Critical appraisal of minimally invasive keyhole surgery for intracranial meningioma in a large case series.

BACKGROUND: Meningioma surgery has evolved over the last 20 years with increased use of minimally invasive approaches including the endoscopic endonasal route and endoscope-assisted and gravity-assisted transcranial approaches. As the "keyhole" concept remains controversial, we present detailed outcomes in a cohort series.
METHODS: Retrospective analysis was done for all patients undergoing meningioma removal at a tertiary brain tumor referral center from 2008-2021. Keyhole approaches were defined as: use of a minimally invasive "retractorless" approach for a given meningioma in which a traditional larger approach is often used instead. The surgical goal was maximal safe removal including conservative (subtotal) removal for some invasive locations. Primary outcomes were resection rates, complications, length of stay and Karnofsky Performance Scale (KPS). Secondary outcomes were endoscopy use, perioperative treatments, tumor control and acute MRI FLAIR/T2 changes to assess for brain manipulation and retraction injury.
RESULTS: Of 329 patients, keyhole approaches were utilized in 193(59%) patients (mean age 59±13; 30 (15.5%) had prior surgery) who underwent 213 operations; 205(96%) were skull base location. Approaches included: endoscopic endonasal (n = 74,35%), supraorbital (n = 73,34%), retromastoid (n = 38,18%), mini-pterional (n = 20,9%), suboccipital (n = 4,2%), and contralateral transfalcine (n = 4,2%). Primary outcomes: Gross total/near total (>90%) resection was achieved in 125(59%) (5% for petroclival, cavernous sinus/Meckel's cave, spheno-cavernous locations vs 77% for all other locations). Major complications included: permanent neurological worsening 12(6%), CSF leak 2(1%) meningitis 2(1%). There were no DVTs, PEs, MIs or 30-day mortality. Median LOS decreased from 3 to 2 days in the last 2 years; 94% were discharged to home with favorable 90-day KPS in 176(96%) patients. Secondary outcomes: Increased FLAIR/T2 changes were noted on POD#1/2 MRI in 36/213(17%) cases, resolving in all but 11 (5.2%). Endoscopy was used in 87/139(63%) craniotomies, facilitating additional tumor removal in 55%. Tumor progression occurred in 26(13%) patients, mean follow-up 42±36 months. CONCLUSIONS & RELEVANCE: Our experience suggests minimally invasive keyhole transcranial and endoscopic endonasal meningioma removal is associated with comparable resection rates and low complication rates, short hospitalizations and high 90-day performance scores in comparison to prior reports using traditional skull base approaches. Subtotal removal may be appropriate for invasive/adherent meningiomas to avoid neurological deficits and other post-operative complications, although longer follow-up is needed. With careful patient selection and requisite experience, these approaches may be considered reasonable alternatives to traditional transcranial approaches.

Introduction

Meningiomas are the most common primary brain tumor with almost 35,000 patients being diagnosed annually in the US [1], and although 85–90% are benign (WHO Grade 1), they frequently encase or become adherent to arteries, veins and cranial nerves, and have a propensity to invade multiple skull base compartments. While surgery remains first-line treatment for meningiomas, the approach used and aggressiveness of removal is highly location-dependent and influenced by other factors such as tumor invasiveness, tumor consistency, prior treatments and surgeons’ philosophy. Innovative skull base surgery approaches developed in the early 1990s generally employed large incisions, extensive bone removal and promoted maximal tumor removal as the primary goal. However, results from multiple series using these approaches indicate that overly aggressive tumor removal can be associated with relatively high rates of permanent cranial nerve deficits and other neurological complications [Journal of neurosurgery. 2011 ">2-Journal of neurological surgery. Part B, Skull base. 2018 ">5]. Furthermore, stereotactic radiosurgery and radiotherapy (SRS or SRT) have long-term control rates of 90% or higher for most recurrent or progressive WHO grade I meningiomas, and some primarily treated cavernous sinus (CS) meningiomas [6, 7]. Thus, over time, restoring or maintaining neurological function and quality of life have gained greater priority and the dictum of maximal safe tumor removal has gained wider acceptance [2, 8–11].

Minimally invasive surgical (MIS) techniques have been increasingly applied across multiple surgical subspecialties often with the aid of endoscopy [Surgical endoscopy. 2013 ">12-Nature Reviews Neurology. 2012 ">15]. Although the concept of minimally invasive brain tumor removal has been promoted for decades, it has remained controversial and not widely practiced. The term “keyhole surgery” was introduced 50 years ago by Donald Wilson in his 1971 technical note, “Limited exposure in cerebral surgery” [16]. Since the 1990s, the keyhole concept has been refined by application of modern micro-neurosurgical techniques and technology including low profile instrumentation, neuro-navigation and high-definition endoscopy. The keyhole concept emphasizes use of tailored and targeted approaches that limit brain exposure through strategically placed craniotomies, minimizing brain manipulation without static brain retractors, facilitated by gravity-assistance, and with the ultimate goal of achieving maximal safe tumor removal [Journal of neurosurgery. 2012 ">17-Operative Neurosurgery. 2005 ">22]. Notably, in the last 20 years, the endoscopic endonasal approach has evolved into an accepted and commonly used minimally invasive route for many midline skull base pathologies including meningiomas, given its ability to facilitate tumor removal without brain retraction. As such, the endonasal craniotomy route to the ventral skull base should arguably be included in the keyhole definition and armamentarium, and by so doing provides a more comprehensive 360-degree keyhole paradigm for meningioma management [Neurosurgery. 2008 ">23-World Neurosurgery. 2020 ">28].

For over a decade, we have used several minimally invasive approaches for brain tumors, particularly for skull base and parafalcine meningiomas that eliminate the need for fixed brain retraction by relying on gravity assistance and endoscopic visualization [Operative Neurosurgery. 2021 ">27-Plos one. 2021 ">35]. Except for our recent report on elderly meningioma patients and that by Burks et al, to our knowledge, there are no prior studies with over 40 patients treated with a minimally invasive keyhole paradigm for all intracranial meningiomas [26, 33]. Herein we report detailed outcomes of our experience with these approaches to intracranial meningiomas including extent of resection, complications, length of stay (LOS), performance status, readmissions, and resection and recurrence rates. We also quantify the degree of parenchymal brain injury from retraction and manipulation injury by measuring acute MRI changes, and to what extent was endoscopy helpful in transcranial approaches for achieving additional tumor removal. We then assess our outcomes in aggregate compared to those reported in prior publications in meningioma patients operated through traditional skull base approaches. With this comprehensive analysis we attempt to answer one overarching question: ‘What is the benefit of keyhole surgery on neurological and overall surgical recovery and can such minimally invasive approaches be considered reasonable alternatives to traditional approaches? Six illustrative case examples are provided in two videos ().

Methods

Patient population & data collection

After institutional review board approval (IRB# JWCI-19-1101), all patients at Saint John’s Health Center, Santa Monica, CA, between January 2008 and January 2021 who underwent surgical removal of an intracranial meningioma were identified. Patient consent was not necessary as data was deidentified. All operations were performed by one of two neurosurgeons (DK, GB) and endonasal operations were performed with otolaryngology collaboration (CG). Data collection included prior treatments, tumor histopathology, size and location on MRI, endoscope usage, extent of resection, complications, length of stay, disposition, readmissions and long-term tumor control.

MIS “keyhole” definition and approach selection

Keyhole approaches were defined as: the use of a minimally invasive approach for a given tumor in which a traditional larger approach may be used instead. These six approaches included the endoscopic endonasal, supraorbital, mini-pterional, retromastoid, suboccipital tentorial and transfalcine routes. This definition follows that detailed by Lan et al in their 2019 consensus paper on keyhole microneurosurgery and aligns with our definition from prior publications on keyhole surgery [21, 27, 28] ( Non-keyhole approaches include convexity craniotomies, pterional, bifrontal and far-lateral approaches. describes the strategy for applying these 6 keyhole approaches and two videos provide 6 case examples. During the study period, traditional open skull base craniotomies including orbito-zygomatic, transpetrosal, translabyrinthine, transcondylar craniotomies were not used. Four patients who underwent a staged operation using one or more keyhole approaches are identified and each keyhole approach was considered as a separate outcome.

Surgical goals, preparation and technique

A goal of maximal safe tumor removal was applied across all tumor locations. However, subtotal removal was typically the goal for three meningioma subtypes given their invasive nature and tendency to encase neurovascular structures: petroclival, CS/Meckel’s cave, and spheno-cavernous locations, as well as some meningiomas with prior surgery and/or radiotherapy [32]. Residual meningioma was deliberately left along neurovascular structures if too adherent or left in the skull base bone if deemed too infiltrative. Four patients had planned staged approaches for large meningiomas (maximal diameter >6 cm: endonasal debulking combined with a pterional, mini-pterional or retromastoid approach.

Total intravenous anesthesia (TIVA) was used to promote rapid emergence from anesthesia [34]. Preoperative tumor embolization was not used. Lumbar drains for CSF diversion were used infrequently and only early in the series. As recently described, all endonasal cases were performed fully endoscopically using a 0° 4-mm rigid endoscope initially; 30° and 45° endoscopes (Karl Storz-America, El Segundo, CA), are used at various stages of the procedure [27, 32]. A pedicled nasoseptal flap (or middle turbinate flap) is harvested in cases of tuberculum and planum meningiomas but not for all CS/Meckel cave meningiomas, depending upon CSF leak grade [27, 32, 33].

Except for the fully endoscopic sitting suboccipital approach, all transcranial keyhole craniotomies are performed initially with the microscope and then with endoscopy as needed for illuminating areas poorly seen with the microscope, and for endoscopic tumor resection. Endoscopy is typically performed with an assistant driving the endoscope. Patient positioning is critical to optimize gravity-assisted exposure and for endoscopy. Our use of the supraorbital and mini-pterional approaches have been well-described [27, 34, 36]. The retromastoid approach is performed with the patient supine or lateral position, utilizing a short linear or curvilinear incision with approximately 2x3cm craniotomy [19]. The suboccipital approach is performed in the sitting or lateral position typically using an approximate 2x2cm craniotomy for tentorial meningiomas. The gravity-assisted transfalcine approach is performed specifically for parafalcine meningiomas that have a rind of edematous overlying eloquent cortex at risk from an ipsilateral approach. The patient is placed in lateral position with tumor side up and inclined in reverse Trendelenburg position with the vertex at 30–45 degrees [29], allowing for gravity-retraction and access from the unaffected contralateral side.

