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Contrast-induced encephalopathy (CIE) is a rare complication of angiography. According to our knowledge, the majority of CIE reports is imaging observations and rarely includes results of cerebrospinal fluid (CSF) tests. Furthermore, among the cases reporting the data for CSF testing, most of the results were normal. Here, we report a case of CIE presenting with significantly elevated levels of CSF protein. We found that the course of improvement in brain imaging findings was not consistent with the severity of clinical manifestations. The diffusion-weighted imaging (DWI) and apparent diffusion coefficient (ADC) sequences were normal. Considering the lack of convenient direct indicators to observe blood-brain barrier (BBB) function, changes in the levels of CSF protein may be related to BBB permeability and recovery and may serve as a potential prognostic marker.

Background: The cerebrospinal fluid (CSF) proteome could offer important insights into central nervous system (CNS) malignancies. To advance proteomic research in pediatric CNS cancer, the current study aims to (1) evaluate past mass spectrometry-based workflows and (2) synthesize previous CSF proteomic data, focusing on both qualitative summaries and quantitative re-analysis. MAIN: In our analysis of 11 studies investigating the CSF proteome in pediatric patients with acute lymphoblastic leukemia (ALL) or primary brain tumors, we observed significant methodological variability. This variability negatively affects comparative analysis of the included studies, as per GRADE criteria for quality of evidence. The qualitative summaries covered 161 patients and 134 non-tumor controls, while the application of validation cohort varied among the studies. The quantitative re-analysis comprised 15 B-ALL vs 6 "healthy" controls and 15 medulloblastoma patients vs 22 non-tumor controls. Certain CSF proteins were identified as potential indicators of specific malignancies or stages of neurotoxicity during chemotherapy, yet definitive conclusions were impeded by inconsistent data. There were no proteins with statistically significant differences when comparing cases versus controls that were corroborated across studies where quantitative reanalysis was feasible. From a gene ontology enrichment, we observed that age disparities between unmatched case and controls may mislead to protein correlations more indicative of age-related CNS developmental stages rather than neuro-oncological disease. Despite efforts to batch correct (HarmonizR) and impute missing values, merging of dataset proved unfeasible and thereby limited meaningful data integration across different studies., Conclusion: Infrequent publications on rare pediatric cancer entities, which often involve small sample sizes, are inherently prone to result in heterogeneous studies-particularly when conducted within a rapidly evolving field like proteomics. As a result, obtaining clear evidence, such as CSF proteome biomarkers for CNS dissemination or early-stage neurotoxicity, is currently impractical. Our general recommendations comprise the need for standardized methodologies, collaborative efforts, and improved data sharing in pediatric CNS malignancy research. We specifically emphasize the possible importance of considering natural age-related variations in CSF due to different CNS development stages when matching cases and controls in future studies., (© 2024. The Author(s).)

Purpose: The lack of reliable diagnostic and/or prognostic biomarkers for multiple sclerosis (MS) is the major obstacle to timely and accurate patient diagnosis in MS patients. To identify new proteins associated with MS we performed a detailed proteomic analysis of cerebrospinal fluid (CSF) of patients newly diagnosed with relapsing-remitting MS (RRMS) and healthy controls., Material: Reflecting significantly higher prevalence of MS in women we included only women patients and controls in the study. To eliminate a potential effect of therapy on the CSF composition, only the therapy-naïve patients were included., Methods: Pooled CSF samples were processed in a technical duplicate, and labeled with stable-isotope coded TMT tags. To maximize the proteome coverage, peptide fractionation using 2D-LC preceded mass analysis using Orbitrap Fusion Tribrid Mass Spectrometer. Differential concentration of selected identified proteins between patients and controls was verified using specific antibodies., Results: Of the identified 900 CSF proteins, we found 69 proteins to be differentially abundant between patients and controls. In addition to several proteins identified as differentially abundant in MS patients previously, we observed several linked to MS for the first time, namely eosinophil-derived neurotoxin and Nogo receptor., Conclusions: Our data confirm differential abundance of several previously proposed protein markers, and provide indirect support for involvement of copper-iron disbalance in MS. Most importantly, we identified two new differentially abundant CSF proteins that seem to be directly connected with myelin loss and axonal damage via TLR2 signaling and Nogo-receptor pathway in women newly diagnosed with RRMS.

Background: Comprehensive data on the cerebrospinal fluid (CSF) profile in patients with COVID-19 and neurological involvement from large-scale multicenter studies are missing so far., Objective: To analyze systematically the CSF profile in COVID-19., Methods: Retrospective analysis of 150 lumbar punctures in 127 patients with PCR-proven COVID-19 and neurological symptoms seen at 17 European university centers RESULTS: The most frequent pathological finding was blood-CSF barrier (BCB) dysfunction (median QAlb 11.4 [6.72-50.8]), which was present in 58/116 (50%) samples from patients without pre-/coexisting CNS diseases (group I). QAlb remained elevated > 14d (47.6%) and even > 30d (55.6%) after neurological onset. CSF total protein was elevated in 54/118 (45.8%) samples (median 65.35 mg/dl [45.3-240.4]) and strongly correlated with QAlb. The CSF white cell count (WCC) was increased in 14/128 (11%) samples (mostly lympho-monocytic; median 10 cells/µl, > 100 in only 4). An albuminocytological dissociation (ACD) was found in 43/115 (37.4%) samples. CSF L-lactate was increased in 26/109 (24%; median 3.04 mmol/l [2.2-4]). CSF-IgG was elevated in 50/100 (50%), but was of peripheral origin, since QIgG was normal in almost all cases, as were QIgA and QIgM. In 58/103 samples (56%) pattern 4 oligoclonal bands (OCB) compatible with systemic inflammation were present, while CSF-restricted OCB were found in only 2/103 (1.9%). SARS-CoV-2-CSF-PCR was negative in 76/76 samples. Routine CSF findings were normal in 35%. Cytokine levels were frequently elevated in the CSF (often associated with BCB dysfunction) and serum, partly remaining positive at high levels for weeks/months (939 tests). Of note, a positive SARS-CoV-2-IgG-antibody index (AI) was found in 2/19 (10.5%) patients which was associated with unusually high WCC in both of them and a strongly increased interleukin-6 (IL-6) index in one (not tested in the other). Anti-neuronal/anti-glial autoantibodies were mostly absent in the CSF and serum (1509 tests). In samples from patients with pre-/coexisting CNS disorders (group II [N = 19]; including multiple sclerosis, JC-virus-associated immune reconstitution inflammatory syndrome, HSV/VZV encephalitis/meningitis, CNS lymphoma, anti-Yo syndrome, subarachnoid hemorrhage), CSF findings were mostly representative of the respective disease., Conclusions: The CSF profile in COVID-19 with neurological symptoms is mainly characterized by BCB disruption in the absence of intrathecal inflammation, compatible with cerebrospinal endotheliopathy. Persistent BCB dysfunction and elevated cytokine levels may contribute to both acute symptoms and 'long COVID'. Direct infection of the CNS with SARS-CoV-2, if occurring at all, seems to be rare. Broad differential diagnostic considerations are recommended to avoid misinterpretation of treatable coexisting neurological disorders as complications of COVID-19., (© 2022. The Author(s).)

Objective: Iron has been implicated in the pathogenesis of brain injury and hydrocephalus after preterm germinal matrix hemorrhage-intraventricular hemorrhage, however, it is unknown how external or endogenous intraventricular clearance of iron pathway proteins affect the outcome in this group., Methods: This prospective multicenter cohort included patients with posthemorrhagic hydrocephalus (PHH) who underwent (1) temporary and permanent cerebrospinal fluid (CSF) diversion and (2) Bayley Scales of Infant Development-III testing around 2 years of age. CSF proteins in the iron handling pathway were analyzed longitudinally and compared to ventricle size and neurodevelopmental outcomes., Results: Thirty-seven patients met inclusion criteria with a median estimated gestational age at birth of 25 weeks; 65% were boys. Ventricular CSF levels of hemoglobin, iron, total bilirubin, and ferritin decreased between temporary and permanent CSF diversion with no change in CSF levels of ceruloplasmin, transferrin, haptoglobin, and hepcidin. There was an increase in CSF hemopexin during this interval. Larger ventricle size at permanent CSF diversion was associated with elevated CSF ferritin (p = 0.015) and decreased CSF hemopexin (p = 0.007). CSF levels of proteins at temporary CSF diversion were not associated with outcome, however, higher CSF transferrin at permanent CSF diversion was associated with improved cognitive outcome (p = 0.015). Importantly, longitudinal change in CSF iron pathway proteins, ferritin (decrease), and transferrin (increase) were associated with improved cognitive (p = 0.04) and motor (p = 0.03) scores and improved cognitive (p = 0.04), language (p = 0.035), and motor (p = 0.008) scores, respectively., Interpretation: Longitudinal changes in CSF transferrin (increase) and ferritin (decrease) are associated with improved neurodevelopmental outcomes in neonatal PHH, with implications for understanding the pathogenesis of poor outcomes in PHH. ANN NEUROL 2021;90:217-226., (© 2021 American Neurological Association.)

