSM resulted in a significantly lower rate of intraoperative arterial injury compared to eTSA. However, this seems not to have caused a significant difference in mortality. Nevertheless, the relatively low number of patients treated with an eTSA may have caused a relatively low power, as the p-interaction value for mortality for TSM approaches significance (p = 0.14). A significant association between intraoperative arterial injury and eTSA was not seen in OGM; again, this may be explained by low power and the small number of studies, but also because of the anterior location of the tumor. Previously, two reviews have described a comparison between eTSA and mTCA for both TSM and OGM. The first review identified a higher GTR rate and less CSF leakage associated with mTCA for both OGM and TSM (p < 0.01 for both, using the chi-squared test and Fisher's exact test, respectively), which is similar to our findings except for the GTR rate for TSM [42]. A second review found significantly more visual improvement (p < 0.01) and CSF leakage (p < 0.01) for eTSA and no difference in mortality (p = 0.15) for TSM and OGM together, similar to our findings. eTSA was also found to be associated with a lower GTR rate (p < 0.01) compared to mTCA, which was only the case in OGM in this meta-analysis [71]. Finally, the authors of a metaanalysis for TSM found that eTSA was significantly associated with CSF leakage (OR: 3.9; 95% CI: 1.15-15.75, p < 0.05) and visual improvement (OR 1.5; 95% CI 1.18, 1.82, p < 0.05), which again is similar to our results [18].
Strengths of this study include an extensive review of the literature and evaluation of outcomes such as arterial injury, length of hospital stay, and blood loss. The use of both fixedand random-effect models, evaluation of heterogeneity between the included studies, and assessment of publication bias ensures a rigorous evaluation of outcomes with appropriate valuation of the results. All outcomes were also subjected to meta-regression for various study characteristics where possible to try to identify sources of heterogeneity between the studies.
There are several limitations of this meta-analysis. First, the decision to discard studies published before 2004 produces a limitation. The decision to do so was based on the assumption that also mTCA outcomes improve over time with continual innovation and that meningiomas were not reported to be resected with an eTSA before that time [26,38]. Regarding the included studies, only case series were identified, resulting in the inability of calculation overall odds ratios. There is probably also a great difference between the population of patients who were deemed eligible for an eTSA resection compared to those resected with mTCA because of the size, extension, and invasion of the tumors (confounding by indication). Furthermore, one could argue that only looking at perioperative outcomes may not be conclusive as especially recurrence happens during follow-up. However, as the GTR and World Health Organization (WHO) grade remain the main prognostic factors for predicting recurrence, opting for eTSA should be done with great caution as high-grade meningiomas may be harder to resect completely [59,74]. However, it was not possible to correct for meningioma size, which is unfortunate as very small meningiomas may show very different results. Furthermore, it was not possible to correct for WHO grade, which could theoretically alter the results [31]. Also, the choice of approach varied greatly among mTCA approach studies [1, 2, 5-7, 9, 47, 51, 56, 64, 70].
Indications for eTSA vary between groups. One group reported operating on all midline meningiomas regardless of size, extension, or configuration except for those tumors that extend from the anterior clinoid process [43]. It has also been suggested that if the tumor extends laterally over the internal carotid artery, chances of GTR are limited [61]. Others have suggested that larger tumors, tumors that extend laterally, involve vasculature, or are calcified are also lesser candidates [23,44]. Therefore, confounding by indication cannot be ruled out, especially since the patients in these studies were not randomized to either treatment. As a result, the exact indications and contraindications for eTSA remain to be determined.
Future studies should, therefore, focus on identifying clear indications for eTSA for OGM and TSM and its safety by direct comparison in a randomized study. Such a study should ideally be conducted in a research setting by experienced surgeons, as its safety has not been prospectively compared to mTCA and as both approaches seem to come with a considerable learning curve, which results in different outcomes [43]. Given the observation that younger patients seem to benefit more from eTSA compared to older patients (p = 0.02, n = 34), it is not unlikely that specific groups might benefit more from one of the approaches [39]. Probably, patients with relatively small (<3 cm) midline TSMs would probably be the best early candidates. These patients may benefit from a potential higher incidence of visual improvement postoperatively and the relative invasiveness of the eTSA approach. Further evaluation could be focused on characteristics such as size, a cortical cuff, and WHO grading to identify the best potential candidates for either approach [40]. However, due to the low incidence of TSMs and OGMs in general and the great variety in anatomical characteristics among them, this may be challenging. Therefore, other trial designs-e.g., a registry-should be considered when answering this question. Also, future improvement of the instruments used (e.g., 3D endoscopes or glues) may improve the results obtained by eTSA over time [33].

Conclusion
This meta-analysis indicates that the endoscopic transsphenoidal approach (eTSA) has not been shown to be superior to the microscopic transsphenoidal approach (mTCA) for either olfactory groove meningiomas (OGMs) or tuberculum sellae menigniomas (TSMs). More specifically, eTSA was associated with lower GTR rate for OGMs and higher rate of arterial injury for TSMs compared to mTCA. Furthermore, eTSA was associated with more CSF leaks in both OGMs and TSMs compared to mTCA. On the other hand, eTSA was associated with a higher rate of visual improvement postoperatively compared to mTCA in TSMs, which was not observed for OGMs. All conclusions should, however, be interpreted with caution because of the limitations of this study.