Functional polymorphisms of macrophage migration inhibitory factor as predictors of morbidity and mortality of pneumococcal meningitis.

Pneumococcal meningitis is the most frequent and critical type of bacterial meningitis. Because cytokines play an important role in the pathogenesis of bacterial meningitis, we examined whether functional polymorphisms of the proinflammatory cytokine macrophage migration inhibitory factor (MIF) were associated with morbidity and mortality of pneumococcal meningitis. Two functional MIF promoter polymorphisms, a microsatellite (-794 CATT5-8; rs5844572) and a single-nucleotide polymorphism (-173 G/C; rs755622) were genotyped in a prospective, nationwide cohort of 405 patients with pneumococcal meningitis and in 329 controls matched for age, gender, and ethnicity. Carriages of the CATT7 and -173 C high-expression MIF alleles were associated with unfavorable outcome (P= 0.005 and 0.003) and death (P= 0.03 and 0.01). In a multivariate logistic regression model, shock [odds ratio (OR) 26.0, P= 0.02] and carriage of the CATT7 allele (OR 5.12,P= 0.04) were the main predictors of mortality. MIF levels in the cerebrospinal fluid were associated with systemic complications and death (P= 0.0002). Streptococcus pneumoniae strongly up-regulated MIF production in whole blood and transcription activity of high-expression MIF promoter Luciferase reporter constructs in THP-1 monocytes. Consistent with these findings, treatment with anti-MIF immunoglogulin G (IgG) antibodies reduced bacterial loads and improved survival in a mouse model of pneumococcal pneumonia and sepsis. The present study provides strong evidence that carriage of high-expression MIF alleles is a genetic marker of morbidity and mortality of pneumococcal meningitis and also suggests a potential role for MIF as a target of immune-modulating adjunctive therapy.

Spontaneous intracranial hypotension is diagnosed by a combination of lipocalin-type prostaglandin D synthase and brain-type transferrin in cerebrospinal fluid.

BACKGROUND: Spontaneous intracranial hypotension (SIH) is caused by cerebrospinal fluid (CSF) leakage. Definitive diagnosis can be difficult by clinical examinations and imaging studies. METHODS: SIH was diagnosed with the following criteria: (i) evidence of CSF leakage by cranial magnetic resonance imaging (MRI) findings of intracranial hypotension and/or low CSF opening pressure; (ii) no recent history of dural puncture. We quantified CSF proteins by ELISA or Western blotting. RESULTS: Comparing with non-SIH patients, SIH patients showed significant increase of brain-derived CSF glycoproteins such as lipocalin-type prostaglandin D synthase (L-PGDS), soluble protein fragments generated from amyloid precursor protein (sAPP) and "brain-type" transferrin (Tf). Serum-derived proteins such as albumin, immunoglobulin G, and serum Tf were also increased. A combination of L-PGDS and brain-type Tf differentiated SIH from non-SIH with sensitivity 94.7% and specificity 72.6%. CONCLUSION: L-PGDS and brain-type Tf can be biomarkers for diagnosing SIH. GENERAL SIGNIFICANCE: L-PGDS and brain-type Tf biosynthesized in the brain appears to be markers for abnormal metabolism of CSF.

Proteoform analysis of lipocalin-type prostaglandin D-synthase from human cerebrospinal fluid by isoelectric focusing and superficially porous liquid chromatography with Fourier transform mass spectrometry.

Lipocalin-type prostaglandin D-synthase (L-PGDS) in cerebrospinal fluid contributes to the maturation and maintenance of the CNS. L-PGDS PTMs may contribute to pathobiology of different CNS diseases, but methods to monitor its proteoforms are limited. Herein, we combined off-gel IEF and superficially porous LC (SPLC) with Fourier transform MS to characterize common cerebrospinal fluid L-PGDS proteoforms. Across 3D physiochemical space (pI, hydrophobicity, and mass), 217 putative proteoforms were observed from 21 to 24 kDa and pI 5-10. Glycoprotein accurate mass information, combined with MS/MS analysis of peptides generated from 2D-fractionated proteoforms, enabled the putative assignment of 208 proteoforms with varied PTM positional occupants. Fifteen structurally related N-glycans at N29 and N56 were observed, with different N-glycan compositional variants being preferred on each amino acid. We also observed that sialic acid content was a major factor for pI shifts between L-PGDS proteoforms. Other putative PTMs characterized include a core-1 HexHexNAc-O-glycan at S7, acetylation at K16 and K138, sulfonation at S41 and T142, and dioxidation at C43 and C145. The IEF-SPLC-MS platform presented provides 30-40× improved peak capacity versus conventional 2DE and shows potential for repeatable proteoform analysis of surrogate PTM-based biomarkers.

