Retrospective validation of a β-trace protein interpretation algorithm for the diagnosis of cerebrospinal fluid leakage

Abstract Background: Cerebrospinal fluid (CSF) leakage is a rare condition that can potentially lead to the development of serious complications. In the last decade, β-trace protein (β-TP) has been shown to be a valuable immunological biomarker that allows prompt and non-invasive identification of CSF leakage. At our institution, the measurement of β-TP has been included in the diagnostic work-up of CSF leakage for more than 10 years. According to our diagnostic algorithm, the presence of CSF in secretion is excluded when β-TP values are <0.7 mg/L, whereas β-TP values ≥1.3 mg/L indicate the presence of CSF in secretion. β-TP values between 0.7 and 1.29 mg/L indicate the presence of CSF if the β-TP ratio (β-TP secretion/β-TP serum) is ≥2. This study aimed to validate this diagnostic algorithm using clinically defined nasal/ear secretions. Methods: We performed a retrospective statistical analysis of three β-TP interpretation strategies using data of 236 samples originating from 121 patients with suspect CSF leakage received at our laboratory between 2004 and 2012. Results: The highest odds ratio was obtained when the proposed algorithm has been used for the interpretation of β-TP results, showing a sensitivity of 98.3% and a specificity of 96%. Positive and negative predictive values were 89.2% and 99.4%, respectively. Conclusions: Our data suggest that the proposed β-TP interpretation algorithm is a valuable tool for the diagnosis of CSF leakage in the clinical practice.

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Interpretable Machine Learning–Based Prediction of Intraoperative Cerebrospinal Fluid Leakage in Endoscopic Transsphenoidal Pituitary Surgery: A Pilot Study

Journal of Neurological Surgery Part B Skull Base ◽

10.1055/s-0041-1740621 ◽

2022 ◽

Author(s):

Pier Paolo Mattogno ◽

Valerio M. Caccavella ◽

Martina Giordano ◽

Quintino G. D'Alessandris ◽

Sabrina Chiloiro ◽

...

Keyword(s):

Machine Learning ◽

Cerebrospinal Fluid ◽

Logistic Regression ◽

Prediction Model ◽

Prediction Models ◽

Cerebrospinal Fluid Leakage ◽

Tumor Diameter ◽

Predictive Values ◽

Multivariable Logistic Regression ◽

Csf Leakage

Abstract Purpose Transsphenoidal surgery (TSS) for pituitary adenomas can be complicated by the occurrence of intraoperative cerebrospinal fluid (CSF) leakage (IOL). IOL significantly affects the course of surgery predisposing to the development of postoperative CSF leakage, a major source of morbidity and mortality in the postoperative period. The authors trained and internally validated the Random Forest (RF) prediction model to preoperatively identify patients at high risk for IOL. A locally interpretable model-agnostic explanations (LIME) algorithm is employed to elucidate the main drivers behind each machine learning (ML) model prediction. Methods The data of 210 patients who underwent TSS were collected; first, risk factors for IOL were identified via conventional statistical methods (multivariable logistic regression). Then, the authors trained, optimized, and audited a RF prediction model. Results IOL reported in 45 patients (21.5%). The recursive feature selection algorithm identified the following variables as the most significant determinants of IOL: Knosp's grade, sellar Hardy's grade, suprasellar Hardy's grade, tumor diameter (on X, Y, and Z axes), intercarotid distance, and secreting status (nonfunctioning and growth hormone [GH] secreting). Leveraging the predictive values of these variables, the RF prediction model achieved an area under the curve (AUC) of 0.83 (95% confidence interval [CI]: 0.78; 0.86), significantly outperforming the multivariable logistic regression model (AUC = 0.63). Conclusion A RF model that reliably identifies patients at risk for IOL was successfully trained and internally validated. ML-based prediction models can predict events that were previously judged nearly unpredictable; their deployment in clinical practice may result in improved patient care and reduced postoperative morbidity and healthcare costs.