Various proteins play a decisive role in the pathology of different neurodegenerative diseases. Nonetheless, most of these proteins can only be detected during a neuropathological assessment, although some non-specific biomarkers are routinely tested for in the cerebrospinal fluid (CSF) as a part of the differential diagnosis of dementia. In antemortem CSF samples from 117 patients with different types of neuropathologically confirmed neurodegenerative disease with dementia, we assessed total-tau (t-tau), phosphorylated-tau (181P) (p-tau), amyloid-beta (1-42) (Aβ42), TAR DNA binding protein (TDP)-43, progranulin (PGRN), and neurofilament light (NfL) chain levels, and positivity of protein 14-3-3. We found t-tau levels and the t-tau/p-tau ratios were significantly higher in prion diseases compared to the other neurodegenerative diseases. Statistically significant differences in the t-tau/Aβ42 ratio predominantly corresponded to t-tau levels in prion diseases and Aβ42 levels in AD. TDP-43 levels were significantly lower in prion diseases. Additionally, the TDP-43/Aβ42 ratio was better able to distinguish Alzheimer's disease from other neurodegenerative diseases compared to using Aβ42 alone. In frontotemporal lobar degeneration, PRGN levels were significantly higher in comparison to other neurodegenerative diseases. There is an increasing need for biomarkers suitable for diagnostic workups for neurodegenerative diseases. It appears that adding TDP-43 and PGRN to the testing panel for neurodegenerative diseases could improve the resolution of differential diagnoses.

Abstract: Carcinomatous meningitis (CM) is a critical issue for physicians. However, no study has reported a simple and useful diagnostic or predictive marker for CM.This study aimed to elucidate the potential markers for diagnosing CM derived from cerebrospinal fluid (CSF).We retrospectively enrolled 78 lung cancer patients with suspected CM during the clinical course, including 42 CM and 36 non-CM patients. We compared the clinical and CSF findings, including carcinoembryonic antigen (CEA), between CM and non-CM patients, and explored the diagnostic markers for early identification of CM as well as the contributing factors for mortality.On CSF analysis, with cutoff values of CEA ≥5 ng/ml, total protein (TP) in CSF ≥45 g/dl, and total cell count (TCC) ≥7 cells/μL, the sensitivity, specificity, and area under the curve (AUC) for CM were 85.7%, 84.6%, and 0.887 (95% CI: 0.758-1.0, P < .001); 80.5%, 69.4%, and 0.755 (95% CI: 0.646-0.865, P < .001); and 56.1%, 100%, and 0.817 (95% CI: 0.722-0.912, P < .001), respectively. TP levels in CSF ≥the patients' age had a sensitivity, specificity, and an AUC of 48.8%, 77.8%, and 0.633 (95% CI: 0.722-0.912, P = .045) for CM, respectively. Among CM patients, patients with 'TP in CSF (>patients' age)" (n = 19, P = .008) showed significantly shorter 90-day survival probability than the residual patients (n = 20). None of the CSF parameters could predict the risk of mortality on Cox regression analysis.The cutoff value of CEA ≥5 ng/ml in CSF is a simple and useful method with a high diagnostic value for CM diagnosis, but not a suitable predicting factor for mortality. 'TP in CSF >patients' age" might be a novel factor for assessing short-term mortality., Competing Interests: The authors have no funding and conflicts of interests to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Cerebrospinal fluid (CSF) analysis is a diagnostic tool for many conditions affecting the central nervous system. Urgent indications for lumbar puncture include suspected central nervous system infection or subarachnoid hemorrhage. CSF analysis is not necessarily diagnostic but can be useful in the evaluation of other neurologic conditions, such as spontaneous intracranial hypotension, idiopathic intracranial hypertension, multiple sclerosis, Guillain-Barré syndrome, and malignancy. Bacterial meningitis has a high mortality rate and characteristic effects on CSF white blood cell counts, CSF protein levels, and the CSF:serum glucose ratio. CSF culture can identify causative organisms and antibiotic sensitivities. Viral meningitis can present similarly to bacterial meningitis but usually has a low mortality rate. Adjunctive tests such as CSF lactate measurement, latex agglutination, and polymerase chain reaction testing can help differentiate between bacterial and viral causes of meningitis. Immunocompromised patients may have meningitis caused by tuberculosis, neurosyphilis, or fungal or parasitic infections. Subarachnoid hemorrhage has a high mortality rate, and rapid diagnosis is key to improve outcomes. Computed tomography of the head is nearly 100% sensitive for subarachnoid hemorrhage in the first six hours after symptom onset, but CSF analysis may be required if there is a delay in presentation or if imaging findings are equivocal. Xanthochromia and an elevated red blood cell count are characteristic CSF findings in patients with subarachnoid hemorrhage. Leptomeningeal carcinomatosis can mimic central nervous system infection. It has a poor prognosis, and large-volume CSF cytology is diagnostic.

The unbiased selection of peptide precursors makes data-independent acquisition (DIA) an advantageous alternative to data-dependent acquisition (DDA) for discovery proteomics, but traditional multiplexed quantification approaches employing mass difference labeling or isobaric tagging are incompatible with DIA. Here, we describe a strategy that permits multiplexed quantification by DIA using mass defect-based N , N -dimethyl leucine (mdDiLeu) tags and high-resolution tandem mass spectrometry (MS 2 ) analysis. Millidalton mass differences between mdDiLeu isotopologues produce fragment ion multiplet peaks separated in mass by as little as 5.8 mDa, enabling up to 4-plex quantification in DIA MS 2 spectra. Quantitative analysis of yeast samples displayed comparable accuracy and precision for MS 2 -based DIA and MS 1 -based DDA methods. Multiplexed DIA analysis of cerebrospinal fluid revealed the dynamic proteome changes in Alzheimer's disease, demonstrating its utility for discovery of potential clinical biomarkers. We show that the mdDiLeu tagging approach for multiplexed DIA is a viable methodology for investigating proteome changes, particularly for low-abundance proteins, in different biological matrices.

Background: The clinical presentations of frontotemporal dementia (FTD) are diverse and overlap with other neurological disorders. There are, as of today, no biomarkers in clinical practice for diagnosing the disorders. Here, we aimed to find protein markers in cerebrospinal fluid (CSF) from patients with FTD, presymptomatic mutation carriers and non-carriers., Methods: Antibody suspension bead arrays were used to analyse 328 proteins in CSF from patients with behavioural variant FTD (bvFTD, n = 16) and progressive primary aphasia (PPA, n = 13), as well as presymptomatic mutation carriers (PMC, n = 16) and non-carriers (NC, n = 8). A total of 492 antibodies were used to measure protein levels by direct labelling of the CSF samples. The findings were further examined in an independent cohort including 13 FTD patients, 79 patients with Alzheimer's disease and 18 healthy controls., Results: We found significantly altered protein levels in CSF from FTD patients compared to unaffected individuals (PMC and NC) for 26 proteins. The analysis show patterns of separation between unaffected individuals and FTD patients, especially for those with a clinical diagnosis of bvFTD. The most statistically significant differences in protein levels were found for VGF, TN-R, NPTXR, TMEM132D, PDYN and NF-M. Patients with FTD were found to have higher levels of TN-R and NF-M, and lower levels of VGF, NPTXR, TMEM132D and PDYN, compared to unaffected individuals. The main findings were reproduced in the independent cohort., Conclusion: In this pilot study, we show a separation of FTD patients from unaffected individuals based on protein levels in CSF. Further investigation is required to explore the CSF profiles in larger cohorts, but the results presented here has the potential to enable future clinical utilization of these potential biomarkers within FTD.

