Challenges in cerebrospinal fluid shunting in patients with glioblastoma

Challenges in cerebrospinal fluid shunting in patients with glioblastoma Background: Cerebrospinal fluid (CSF) circulation disturbances may occur during the course of disease in patients with glioblastoma. Ventriculoperitoneal shunting has generally been recommended to improve symptoms in glio- blastoma patients. Shunt implantation for patients with glioblastoma, however, presents as a complex situation and produces different problems to shunting in other contexts. Information on complications of shunting glioma patients has rarely been the subject of investigation. In this retrospective study, we analysed restropectively the course and outcome of glioblastoma-related CSF circulation disturbances after shunt management in a consecutive series of patients within a period of over a decade. Methods: Thirty of 723 patients with histopathologically-confirmed glioblastoma diagnosed from 2002 to 2016 at the Department of Neurosurgery, Hannover Medical School, underwent shunting for CSF circulation disorders. Treatment history of glioblastoma and all procedures associated with shunt implementation were analyzed. Data on follow-up, time to progression and survival rates were obtained by review of hospital charts and supplemented by phone interviews with the patients, their relations or the primary physicians. Results: Mean age at the time of diagnosis of glioblastoma was 43 years. Five types of CSF circulation disturbances were identified: obstructive hydrocephalus (n = 9), communicating hydrocephalus (n = 15), external hydrocephalus (n = 3), trapped lateral ventricle (n = 1), and expanding fluid collection in the resection cavity (n = 2). All patients showed clinical deterioration. Procedures for CSF diversion were ventriculoperitoneal shunt (n = 21), subduroperito- neal shunt (n = 3), and cystoperitoneal shunt (n = 2). In patients with lower Karnofsky Performance Score (KPS) (< 60), there was a significant improvement of median KPS after shunt implantation (p = 0.019). Shunt revision was neces- sary in 9 patients (single revision, n = 6; multiple revisions, n = 3) due to catheter obstruction, catheter dislocation, valve defect, and infection. Twenty-eight patients died due to disease progression during a median follow-up time of 88 months. The median overall survival time after diagnosis of glioblastoma was 10.18 months. Conclusions: CSF shunting in glioblastoma patients encounters more challenge and is associated with increased risk of complications, but these can be usually managed by revision surgeries. CSF shunting improves neurological func- tion temporarily, enhances quality of life in most patients although it is not known if survival rate is improved. Keywords: Glioblastoma, Ventriculoperitoneal shunt, Hydrocephalus, Cerebrospinal fluid *Correspondence: hong.bujung@mh-hannover.de Department of Neurosurgery, Hannover Medical School, Hannover, Germany Full list of author information is available at the end of the article © The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creat iveco mmons .org/licen ses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/ publi cdoma in/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Hong et al. Fluids Barriers CNS (2018) 15:16 Page 2 of 9 After CSF shunting, all patients had X-ray shuntograms Background confirming valve settings and the location of catheters. Glioblastoma still has a dismal prognosis: significantly Microsurgical resection for tumor removal was per- limiting quality of life and survival of patients suffering formed according to standard surgical techniques from this aggressive tumor [1, 2]. Maximal safe surgical for tumors not involving eloquent areas of the brain. resection followed by adjuvant combined radiochemo- Depending on tumor localization, neuronavigation, elec- therapy is one of the most important factors to improve trophysiological mapping, and/or 5-aminolevulinic acid overall survival of patients [3–5]. Cerebrospinal fluid (5-ALA) were applied intraoperatively [16, 17]. Gross (CSF) circulation disturbances may occur during the total microsurgical resection was achieved when the neu- course of disease and reduce a patient’s quality of life as rosurgeon determined that all areas of visible tumor were well as treatment capability significantly. Neurological resected intraoperatively. Resection was defined as sub - deterioration associated with the development of hydro- total when remnants of tumor were left behind. cephalus has been observed in 5–10% of patients with Shunt surgery was performed after diagnosis of a clin- glioblastoma [6–13]. ically-relevant CSF circulation disturbance. Depending Ventriculoperitoneal shunting has generally been on the cause of the CSF circulation disturbance, ventricu- recommended to improve symptoms in glioblastoma loperitoneal, subduroperitoneal, or cystoperitoneal CSF patients with CSF circulation disturbances [6–13]. diversion was performed. Programmable valve systems Shunt implantation in patients with glioblastoma, how- were implanted in 28 patients. While only four patients ever, presents as a complex situation and produces dif- had a programmable valve (Codman & Shurtleff, Inc. ferent problems to shunting in other contexts [14, 15]. Raynham, USA), in 24 patients, this was combined with Although hydrocephalus is seen in a significant number implantation of a gravitational anti-siphon device [18]. of patients with glioblastoma, there are only a few studies Two patients received a medium pressure CSF-flow con - which have concentrated on outcome of CSF shunting in trol valve system (Medtronic, Minneapolis, MN, USA). this fragile group of patients [6, 8–13, 27]. Even more so, Due to poor accessibility of the ventricle system, a neuro- information on complications of shunting rarely has been navigation system was used for insertion of the ventricu- the subject of investigation [11–13, 54]. lar catheter in three patients [16, 17]. Against this background, we sought to analyse the course and outcome of glioblastoma-related CSF circula- Statistical methods tion disturbances after shunt management in a consecu- Sigma Stat software (version 3.5; Systat Software, Inc. tive series of patients within a period of over a decade. California, USA) was used for statistical analysis. To ana- lyse the differences between groups, Student’s t test was Methods used. The survival rate was estimated by the Kaplan– For this retrospective study a data base of 723 glio- Meier method. Summary data were presented as median. blastoma patients with histopathologically-confirmed Statistical significance was defined as a probability value glioblastoma diagnosed from 2002 to 2016 at the Depart- less than 0.05. Measures were presented as mean ± stand- ment of Neurosurgery, Hannover Medical School, was ard deviations. reviewed. All patients that underwent shunting for CSF circulation disorders were included. Treatment history of Results glioblastoma, including surgical interventions and post- Patient characteristics operative therapy were reviewed. In addition, all proce- Overall, 30/723 patients with histopathologically-proven dures associated with shunt implementation, including glioblastoma (4.2%) underwent CSF shunting procedures type of shunt, technical problems, and complications, during the study period. Patient characteristics are pre- were analysed. Data on follow-up, time to progression sented in Table  1. Mean age at the time of diagnosis of and survival rates were obtained by review of hospital glioblastoma