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NEUROCIRUGÍA www.elsevier.es/neurocirugia
Clinical Research
Postoperative CSF leakages after transsphenoidal surgery for pituitary adenomas: Analysis of a series of 302 surgical procedures夽 ˜ b,f , Amparo Platero c , Francisco J. Tarazona d,f , Pedro Riesgo a,f,∗ , Paz Marino Carmen Fajardo e,f , José L. Llácer a,f , Vicente Rovira a , Rubén Rodríguez a,g , Alain Flor-Goikoetxea a , José Piquer a,g a
Servicio de Neurocirugía, Hospital Universitario de la Ribera, Alzira, Valencia, Spain Unidad Docente Multidisciplinar de Atención Familiar y Comunitaria, Castellón, Spain c Servicio de Otorrinolaringología, Hospital Universitario de la Ribera, Alzira, Valencia, Spain d Servicio de Medicina Interna, Hospital Universitario de la Ribera, Alzira, Valencia, Spain e Servicio de Endocrinología, Hospital Universitario de la Ribera, Alzira, Valencia, Spain f Facultad de Medicina, Universidad Católica de Valencia «San Vicente Mártir», Valencia, Spain g Cátedra de Neurociencias, CEU Universidad Cardenal Herrera/Fundación Vithas-NISA Valencia, Valencia, Spain b
a r t i c l e
i n f o
a b s t r a c t
Article history:
Introduction: Transsphenoidal surgical removal is the preferred treatment of most pituitary
Received 3 August 2018
adenomas. Postoperative cerebrospinal fluid (CSF) leakage is the leading cause of morbidity
Accepted 14 March 2019
after this procedure, with an incidence rate that varies from 0.5 to 15% in the main published
Available online 12 July 2019
series.
Keywords:
tive CSF leakage in a sample of surgeries performed at the University Hospital of La Ribera
Postoperative CSF leak
by the same surgical team. The secondary objectives were to: ascertain the distinctive fea-
Objectives: The primary objective of this study was to establish the incidence of postopera-
Transsphenoidal surgery
tures between patients with and without postoperative CSF leakage, identify risk factors for
Pituitary adenoma
their development, evaluate the relationship between the surgical technique for closing the
Surgical complications
sella turcica and the onset of postoperative CSF leakage and evaluate different treatment regimens for this complication. Methods: The data of 302 consecutive transsphenoidal surgical procedures for pituitary adenoma removal which were performed between 1999 and 2017 were retrospectively reviewed. Results and conclusions: The incidence of postoperative CSF leakage in our series was 2.3% (in accordance with similar published studies). It was possible to correlate intraoperative CSF
DOI of original article: https://doi.org/10.1016/j.neucir.2019.03.003. ˜ P, Platero A, Tarazona FJ, Fajardo C, Llácer JL, et al. Fístulas posquirúrgicas de líquido Please cite this article as: Riesgo P, Marino cefalorraquídeo tras cirugía transesfenoidal de adenomas hipofisarios: análisis de una serie de 302 intervenciones. Neurocirugia. 2019. https://doi.org/10.1016/j.neucir.2019.03.003 ∗ Corresponding author. E-mail address:
[email protected] (P. Riesgo). ˜ ˜ S.L.U. All rights reserved. 2529-8496/© 2019 Sociedad Espanola de Neurocirug´ıa. Published by Elsevier Espana, 夽
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leakage with two variables: pituitary macroadenoma and tumours with suprasellar extension (p < 0.005). This correlation did not exist for postoperative CSF leakage. We found a statistically significant correlation between intraoperative and postoperative CSF leakage (p < 0.005). Due to the low incidence of postoperative CSF leakage in our series, it was not possible to identify risk factors for its development. ˜ ˜ S.L.U. All rights © 2019 Sociedad Espanola de Neurocirug´ıa. Published by Elsevier Espana, reserved.