Background/objective: Subarachnoid hemorrhage (SAH) is a devastating neurologic event for which markers to assess poor outcome are needed. Elevated cerebrospinal fluid (CSF) protein may result from inflammation and blood-brain barrier (BBB) disruption that occurs during SAH. We sought to determine if CSF protein level is associated with functional outcome after SAH., Methods: We prospectively collected single-center demographic and clinical data for consecutive patients admitted with spontaneous SAH. Inclusion required an external ventricular drain and daily CSF protein and cellular counts starting within 48 hours of symptom onset and extending through 7 days after onset. Seven-day average CSF protein was determined from daily measured values after correcting for contemporaneous CSF red blood cell (RBC) count. Three-month functional outcome was assessed by telephone interview with good outcome defined as modified Rankin score 0-3. Variables univariately associated with outcome at P less than .25 and measures of hemorrhage volume were included for binary logistic regression model development., Results: The study included 130 patients (88% aneurysmal SAH, 69% female, 54.8 ± 14.8 years, Glasgow Coma Scale [GCS] 14 [7-15]). Three-month outcome assessment was complete in 112 (86%) patients with good functional outcome in 74 (66%). CSF protein was lower in good outcome (35.3 [20.4-49.7] versus 80.5 [40.5-115.5] mg/dL; P < .001). CSF protein was not associated with cerebral vasospasm, but delayed radiographic infarction on 3 to 12-month neuroimaging was associated with higher CSF protein (46.3 [32.0-75.0] versus 30.2 [20.4-47.8] mg/dL; P = .023). Good 3-month outcome was independently associated with lower CSF protein (odds ratios [OR] .39 [.23-.70] for 75th versus 25th percentile of protein; P = .001) and higher admission GCS (OR 1.23 [1.10-1.37] for good outcome per GCS point increase; P < .001). Parenchymal hematoma predicted worse outcome (OR 6.31 [1.58-25.25]; P = .009). Results were similar after excluding nonaneurysmal SAH and after including CSF RBC count, CT score, and intraventricular hemorrhage volume in models., Conclusions: Elevated average CSF protein is associated with poor outcome after spontaneous SAH. Further research should investigate if elevated CSF protein identifies patients in whom mechanisms such as BBB disruption contribute to poor outcome., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Aims: The exact pathogenesis of neuromyelitis optica spectrum disorder (NMOSD) remains unclear. A variety of cytokines are involved, but few studies have been performed to explore the novel roles of interleukin-22 (IL-22) and interleukin-35 (IL-35) in NMOSD. Therefore, this study was designed to investigate serum levels of IL-22 and IL-35, and their correlations with clinical and laboratory characteristics in NMOSD., Methods: We performed a cross-section study, 18 patients with acute NMOSD, 23 patients with remission NMOSD, and 36 healthy controls were consecutively enrolled. Serum levels of IL-22 and IL-35 were measured by enzyme-linked immunosorbent assay (ELISA). The correlations between serum IL-22 and IL-35 levels and clinical and laboratory characteristics were evaluated by Spearman's rank or Pearson's correlation coefficient., Results: The serum levels of IL-22 and IL-35 were significantly lower in patients with acute NMOSD and remission NMOSD than in healthy controls (IL-22: 76.96 ± 13.62 pg/mL, 87.30 ± 12.79 pg/mL, and 94.02 ± 8.52 pg/mL, respectively, P < .0001; IL-35: 45.52 ± 7.04 pg/mL, 57.07 ± 7.68 pg/mL, and 60.05 ± 20.181 pg/mL, respectively, P < .0001). Serum levels of IL-35 were negatively correlated with EDSS scores and cerebrospinal fluid protein levels (r = -.5438, P = .0002 and r = -.3523, P = .0258, respectively) in all patients., Conclusions: Lower serum levels of IL-22 and IL-35 are associated with disease status in NMOSD. Additionally, lower serum levels of IL-35 are associated with disease severity in NMOSD., (© 2019 The Authors. CNS Neuroscience & Therapeutics Published by John Wiley & Sons Ltd.)

Aims: Cognitive impairment is a common symptom in the trajectory of Parkinson's disease (PD). However, the pathological underpinning is not fully known. We aimed to explore the critical structural alterations in the process of cognitive decline and its relationships with the dopaminergic deficit and the level of related cerebrospinal fluid (CSF) proteins., Methods: Ninety-four patients with PD and 32 controls were included in this study. Neuropsychological tests were performed at baseline and after 28 months to identify which patients had normal cognition and which ones developed PD-MCI after follow-up ("converters"). Gray matter atrophy was assessed in cross-sectional and longitudinal analyses, respectively. The associations between altered GMV with dopamine transporter (DAT) results and the level of CSF proteins were assessed., Results: Among the 94 patients with normal cognition at baseline, 24 (mean age, 63.1 years) developed PD-MCI after 28 months of follow-up, and 70 (mean age, 62.3 years) remained nonconverters. The converters showed significant right temporal atrophy at baseline and extensive atrophy in temporal lobe at follow-up. Progressive bilateral frontal lobe atrophy was found in the converters. Baseline right temporal atrophy was correlated with the striatal dopaminergic degeneration in the converters. No correlation was found between the right temporal atrophy and the alterations of CSF proteins., Conclusion: Early atrophy in temporal lobes and progressive atrophy in frontal lobes might be a biomarker for developing multidomain impairment of cognition and converting to PD-MCI. Furthermore, cognition-related temporal atrophy might be associated with dopaminergic deficit reflected by DAT scan but independent of CSF proteins in patients with PD who convert to PD-MCI., (© 2019 The Authors. CNS Neuroscience & Therapeutics Published by John Wiley & Sons Ltd.)

Introduction: Recent literature has concluded that cerebrospinal fluid total protein (CSF-TP) upper reference limits (URL) should be higher than 45 mg/dl and stratified by age., Methods: Data-driven URLs were applied to the analysis of a cohort of patients with correctly and incorrectly diagnosed chronic inflammatory demyelinating polyneuropathy (CIDP). Descriptive statistics were calculated, and exploratory analyses were used to test the impact of different CSF-TP URLs on sensitivity and specificity of CIDP diagnosis., Results: The adoption of higher and age-dependent CSF-TP URLs reduced the sensitivity of CSF analysis slightly (from 95% to 84%-86%); however, the overall CIDP detection rate was unchanged. Twelve of 36 (33%) false-positive diagnoses occurred with CSF-TP elevation as the sole supportive criteria. By applying updated CSF-TP URLs, the specificity of CSF analysis increased from 39% to 57%-64%., Discussion: Implementation of data-driven CSF-TP URLs improves CIDP diagnostic specificity without compromising sensitivity, thereby lessening CIDP misdiagnosis. Muscle Nerve 60: 180-183, 2019., (© 2019 Wiley Periodicals, Inc.)

Bacterial meningitis is a life-threatening condition. Vancomycin (VCM) is one of the antibiotics used as empirical therapy for bacterial meningitis. It is essential to maintain an adequate concentration of VCM in cerebrospinal fluid (CSF) to treat bacterial meningitis effectively. VCM administered intravenously must pass the blood-brain barrier (BBB) to enter the CSF and the extent of VCM penetration into CSF varies widely among patients. Previous report indicated that CSF albumin level is useful for estimation of VCM CSF penetration. However, CSF albumin level is not measured in routine practice. We focused on CSF protein concentration that is generally examined at the beginning of diagnosis and treatment of bacterial meningitis. We examined the relationship between CSF protein concentration/serum albumin ratio and the extent of VCM penetration into CSF. This retrospective study involved 7 patients admitted to our hospital who were treated with VCM for suspected bacterial meningitis. The VCM concentrations in serum and CSF were 17.6 ± 7.2 μg/mL and 3.31 ± 3.14 μg/mL, respectively. The serum VCM concentrations showed no significant correlation with CSF VCM concentrations. On the other hand, the protein concentration in CSF/serum albumin ratio showed a strong positive correlation with the VCM CSF/serum ratio (r = 0.877, p < 0.005). Our study indicates that the ratio of CSF protein concentration/serum albumin is likely useful for estimating the approximate VCM CSF/serum ratio. This could contribute to an improvement in the treatment of bacterial meningitis., (Copyright © 2018 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: The cerebrospinal fluid total protein level (CSF-TP) is commonly used as a potential marker of infectious or immune disease of the CNS and PNS. Recent laboratory reference studies indicate that the antiquated single upper reference limit of 0.45 g/L commonly used by hospital laboratories and widely quoted in medical literature is a significant underestimation., Methods: We distributed worldwide a web-based survey comprised of three questions: 1. What is the CSF-TP upper limit used at your institution? 2. What is the source of this upper limit? 3. Do you adjust your upper limit according to age?, Results: A total of 473 unique responses were obtained from North America (37.5%), South America (5.5%), Europe (29.4%), Africa (4%), Asia (21.6%) and Oceania (1.7%). A strong preponderance (86.8%) of institutions reported an upper limit of 0.45 g/L or less. Only 4% reported making age-partitioned adjustments., Conclusions: Worldwide, a strong majority of hospital laboratories presently use an underestimation of CSF-TP upper reference value, particularly for older adults. Recent well powered laboratory reference studies support higher values with age adjustment., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background and Objective: Plasma homocysteine (Hcy) levels have been investigated among patients with multiple sclerosis (MS). However, the changes in Hcy levels and the association between Hcy levels and inflammatory/immune/cerebrospinal fluid (CSF) parameters in neuromyelitis optica spectrum disorder (NMOSD) patients have not been investigated yet., Methods: Case data were collected from 97 acute-phase NMOSD patients and 39 stable-phase NMOSD patients. Patients in the acute phase were divided into 2 groups based on the EDSS score with cutoff equal to 4. Hcy levels, immunoglobulins (Ig) A, G, and M, complement 3 and 4, CH50, C-reactive protein, erythrocyte sedimentation rate (ESR), and CSF examination including white blood cells and total protein were determined., Results: No significant differences in Hcy levels are observed between acute-phase and stable-phase NMOSD patients. Hcy and ESR levels were significantly higher in acute-phase NMOSD patients with EDSS score ≥4. Besides, EDSS is positively correlated with Hcy level, ESR, 1/aquaporin-4 titer and Hcy level is negatively correlated with IgM in acute-phase NMOSD patients., Conclusion: Elevated plasma Hcy has the potential to affect the pathogenesis or progression of NMOSD., (© 2019 S. Karger AG, Basel.)