was 43  years (range 1 to 79  years). Initial charts and supplemented by phone interviews with the surgical treatment included stereotactic biopsy (n = 7), patients, their relations or the primary physicians. partial resection (n = 6), subtotal resection (n = 8), Radiological evaluation of glioblastoma and tumor pro- and complete resection (n = 9). Two of 7 patients, who gression, in general, was made using contrast-enhanced had stereotactic biopsy, underwent subsequent surgi- MRI. CSF circulation disturbance was defined as dispro - cal resection after confirmation of the histopathological portionate enlargement of inner and/or outer CSF spaces diagnosis of glioblastoma, since tumor location was con- within the cranial vault or CSF collections in the resec- sidered accessible. In 18 patients the infiltrated ependy - tion cavity in postoperative imaging studies associated mal wall of the ventricle system was opened during with the appearance of new clinical symptoms. Follow- surgical resection. up MRIs were obtained regularly at 3  months intervals. Hong et al. Fluids Barriers CNS (2018) 15:16 Page 3 of 9 Table 1 Demographics and  clinical characteristics hydrocephalus (n = 3) (Fig.  1g), trapped lateral ventri- of glioma patient group cle (n = 1) (Fig.  1j), and expanding CSF collection in the resection cavity (n = 2) (Fig.  1m). All patients showed Variable n (%) clinical deterioration, mainly due to increase of intrac- Sex ranial pressure, predominantly presenting with head- Male 20 (66.7) ache, drowsiness, psychomotor slowing, hemiparesis, or Female 10 (33.3) aphasia. Age at diagnosis < 60 23 (76.7) Treatment for CSF diversion ≥ 60 7 (23.3) In five patients, a rapid symptomatic progression of Number of microsurgical tumor resections prior to shunt implantation hydrocephalus, as confirmed in the initial radiological None 5 (16.7) images, was detected, so that a CSF shunt was implanted 1 time 17 (56.7) prior to surgical tumor resection. The other patients 2 times 3 (10.0) had one (n = 17) or repeated (n = 8) surgical tumor 3 times 4 (13.3) resection prior to shunt implantation. The type of CSF 4 times 1 (3.3) diversion included ventriculoperitoneal (n = 21), sub- Type of CSF circulation disturbance duroperitoneal (n = 3), and cystoperitoneal shunting Obstructive hydrocephalus 9 (30.0) (n = 2). In four patients, two catheters were inserted in Communicating hydrocephalus 15 (50.0) separate intracranial compartments due to combined External hydrocephalus 3 (10.0) causes of CSF circulation disturbances. Three patients Trapped ventricle 1 (3.3) who underwent subduroperitoneal shunting had pre- Expanding CSF collection in resection cavity 2 (6.7) viously undergone subdural drainage via a burr hole. Type of CSF diversion Shunting was performed for persistent subdural CSF Ventriculoperitoneal 21 (70.0) collection with impaired consciousness or focal neuro- Subduroperitoneal 3 (10.0) logical signs. Depending on the clinical and radiologi- Cystoperitoneal 2 (6.7) cal findings, the programmable valve was initially set Combined two catheters to 6–8  cm H O (n = 24) for the ProGAV valve system ® ® Frontal horn + temporal horn 2 (6.7) and to 50–140 mm Hg (n = 4) for the Co dman Hakim Frontal horn bilateral 1 (3.3) valve system. CSF sampling from 11 patients taken at Expanding cyst + temporal horn 1 (3.3) shunt surgery showed no cytological evidence of tumor CSF cerebrospinal fluid dissemination. Shunt failure and revision surgery Treatment In five patients with programmable valve system, the After histopathological confirmation of glioblastoma, valve pressure settings were subsequently adjusted due temozolomide (TMZ) was administered in 14 patients to over- or underdrainage as determined on clinical and concurrently with radiotherapy according to current radiological findings. standard therapy [19]. One patient received ACNU/ Shunt failure occurred in nine patients. The main VM26 within the NOA-1 protocol [20]. Three children symptoms of shunt failure were impairment of con- were treated in accordance to HIT-GBM (German Soci- sciousness (n = 10), cephalgia (n = 8), and focal neurolog- ety of Paediatric Oncology and Haematology) treatment ical deficits (n = 5). Other symptoms included seizures, protocols. Eighteen patients received conventional- gait disorder, and aphasia (n = 5). In three patients, rou- fractionated partial brain radiotherapy with a total dose tine follow-up imaging showed persistent hydrocephalus, of 54–60  Gy (single dose, 1.8–2.0  Gy) starting within and valve malfunction. Neither specific symptoms nor 6  weeks after initial resection. Eight patients underwent new neurological deficits were evident in these patients. one or more microsurgical resections for recurrent GBM, A total of 16 revision surgeries were performed in of whom three patients tumor resection once, 5 patients 9 (30.0%) adult patients (7 men, 2 women; mean age twice, and 1 patient 3 times. 55 years) due to various complications (Table 2), of which 11 (68.8%) revision surgeries were performed within the CSF circulation problems first year after shunt implantation. Overall, three patients Overall, five types of CSF circulation disturbances were (10%) required multiple revision surgeries (2 revision identified: obstructive hydrocephalus (n = 9) (Fig.  1a), surgeries, n = 1; 3 revision surgeries, n = 1; 6 revision sur- communicating hydrocephalus (n = 15) (Fig. 1d), external geries, n = 1). In three patients, the anti-siphon device Hong et al. Fluids Barriers CNS (2018) 15:16 Page 4 of 9 was removed over the course of disease. The patient with 6 revision surgeries had delayed shunt malfunction, which occurred approximately 3  years after the time of implantation. Outcome Twenty-two patients temporarily benefitted from shunt - ing with subsequent improvement of consciousness and neurological symptoms. Overall, the median KPS improved significantly from 50 to 70 after shunt implan - tation (p = 0.008 of which, six patients remained stable at a median KPS of 70 at 3  months postoperatively. The other two patients deteriorated further due to tumor pro- gression within a median follow-up time of 5.5  months. When patients were dichotomized in two groups, there was a significant improvement of the median KPS after shunt implantation in those with a lower KPS (< 60) prior to shunt implantation (p = 0.019), while improve- ment in those with a higher prior KPS (≥ 60) did not reach statistical significance. The follow-up time of all patients ranged from 1 to 138  months with a median of 10  months. Twenty-eight patients died due to disease progression. Two patients were still alive at the time of writing manuscript. The median overall survival (mOS) time after diagnosis of glioblastoma was 10  months (Fig. 2). The two-year survival rate was 23.3%, 3-year sur - vival rate 16.7%, and 5-year survival rate 6.7%. Discussion Despite the development of hydrocephalus and the sub- sequent need for shunting in patients with glioblastoma is not an uncommon problem, this topic has attracted relatively little attention. Here we show that although Fig. 1 Images of glioblastoma patients: left column T1-weighted MR image after administration of gadolinium, centre collumn shunting may not prolong overall survival, it significantly native CT scan showing CSF circulation disturbances and right improves functional performance if only at least tempo- collumn postoperative native CT scan after shunt placement. a A rarily. The fact that there is relatively little information 41-year-old woman shows a pontomesencephalic