BACKGROUND:
Incisional cerebrospinal fluid (iCSF) leakage is a serious complication after intradural cranial surgery.
OBJECTIVE:
To determine the incidence and risk factors of iCSF leakage after craniotomy. Secondarily, the complications after iCSF leakage and the success rate of iCSF leakage treatment was studied.
METHODS:
All patients who underwent an intradural cranial surgery from 2017 to 2018 at 5 neurosurgical centers were retrospectively included. Data were retrieved from medical records with 2 months of follow-up. First, univariate regression analyses were performed. Subsequently, identified risk factors were evaluated in a multivariate regression analysis.
RESULTS:
In total 2310 consecutive patients were included. Total iCSF leakage rate was 7.1% (n = 165). Younger age, male, higher body mass index, smoking, infratentorial surgery, and use of a dural substitute were associated with increased iCSF leakage risk, and use of a sealant reduced that risk. The odds for developing a wound infection and/or meningitis were 15 times higher in patients with iCSF leakage compared with patients without leakage. Initial conservative iCSF leakage treatment failed in 48% of patients. In 80% of cases, external cerebrospinal fluid drainage ceased the iCSF leakage. A total of 32% of patients with iCSF leakage required wound revision surgery.
CONCLUSION:
iCSF leakage risk increases by younger age, higher body mass index, smoking, infratentorial craniotomy, and dural substitute use, whereas sealant use reduced the risk for iCSF leakage. The leak increases the risk of postoperative infections. When iCSF leakage occurs, immediate external cerebrospinal fluid drainage or wound revision should be considered.
KEY WORDS: Cerebrospinal fluid leakage, Craniotomy, Craniectomy, Complication, Dura
ABBREVIATIONS:
- aOR
adjusted odds ratio
- BMI
body mass index
- iCSF
incisional cerebrospinal fluid
- OR
odds ratio
- PMC
pseudomeningocele.
Cerebrospinal fluid (CSF) leakage is a complication after intradural cranial surgery, which may have severe consequences. It is associated with wound infection, meningitis, and pneumocephalus, and may require prolonged admission and additional treatment.1-3 The definition of CSF leakage in the current literature is often unclear and can both include incisional CSF leakage (incisional cerebrospinal fluid [iCSF] leakage) and pseudomeningocele (PMC).4 Incisional CSF leakage is defined as CSF leakage through the skin, whereas PMC is an extradural subcutaneous collection of CSF. In general, iCSF has more severe clinical consequences, whereas PMC can often be treated conservatively.5,6
Various studies identified risk factors for CSF leakage, which can be divided into the patient and surgery-related risks. Patient-related risk factors include male sex, younger age, higher body mass index (BMI), and diabetes.7-9 In addition, cigarette smoking is associated with compromised surgical wound healing and was included in the data.10 Surgery-related factors that have been reported to increase CSF leakage are infratentorial surgery and longer surgery time.8,9 Sealants as a preventative measure for CSF leakage, as well as dural substitutes, are associated with a reduced risk of CSF leakage.11 These studies, however, included relatively small and selected patient populations. Moreover, the definitions of CSF leakage in these publications were not uniform and often also included PMC. Thus far, the incidence and risk factors of CSF leakage have not been validated in a general neurosurgical population with a clinically meaningful definition of CSF leakage.
The primary objective of this study was to determine the incidence of iCSF and risk factors for iCSF leakage in a large international multicenter cohort. The secondary objectives were to establish the incidence of secondary complications, including wound infection and meningitis, in relation to iCSF leakage and to determine the proportion of patients requiring invasive treatment. A better understanding of the incidence of iCSF and its risk factors may aid preoperative counseling and the development of preventative strategies to reduce iCSF leakage.
METHODS
Study Design
Six large neurosurgical centers were invited to participate in this study. These centers were selected based on their large volume and prior collaborations in different studies. Finally, 5 of the 6 centers participated in this retrospective cohort study, 3 in Europe and 2 in the United States. There was no previous check if CSF leakage management was consistent within the center or between centers. The study was approved by the responsible institutional review boards, and informed consent waivers were granted (UIC IRB no. 2019-0523, UNM IRB no. 20-133, and ETZ IRB no. L0790.2019). All patients who underwent intradural cranial surgery (ie, all craniotomies in which the dura was opened) were included between September 1, 2017, and September 1, 2018. In all participating centers, preoperative prophylactic antibiotics consisted of cephalosporins 2 g as recommended in national guidelines.12,13 Patients who died within a month after surgery or were lost to follow-up were excluded. The inclusion and exclusion criteria are shown in Table 1.