Outcome and statistical analysis

The primary and secondary outcomes analyses detailed below attempt to answer the question of benefit of keyhole surgery approaches in terms of neurological and overall surgical recovery. Primary outcomes included extent of tumor resection, complications, hospital LOS, reoperations and readmissions within 90 days, 30-day mortality, KPS, and cranial (CN) outcomes. A favorable KPS at ≥90 days follow-up was defined as improved or unchanged from preoperative KPS. As previously published, resection rates were categorized as: gross total resection (GTR), near total resection (NTR ≥ 90% tumor resection), or subtotal resection (< 90%) [27, 28]. Simpson resection classification was not assessed given that most patients had invasive skull base meningiomas in which complete tumor resection and removal of involved bone and dura is typically not feasible [27, 28, 37].

Three secondary outcomes were included: 1) To quantify approach-related trauma of tumor removal, post-operative day #1 or 2 MRIs were independently assessed by a neuroradiologist (JR) for new FLAIR/T2 signal changes in the peritumoral and surgical approach areas [27]. New FLAIR/T2 change in the axial plane around the resection area or approach trajectory was quantified by maximal diameters. Persistence or resolution was documented on 3-month postoperative MRI. 2) To assess the utility of endoscopic visualization for transcranial operations, as previously published, it was determined if endoscopy facilitated additional tumor removal [27, 34] 3) To assess tumor progression or recurrence, sequential postoperative MRIs and need for additional treatment (repeat surgery and/or radiotherapy) were quantified for each patient.

The statistical comparison of the mean in the data amongst different groups was performed using ANOVA and independent Student’s t-test. Univariate analysis was done using Chi-square or Fisher’s exact test when applicable. Binomial multivariate analysis was done using logistic regression analysis and p-values less than 0.05 were considered statistically significant. Tumor control data for testing binomial variables were plotted using Cox Regression and Kaplan-Meier analysis.

Results

Demographics

Of 329 patients, keyhole approaches were used in 193 (59%) (74% female, mean age 59±13, mean follow up 42±36 months; WHO Grade I: 173/193(89.6%), Grade II: 19/193(9.8%), Grade III: 1/193(0.6%)); 32(9.7%) had prior radiation. The 213 keyhole operations included 205 (96%) for skull base location and 47(22%) were in patients with prior surgery. Operative approaches used included: endonasal (n = 74), supraorbital (n = 73), retromastoid (n = 38), mini-pterional (n = 20), sitting suboccipital (n = 4), and contralateral gravity-assisted transfalcine (n = 4) (). Four patients had planned staged operations using two approaches for large meningiomas (endonasal combined with a pterional n = 1, supraorbital n = 1, mini-pterional n = 1 or retromastoid approach n = 1). Lumbar drains were used in 5/74(7%) endonasal operations all prior to 2013, and 1/139 (0.7%) transcranial operation in 2017.

Primary outcomes

Resection rates by approach and tumor location

As shown in Tables , GTR was achieved in 85(40%) operations while GTR/NTR (>90% resection) was achieved in 125(59%) operations. By meningioma location, GTR/NTR rates were highest for frontal fossa, parafalcine tentorial, olfactory groove and planum meningiomas (N = 158, range 84–100%), and lowest for invasive spheno-cavernous, CS/Meckel’s cave and petroclival locations (N = 55, range 5–6%) (). Excluding these invasive subgroups (petroclival, CS/MC and spheno-cavernous), GTR/NTR was achieved in 114/136 (84%) first-time operations. Dense adherence to neurovascular structures was associated with 36% GTR/NTR versus 100%, without dense adhesions (p<0.001) (). All patients with STR/NTR had at least one risk factor (prior surgery, radiotherapy, invasion cavernous sinus/Meckel’s cave/infratemporal fossa/orbit).

Clinical outcomes and complications

Major complications occurred in 23/193 (11.9%) patients (). Permanent neurological worsening occurred in 12(6%) patients including 4 with strokes and 8 with cranial nerve injuries (). Reoperations were needed in 10(5%) patients, (two for CSF leaks); 2(1%) patients had meningitis No patients developed perioperative DVT, PE or MI. Three patients all with multiple prior surgeries, died of disease progression at 80, 229, and 3508 days after their last operation.

Discharge to home, functional outcomes and readmissions

Of 213 operations, 201(94%) resulted in patients being discharged to home and 12(6%) to skilled nursing facility or rehabilitation (). Median LOS was higher for patients discharged to rehabilitation or skilled nursing facility versus home (5 vs 2, p = 0.012). Over 11 years, median LOS decreased: 3 days (first 71 cases), 3 days (middle 71 cases) and 2 days (last 71 cases), p = 0.013. Longer LOS (LOS≥ 4) was associated with major complications (22% vs 7%, p = 0.005), discharge to rehabilitation or nursing facility (67% vs. 28%, p = 0.008). Ninety-day readmissions occurred in 6 (2.8%) cases, including 4 who required surgery.

Of 184/193 (95%) patients with available follow-up, favorable 90-day KPS was noted in 176(96%): improved in 126/176(72%) and stable in 50/176 (28%). Mean KPS for the entire cohort improved postoperatively from 72.3 to 82.4 (p<0.001).

Secondary outcomes

Acute MRI changes in region of approach

Of 213 operations, POD 1 or 2 MRIs showed regional increase in FLAIR/T2 signal in 36(16.9%), highest in the retromastoid cohort (37.5%) (Table 2). FLAIR/T2 averaged 8±5 mm in maximal diameter and completely resolved in all but 11(5.2%) cases on follow-up MRI. No patients with increased FLAIR had attributable neurological deficits to their FLAIR changes.

Table 2

Meningioma characteristics, resection rates & surgical parameters for 213 keyhole operations.

	Endonasal (n = 74)	Supraorbital (n = 73)	Mini-pterional (n = 20)	Retromastoid (n = 38)	Suboccipital (n = 4)	Transfalcine (n = 4)	Total (n = 213)
GTR	17 (23%)	34 (46.6%)	10 (50%)	19 (50%)	2 (50%)	3 (75%)	85 (40%)
GTR/NTR	22 (29.7%)	54 (74%)	14 (70%)	28 (73.7%)	3 (75%)	4 (100%)	125 (58.7%)
Redo Surgery (had prior surgery)	24 (32.4%)	16 (21.9%)	3 (15%)	3 (7.9%)	1 (25%)	0	47 (22.1%)
Invasion to CS/MC/Orbit /ITF	40 (54%)	15 (21%)	10 (50%)	9 (24%)	0	0	74 (35%)
Median Skull Base Compartments Occupied	2	2	2	2	1	1	2
Mean Max Tumor Diameter (mm)	29.1 ± 13.2	28.5 ± 13.0	29.7 ± 14.1	32.1 ± 13.5	26.5 ± 12.5	40.0 ± 21.2	29.7 ± 13.4
Use of Endoscopy	74 (100%)	54/73 (74%)	5/20 (25%)	21/38 (55%)	3/4 (75%)	4/4 (100%)	161/213 (76%)
New/Worsened FLAIR/T2 Changes (mean diam, mm)	2/74	11/73	4/20	18/48	1/4	0/4	36/213
	2.7%	15.1%	20.0%	37.5%	25%	0	(16.9%)
	(2.5mm)	(6.9 mm)	(9.5 mm)	(8.1 mm)	(11 mm)	(NA)	(7.67 mm)
Persistent FLAIR Changes at 3 months or more postop	1/74 (1.4%)	2/73 (2.7%)	2/20 (10%)	6/48 (12.5%)	0	0	11/213 (5.2%)
Median LOS	3	3	2	2	3	2	3

Abbreviations: GTR: gross total resection, NTR: near total resection, CS: cavernous Sinus, MC: Meckel’s cave. LOS: length of stay, Max: maximum

Utility of endoscopy

Endoscopy was used in 161(76%) keyhole operations, including all 74 endonasal cases and 87/139(63%) transcranial cases (Table 2). Of 87 endoscope-assisted transcranial cases, in 48(55%) it facilitated additional tumor removal.

Long-term tumor progression or recurrence

Mean follow-up for the 193 patients was 41±36 months. Recurrence after GTR was seen in 1(1.2%) patient, while progression of residual tumor occurred in 26(24.1%) patients, for an overall recurrence/progression rate of 13.9% (27/193). As per Kaplan-Meier analysis, mean time to recurrence or progression was 23.7 ± 27.3 months (range 3–94 months). Of these 27 patients, 4 had repeat surgery only, 11 SRT only, 2 SRS followed by another surgery and 10 were observed or medically managed.

Discussion

MIS philosophy applied to meningiomas

MIS techniques aim to minimize collateral damage to normal tissues while achieving the surgical goal, be it tumor resection, valve replacement or disc replacement [12, 13, 15, 38, 39]. Striking that balance while being cost-effective and maximizing patients’ quality of life is the ultimate “sweet spot” of any surgical procedure [38, 40]. We propose that the present series of MIS approaches and prior series from our group and others for intracranial meningioma are a step forward for neurosurgery and endoscopic skull base surgery, demonstrating the potential effectiveness of this keyhole paradigm [19–21, 28, 34]. In attempting to answer our central question, we suggest these results show a potential benefit of keyhole meningioma surgery on neurological and overall patient recovery, and thus offer a reasonable and in some instances, a preferred alternative to traditional approaches.

This evolution of keyhole surgery is in part a result of cross-specialty collaboration. The adoption of the endoscope into transsphenoidal surgery that began in the 1990s with our colleagues in otorhinolaryngology, has transformed not only pituitary surgery but also the entire field of skull base surgery. Most pituitary adenomas are now removed through an endoscopic endonasal approach, and as we show here, many midline skull base meningiomas can be removed via the endonasal route [27, 41, 42]. Furthermore, the endoscope was used in almost two thirds of transcranial keyhole approaches and helped facilitate additional tumor removal in 55% of these operations.