Fístulas posquirúrgicas de líquido cefalorraquídeo tras cirugía transesfenoidal de adenomas hipofisarios: análisis de una serie de 302 intervenciones r e s u m e n Palabras clave:
Introducción: El tratamiento de elección para la mayor parte de los adenomas hipofisarios
Fístula de LCR posquirúrgica
es su resección quirúrgica por vía transesfenoidal. Las fístulas posquirúrgicas de líquido
Cirugía transesfenoidal
cefalorraquídeo (LCR) constituyen una de las complicaciones más características y poten-
Adenoma hipofisario
cialmente graves de este tratamiento. Su incidencia es variable para las principales series
Complicaciones quirúrgicas
publicadas en la literatura, con un rango del 0,5 al 15%. Objetivos: El objetivo principal de nuestro trabajo fue establecer la incidencia de fístulas de LCR tras cirugía transesfenoidal en una muestra de 302 intervenciones realizadas en pacientes afectos de adenomas hipofisarios en el Hospital Universitario de la Ribera y por un mismo equipo quirúrgico. Como objetivos secundarios se plantearon: conocer las características diferenciales entre pacientes con y sin fístulas posquirúrgicas de LCR, detectar factores de riesgo para su desarrollo, valorar la relación entre la técnica de cierre de la silla turca y la aparición de fístulas posquirúrgicas de LCR y valorar las diferentes pautas de tratamiento de la complicación. Métodos: Se realizó un estudio descriptivo retrospectivo basado en una revisión sistemática de 302 casos de adenomas hipofisarios intervenidos en nuestro centro a través de una vía ˜ de abordaje transesfenoidal entre los anos 1999 y 2017. Resultados y conclusiones: La incidencia de fístulas posquirúrgicas de LCR en nuestra serie fue del 2,3% (concordante con la descrita en series amplias previamente publicadas). La aparición de una fístula intraoperatoria de LCR se correlacionó con dos variables del estudio: macroadenomas y tumores con extensión supraselar (p < 0,005). Esta correlación no existió para fístulas posquirúrgicas. Sí fue posible establecer una relación estadísticamente significativa entre la aparición de fístulas intraoperatorias y posquirúrgicas de LCR (p < 0,005). La baja incidencia de fístulas posquirúrgicas de LCR tras cirugía transesfenoidal de adenomas hipofisarios en nuestra casuística no permitió identificar factores de riesgo para su desarrollo. ˜ ˜ S.L.U. Todos de Neurocirug´ıa. Publicado por Elsevier Espana, © 2019 Sociedad Espanola los derechos reservados.
Introduction Pituitary adenomas (PA) represent approximately 10% of intracranial tumours1 and transsphenoidal surgical removal is, at present, first-choice therapy for many.2–8 The aim of this surgical treatment is to achieve control of the compressive symptoms the tumour mass exerts on the adjacent structures, remission of hormone hyperproduction for functioning tumours and the preservation of normal pituitary function.9 Although transsphenoidal surgery (TS) for PA is considered safe due to its low perioperative morbidity and mortality rates,10 it is not free of possible complications, with
cerebrospinal fluid (CSF) leaks being one of the most characteristic and potentially severe.11 The purpose of our article is to analyse and describe the incidence and risk factors for the development of postoperative CSF leaks after TS in a series of interventions on patients with PA at Hospital Universitario de la Ribera [Ribera University Hospital].
Material and methods From January 1999 to February 2017, a total of 302 surgical interventions involving transsphenoidal tumour resection were performed at our hospital on patients diagnosed with
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PA. Our study retrospectively analyses and describes the incidence and risk factors for the development of postoperative CSF leaks in this series of cases. All patients signed an informed consent form which included authorisation for the use of data and graphic or biological material for teaching or scientific purposes. This study was authorised by the Hospital Universitario de la Ribera Ethics and Research Committee and was developed by one of the authors (PM) as a final thesis for their degree in Medicine and Surgery. All were assessed clinically, endocrinologically and radiologically. Depending on their functional profile, a preoperative diagnosis of prolactinoma, non-functioning adenoma, acromegaly, Cushing’s disease or thyrotropinoma was established for each case. In all cases, a pituitary MRI and a sinus CT were performed with coronal and sagittal reconstructions. The imaging tests were always reviewed by a neuroradiologist. The radiological report included diagnosis by imaging, lesion size, cavernous sinus invasion following the Knosp et al. classification,12 tumour extension to the sphenoid sinus and suprasellar space, the existence or not of compression of the optic chiasm, the existence or not of intratumoral bleeding and the degree of pneumatisation and septal pattern in the sphenoid sinus. The interventions were performed by the same team consisting of an otolaryngologist and a neurosurgeon. In all cases, a transseptal transsphenoidal microsurgical approach was used through nasal access, with the aim of performing as extensive as possible selective resection of the PA.