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Cerebrospinal fluid outflow resistance as a diagnostic marker of spontaneous cerebrospinal fluid leakage

Journal of Neurosurgery Spine ◽

10.3171/2017.1.spine16548 ◽

2017 ◽

Vol 27 (2) ◽

pp. 227-234 ◽

Cited By ~ 13

Author(s):

Jürgen Beck ◽

Christian Fung ◽

Christian T. Ulrich ◽

Michael Fiechter ◽

Jens Fichtner ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Spontaneous Intracranial Hypotension ◽

Volume Index ◽

Csf Leak ◽

Cerebrospinal Fluid Leakage ◽

Outflow Resistance ◽

Opening Pressure ◽

Csf Dynamics ◽

Predictive Values ◽

Csf Leakage

OBJECTIVESpinal CSF leakage causes spontaneous intracranial hypotension (SIH). The aim of this study was to characterize CSF dynamics via lumbar infusion testing in patients with and without proven spinal CSF leakage in order to explore possible discriminators for the presence of an open CSF leak.METHODSThis analysis included all patients with suspected SIH who were treated at the authors’ institution between January 2012 and February 2015. The gold standard for “proven” CSF leakage is considered to be extrathecal contrast accumulation after intrathecal contrast injection. To characterize CSF dynamics, the authors performed computerized lumbar infusion testing to measure lumbar pressure at baseline (opening pressure) and at plateau, as well as pulse amplitude, CSF outflow resistance (RCSF), craniospinal elastance, and pressure-volume index.RESULTSThirty-one patients underwent clinical imaging and lumbar infusion testing and were included in the final analysis. A comparison of the 14 patients with proven CSF leakage with the 17 patients without leakage showed a statistically significantly lower lumbar opening pressure (p < 0.001), plateau pressure (p < 0.001), and RCSF (p < 0.001) in the group with leakage. Sensitivity, specificity, and positive and negative predictive values for an RCSF cutoff of ≤ 5 mm Hg/(ml/min) were 0.86, 1.0, 1.0, and 0.89 (area under the curve of 0.96), respectively. The median pressure-volume index was higher (p = 0.003), and baseline (p = 0.017) and plateau (p < 0.001) pulse amplitudes were lower in patients with a proven leak.CONCLUSIONSLumbar infusion testing captures a distinct pattern of CSF dynamics associated with spinal CSF leakage. RCSF assessed by computerized lumbar infusion testing has an excellent diagnostic accuracy and is more accurate than evaluating the lumbar opening pressure. The authors suggest inclusion of RCSF in the diagnostic criteria for SIH.

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Cerebrospinal fluid leakage after cranial surgery in the pediatric population—a systematic review and meta-analysis

Child s Nervous System ◽

10.1007/s00381-021-05036-8 ◽

2021 ◽

Author(s):

Emma M. H. Slot ◽

Kirsten M. van Baarsen ◽

Eelco W. Hoving ◽

Nicolaas P. A. Zuithoff ◽

Tristan P. C van Doormaal

Keyword(s):

Risk Factors ◽

Systematic Review ◽

Cerebrospinal Fluid ◽

Pediatric Population ◽

Meta Analysis ◽

Leakage Rate ◽

Csf Leak ◽

Cerebrospinal Fluid Leakage ◽

Cranial Surgery ◽

Csf Leakage

Abstract Background Cerebrospinal fluid (CSF) leakage is a common complication after neurosurgical intervention. It is associated with substantial morbidity and increased healthcare costs. The current systematic review and meta-analysis aim to quantify the incidence of cerebrospinal fluid leakage in the pediatric population and identify its risk factors. Methods The authors followed the PRISMA guidelines. The Embase, PubMed, and Cochrane database were searched for studies reporting CSF leakage after intradural cranial surgery in patients up to 18 years old. Meta-analysis of incidences was performed using a generalized linear mixed model. Results Twenty-six articles were included in this systematic review. Data were retrieved of 2929 patients who underwent a total of 3034 intradural cranial surgeries. Surprisingly, only four of the included articles reported their definition of CSF leakage. The overall CSF leakage rate was 4.4% (95% CI 2.6 to 7.3%). The odds of CSF leakage were significantly greater for craniectomy as opposed to craniotomy (OR 4.7, 95% CI 1.7 to 13.4) and infratentorial as opposed to supratentorial surgery (OR 5.9, 95% CI 1.7 to 20.6). The odds of CSF leakage were significantly lower for duraplasty use versus no duraplasty (OR 0.41 95% CI 0.2 to 0.9). Conclusion The overall CSF leakage rate after intradural cranial surgery in the pediatric population is 4.4%. Risk factors are craniectomy and infratentorial surgery. Duraplasty use is negatively associated with CSF leak. We suggest defining a CSF leak as “leakage of CSF through the skin,” as an unambiguous definition is fundamental for future research.