glioblastoma available on this issue most likely is due to circumstances in with compression of the aqueduct. b Widening of the lateral which may have excluded these patients from larger stud- ventricles due to obstructive hydrocephalus. c Reduction of ventricular size after implantation of a ventriculoperitoneal shunt. d ies or outcomes. Even less information is available on A 64-year-old man shows a glioblastoma in the left temporomesial shunt complication during follow-up in this group of lobe. e Ventricular enlargement due to communicating patients as summarized in Table 3. hydrocephalus. f The intracranial catheter in situ after implantation Among the aforementioned types of CSF circulation of a ventriculoperitoneal shunt. g A 1-year-old boy shows a midline disturbances, communicating hydrocephalus appears to glioblastoma, which resulted initially in obstructive hydrocephalus. h External hydrocephalus with extensive subdural hygroma. i After be the most frequent one. Communicating hydrocepha- implantation of a subduroperitoneal shunt. j A 43-year-old woman lus may occur due to entry of blood into the CSF spaces shows a glioblastoma in the left parietal lobe/subcortical white during surgery, due to elevated CSF protein, secondary matter. k Three weeks after tumor resection, CT imaging reveals to radiotherapy-induced fibrosis of arachnoid granula - isolated extension of the left posterior horn with local compression tions, or to leptomeningeal dissemination of tumor cells of adjacent structures and midline shift. l A shunt catheter in the posterior horn after implantation of a ventriculoperitoneal shunt. m [6–9, 21–24]. All these events may finally result in oblit - A 69-year-old man shows a glioblastoma in the left temporal lobe. eration of the subarachnoid spaces over the surface of the n A space occupying fluid collection in the resection cavity. o The brain with reduction of CSF absorption. Some authors proximal shunt catheter inserted in the resection reported a significant correlation between ventricu - lar opening during tumor resection and development Hong et al. Fluids Barriers CNS (2018) 15:16 Page 5 of 9 Table 2 Indications for revision surgery in nine patients with shunt malfunction on 16 occasions Indication n Type of surgical revision Wound dehiscence with pneumocephalus 1 Wound revision Delayed fluid collection in resection cavity 1 Additional cystoperitoneal shunt implantation Valve and proximal catheter obstruction 3 Catheter replacement Proximal catheter obstruction 1 Valve and catheter replacement Proximal catheter dislocation 1 Reinsertion Distal catheter dislocation 1 Reinsertion Valve malfunction 3 Valve replacement Delayed trapped ventricle and CSF collection in cavity, valve malfunction 1 New implantation of proximal shunt catheters without anti-siphon device Intracerebral abscess 1 Removal of ventriculoperitoneal shunt, implantation of external ventricle drainage Delayed trapped ventricle and CSF collection in cavity 1 New implantation of proximal catheters Persistent hydrocephalus despite adjustment of programmable valve 2 Removal of anti-siphon device CSF cerebrospinal fluid The second most common type of CSF circulation disturbances in glioblastoma is obstructive hydrocepha- lus, which is caused by the obstruction of CSF path- ways, mostly due to compression of the 3rd or the 4th ventricle, as typically detected in midline, cerebellar, or thalamic glioblastoma [27]. External hydrocephalus, trapped ventricle, and expanding space-occupying fluid collection in the resection cavity are seen more rarely. The pathological mechanism behind the development of external hydrocephalus is not fully understood. Some investigators have suggested that CSF absorption failure by widespread leptomeningeal and subependymal tumor metastases with simultaneous loss of ventricular compli- ance could be the underlying causes for the CSF collec- tions in the subdural space [9, 28]. Others hypothesized that differential pressure between the ventricles and the subarachnoid spaces would allow CSF to pass from the ventricles to the subarachnoid space, and thus, result in CSF accumulation in the resection cavity or in the sub- Fig. 2 A Kaplan–Meier plot demonstrates overall survival in the dural space [29, 30]. Trapped ventricles occur typically as cohort of 30 patients with glioblastoma who underwent shunt a complication of intraventricular hemorrhage [31–33]. implantation due to CSF disturbances Entry of blood in the ventricles during the surgery may result in adhesions and scarring of the ventricular wall, finally sealing off the posterior horn. CSF shunting is of hydrocephalus [6, 9, 25], which, however, was not the treatment of choice to relieve the rapid ventricular confirmed in other studies [10]. Multiple microsurgi - dilatation. cal resection for recurrent glioblastoma is likely to pro- Given the complexity of the development of CSF dis- long survival [26]. However, it is also associated with an turbances and the clinical condition, shunting in glio- increased risk for communicating hydrocephalus [6]. blastoma patients presents frequent challenges since Furthermore, previous radiotherapy increases the pro- treatment appears to be associated with increased risks duction of transforming growth factor-ß (TGF-ß) in for peri- and intraoperative complications. A higher inci- cerebral tissues and glioma cells, supporting the trans- dence of shunt complications has been reported in the formation of fibroblasts into myofibroblasts, which pro - few studies focussing on this issue. Roth and colleagues motes fibrosis of arachnoid granulations [21, 23]. have indicated that 8 of 16 glioblastoma patients with Hong et al. Fluids Barriers CNS (2018) 15:16 Page 6 of 9 Table 3 Reported studies of cerebrospinal fluid shunting in patients with glioblastoma Author, year Frequency, n (%) Type of CSF circulation disturbance Shunt complication Marquardt et al. 2002 [7] 12/351 malignant gliomas (3.4) CH (n = 12) Multiple surgeries due to multiloculated hydrocephalus (n = 1) Inamasu et al. 2003 [8] 5/50 GBM (10) CH (n = 5) None reported Roth et al. 2008 [11] 16/530 GBM (3) CH (n = 16) Infection (n = 6), shunt malfunction (n = 1), overdrainage and hemorrhage (n = 1) Montano et al. 2011 [6] 11/124 GBM (8.9) CH (n = 7), OH (n = 2), fluid in resec- None reported tion cavity (n = 2) de la Fuente et al. 2014 [12] 41/2433 gliomas WHO grade II–IV (1.7) CH (n = 41) Meningitis (n = 5), subdural hematoma (n = 5), haemorrhage (n = 1), infection (n = 6) Fischer et al. 2014 [9] 11/151 GBM (7.3) CH (n = 11) n.a. Esquanazi et al., 2017 [27] 20/57 thalamic GBM (35) OH (n = 20) n.a. Behling et al. 2017 [10] 13/229 GBM (5.7) IH (n = 11), EH (n = 2) n.a. Castro et al. 2017 [13] 64/841 GBM (7.6) CH (n = 42), OH (n = 22) Infection (n = 10), catheter occlusion (n = 1), combined overdrainage, ven- triculitis and haemorrhage (n = 1) GBM glioblastoma; CH communicating hydrocephalus; OH obstructive hydrocephalus; IH internal hydrocephalus; EH external hydrocephalus; CSF cerebrospinal fluid; n.a. not available ventriculoperitoneal shunts had shunt-related complica- higher risk for misplaced catheters [34]. In cases of poor tions, of which 3 patients died due to such complications accessibility to the ventricular system, neuronavigation is [11]. De la Fuente analysed 62 patients with supratento- a valuable tool for achieving adequate placement of ven- rial glioma, of which 41 had glioblastoma. Among these tricular catheter [16, 17]. In cases of multiple CSF-filled patients, 27% had complications related to