TABLE 1.
Inclusion and Exclusion Criteria
| Inclusion criteria | Exclusion criteria |
|---|---|
| Patient underwent intradural supratentorial, infratentorial cranial surgery | Surgery via burr hole(s)a |
| Follow-up in the same neurosurgical center | Transphenoidal surgery |
| No or insufficient report of the operative procedure or inadequate follow-up | |
| Death within 1 mo of surgery | |
| Treatment of complication in another center |
Surgeries including, but not limited to, burr hole evacuation of chronic subdural hematoma abscesses or empyemas, stereotactic biopsies, and endoscopic surgeries.
Data Collection
All data were retrospectively collected. The patient characteristics were age, sex, preoperative dexamethasone use, history of radiation therapy, diabetes, BMI, and smoking. Dexamethasone use was defined as present if administered more than 1 day preoperatively because a single preoperative dexamethasone dose does not increase the risk of delayed wound healing.14,15
Surgical characteristics included indication, urgency level, reoperation (yes/no), location of craniotomy (supratentorial or infratentorial), use of dural substitute, and use of a sealant. The surgical indication was classified into trauma, vascular, tumor, epilepsy, or “other,” which consisted of surgery for Chiari decompression, abscess or empyema evacuation, and primary dural defect closure. Surgery was regarded as a reoperation if the surgical approach was the same route as a previous procedure(s). If a device was sutured in or used as overlay to close a dural gap, it was defined as a substitute. If the dura could be primarily closed, or closed with help of a substitute, and a device (eg, a tissue adhesive or hemostatic agent) was applied to augment the closure, it was defined as a sealant.
The primary outcome measure was iCSF leakage, defined as clinically diagnosed CSF leakage through the skin. Confirmation through a beta-2-transferrin test was not per definition needed but was noted.16 The secondary outcome measures collected were wound infections and meningitis requiring treatment. Wound infection was further subdivided into 2 categories consisting of superficial infection, requiring only antibiotics, and deep wound infection, requiring revision surgery. Meningitis was defined as clinical suspicion for meningitis in combination with antibiotic treatment for meningitis. The type of treatment was reviewed when iCSF leakage occurred. There were 3 types of treatment: conservative treatment, external drainage placement, and operative wound revision. Conservative management consisted of a nonoperative intervention as pressure bandage for wound compression and/or additional wound suturing. External drainage placement included ventricular or lumbar drainage placement. The choice what type of drainage placement was based on the discretion of the surgeon. Additional days of hospitalization because of iCSF leakage were calculated by determining the extra days of admission because of iCSF leakage or counting the days of readmission because of iCSF leakage. If the extra days of admission because of iCSF leakage were not clear (eg, because of other complications), the patient was excluded from this analysis.
Statistical Analysis
SPSS statistic software program version 26 (IBM) was used. Differences in baseline characteristics among patients with and without iCSF leakage were evaluated using χ2 test (categorical) or Mann–Whitney U test (ordinal or continuous). The incidence of iCSF leakage and related complications is presented as the number and proportion of the total population. Univariate logistic regression analysis was performed for patient and surgical characteristics to assess their relationship with iCSF leakage and between iCSF leakage and infection. Multivariate logistic regression analysis was performed with sex, age, diabetes mellitus, BMI, smoking, dural substitute use, sealant use, infratentorial surgery, and significant risk factor(s) from univariate analysis as risk factors.7-9 We checked for collinearity using a variance inflation factor.
RESULTS
Incisional CSF Leakage and Risk Factors
A total of 2310 patients were included. Baseline characteristics and their relation with iCSF are shown in Table 2. iCSF leakage occurred in 165 of 2310 (7.1%) patients: 63 of 540 (11.7%) infratentorial surgeries, and 102 of 1770 (5.8%) supratentorial surgeries. Chiari decompressive surgery had the highest risk for iCSF leakage with 33% (6 of 18 patients). The median time between surgery and diagnosis of iCSF leakage was 9 days (range 0-122). An iCSF leakage was diagnosed by a physical examination in 82% and confirmed with beta-2-transferrin testing in 18%.