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CT-Guided Autologous Blood Patch for High-Level Cervical Cerebrospinal Fluid Leakage: Imaging Characteristics and Treatment Safety and Efficiency

European Neurology ◽

10.1159/000515590 ◽

2021 ◽

pp. 1-7

Author(s):

Xiaofeng He ◽

Yueyong Xiao ◽

Xiao Zhang ◽

Xiaobo Zhang ◽

Xin Zhang ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Epidural Space ◽

Autologous Blood ◽

Cerebrospinal Fluid Leakage ◽

Imaging Features ◽

Ct Guided ◽

Iodinated Contrast ◽

Blood Patch ◽

Csf Leakage ◽

High Level

Introduction: Epidural blood patches (EBPs) are rarely performed at the high-level cervical levels. The aim of the study was to investigate the imaging features, safety, and effectiveness of CT-guided percutaneous EBPs for high-level cervical cerebrospinal fluid (CSF) leakage. Methods: Twenty-five patients with spontaneous high-level (C1–C3) CSF leakage on MRI and CT imaging, including 2 patients with intracranial epidural hematoma caused by CSF, were treated with EBP. Two needles were inserted into the C1–3 bilateral epidural space. The needle location was confirmed by injection of both 3–5mL sterile air and a diluted iodinated contrast agent to delineate its spatial diffusion. The patient’s blood 11.1 ± 3.1 mL was slowly injected to make a patch; the distribution in epidural space was monitored with intermittent CT scanning. Results: The typical manifestation of CSF leakage was the high signal outside the C1–3 cervical dura on MR T2W fat inhibition images and low density in cervical muscle space on CT images. Twenty patients suffered from headaches and were able to sit and walk 24 h after the operation. Four patients, with partial relief of headache and a small but persistent CSF leakage, were re-treated with EBS. One patient underwent a third operation because of a persistent CSF leakage on MRI. Conclusions: Imaging of water at the surrounding epidural space of high cervical level is a typical feature of dural rupture on both MRI and CT. CT-guided EBP is safe and efficient for the high-level cervical CSF leakage, especially for cases in which conservative treatments failed.

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Acquired Chiari I malformation secondary to spontaneous spinal cerebrospinal fluid leakage and chronic intracranial hypotension syndrome in seven cases

Journal of Neurosurgery ◽

10.3171/jns.1998.88.2.0237 ◽

1998 ◽

Vol 88 (2) ◽

pp. 237-242 ◽

Cited By ~ 106

Author(s):

John L. D. Atkinson ◽

Brian G. Weinshenker ◽

Gary M. Miller ◽

David G. Piepgras ◽

Bahram Mokri

Keyword(s):

Cerebrospinal Fluid ◽

Intracranial Hypotension ◽

Chiari I Malformation ◽

Csf Leak ◽

Cerebrospinal Fluid Leakage ◽

Content Type ◽

Intracranial Hypotension Syndrome ◽

Csf Leakage ◽

Chiari I ◽

Fine Print

Object. Spontaneous spinal cerebrospinal fluid (CSF) leakage with development of the intracranial hypotension syndrome and acquired Chiari I malformation due to lumbar spinal CSF diversion procedures have both been well described. However, concomitant presentation of both syndromes has rarely been reported. The object of this paper is to present data in seven cases in which both syndromes were present. Three illustrative cases are reported in detail. Methods. The authors describe seven symptomatic cases of spontaneous spinal CSF leakage with chronic intracranial hypotension syndrome in which magnetic resonance (MR) images depicted dural enhancement, brain sagging, loss of CSF cisterns, and acquired Chiari I malformation. Conclusions. This subtype of intracranial hypotension syndrome probably results from chronic spinal drainage of CSF or high-flow CSF shunting and subsequent loss of brain buoyancy that results in brain settling and herniation of hindbrain structures through the foramen magnum. Of 35 cases of spontaneous spinal CSF leakage identified in the authors' practice over the last decade, MR imaging evidence of acquired Chiari I malformation has been shown in seven. Not to be confused with idiopathic Chiari I malformation, ideal therapy requires recognition of the syndrome and treatment directed to the site of the spinal CSF leak.

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Cerebrospinal fluid leakage into the subdural space: possible influence on the pathogenesis and recurrence frequency of chronic subdural hematoma and subdural hygroma

Journal of Neurosurgery ◽

10.3171/jns/2008/108/2/0275 ◽

2008 ◽

Vol 108 (2) ◽

pp. 275-280 ◽

Cited By ~ 29

Author(s):

Rudolf A. Kristof ◽

Jochen M. Grimm ◽

Birgit Stoffel-Wagner

Keyword(s):