Keyhole meningioma surgery aims to limit brain exposure and manipulation, accessing tumors through smaller strategically placed craniotomies, including ventral skull base craniotomies via the endoscopic endonasal approach, without static brain retractors, facilitated by gravity-assistance, low profile instrumentation and endoscopy, with the goal of achieving maximal safe tumor removal [Journal of neurosurgery. 2012 ">17-Neurosurgical review. 2019 ">21]. Despite the benefits of visualization, there is ample evidence that fixed brain retractors can cause acute and lasting brain injury [17, 43]. Recent reports highlight the potential for retraction injury and associated complications with traditional craniotomies for tuberculum and planum meningiomas [Journal of neurosurgery. 2017 ">44-Journal of Neurosurgery. 2017 ">46]. A major benefit of keyhole retractorless and gravity-assisted endoscopic approaches and the endoscopic endonasal approach may be in less brain exposure and parenchymal manipulation [17, 18, 20, 21, 27, 46, 47]. This advantage was evidenced by the absence of early postoperative FLAIR/T2 changes along the surgical corridor in 82% of patients in this series including 100% of endonasal approaches; for 36 patients with FLAIR/T2 increases, these were small and resolved in all but 5% of patients.

For a neoplasm as diverse in location and invasiveness as meningioma, the surgical team should be facile working through multiple surgical corridors with both microscope and endoscope (see Table 1). Using TIVA anesthesia, smaller scalp and muscle incisions, minimal monopolar cautery, and focused craniotomies to minimize brain exposure, appears to promote rapid healing, less post-operative pain and a greater willingness and ability for patients to mobilize and leave the hospital [34, 35]. Adoption of MIS techniques have been a key component of success in enhanced recovery protocols in other surgical subspecialties which we are adopting as well in all of our brain tumor patients [34, 48]. Having reliable skull base closure techniques especially for endonasal, supraorbital and retromastoid routes where bony sinus and mastoid air cell entry frequently occurs is also essential to avoid CSF leaks and meningitis. This preventative strategy includes liberal use of abdominal fat grafts to obliterate sinus or air cell entry after craniotomy and a graded repair approach for skull base reconstruction including fat grafts and nasoseptal flaps in endonasal surgery without lumbar CSF drainage [33, 36, 49].

Table 1

Surgical decision making for keyhole meningioma removal.

Meningioma Location	Factors for Surgical Decision Making	Approach Selection
Olfactory Groove/Anterior Planum	Olfaction preservation	Supraorbital
Posterior Planum/Tuberculum Sella	1. Proportion of tumor above the planum2. Sellar depth3. Tuberculum angle3. Optic canal Invasion4. Extent of tumor extension lateral to supraclinoid ICA5. Maximal tumor diameter	Majority of tumor below planum, deep sella, steep (acute) tuberculum angle, minimal lateral extension, small size (under 3 cm): Favor EndonasalMedial optic canal invasion: Favor EndonasalMajority of tumor above planum, shallow sella, broad tuberculum angle, significant lateral extension, lack of medial optic canal invasion, larger size (over 3 cm): Favor Supraorbital
Clinoidal	Extension into middle fossa	Predominantly above the lesser wing: favor Supraorbital Predominantly within the middle fossa: favor Mini-pterional
Sphenoid Wing	Angle of Attack with respect to the Optic Chiasm and Supraclinoid Carotid	Mini-pterional
Spheno-Orbital/Spheno Cavernous	Angle of attack with respect to the optic chiasm and supraclinoid carotid artery	Mini-pterional ± orbitotomy
Cavernous Sinus/ Meckel’s Cave, Spheno-cavernous	Surgical goal of decompression	Endonasal
Petroclival/ CP Angle/ Foramen Magnum	Clival and CP Angle component	If substantial petrous and posterior CP angle component posterolateral to CN VI: Favor RetromastoidIf substantial clival component more anterior: Favor Endonasal ± Retromastoid
Tentorial	Proximity to convexity	If away from convexity–Suboccipital sitting gravity-assisted endoscopic-assisted or fully endoscopic
Falx	Abutting primary motor or sensory cortex with overlying ipsilateral cortex	Contralateral gravity-assisted trans- falcine endoscopic

Complication rates, functional recovery and LOS compared to prior reports

To be valid and to show benefit in terms of neurological and overall surgical recovery, the MIS keyhole concept should yield low rates of new neurological deficits, CSF leaks and high rates of functional outcomes. Our results in terms of infrequent complications, short LOS and improved post-operative KPS scores support this approach. New cranial neuropathy was observed in only 4% of patients. Lumbar drains were used in only 3% of operations, while post-operative CSF leak rate and meningitis rates were only 1%. There were no cases of perioperative DVT, PE, MI or 30-day mortality. The absence of thromboembolic events is likely due in part to our high patient functionality with few neurovascular complication, early ambulation and limited perioperative narcotic use, and compares favorably to the 2.7–4.1% incidence of PE/DVT recently published [50, 51].

Prior studies and our experience demonstrate that complications impact quality of life, lengthen hospital stay, increase costs and often require reoperations and readmissions [29, 36, 38–40]. Compared to our outcomes of 3-day median LOS, 94% discharged to home, and 7% 90-day readmission rate, and no 30-day mortality, recent reports encompassing all intracranial meningiomas have documented LOS for skull base and other meningioma patients ranging from 4–11 days, discharge to home ranging from 70–83.4%, 90-day readmission rates of 9.2–17.9%, and 30-day mortality ranging from 0–5.4% [World neurosurgery. 2019 ">52-Part B, Skull base. 2019 ">56]. This comparison is notable, given our series is comprised predominantly (96%) of skull base meningiomas (which are generally considered to be of higher complexity and risk profile than convexity meningiomas), while these 5 series include all intracranial meningiomas. A rapid complication-free recovery also benefits those patients who may have more aggressive (WHO Graded 2 or 3) or previously-treated meningiomas who may need to begin adjuvant therapy shortly after surgery [37].

In our recent publication on streamlining brain tumor care during the COVID-19 pandemic, we highlighted the importance and utility of an all-encompassing minimally invasive 360-degree approach to brain tumor surgery (for all tumor types), as a foundation for being able to not monitor many patients in the ICU and allowing for early hospital discharge, typically on POD#1 or #2 [35]. In this case control series of 293 patients, from pre-pandemic to pandemic, ICU utilization decreased from 54% to 29% of operations (p<0.001) and hospital LOS≤1 day increased from 12.2% to 41.4%, p<0.001, respectively. We believe that more routine and rigorous patient education on early discharge, recovery room assessment for non-ICU admission and earlier mobilization, layered upon a foundation of MIS, TIVA anesthesia and early post-operative imaging contributed to these significant and favorable trends (including our median LOS of 2 days in the last tertile of patients in this meningioma cohort).

Balancing goals of maximal tumor removal and complication avoidance

Perhaps the most serious critique of keyhole meningioma surgery is that ultimately the patient is not well-served because overly conservative tumor removal leads to the eventual need for repeat surgery, radiosurgery, or possibly both. This issue is the essence of the second part of our central question: ‘can keyhole approaches be considered reasonable alternatives to traditional approaches?’ Our overall meningioma resection rates for all locations except petroclival meningiomas are comparable to prior reports [8, 9, 44–46, 56], and our progression/recurrence rate of 14% is similar to prior reports (almost all in patients who underwent NTR or STR), although this rate will undoubtedly increase with longer follow-up [8, 57–62]. First-time resection rates for anterior cranial fossa and suprasellar meningiomas in the literature vary widely, ranging from 63% to 100%, with recurrence/progression rates ranging from 2% to 14% [19, 63, 64]. Considering petroclival meningiomas, we did not achieve GTR in any of 17 operations and had one new CN deficit (6%). In multiple series of petroclival meningiomas approached through traditional skull base approaches including the retromastoid approach, the GTR rate ranged from 21%-76% but permanent CN and other neurovascular complications ranged from 22%-54% [2–5, 65–71]. Collectively, these reports indicate that overly aggressive attempts at GTR, will likely be associated with a relatively high rate of permanent neurovascular morbidity and lower quality of life for many patients; thus we prefer a more conservative surgical approach for such invasive skull base meningiomas as other groups have also recommended [8, 10, 57–61, 72, 73].

A growing collective experience places functional preservation as a higher priority than GTR resection, as highlighted by recent reports [2, 8, 9, 37]. The beneficial impact of this approach for a given patient is a greater likelihood of no new postoperative neurological deficits and preserved or improved QOL while acknowledging that for many patients their meningioma becomes a chronic illness that warrants long-term monitoring with a higher likelihood of tumor progression and need for additional surgery, SRS/SRT or possible medical therapies in the years after non-GTR resection [8, 10, 57–61, 72, 73].

We highlight in Table 3 and S2 Table the factors most commonly responsible for not achieving a GTR which include invasiveness into the skull base and dense adherence to critical neurovascular structures. Heeding such anatomical realities accounts in large part for our low neurovascular complication rate but relatively high residual tumor rate for some locations. Overall, our results and those of other centers, seem to indicate a keyhole paradigm applied to meningiomas is a reasonable alternative to traditional skull base approaches, given our low neurovascular and systemic complication rates and short LOS, although further validation with longer follow-up at multiple centers is needed [19–22, 27, 28, 42].

Table 3

Resection rates in 213 keyhole approaches by meningioma location, invasiveness & use of endoscopy.