ventriculoper- compartments, insertion of separate catheters or even itoneal shunts [12]. Further, a more recent study reported separate shunt systems is sometimes necessary. Such sur- that shunt complications required surgical revision in 4 geries need to consider existing scars and previous cra- of 12 (33%) high-grade glioma patients with ventriculo-/ niotomies when draining the CSF compartments, thus cystoperitoneal shunts [34]. In our study, shunt failure making shunt surgery more challenging. Interestingly, affected mainly the ventricular catheter and the valve there are hardly any studies in the literature dealing with system. Hence, proximal complications appear to be the the role of multiple intracranial catheters in patients with major causes of shunt dysfunction, whereas abdominal ventriculoperitoneal shunts. complications do not appear to occur more frequently Radiation and chemotherapy are prone to weaken the in glioblastoma. Shunt complications are manifest most immune system [41]. Temozolomid chemotherapy which frequently within the first year after implantation. Some may induce lymphopenia and myelosuppression has authors have suggested elevation of CSF protein lev- been associated with poor immune surveillance lead- els and dissemination of tumor cells to be the causes ing to opportunistic infection in patients with malignant for proximal obstruction and valve defects [9, 34, 35]. glioma [42, 43]. Other alkylating agents, such as Lomus- The clinical symptoms of shunt failure in glioblastoma tine (CCNU) and PCV (Procarbazine—CCNU—Vincris- patients are not always readily recognizable, particularly tine) induce predominantly neutropenia which can also in patients with a lower KPS, impaired consciousness, or increase the risk of infection [44]. Especially the com- pre-existing focal neurological deficits. Regular follow-up bination of previous surgeries and radiochemotherapy CT or MR scans might provide evidence for shunt failure. can considerably contribute to wound-healing impair- Cohen et al. [36], however, found no correlation between ment. Furthermore, prolonged corticosteroid application, clinical symptoms and radiological findings of shunt immobility, long hospitalisation and advanced age are failure. other unfavorable factors often present in glioblastoma Shift of anatomical landmarks as a result of perifo- which increase the risk for infection [45, 46]. In some cal edema, tumor growth, or distention of the resec- studies, up to 50% of glioblastoma patients with ventricu- tion cavity during the course of treatment can make the loperitoneal shunts experienced infection within 2 weeks implantation of the proximal catheter technically more after surgery [11]. In a recent study, Beez et  al. reported challenging in some instances [37–40] resulting in a 4 revision surgeries due to infection in 12 patients with Hong et al. Fluids Barriers CNS (2018) 15:16 Page 7 of 9 high grade glioma and ventriculo-/cystoperitoneal shunts for CSF shunting and close postoperative follow-up is [34]. When shunt removal is inevitable, temporary exter- necessary. nal ventricle drainage is required. Shunt infection may be lethal in such patients [11]. Abbreviations Disease progress is associated with declined physical 5-ALA: 5-Aminolevulenic acid; CSF: cerebrospinal fluid; CT: computer tomog- activity and some patients may be confined to bed for a raphy; GBM: glioblastoma; HIT-GBM: Hirntumor-Glioblastoma Multiforme; Gy: gray; KPS: Karnofsky Performance Score; mOS: median overall survival; MRI: long time. When patients are mobile, the integration of magnetic resonance imaging; NOA: Neuroonkologische Arbeitsgemeinschaft; a gravity-assisted shunt valve can reduce the problem of PCV: Procarbazine—CCNU—Vincristine; TGF-ß: transforming growth factor-ß; siphoning and the occurrence of over drainage, and thus TMZ: temozolomide. avoid posture-related headaches and the risk of subdural Authors’ contributions hygromas or hematoma [18, 47]. When patients are bed- BH collected the data, designed the study, and drafted the manuscripts. MP ridden, however, gravity-assisted shunt valves should drafted the manuscripts. HEH performed statistical data analyses. CH collected the data. MN: designed the study. JKK drafted the manuscripts. All authors be avoided, since they may carry risk of underdrainage read and approved the final manuscript. and persistent hydrocephalus [48]. A particular problem arises in such instances when patients are mobile ini- Author details Department of Neurosurgery, Hannover Medical School, Hannover, Germany. tially but become bedridden in a later stage of the dis- Institute for Pathology, Department for Neuropathology, Hannover Medical ease as detected in three patients of our series, making 3 School, Hannover, Germany. Department of Neurosurgery, Cologne Mehr- additional surgery to remove the gravity-assisted device heim Medical Center, University of Witten/Herdecke, Cologne, Germany. unavoidable. Acknowledgements Although dissemination of glioblastoma within the Not applicable. ventricular system is well known [49], intraperitoneal Competing interests metastasis via a ventriculoperitoneal shunt appears to The authors declare that they have no competing interests. occur very rarely [50–56]. We did not find any evidence of peritoneal seeding in any patient of our series. It has Availability of data and materials The datasets used and analysed during the current study are available from to be mentioned, however, that manifestation of glioblas- the corresponding author on reasonable request. toma in the abdominal cavity following ventriculoperito- neal shunting has been detected mainly by postmortem Ethics approval and consent to participate For this retrospective study no approval of the ethics committee is needed at autopsy. Nevertheless, thus far, there is no systematic the authors’ institution. study using appropriate methods to detect metastatic seeding of glioblastoma cells into the peritoneal cavity via Consent for publication All images and personal information are de-identified in this manuscript. a shunt system intra vitam. Thus, the true incidence of intraperitoneal metastasis through shunting remains to Funding be elucidated. No funding received from any institution and/or foundation. We acknowledge several limitations of our study, par- ticularly related to its retrospective characters. We can- Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in pub- not determine the role of CSF shunt on survival time lished maps and institutional affiliations. since the median KPS was quite low indicating a popu- lation with poorer prognosis. 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Gliosarcoma with multiple extracranial metastases. Case report. Neurol Med Chir. 1989;29:938–43. Ready to submit your research ? Choose BMC and benefit from: fast, convenient online submission thorough peer review by experienced researchers in your field rapid publication on acceptance support for research data, including large and complex data types • gold Open Access which fosters wider collaboration and increased citations maximum visibility for your research: over 100M website views per year At BMC, research is always in progress. Learn more biomedcentral.com/submissions http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Fluids and Barriers of the CNS Springer Journals

Challenges in cerebrospinal fluid shunting in patients with glioblastoma

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Abstract