α-Synuclein in human cerebrospinal fluid is principally derived from neurons of the central nervous system.

The source of Parkinson disease-linked α-synuclein (aSyn) in human cerebrospinal fluid (CSF) remains unknown. We decided to measure the concentration of aSyn and its gradient in human CSF specimens and compared it with serum to explore its origin. We correlated aSyn concentrations in CSF versus serum (Q(aSyn)) to the albumin quotient (Q(albumin)) to evaluate its relation to blood-CSF barrier function. We also compared aSyn with several other CSF constituents of either central or peripheral sources (or both) including albumin, neuron-specific enolase, ß-trace protein and total protein content. Finally, we examined whether aSyn is present within the structures of the choroid plexus (CP). We observed that Q(aSyn) did not rise or fall with Q(albumin) values, a relative measure of blood-CSF barrier integrity. In our CSF gradient analyses, aSyn levels decreased slightly from rostral to caudal fractions, in parallel to the recorded changes for neuron-specific enolase; the opposite trend was recorded for total protein, albumin and ß-trace protein. The latter showed higher concentrations in caudal CSF fractions due to the diffusion-mediated transfer of proteins from blood and leptomeninges into CSF in the lower regions of the spine. In postmortem sections of human brain, we detected highly variable aSyn reactivity within the epithelial cell layer of CP in patients diagnosed with a range of neurological diseases; however, in sections of mice that express only human SNCA alleles (and in those without any Snca gene expression), we detected no aSyn signal in the epithelial cells of the CP. We conclude from these complementary results that despite its higher levels in peripheral blood products, neurons of the brain and spinal cord represent the principal source of aSyn in human CSF.

Proteomic profiling of cerebrospinal fluid identifies prostaglandin D2 synthase as a putative biomarker for pediatric medulloblastoma: A pediatric brain tumor consortium study.

The aims of this study were to demonstrate the feasibility of centrally collecting and processing high-quality cerebrospinal fluid (CSF) samples for proteomic studies within a multi-center consortium and to identify putative biomarkers for medulloblastoma in CSF. We used 2-DE to investigate the CSF proteome from 33 children with medulloblastoma and compared it against the CSF proteome from 25 age-matched controls. Protein spots were subsequently identified by a combination of in-gel tryptic digestion and MALDI-TOF TOF MS analysis. On average, 160 protein spots were detected by 2-DE and 76 protein spots corresponding to 25 unique proteins were identified using MALDI-TOF. Levels of prostaglandin D2 synthase (PGD2S) were found to be six-fold decreased in the tumor samples versus control samples (p<0.00001). These data were further validated using ELISA. Close examination of PGD2S spots revealed the presence of complex sialylated carbohydrates at residues Asn(78) and Asn(87) . Total PGD2S levels are reduced six-fold in the CSF of children with medulloblastoma most likely representing a host response to the presence of the tumor. In addition, our results demonstrate the feasibility of performing proteomic studies on CSF samples collected from patients at multiple institutions within the consortium setting.

The role of macrophage migration inhibitory factor in Alzheimer's disease.

Previous studies have shown that amyloid beta protein (Abeta ), the essential molecule for the formation of toxic oligomers and, subsequently, Alzheimer plaques, has been associated in vivo with the immune modulator, macrophage migration inhibitory factor (MIF) (17). To further investigate this association in vivo we used the APP transgenic mouse model. Serial brain sections of transgenic APP mice were stained for Abeta plaques and MIF and we observed MIF immunolabeling in microglial cells in association with Abeta plaques in the transgenic mouse brain sections. In addition, functional studies in murine and human neuronal cell lines revealed that Abeta-induced toxicity could be reversed significantly by a small molecule inhibitor of MIF (ISO-1). Finally, to elucidate the role of MIF in Alzheimer's Disease (AD) we measured MIF levels in the brain cytosol and cerebrospinal fluid (CSF) of AD patients and age-matched controls. Our results demonstrate a marked increase of MIF levels within the CSF of AD patients compared with controls. Combined, our results indicate a strong role for MIF in the pathogenesis of AD and furthermore suggest that inhibition of MIF may provide a valuable avenue of investigation for the prevention of disease onset, progression and/or severity.