Re-emerging scrub typhus is gaining recognition as an important cause of paediatric meningoencephalitis in tropics. We studied the clinical profile of scrub typhus meningoencephalitis (STME) in children <12 years. Of 270 serology-confirmed cases of scrub typhus, 14 (5%) had features consistent with STME and 9 (64%) of these children were between 5 and 12 years of age; 12 (85%) children presented to the hospital during the second week of illness. Fever, headache and altered sensorium were observed in all children, while meningeal signs, papilledema and seizures were observed in 8 (57%), 7 (50%) and 6 (43%) children, respectively. The mean CSF protein level, glucose level, cell count and percentage of lymphocytes were 75 mg/dl, 46 mg/dl, 41 cells and 86%, respectively. STME should be considered in febrile children from endemic area with neurological features, such as headache or altered sensorium. Lumbar puncture is mandatory to confirm STME and rule out close differential diagnosis, such as pyogenic and tubercular meningitis.

Surgery on the arch or descending aorta is associated with significant risk of neurological complications. As a consequence of intubation and sedation, early neurologic injury may remain unnoticed. Biomarkers to aid in the initial diagnostics could prove of great value as immediate intervention is critical. Twenty-three patients operated in the thoracic aorta with significant risk of perioperative neurological injury were included. Cerebrospinal fluid (CSF) and serum were obtained preoperatively and in the first and second postoperative days and assessed with a panel of 92 neurological-related proteins. Three patients suffered spinal cord injury (SCI), eight delirium, and nine hallucinations. There were markers in both serum and CSF that differed between the affected and non-affected patients (SCI; IL6, GFAP, CSPG4, delirium; TR4, EZH2, hallucinations; NF1). The study identifies markers in serum and CSF that reflect the occurrence of neurologic insults following aortic surgery, which may aid in the care of these patients.

Objective: Cerebrospinal fluid (CSF) markers of neurodegeneration [neurofilament light chain (NFL), total Tau (T-Tau)], tau pathology [phosphorylated tau (p-Tau)], glial cell damage or activation [glial fibrillary acidic protein (GFAP)], and brain amyloidosis [β-amyloid 1-42 (Aβ42)] are useful for diagnosis and prognosis in several neurodegenerative disorders. In this paper we investigate these markers and their relationship to key clinical milestones in patients with advanced Parkinson´s disease (PD) operated at our center with subthalamic nucleus deep brain stimulation (STN-DBS) for at least 15 years ago., Patients and Methods: Retrospective analysis of available cerebrospinal fluid and clinical data in PD-patients, 15 years or more after they underwent STN-DBS surgery. All PD-patients implanted with STN-DBS at Sahlgrenska University Hospital before January 1, 2001, were regularly assessed until January 10, 2018, or until death, or until lost to follow-up., Results: Twenty three PD patients were operated with STN-DBS. Sixteen of these (six females and ten males) underwent at least one lumbar puncture (LP) immediately prior to or after STN-DBS. Their age at the latest available LP was 64 (55-75) years [median (range)], PD duration 20 (11-33) years, and Hoehn & Yahr (H&Y) stage 3 (2-4). Time between DBS operation and the last LP was 4.5 (0.3-10.8) years. Time from the last LP to the last follow up was 6 (0.1-18) years, and for the entire cohort 115 person-years. On January 10, 2018, four PD-patients (25%) were still alive. All preoperative CSF marker levels were normal. Between two days and six months after DBS, NFL and GFAP levels increased sharply but they normalized thereafter in most patients, and were normal up to almost 11 years after neurosurgery. Over time, all patients deteriorated slowly. At the last follow up, H&Y was 5 (3-5) and 12/16 were demented. There was no significant correlation between postoperative (> 6 months) CSF NFL, GFAP, T-Tau, p-Tau, β-amyloid levels and the presence of dementia, psychosis, inability to walk or need for nursing home at the time for LP, nor for presence of dementia at the last follow up or for death as of January 10, 2018., Conclusion: CSF protein biomarkers remain normal despite long PD duration, severe disability, and chronic STN-DBS. They cannot be used for PD staging or prognostication but may indicate brain damage caused by other pathological factors., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Phacomatoses are a special group of familial hamartomatous syndromes with unique neuro-cutaneous manifestations as well as disease characteristic tumors. Neurofibromatosis 2 (NF2) and tuberous sclerosis complex (TSC) are representatives of this family. Vestibular schwannoma (VS) and subependymal giant cell tumor (SGCT) are two of the most common intracranial tumors associated with NF2 and TSC, respectively. These tumors can present with obstructive hydrocephalus due to their location adjacent to or in the ventricles. However, both tumors are also known to have a unique association with an elevated protein concentration in the cerebrospinal fluid (CSF), sometimes in association with non-obstructive (communicating) hydrocephalus (HCP), the causality of which has been unclear. Furthermore, SGCTs have repeatedly been shown to have a predisposition for CSF clotting, causing debilitating obstructions and recurrent malfunctions in shunted patients. However, the exact relation between high protein levels and spontaneous clotting of the CSF is not clear, nor is the mechanism understood by which CSF may clot in SGCTs. Elevated protein levels in the CSF are thought to be caused by increased vascular permeability and dysregulation of the blood-brain barrier. The two presumed underlying pathophysiologic mechanisms for that, in the context of tumorigenesis, are angiogenesis and inflammation. Both mechanisms are correlated to the Pi3K/Akt/mTOR pathway which is a major tumorigenesis pathway in nearly all phacomatoses. In this review, we discuss the influence of angiogenesis and inflammation on vascular permeability in VSs and SGCTs at the phenotypic level as well as their possible genetic and molecular determinants. Part I describes the historical perspectives and clinical aspects of the relationship between vascular permeability, abnormal CSF protein levels, clotting of the CSF, and communicating HCP. Part II describes different cellular and molecular pathways involved in angiogenesis and inflammation in these two tumors and the correlation between inflammation and coagulation. Interestingly, while increased angiogenesis can be observed in both VS and SGCT, inflammatory processes seem more prominent in SGCT. Both pathologies are characterized by different subgroups of tumor-associated macrophages (TAM): the pro-inflammatory, M1 type is predominating in SGCTs while pro-angiogenetic, M2 type is predominating in VSs. We suggest that lack of NF2 protein in VS and lack of TSC1/2 proteins in SGCT determine this fundamental difference between the two tumor types, by defining the predominant TAM type. Since inflammatory reactions and coagulation processes are tightly connected, a "pro-inflammatory state" of SGCT can be used to explain the observed associated enhanced CSF clotting process. These distinct cellular and molecular differences may have direct therapeutic implications on tumors that are unique to certain phacomatoses or those with similar genetics.

