The transnasal transsphenoidal approach is the standard surgical approach nowadays for most pituitary tumors1 because it is associated with low morbidity and quick patient recovery,2–5 whereas the transcranial approach is reserved mainly for large and complex adenomas.6–8 Nevertheless, it remains a challenge to further improve patient comfort and further reduce postoperative morbidity.
Until now, postoperative CSF (pCSF) leaks and infections of the CNS such as meningitis are two recurring complications that remain a matter of debate.2–5 Meticulous repair of intraoperative CSF (iCSF) leaks and sellar reconstruction are of utmost importance in order to avoid these complications. However, there is no standard surgical technique.9
A variety of methods for sellar and dural reconstruction have been described in which either autologous10,11 or synthetic tissue is used.12–14 The use of fascia lata, nasoseptal flaps, or the transplantation of paraumbilical fat have been reported to reduce pCSF leaks,10,15 but they carry the risk of side effects and complications such as postoperative hematomas, pain or infections in the area of the graft, cosmetically unappealing abdominal and thigh scars, or anosmia. They can lead to patient discomfort, although the main surgical goal in terms of tumor resection without occurrence of a CSF fistula is achieved.2,16,17 A recent survey by Májovský et al. found that many neurosurgeons continue to use autologous material for sellar closure despite such potential complications.9
For many years we have been using a standardized technique for iCSF leak repair and sellar closure in which artificial material is used. Here, we revisited our technique and the surgical results in terms of the number of iCSF leaks, pCSF leaks, and CNS infections to challenge the more invasive methods with autologous material described above. In addition, risk factors for these complications were identified.
Methods
All patients undergoing transnasal transsphenoidal resection for a histologically proven pituitary adenoma between January 2013 and December 2019 were retrospectively screened. Patients with other tumor entities such as craniopharyngiomas or meningiomas were excluded because in our practice alternative techniques for dural repair and sellar closure are being used for extended transsphenoidal approaches and/or primarily intradural tumors.
All surgeries have been performed by the same surgeon, either by himself or by another surgeon under his intraoperative supervision. Only patients with documentation of iCSF leak repair and sellar reconstruction in the surgical report were included. If only a small amount of CSF flow without identification of a defect in the diaphragm was encountered, the leak was classified according to Esposito et al.10 as a minor leak (grade 1), whereas obvious CSF flow with or without a defect of the diaphragm was classified as a major leak (grade 2). The primary outcome measure was the number of pCSF leaks. The secondary outcome was the number of proven CNS infections. To identify risk factors for iCSF and pCSF leaks and CNS infections, clinical, histological, and perioperative data from the electronic medical record were collected and analyzed. Preoperative contrast-enhanced MR images were reviewed by a trained specialist in pituitary surgery for assessment of Knosp grading. The extent of resection was indicated according to the evaluation of postoperative MR images by the surgeon and/or radiologist at follow-up. This study has been approved by the local ethics committee.
Surgical Procedure
The transnasal transsphenoidal surgeries were performed either microsurgically, endoscopically, or with a combination of those methods. Disinfection of outer and inner nostrils was performed using a mucosal disinfectant (Octenisept). Afterward adrenaline-soaked cottonoids were placed in both nostrils and sterile draping was applied in a standard fashion. A mononostril approach was chosen for microsurgical procedures, and a binostril approach for endoscopic surgeries.
Sellar exposure extended routinely from one cavernous sinus to the other and from the sellar tubercle to the sellar floor; this was verified by radiography and/or neuronavigation. The dura mater was incised in a cruciate fashion. Ring curettes, dissectors, and grasping forceps were used for tumor resection.
In case of an iCSF leak after tumor resection, the defect in the diaphragm or suspected origin of CSF flow was covered by a thrombin- and fibrin-soaked gel foam (TachoSil). It was essential that the entire defect in the diaphragm, including the edges, was covered with this material. If no further CSF flow was evident during the Valsalva maneuver, a second thrombin- and fibrin-impregnated gel foam was used to cover the sellar opening. Here it was important that the edges of the sellar opening were cleared of mucosa, ensuring an adequate fixation of the gel foam. A gelatin sponge (Gelitta) was inserted in the sphenoid sinus for fixation (Fig. 1). Both nostrils were rinsed with iodine-containing disinfectant. Nasal tamponades were used for 1 to 2 days after surgery. A lumbar drain was not routinely placed.