TABLE 2.
Patient and Operative Characteristics and Univariate Analysis for iCSF Leakage
| Reference value | Total no. (%) | iCSF | No iCSF | OR | (95% CI) | |
|---|---|---|---|---|---|---|
| Total | 2310 | 165 (7%) | 2145 (93%) | |||
| Patient characteristics | ||||||
| Sex | Male | 1117 | 81 (50%) | 1036 (48%) | 1.03 | (0.75-1.42) |
| Agea | Years | 52 (±19) | 47 (±20) | 52 (±19) | 0.99 | (0.98-0.99) |
| BMIa | kg/m2 | 26 (±6) | 27 (±6) | 26 (±6) | 1.02 | (0.99-1.04) |
| Smoking | Yes | 461 (20%) | 38 (23%) | 423 (20%) | 1.22 | (0.84-1.78) |
| Missing | 120 (5%) | |||||
| Alcohol consumption | Yes | 828 (36%) | 53 (34%) | 775 (39%) | 0.82 | (0.58-1.16) |
| Missing | 156 (7%) | |||||
| Diabetes | Yes | 226 (10%) | 13 (8%) | 213 (10%) | 1.29 | (0.72-2.31) |
| Hepatic dysfunction | Yes | 43 (2%) | 3 (2%) | 40 (2%) | 0.97 | (0.30-3.18) |
| Renal dysfunction | Yes | 111 (5%) | 12 (7%) | 99 (5) | 1.62 | (0.87-3.02) |
| Increased bleeding risk | Yes | 129 (6%) | 9 (5.5%) | 120 (6%) | 1.03 | (0.51-2.06) |
| Thyroid dysfunction | Yes | 150 (6%) | 9 (5%) | 141 (7%) | 0.82 | (0.41-1.64) |
| Dexamethasone use | Yes | 441 (19%) | 32 (19%) | 409 (19%) | 1.02 | (0.68-1.53) |
| History of radiation therapy | Yes | 138 (6.0%) | 13 (7.9%) | 125 (5.8%) | 1.38 | (0.76-2.50) |
| Operative characteristics | ||||||
| Hospital | No. 1 | 754 (100%) | 77 (10%) | 677 (90%) | 3.64 | (1.56-8.48) |
| No. 2 | 506 (100%) | 15 (3%) | 491 (97%) | 1.26 | (0.48-3.31) | |
| No. 3 | 457 (100%) | 52 (11%) | 405 (89%) | 4.11 | (1.74-9.73) | |
| No. 4 | 395 (100%) | 15 (4%) | 380 (96%) | 0.98 | (0.37-2.56) | |
| No. 5b | 198 (100%) | 6 (3%) | 192 (97%) | 1.00 | ||
| Indication of surgery | Tumor | 1297 (56%) | 102 (62%) | 1195 (56%) | 1.83 | (1.20-2.78) |
| Epilepsy | 137 (5.9%) | 11 (7%) | 126 (6) | 1.87 | (0.91-3.83) | |
| Trauma | 141 (6.1%) | 14 (7%) | 127 (6%) | 2.36 | (1.22-4.58) | |
| Other | 63 (2.7%) | 8 (4%) | 55 (3%) | 3.11 | (1.36-7.12) | |
| Vascularb | 672 (29%) | 30 (18%) | 642 (30%) | 1.00 | ||
| Location of craniotomy | Infratentorial | 540 (23%) | 63 (38%) | 477 (22%) | 2.16 | (1.55-3.01) |
| Reoperation | Yes | 259 (11%) | 23 (14%) | 236 (11%) | 1.31 | (0.83-2.08) |
| Urgency level | Yes | 1890 (82%) | 133 (81%) | 1757 (82%) | 1.09 | (0.73-1.63) |
| Dural substitute use | Elective | 1016 (44%) | 95 (58%) | 921 (43%) | 1.80 | (1.31-2.49) |
| Sealant use | Yes | 1232 (53%) | 79 (48%) | 1153 (54%) | 0.79 | (0.58-1.09) |
BMI, body mass index; iCSF, incisional cerebrospinal fluid; OR, odds ratio.