The molecular mechanisms underlying seizure susceptibility in preeclampsia are unknown. We hypothesized that altered expression of distinct proteins in the cerebrospinal fluid (CSF) may reflect pathophysiological changes in the central nervous system that contribute to the neurological manifestations of severe preeclampsia. We obtained CSF samples from 13 patients with preeclampsia and 14 control patients during spinal anesthesia before delivery and analyzed them by SOMAscan, an aptamer-based proteomics platform for alterations in 1310 protein levels. Ingenuity Pathway Analysis was conducted to highlight relationships between preeclampsia-specific proteins found to be significantly altered. For 2 of the target proteins, we validated the difference in CSF concentrations by ELISA. SOMAscan revealed 82 proteins, whose expression levels were significantly different ( P <0.05) in CSF from patients with preeclampsia versus controls. Principal component analysis achieved perfect separation of the preeclampsia and control groups in 2 dimensions. The differentially expressed proteins converge around 4 signaling molecules: TGF-β (transforming growth factor-β), VEGFA (vascular endothelial growth factor A), angiotensinogen, and IL-6 (interleukin-6). Within the TGF-β pathway, upregulation of activin A (301.6±47.4 versus 151.6±20.5 pg/mL; P =0.0074) and follistatin-related gene (5129±347 versus 3016±188 pg/mL; P <0.0001) in preeclampsia was confirmed by ELISA. In summary, signaling pathways important for vascular remodeling, inflammation, and neuronal growth, signaling, and electrophysiology were well represented among the proteins found to be altered in CSF in patients with preeclampsia., (© 2018 American Heart Association, Inc.)

Normal pressure hydrocephalus (NPH) was the first type of dementia ever described that can be treated using ventriculoperitoneal shunting surgery. Three typical clinical symptoms of NPH include gait disturbance, progressive cognitive dysfunction, and urinary incontinence. Although there are articles that have discovered several cerebrospinal fluid (CSF) protein biomarkers associated with NPH; however, studies examining individual and total protein concentrations from the ventricular CSF before and after shunting surgery are lacking. This study used proteomics to calculate the CSF individual and total protein concentrations before, and one week, one month and three months after the shunting surgery. Parameters of cadence, step length, walking speed, and percentages of single- and double-limb support in a gait cycle were measured. Protein concentrations associated with anti-oxidation, aging, and in the prevention of neurotoxic agent production increased by at least 2-folds after the surgery, indicating that the brain may become less susceptible to neurodegeneration. These proteins were alpha-1B-glycoprotein, apolipoproteins A-1 & A-IV, prostaglandin-H2 D-isomerase, alpha-1-antitrypsin, and serotransferrin. In gait analysis, lower cadence, decreased double-limb support, longer step length, and increased single-limb support were observed after the surgery, indicating a more stable walking balance. These changes lasted for a period of at least 3 months. As a result, shunting surgery may be recommended for geriatric patients with confirmed diagnosis of normal pressure hydrocephalus., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Introduction and Objective: The albumin-cytologic dissociation in cerebrospinal fluid (CSF) supports the diagnosis of Guillain-Barre syndrome (GBS) but does not support the prognosis, so the aim of this study is to determine the usefulness of protein numbers in the CSF to predict progression in paediatric patients., Patients and Methods: A diagnostic test was performed in paediatric patients with GBS, analysing sociodemographic, clinical and protein variables in CSF as well as electromyography. The presence of dysautonomia was also documented., Results: Data were analysed from 23 patients, predominantly males (87%), school age (43.5%) and history of digestive infection (73.9%). Using the ROC curve, an area under the curve of 0.966 with best CSF protein cut-off point of 87-92 proteins/mm was found for the presence of dysautonomias and to evaluate the poor response to treatment with 0.969 intravenous immunoglobulin with better cut-off point in 157 proteins/mm., Conclusion: The amount of proteins in the CSF can be used as a prognostic indicator and severity, such that proteins greater than 100 in CSF translate into a torpid evolution and with greater complications., (Copyright © 2017 Elsevier España, S.L.U. All rights reserved.)

Background: Neuroinflammation has gained increasing attention as a potential contributing factor in Alzheimer's disease (AD) pathology. A clinical cerebrospinal fluid biomarker capable of monitoring this process during the course of the disease has yet to emerge, chiefly owing to contradictory research findings. In this study, we sought to clarify the utility of inflammatory biomarkers in diagnostic procedures of AD in three steps: (1) to screen for proteins that are robustly detectable in cerebrospinal fluid; (2) based on this analysis, to explore any associations between the analytically robust markers and salient pathological features of AD; and (3) to determine the discriminative power of these markers in the clinical diagnosis of AD., Methods: From a total of 46 proteins, 15 that were robustly detectable in cerebrospinal fluid were identified. A subsequent analysis of these markers in a cohort of 399 patients (nondemented subjects, patients with mild cognitive impairment [MCI], and patients with AD, supplemented by smaller cohorts of other diseases) was conducted. Fluid biomarker data were related to AD pathology and neuropsychological markers and adjusted for confounders such as age, sex, apolipoprotein E genotype, and biobank storage time., Results: Cerebrospinal fluid levels of C-reactive protein and soluble TREM2 differed between nondemented subjects, patients with MCI, or patients with AD and were associated with amyloid and tau pathology. Several markers were associated with tau pathology only or with other neurodegenerative diseases. Correlations between neuropsychological performance and inflammatory markers were weak, but they were most prominent in AD and for the most challenging cognitive tests. All investigated covariates had significant influence, with varying effects across the markers. Still, none of the markers achieved discriminative power of more than 70% to distinguish between patient groups defined by clinical or neuropathological categories., Conclusions: Basic analytical considerations proved indispensable for this type of study because only one-third of the tested markers were robustly detectable in cerebrospinal fluid. Detectable inflammatory protein markers were associated in multiple ways with AD pathology. Yet, even significantly associated markers were not powerful enough in terms of effect strength, sensitivity, and specificity, and hence they were not suited for direct use in clinical diagnostic practice. Targets other than those most commonly considered in this field of research might provide results with better clinical applicability.

We treated 437 cases of adult aseptic meningitis and 12 cases (including 2 recurrent patients; age, 31.8 ± 8.9 years; 7 females) of herpes simplex meningitis from 2004 to 2016. The incidence rate of adult herpes simplex meningitis in the cases with aseptic meningitis was 2.7%. One patient was admitted during treatment of genital herpes, but no association was observed between genital herpes and herpes simplex meningitis in the other cases. The diagnoses were confirmed in all cases as the cerebrospinal fluid (CSF) was positive for herpes simplex virus (HSV)-DNA. For diagnosis confirmation, the DNA test was useful after 2-7 days following initial disease onset. Among other types of aseptic meningitis, the patients with herpes simplex meningitis showed relatively high white blood cell counts and relatively high CSF protein and high CSF cell counts. CSF cells showed mononuclear cell dominance from the initial stage of the disease. During same period, we also experienced 12 cases of herpes simplex encephalitis and 21 cases of non-hepatic acute limbic encephalitis. Notably, the patients with herpes simplex meningitis were younger and their CSF protein and cells counts were higher than those of the patients with herpes simplex encephalitis.

This report presents a case of a 71-year-old woman with Fisher syndrome who had posterior reversible encephalopathy syndrome (PRES) before the initiation of intravenous immunoglobulin (IVIg) treatment. She had symptoms of common cold 2 weeks before the onset of PRES. On the day of the onset, she began to stagger while walking. On day 2, she developed hypertension, vision impairment, and limb weakness and was admitted to the hospital. On day 3, she was provided steroid pulse therapy. On day 4, she developed convulsions and right imperfection single paralysis and was transferred to the our hospital. During the transfer, the patient was conscious. Her blood pressure was high at 198/107 mmHg. She had mild weakness in her limbs and face, light perception in both eyes, dilation of both pupils, total external ophthalmoplegia, no tendon reflexes, and limb and trunk ataxia. We diagnosed PRES because of the high signal intensities observed on T 2 -weighted MRI on both sides of the parietal and occipital lobes. We also diagnosed Fisher syndrome because of a positive anti-GQ1b immunoglobulin G antibody test and albuminocytologic dissociation in the cerebrospinal fluid. PRES showed prompt improvement with antihypertensive therapy, whereas Fisher syndrome slowly improved over a course of 2 months. This case is the first report of PRES without IVIg suggesting that Fisher syndrome induces hypertension and causes PRES.

Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is a form of autoimmune encephalopathy that presents with a wide variety of symptoms, including neuropsychiatric manifestations. The authors' aim for this study was to analyze the results of paraclinical studies of patients with a diagnosis of anti-NMDAR encephalitis and the association between symptom onset and diagnosis, and start of immunotherapy. Retrospective data of 29 patients with anti-NMDAR encephalitis were gathered and analyzed. Abnormal EEG was found in 27 patients (93.1%), whereas MRI was abnormal in 19 patients (65.5%). In contrast, an inflammatory pattern on CSF analysis was found in only 13 patients (44.8%). The absence of pleocytosis or increased proteins in the CSF was associated with a longer time from symptom onset to diagnosis and treatment (p = 0.003). The authors conclude that noninflammatory CSF may delay the correct diagnosis and start of immunotherapy in anti-NMDAR encephalitis. In the presence of suggestive clinical features, extensive studies including EEG are recommended.