Lateral view of the sphenoid sinus, the opened sella, and the diaphragm. iCSF leak (arrow) before (A) and after (B) application of the described technique. The asterisk marks the gelatin sponge, and the triangle marks the thrombin- and fibrin-soaked gel foam. © Moritz Ueberschaer, published with permission.
Statistical Analysis
A comparison of baseline variables between patient cohorts was performed using the chi-square test for categorical variables, the t-test for parametric variables, and the Mann-Whitney U-test for nonparametric variables. Multivariate analysis was performed using binary logistic regression models to estimate p value, hazard ratio, and 95% confidence interval. Statistical analysis was performed using a standard software package (SPSS Statistics version 25, IBM Corp.). The significance level was set at p < 0.05.
Results
Demographic Data
Among 417 surgeries for sellar tumors performed between January 2013 and December 2019, 368 transsphenoidal resections of pituitary adenomas in 357 patients were identified. Nine of 368 procedures had to be excluded because the surgical technique was not sufficiently documented (Fig. 2), and so 359 procedures in 348 patients were included in the final analysis.
Flowchart of patient selection and occurrence of CSF fistulas and meningitis.
The median age was 54 years (range 11–87 years), with a balanced sex distribution (177 female/171 male). There were 310 de novo and 49 recurrent tumors. In total, 307 of 359 tumors were macroadenomas, and 128 tumors were functioning adenomas according to preoperative laboratory tests (74 growth hormone, 27 adrenocorticotropic hormone, 25 prolactinoma, 2 thyroid-stimulating hormone). A total of 336 procedures were performed microsurgically, 20 endoscopically, and 3 were combined. Preoperative Knosp grade18,19 was available for 330 patients and the median grade was 2 (13 grade 0; 95 grade 1; 105 grade 2; 53 grade 3a; 17 grade 3b; 47 grade 4) (Table 1).
Demographic and descriptive data in patients who underwent surgery for pituitary adenomas
| No./Total (%) | No./Total w/ iCSF Leak (%) | No./Total w/ pCSF Leak (%) | No./Total w/ Meningitis (%) | |
|---|---|---|---|---|
| Female sex | 177 (50.9) | 42/96 (43.8) | 2/3 (66.7) | 2/3 (66.7) |
| Median age in yrs, range | 54, 11–87 | 54, 11–87 | 38, 38–43 | 38, 18–53 |
| De novo tumors | 310 (86.4) | 75/310 (24.2) | 3/310 (0.97) | 3/310 (0.97) |
| Recurrent tumors | 49 (13.6) | 21/49 (42.9) | 0/49 (0) | 0/49 (0) |
| Microadenomas | 52 (14.5) | 6/52 (11.5) | 0/52 (0) | 0/52 (0) |
| Macroadenomas | 307 (85.5) | 90/307 (29.3) | 3/307 (0.98) | 3/307 (0.98) |
| Tumor type | ||||
| Nonfunctioning adenomas | 231 (64.3) | 71/231 (30.7) | 2/231 (0.9) | 2/231 (0.9) |
| GH adenoma | 74 (20.6) | 14/74 (18.9) | 1/74 (1.4) | 1/74 (1.4) |
| ACTH adenoma | 27 (7.5) | 7/27 (25.9) | 0/27 (0) | 0/27 (0) |
| Prolactinoma | 25 (7.0) | 4/25 (16.0) | 0/25 (0) | 0/25 (0) |
| Other | 2 (0.6) | 0/2 (0) | 0/2 (0) | 0/2 (0) |
| Knosp grade | ||||
| 0 | 13/330 (3.9) | 2/91 (2.2) | 0/330 (0) | 0/330 (0) |
| 1 | 95/330 (28.8) | 23/91 (25.3) | 1/330 (0.3) | 1/330 (0.3) |
| 2 | 105/330 (31.8) | 31/91 (34.1) | 0/330 (0) | 1/330 (0.3) |
| 3 | 70/330 (21.2) | 19/91 (20.9) | 1/330 (0.3) | 1/330 (0.3) |
| 4 | 47/330 (14.2) | 16/91 (17.6) | 1/330 (0.3) | 0/330 (0) |
| Surgical technique | ||||
| Microsurgical | 336 (93.6) | 86/336 (25.6) | 3/336 (0.9) | 3/336 (0.9) |
| Endoscopic | 20 (5.6) | 10/20 (50.0) | 0/20 (0) | 0/20 (0) |
| Combined | 3 (0.8) | 1/3 (33.3) | 0/3 (0) | 0/3 (0) |
ACTH = adrenocorticotropic hormone; GH = growth hormone.