Background: Cerebrospinal fluid (CSF) circulation disturbances may occur during the course of disease in patients with glioblastoma. Ventriculoperitoneal shunting has generally been recommended to improve symptoms in glio- blastoma patients. Shunt implantation for patients with glioblastoma, however, presents as a complex situation and produces different problems to shunting in other contexts. Information on complications of shunting glioma patients has rarely been the subject of investigation. In this retrospective study, we analysed restropectively the course and outcome of glioblastoma-related CSF circulation disturbances after shunt management in a consecutive series of patients within a period of over a decade. Methods: Thirty of 723 patients with histopathologically-confirmed glioblastoma diagnosed from 2002 to 2016 at the Department of Neurosurgery, Hannover Medical School, underwent shunting for CSF circulation disorders. Treatment history of glioblastoma and all procedures associated with shunt implementation were analyzed. Data on follow-up, time to progression and survival rates were obtained by review of hospital charts and supplemented by phone interviews with the patients, their relations or the primary physicians. Results: Mean age at the time of diagnosis of glioblastoma was 43 years. Five types of CSF circulation disturbances were identified: obstructive hydrocephalus (n = 9), communicating hydrocephalus (n = 15), external hydrocephalus (n = 3), trapped lateral ventricle (n = 1), and expanding fluid collection in the resection cavity (n = 2). All patients showed clinical deterioration. Procedures for CSF diversion were ventriculoperitoneal shunt (n = 21), subduroperito- neal shunt (n = 3), and cystoperitoneal shunt (n = 2). In patients with lower Karnofsky Performance Score (KPS) (< 60), there was a significant improvement of median KPS after shunt implantation (p = 0.019). Shunt revision was neces- sary in 9 patients (single revision, n = 6; multiple revisions, n = 3) due to catheter obstruction, catheter dislocation, valve defect, and infection. Twenty-eight patients died due to disease progression during a median follow-up time of 88 months. The median overall survival time after diagnosis of glioblastoma was 10.18 months. Conclusions: CSF shunting in glioblastoma patients encounters more challenge and is associated with increased risk of complications, but these can be usually managed by revision surgeries. CSF shunting improves neurological func- tion temporarily, enhances quality of life in most patients although it is not known if survival rate is improved. Keywords: Glioblastoma, Ventriculoperitoneal shunt, Hydrocephalus, Cerebrospinal fluid *Correspondence: hong.bujung@mh-hannover.de Department of Neurosurgery, Hannover Medical School, Hannover, Germany Full list of author information is available at the end of the article © The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creat iveco mmons .org/licen ses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/ publi cdoma in/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Hong et al. Fluids Barriers CNS (2018) 15:16 Page 2 of 9 After CSF shunting, all patients had X-ray shuntograms Background confirming valve settings and the location of catheters. Glioblastoma still has a dismal prognosis: significantly Microsurgical resection for tumor removal was per- limiting quality of life and survival of patients suffering formed according to standard surgical techniques from this aggressive tumor [1, 2]. Maximal safe surgical for tumors not involving eloquent areas of the brain. resection followed by adjuvant combined radiochemo- Depending on tumor localization, neuronavigation, elec- therapy is one of the most important factors to improve trophysiological mapping, and/or 5-aminolevulinic acid overall survival of patients [3–5]. Cerebrospinal fluid (5-ALA) were applied intraoperatively [16, 17]. Gross (CSF) circulation disturbances may occur during the total microsurgical resection was achieved when the neu- course of disease and reduce a patient’s quality of life as rosurgeon determined that all areas of visible tumor were well as treatment capability significantly. Neurological resected intraoperatively. Resection was defined as sub - deterioration associated with the development of hydro- total when remnants of tumor were left behind. cephalus has been observed in 5–10% of patients with Shunt surgery was performed after diagnosis of a clin- glioblastoma [6–13]. ically-relevant CSF circulation disturbance. Depending Ventriculoperitoneal shunting has generally been on the cause of the CSF circulation disturbance, ventricu- recommended to improve symptoms in glioblastoma loperitoneal, subduroperitoneal, or cystoperitoneal CSF patients with CSF circulation disturbances [6–13]. diversion was performed. Programmable valve systems Shunt implantation in patients with glioblastoma, how- were implanted in 28 patients. While only four patients ever, presents as a complex situation and produces dif- had a programmable valve (Codman & Shurtleff, Inc. ferent problems to shunting in other contexts [14, 15]. Raynham, USA), in 24 patients, this was combined with Although hydrocephalus is seen in a significant number implantation of a gravitational anti-siphon device [18]. of patients with glioblastoma, there are only a few studies Two patients received a medium pressure CSF-flow con - which have concentrated on outcome of CSF shunting in trol valve system (Medtronic, Minneapolis, MN, USA). this fragile group of patients [6, 8–13, 27]. Even more so, Due to poor accessibility of the ventricle system, a neuro- information on complications of shunting rarely has been navigation system was used for insertion of the ventricu- the subject of investigation [11–13, 54]. lar catheter in three patients [16, 17]. Against this background, we sought to analyse the course and outcome of glioblastoma-related CSF circula- Statistical methods tion disturbances after shunt management in a consecu- Sigma Stat software (version 3.5; Systat Software, Inc. tive series of patients within a period of over a decade. California, USA) was used for statistical analysis. To ana- lyse the differences between groups, Student’s t test was Methods used. The survival rate was estimated by the Kaplan– For this retrospective study a data base of 723 glio- Meier method. Summary data were presented as median. blastoma patients with histopathologically-confirmed Statistical significance was defined as a probability value glioblastoma diagnosed from 2002 to 2016 at the Depart- less than 0.05. Measures were presented as mean ± stand- ment of Neurosurgery, Hannover Medical School, was ard deviations. reviewed. All patients that underwent shunting for CSF circulation disorders were included. Treatment history of Results glioblastoma, including surgical interventions and post- Patient characteristics operative therapy were reviewed. In addition, all proce- Overall, 30/723 patients with histopathologically-proven dures associated with shunt implementation, including glioblastoma (4.2%) underwent CSF shunting procedures type of shunt, technical problems, and complications, during the study period. Patient characteristics are pre- were analysed. Data on follow-up, time to progression sented in Table  1. Mean age at the time of diagnosis of and survival rates were obtained by review of hospital glioblastoma was 43  years (range 1 to 79  years). Initial charts and supplemented by phone interviews with the surgical treatment included stereotactic biopsy (n = 7), patients, their relations or the primary