Neurochemical measures co-vary with personality traits: forensic psychiatric findings replicated in a general population sample.

Neurobiological markers in cerebrospinal fluid (CSF) and in serum, previously found to co-vary with destructive personality traits in violent offenders, were explored in a general population sample of 21 patients undergoing knee surgery. Results on the Karolinska Scales of Personality (KSP) and the Temperament and Character Inventory (TCI) were compared with CSF/serum albumin ratios and serum concentrations of beta-trace protein (betaTP) (as markers for blood-brain barrier (BBB) permeability), to CSF/serum albumin ratios between the dopamine and serotonin metabolites homovanillic acid (HVA)/5-hydroxyindoleacetic acid (HIAA) and to CSF and serum ratios between activated thyroid hormone (T3) and its precursor T4. Serum betaTP concentrations correlated with CSF/serum albumin ratios (P=0.018), but not with preoperative serum creatinine concentrations. Serum betaTP correlated significantly with Monotony Avoidance and Impulsiveness; CSF HVA/5-HIAA ratios with Irritability and low Cooperativeness. The betaTP is a potential serum marker for the integrity of the BBB that does not necessitate lumbar puncture. Thyroid hormones did not correlate with personality traits. As reported in forensic psychiatric patients, aggressive, unempathic personality traits were thus associated with increased dopaminergic activity in relation to the serotonergic activity and impulsivity to increased BBB permeability also in a general population group.

Serum and cerebrospinal fluid cytokines in children with acute encephalopathy.

BACKGROUND: The pathogenesis of acute encephalopathy (AE) remains unclear, and a biomarker has not been identified. METHODS: Levels of 49 cytokines and chemokines, including osteopontin (OPN), were measured in serum and cerebrospinal fluid (CSF) of children with AE (n = 17) or febrile convulsion (FC; n = 8; control group). The AE group included acute necrotizing encephalopathy (n = 1), acute encephalopathy with biphasic seizures and late reduced diffusion (AESD; n = 3), clinically mild encephalitis/encephalopathy with a reversible splenial lesion (MERS; n = 4), and unclassified acute encephalopathy (UCAE; n = 9) that does not meet the criteria of syndrome classification. Five individuals with AE had neurological sequelae or death (poor prognosis), whereas 12 were alive without neurological sequelae (good prognosis). RESULTS: The CSF:serum ratios of OPN, CC chemokine ligand (CCL)4, and interleukin (IL)-10 were significantly higher in AE than in FC. The CSF levels of macrophage inhibitory factor (MIF) and leukemia inhibitory factor (LIF) were significantly higher in the poor-prognosis group than in the good-prognosis group. The CSF:serum ratios of OPN were significantly higher in AESD and in MERS than in FC. The CSF:serum ratios of MIF and OPN were higher in MERS than in UCAE or FC. CONCLUSION: Our results suggest that microglia-related cytokines and chemokines such as OPN, MIF, and LIF could be novel biomarkers of AE, in addition to the previously reported IL-10 and CCL4, and that MIF and LIF may be markers of poor prognosis.

Decreased intrathecal synthesis of prostaglandin D2 synthase in the cerebrospinal fluid of patients with acute inflammatory demyelinating polyneuropathy.

Prostaglandin D(2) synthase (PGDS) is the most abundant brain protein in cerebrospinal fluid (CSF) and is tied closely with inflammatory processes. This study investigated whether CSF PGDS levels in patients with acute inflammatory demyelinating polyneuropathy (AIDP) are altered. The results suggest that PGDS concentration is significantly increased in the CSF of AIDP patients compared with the control patients (p<0.05) due to a blood-CSF barrier dysfunction, whereas the intrathecal synthesis of PGDS, reflected by the CSF PGDS/albumin ratio, is significantly decreased in AIDP compared with the control group (p<0.05). The changes of CSF PGDS/albumin ratio are only observed in AIDP patients, but not in Miller Fisher Syndrome (MFS), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), or multiple sclerosis (MS) patients.

Reduced levels of amyloid-beta-binding proteins in cerebrospinal fluid from Alzheimer's disease patients.