Statistical study The data was obtained from the electronic medical records ® used in our hospital (SIAS software, Ribera Salud II UTE, Alzira, Comunidad Valenciana, Spain). Our study included a large number of variables in the statistical analysis which were selected after reviewing the literature related to the subject: age of the patient at the time of surgery; gender; clinical diagnosis; previous TS, previous radiotherapy; size of the adenoma (microadenoma or macroadenoma and larger diameter); invasion of the cavernous sinus12 ; sphenoid sinus invasion; suprasellar extension; date of surgery; degree of resection; pathology diagnosis; diagnosis of atypical adenoma; intraoperative CSF leak; postoperative CSF leak; skull-base reconstruction technique; treatment of postoperative leaks by lumboperitoneal CSF shunt; treatment of postoperative leaks by revision of the approach; number of surgical revisions required; resolution of the leak; and deaths. The data related to these variables were collected in an Excel spreadsheet file, 2003 version. The statistical analysis was performed with the SPSS program version 21.0 for Windows (Released 2012, Armonk, NY: IBM Corp). The categorical variables were described as gross value and percentages and the quantitative variables as central value, mean, standard deviation and 95% confidence interval. In the bivariate analysis, the Pearson chi square test was used for the comparison of means and the Mantel-Haenszel test
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statistic to detect linear trends in proportions. A p value <0.05 was considered significant.
Results Our series included 302 interventions; 167 (55.3%) were on females and 135 on males (44.3%), with a mean age of 47.7 ± 14.8 years (13–91). The endocrinological diagnosis was non-functioning PA in 110 (36.4%) cases, acromegaly in 87 (28.8%), Cushing’s disease in 74 (24.5%), prolactinoma in 13 (4.3%) and thyrotropinoma in 3 (1%). In 10 cases (3.3%) a pituitary apoplexy was diagnosed. In 27 cases (8.9%) there was a history of previous TS and 3 patients (1%) had been treated with radiotherapy applied to the sellar region. Based on the imaging study performed with pituitary MRI, 227 cases (75.2%) were classified as macroadenomas and 72 (23.8%) as microadenomas; in 3 cases (1%), diagnosed with Cushing’s disease, there were no tumour images. The mean diameter of the tumours was 19.0 ± 15.2 mm (0–76). There was no invasion of the cavernous sinus in 132 cases (43.7%), there was grade 1 invasion according to the Knosp classification in 64 (21.2%), grade 2 in 43 (14.2%), grade 3 in 40 (13.2%) and grade 4 in 23 cases (7.6%). In 79 cases (26.2%) there was invasion of the sphenoid sinus and 130 tumours (43%) had suprasellar extension. In 192 cases the degree of resection was total (63.6%), in 50 it was subtotal (16.6%), in 58 partial (19.2%) and in 2 it was not assessable (0.6%). In 61 interventions (20.2%) an intraoperative CSF leak occurred. After completion of the tumour resection, the closure technique used systematically in the first 12 interventions (4%), performed from 1999 to 2003, was an autologous fat and fascia ® lata graft sealed with fibrin gel (Tissucol , Baxter, Deerfield, IL, USA). In the subsequent group of 33 interventions (10.9%), performed from 2003 to 2007, a fat and abdominal wall fascia graft sealed with fibrin gel was used systematically. In the remaining 257 interventions (85.1%), the skull-base reconstruction was performed with the same technique only in cases where an intraoperative CSF leak occurred; the others had only the partial filling of the sellar space and the sphenoid sinus with fibrin gel. There were a total of 7 (2.3%) cases of postoperative CSF leak after TS for PA. Five cases (71.4%) were macroadenomas, and 2 (28.6%) microadenomas. The mean maximum diameter was 17.7 mm. In 5 cases (71.4%) there was suprasellar extension and invasion of the sphenoid sinus. One of the patients had undergone previous TS. In 4 of the cases (57.1%) an intraoperative CSF leak had been identified and sellar reconstruction had then been carried out. Five cases of CSF leak appeared in the immediate postoperative period: one on day seven after aggressive mechanical ventilation parameters had been necessary because of a respiratory complication; and in the others it was delayed, occurring 2 months after the surgery. The patient who developed a late-onset CSF leak had Staphylococcus aureus meningitis at the time of hospital admission. There was only
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one other case of postoperative meningitis in our series, in a patient who did not have a postoperative CSF leak. The bivariate statistical analysis identified a statistically significant correlation between macroadenomas and suprasellar extension of the tumour and the occurrence of intraoperative CSF leaks. Lastly, the identification of an intraoperative CSF leak during TS for pituitary adenomas was the only factor for which a statistically significant correlation was found (p < 0.014) with the development of postoperative CSF leaks in our series. One of the cases that appeared soon after surgery was treated by placement of an external lumbar drainage system for 5 days. The remaining cases returned to theatre within 24 h after the onset of CSF rhinorrhoea, with revision of the approach, creation of a new seal and reconstruction of the floor of the sella turcica and the sphenoid sinus with autologous fascia, muscle and fat grafts. Fibrin gel was used as sealing material after reconstruction in all these cases. In the patient on mechanical ventilation, an external lumbar drainage system was also inserted which was maintained for 7 days. In all cases the postoperative CSF leak resolved after treatment. The patient who suffered a respiratory complication and required aggressive and prolonged mechanical ventilation developed sepsis with multi-organ failure and died on day 45 post-surgery. This patient had had a CSF leak which resolved after treatment (described above) and she did not have meningitis. The post-mortem established the cause of death as bilateral necrotising pneumonia. The mortality rate in our series was 0.3%.