iCSF and pCSF Leaks
In total, 96 iCSF leaks (26.7%) were documented and classified as major leaks in 36 of 348 patients (10.3%) and minor leaks in 60 of 348 patients (17.2%) (Table 2). In 94 of 96 patients (97.9%), the technique described above was used for repair of the iCSF leak. In 2 of 96 patients (2.1%), an additional layer of collagen matrix (DuraGen) was used as an inlay.
Incidence of iCSF and pCSF leaks and meningitis in patients who underwent surgery for pituitary adenomas
| No. | % | |
|---|---|---|
| iCSF leaks | 96 | 26.7 |
| Major | 36 | 37.5 |
| Minor | 60 | 62.5 |
| pCSF leaks | 3 | 0.8 |
| Meningitis | 3 | 0.8 |
Risk factors for an iCSF leak according to univariate analysis were macroadenomas (p = 0.006) and recurrent adenomas (p = 0.032). An iCSF leak was encountered less often in functioning adenomas (p = 0.025). However, this could be due to the fact that almost all microadenomas were also functioning adenomas (50/52). Multivariate analysis showed that a recurrent tumor was an independent risk factor (p = 0.021), whereas macroadenomas were not (p = 0.051) (Table 3).
Risk factors for iCSF leaks according to uni- and multivariate analysis
| Univariate Analysis | Multivariate Analysis | |
|---|---|---|
| Macroadenoma | p = 0.006 | NS (p = 0.051) |
| Nonfunctioning adenoma | p = 0.025 | NS (p = 0.38) |
| Recurrent adenoma | p = 0.032 | p = 0.021 |
| Revision surgery | NS (p > 0.99) | |
| Intrasellar bleeding | NS (p = 0.54) | |
| Op technique; microscope/endoscope | NS (p = 0.15) |
NS = not significant.
In total, 3 pCSF leaks (0.8%) occurred during the postoperative course. In 1 of the 3 patients, the postoperative fistula was successfully treated by a lumbar drain for 5 days. The other 2 patients required revision surgery, with skull base reconstruction achieved using a nasoseptal flap. An iCSF leak was a significant risk factor for pCSF leak (p = 0.005). Revision surgeries were significantly more frequent in the case of a pCSF leak (p = 0.001) (Table 4).
Risk factors for pCSF leaks according to uni- and multivariate analysis
| Univariate Analysis | Multivariate Analysis | |
|---|---|---|
| iCSF leak | p = 0.005 | NS (p = 0.99) |
| Revision surgery | p = 0.001 | p = 0.008 |
| Intrasellar bleeding | p = 0.008 | NS (p = 0.45) |
| Op technique; microscope/endoscope | NS (p = 0.88) | |
| Macroadenoma | NS (p > 0.99) | |
| Recurrent adenoma | NS (p = 0.44) | |
| Functioning adenoma | NS (p > 0.99) |
CNS Infections
In total, 3 of 359 patients (0.8%) developed a postoperative CNS infection with clinical signs of meningitis and typical CSF laboratory findings. In 1 patient, Haemophilus influenzae was detected as the causative organism. This patient did not have an iCSF leak but experienced an upper respiratory tract infection. The other 2 patients with postoperative CNS infection had iCSF leaks. One patient with a minor iCSF leak also had a pCSF leak requiring a lumbar drain, with subsequent secondary CSF infection. The other patient had a major iCSF leak, but no signs of a pCSF leak. No causative organism was detected in these patients. pCSF leak was a significant risk factor for postoperative meningitis (p = 0.033) (Table 5). All patients recovered after antibiotic therapy without sequelae. No patient developed a host reaction or obvious infection caused by the application of synthetic material.