Amyloid-beta(Abeta) aggregation is a major hallmark of Alzheimer's disease (AD). Previous studies have suggested that only unbound Abeta can take part in the aggregation process. Therefore, endogenous Abeta-binding proteins may have an important role in preventing AD. Here, we analyzed cerebrospinal fluid (CSF) samples from 35 subjects with AD, 18 subjects with frontotemporal dementia (FTD) and 29 non-demented controls to test if reduced Abeta-binding capacity in CSF is a specific feature of AD. A panel of known Abeta-binding CSF proteins, including beta-trace/prostaglandin D2 synthase (beta-trace), transthyretin (TTR), cystatin C (CysC) and alpha(1)-antitrypsin (AAT), were quantified and related to diagnosis and CSF levels of Abeta(1-38), Abeta(1-40) and Abeta(1-42). AD patients displayed a mild reduction in the CSF levels of beta-trace (p=0.020), CysC (p=0.017), AAT (p=0.019) and TTR (p=0.012) compared with controls. While the reductions in AAT and TTR were AD-specific, the levels of beta-trace and CysC were also reduced in FTD. As expected, CSF Abeta(1-42) was reduced in AD compared with controls (p=0.00005) and with FTD patients (p=0.015). Positive correlations between Abeta(1-42) and beta-trace, CysC and TTR, respectively, were seen only in the AD group, suggesting that deficient Abeta-binding capacity in CSF may contribute to the amyloidogenic process in AD.

Upregulation of MIF as a defense mechanism and a biomarker of Alzheimer's disease.

BACKGROUND: Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine. Chronic inflammation induced by amyloid ß proteins (Aß) is one prominent neuropathological feature in Alzheimer's disease (AD) brain. METHODS: Elisa, Western blot, and immunohistochemical staining analysis were performed to examine the level of MIF protein in CSF and brain tissues. MTT and LDH assays were used to examine the neurotoxicity, and the Morris Water Maze test was performed to examine the cognitive function in the MIF+/-/APP23 transgenic mice. RESULTS: MIF expression was upregulated in the brain of AD patients and AD model mice. Elevated MIF concentration was detected in the cerebrospinal fluid of AD patients but not in that of the patients suffering from mild cognitive impairment and vascular dementia. Reduced MIF expression impaired learning and memory in the AD model mice. MIF expression largely associates with Aß deposits and microglia. The binding assay revealed a direct association between MIF and Aß oligomers. Neurons instead of glial cells were responsible for the secretion of MIF upon stimulation by Aß oligomers. In addition, overexpression of MIF significantly protected neuronal cells from Aß-induced cytotoxicity. CONCLUSION: Our study suggests that neuronal secretion of MIF may serve as a defense mechanism to compensate for declined cognitive function in AD, and increased MIF level could be a potential AD biomarker.

CSF proteomic analysis reveals persistent iron deficiency-induced alterations in non-human primate infants.

Iron deficiency (ID) anemia during infancy results in long-term neurological consequences, yet the mediating mechanisms remain unclear. Infant monkeys often become naturally anemic during the first 6 months of life, presenting an opportunity to determine the effect of developmental iron deficiency. After weaning, animals were chosen randomly for supplementation with oral iron or, fed a standard commercial chow diet. The control group was never iron deficient. ID anemia was corrected by 12 months in both groups, as indicated by hematological parameters. CSF was collected for proteomic analysis at 12 months of age to assess the impact of developmental ID on the brain. The CSF proteome for both formerly iron deficient groups was similar and revealed 12 proteins with expression levels altered at least twofold. These proteins were identified by matrix assisted laser desorption ionization time-of-flight spectrometry and included prostaglandin D synthase, olfactory receptors and glial fibrillary acidic protein. Thus the proteomic analysis reveals a persistent effect of ID and provides insights into reports of disturbed sleep, hypomyelination and other behavioral alterations associated with ID. Furthermore, alterations in the CSF proteome despite normal hematologic parameters indicate that there is a hierarchical system that prioritizes repletion of red cell mass at the expense of the brain.

Pharmacokinetics of recombinant human lipocalin-type prostaglandin D synthase/beta-trace in canine.

Lipocalin-type prostaglandin (PG) D synthase (L-PGDS) is identical to beta-trace, a major protein in human cerebrospinal fluid (CSF), and acts as both a PGD(2)-producing enzyme and as an extracellular transporter for lipophilic ligands. In this study, we investigated the pharmacokinetics of recombinant human L-PGDS (rh-L-PGDS) in canines. After an intravenous bolus injection of rh-L-PGDS, the serum concentration decreased bi-exponentially with a half-life of the terminal line phase of 0.77h, which was markedly shorter than that of other proteins with the same molecular weight as that of rh-L-PGDS. The distribution volume was 55.4ml/kg, which was close to the volume of canine circulation plasma, indicating that the administrated rh-L-PGDS was distributed mainly in the blood. Only 10.3% of the administered rh-L-PGDS was excreted to the urine, suggesting that rh-L-PGDS was actively degraded within the body. After an intrathecal injection, the peak serum concentration of rh-L-PGDS was observed at 4-5h. The area under the plasma concentration-time curve obtained for 12h after the intrathecal injection was one third of the value for 3h after the intravenous injection, suggesting that at least one third of the intrathecally injected rh-L-PGDS shifted to the blood.