Mean (SD).
Reference value with lowest iCSF leakage rate.
Univariate analysis identified younger age, infratentorial surgery, primary dural substitute use, and an indication of surgery as risk factors for iCSF leakage. The risk of iCSF leakage was highest for trauma surgery. A significant difference in iCSF leakage risk was also observed among hospitals (Table 2).
Multivariate regression analysis showed that younger age, male sex, higher BMI, smoking, infratentorial surgery, hospital of admission, the indication of surgery, and use of a dural substitute were associated with higher iCSF leakage risk. By contrast, the use of sealant was associated with lower risk of iCSF leakage (Table 3). Although younger age, male sex, and higher BMI may not be clinically relevant, considering their low odds ratio (OR) (0.98, 1.02, and 1.05, respectively), hospital of admission and trauma surgery showed relatively strong effects with Ors of 9.53 and 5.11, respectively. The variance inflation factor varied but never exceeded 1.3, indicating low correlation between the risk factors tested in the multivariate model.
TABLE 3.
Multivariate Analysis for the Risk for iCSF Leakage
| Covariate | Reference value | aOR | CI 95% |
|---|---|---|---|
| Sex | Male | 1.02 | 1.01-1.03 |
| Agea | Years | 0.98 | 0.98-0.99 |
| BMIa | kg/m2 | 1.05 | 1.02-1.08 |
| Diabetes mellitus | Yes | 1.39 | 0.73-2.65 |
| Smoking | Yes | 1.63 | 1.07-2.46 |
| Hospital | No. 1 | 7.85 | 3.16-19.5 |
| No. 2 | 2.66 | 0.95-7.42 | |
| No. 3 | 9.53 | 3.63-25.01 | |
| No. 4 | 2.20 | 0.80-6.08 | |
| No. 5b | |||
| Reoperation | Yes | 1.01 | 0.62-1.62 |
| Indication of surgery | Tumor | 2.28 | 1.42-3.66 |
| Epilepsy | 1.75 | 0.74-4.15 | |
| Trauma | 5.11 | 2.27-11.47 | |
| Other | 3.88 | 1.50-10.03 | |
| Vascularb | |||
| Tentorium | Infratentorial | 2.79 | 1.87-4.15 |
| Dural substitute use | Yes | 1.55 | 1.07-2.25 |
| Sealant use | Yes | 0.62 | 0.42-0.92 |
aOR, adjusted odds ratio; BMI, body mass index.
Continuous variable.
Reference value with lowest iCSF leakage rate.
Complications and Treatment of iCSF Leakage
Surgical site infection occurred in 81 of 165 (49%) patients with iCSF leakage, of which 47 (28%) had meningitis and/or deep wound infection. In 67% of the patients, iCSF leakage was followed by wound infection. In 24% of the patients, iCSF leakage presented with wound infection. And in 9% of the patients, wound infection occurred first and was followed by an iCSF leakage. The OR for surgical site infection, including superficial and deep wound infection and meningitis, after iCSF leakage was 14.7 (95% CI: 10.3-20.9), and 12.2 (8.0-18.4) for deep wound infection and/or meningitis only compared with patients without iCSF leakage. Patients with iCSF leakage without secondary complications were hospitalized 8 (±6) extra days on average. Patients with iCSF leakage complicated by meningitis and/or deep wound infection were hospitalized significantly longer than patients without meningitis and/or deep wound infection, 21 (±29) vs days 8 (±6) days (P < .05), respectively.
In 18 of 165 (11%) patients, the iCSF leakage ceased spontaneously. Ninety-eight of 165 (59%) patients were initially treated conservatively with a pressure bandage and/or additional sutures. However, conservative treatment failed in 47 of 98 (48%) patients, and CSF drain placement with or without surgical wound revision was necessary. External lumbar or ventricular CSF drainage was used to treat iCSF leakage in 71 of the 165 (43%) patients, as initial treatment or after conservative treatment. Fourteen of 71 (20%) required wound revision surgery, despite external iCSF drainage. In total, 51 of 165 (31%) patients with iCSF leakage were surgically revised, most of them because of secondary complication of wound infection.