Risk factors for postoperative meningitis according to univariate analysis
| Univariate Analysis | |
|---|---|
| iCSF leak | NS (p = 0.18) |
| pCSF leak | p = 0.033 |
| Revision surgery | NS (p = 0.18) |
| Intrasellar bleeding | NS (p > 0.99) |
| Macroadenoma | NS (p > 0.99) |
| Recurrent adenoma | NS (p > 0.99) |
| Op technique; microscope/endoscope | NS (p = 0.9) |
Clinical and Biochemical Outcome
Documentation of postoperative MRI findings was available for 339 of 359 cases (94.4%). A gross-total resection was achieved in 270 of 339 patients (79.6%). A detailed listing of the extent of resection in relation to Knosp grading (available for 312 patients) is shown in Table 6.
Functional and oncological outcome data in patients who underwent surgery for pituitary adenomas
| No./Total (%) | |
|---|---|
| Gross-total resection* | 270/339 (79.6) |
| Knosp 0 | 10/11 (90.9) |
| Knosp 1 | 79/88 (89.8) |
| Knosp 2 | 83/99 (83.8) |
| Knosp 3a | 27/51 (52.9) |
| Knosp 3b | 11/17 (64.7) |
| Knosp 4 | 10/46 (21.7) |
| Tumor recurrence | 36/339 (10.6) |
| Treatment of recurrence | |
| Surgery | 12/36 (33.3) |
| CyberKnife radiation | 13/36 (36.1) |
| External-beam radiation | 4/36 (11.1) |
| Surgery & radiation | 5/36 (13.9) |
| Watch & wait | 2/36 (5.6) |
| Biochemical remission | |
| w/ surgery | 62/111 (55.9) |
| w/ surgery & additional meds | 41/111 (36.9) |
| No control despite surgery & meds | 8/111 (7.2) |
| Surgical remission according to Knosp grade | |
| Knosp 0 | 8/10 (80.0) |
| Knosp 1 | 29/47 (61.7) |
| Knosp 2 | 17/26 (65.4) |
| Knosp 3a | 1/6 (16.7) |
| Knosp 3b | 3/13 (23.1) |
| Visual field deficits | 159/355 (44.8) |
| Improved | 125/159 (78.6) |
| Stable | 27/159 (17.0) |
| Worsened | 7/159 (4.4) |
| Visual acuity | 123/355 (34.6) |
| Improved | 77/123 (62.6) |
| Stable | 44/123 (35.8) |
| Worsened | 2/123 (1.6) |
| Double vision | 18/355 (5.1) |
| Improved | 14/18 (77.8) |
| Stable | 4/18 (22.2) |
| Worsened/new | 6/355 (1.7) |
Meds = medications.
According to postoperative MRI.
The median time to follow-up was 31 months (range 1–107 months). Tumor recurrence occurred in 36 of 339 patients (10.6%), which was treated in most cases by repeat surgery and/or CyberKnife radiation.
Of 159 patients who presented with preoperative visual field impairment, 125 (78.6%) showed significant improvement in the postoperative course. Seven patients (4.4%) showed a slightly worsened and 27 patients (17.0%) had an unchanged visual field. One of the 7 patients with visual field deterioration had to be operated on again due to postoperative hemorrhage. The remaining patients had neither an intraoperative nor an imaging correlate to their clinical deterioration.
A total of 123 patients had preoperative visual acuity deficits. However, a relevant proportion of these patients had additional ocular disease (cataract, glaucoma, etc.). Visual acuity improved in 77 patients (62.6%), whereas it remained unchanged in 44 patients (35.8%). Two patients (1.6%) presented worsening of visual acuity. One of these patients underwent consecutive transcranial tumor resection for residual tumor. A total of 18 patients had preoperative oculomotor dysfunction. The symptoms improved in 14 patients (77.8%) and remained unchanged in the remaining patients (22.2%). Six of 355 cases (1.7%) presented with new double vision after surgery.
Endocrinological follow-up was available in 111 of 128 patients (86.7%) with functioning adenomas. Biochemical remission was achieved in 62 of 111 patients (55.9%) by surgery alone. A total of 41 of 111 patients (36.9%) had mild residual hormonal activity postoperatively. In these patients additional drug therapy resulted in biochemical remission. In the remaining patients (7.2%), adequate biochemical control could not be achieved (Table 6). In patients with residual biochemical activity, either postoperative MRI failed to detect tumor remnants or tumor remnants were located in the cavernous sinus and were considered difficult to access.