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

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 beta -trace protein (beta TP) in the subdural fluid (betaTPSF) and serum (betaTPSER), and the CSDH/SH recurrence rate. The betaTPSF was considered to indicate an admixture of CSF to the subdural fluid if betaTPSF/betaTPSER>2. RESULTS: The median beta TPSF level for the whole patient group was 4.29 mg/L (range 0.33-51 mg/L). Cerebrospinal fluid leakage, as indicated by betaTPSF/betaTPSER>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 betaTPSF 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 betaTP 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 betaTPSF 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.

Is open-angle glaucoma caused by impaired cerebrospinal fluid circulation: around the optic nerve?

Chronic open-angle glaucoma is the most frequent type of glaucoma and a leading cause for blindness. The role of intraocular pressure (IOP) in the pathogenesis of open-angle glaucoma has been challenged by patients with typical glaucomatous optic disc changes and visual field loss in whom the IOP never exceeded normal values (normal-tension glaucoma), as well as by patients with persistently elevated IOP who do not develop glaucomatous disc or field changes. Recent research has demonstrated that the cerebrospinal fluid (CSF) is not evenly distributed in all CSF spaces and that the subarachnoid space of the optic nerve can turn into a CSF compartment on its own. The biochemical components in this optic nerve compartment can differ markedly from normal CSF and some of its components (such as L-PGDS) may produce a toxic effect on the optic nerve and may therefore play an important role in the pathophysiology of open-angle glaucoma.

Deficiency of dolichol-phosphate-mannose synthase-1 causes congenital disorder of glycosylation type Ie.

Congenital disorders of glycosylation (CDG), formerly known as carbohydrate-deficient glycoprotein syndromes, lead to diseases with variable clinical pictures. We report the delineation of a novel type of CDG identified in 2 children presenting with severe developmental delay, seizures, and dysmorphic features. We detected hypoglycosylation on serum transferrin and cerebrospinal fluid beta-trace protein. Lipid-linked oligosaccharides in the endoplasmic reticulum of patient fibroblasts showed an accumulation of the dolichyl pyrophosphate Man(5)GlcNAc(2) structure, compatible with the reduced dolichol-phosphate-mannose synthase (DolP-Man synthase) activity detected in these patients. Accordingly, 2 mutant alleles of the DolP-Man synthase DPM1 gene, 1 with a 274C>G transversion, the other with a 628delC deletion, were detected in both siblings. Complementation analysis using DPM1-null murine Thy1-deficient cells confirmed the detrimental effect of both mutations on the enzymatic activity. Furthermore, mannose supplementation failed to improve the glycosylation status of DPM1-deficient fibroblast cells, thus precluding a possible therapeutic application of mannose in the patients. Because DPM1 deficiency, like other subtypes of CDG-I, impairs the assembly of N-glycans, this novel glycosylation defect was named CDG-Ie.

A gel-based proteomic comparison of human cerebrospinal fluid between inflicted and non-inflicted pediatric traumatic brain injury.

Traumatic brain injury (TBI) is the most common cause of traumatic death in infancy, and inflicted TBI (iTBI) is the predominant cause. Like other central nervous system pathologies, TBI changes the composition of cerebrospinal fluid (CSF), which may represent a unique clinical window on brain pathophysiology. Proteomic analysis, including two-dimensional (2-D) difference in gel electrophoresis (DIGE) combined with mass spectrometry (MS), was used to compare the CSF protein profile of two pooled samples from pediatric iTBI (n = 13) and non-inflicted TBI (nTBI; n = 13) patients with severe injury. CSF proteins from iTBI and nTBI were fluorescently labeled in triplicate using different fluorescent Cy dyes and separated by 2-D gel electrophoresis. Approximately 250 protein spots were found in CSF, with 90% between-gel reproducibility of the 2-D gel. Following in-gel digestion, the tryptic peptides were analyzed by MS for protein identification. The acute phase reactant, haptoglobin (HP) isoforms, showed an approximate fourfold increase in nTBI versus iTBI. In contrast, the levels of prostaglandin D(2) synthase (PGDS) and cystatin C (CC) were 12-fold and sevenfold higher in iTBI versus nTBI, respectively. The changes of HP, PGDS, and CC were confirmed by Western blot. These initial results with conventional gel-based proteomics show new protein changes that may ultimately help to understand pathophysiological differences between iTBI and nTBI.

