Intracranial Hypotension and Cerebrospinal Fluid Leak.

Review of the clinical presentation, imaging findings, and management of headache secondary to intracranial hypotension.

Volume of cerebrospinal fluid drainage as a predictor for pretreatment aneurysmal rebleeding.

OBJECTIVE Initiation of external CSF drainage has been associated with a significant increase in rebleeding probability after aneurysmal subarachnoid hemorrhage (aSAH). However, the implications for acute management are uncertain. The purpose of this study was to evaluate the role of the amount of drained CSF on aneurysmal rebleeding. METHODS Consecutive patients with aSAH were analyzed retrospectively. Radiologically confirmed cases of aneurysmal in-hospital rebleeding were identified and predictor variables for rebleeding were retrieved from hospital records. Clinical predictors were identified through multivariate analysis, and logistic regression analysis was performed to ascertain the cutoff value for the rebleeding probability. RESULTS The study included 194 patients. Eighteen cases (9.3%) of in-hospital rebleeding could be identified. Using multivariate analysis, in-hospital rebleeding was significantly associated with initiation of CSF drainage (p = 0.001) and CSF drainage volume (63 ml [interquartile range (IQR) 55-69 ml] vs 25 ml [IQR 10-35 ml], p < 0.001). Logistic regression showed that 58 ml of CSF drainage within 6 hours results in a 50% rebleeding probability. The relative risk (RR) for rebleeding after drainage of more than 60 ml in 6 hours was 5.4 times greater compared with patients with less CSF drainage (RR 5.403, 95% CI 2.481-11.767; p < 0.001, number needed to harm = 1.687). CONCLUSIONS Volume of CSF drainage was highly correlated with the probability of in-hospital aneurysmal rebleeding. These findings suggest that the rebleeding probability can be affected in acute management should the placement of an external ventricular catheter be necessary. This finding necessitates meticulous control of the amount of drained CSF and the development of a definitive treatment protocol for this group of patients.

Barrier dysfunction or drainage reduction: differentiating causes of CSF protein increase.

BACKGROUND: Cerebrospinal fluid (CSF) protein analysis is an important element in the diagnostic chain for various central nervous system (CNS) pathologies. Among multiple existing approaches to interpreting measured protein levels, the Reiber diagram is particularly robust with respect to physiologic inter-individual variability, as it uses multiple subject-specific anchoring values. Beyond reliable identification of abnormal protein levels, the Reiber diagram has the potential to elucidate their pathophysiologic origin. In particular, both reduction of CSF drainage from the cranio-spinal space as well as blood-CNS barrier dysfunction have been suggested ρas possible causes of increased concentration of blood-derived proteins. However, there is disagreement on which of the two is the true cause. METHODS: We designed two computational models to investigate the mechanisms governing protein distribution in the spinal CSF. With a one-dimensional model, we evaluated the distribution of albumin and immunoglobulin G (IgG), accounting for protein transport rates across blood-CNS barriers, CSF dynamics (including both dispersion induced by CSF pulsations and advection by mean CSF flow) and CSF drainage. Dispersion coefficients were determined a priori by computing the axisymmetric three-dimensional CSF dynamics and solute transport in a representative segment of the spinal canal. RESULTS: Our models reproduce the empirically determined hyperbolic relation between albumin and IgG quotients. They indicate that variation in CSF drainage would yield a linear rather than the expected hyperbolic profile. In contrast, modelled barrier dysfunction reproduces the experimentally observed relation. CONCLUSIONS: High levels of albumin identified in the Reiber diagram are more likely to originate from a barrier dysfunction than from a reduction in CSF drainage. Our in silico experiments further support the hypothesis of decreasing spinal CSF drainage in rostro-caudal direction and emphasize the physiological importance of pulsation-driven dispersion for the transport of large molecules in the CSF.

Evaluation of Spontaneous Spinal Cerebrospinal Fluid Leaks Disease by Computerized Image Processing.

BACKGROUND: Spontaneous Spinal Cerebrospinal Fluid Leaks (SSCFL) is a disease based on tears on the dura mater. Due to widespread symptoms and low frequency of the disease, diagnosis is problematic. Diagnostic lumbar puncture is commonly used for diagnosing SSCFL, though it is invasive and may cause pain, inflammation or new leakages. T2-weighted MR imaging is also used for diagnosis; however, the literature on T2-weighted MRI states that findings for diagnosis of SSCFL could be erroneous when differentiating the diseased and control. One another technique for diagnosis is CT-myelography, but this has been suggested to be less successful than T2-weighted MRI and it needs an initial lumbar puncture. OBJECTIVES: This study aimed to develop an objective, computerized numerical analysis method using noninvasive routine Magnetic Resonance Images that can be used in the evaluation and diagnosis of SSCFL disease. METHODS: Brain boundaries were automatically detected using methods of mathematical morphology, and a distance transform was employed. According to normalized distances, average densities of certain sites were proportioned and a numerical criterion related to cerebrospinal fluid distribution was calculated. RESULTS: The developed method was able to differentiate between 14 patients and 14 control subjects significantly with p = 0.0088 and d = 0.958. Also, the pre and post-treatment MRI of four patients was obtained and analyzed. The results were differentiated statistically (p = 0.0320, d = 0.853). CONCLUSIONS: An original, noninvasive and objective diagnostic test based on computerized image processing has been developed for evaluation of SSCFL. To our knowledge, this is the first computerized image processing method for evaluation of the disease. Discrimination between patients and controls shows the validity of the method. Also, post-treatment changes observed in four patients support this verdict.