Background: Reference intervals are vital for interpretation of laboratory results. Many existing reference intervals for cerebrospinal fluid total protein (CSF-TP) are derived from old literature because of the invasive nature of sampling. The objective of this study was to determine reference intervals for CSF-TP using available patient data., Methods: Twenty years of hospital database information was mined for previously reported CSF-TP results. Associated demographic, laboratory, and clinical diagnosis (International Classification of Diseases 9/10 codes) details were extracted. CSF-TP results included 3 different analytical platforms: the Siemens Vista 1500, Beckman Lx20, and Roche Hitachi 917. From an initial data set of 19591 samples, the following exclusion criteria were applied: incomplete data, white blood cells (WBCs) >5 × 10 6 /L, red blood cells (RBCs) >50 × 10 6 /L, and glucose <2.5 mmol/L. Patient charts were reviewed in detail to exclude 60 different conditions for which increases in CSF-TP would be expected. A total of 6068 samples were included; 63% of the samples were from females. Continuous reference intervals were determined using quantile regression. Age- and sex-partitioned intervals were established using the quantile regression equation and splitting age-groups into 5-year bins., Results: CSF-TP showed a marked age dependence, and males had significantly higher CSF-TP than females across all ages. CSF-TP results from the 3 different instruments and manufacturers showed small (approximately 0.04 g/L), but statistically significant, differences. CSF-TP showed weak, but again statistically significant, correlation with WBC and RBC but was independent of serum total protein and creatinine., Conclusions: The age dependence of CSF-TP supports that age-partitioned reference intervals will be more accurate than a single cutoff, particularly in patients with advancing age., (© 2017 American Association for Clinical Chemistry.)

Background: Research has been going on to formulate diagnostic criteria for TBM. Two criteria that have been studied and validated in high TB prevalence areas are the Youssef criteria (Rule 1) and Thwaites criteria (Rule 2). In our study we aimed to compare the different features of TBM and acute bacterial meningitis., Methods: This retrospective study was done at Northwest General Hospital & Research Centre (NWGH&RC), Peshawar, Pakistan. Patients who were clinically diagnosed with TB meningitis or bacterial meningitis at the time of presentation were included in the study., Results: Lab parameters for both groups were compared using independent sample T tests. We plotted ROC curves for Rule 1 and Rule 2. For Rule 1, at cut off value 2 it has a sensitivity of 97.5% and a specificity of 47.2%. For Rule 2, area at cut off value 3.5, sensitivity was 95% and specificity was 23.5%. We also plotted CSF protein to glucose ratio of our sample on an ROC curve and looked for measures of sensitivity and specificity. At cut off point 2 the sensitivity was 93% and specificity was 66.66%., Conclusion: It should be noted that although sensitivity for all three indices were high, specificity of all three tests was not very encouraging. We would like to emphasize that these indices can be useful in screening for patients with suspected TBM but they do not have the specificity to act as the sole test for initiation and continuance of therapy., (Copyright © 2017 Tuberculosis Association of India. Published by Elsevier B.V. All rights reserved.)

In our multicenter cohort of infants ≤60 days of age, we identified 2646 infants with a traumatic lumbar puncture, of which 31 (1.2%) had bacterial meningitis. For every 1000 cerebrospinal fluid red blood cells/mm, cerebrospinal (cerebrospinal fluid) protein increased 1.1 mg/dL (95% confidence interval: 1.0-1.2 mg/dL).

See Mander et al. (doi:10.1093/awx174) for a scientific commentary on this article.Sleep deprivation increases amyloid-β, suggesting that chronically disrupted sleep may promote amyloid plaques and other downstream Alzheimer's disease pathologies including tauopathy or inflammation. To date, studies have not examined which aspect of sleep modulates amyloid-β or other Alzheimer's disease biomarkers. Seventeen healthy adults (age 35-65 years) without sleep disorders underwent 5-14 days of actigraphy, followed by slow wave activity disruption during polysomnogram, and cerebrospinal fluid collection the following morning for measurement of amyloid-β, tau, total protein, YKL-40, and hypocretin. Data were compared to an identical protocol, with a sham condition during polysomnogram. Specific disruption of slow wave activity correlated with an increase in amyloid-β40 (r = 0.610, P = 0.009). This effect was specific for slow wave activity, and not for sleep duration or efficiency. This effect was also specific to amyloid-β, and not total protein, tau, YKL-40, or hypocretin. Additionally, worse home sleep quality, as measured by sleep efficiency by actigraphy in the six nights preceding lumbar punctures, was associated with higher tau (r = 0.543, P = 0.045). Slow wave activity disruption increases amyloid-β levels acutely, and poorer sleep quality over several days increases tau. These effects are specific to neuronally-derived proteins, which suggests they are likely driven by changes in neuronal activity during disrupted sleep., (© The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

To describe the key diagnostic features of pediatric Guillain-Barré syndrome (GBS) and validate the Brighton criteria. Retrospective cohort study of all children (<18 years) diagnosed with GBS between 1987 and 2013 at Sophia Children's Hospital, Erasmus MC, Rotterdam. Clinical information was collected and the sensitivity of the Brighton criteria was calculated. 67 children (35 boys) were included, with a median age of 5.0 years [interquartile range (IQR) 3.0-10.0 years]. Bilateral limb weakness was present at hospital admission in 93% of children, and at nadir in all patients. Children presented with tetraparesis in 70% or with paraparesis in 23%. Reduced reflexes in paretic limbs were observed at hospital admission in 82% and during follow-up in all children. The progressive phase lasted median 6 days (IQR 3-8 days) and less than 4 weeks in all children. A monophasic disease course was seen in 97%, including 5 children with a treatment-related fluctuation. Two children had a later relapse at 9 weeks and 19 weeks after onset. 77% of the children showed an elevated protein level in CSF. Nerve conduction studies showed evidence for a poly(radiculo)neuropathy in 91% of the children. 46 children had a complete data set, the sensitivity of the Brighton criteria level 1 was 72% (95% CI 57-84) and 96% (95% CI 85-99) for level 2 and 98% (95% CI 88-100) for level 3. The majority of the pediatric GBS patients presented in this cohort fulfilled the current diagnostic criteria.

In the current study, we conducted a quantitative in-depth proteome and deglycoproteome analysis of cerebrospinal fluid (CSF) from relapsing-remitting multiple sclerosis (RRMS) and neurological controls using mass spectrometry and pathway analysis. More than 2000 proteins and 1700 deglycopeptides were quantified, with 484 proteins and 180 deglycopeptides significantly changed between pools of RRMS and pools of controls. Approximately 300 of the significantly changed proteins were assigned to various biological processes including inflammation, extracellular matrix organization, cell adhesion, immune response, and neuron development. Ninety-six significantly changed deglycopeptides mapped to proteins that were not found changed in the global protein study. In addition, four mapped to the proteins oligo-myelin glycoprotein and noelin, which were found oppositely changed in the global study. Both are ligands to the nogo receptor, and the glycosylation of these proteins appears to be affected by RRMS. Our study gives the most extensive overview of the RRMS affected processes observed from the CSF proteome to date, and the list of differential proteins will have great value for selection of biomarker candidates for further verification.

Background: Identify if glycorrhachia and cerebrospinal fluid protein could influence the time of sensory block to T10, the duration and the metameric block's level, after a standard dose of Ropivacaine., Methods: 80 patients, ASA I - III undergoing to transurethral prostate resection with spinal anesthesia in a prospected open study were recruited. A 0.2 ml liquor's sample was taken; glycorrhachia, by glycemic stix and CSF protein, by urinary stix, were got, before Ropivacaine 0.5% 15 mg injection (0.10 - 0.15 mlsec). After anti-trendelemburg, with 30 ° tilting for 15 min, the onset of sensory block to T10, the maximum metameric level to 15' and the time of sensory block were reported. The data collection were analyzed using the software language R., Results: A significant correlation liquor specific weigh preoperative glycemia (0.749), liquoral specific weigh glycorrhachia (rho = 0.751; R2 = 0.564; P 0.05) and specific weigh CSF protein (rho = 0.684; R2 = 0.468; P 0.05) were reported. Inverse relation CSF weightsensory block level (rho -0.789, P 0.05, R2 0.621) was evidenced. Inverse relation onset time to T10 glycorrhachia (84%) and cephalic block glycorrhachia (76%) were found. Inverse correlation onset time to T 10 CSF protein and cephalic block proteinorrachia was respectively 84% and 67%. A rho of 0.712 with R2 of 51% BMI onset to T10 and rho of 0.681 with R2 of 51% BMI maximum cephalic block with P 0.05 were reported., Conclusions: The predictability of a iso-hypobaric local anesthetic could reduce the risk of procedure failure and adverse events by further cephalic spread.