physicians. partial resection (n = 6), subtotal resection (n = 8), Radiological evaluation of glioblastoma and tumor pro- and complete resection (n = 9). Two of 7 patients, who gression, in general, was made using contrast-enhanced had stereotactic biopsy, underwent subsequent surgi- MRI. CSF circulation disturbance was defined as dispro - cal resection after confirmation of the histopathological portionate enlargement of inner and/or outer CSF spaces diagnosis of glioblastoma, since tumor location was con- within the cranial vault or CSF collections in the resec- sidered accessible. In 18 patients the infiltrated ependy - tion cavity in postoperative imaging studies associated mal wall of the ventricle system was opened during with the appearance of new clinical symptoms. Follow- surgical resection. up MRIs were obtained regularly at 3  months intervals. Hong et al. Fluids Barriers CNS (2018) 15:16 Page 3 of 9 Table 1 Demographics and  clinical characteristics hydrocephalus (n = 3) (Fig.  1g), trapped lateral ventri- of glioma patient group cle (n = 1) (Fig.  1j), and expanding CSF collection in the resection cavity (n = 2) (Fig.  1m). All patients showed Variable n (%) clinical deterioration, mainly due to increase of intrac- Sex ranial pressure, predominantly presenting with head- Male 20 (66.7) ache, drowsiness, psychomotor slowing, hemiparesis, or Female 10 (33.3) aphasia. Age at diagnosis < 60 23 (76.7) Treatment for CSF diversion ≥ 60 7 (23.3) In five patients, a rapid symptomatic progression of Number of microsurgical tumor resections prior to shunt implantation hydrocephalus, as confirmed in the initial radiological None 5 (16.7) images, was detected, so that a CSF shunt was implanted 1 time 17 (56.7) prior to surgical tumor resection. The other patients 2 times 3 (10.0) had one (n = 17) or repeated (n = 8) surgical tumor 3 times 4 (13.3) resection prior to shunt implantation. The type of CSF 4 times 1 (3.3) diversion included ventriculoperitoneal (n = 21), sub- Type of CSF circulation disturbance duroperitoneal (n = 3), and cystoperitoneal shunting Obstructive hydrocephalus 9 (30.0) (n = 2). In four patients, two catheters were inserted in Communicating hydrocephalus 15 (50.0) separate intracranial compartments due to combined External hydrocephalus 3 (10.0) causes of CSF circulation disturbances. Three patients Trapped ventricle 1 (3.3) who underwent subduroperitoneal shunting had pre- Expanding CSF collection in resection cavity 2 (6.7) viously undergone subdural drainage via a burr hole. Type of CSF diversion Shunting was performed for persistent subdural CSF Ventriculoperitoneal 21 (70.0) collection with impaired consciousness or focal neuro- Subduroperitoneal 3 (10.0) logical signs. Depending on the clinical and radiologi- Cystoperitoneal 2 (6.7) cal findings, the programmable valve was initially set Combined two catheters to 6–8  cm H O (n = 24) for the ProGAV valve system ® ® Frontal horn + temporal horn 2 (6.7) and to 50–140 mm Hg (n = 4) for the Co dman Hakim Frontal horn bilateral 1 (3.3) valve system. CSF sampling from 11 patients taken at Expanding cyst + temporal horn 1 (3.3) shunt surgery showed no cytological evidence of tumor CSF cerebrospinal fluid dissemination. Shunt failure and revision surgery Treatment In five patients with programmable valve system, the After histopathological confirmation of glioblastoma, valve pressure settings were subsequently adjusted due temozolomide (TMZ) was administered in 14 patients to over- or underdrainage as determined on clinical and concurrently with radiotherapy according to current radiological findings. standard therapy [19]. One patient received ACNU/ Shunt failure occurred in nine patients. The main VM26 within the NOA-1 protocol [20]. Three children symptoms of shunt failure were impairment of con- were treated in accordance to HIT-GBM (German Soci- sciousness (n = 10), cephalgia (n = 8), and focal neurolog- ety of Paediatric Oncology and Haematology) treatment ical deficits (n = 5). Other symptoms included seizures, protocols. Eighteen patients received conventional- gait disorder, and aphasia (n = 5). In three patients, rou- fractionated partial brain radiotherapy with a total dose tine follow-up imaging showed persistent hydrocephalus, of 54–60  Gy (single dose, 1.8–2.0  Gy) starting within and valve malfunction. Neither specific symptoms nor 6  weeks after initial resection. Eight patients underwent new neurological deficits were evident in these patients. one or more microsurgical resections for recurrent GBM, A total of 16 revision surgeries were performed in of whom three patients tumor resection once, 5 patients 9 (30.0%) adult patients (7 men, 2 women; mean age twice, and 1 patient 3 times. 55 years) due to various complications (Table 2), of which 11 (68.8%) revision surgeries were performed within the CSF circulation problems first year after shunt implantation. Overall, three patients Overall, five types of CSF circulation disturbances were (10%) required multiple revision surgeries (2 revision identified: obstructive hydrocephalus (n = 9) (Fig.  1a), surgeries, n = 1; 3 revision surgeries, n = 1; 6 revision sur- communicating hydrocephalus (n = 15) (Fig. 1d), external geries, n = 1). In three patients, the anti-siphon device Hong et al. Fluids Barriers CNS (2018) 15:16 Page 4 of 9 was removed over the course of disease. The patient with 6 revision surgeries had delayed shunt malfunction, which occurred approximately 3  years after the time of implantation. Outcome Twenty-two patients temporarily benefitted from shunt - ing with subsequent improvement of consciousness and neurological symptoms. Overall, the median KPS improved significantly from 50 to 70 after shunt implan - tation (p = 0.008 of which, six patients remained stable at a median KPS of 70 at 3  months postoperatively. The other two patients deteriorated further due to tumor pro- gression within a median follow-up time of 5.5  months. When patients were dichotomized in two groups, there was a significant improvement of the median KPS after shunt implantation in those with a lower KPS (< 60) prior to shunt implantation (p = 0.019), while improve- ment in those with a higher prior KPS (≥ 60) did not reach statistical significance. The follow-up time of all patients ranged from 1 to 138  months with a median of 10  months. Twenty-eight patients died due to disease progression. Two patients were still alive at the time of writing manuscript. The median overall survival (mOS) time after diagnosis of glioblastoma was 10  months (Fig. 2). The two-year survival rate was 23.3%, 3-year sur - vival rate 16.7%, and 5-year survival rate 6.7%. Discussion Despite the development of hydrocephalus and the sub- sequent need for shunting in patients with glioblastoma is not an uncommon problem, this topic has attracted relatively little attention. Here we show that although Fig. 1 Images of glioblastoma patients: left column T1-weighted MR image after administration of gadolinium, centre collumn shunting may not prolong overall survival, it significantly native CT scan showing CSF circulation disturbances and right improves functional performance if only at least tempo- collumn postoperative native CT scan after shunt placement. a A rarily. The fact that there is relatively little information 41-year-old woman shows a pontomesencephalic glioblastoma available on this issue most likely is due to circumstances in with compression of the aqueduct. b Widening of the lateral which may have excluded these patients from larger stud- ventricles due to