DISCUSSION
The overall incidence of iCSF leakage after craniotomy in our large multicenter cohort was 7.1%, which was slightly less than the mean CSF leakage rate found in our systematic review (8.2%-8.5%).4 This may be explained by the broader definition of CSF leakage applied in the existing body of literature. Furthermore, it may be related to the higher proportion of infratentorial surgeries in the systematic review (31% vs 23%), an independent risk factor for iCSF leakage, as shown in the current study.
Risk factors for iCSF leakage were younger age, higher BMI, infratentorial surgery, and dural substitute use, comparable with the existing literature.7-9 Moreover, hospital of admission, the indication of surgery, and smoking were also associated with higher iCSF leakage risk, which has not been extensively discussed in the literature before.
There were institutional differences in iCSF leakage rate, even after correction for other risk factors. This finding suggests that there are other institutional differences, such as in closure technique, type of anesthesia, and postoperative care, that may contribute to iCSF leakage risk. Another reason might be the difference in how accurate iCSF leakage is diagnosed and treated. The retrospective design of this study did not permit reliable identification of these factors and subsequent deeper analysis.
The risk of iCSF leakage was the highest for trauma surgery. A possible cause could be a large craniotomy without replacement of the bone flap.17,18 This replacement was not separately scored in our study. Second cause could be that these patients likely develop higher intracranial pressure and hydrocephalus.19 Finally, the dura cannot be closed watertight in decompression surgery.
The use of a dural substitute use was also associated with a higher risk of iCSF leakage. However, the exact relation between the size of dural defect, type of dural substitute, and risk for iCSF leakage remains unknown. In the current literature, different types of dural substitutes for dural closure have been evaluated,20-23 but studies of high methodological quality with adequate sample size are lacking.
Dural sealant use was associated with reduced iCSF leakage risk. Contrary to this finding, our prior systematic review evaluating the effectiveness of dural sealants in preventing iCSF leakage showed no association.4 A reason for this difference might be the use of different types of sealants. Currently, numerous different types of sealants are available. An in vitro model showed a remarkable difference in adhesive strength among clinically used dural sealants in the same conditions.24 The effectiveness of sealants has not been extensively studied thus far. In particular, the preventative use of sealants for infratentorial surgery and dural substitute use are of interest based on the results of the current study.
Interestingly, younger age was associated with increased iCSF leakage risk. Although the OR for 1 year is very small, it becomes relevant when relatively young patients are compared with elderly patients. Prior studies support association of iCSF leakage with younger age,8,18,25 although the etiology is not completely understood. Kehler et al18 suggested that iCSF leakage occurs less frequently in elderly patients because invasive procedures such as craniectomy and cerebellopontine-angle surgeries are performed less in this population. Another reason may be that younger patients are likely to resume mobilization faster than the elderly and maybe more active, increasing intracranial pressure.
Patients with iCSF leakage were more likely to develop a superficial wound infection and deep wound infection, and/or meningitis. This is in accordance with the relative risk of meningitis described in previous studies.26,27 Incisional CSF leakage compromises wound healing and allow bacterial migration into the wound.
Although conservative treatment of iCSF leakage with a pressure bandage and cutaneous suture(s) placement has clear benefits (ie, no immobilization, easily executable, and low costs), it failed in 48% of the patients in which this strategy was applied, thus leading to futile prolonged hospitalization and increased healthcare costs in these patients. The success rate of external CSF drainage to treat incisional CSF leakage, primary or secondary after failed conservative treatment, was 80%. Altaf et al28 showed comparable success rates as in this study. The results of this study support their recommendation to combine conservative treatment with lumbar CSF drainage for iCSF leakage.
Limitations
Our study is subject to several limitations. First, because of the retrospective design of this study, the quality and availability depend on the data reported in the medical records. The use of dural substitutes and sealants, for example, may not always have been noted in the operative reports, which may cause underestimation of the use of these materials. This type of information bias would have led to a less pronounced preventative result than currently reported. Likewise, iCSF leakage resolving after additional suture placement may not have been described in patient files and therefore missed. Second, information such as the size of the dural defect, the size or amount of dural sealant and dural substitute use, and the watertightness of the dura after closure was lacking. The risk of iCSF leakage may also related to these factors, which is not evaluated in this study. Third, some patients may have been treated in another center for complications without communication to the center of primary surgery. This differential misclassification may have caused an underestimation of the postoperative iCSF leakage rate. Finally, selection bias may have caused underestimation of the iCSF leakage rate is this study as well. Patients who died within 1 month after surgery were excluded. This potentially includes patients who died of meningitis after iCSF leakage and patients in poor clinical condition with risk of iCSF leakage such as trauma cases.