Cerebrospinal fluid (CSF) has been extensively studied to explore biochemical alterations in subjects with neurodegenerative disorders. In Alzheimer's disease, levels of increased CSF tau protein and decreased levels of β-amyloid 1-42 (Aβ42) have been shown to correlate with brain plaque formation and tangle pathology. Intracellular Lewy inclusions containing aggregated α-synuclein (α-syn) represent a pathological hallmark of Parkinson's disease (PD). In most - but not all - studies published to date total CSF α-syn concentrations have been found to be decreased in disorders related to α-syn pathology, that is, PD, dementia with Lewy bodies and multiple system atrophy. However, these reports show extensive signal overlap among tested individuals, thereby diminishing its potential for routine use in clinical practice. To investigate potential biological (i.e., non-technical) confounders of reported CSF levels for α-syn, Aβ42, and tau in PD and related disorders, we carried out a methodical review of known factors that underlie signal variability and speculate on those that have not yet been tested. We discuss several biological factors, such as neuropathology, demographics, clinical phenotype, progression and duration of disease, concomitant illnesses and, last but not least, pharmacotherapy, which in isolation or combination can substantially alter values for CSF proteins of interest. Enhanced implementation of standardized clinical protocols, streamlined operating procedures, and further progress in the development of validated assays for CSF proteins have the potential to (i) inform us as to the pathogenesis of disease, (ii) support the laboratory-based diagnosis for symptomatic subjects in the future, and (iii) facilitate breakthrough therapies to alter the course of neurodegenerative disorders, such as PD and Alzheimer's disease. Cerebrospinal fluid (CSF) has been extensively studied to explore biochemical alterations in subjects with neurodegenerative disorders. To investigate potential biological confounders of reported CSF levels for α-synuclein (α-Syn), amyloid-β 1-42(Aβ42) and tau protein in Parkinson's disease and related disorders, we reviewed the current literature for known factors that underlie signal variability and speculate on those that have not yet been tested. This article is part of a special issue on Parkinson disease., (© 2016 International Society for Neurochemistry.)

Background: Guillain-Barré syndrome is an acquired polyradiculo-neuropathy, often preceded by an antecedent event. It is a monophasic disease but a recurrence rate of 1-6 % is documented in a subset group of patients. Patients with Guillain-Barré syndrome show cerebrospinal fluid albuminocytologic dissociation. Normal cerebrospinal fluid protein levels during both initial and recurrent episodes of Guillain-Barré syndrome is a rare occurrence and has not been described earlier in the literature., Case Presentation: Twenty-five-year-old Sri Lankan female with past history of complete recovery following an acute inflammatory demyelinating polyneuropathy (AIDP) variant of Guillain-Barré syndrome 12 years back presented with acute, ascending symmetrical flaccid quadriparasis extending to bulbar muscles, bilateral VII cranial nerves and respiratory compromise needing mechanical ventilation. Nerve conduction study revealed AIDP variant of Guillain-Barré syndrome. Cerebrospinal fluid analysis done after 2 weeks were normal during both episodes without albuminocytologic dissociation. She was treated with intravenous immunoglobulin resulting in a remarkable recovery. Both episodes had a complete clinical recovery in three and four months' time respectively, rather a faster recovery than usually expected., Conclusion: Recurrence of Guillain-Barré syndrome can occur in a subset of patients with Guillain-Barré syndrome even after many years of asymptomatic period. Normal cerebrospinal fluid profile does not exclude Guillain-Barré syndrome and may occur in subsequent recurrences of Guillain-Barré syndrome arising the need for further studies to identify the pathophysiology and the possibility of a different subtype of Guillain-Barré syndrome.

Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive, multiple malformation syndrome with neurocognitive impairment. SLOS arises from mutations in the 7-dehydrocholesterol reductase gene which results in impaired enzymatic conversion of 7-dehydrocholesterol to cholesterol. In the current work, we sought to measure proteins that were altered in the cerebrospinal fluid from SLOS patients compared to pediatric controls. Using a multi-analyte antibody-based assay, we found that 12 proteins are altered in SLOS patients. Validation studies were carried out and the findings from this study suggest alterations in extracellular matrix remodeling and further evidence of oxidative stress within the disease pathophysiology. The results of this study will be used to explore biological pathways altered in SLOS and identifies a set of CSF proteins that can be evaluated as biomarkers in future therapeutic trials. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Objectives: Electrical neuromodulation by spinal cord stimulation (SCS) is a well-established method for treatment of neuropathic pain. However, the mechanism behind the pain relieving effect in patients remains largely unknown. In this study, we target the human cerebrospinal fluid (CSF) proteome, a little investigated aspect of SCS mechanism of action., Methods: Two different proteomic mass spectrometry protocols were used to analyze the CSF of 14 SCS responsive neuropathic pain patients. Each patient acted as his or her own control and protein content was compared when the stimulator was turned off for 48 hours, and after the stimulator had been used as normal for three weeks., Results: Eighty-six proteins were statistically significantly altered in the CSF of neuropathic pain patients using SCS, when comparing the stimulator off condition to the stimulator on condition. The top 12 of the altered proteins are involved in neuroprotection (clusterin, gelsolin, mimecan, angiotensinogen, secretogranin-1, amyloid beta A4 protein), synaptic plasticity/learning/memory (gelsolin, apolipoprotein C1, apolipoprotein E, contactin-1, neural cell adhesion molecule L1-like protein), nociceptive signaling (neurosecretory protein VGF), and immune regulation (dickkopf-related protein 3)., Conclusion: Previously unknown effects of SCS on levels of proteins involved in neuroprotection, nociceptive signaling, immune regulation, and synaptic plasticity are demonstrated. These findings, in the CSF of neuropathic pain patients, expand the picture of SCS effects on the neurochemical environment of the human spinal cord. An improved understanding of SCS mechanism may lead to new tracks of investigation and improved treatment strategies for neuropathic pain., (© 2016 International Neuromodulation Society.)

Neurological involvement in the form of meningitis or meningoencephalitis, although well documented in scrub typhus, has not been extensively studied in the pediatric population. We report the clinical and laboratory profile of 96 children with scrub typhus and compared those with and without meningitis. Twenty seven (28%) children had clinical and laboratory evidence of meningitis. The most frequent presenting features were fever (100%), meningeal signs (66.6%), nausea and vomiting (56.3%), seizures (55.5%) and altered sensorium (51.8%). The children with meningitis presented early and had significantly lower respiratory and renal impairments when compared with the non-meningitis group. Cerebrospinal fluid (CSF) analysis revealed elevated total leukocyte count (86.73 ± 94.50 cells/mm(3)), mononuclear pleocytosis (lymphocyte percentage of 76.85 ± 15.86), elevated proteins (108.33 ± 52.63 mg%) and normal CSF glucose (64.18 ± 15.92 mg%). We conclude that meningitis is a common and early complication of childhood scrub typhus. The CSF reveals a lymphocytic pleocytosis, raised proteins and a normal glucose level. These children respond promptly to appropriate antibiotics as do children without meningitis., (© The Author [2016]. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

The objective of this study was to develop and apply a novel multiplex panel of solid-phase proximity ligation assays (SP-PLA) requiring only 20 μL of samples, as a tool for discovering protein biomarkers for neurological disease and treatment thereof in cerebrospinal fluid (CSF). We applied the SP-PLA to samples from two sets of patients with poorly understood nervous system pathologies amyotrophic lateral sclerosis (ALS) and neuropathic pain, where patients were treated with spinal cord stimulation (SCS). Forty-seven inflammatory and neurotrophic proteins were measured in samples from 20 ALS patients and 15 neuropathic pain patients, and compared to normal concentrations in CSF from control individuals. Nineteen of the 47 proteins were detectable in more than 95% of the 72 controls. None of the 21 proteins detectable in CSF from neuropathic pain patients were significantly altered by SCS. The levels of the three proteins, follistatin, interleukin-1 alpha, and kallikrein-5 were all significantly reduced in the ALS group compared to age-matched controls. These results demonstrate the utility of purpose designed multiplex SP-PLA panels in CSF biomarker research for understanding neuropathological and neurotherapeutic mechanisms. The protein changes found in the CSF of ALS patients may be of diagnostic interest.