Tumor Location (N)	Overall GTR/NTR (n = 213)	First-time Surgery GTR/NTR (n = 166)	Overall GTR (n = 213)	First-time Surgery GTR (n = 166)	Use of Endoscopy (n = 213)
Frontal Fossa (8)	8 (100%)	8/8 (100%)	8 (100%)	8/8 (100%)	7 (88%)
Parafalcine (4)	4 (100%)	4/4 (100%)	3 (75%)	3/4 (75%)	4 (100%)
Tentorial (18)	17 (94%)	17/17 (100%)	13 (72%)	13/17 (77%)	12 (67%)
Olfactory Groove (14)	12 (86%)	11/12 (92%)	9 (64%)	8/12 (67%)	14 (100%)
Planum Sphenoidale (12)	10 (84%)	8/10 (80%)	4 (33%)	3/10 (30%)	9 (75%)
Clinoidal (19)	14 (74%)	13/15 (87%)	8 (42%)	8/15 (53%)	12 (63%)
Tuberculum Sellae (39)	28 (72%)	26/31 (84%)	22 (56%)	22/31 (71%)	33 (85%)
Cerebellopontine Angle (23)	16 (70%)	14/21 (67%)	9 (39%)	8/21 (38%)	14 (61%)
Sphenoid Wing (16)	10 (62.5%)	10/15 (67%)	7 (44%)	7/15 (47%)	7 (44%)
Spheno-orbital (5)	3 (60%)	3/3 (100%)	1 (20%)	1/3 (33%)	1 (20%)
Total	122/158 = 77%	114/136 = 84%	84/158 = 53%	81/136 = 60%
Petroclival (17)*	1 (6%)	1/9 (11%)	0 (0%)	0/9 (0%)	14 (82%)
CS/MC (19)*	1 (5%)	0/10 (0%)	0 (0%)	0/10 (0%)	18 (95%)
Spheno-cavernous (19)*	1 (5%)	1/11 (10%)	1 (5%)	1/11 (10%)	16 (84%)
Total	3/55 = 5%	2/30 = 7%	1/55 = 2%	1/30 = 3%
TOTAL	125 (59%)	116 (70%)	85 (40%)	82 (49%)	161 (76%)
Dense adherence to critical neurovascular structures
Yes (N = 138)	50 (36%)		20 (15%)
No (N = 75)	75 (100%)		65 (87%)
p-value	p<0.001		p<0.001

Abbreviations: GTR: gross total resection, NTR: near total resection, CS: cavernous Sinus, MC: Meckel’s cave.

*These 3 locations represent a subset of 55 invasive skull base meningiomas in which conservative (subtotal) removal was the surgical goal. Of these 55 cases; 7 patients had tumor progression treated with repeat surgery and/or SRS/SRT.

Of 17 operations for petroclival meningioma (in 13 patients), 14 were approached via the endonasal route for conservative debulking and 3 via the retromastoid route; 13/17 (76%) operations and 9/13 (69%) patients had meningiomas that extended into multiple compartments including CS, Meckel’s cave, and/or sellar/suprasellar areas, 8/13 (61%) had prior surgery and 7 (54%) had prior radiation.

Study limitations and bias

The major limitation of this study is its retrospective nature, heterogenous meningioma patient population, and our selection bias for using these 6 keyhole approaches without a comparison cohort of patients treated with traditional skull base approaches or other relatively new minimally invasive approaches such as the endoscopic transorbital route [74, 75]. We specifically did not compare clinical outcomes in the keyhole cohort to the 136 (41%) non-keyhole patient cohort. Also, the follow-up in our patients averaged 44 months which is relatively short. Longer follow-up is necessary to assess the efficacy of this approach more fully and determine how many patients who underwent NTR or STR ultimately need radiotherapy or additional surgery.

Conclusions

A minimally invasive keyhole paradigm applied to skull base and other select meningiomas can yield reasonable tumor resection rates with low rates of neurovascular and systemic complications, short LOS and high rates of functional outcomes. While traditional skull base approaches remain useful and effective, we suggest that with increasing experience, transcranial and endonasal keyhole approaches can be considered part of the surgical armamentarium for many intracranial meningiomas.

Six keyhole approaches animated GIF.

The corresponding GIF animation of the 6 approaches illustrated in Fig 1.

Fig 1

(1A) Drawing depicting 6 keyhole approaches for meningioma removal: endonasal, supraorbital, minipterional, retromastoid, suboccipital sitting gravity-assisted and transfalcine gravity-assisted, along with the total number of surgeries for each approach. (1B) A composite of the 6 keyhole approaches.

(GIF)

Click here for additional data file.

Keyhole and traditional approaches used for skull base and non-skull base meningiomas.

A breakdown of number of cases in which keyhole and traditional approaches were used for skull base and non-skull base meningiomas.

(DOCX)

Click here for additional data file.

Multivariate regression analysis for tumor resection and progression.

Preoperative factors limiting GTR and factors predicting progression are analyzed using multivariate binomial and cox regression analysis.

(DOCX)

Click here for additional data file.

Cranial nerve outcomes in 193 patients undergoing Keyhole meningioma removal.

A breakdown of the cranial nerve outcomes and recovery for patients undergoing keyhole meningioma surgery.

(DOCX)

Click here for additional data file.

Anterior cranial fossa case examples.

Illustrative case examples of 3 anterior cranial fossa meningiomas: 1) tuberculum sella meningioma approached via endoscopic endonasal route, 2) olfactory groove meningioma approached via supraorbital route; 3) clinoidal meningioma approached via supraorbital route.

(DOCX)

Click here for additional data file.

Three meningioma illustrative case examples.

Illustrative case examples of 3 meningiomas: 1) petroclival meningioma approached via retromastoid route, 2) tentorial meningioma approached via suboccipital sitting position route; 3) falx meningioma approached via transfalcine gravity-assisted route.

(DOCX)

Click here for additional data file.

(XLSX)

Click here for additional data file.

16 Mar 2022

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Reviewer #1: The authors put forth a commendable effort to document their long-standing experience with minimally invasive approaches for intracranial meningiomas, which is a general trend in not only neurosurgery but other surgical subspecialties. The authors present a tremendous amount of primary data for the reader to review, which is important but becomes somewhat overwhelming for the reader. This is compounded somewhat by the weak connection between the two aims presented in the introduction and the methods/data with which they plan to assess these aims. Specific comments are below.

- endoscopic endonasal is fundamentally different--> really keyhole approach?

- comparable resection rates for endoscopic vs transcranial approaches? what's the comparison group?

Introduction

- There was overall good explanation of history leading up to current question/objective, but it's never really define what "minimally invasive" or "keyhole" surgery is, or whether that definition has changed over time. Some verbiage from the Discussion may be helpful here.

- Consider rewording line 95 to : Herein we report detailed outcomes "of our experience with minimally invasive approaches to intracranial meningiomas" including extent of resection, complications, LOS, performance status, readmissions, and resection and recurrence rates.

- LOS--> spell out length of stay pg 4 line 96

- The authors list two aims for the study, but it is never clearly stated what the criteria are in planning to answer those questions. Regarding the first question, ‘Is the benefit of a keyhole approach only on soft tissue & bone or also on the brain, and overall surgical recovery?', I assume many of the primary and some of the secondary outcomes (eg FLAIR changes) are aimed to answer this? How do you define overall surgical recovery (LOS, KPS)? What about soft tissue/bone? Regarding the second aim ‘Are keyhole approaches reasonable alternatives to traditional approaches? There is no mention of how this will be answered by the study; ie there is no comparison cohort, either from the institution's historical dataset or from the literature. The authors' data are placed into some context in the discussion, as compared to published literature, but this is not done in a systematic fashion as would be suggested by the second aim. If it, in fact, was not the intention of the paper, then consider rewording or removing this. Connecting the definitions of the outcomes with the aims should be included in the Methods.

Methods

- change tense to past in 2nd paragraph

- what other traditional skull base approaches do you include (line 118)? If no more, just remove this phrase.

Table 1-

under Falx, approach selection: do you mean trans-falcine instead of trans-tentorial?

Results:

What did you classify as an MIS operation in the same patients? Did you include patients that were multiply operated on for recurrences as two separate events? What about staged procedures? This should be made more clear in the Methods.

Discussion:

Was there any consideration of the COVID-19 pandemic as a contributor to shorter LOS in 2020-2021?

There is some debate as to whether endoscopic endonasal procedures are "minimally invasive" and categorized along with open craniotomies. Please comment.

The context for the current dataset was well set in this discussion, as it was compared to published series using traditional techniques; a range of percentages from previously published series in (page 19 second paragraph) would be helpful.

Reviewer #2: The authors report a single-center cohort study of 329 patients who underwent neurosurgical resection of an intracranial meningioma during the study period, 2008-2021, focusing on individuals treated with keyhole approaches (rather than conventional craniotomies), which were applied for the resection of 213 operations on 193 patients. Parameters studied include a range of operative details, outcomes, and complications, all reported through a predominantly descriptive approach to analysis.

Overall, the review is an well-presented and timely series that describes a relatively large experience and will likely be of interest to many in the neurosurgical readership. Several issues warrant further attention prior to consideration for publication:

1. The major issue with this paper, which is manifest in several distinct ways, is the overenthusiastic scope. In my view, the authors are trying to accomplish far too much with a single study, which has rendered the manuscript difficult to ready, digest, or consider for generalization and potential applications to one's own practice. I would strongly recommend consideration for a balkanization of the work into several daughter projects—perhaps one descriptive analysis of the group's minimally invasive cranial practice, followed by others focusing on smaller study questions, such as the role of "dense adherence" between the tumor and surrounding neurovascular structures as an predictor of a subtotal resection, or difference between conventional and minimally invasive outcomes

2. To that same end, candidly, the great majority of neurosurgeons would parse the endoscopic endonasal separately from the other keyhole approaches described—in particular, those with skull base expertise. Although both may be classified under the heading of "minimally invasive approaches," most of the factors that go into patient selection, operative planning, outcomes, etc. for endoscopic endonasal surgery are quite distinct from trans-cranial operations. The data from these patients would likely constitute an interesting stand-alone analysis; however, at the authors' discretion, leaving them in place as part of a larger descriptive-only series of "minimally invasive approaches" would not be unreasonable, (though any formal or informal comparisons would have to be stricken from such an analysis)

3. The authors have selected a very ambiguous definition for keyhole approaches, which would likely be subject to much debate within the skull base community. Additionally, they combine approaches with very different indications, risk profiles, etc. into a single analysis, for example the mini-pterional and retro-mastoid. Finally, many of the approaches sited as "keyhole" approaches are not practiced as such by all neurosurgeons, for example the trans-falcine approach, which refers to intra-cranial aspects of the dissection and approach rather than the craniotomy proper, and which can therefore be performed via a range of access ports of both large and small size. Considerable attention is required to better clarify and qualify these distinctions within the broader and highly diverse context of complex cranial surgery

4. Given the very heterogeneous sample, the results of any statistical testing conducted in this analysis would be subject to a very guarded interpretation at best. The authors should strongly consider removing all non-descriptive statistics from the main manuscript, and save them for separate subgroup analyses that would be reported separately, and where more homogeneity within the sample would potentially provide more meaningful interpretation

5. The decision to analyze GTR and NTR (defined as 90-99% resection) as a single subgroup is controversial, and not consistent with most contemporary data regarding the phenotypic behavior of incompletely resected meningiomas. A more robust approach would be to combine NTR and STR, given that the presence of any known residual solid tumor is well-known to increase the risk of disease recurrence, and the need for additional treatments in the future

Reviewer #3: This is a nice institutional report on use of minimally invasive approaches for intracranial meningiomas in 193 patients. They have used various approaches including endoscopic, minipterional, suboccipital approaches with or without the use of endoscopes and have shown great outcome in terms of resection rate, postoperative complications and clinical outcome at follow up. The choice and rationality of various approaches have been described in detail along with illustrative cases and operative videos. I would commend the authors for their sincere efforts in compiling such detailed report.