Discussion
Various techniques for iCSF leak repair and sellar reconstruction have been described. A recent systematic review describes the heterogeneity of methods for sellar reconstruction and CSF leak repair.11 Although some techniques have been published in which synthetic materials have been used with satisfying results,12,13,20 many surgeons still prefer to use autologous material such as fascia and fat.4,21–24
In our experience, the use of synthetic materials as described above is associated with a low risk for pCSF fistulas (0.8%) and CNS infections (0.8%). The large patient series of Ciric et al.4 and Agam et al.2 reported a slightly higher number of pCSF leaks (ranging from 2.6% to 3.9%) with the use of autologous material for iCSF leak repair and sellar closure. However, these patient cohorts also included some extended transsphenoidal approaches that might explain the slightly increased number of pCSF leaks. Accordingly, the number of iCSF leaks was higher in some of these patient cohorts.10,13 Nevertheless, the review of Khan et al.11 reported a pooled incidence of 4.6% for pCSF leaks in transsphenoidal procedures excluding the extended approaches, which is considerably higher compared to 0.8% in our series. In this review a wide range of surgical techniques was covered, none of which were clearly superior.
The large meta-analysis of Zhou et al.,25 focusing on risk factors for postoperative CNS infection, found an iCSF leak to be a predisposing condition for a pCSF fistula and ensuing CNS infection, which is consistent with our findings. In both the meta-analysis and our patient population, individuals with recurrent tumors and macroadenomas were at risk for an iCSF leak.
Given that a conservative surgical approach could also explain a lower rate of iCSF leaks, we evaluated both the imaging and functional outcomes of the cohort. The results show that the endocrinological outcome and the rate of complete tumor resections as well as the visual outcome are in line with other published reports.26–28 Thus, we assume that there is no bias due to a conservative surgical approach.
The number of patients with postoperative meningitis was comparably low, with 0.8% in our series and 0.45%–1% in the aforementioned studies.4 Esposito et al. suggested a graded repair depending on the extent of the iCSF leak.10 In our experience this was not necessary when our technique as described above was applied for grade 1 and 2 CSF leaks.
None of our patients developed a host reaction or obvious infection caused by the application of synthetic material. Furthermore, we did not experience any interfering imaging artifacts on CT or MRI with the described technique. Occasionally the differentiation between tumor remnant, scar tissue, and the synthetic material was difficult on postoperative MRI. This problem is also encountered using autologous material, as described by Kremer et al.29 Other disadvantages of autologous materials such as time-consuming separate incisions that cause cosmetically unappealing abdominal and thigh scars could be avoided.
To our knowledge, this is the largest cohort in which a specific technique has been studied for skull base reconstruction after transsphenoidal resection of pituitary adenomas using synthetic material. In contrast to the publication by Seda et al.,14 which also describes a surgical technique in which synthetic material (fibrin glue) is used, in our experience a lumbar drain is not required postoperatively.
As Khan et al.11 noted in their review, to date there has been a wide range of surgical techniques used, none of which are clearly superior. Although we are aware that the retrospective study design does not allow us to demonstrate superiority over other surgical techniques, we were able to show that our technique is safe and effective. A prospective randomized trial with a more invasive technique in the control arm seems barely justifiable in light of our satisfying results.
Conclusions
Patients with recurrent adenomas are at risk of an iCSF leakage with a subsequently higher risk for a pCSF leak. Furthermore, a pCSF leak was the predominant risk factor for postoperative meningitis. Overall, our surgical technique, in which we used solely synthetic material for sellar closure, resulted in a very low rate of pCSF leaks and meningitis. Hence, this technique is safe and improves patient comfort by avoiding the disadvantages of autologous graft harvesting.
Disclosures
Dr. Tonn received research grants from Munich Surgical Imaging and Novocure.
Author Contributions
Conception and design: Ueberschaer. Acquisition of data: Ueberschaer, Katzendobler. Analysis and interpretation of data: Ueberschaer, Biczok, Greve. Drafting the article: Ueberschaer. Critically revising the article: Katzendobler, Biczok, Schmutzer, Greve, Tonn, Thorsteinsdottir, Rachinger. Approved the final version of the manuscript on behalf of all authors: Ueberschaer. Statistical analysis: Biczok, Greve. Administrative/technical/material support: Rachinger.
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