Tau protein as a possible marker of cerebrospinal fluid leakage in cerebrospinal fluid rhinorrhoea: A pilot study.

INTRODUCTION: The management of posttraumatic cerebrospinal fluid (CSF) rhinorrhoea remains a clinical challenge. Cerebrospinal fistula is a dural defect responsible for possible CSF leakage into the contiguous air-filled cavities located at the skull base. The risk of central nervous system infection in these conditions is severe and can be life threatening. Consequently, a specific CSF biomarker might be used in case of difficult diagnosis of CSF rhinorrhoea. CSF Tau protein is a neuronal protein, commonly assessed for diagnosis of Alzheimer Disease (AD). The aim of this study was to determine whether the Tau protein could be a relevant marker of CSF leakage. MATERIALS AND METHODS: Tau protein measurement was performed by enzyme-linked immunosorbent assay in 13 patients with CSF leakage (CSF rhinorrhoea group), and 8 patients with spontaneous aqueous rhinorrhoea (non-CSF leakage group). The serum concentration of Tau protein was measured by ELISA in both CSF rhinorrhoea group and non-CSF leakage group. RESULTS: In patients with CSF leakage, CSF Tau protein median concentration was 479 ng/L (197 - 2325 ng/L). On the other hand, the Tau protein concentration was below the lower limit of quantification (LLoQ) (< 87 ng/L) in non-CSF leakage group. Serum Tau protein concentration by ELISA was also below LLoQ (< 87 ng/L) for all subjects. CONCLUSION: ELISA measurement of Tau protein in rhinorrhoea fluid may be a reliable and relevant marker for detecting the presence of CSF in the nasal discharge and sign the existence of a CSF leakage.

Diagnosis of cerebrospinal fluid rhinorrhea: an evidence-based review with recommendations.

BACKGROUND: Diagnostic strategies employed for cases of cerebrospinal fluid (CSF) rhinorrhea vary widely due to limited evidence-based guidance. METHODS: A systematic review of the literature was performed using PubMed, EMBASE, and Cochrane databases from January 1990 through September 2014, to examine 9 diagnostic and localization modalities for CSF rhinorrhea. Benefit-harm assessments, value judgments and recommendations were made based on the available evidence. Study exclusion criteria were language other than English, pre-1990 studies, case reports, and nonrhinologic leak. All authors agreed on recommendations through an iterative process. RESULTS: We reviewed 68 studies examining 9 practices pertinent to the diagnosis of CSF rhinorrhea, with a highest aggregate grade of evidence of C. The literature does not support the use of the ring sign, glucose testing, radionuclide cisternography (RNC), or computed tomography cisternography (CTC) for identification of CSF leak. Beta-2 transferrin is the most reliable confirmatory test for CSF leak. High-resolution CT (HRCT) is then recommended as the first-line study for localization. Magnetic resonance cisternography (MRC) should be used for CSF leak identification as a second line for each of these if beta-2 transferrin is not available or if HRCT is ambiguous. Intrathecal fluorescein (IF) may also be of benefit in certain clinical scenarios. CONCLUSION: Despite relatively low levels of evidence, recommendations for the diagnosis and management of CSF rhinorrhea can be made based on the current literature. Higher-level studies are needed to better determine optimal diagnostic and clinical management approaches.

Traumatic CSF leaks of the anterior skull base.

Traumatic CSF leaks of the anterior skull base. Skull base fractures are a frequent complication of high-impact trauma; due to the inherent anatomic relationships of the skull base, they may be associated with significant intracranial complications, including CSF leakage, and their detection is therefore important. The ethmoid roof and the cribriform plate region are the sites most vulnerable to fractures and dural tears. Rhinorrhoea is a non-specific finding; the presence of CSF in a sample must be confirmed with beta 2 transferin or beta trace protein. Accurate identification of the leakage site is necessary for a successful surgical treatment. Various modalities are available for this purpose, such as CT scan and MRI. Persistent CSF rhinorrhoea necessitates surgical intervention, due to the risk of meningitis. Continued improvements in endoscopic reconstruction techniques have led to fewer open surgeries for repair. Smaller defects can be closed with fat gasket technique or free grafts, while larger defects necessitate a multilayer closure with local vascularized flaps. These techniques have shown consistently high success rates.