Few comments i would request the authors to address,

1. I feel the benefits of minimally approaches are partially offset by the high rate of reoperations due to residual disease. Overall reoperation rate of 22.1% including 32.4% in endoscopic endonasal cases, 21.9% in supraorbital cases seems high. Please comment.

2. Please explain the high rate of new/worsened FLAIR changes with suboccipital and retrosigmoid approaches.

3. The secondary analysis is poor. I do not see any relevant result or discussion on factors affecting the GTR or complications. Although there is a supplementary table (Table-2), not much has been discussed on it.

**********

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13 Apr 2022

PONE-D-22-03249 Reviewer response: Critical appraisal of minimally invasive keyhole surgery for intracranial meningioma in a large case series at a single institution. Thakur et al

Please note: all page and line numbers refer to the “track changes” version of the manuscript.

Reviewer #1: The authors put forth a commendable effort to document their long-standing experience with minimally invasive approaches for intracranial meningiomas, which is a general trend in not only neurosurgery but other surgical subspecialties. The authors present a tremendous amount of primary data for the reader to review, which is important but becomes somewhat overwhelming for the reader. This is compounded somewhat by the weak connection between the two aims presented in the introduction and the methods/data with which they plan to assess these aims. Specific comments are below.

- endoscopic endonasal is fundamentally different--> really keyhole approach?

Response:

We appreciate this comment but would like to stress that this paper is meant to describe a global approach to meningiomas using a 360-degree minimally invasive paradigm. As such, even though the endoscopic endonasal approach is not transcranial, it is fully aligned with the “keyhole concept” which stresses a “minimally invasive concept of microsurgery based on tailored, targeted, and direct microneurosurgical techniques” and is “a combination of modern microsurgical techniques, preoperative imaging, neuroendoscopy, and the modern concept of minimally invasive surgery”, as described by Lan et al (ref #21) in their consensus paper on keyhole neurosurgery. The fact that the endonasal approach is performed with an endoscope, and was used in 35% of all keyhole meningioma operations in this series, strongly argues that the endonasal route be included in any such analysis of minimally invasive keyhole surgery. This idea is exemplified by using a minimally invasive endonasal approach for managing specific skull base meningiomas as opposed to performing a traditional skull base approach such as an orbito-zygomatic approach with clinoidectomy for optic nerve decompression for a tuberculum sella meningioma. This point and the overall concept of the paper has now been further highlighted and detailed in the 2nd paragraph on page 4, lines 89-99 with additional supportive references added. We also note that we have already published peer-reviewed papers assessing minimally invasive keyhole meningioma surgery in elderly patients that included the endoscopic endonasal approach (Thakur et al 2020, ref #28) and in comparing two keyhole approaches, the endonasal versus supraorbital, for removal of tuberculum sella meningiomas (Mallari et al 2021, ref#27).

- comparable resection rates for endoscopic vs transcranial approaches? what's the comparison group?

Response:

Excellent point raised. The comparison group is to prior publications for skull base meningiomas as we now highlight in the introduction (page 5 lines 105-116 and discussion. We add a new heading in the discussion on page 20: Complication rates, functional recovery and LOS compared to prior reports: to highlight our outcomes compared to prior publications. We also do the same on resection and remission rates in the discussion section on page 21 “Balancing goals of maximal tumor removal and complication avoidance:” This point of comparison to prior reports has also been clarified in the conclusion section of the abstract and in the introduction to reflect our intention.

Introduction

- There was overall good explanation of history leading up to current question/objective, but it's never really defined what "minimally invasive" or "keyhole" surgery is, or whether that definition has changed over time. Some verbiage from the Discussion may be helpful here.

Response:

We agree. We have added more detail about the “keyhole” surgical concept in the introduction (as noted above) in lines 89-99 on page 4.

- Consider rewording line 95 to : Herein we report detailed outcomes "of our experience with minimally invasive approaches to intracranial meningiomas" including extent of resection, complications, LOS, performance status, readmissions, and resection and recurrence rates. - LOS--> spell out length of stay pg 4 line 96

Response:

Thank you. This change has been made (now on lines 105-107).

- The authors list two aims for the study, but it is never clearly stated what the criteria are in planning to answer those questions. Regarding the first question, ‘Is the benefit of a keyhole approach only on soft tissue & bone or also on the brain, and overall surgical recovery?', I assume many of the primary and some of the secondary outcomes (eg FLAIR changes) are aimed to answer this? How do you define overall surgical recovery (LOS, KPS)? What about soft tissue/bone? Regarding the second aim ‘Are keyhole approaches reasonable alternatives to traditional approaches? There is no mention of how this will be answered by the study; ie there is no comparison cohort, either from the institution's historical dataset or from the literature. The authors' data are placed into some context in the discussion, as compared to published literature, but this is not done in a systematic fashion as would be suggested by the second aim. If it, in fact, was not the intention of the paper, then consider rewording or removing this. Connecting the definitions of the outcomes with the aims should be included in the Methods.

Response:

We agree that there was a “weak connection” between the two aims (we call them questions) posed in the introduction and have now attempted to clearly address this important issue. In this revision, we have now combined these two questions into one overarching Question on page 5 at end of introduction (lines 114-116): ‘What is the benefit of keyhole surgery on neurological and overall surgical recovery, and can such minimally invasive approaches be considered reasonable alternatives to traditional approaches?’ We have also more clearly indicated how this question is answered in the introduction, methods, results and discussion. In the introduction (lines 105-112), we now clarify that this question is answered by our clinical outcome measures (both primary and secondary as defined in the methods). This point has been highlighted in the methodology under Outcome and Statistical Analysis (page 10, lines 187-189). We then address this question in the discussion further in the first paragraph (page 18, lines 306-309) and in section heading (page 20): Complication rates, functional recovery and LOS compared to prior reports, by comparing our overall results (especially focused on complications and LOS) with prior publications using traditional skull base approaches, and similarly on extent of resection and recurrence, in the next discussion section (page 21): Balancing goals of maximal tumor removal and complication avoidance.

Methods

- change tense to past in 2nd paragraph

- what other traditional skull base approaches do you include (line 118)? If no more, just remove this phrase.

Response:

This tense has been changed to past tense and the traditional skull base approaches section has been revised as requested in the same paragraph.

Table 1-

under Falx, approach selection: do you mean trans-falcine instead of trans-tentorial?

Response:

Thank you for noting this; we did mean trans-falcine. This has been corrected.

Results:

What did you classify as an MIS operation in the same patients? Did you include patients that were multiply operated on for recurrences as two separate events? What about staged procedures? This should be made more clear in the Methods.

Response:

This is an important point. All patients included in the keyhole cohort had an MIS approach. Being reoperated on for a recurrence is thus considered an outcome measure which we have in the results section as a secondary outcome (page 17, lines 291-296). Our overall recurrence rate was 13.9% (27/193) and of these 6 (3%) patients had repeat surgery with or without SRT or SRS. Regarding staged procedures, of the 4 patients, only one had a traditional pterional craniotomy combined with an endonasal approach (as detailed now page 11 lines 221-222).

Discussion:

Was there any consideration of the COVID-19 pandemic as a contributor to shorter LOS in 2020-2021?

There is some debate as to whether endoscopic endonasal procedures are "minimally invasive" and categorized along with open craniotomies. Please comment.

Response:

The reviewer raises an important point regarding the impact of the pandemic on LOS. In fact, we have published on this very topic and ICU utilization for all brain tumor patients (Mallari et al ref # 35 published in PLOS One in 2021). Even though COVID did play a role in considering earlier discharge, our use of MIS keyhole approaches began more than a decade before the pandemic allowing us to have a shorter LOS compared to other similar meningioma skull base cohort series. However, we now point out in the discussion (page 21, lines 366-376) that the median LOS in the last 71 cases was also likely further encouraged by our efforts to further reduce LOS and ICU given the resource and bed demands of the pandemic; we briefly describe the results of this paper.

Regarding whether endoscopic endonasal should be considered a “minimally invasive” approach and categorized with transcranial approaches, we have expanded upon this point in the introduction (page 4) and the discussion (page 18) as noted above. We emphasize that by including the endonasal route, we are endorsing a 360-degree minimally invasive keyhole approach that argues strongly to use the optimal route that minimizes brain and cranial nerve manipulation, promotes a rapid recovery yet allows maximal safe tumor removal. Thus, we respectfully argue that the endonasal approach be included in this “minimally invasive” armamentarium as we have already done in multiple prior reports (Thakur et al 2020, ref #28; Mallari et al 2021, ref #27; Mallari et al, 2021, ref #35).

The context for the current dataset was well set in this discussion, as it was compared to published series using traditional techniques; a range of percentages from previously published series in (page 19 second paragraph) would be helpful.

Response:

Thanks for this suggestion. On page 20, we had already provided a range of percentages on neurological and other complications, LOS and readmission rates. We also provide resection rates from the literature for different meningioma locations on pages 21-22 (lines 386-392).

Reviewer #2: The authors report a single-center cohort study of 329 patients who underwent neurosurgical resection of an intracranial meningioma during the study period, 2008-2021, focusing on individuals treated with keyhole approaches (rather than conventional craniotomies), which were applied for the resection of 213 operations on 193 patients. Parameters studied include a range of operative details, outcomes, and complications, all reported through a predominantly descriptive approach to analysis.

Overall, the review is an well-presented and timely series that describes a relatively large experience and will likely be of interest to many in the neurosurgical readership. Several issues warrant further attention prior to consideration for publication:

1. The major issue with this paper, which is manifest in several distinct ways, is the overenthusiastic scope. In my view, the authors are trying to accomplish far too much with a single study, which has rendered the manuscript difficult to ready, digest, or consider for generalization and potential applications to one's own practice. I would strongly recommend consideration for a balkanization of the work into several daughter projects—perhaps one descriptive analysis of the group's minimally invasive cranial practice, followed by others focusing on smaller study questions, such as the role of "dense adherence" between the tumor and surrounding neurovascular structures as an predictor of a subtotal resection, or difference between conventional and minimally invasive outcomes.