The optic nerve: a new window into cerebrospinal fluid composition?

Cerebrospinal fluid (CSF) pressure and composition are generally thought to be homogeneous within small limits throughout all CSF compartments. CSF sampled during lumbar puncture therefore should be representative for all CSF compartments. On the basis of clinical findings, histology and biochemical markers, we present for the first time strong evidence that the subarachnoid spaces (SAS) of the optic nerve (ON) can become separated from other CSF compartments in certain ON disorders, thus leading to an ON sheath compartment syndrome. This may result in an abnormal concentration gradient of CSF molecular markers determined in locally sampled CSF compared with CSF taken during lumbar puncture.

Optic nerve compartment syndrome in a patient with optic nerve sheath meningioma.

PURPOSE: To report a patient with optic nerve (ON) sheath meningioma, unilateral optic disc swelling, and inhomogeneous cerebrospinal fluid (CSF) composition between lumbar CSF and CSF from the subarachnoid space (SAS) of the affected ON. METHODS: A 39-year-old woman presented with unilateral optic disc swelling and slight deterioration of visual function in the left eye. Extensive laboratory workup and magnetic resonance imaging (MRI) of the brain and orbits were performed. As radiotherapy was refused by the patient, ON sheath fenestration (ONSF) was offered and performed in order to stop deterioration. CSF from the SAS of the ON was sampled. RESULTS: Laboratory workup was within normal limits. MRI of the left orbit demonstrated enhancement of the dura in the precanalicular portion of the ON and distension of the SAS, most prominent in the bulbar portion of the ON. On lumbar puncture the opening pressure measured 19 (cm H2O). Compared to the lumbar CSF the CSF of the affected ON SAS showed markedly elevated measurements for albumin, IgG, and beta-trace protein. Visual function remained stable over a follow-up time of 18 months. CONCLUSIONS: Composition of CSF is considered to be homogenous throughout all CSF spaces. In this patient the authors found a marked concentration-gradient of albumin, IgG, and beta-trace protein between the CSF in the spinal canal and the CSF in the SAS of the affected ON. Based on the radiologic features of the left ON and the dissociated beta-trace protein concentrations in the CSF of the SAS of the ON and the lumbar CSF, the diagnosis of an ON sheath compartment syndrome due to an ON sheath meningioma was made.

Sample-dependent diagnostic accuracy of prostaglandin D synthase in cerebrospinal fluid leak.

BACKGROUND: Prostaglandin D2 synthase, commonly known as ß-trace protein (ßTP), is an excellent biomarker for the assessment of cerebrospinal fluid (CSF) leaks. Despite being widely used, the limits for the diagnostic values of ßTP are not well established to date, and currently suggested cut-off values in literature range from 0.25 to 6.0mg/L. Sample-specific and more accurate thresholds are a current need. METHODS: A retrospective observational study, performed in a tertiary-care hospital, between January 2006 and January 2014. A total of 74 patients were included, with a definitive diagnosis after initial leak suspicion and at least one determination of ßTP using a nephelometry-based assay. A total of 46 CSF samples were included in the control group. Samples were obtained from nasal secretions, ear secretions or spinal surgical injury, directly using sterile Eppendorf tubes. The analysis of 3 different cut-off values was performed and the receiver operating curve (ROC) analyses were calculated. RESULTS: Initial diagnostic suspicion was confirmed in 51% of cases, most of which were of postoperative origin (51%) and traumatic (26%). The ßTP median concentration in different samples was significantly higher in the presence of cerebrospinal fluid fistula, regardless of sample type (22.0mg/L vs. 0.24mg/L, 95% confidence interval: 19.0-30.8 vs. 0.08-0.40; p<0.001). Data from contingency tables show 100% sensitivity and specificity, depending on sample type and the cut-off value used: for rhinorrhea and otorrhea samples, the most appropriate it was 0.7mg/L, while values >2.0mg/L could be used for spine postoperative fluid leakage samples. CONCLUSIONS: The cut off value for ßTP in the diagnosis and follow-up of cerebrospinal fluid leaks should be modified depending on the type of secretion (sample type), for a better diagnostic accuracy.