Evaluation of high resolution gel ß(2)-transferrin for detection of cerebrospinal fluid leak.

BACKGROUND: Cerebrospinal fluid (CSF) leaks are potentially life-threatening conditions that can be diagnosed by detection of ß(2)-transferrin using protein electrophoresis. Another less commonly available test is ß-trace protein quantitation using immunoassay. The objectives of this study were to evaluate a new immunofixation-based ß(2)-transferrin test for detection of CSF leaks and to compare it to an existing agarose gel electrophoresis test and ß-trace protein immunoassay. METHODS: For method comparison, 63 consecutive samples from physician-ordered ß(2)-transferrin tests were analyzed using two different electrophoresis methods, agarose gel fractionation followed by acid-violet staining, and high resolution agarose gel electrophoresis followed by ß(2)-transferrin immunofixation. A subset of samples (16/63) were analyzed for ß-trace protein. Results were compared against patient chart data for the presence of a CSF leak. Additional studies were performed to assess the stability, detection limit, and analytical specificity of the ß(2)-transferrin immunofixation test. RESULTS: The ß(2)-transferrin immunofixation test had a sensitivity of 100 % (40/40) and specificity of 71 % (12/17) for detection of CSF leaks. By comparison, the agarose gel test had a sensitivity of 87 % (35/40) and specificity of 94 % (16/17). ß-trace protein had a sensitivity of 100 % (10/10) and specificity of 86 % (5/6). Serum and saliva could be differentiated from CSF by the ß(2)-transferrin immunofixation test based on their migration patterns. However, whole blood samples appeared positive for ß(2)-transferrin at a threshold of ~ 4 g/L hemoglobin. At a cut-off of 3 mg/L, ß-trace protein was increased in 10/10 cases with documented CSF leak and in 1/6 patients without CSF leak. CONCLUSIONS: Both the new immunofixation test for ß(2)-transferrin and the ß-trace protein were effective at detecting CSF leaks. Users of the ß(2)-transferrin immunofixation test should be cautioned against interpreting samples with blood contamination.

Effects of phenytoin sodium on dura mater healing in a rat model of CSF leakage.

AIM: Cerebro-spinal fluid (CSF) leakage caused by defects on the dura mater after trauma or some neurosurgical interventions is an important issue. In this study, we investigated the effects of local and systemic use of phenytoin sodium on dural healing. MATERIAL AND METHODS: Thirty-six male Wistar rats were divided into control, local phenytoin and systemic phenytoin groups with 12 rats in each. For each group, a dura defect was created at thoracic segment. Subjects were sacrificed at following 1st and 6th weeks and damaged segments were isolated. The results were compared histopathologically by Hematoxylin-Eosin and Masson-Trichrome staining. Criteria for the rate of collagen, neovascularization, and granulation formation were assessed semi quantitatively according to the histological assessment scale modified by Ozisik et al. RESULTS: Better healing was achieved in the systemic and local phenytoin groups than in the control group. The level of healing was significantly higher in the systemic group in both early and late periods than in other groups (p < 0.01). The level of healing in the late-local group was also statistically significantly higher than that in the control group. CONCLUSION: We observed that both systemic and local uses of phenytoin sodium (especially systemic) have positive effects on dura healing.

Occult orbito-cranial penetrating injury by pencil: role of beta tracer protein as a marker for cerebrospinal fluid leakage.

Orbito-cranial foreign bodies present a treacherous situation that can escape detection. The only evidence of these foreign bodies may be the entry wound in the form of a small lid laceration. A two-year-old boy presented with right upper lid laceration following a fall two hours back. Analysis of the fluid around the wound revealed a beta-tracer protein (beta-TP) value of 33.5 mg/l suggestive of cerebrospinal fluid (CSF). Three-dimensional computed tomography (CT) scan revealed a foreign body measuring 4.2 cm x 0.8 cm passing from the orbital roof to the frontal lobe. The foreign body tract was explored through the eyelid laceration and a broken pencil was removed followed by dural patch graft. The patient developed no ocular or intracranial complications. Beta-TP, a highly specific marker of CSF is routinely used in screening patients of neurosurgery and otolaryngology with CSF leaks, however, its use has never been reported in ophthalmic literature based on an online PubMed search.