Response:

We appreciate the reviewer’s critique and agree that we have been expansive and inclusive in terms of this large meningioma data set. However, we would argue that in many if not most prior publications on meningioma surgery, a comprehensive review is not undertaken. For example, many papers will focus only on extent of resection and recurrence, while others will focus on complications, length of stay and/or quality of life. We suggest that to answer our central question (Introduction page 5), ‘What is the benefit of keyhole surgery on neurological and overall surgical recovery, and can such minimally invasive approaches be considered reasonable alternatives to traditional approaches?’ the entire patient experience needs to be considered to understand how patients fare and thus help derive an optimal approach for each patient. So, in that context we have attempted to look at our overall approach for meningiomas including all surgical approaches (including endoscopic endonasal) and look at our detailed outcomes. Only by completing such a comprehensive analysis, can the total impact of this approach be assessed. Thus, as we emphasize in the discussion, having a high rate of GTR or NTR but with an equally high rate of permanent neurological complications (as has been shown in many articles detailing outcomes of traditional skull base approaches) is not what the neurosurgical community should be striving for. While we note that we have some of the lowest complication rates and LOS in the literature, we acknowledge that ours is only one experience, and we need longer follow-up of this keyhole paradigm.

Additionally, we respectfully request that we not “balkanize” our results into smaller papers, and in fact, we have already done four such “balkanized” papers including: endonasal versus supraorbital for tuberculum sella meningiomas (Mallari et al, 2021, ref #27); invasive parasellar meningiomas treated by endoscopic endonasal route (Sivakumar et al 2019, ref #32 ), supraorbital versus minipterional approach for all tumors (Avery et al 2021; ref #34), and endoscope-assisted transfalcine approach (Barkhoudarian et al, 2017, ref #29). Thus, as we indicated on page 4 of introduction, this paper and analysis is trying to take a broader perspective on overall meningioma management focusing on the potential benefits of this 360-degree keyhole paradigm.

2. To that same end, candidly, the great majority of neurosurgeons would parse the endoscopic endonasal separately from the other keyhole approaches described—in particular, those with skull base expertise. Although both may be classified under the heading of "minimally invasive approaches," most of the factors that go into patient selection, operative planning, outcomes, etc. for endoscopic endonasal surgery are quite distinct from trans-cranial operations. The data from these patients would likely constitute an interesting stand-alone analysis; however, at the authors' discretion, leaving them in place as part of a larger descriptive-only series of "minimally invasive approaches" would not be unreasonable, (though any formal or informal comparisons would have to be stricken from such an analysis)

Response:

We appreciate this sentiment but as detailed above in prior responses, we have already written such stand-alone papers comparing keyhole approaches. For example, in managing tuberculum sella meningiomas by endonasal vs supraorbital route (Mallari et al, 2021, ref #27). In that paper we emphasize that the endonasal and supraorbital approaches are complimentary keyhole approaches and need to be considered together as to which is the optimal approach. Thus, we respectfully disagree and instead believe that including endoscopic endonasal in the keyhole paradigm and armamentarium is appropriate and is needed to help further advance the field of skull base surgery.

3. The authors have selected a very ambiguous definition for keyhole approaches, which would likely be subject to much debate within the skull base community. Additionally, they combine approaches with very different indications, risk profiles, etc. into a single analysis, for example the mini-pterional and retro-mastoid. Finally, many of the approaches sited as "keyhole" approaches are not practiced as such by all neurosurgeons, for example the trans-falcine approach, which refers to intra-cranial aspects of the dissection and approach rather than the craniotomy proper, and which can therefore be performed via a range of access ports of both large and small size. Considerable attention is required to better clarify and qualify these distinctions within the broader and highly diverse context of complex cranial surgery

Response:

We appreciate the concern about possible ambiguity of the definition of the keyhole approach. However, as we have attempted to emphasize in other responses to Reviewer #1 and #2, and in the revised manuscript methods section, we have clarified our definition of “keyhole approach”. We believe that all 6 approaches we include meet the criteria as defined in the consensus statement for keyhole concept (Lan et al 2019, ref#21) and in our prior papers. Inclusion of the trans-falcine approach for parafalcine meningiomas does introduce heterogeneity in the data albeit not significantly since the patient population in this group is only 2% of the cohort. Additionally, the parafalcine meningiomas included in the analysis are underlying eloquent cortex where use of a port would not be appropriate as it would undoubtedly disrupt the eloquent cortex one is trying save. Importantly, the transfalcine approach for removing falx meningiomas cannot be safely done ( in our opinion) without endoscopic angled visualization which allows one to achieve complete meningioma removal without brain retraction. Applying endoscopy (when needed) is one of the key technological tenets of MIS keyhole brain tumor surgery as stressed by Lan et al (2019).

4. Given the very heterogeneous sample, the results of any statistical testing conducted in this analysis would be subject to a very guarded interpretation at best. The authors should strongly consider removing all non-descriptive statistics from the main manuscript, and save them for separate subgroup analyses that would be reported separately, and where more homogeneity within the sample would potentially provide more meaningful interpretation

Response:

Thank you for the suggestion. The heterogeneity is certainly a limitation of the study which has been added in the limitation section (page 23, line 413). However, we have used Binomial Multivariate Regression analysis to minimize confounding factors, and which as requested by the reviewers is reported only in the supplemental data and not in the main manuscript.

5. The decision to analyze GTR and NTR (defined as 90-99% resection) as a single subgroup is controversial, and not consistent with most contemporary data regarding the phenotypic behavior of incompletely resected meningiomas. A more robust approach would be to combine NTR and STR, given that the presence of any known residual solid tumor is well-known to increase the risk of disease recurrence, and the need for additional treatments in the future

Response:

We agree with the reviewer that our grouping approach of GTR with NTR is somewhat controversial, however we emphasize throughout the paper that our surgical goal is always “maximal safe tumor removal” and we do show the GTR rates for the different approaches and tumor locations in both Tables 2 and 3. Given the highly invasive skull base tumor population, the frequent finding of vascular encasement, and that many patients had prior surgery and/or radiation, settling for NTR in many cases is a reasonable goal. Thus, we respectfully request to leave the GTR/NTR grouping as is, believing that keeping this grouping aligns with an overall minimally invasive paradigm that also strives for a low complication rate, short LOS and high QOL. Furthermore, although the results are limited by relatively shorter follow up, our tumor control rates are comparable to previously published rates as noted in the discussion (page 21, lines 381-385).

Reviewer #3: This is a nice institutional report on use of minimally invasive approaches for intracranial meningiomas in 193 patients. They have used various approaches including endoscopic, minipterional, suboccipital approaches with or without the use of endoscopes and have shown great outcome in terms of resection rate, postoperative complications and clinical outcome at follow up. The choice and rationality of various approaches have been described in detail along with illustrative cases and operative videos. I would commend the authors for their sincere efforts in compiling such detailed report.

Response:

We appreciate the acknowledgement. Thank you.

Few comments I would request the authors to address,

1. I feel the benefits of minimally approaches are partially offset by the high rate of reoperations due to residual disease. Overall reoperation rate of 22.1% including 32.4% in endoscopic endonasal cases, 21.9% in supraorbital cases seems high. Please comment.

Response:

Thank you for this comment and sorry for the confusion. The actual reoperation rate for tumor progression was 3.1%. To clarify, those rates of 22.1% (overall), 32.4% (endonasal) and 21.9 (supraorbital) listed in Table 2 indicate patients who came to us after having prior surgery. We have clarified this point in Table 2. The overall rate of tumor progression for the entire cohort during the study period (as we state in the results section on page 17, lines 291-293): Long-term tumor progression or recurrence) was 13.9% (27/193 patients) including 3.1% (6 patients) who had repeat surgery with or without SRS or SRT.

2. Please explain the high rate of new/worsened FLAIR changes with suboccipital and retrosigmoid approaches.

Response:

The higher rate of FLAIR changes at 3 months (12.5%) for the retromastoid approach may be related to the fact that this approach for many such meningiomas (CP angle and petroclival), the cerebellar hemisphere partially obstructs tumor access, and despite excellent neuroanesthesia, positioning and opening of cisterns for CSF creating a relaxed posterior fossa, some manipulation of the cerebellar hemisphere is unavoidable which may lead to new FLAIR changes in some cases. That said, since there is little data on early postoperative FLAIR changes in skull base meningioma series, we feel our rate of FLAIR changes is difficult to compare to prior reports. Notably, persistent FLAIR changes at 3 months were noted only in 5% of patients and were quite small and did not seem to correlate with lasting neurological deficits (Table 2). Overall, these rates appear to be quite low (including for retromastoid approach) compared for example to Bander et al (ref #46) which had a mean post-operative FLAIR volume of 8.3 cm3 in patients who had traditional transcranial removal of tuberculum meningiomas.

3. The secondary analysis is poor. I do not see any relevant result or discussion on factors affecting the GTR or complications. Although there is a supplementary table (Table-2), not much has been discussed on it.

Response:

Thank you for the suggestion. We highlight the factors influencing resectability in Table 3 and supplemental Table 2. The most important information in supplemental Table 2 is emphasizing that Invasion to CS-MC-Orbit-ITF/ Adherence to neurovascular structures strongly predicted non-GTR. This point is now addressed in a new section of the discussion (page 22, lines 404-411).

Submitted filename: Meningioma Keyhole PLOS ONE Reviewer Response 4-4-2022.docx

Click here for additional data file.

24 May 2022

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Reviewer #1: All comments have been appropriately addressed, particularly the methodology, the rationale for including endoscopic endonasal approaches, and their comparison groups. The manuscript is now fit for publication.

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30 Jun 2022

PONE-D-22-03249 Reviewer response: Critical appraisal of minimally invasive keyhole surgery for intracranial meningioma in a large case series at a single institution. Thakur et al

Please note: all page and line numbers refer to the “track changes” version of the manuscript.