Discussion The surgical removal of PA by TS is currently first-choice therapy for many cases of PA.13 The appearance of CSF rhinorrhoea due to a postoperative CSF leak is one of the typical complications of TS. It is a serious complication because it increases the likelihood of secondary meningitis, which can lead to postoperative death. The incidence of postoperative CSF leaks after TS for pituitary adenomas varies, but is reported in 0.5%–15% of cases.13–18 Seven of our patients developed this complication, with an incidence in our case series of 2.3%, which is within the range of large series published in the literature. Numerous published studies have linked multiple clinical, radiological or surgical factors to the development of postoperative CSF leak after TS for PA. Among the clinical features, it is worth mentioning a high BMI,16 the age of the patients, having previously undergone TS or having had prior local radiotherapy.13,19 In terms of radiological characteristics, CSF leak has been associated with larger adenomas and a tendency to local invasion with extension into the parasellar space. Surgical characteristics include poor definition of the tumour borders and greater consistency of the lesion.13 However, the existence of an intraoperative CSF leak, taken in isolation, is the factor a larger number of authors associate with the development of postoperative leaks.13–15,17,20–22 Our study included a large number of variables in the statistical analysis which were selected after reviewing the
literature related to the subject: age of the patient at the time of surgery; gender; clinical diagnosis; previous TS, previous radiotherapy; size of the adenoma (microadenoma or macroadenoma and larger diameter); invasion of the cavernous sinus12 ; sphenoid sinus invasion; suprasellar extension; date of surgery; degree of resection; pathology diagnosis; diagnosis of atypical adenoma; intraoperative CSF leak; postoperative CSF leak; skull-base reconstruction technique; or death. The low incidence of postoperative CSF leak after TS for PA among our cases meant that we were unable to obtain statistically significant data identifying any of the variables studied as a prognostic factor for the development of this complication. A statistically significant correlation was found between macroadenomas and suprasellar extension of the tumour and intraoperative CSF leak. The identification of an intraoperative CSF leak was the only factor for which a statistically significant correlation was found with the development of postoperative CSF leaks in our series. There are different options for closure and reconstruction of the sellar space after transsphenoidal surgical resection of PA.23 Some authors perform systematic reconstruction with different types of autologous graft, with certain differences in the technique and tissue used depending on whether or not an intraoperative CSF leak is detected.21,24,25 Other authors, such as Romero et al.,15 choose to systematically use an artificial dural substitute and a fibrin gel seal, regardless of whether or not they detect an intraoperative leak.26,27 Our closure technique has varied over the period of time of the study, from systematic reconstruction in the first 45 interventions to reconstruction only in cases of intraoperative leak. Not performing systematic reconstruction in the absence of an intraoperative CSF leak did not lead to an increase in the incidence of postoperative leaks in our case series. There have been reports in the literature of an association between the experience of the surgical team and the outcomes and complication rate in TS for PA.20,28 In an article published by Ciric et al.21 in 1997, a total of 14 specific complications were analysed, including post-surgical CSF leaks after TS for PA, collecting data from 958 surgeons treating pituitary disease and separating them into three groups according to the number of previous interventions they had carried out (<200, 200–500, >500). These authors concluded that there was a correlation between a lower incidence of postoperative leak and a greater number of surgical interventions. On our part, considering two consecutive homogeneous groups within the surgical series (Fig. 1), the first of 147 cases operated on consecutively in the 1999–2010 time interval versus the second, of 155 cases consecutively operated on in the 2010–2017 period, there was a lower incidence of postoperative CSF leaks in the second (4.1% versus 0.6%). The decrease in the incidence of postoperative CSF leaks between these two consecutive groups of patients could corroborate the idea, as it is probably related to the acquisition of greater experience, according to the learning curve of the surgical team. Over the course of recent years there has been a significant increase in the use of techniques involving an endoscopic approach to PA. Advantages include the ability to expand
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Fig. 1 – Incidence of postoperative cerebrospinal fluid (CSF) leaks in relation to all transsphenoidal surgery (TS) in pituitary adenomas (PA) included in this study.