Dickkopf-related Protein 3 as a Sensitive and Specific Marker for Cerebrospinal Fluid Leaks.

HYPOTHESIS: Cerebrospinal fluid (CSF) can be identified by using an enzyme-linked immunosorbent assay (ELISA) for Dickkopf-related protein 3 (DKK3). BACKGROUND: Cerebrospinal fluid leakage from the subarachnoid space is a potentially alarming condition that, left unrepaired, may result in increased risk of meningitis and encephalitis. Current biochemical methods of CSF leak detection involve using beta-2-transferrin-based or beta trace protein-based assays, both of which, at present, have limitations that hinder practical clinical application. This study presents the immunological detection of the CSF-enriched protein DKK3 as a method for detection of a CSF leak. METHODS: Antibodies against DKK3 were generated in rabbits and goats immunized with recombinant human DKK3. Varying dilutions and combinations of human CSF and serum were tested on immunoblots and sandwich ELISA using antibodies to DKK3. RESULTS: ELISA data show that there is a negligible amount of detectable DKK3 in serum samples compared with CSF samples. Inclusion of sera (up to 30%) in a sample containing CSF failed to produce a positive signal, whereas concentrations of CSF as low as 1% produced a positive signal. The minimum concentration required for reliable CSF detection in a sandwich ELISA was determined to be 0.5  µl. CONCLUSION: ELISA sandwich assays for DKK3 can reliably detect the presence of as little as 0.5 µl of human CSF, even in the presence of excessive serum. This study provides quantitative evidence of the utility of DKK3 immunoreactivity as an assay for the presence of CSF in samples that contain contaminating sera. The robustness of this assay has allowed for the development of a rapid, point of care test for the detection of CSF in clinical and surgical setting.

CSF Levels of Angiopoietin-2 Do Not Differ between Patients with CSF Fluid Leakage Syndrome and Controls.

CSF abnormalities have been reported in CSF leakage syndrome. However, the mechanism for these CSF changes is actually unknown and they may indicate impaired CSF flow or blood-CSF barrier. Angiopoietin-2 (Ang-2), a protein which is expressed and released by endothelial cells, has been associated with increased vascular permeability. In the assumption that CSF changes are due to an impaired blood-CSF barrier, we hypothesized that subjects with persistent CSF leakage may have increased CSF Ang-2 levels. We enrolled 10 subjects with a clinically definite diagnosis of persisting CSF leakage syndrome and 10 control subjects. In CSF analyses, CSF to serum albumin ratio (Qalb) was the most frequently increased parameter indicating a disturbed blood-CSF barrier function. Comparison of the mean CSF Ang-2 levels, CSF to serum Ang-2 ratio (QAng-2), and QAng-2/Qalb between the control and CSF leakage patients did not show any significant difference. We suggest that the increase of Qalb results from a low CSF flow. Future studies with phase contrast-MRI in conjunction with CSF analyses before and after epidural blood patch treatment are required to address this question. It would be of particular interest whether Qalb can be used as a marker for successful nontargeted epidural blood patch treatment.

False negative ß-2 transferrin in the diagnosis of cerebrospinal fluid leak in the presence of Streptococcus pneumoniae.

OBJECTIVES/HYPOTHESIS: The objectives of this study were to examine the presence of ß-2 transferrin (ß2TRNSF) in cerebrospinal fluid (CSF) contaminated in vitro by various bacteria and explore the mechanism (passive or active) responsible for ß2TRNSF elimination. Early diagnosis of CSF leakage may change treatment decisions and minimize the risk of meningitis and encephalitis. ß2TRNSF is a protein present exclusively in CSF. Its detection is highly useful in cases of CSF leakage, although it has never been examined in the presence of central nervous system infection. STUDY DESIGN: Prospective patient analysis. METHODS: Sterile CSF drawn from patients was contaminated in vitro with several microorganisms chosen for their ability to cause neurosurgical-related infections: Streptococcus pneumoniae, methicillin-sensitive Staphylococcus aureus, Staphylococcus epidermidis, and Pseudomonas aeruginosa. ß2TRNSF was examined at two time points: following immediate inoculation (t0) and following an overnight incubation (t18) over various bacterial concentrations. Samples of CSF inoculated with S pneumoniae were also examined in the presence of ciprofloxacin. For ß2TRNSF analysis we used immunoblotting electrophoresis and enzyme-linked immunosorbent assay (ELISA). RESULTS: CSF samples collected from nine patients were analyzed. ß2TRNSF was not detected following S pneumoniae inoculation at both time points when immunoblotting electrophoresis was used. Quantitative analysis using ELISA demonstrated significant ß2TRNSF concentration decrease. The addition of ciprofloxacin led to the same results. CONCLUSIONS: CSF leak detection using ß2TRNSF may be deceiving in the presence of a S pneumoniae cerebral nervous system infection. A passive process is suggested, as ß2TRNSF disappeared either immediately or following incubation with inactive bacteria.