Reviewer #1: The authors put forth a commendable effort to document their long-standing experience with minimally invasive approaches for intracranial meningiomas, which is a general trend in not only neurosurgery but other surgical subspecialties. The authors present a tremendous amount of primary data for the reader to review, which is important but becomes somewhat overwhelming for the reader. This is compounded somewhat by the weak connection between the two aims presented in the introduction and the methods/data with which they plan to assess these aims. Specific comments are below.

- endoscopic endonasal is fundamentally different--> really keyhole approach?

Response:

We appreciate this comment but would like to stress that this paper is meant to describe a global approach to meningiomas using a 360-degree minimally invasive paradigm. As such, even though the endoscopic endonasal approach is not transcranial, it is fully aligned with the “keyhole concept” which stresses a “minimally invasive concept of microsurgery based on tailored, targeted, and direct microneurosurgical techniques” and is “a combination of modern microsurgical techniques, preoperative imaging, neuroendoscopy, and the modern concept of minimally invasive surgery”, as described by Lan et al (ref #21) in their consensus paper on keyhole neurosurgery. The fact that the endonasal approach is performed with an endoscope, and was used in 35% of all keyhole meningioma operations in this series, strongly argues that the endonasal route be included in any such analysis of minimally invasive keyhole surgery. This idea is exemplified by using a minimally invasive endonasal approach for managing specific skull base meningiomas as opposed to performing a traditional skull base approach such as an orbito-zygomatic approach with clinoidectomy for optic nerve decompression for a tuberculum sella meningioma. This point and the overall concept of the paper has now been further highlighted and detailed in the 2nd paragraph on page 4, lines 89-99 with additional supportive references added. We also note that we have already published peer-reviewed papers assessing minimally invasive keyhole meningioma surgery in elderly patients that included the endoscopic endonasal approach (Thakur et al 2020, ref #28) and in comparing two keyhole approaches, the endonasal versus supraorbital, for removal of tuberculum sella meningiomas (Mallari et al 2021, ref#27).

- comparable resection rates for endoscopic vs transcranial approaches? what's the comparison group?

Response:

Excellent point raised. The comparison group is to prior publications for skull base meningiomas as we now highlight in the introduction (page 5 lines 105-116 and discussion. We add a new heading in the discussion on page 20: Complication rates, functional recovery and LOS compared to prior reports: to highlight our outcomes compared to prior publications. We also do the same on resection and remission rates in the discussion section on page 21 “Balancing goals of maximal tumor removal and complication avoidance:” This point of comparison to prior reports has also been clarified in the conclusion section of the abstract and in the introduction to reflect our intention.

Introduction

- There was overall good explanation of history leading up to current question/objective, but it's never really defined what "minimally invasive" or "keyhole" surgery is, or whether that definition has changed over time. Some verbiage from the Discussion may be helpful here.

Response:

We agree. We have added more detail about the “keyhole” surgical concept in the introduction (as noted above) in lines 89-99 on page 4.

- Consider rewording line 95 to : Herein we report detailed outcomes "of our experience with minimally invasive approaches to intracranial meningiomas" including extent of resection, complications, LOS, performance status, readmissions, and resection and recurrence rates. - LOS--> spell out length of stay pg 4 line 96

Response:

Thank you. This change has been made (now on lines 105-107).

- The authors list two aims for the study, but it is never clearly stated what the criteria are in planning to answer those questions. Regarding the first question, ‘Is the benefit of a keyhole approach only on soft tissue & bone or also on the brain, and overall surgical recovery?', I assume many of the primary and some of the secondary outcomes (eg FLAIR changes) are aimed to answer this? How do you define overall surgical recovery (LOS, KPS)? What about soft tissue/bone? Regarding the second aim ‘Are keyhole approaches reasonable alternatives to traditional approaches? There is no mention of how this will be answered by the study; ie there is no comparison cohort, either from the institution's historical dataset or from the literature. The authors' data are placed into some context in the discussion, as compared to published literature, but this is not done in a systematic fashion as would be suggested by the second aim. If it, in fact, was not the intention of the paper, then consider rewording or removing this. Connecting the definitions of the outcomes with the aims should be included in the Methods.

Response:

We agree that there was a “weak connection” between the two aims (we call them questions) posed in the introduction and have now attempted to clearly address this important issue. In this revision, we have now combined these two questions into one overarching Question on page 5 at end of introduction (lines 114-116): ‘What is the benefit of keyhole surgery on neurological and overall surgical recovery, and can such minimally invasive approaches be considered reasonable alternatives to traditional approaches?’ We have also more clearly indicated how this question is answered in the introduction, methods, results and discussion. In the introduction (lines 105-112), we now clarify that this question is answered by our clinical outcome measures (both primary and secondary as defined in the methods). This point has been highlighted in the methodology under Outcome and Statistical Analysis (page 10, lines 187-189). We then address this question in the discussion further in the first paragraph (page 18, lines 306-309) and in section heading (page 20): Complication rates, functional recovery and LOS compared to prior reports, by comparing our overall results (especially focused on complications and LOS) with prior publications using traditional skull base approaches, and similarly on extent of resection and recurrence, in the next discussion section (page 21): Balancing goals of maximal tumor removal and complication avoidance.

Methods

- change tense to past in 2nd paragraph

- what other traditional skull base approaches do you include (line 118)? If no more, just remove this phrase.

Response:

This tense has been changed to past tense and the traditional skull base approaches section has been revised as requested in the same paragraph.

Table 1-

under Falx, approach selection: do you mean trans-falcine instead of trans-tentorial?

Response:

Thank you for noting this; we did mean trans-falcine. This has been corrected.

Results:

What did you classify as an MIS operation in the same patients? Did you include patients that were multiply operated on for recurrences as two separate events? What about staged procedures? This should be made more clear in the Methods.

Response:

This is an important point. All patients included in the keyhole cohort had an MIS approach. Being reoperated on for a recurrence is thus considered an outcome measure which we have in the results section as a secondary outcome (page 17, lines 291-296). Our overall recurrence rate was 13.9% (27/193) and of these 6 (3%) patients had repeat surgery with or without SRT or SRS. Regarding staged procedures, of the 4 patients, only one had a traditional pterional craniotomy combined with an endonasal approach (as detailed now page 11 lines 221-222).

Discussion:

Was there any consideration of the COVID-19 pandemic as a contributor to shorter LOS in 2020-2021?

There is some debate as to whether endoscopic endonasal procedures are "minimally invasive" and categorized along with open craniotomies. Please comment.

Response:

The reviewer raises an important point regarding the impact of the pandemic on LOS. In fact, we have published on this very topic and ICU utilization for all brain tumor patients (Mallari et al ref # 35 published in PLOS One in 2021). Even though COVID did play a role in considering earlier discharge, our use of MIS keyhole approaches began more than a decade before the pandemic allowing us to have a shorter LOS compared to other similar meningioma skull base cohort series. However, we now point out in the discussion (page 21, lines 366-376) that the median LOS in the last 71 cases was also likely further encouraged by our efforts to further reduce LOS and ICU given the resource and bed demands of the pandemic; we briefly describe the results of this paper.

Regarding whether endoscopic endonasal should be considered a “minimally invasive” approach and categorized with transcranial approaches, we have expanded upon this point in the introduction (page 4) and the discussion (page 18) as noted above. We emphasize that by including the endonasal route, we are endorsing a 360-degree minimally invasive keyhole approach that argues strongly to use the optimal route that minimizes brain and cranial nerve manipulation, promotes a rapid recovery yet allows maximal safe tumor removal. Thus, we respectfully argue that the endonasal approach be included in this “minimally invasive” armamentarium as we have already done in multiple prior reports (Thakur et al 2020, ref #28; Mallari et al 2021, ref #27; Mallari et al, 2021, ref #35).

The context for the current dataset was well set in this discussion, as it was compared to published series using traditional techniques; a range of percentages from previously published series in (page 19 second paragraph) would be helpful.

Response:

Thanks for this suggestion. On page 20, we had already provided a range of percentages on neurological and other complications, LOS and readmission rates. We also provide resection rates from the literature for different meningioma locations on pages 21-22 (lines 386-392).

Reviewer #2: The authors report a single-center cohort study of 329 patients who underwent neurosurgical resection of an intracranial meningioma during the study period, 2008-2021, focusing on individuals treated with keyhole approaches (rather than conventional craniotomies), which were applied for the resection of 213 operations on 193 patients. Parameters studied include a range of operative details, outcomes, and complications, all reported through a predominantly descriptive approach to analysis.

Overall, the review is an well-presented and timely series that describes a relatively large experience and will likely be of interest to many in the neurosurgical readership. Several issues warrant further attention prior to consideration for publication:

1. The major issue with this paper, which is manifest in several distinct ways, is the overenthusiastic scope. In my view, the authors are trying to accomplish far too much with a single study, which has rendered the manuscript difficult to ready, digest, or consider for generalization and potential applications to one's own practice. I would strongly recommend consideration for a balkanization of the work into several daughter projects—perhaps one descriptive analysis of the group's minimally invasive cranial practice, followed by others focusing on smaller study questions, such as the role of "dense adherence" between the tumor and surrounding neurovascular structures as an predictor of a subtotal resection, or difference between conventional and minimally invasive outcomes.

Response:

We appreciate the reviewer’s critique and agree that we have been expansive and inclusive in terms of this large meningioma data set. However, we would argue that in many if not most prior publications on meningioma surgery, a comprehensive review is not undertaken. For example, many papers will focus only on extent of resection and recurrence, while others will focus on complications, length of stay and/or quality of life. We suggest that to answer our central question (Introduction page 5), ‘What is the benefit of keyhole surgery on neurological and overall surgical recovery, and can such minimally invasive approaches be considered reasonable alternatives to traditional approaches?’ the entire patient experience needs to be considered to understand how patients fare and thus help derive an optimal approach for each patient. So, in that context we have attempted to look at our overall approach for meningiomas including all surgical approaches (including endoscopic endonasal) and look at our detailed outcomes. Only by completing such a comprehensive analysis, can the total impact of this approach be assessed. Thus, as we emphasize in the discussion, having a high rate of GTR or NTR but with an equally high rate of permanent neurological complications (as has been shown in many articles detailing outcomes of traditional skull base approaches) is not what the neurosurgical community should be striving for. While we note that we have some of the lowest complication rates and LOS in the literature, we acknowledge that ours is only one experience, and we need longer follow-up of this keyhole paradigm.