obstructive hydrocephalus. c Reduction of ventricular size after implantation of a ventriculoperitoneal shunt. d ies or outcomes. Even less information is available on A 64-year-old man shows a glioblastoma in the left temporomesial shunt complication during follow-up in this group of lobe. e Ventricular enlargement due to communicating patients as summarized in Table 3. hydrocephalus. f The intracranial catheter in situ after implantation Among the aforementioned types of CSF circulation of a ventriculoperitoneal shunt. g A 1-year-old boy shows a midline disturbances, communicating hydrocephalus appears to glioblastoma, which resulted initially in obstructive hydrocephalus. h External hydrocephalus with extensive subdural hygroma. i After be the most frequent one. Communicating hydrocepha- implantation of a subduroperitoneal shunt. j A 43-year-old woman lus may occur due to entry of blood into the CSF spaces shows a glioblastoma in the left parietal lobe/subcortical white during surgery, due to elevated CSF protein, secondary matter. k Three weeks after tumor resection, CT imaging reveals to radiotherapy-induced fibrosis of arachnoid granula - isolated extension of the left posterior horn with local compression tions, or to leptomeningeal dissemination of tumor cells of adjacent structures and midline shift. l A shunt catheter in the posterior horn after implantation of a ventriculoperitoneal shunt. m [6–9, 21–24]. All these events may finally result in oblit - A 69-year-old man shows a glioblastoma in the left temporal lobe. eration of the subarachnoid spaces over the surface of the n A space occupying fluid collection in the resection cavity. o The brain with reduction of CSF absorption. Some authors proximal shunt catheter inserted in the resection reported a significant correlation between ventricu - lar opening during tumor resection and development Hong et al. Fluids Barriers CNS (2018) 15:16 Page 5 of 9 Table 2 Indications for revision surgery in nine patients with shunt malfunction on 16 occasions Indication n Type of surgical revision Wound dehiscence with pneumocephalus 1 Wound revision Delayed fluid collection in resection cavity 1 Additional cystoperitoneal shunt implantation Valve and proximal catheter obstruction 3 Catheter replacement Proximal catheter obstruction 1 Valve and catheter replacement Proximal catheter dislocation 1 Reinsertion Distal catheter dislocation 1 Reinsertion Valve malfunction 3 Valve replacement Delayed trapped ventricle and CSF collection in cavity, valve malfunction 1 New implantation of proximal shunt catheters without anti-siphon device Intracerebral abscess 1 Removal of ventriculoperitoneal shunt, implantation of external ventricle drainage Delayed trapped ventricle and CSF collection in cavity 1 New implantation of proximal catheters Persistent hydrocephalus despite adjustment of programmable valve 2 Removal of anti-siphon device CSF cerebrospinal fluid The second most common type of CSF circulation disturbances in glioblastoma is obstructive hydrocepha- lus, which is caused by the obstruction of CSF path- ways, mostly due to compression of the 3rd or the 4th ventricle, as typically detected in midline, cerebellar, or thalamic glioblastoma [27]. External hydrocephalus, trapped ventricle, and expanding space-occupying fluid collection in the resection cavity are seen more rarely. The pathological mechanism behind the development of external hydrocephalus is not fully understood. Some investigators have suggested that CSF absorption failure by widespread leptomeningeal and subependymal tumor metastases with simultaneous loss of ventricular compli- ance could be the underlying causes for the CSF collec- tions in the subdural space [9, 28]. Others hypothesized that differential pressure between the ventricles and the subarachnoid spaces would allow CSF to pass from the ventricles to the subarachnoid space, and thus, result in CSF accumulation in the resection cavity or in the sub- Fig. 2 A Kaplan–Meier plot demonstrates overall survival in the dural space [29, 30]. Trapped ventricles occur typically as cohort of 30 patients with glioblastoma who underwent shunt a complication of intraventricular hemorrhage [31–33]. implantation due to CSF disturbances Entry of blood in the ventricles during the surgery may result in adhesions and scarring of the ventricular wall, finally sealing off the posterior horn. CSF shunting is of hydrocephalus [6, 9, 25], which, however, was not the treatment of choice to relieve the rapid ventricular confirmed in other studies [10]. Multiple microsurgi - dilatation. cal resection for recurrent glioblastoma is likely to pro- Given the complexity of the development of CSF dis- long survival [26]. However, it is also associated with an turbances and the clinical condition, shunting in glio- increased risk for communicating hydrocephalus [6]. blastoma patients presents frequent challenges since Furthermore, previous radiotherapy increases the pro- treatment appears to be associated with increased risks duction of transforming growth factor-ß (TGF-ß) in for peri- and intraoperative complications. A higher inci- cerebral tissues and glioma cells, supporting the trans- dence of shunt complications has been reported in the formation of fibroblasts into myofibroblasts, which pro - few studies focussing on this issue. Roth and colleagues motes fibrosis of arachnoid granulations [21, 23]. have indicated that 8 of 16 glioblastoma patients with Hong et al. Fluids Barriers CNS (2018) 15:16 Page 6 of 9 Table 3 Reported studies of cerebrospinal fluid shunting in patients with glioblastoma Author, year Frequency, n (%) Type of CSF circulation disturbance Shunt complication Marquardt et al. 2002 [7] 12/351 malignant gliomas (3.4) CH (n = 12) Multiple surgeries due to multiloculated hydrocephalus (n = 1) Inamasu et al. 2003 [8] 5/50 GBM (10) CH (n = 5) None reported Roth et al. 2008 [11] 16/530 GBM (3) CH (n = 16) Infection (n = 6), shunt malfunction (n = 1), overdrainage and hemorrhage (n = 1) Montano et al. 2011 [6] 11/124 GBM (8.9) CH (n = 7), OH (n = 2), fluid in resec- None reported tion cavity (n = 2) de la Fuente et al. 2014 [12] 41/2433 gliomas WHO grade II–IV (1.7) CH (n = 41) Meningitis (n = 5), subdural hematoma (n = 5), haemorrhage (n = 1), infection (n = 6) Fischer et al. 2014 [9] 11/151 GBM (7.3) CH (n = 11) n.a. Esquanazi et al., 2017 [27] 20/57 thalamic GBM (35) OH (n = 20) n.a. Behling et al. 2017 [10] 13/229 GBM (5.7) IH (n = 11), EH (n = 2) n.a. Castro et al. 2017 [13] 64/841 GBM (7.6) CH (n = 42), OH (n = 22) Infection (n = 10), catheter occlusion (n = 1), combined overdrainage, ven- triculitis and haemorrhage (n = 1) GBM glioblastoma; CH communicating hydrocephalus; OH obstructive hydrocephalus; IH internal hydrocephalus; EH external hydrocephalus; CSF cerebrospinal fluid; n.a. not available ventriculoperitoneal shunts had shunt-related complica- higher risk for misplaced catheters [34]. In cases of poor tions, of which 3 patients died due to such complications accessibility to the ventricular system, neuronavigation is [11]. De la Fuente analysed 62 patients with supratento- a valuable tool for achieving adequate placement of ven- rial glioma, of which 41 had glioblastoma. Among these tricular catheter [16, 17]. In cases of multiple CSF-filled patients, 27% had complications related to ventriculoper- compartments, insertion of separate catheters or even itoneal shunts [12]. Further, a more recent study reported separate shunt systems is sometimes necessary. Such sur- that shunt complications