CONCLUSION
Incisional CSF leakage is a frequent (7.1%) and clinically meaningful complication after intradural cranial surgery, substantially increasing infection risk and prolonging the hospital stay. Age, BMI, smoking, infratentorial surgery, the indication of surgery, hospital of admission, dural substitute use, and dural sealant use were shown to be factors significantly associated with iCSF leakage in this study population. Because conservatively managing iCSF leakage proves insufficiency, immediate external CSF drainage and/or wound revision surgery should be considered.
Footnotes
A poster presentation in an abstract form with the preliminary results (4 of 5 neurosurgical centers were included at that moment) was shown at the virtual congress of European Association of Neurosurgical Societies (EANS) congress on 10th July 2021.
Contributor Information
Emma M. H. Slot, Email: [email protected].
Mare Kollen, Email: [email protected].
Menno R. Germans, Email: [email protected].
Sepideh Amin-Hanjani, Email: [email protected].
Andrew P. Carlson, Email: [email protected].
Kashif Majeed, Email: [email protected].
Paul R. A. M. Depauw, Email: [email protected].
Pierre A. Robe, Email: [email protected].
Luca Regli, Email: [email protected].
Fady T. Charbel, Email: [email protected].
Tristan P. C. van Doormaal, Email: [email protected].
Funding
This study did not receive any funding or financial support. Paul R. A. M. Depauw reports funding from NIH.
Disclosures
Andrew P. Carlson and Luca Regli report financial relationships with Polyganics (funds to institution). Ahmet Kinaci's PhD position was funded by Polyganics B.V., the Netherlands. Emma M.H. Slot's PhD position was funded by Polyganics B.V., the Netherlands. Tristan van Doormaal did consultancy work for Polyganics B.V. at the time of this research. The other authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article.
COMMENTS
The authors present an interesting analysis of risk factors associated with CSF leak after craniotomy. This is a fairly large multi-institutional study with over 2000 patients. The authors identified several factors associated with increased risk of CSF leak, including trauma case, obesity, smoking, posterior fossa surgery, and the employment of dural substitutes and sealants. Although the risk factors are not surprising, the increased risk associated with dural substitute and sealant use is curious and may be an epiphenomenon of the primary defect requiring repair. The authors recommend early CSF drainage or wound revision and repair in cases where postoperative CSF leak is encountered and report an 80% success rate when this approach is used.
Carlos David
Chapel Hill, North Carolina, USA
CSF leaks, and their successful management, are one of the salient differences between neurosurgery and other surgical specialties. This retrospective series of 2310 patients sheds light on this important and vexing problem. Wound infections and meningitis are well-known sequelae motivating one of my favorite senior residents to always ask after every presentation of a postoperative patient, “Is the wound dry?” (personal communication). Although easy to understand on a superficial level, pun intended, the pathophysiology of CSF leak on a more profound level is difficult to comprehend. Why for example should “daily tap and wrap” work when the brain is producing 450 cc every 24 hours? From this vantage point, the authors provide important information for every neurosurgeon. First, they highlight the severe consequences of an ongoing leak with respect to wound healing, infection, and meningitis. The authors appropriately draw attention to higher BMI, smoking, infratentorial surgery, and the use of dural substitutes as risk factors that mandate increased attention to wound closure in a watertight fashion. Finally, the authors have found solutions to incorporate into clinical practice. They document the efficacy of dural sealants and proscribe early wound revision. The suggestion that CSF diversion should be used more often is novel. The observation that dural substitutes are associated with an increased risk of CSF leak suggests an opportunity for improvement of the dural substitutes available. The paper provides critical information that should decrease the morbidity of this serious complication.
Michael W. Groff
Boston, Massachusetts, USA
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