Analysis of the cerebrospinal fluid (CSF) proteome has proven valuable to the study of neurodegenerative disorders. To identify new protein/pathway alterations and candidate biomarkers for amyotrophic lateral sclerosis (ALS), we performed comparative proteomic profiling of CSF from sporadic ALS (sALS), healthy control (HC), and other neurological disease (OND) subjects using label-free liquid chromatography-tandem mass spectrometry (LC-MS/MS). A total of 1712 CSF proteins were detected and relatively quantified by spectral counting. Levels of several proteins with diverse biological functions were significantly altered in sALS samples. Enrichment analysis was used to link these alterations to biological pathways, which were predominantly related to inflammation, neuronal activity, and extracellular matrix regulation. We then used our CSF proteomic profiles to create a support vector machines classifier capable of discriminating training set ALS from non-ALS (HC and OND) samples. Four classifier proteins, WD repeat-containing protein 63, amyloid-like protein 1, SPARC-like protein 1, and cell adhesion molecule 3, were identified by feature selection and externally validated. The resultant classifier distinguished ALS from non-ALS samples with 83% sensitivity and 100% specificity in an independent test set. Collectively, our results illustrate the utility of CSF proteomic profiling for identifying ALS protein/pathway alterations and candidate disease biomarkers.

Background: Tuberculous meningitis is the most lethal form of tuberculosis, but current diagnostic methods are inadequate. The measurement of cerebrospinal fluid parameters can provide early information for diagnosis. The present study focus on the validity of the cut-off value of cerebrospinal fluid parameters according to the Lancet consensus of scoring system for diagnosis of tuberculous meningitis., Method: A total of 100 confirmed patients were enrolled in this study. We evaluated significance of protein level (>1 g/l), chloride level (<120 mmol/l), glucose level (<2.2 mmol/l), cell counts (10-500 cells/μl, lymphocytic pleocytosis (>50%), and neutrophil predominance (>50%) in early diagnosis of tuberculous meningitis., Result: The cerebrospinal fluid parameters were significantly different between the tuberculous meningitis group and the control group. The independent factors for diagnosis of tuberculous meningitis were protein level (>1 g/l), glucose level (<2.2 mmol/l), cell counts (10-500 cells/μl and neutrophil predominance >50%). Neutrophil predominance (>50%) performed the best with the area under the curve of 89.7%. The sensitivity of protein level (>1 g/l), glucose level (<2.2 mmol/l), cell counts (10-500 cells/μl) and neutrophil predominance (>50%) for diagnosis of tuberculous meningitis were 66%, 58%, 86%, and 54%, and the specificity were 84%, 98%, 32%, and 98%. There are 84% patients in tuberculous meningitis group at least having two positive parameters among the four independent parameters, while only 10% in control group., Conclusion: The cerebrospinal fluid parameters can help the clinicians to make a prompt diagnosis in the early stage of the disease., (© 2015 Wiley Periodicals, Inc.)

Tau protein is a phosphorylated microtubule-associated protein, principally localized at neuronal level in the central nervous system (CNS). Tau levels in the cerebrospinal fluid (CSF) are considered to index both axonal and neuronal damage. To date, however, no study has specifically evaluated the CSF levels of tau proteins in patients with status epilepticus (SE). We evaluated these established biomarkers of neuronal damage in patients with SE who received a lumbar puncture during SE between 2007 and 2014. Status epilepticus cases due to acute structural brain damage, including CNS infection, were excluded. Clinical, biological, therapeutic, and follow-up data were collected. Group comparison between patients stratified according to SE response to antiepileptic drugs (AEDs), disability, and epilepsy outcomes were performed. Twenty-eight patients were considered for the analyses (mean age 56 years): 14 patients had abnormally high CSF t-tau level, six patients had abnormally high CSF p-tau level, and only three patients had abnormally low Aβ1-42 level. Cerebrospinal fluid t-tau value was higher in patients who developed a refractory SE compared to patients with seizures controlled by AED. Cerebrospinal fluid t-tau values were positively correlated with SE duration and were higher in patients treated with propofol anesthesia compared to patients that had not received this treatment. Patients with higher CSF t-tau had higher risk of developing disability (OR = 32.5, p = 0.004) and chronic epilepsy (OR = 12; p = 0.016) in comparison with patients with lower CSF t-tau level. Our results suggest that CSF t-tau level might be proposed as a biomarker of SE severity and prognosis. Prospective studies are needed to evaluate the effects of propofol on tau pathology in this setting. This article is part of a Special Issue entitled "Status Epilepticus"., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Study Design: Prospective study., Objective: To identify proteins with differential expression in the cerebrospinal fluid (CSF) from 15 clinically normal (control) dogs and 15 dogs with cervical spondylomyelopathy (CSM)., Summary of Background Data: Canine CSM is a spontaneous, chronic, compressive cervical myelopathy similar to human cervical spondylotic myelopathy. There is a limited knowledge of the molecular mechanisms underlying these conditions. Differentially expressed CSF proteins may contribute with novel information about the disease pathogenesis in both dogs and humans., Methods: Protein separation was performed with 2-dimensional electrophoresis. A Student t test was used to detect significant differences between groups (P < 0.05). Three comparisons were made: (1) control versus CSM-affected dogs, (2) control versus non-corticosteroid-treated CSM-affected dogs, and (3) non-corticosteroid-treated CSM-affected versus corticosteroid-treated CSM-affected dogs. Protein spots exhibiting at least a statistically significant 1.25-fold change between groups were selected for subsequent identification with capillary-liquid chromatography tandem mass spectrometry., Results: A total of 96 spots had a significant average change of at least 1.25-fold in 1 of the 3 comparisons. Compared with the CSF of control dogs, CSM-affected dogs demonstrated increased CSF expression of 8 proteins including vitamin D-binding protein, gelsolin, creatine kinase B-type, angiotensinogen, α-2-HS-glycoprotein, SPARC (secreted protein, acidic, rich in cysteine), calsyntenin-1, and complement C3, and decreased expression of pigment epithelium-derived factor, prostaglandin-H2 D-isomerase, apolipoprotein E, and clusterin. In the CSF of CSM-affected dogs, corticosteroid treatment increased the expression of haptoglobin, transthyretin isoform 2, cystatin C-like, apolipoprotein E, and clusterin, and decreased the expression of angiotensinogen, α-2-HS-glycoprotein, and gelsolin., Conclusion: Many of the differentially expressed proteins are associated with damaged neural tissue, bone turnover, and/or compromised blood-spinal cord barrier. The knowledge of the protein changes that occur in CSM and upon corticosteroid treatment of CSM-affected patients will aid in further understanding the pathomechanisms underlying this disease., Level of Evidence: N/A.

Purpose: To evaluate a clinical observation that prepubertal children with idiopathic intracranial hypertension (IIH) have low cerebrospinal fluid (CSF) protein levels compared to healthy children and pubertal patients with IIH., Methods: The medical records of prepubertal and pubertal IIH patients and controls seen in the pediatric neuro-ophthalmology clinic at Duke between 2003 and 2013 were retrospectively reviewed. The control group consisted of children who had normal intracranial pressure on lumbar puncture performed to evaluate for headaches or anomalous-looking optic nerves. The records were analyzed with attention to demographic characteristics, clinical presentation, course, and lumbar puncture results., Results: A total of 23 prepubertal children with IIH (age range, 0.75-13 years), 16 pubertal patients with IIH (age range, 13-21 years), and 12 controls (age range 3-14 years) were included. CSF analysis revealed that prepubertal children with IIH had significantly lower CSF protein levels (17.3 ± 5.7 mg/dL) compared to pubertal subjects with IIH (23.4 ± 8.4 mg/dL; P = 0.019) or healthy controls (23.5 ± 6.4 mg/dL; P = 0.011). Furthermore, 9 of 23 prepubertal IIH patients (39%) had abnormally low CSF protein level (<15 mg/dL), compared to zero pubertal IIH patients (P = 0.005) and zero controls (P = 0.015). Acetazolamide increased CSF protein level in 100% of patients who underwent repeat lumbar puncture after starting the medication (average increase, 10.3 ± 6.6 mg/dL)., Conclusions: Low CSF protein level may have diagnostic utility as a biomarker for prepubertal IIH. Furthermore, this finding suggests that some cases of prepubertal IIH may be caused by CSF overproduction rather than decreased CSF resorption., (Copyright © 2015 American Association for Pediatric Ophthalmology and Strabismus. Published by Elsevier Inc. All rights reserved.)