required surgical revision in 4 geries need to consider existing scars and previous cra- of 12 (33%) high-grade glioma patients with ventriculo-/ niotomies when draining the CSF compartments, thus cystoperitoneal shunts [34]. In our study, shunt failure making shunt surgery more challenging. Interestingly, affected mainly the ventricular catheter and the valve there are hardly any studies in the literature dealing with system. Hence, proximal complications appear to be the the role of multiple intracranial catheters in patients with major causes of shunt dysfunction, whereas abdominal ventriculoperitoneal shunts. complications do not appear to occur more frequently Radiation and chemotherapy are prone to weaken the in glioblastoma. Shunt complications are manifest most immune system [41]. Temozolomid chemotherapy which frequently within the first year after implantation. Some may induce lymphopenia and myelosuppression has authors have suggested elevation of CSF protein lev- been associated with poor immune surveillance lead- els and dissemination of tumor cells to be the causes ing to opportunistic infection in patients with malignant for proximal obstruction and valve defects [9, 34, 35]. glioma [42, 43]. Other alkylating agents, such as Lomus- The clinical symptoms of shunt failure in glioblastoma tine (CCNU) and PCV (Procarbazine—CCNU—Vincris- patients are not always readily recognizable, particularly tine) induce predominantly neutropenia which can also in patients with a lower KPS, impaired consciousness, or increase the risk of infection [44]. Especially the com- pre-existing focal neurological deficits. Regular follow-up bination of previous surgeries and radiochemotherapy CT or MR scans might provide evidence for shunt failure. can considerably contribute to wound-healing impair- Cohen et al. [36], however, found no correlation between ment. Furthermore, prolonged corticosteroid application, clinical symptoms and radiological findings of shunt immobility, long hospitalisation and advanced age are failure. other unfavorable factors often present in glioblastoma Shift of anatomical landmarks as a result of perifo- which increase the risk for infection [45, 46]. In some cal edema, tumor growth, or distention of the resec- studies, up to 50% of glioblastoma patients with ventricu- tion cavity during the course of treatment can make the loperitoneal shunts experienced infection within 2 weeks implantation of the proximal catheter technically more after surgery [11]. In a recent study, Beez et  al. reported challenging in some instances [37–40] resulting in a 4 revision surgeries due to infection in 12 patients with Hong et al. Fluids Barriers CNS (2018) 15:16 Page 7 of 9 high grade glioma and ventriculo-/cystoperitoneal shunts for CSF shunting and close postoperative follow-up is [34]. When shunt removal is inevitable, temporary exter- necessary. nal ventricle drainage is required. Shunt infection may be lethal in such patients [11]. Abbreviations Disease progress is associated with declined physical 5-ALA: 5-Aminolevulenic acid; CSF: cerebrospinal fluid; CT: computer tomog- activity and some patients may be confined to bed for a raphy; GBM: glioblastoma; HIT-GBM: Hirntumor-Glioblastoma Multiforme; Gy: gray; KPS: Karnofsky Performance Score; mOS: median overall survival; MRI: long time. When patients are mobile, the integration of magnetic resonance imaging; NOA: Neuroonkologische Arbeitsgemeinschaft; a gravity-assisted shunt valve can reduce the problem of PCV: Procarbazine—CCNU—Vincristine; TGF-ß: transforming growth factor-ß; siphoning and the occurrence of over drainage, and thus TMZ: temozolomide. avoid posture-related headaches and the risk of subdural Authors’ contributions hygromas or hematoma [18, 47]. When patients are bed- BH collected the data, designed the study, and drafted the manuscripts. MP ridden, however, gravity-assisted shunt valves should drafted the manuscripts. HEH performed statistical data analyses. CH collected the data. MN: designed the study. JKK drafted the manuscripts. All authors be avoided, since they may carry risk of underdrainage read and approved the final manuscript. and persistent hydrocephalus [48]. A particular problem arises in such instances when patients are mobile ini- Author details Department of Neurosurgery, Hannover Medical School, Hannover, Germany. tially but become bedridden in a later stage of the dis- Institute for Pathology, Department for Neuropathology, Hannover Medical ease as detected in three patients of our series, making 3 School, Hannover, Germany. Department of Neurosurgery, Cologne Mehr- additional surgery to remove the gravity-assisted device heim Medical Center, University of Witten/Herdecke, Cologne, Germany. unavoidable. Acknowledgements Although dissemination of glioblastoma within the Not applicable. ventricular system is well known [49], intraperitoneal Competing interests metastasis via a ventriculoperitoneal shunt appears to The authors declare that they have no competing interests. occur very rarely [50–56]. We did not find any evidence of peritoneal seeding in any patient of our series. It has Availability of data and materials The datasets used and analysed during the current study are available from to be mentioned, however, that manifestation of glioblas- the corresponding author on reasonable request. toma in the abdominal cavity following ventriculoperito- neal shunting has been detected mainly by postmortem Ethics approval and consent to participate For this retrospective study no approval of the ethics committee is needed at autopsy. Nevertheless, thus far, there is no systematic the authors’ institution. study using appropriate methods to detect metastatic seeding of glioblastoma cells into the peritoneal cavity via Consent for publication All images and personal information are de-identified in this manuscript. a shunt system intra vitam. Thus, the true incidence of intraperitoneal metastasis through shunting remains to Funding be elucidated. No funding received from any institution and/or foundation. We acknowledge several limitations of our study, par- ticularly related to its retrospective characters. We can- Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in pub- not determine the role of CSF shunt on survival time lished maps and institutional affiliations. since the median KPS was quite low indicating a popu- lation with poorer prognosis. Furthermore, we did not Received: 27 February 2018 Accepted: 11 May 2018 study systematically the possibility of seeding of glio- blastoma cells via the shunt system. In addition, it would have been be interesting to compare outcome between References shunted and non-shunted GBM patients in a larger study. 1. de Robles P, Fiest KM, Frolkis AD, Pringheim T, Atta C, St Germaine- Smith C, et al. The worldwide incidence and prevalence of primary brain tumors: a systematic review and meta-analysis. Neuro Oncol. Conclusions 2015;17:776–83. Different types of CSF circulation disturbances may 2. Emmanuel C, Lawson T, Lelotte J, Fomekong E, Vaz G, Renard L, et al. occur during the course of disease in patients with glio- Long-term survival after glioblastoma resection: hope despite poor prognosis factors. J Neurosurg Sci. 2018. https ://doi.org/10.23736 /S0390 blastoma. Shunting achieved temporary improvement -5616.18.04180 -2. for functional performance in the majority of the patients 3. 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Fluids and Barriers of the CNSSpringer Journals

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