Additionally, we respectfully request that we not “balkanize” our results into smaller papers, and in fact, we have already done four such “balkanized” papers including: endonasal versus supraorbital for tuberculum sella meningiomas (Mallari et al, 2021, ref #27); invasive parasellar meningiomas treated by endoscopic endonasal route (Sivakumar et al 2019, ref #32 ), supraorbital versus minipterional approach for all tumors (Avery et al 2021; ref #34), and endoscope-assisted transfalcine approach (Barkhoudarian et al, 2017, ref #29). Thus, as we indicated on page 4 of introduction, this paper and analysis is trying to take a broader perspective on overall meningioma management focusing on the potential benefits of this 360-degree keyhole paradigm.

2. To that same end, candidly, the great majority of neurosurgeons would parse the endoscopic endonasal separately from the other keyhole approaches described—in particular, those with skull base expertise. Although both may be classified under the heading of "minimally invasive approaches," most of the factors that go into patient selection, operative planning, outcomes, etc. for endoscopic endonasal surgery are quite distinct from trans-cranial operations. The data from these patients would likely constitute an interesting stand-alone analysis; however, at the authors' discretion, leaving them in place as part of a larger descriptive-only series of "minimally invasive approaches" would not be unreasonable, (though any formal or informal comparisons would have to be stricken from such an analysis)

Response:

We appreciate this sentiment but as detailed above in prior responses, we have already written such stand-alone papers comparing keyhole approaches. For example, in managing tuberculum sella meningiomas by endonasal vs supraorbital route (Mallari et al, 2021, ref #27). In that paper we emphasize that the endonasal and supraorbital approaches are complimentary keyhole approaches and need to be considered together as to which is the optimal approach. Thus, we respectfully disagree and instead believe that including endoscopic endonasal in the keyhole paradigm and armamentarium is appropriate and is needed to help further advance the field of skull base surgery.

3. The authors have selected a very ambiguous definition for keyhole approaches, which would likely be subject to much debate within the skull base community. Additionally, they combine approaches with very different indications, risk profiles, etc. into a single analysis, for example the mini-pterional and retro-mastoid. Finally, many of the approaches sited as "keyhole" approaches are not practiced as such by all neurosurgeons, for example the trans-falcine approach, which refers to intra-cranial aspects of the dissection and approach rather than the craniotomy proper, and which can therefore be performed via a range of access ports of both large and small size. Considerable attention is required to better clarify and qualify these distinctions within the broader and highly diverse context of complex cranial surgery

Response:

We appreciate the concern about possible ambiguity of the definition of the keyhole approach. However, as we have attempted to emphasize in other responses to Reviewer #1 and #2, and in the revised manuscript methods section, we have clarified our definition of “keyhole approach”. We believe that all 6 approaches we include meet the criteria as defined in the consensus statement for keyhole concept (Lan et al 2019, ref#21) and in our prior papers. Inclusion of the trans-falcine approach for parafalcine meningiomas does introduce heterogeneity in the data albeit not significantly since the patient population in this group is only 2% of the cohort. Additionally, the parafalcine meningiomas included in the analysis are underlying eloquent cortex where use of a port would not be appropriate as it would undoubtedly disrupt the eloquent cortex one is trying save. Importantly, the transfalcine approach for removing falx meningiomas cannot be safely done ( in our opinion) without endoscopic angled visualization which allows one to achieve complete meningioma removal without brain retraction. Applying endoscopy (when needed) is one of the key technological tenets of MIS keyhole brain tumor surgery as stressed by Lan et al (2019).

4. Given the very heterogeneous sample, the results of any statistical testing conducted in this analysis would be subject to a very guarded interpretation at best. The authors should strongly consider removing all non-descriptive statistics from the main manuscript, and save them for separate subgroup analyses that would be reported separately, and where more homogeneity within the sample would potentially provide more meaningful interpretation

Response:

Thank you for the suggestion. The heterogeneity is certainly a limitation of the study which has been added in the limitation section (page 23, line 413). However, we have used Binomial Multivariate Regression analysis to minimize confounding factors, and which as requested by the reviewers is reported only in the supplemental data and not in the main manuscript.

5. The decision to analyze GTR and NTR (defined as 90-99% resection) as a single subgroup is controversial, and not consistent with most contemporary data regarding the phenotypic behavior of incompletely resected meningiomas. A more robust approach would be to combine NTR and STR, given that the presence of any known residual solid tumor is well-known to increase the risk of disease recurrence, and the need for additional treatments in the future

Response:

We agree with the reviewer that our grouping approach of GTR with NTR is somewhat controversial, however we emphasize throughout the paper that our surgical goal is always “maximal safe tumor removal” and we do show the GTR rates for the different approaches and tumor locations in both Tables 2 and 3. Given the highly invasive skull base tumor population, the frequent finding of vascular encasement, and that many patients had prior surgery and/or radiation, settling for NTR in many cases is a reasonable goal. Thus, we respectfully request to leave the GTR/NTR grouping as is, believing that keeping this grouping aligns with an overall minimally invasive paradigm that also strives for a low complication rate, short LOS and high QOL. Furthermore, although the results are limited by relatively shorter follow up, our tumor control rates are comparable to previously published rates as noted in the discussion (page 21, lines 381-385).

Reviewer #3: This is a nice institutional report on use of minimally invasive approaches for intracranial meningiomas in 193 patients. They have used various approaches including endoscopic, minipterional, suboccipital approaches with or without the use of endoscopes and have shown great outcome in terms of resection rate, postoperative complications and clinical outcome at follow up. The choice and rationality of various approaches have been described in detail along with illustrative cases and operative videos. I would commend the authors for their sincere efforts in compiling such detailed report.

Response:

We appreciate the acknowledgement. Thank you.

Few comments I would request the authors to address,

1. I feel the benefits of minimally approaches are partially offset by the high rate of reoperations due to residual disease. Overall reoperation rate of 22.1% including 32.4% in endoscopic endonasal cases, 21.9% in supraorbital cases seems high. Please comment.

Response:

Thank you for this comment and sorry for the confusion. The actual reoperation rate for tumor progression was 3.1%. To clarify, those rates of 22.1% (overall), 32.4% (endonasal) and 21.9 (supraorbital) listed in Table 2 indicate patients who came to us after having prior surgery. We have clarified this point in Table 2. The overall rate of tumor progression for the entire cohort during the study period (as we state in the results section on page 17, lines 291-293): Long-term tumor progression or recurrence) was 13.9% (27/193 patients) including 3.1% (6 patients) who had repeat surgery with or without SRS or SRT.

2. Please explain the high rate of new/worsened FLAIR changes with suboccipital and retrosigmoid approaches.

Response:

The higher rate of FLAIR changes at 3 months (12.5%) for the retromastoid approach may be related to the fact that this approach for many such meningiomas (CP angle and petroclival), the cerebellar hemisphere partially obstructs tumor access, and despite excellent neuroanesthesia, positioning and opening of cisterns for CSF creating a relaxed posterior fossa, some manipulation of the cerebellar hemisphere is unavoidable which may lead to new FLAIR changes in some cases. That said, since there is little data on early postoperative FLAIR changes in skull base meningioma series, we feel our rate of FLAIR changes is difficult to compare to prior reports. Notably, persistent FLAIR changes at 3 months were noted only in 5% of patients and were quite small and did not seem to correlate with lasting neurological deficits (Table 2). Overall, these rates appear to be quite low (including for retromastoid approach) compared for example to Bander et al (ref #46) which had a mean post-operative FLAIR volume of 8.3 cm3 in patients who had traditional transcranial removal of tuberculum meningiomas.

3. The secondary analysis is poor. I do not see any relevant result or discussion on factors affecting the GTR or complications. Although there is a supplementary table (Table-2), not much has been discussed on it.

Response:

Thank you for the suggestion. We highlight the factors influencing resectability in Table 3 and supplemental Table 2. The most important information in supplemental Table 2 is emphasizing that Invasion to CS-MC-Orbit-ITF/ Adherence to neurovascular structures strongly predicted non-GTR. This point is now addressed in a new section of the discussion (page 22, lines 404-411).

Submitted filename: Meningioma Keyhole PLOS ONE Reviewer Response 4-4-2022.docx

Click here for additional data file.

4 Jul 2022

Critical appraisal of minimally invasive keyhole surgery for intracranial meningioma in a large case series

PONE-D-22-03249R2

Dear Dr. Kelly,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

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18 Jul 2022

PONE-D-22-03249R2

Critical appraisal of minimally invasive keyhole surgery for intracranial meningioma in a large case series

Dear Dr. Kelly:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

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on behalf of

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PLOS ONE

Table 4

Major and minor complications, readmissions, reoperations and discharge status in 193 patients undergoing 213 keyhole operations for meningioma.

Major Surgical Complications (n = 23 patients)	25
Permanent Neurological Worsening	12(6%)
• Stroke	4(2%)
• New or Worsening Cranial Nerve Dysfunction	8 (4%)
Transient Neurological Worsening	1(0.5%)
• Persistent seizures with transient hemiparesis	1
Reoperations	10(5%)
• Delayed hematoma evacuation	2
• Reoperation for residual tumor (same admission)	2
• Reoperation for residual tumor (readmission)	1
• CSF leak repair	2
• Revision of sellar reconstruction (no CSF leak)	2
• Epistaxis needing surgical intervention	1
Meningitis	2 (1%)
Total Major Complications by Operation (p = 0.45)
• Redo-operation	7/47 (15%)
• First-time operation	18/166 (11%)
Minor Complications
• Sinusitis	3
• Mucocele	1
• Forehead numbness	11
• Frontalis paresis	7
• Frontalis palsy	2
• Delayed wound dehiscence	1
• Hardware malposition	1
Systemic Complications	2 (1%)
• Aspiration Pneumonia	1
• UTI	1
• DVT/PE/ MI	0
Delayed Radiation Induced Optic Neuropathy	1
Discharge to Home	201/213 (94%)
Readmissions Requiring Surgical Intervention (n = 4/213)	2%
• Residual tumor needing more surgery	1
• Delayed hematoma needing surgery	1
• CSF leak repair
• Epistaxis	1
Readmissions Managed Medically (n = 2/213)	1%
• UTI, Atrial fibrillation
• Hyponatremia	1

* One patient had both CSF leak and meningitis; one patient who had stroke had a multiply recurrent meningioma with prior surgery and RT and was the only mortality in the series