Cerebrospinal Fluid ◽

Recurrence Rate ◽

Subdural Hematoma ◽

Chronic Subdural Hematoma ◽

Postoperative Recurrence ◽

Cerebrospinal Fluid Leakage ◽

Subdural Space ◽

Subdural Hygroma ◽

Fluid Leakage ◽

Csf Leakage

Object The purpose of this study was to clarify whether cerebrospinal fluid (CSF) leakage into the subdural space is involved in the genesis of chronic subdural hematoma (CSDH) and subdural hygroma (SH) and to clarify whether this leakage of CSF into the subdural space influences the postoperative recurrence rate of CSDH and SH. Methods In this prospective observational study, 75 cases involving patients treated surgically for CSDH (67 patients) or SH (8 patients) were evaluated with respect to clinical and radiological findings at presentation, the content of β -trace protein (β TP) in the subdural fluid (βTPSF) and serum (βTPSER), and the CSDH/SH recurrence rate. The βTPSF was considered to indicate an admixture of CSF to the subdural fluid if βTPSF/βTPSER > 2. Results The median β TPSF level for the whole patient group was 4.29 mg/L (range 0.33–51 mg/L). Cerebrospinal fluid leakage, as indicated by βTPSF/βTPSER > 2, was found to be present in 93% of the patients with CSDH and in 100% of the patients with SH (p = 0.724). In patients who later had to undergo repeated surgery for recurrence of CSDH/SH, the βTPSF concentrations (median 6.69 mg/L, range 0.59–51 mg/L) were significantly higher (p = 0.04) than in patients not requiring reoperation (median 4.12 mg/L, range 0.33–26.8 mg/L). Conclusions As indicated by the presence of βTP in the subdural fluid, CSF leakage into the subdural space is present in the vast majority of patients with CSDH and SH. This leakage could be involved in the pathogenesis of CSDH and SH. Patients who experience recurrences of CSDH and SH have significantly higher concentrations of βTPSF at initial presentation than patients not requiring reoperation for recurrence. These findings are presented in the literature for the first time and have to be confirmed and expanded upon by further studies.

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Spontaneous Cerebrospinal Fluid Leakage and Middle Ear Encephalocele in Seven Patients

Ear Nose & Throat Journal ◽

10.1177/014556130007900510 ◽

2000 ◽

Vol 79 (5) ◽

pp. 372-378 ◽

Cited By ~ 12

Author(s):

Rakesh B. Patel ◽

Jed A. Kwartler ◽

Richard M. Hodosh ◽

Soly Baredes

Keyword(s):

Cerebrospinal Fluid ◽

Hearing Loss ◽

Middle Ear ◽

Diagnostic Methods ◽

Cerebrospinal Fluid Leakage ◽

Recurrent Meningitis ◽

Lumbar Drain ◽

Csf Leakage ◽

History Of ◽

Conductive Hearing

Isolated cases of spontaneous cerebrospinal fluid (CSF) leakage with and without middle ear encephalocele have been reported. These leaks are usually accompanied by episodes of recurrent meningitis, hearing loss, or chronic headache. In this article, we report seven new cases of spontaneous CSF leakage. Six of these patients had conductive hearing loss and serous otitis media, and three had recurrent meningitis. Prior to a definitive diagnosis, six patients had received myringotomy tubes, which produced profuse clear otorrhea. Three patients had positive beta-2 transferrin assays. Computed tomography and magnetic resonance imaging confirmed a defect in the temporal bone tegmen. A combined transmastoid and middle fossa surgical approach with a three-layer closure was used to repair the tegmen defect. All patients had a lumbar drain placed prior to surgery. In addition to describing the seven new cases, we review the history of CSF leakage and discuss diagnostic methods, surgical findings, and our recommendations for management.

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Single-Arm, Open-Label, Multicenter Study to Evaluate the Safety and Performance of Dura Sealant Patch in Reducing Cerebrospinal Fluid Leakage Following Elective Cranial Surgery: The ENCASE Trial Study Protocol

Neurosurgery ◽

10.1093/neuros/nyz396 ◽

2019 ◽

Author(s):

Tristan P C van Doormaal ◽

Menno R Germans ◽

Mariska Sie ◽

Bart Brouwers ◽

Jorn Fierstra ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Primary Endpoint ◽