the resection of lesions thanks to the greatly improved the visual field. These techniques are considered to be minimally invasive and they are attributed a low incidence of complications compared to microsurgery techniques. Nevertheless, in terms of the incidence of postoperative CSF leaks after PA surgery, it might be thought that the greater scope of the endoscopic approaches (particularly the extended ones), with greater disruption of bone and meningeal structures in the skull base, could perhaps make this complication more likely to occur, despite using advanced preventive sealing techniques, such as naso-septal flaps. We have no data of our own that we can provide in relation to the endoscopic technique. As an example, however, in 2014 Halvorsen et al.28 compared the incidence of complications in a series of 506 patients who were operated on in the same centre from 2002 to 2011. The first 268 had a microsurgery technique and the remaining 238 an endoscopic technique. They reported postoperative CSF leaks as the most common complication in their series (4.7%) and found no statistically significant differences according to the surgical technique used. Expanding on this subject, to our knowledge, there is no available evidence to help us determine which of the two techniques has a greater risk of producing this complication. There are two main treatment options for CSF leaks after TS. The first consists of the revision of the approach and the packing in multiple layers of the area corresponding to the sellar diaphragm, the floor of the sella turcica and the sphenoid sinus. Fat, fascia, muscle and autologous bone are usually used for this, as well as sealing with different materials such as synthetic polymers and metal meshes. There is also the alternative of using a lumbar CSF drainage system (external or internal) to reduce intracranial pressure and thereby facilitate healing of the dehisced area through which the leak has occurred.19,29,30 In our practice, surgical revision of the approach within the first 24 h after development of postoperative CSF rhinorrhoea
is the treatment of choice for this complication, as it allows the skull base to be sealed and prevents communication of the surgical area with the intracranial space immediately which, in our opinion, decreases the likelihood of life-threatening postoperative meningitis. The use of external lumbar drainage as exclusive treatment of a postoperative CSF leak is an alternative measure which we only consider as an exception in cases of CSF rhinorrhoea with very low output. One of our patients began to report a sensation of swallowing fluid 48 h after surgery and she was found to have CSF rhinorrhoea, with exit of a few droplets of CSF, which appeared exclusively during prolonged provocative manoeuvres. She was treated by placement of an external lumbar CSF drainage system for 5 days, which resolved the symptoms. In cases of CSF leaks considered difficult to resolve, we opted to combine temporary insertion of a lumbar CSF drainage system with early surgical revision and reconstruction. This was the case with one of our patients, who developed high-output CSF rhinorrhoea on day seven postsurgery after the use of aggressive mechanical ventilation to treat severe respiratory distress. In view of the possibility of further recurrence of a previously treated difficult-to-resolve leak, although this did not occur in any of our patients, we propose the option of performing an additional transsphenoidal surgical revision and implanting a definitive lumboperitoneal shunt system.
Conclusions The incidence of post-surgical CSF leak after TS for pituitary adenomas in our series of 302 interventions at Hospital Universitario de la Ribera from 1999 to 2017 was 2.3% and is within the range published in the referenced series from the literature.
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A statistically significant correlation was found between macroadenomas and/or existence of suprasellar extension of the adenoma and intraoperative CSF leak. An intraoperative CSF leak during TS for pituitary adenomas was the only factor for which a statistically significant correlation was found with the development of postoperative CSF leaks in our series. Not performing systematic reconstruction of the floor of the sella turcica in the absence of an intraoperative CSF leak did not lead to an increase in the incidence of postoperative leaks. The retrospective and observational nature of our study are limitations. Moreover, although the case series studied initially seemed suitable for our objectives, the low incidence of postoperative CSF leaks after TS for PA in our series did not enable us to identify specific risk factors.
Conflicts of interest The authors declare that they have no conflicts of interest.
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