Traumatic cerebrospinal fluid leaks.

This article discusses the epidemiology, diagnosis, and management of traumatic cerebrospinal fluid (CSF) leaks. An overview of traumatic CSF leaks is presented, and both conservative and operative therapies are reviewed. Management decisions are discussed based on the current literature. Controversial clinical topics are addressed, including the use of prophylactic antibiotics and the timing of surgical repair.

Cerebrospinal fluid leakage--reliable diagnostic methods.

Prompt diagnosis and early treatment of cerebrospinal fluid (CSF) leakage minimizes the risk of severe complications. In patients presenting with clear fluid nasal discharge it is important to identify the nature of the rhinorrhea. The CSF leakage may occur as post-traumatic, iatrogenic, spontaneous or idiopathic rhinorrhea. The differential diagnosis of CSF rhinorrhea often presents a challenging problem. The confirmation of CSF rhinorrhea and localization of the leakage may be diagnosed by CT, MRI cisternography and MRI cisternography in combination with single photon emission tomography or radioisotopic imaging. Although these methods allow estimation of the CSF leakage with high accuracy, they are expensive and invasive procedures. Therefore, biochemical methods are still used in the differentiation. Although the most common diagnostic method for screening CSF leakage is glucose oxidase, its diagnostic sensitivity and specificity is generally unsatisfactory. False negative results may occur with bacterial contamination and false positive results are common in diabetic patients. Glucose detection is not recommended as a confirmatory test. As such, other biomarkers of the CSF leakage, such as beta-2-transferrin (beta-2 trf) and beta-trace protein (betaTP) are necessary to identify and confirm of this condition.

Testing biomechanical strength of in vitro cerebrospinal fluid leak repairs.

OBJECTIVES: Repair of cerebrospinal fluid (CSF) leaks with grafts can be augmented with various adjuncts to improve approximation such as tissue adhesives and sutures. Here we test various adjuncts in an in vitro model of CSF leak repairs. METHODS: A novel pressure testing system was designed to evaluate the burst pressures of in vitro CSF leak repairs. Porcine pericranium grafts were harvested and used to repair a 0.5 X 0.5 cm dural defect. These grafts were sealed in place with no adjunct (control), Tisseel fibrin glue (Baxter, Mississauga, ON), suture, U-CLIPs (a self-closing suture substitute; Medtronic, Toronto, ON), or combined suture and Tisseel. Tisseel samples were tested both as underlay and overlay repairs. Samples were incubated overnight in serum and subjected to burst pressure testing, and pressure-time graphs were recorded. Experiments were conducted five times. RESULTS: Mean burst pressures (measured in pounds per square inch) for grafts sealed in place with Tisseel were significantly higher than all other adjuncts (14.9 Tisseel vs 3.9 control vs 4.1 U-CLIP vs 6.2 suture psi; p < .05). U-CLIPs and sutures did not increase burst strength over controls, and sutures did not have a synergistic effect with Tisseel (12.1 psi). Grafts tested with Tisseel were stronger when tested as underlay than as overlay (14.9 vs 3.0 psi). Three patterns of graft failure were observed based on unique pressure-time graphs. CONCLUSIONS: In vitro burst pressure testing demonstrates that Tisseel improves the strength of CSF leak repairs.

CSF rhinorrhea secondary to use of a Mayfield head clamp.

Various complications with use of a Mayfield head clamp have been reported, from minor skin necrosis and lacerations to the more significant extradural hematomas and meningitis. To the best of our knowledge, our report describes for the first time in the medical literature, the uncommon complication of frontal sinus fracture and cerebrospinal fluid leak caused by a scalp pin of a head clamp used during a frontal craniotomy. The cerebrospinal fluid leak settled with conservative management, and no surgical intervention was necessary. Clinicians should appreciate the possibility of such a complication and assess preoperative scans for frontal sinuses that extend to a high level, as in our patient.