Multicenter Study ◽

Controlled Trial ◽

Cerebrospinal Fluid Leakage ◽

Open Label ◽

Cranial Surgery ◽

Dural Closure ◽

Csf Leakage ◽

And Performance

Abstract BACKGROUND Cerebrospinal fluid (CSF) leakage is one of the most common neurosurgical complications, occurring in 4% to 32% of surgical cases, with a higher incidence in complicated skull base surgery, intradural spine surgery, and the surgery of the posterior fossa. Our group developed a Dural Sealant Patch (DSP) for watertight dural closure after cranial surgery. OBJECTIVE To clinically study for the first time the safety and performance of the DSP as a means of reducing CSF leakage in patients undergoing elective cranial intradural surgery with a dural closure procedure. METHODS We will conduct an open-label, single-arm, multicenter study with a 360 d (12 mo) follow-up. A total of 40 patients will be enrolled at 3 sites. The primary endpoint is a combination of occurrences of one of the following events: postoperative percutaneous CSF leakage, intraoperative leakage at 20 cm H2O, or postoperative wound infection. The secondary endpoints are pseudomeningocele and thickness of dura + DSP. EXPECTED OUTCOMES Not more than 3 patients will meet the primary endpoint suggesting safety and efficacy. DISCUSSION As a next step, a randomized controlled trial against the best current practice will follow to evaluate if DSP reduces CSF leakage while its safety is noninferior.

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Clipping Technique for the Repair of the Intraoperative Cerebrospinal Fluid Leakage during Transsphenoidal Pituitary Tumor Surgery

Operative Neurosurgery ◽

10.1093/ons/opy408 ◽

2019 ◽

Vol 17 (4) ◽

pp. 382-388

Author(s):

Eui Hyun Kim ◽

Ju Hyung Moon ◽

Sun Ho Kim

Keyword(s):

Cerebrospinal Fluid ◽

Pituitary Adenoma ◽

Anterior Pituitary ◽

Pituitary Function ◽

Cerebrospinal Fluid Leakage ◽

Arachnoid Membrane ◽

Csf Rhinorrhea ◽

Csf Leakage ◽

Anterior Pituitary Function ◽

Clipping Technique

Abstract BACKGROUND During transsphenoidal surgery (TSS) for a pituitary adenoma with a large suprasellar extension, cerebrospinal fluid (CSF) leakage commonly develops from a defect in the arachnoid recess or the arachnoid membrane. OBJECTIVE To evaluate the usefulness of a newly developed clipping technique for the repair of intraoperative CSF leakage. METHODS Between September 2012 and November 2016, 698 patients with pituitary adenoma were operated on with TSS. Intraoperative CSF leakage was encountered in 301 patients (43.1%). The clipping technique was used to repair CSF leakage in 144 patients: from the arachnoid recess in 100 patients and from the arachnoid membrane in 44 patients. The clipping technique used titanium clips and a newly designed clip applier. We evaluated anterior pituitary function of the patients whose CSF leakage was closed by clipping, and compared this with function in another patient group treated with different repair techniques. RESULTS We successfully applied clip technique in 140 out of 144 patients. This clipping technique was faster and easier for repairing CSF leakage than our previously published suture technique. In our early series, 4 patients developed unexpected CSF rhinorrhea after TSS. We found no difference in anterior pituitary function between a clipping group and others. Although titanium clip was identified on postoperative MRI, its metallic scattered artifact was very minimal and did not hinder the detection of possible remnant and recurrent tumors. CONCLUSION This clipping technique is a very simple and reliable method for repairing intraoperative CSF leakage when properly applied with caution.

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Cerebrospinal fluid leakage in Gorham-Stout disease due to dura mater involvement after progression of an osteolytic lesion in the thoracic spine

Journal of Neurosurgery Spine ◽

10.3171/2014.8.spine131064 ◽

2014 ◽

Vol 21 (6) ◽

pp. 956-960 ◽

Cited By ~ 8

Author(s):

Eric Jose Suero Molina ◽

Thomas Niederstadt ◽

Vincent Ruland ◽

Gian Kayser ◽

Walter Stummer ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Disease Control ◽

Dura Mater ◽

Thoracic Spine ◽

Osteolytic Lesion ◽

Bone Matrix ◽

Lymphatic Vessels ◽

Cerebrospinal Fluid Leakage ◽

Csf Leakage ◽

Neurosurgical Intervention

Patients with Gorham-Stout disease (GSD), a rare disease of poorly understood etiopathophysiology, suffer from progressive osteolysis. Destruction of bone matrix is caused by lymphatic vessels, which can lead to CSF leakage if parts of bony structures adjacent to CSF spaces are involved. So far, fewer than 200 patients have been reported in the literature; only 4 of these patients presented with CSF leakage. The authors report the case of a 30-year-old man with GSD and CSF leakage due to dura mater involvement after progression of an osteolytic lesion in the thoracic spine. Neurosurgical intervention, including dura repair, was needed. Experimental medical therapy with rapamycin was started, leading to disease control for more than 12 months. Progression of GSD can lead to destruction of the meninges, causing CSF leakage. The authors review 4 other cases reported in the literature and discuss therapeutic options.

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