Assessing cerebrospinal fluid rhinorrhea: a two-dimensional electrophoresis approach.

Assessment of nasal cerebrospinal fluid (CSF) fistula commonly relies on the determination of CSF markers in an aqueous rhinorrhea, such as the beta2-transferrin immunofixation assay. While generally reliable, false positive and false negative results have been reported for most of the laboratory tests yet available. Based on the hypothesis that the simultaneous assessment of several CSF markers may yield an increased sensitivity and specificity, we used a proteomics, two-dimensional electrophoresis 2-DE based approach to study samples of nasal secretions obtained from 18 patients suspected of CSF rhinorrhea. Since CSF, nasal mucus and plasma may coexist in the nasal cavities, we first defined five specific markers for each of these biological fluids (transferrin, prostaglandin-D synthase, transthyretin, and two unknown trains of spots for CSF, immunoglobulin A (IgA) S-chain, lipocortin-1, lipocalin-1, prolactine-inducible protein and palatal lung nasal epithelium clone protein for mucus, haptoglobin alpha1/2- and beta-chains, fibrinogen alpha-, beta- and gamma-chains for plasma). Gels from the rhinorrhea patients were then compared to these 2-DE reference maps to determine the presence or absence of the defined markers, and clinical data were independently compared to the results of the 2-DE study. In all cases, the biological fluid(s) anticipated to be present in the nasal secretions based on clinical data were correctly identified by 2-DE. Moreover, an excellent correlation was found in nine patients who underwent extensive workup for suspected CSF rhinorrhea, since CSF was found by the 2-DE method in four patients in whom a CSF fistula was confirmed, whereas the test was negative in five patients in whom a CSF fistula was excluded. In the remaining patients, mucus, sometimes contamined with blood, was found to be the major component of the nasal secretions, confirming that clear mucus may mimick CSF rhinorrhea. These preliminary results suggest that a 2-DE-based multimarker approach is a valid, sensitive, and specific method to assess the presence of CSF in occult rhinorrhea.

Usefulness of beta 2-transferrin assay in the detection of cerebrospinal fluid leaks following head injury.

The clinical value of analyzing various fluids and exudates for beta 2-transferrin (beta 2-Tfn) to detect cerebrospinal fluid (CSF) leakage following head trauma was reviewed in a series of 11 cases. Qualitative detection of beta 2-Tfn was performed by agarose gel electrophoresis of tears, ear and nose exudates, cerebral cyst fluid, and wound discharge fluid in different cases. In each instance the presence of beta 2-Tfn in the analyzed fluid supported the diagnosis of a CSF leak. Equally, the demonstration of the absence of beta 2-Tfn in the fluid excluded the diagnosis of such a leak. Neither false-positive nor false-negative results were found, as indicated by separate radiological investigations and/or subsequent clinical assessment of patients. The detection of beta 2-Tfn in suspect fluids thus provides a highly sensitive and selective, rapid, and noninvasive test for the detection of CSF leakage in cases of head trauma.

Alternative pathways for drainage of cerebrospinal fluid in the canine brain.

Although the brain has no formal lymphatic system, a substantial quantity of cerebrospinal fluid (CSF) has nonetheless been shown to drain via cervical lymphatics. To pursue further the issue of alternative drainage pathways for CSF, we infused a solution of Ringer's lactate (RL) into the cisterna magna of the dog brain and monitored both the flow and concentration of total protein of cervical lymph. This maneuver promoted a nearly three-fold rise in intracranial pressure and was accompanied by a rise in cervical lymph flow and fall in its protein content. In addition, a profuse nasal discharge (11.4 ml/hr) developed with a moderately high protein content of the rhinorrhea fluid (1.8 g/dl), along with similar appearance times of Evans blue dye (instilled in the cisterna magna) in both cervical lymph and the rhinorrhea fluid (48-70 minutes after infusion). These findings suggest alternative drainage pathways for CSF besides the arachnoid villi (Pacchionian bodies) including connections with lymphatics in the neck and along the olfactory nerve, and around the cribiform plate to the nasal submucosa, and with proptosis, perhaps also through the aqueous humor-canal of Schlemm and nasolacrimal duct.