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Purpose: Infantile epileptic spasms syndrome (IESS) with epileptic spasms as the main seizure type, is treated with adrenocorticotropic hormone (ACTH). This study, for the first time, examines the effects of epileptic spasms and ACTH on blood-brain barrier (BBB) permeability in patients with IESS of unknown etiology., Methods: We prospectively evaluated the changes in BBB permeability in patients with IESS of unknown etiology at the Saitama Children's Medical Center between February 2012 and February 2024. We compared the levels of serum-albumin, cerebrospinal fluid (CSF)-albumin, Q-albumin, and CSF-neuron-specific enolase (NSE) before and after ACTH therapy. We also assessed the correlation between the frequency of epileptic spasms and these markers., Results: Overall, 16 patients with IESS (8 males) were included in the study. The median age at IESS onset was 5 (range, 2-9) months. The median duration between the epileptic spasms onset and the serum and CSF sample examination before ACTH therapy was 26 (range, 1-154) days. After ACTH therapy, CSF-albumin and Q-albumin levels significantly decreased (CSF-albumin: 13.5 (9.0-32.0) mg/dL vs 11.0 (7.0-19.0) mg/dL, p = 0.001. Q-albumin: 3.7× 10 -3 (2.2 × 10 -3 -7.3 × 10 -3 ) vs 2.8× 10 -3 (1.9 × 10 -3 -4.5 × 10 -3 ), p = 0.003). No correlation was observed between the epileptic spasms frequency and levels of serum-albumin, CSF-albumin, Q-albumin, and CSF-NSE (Spearman's coefficient: r = 0.291, r = 0.141, r = 0.094, and r = -0.471, respectively)., Conclusion: ACTH therapy is one of the factors that play a role in restoring BBB permeability in patients with IESS of unknown etiology. Our findings may be useful in elucidating the mechanism of ACTH action and IESS pathophysiology., Competing Interests: Declaration of competing interest Shin-ichiro Hamano has received funds for speaker honoraria and travel from Eisai Co. Ltd., Daiichi Sankyo Co. Ltd., and UCB Japan Co. Ltd. Akira Oka has received funds for speaker honoraria and travel from Eisai Co. Ltd. and Nippon Shinyaku Co. Ltd. Kenjiro Kikuchi has received research funding from Syneos health clinical Co. Ltd. for clinical trial of Zogenix. The other authors have nothing to disclose conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Alterations in the CSF/serum albumin ratio (Qalb) is currently recognized as one of the most reliable markers of blood-brain barrier impairment and blood-CSF barrier permeability, but its potential role as a biomarker in the differential diagnosis of neurological diseases has been poorly analysed., Methods: We evaluated Qalb and core CSF biomarkers (Tau, p-Tau and Aβ42) in a large patient population of neurological and neurodegenerative cases. Diagnostic test evaluation was assessed by ROC-AUC analysis., Results: In the differential diagnostic analysis, increased Qalb was found in dementia with Lewy bodies (DLB) patients compared to other diseases, either individually or stratified in non-dementia and dementia groups. When clinical groups were analysed individually and compared to controls, Qalb was also increased in stroke and Parkinson's disease dementia (PDD) cases, but not in Parkinson's disease (PD). Qalb in DLB cases correlate with CSF Aβ42 levels but not with Tau and p-Tau levels. Due to the lower CSF Aβ42 levels in DLB compared to PD and PDD, the potential clinical applicability of Qalb with respect to the DLB diagnosis is increased in combination with CSF Aβ42 analysis., Conclusions: The present study demonstrates increased Qalb in synucleinopathies associated with dementia revealing a potential new clinical approach for the differential diagnosis of DLB., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: Neuromyelitis optica (NMO, Devic disease) is a severely disabling autoimmune disorder of the CNS, which was considered a subtype of multiple sclerosis (MS) for many decades. Recently, however, highly specific serum autoantibodies (termed NMO-IgG or AQP4-Ab) have been discovered in a subset (60-80%) of patients with NMO. These antibodies were subsequently shown to be directly involved in the pathogenesis of the condition. AQP4-Ab positive NMO is now considered an immunopathogenetically distinct disease in its own right. However, to date little is known about the cerebrospinal fluid (CSF) in AQP4-Ab positive NMO., Objective: To describe systematically the CSF profile of AQP4-Ab positive patients with NMO or its formes frustes, longitudinally extensive myelitis and optic neuritis., Material and Methods: Cytological and protein biochemical results from 211 lumbar punctures in 89 AQP4-Ab positive patients of mostly Caucasian origin with neuromyelitis optica spectrum disorders (NMOSD) were analysed retrospectively., Results: CSF-restricted oligoclonal IgG bands, a hallmark of MS, were absent in most patients. If present, intrathecal IgG (and, more rarely, IgM) synthesis was low, transient, and, importantly, restricted to acute relapses. CSF pleocytosis was present in around 50% of samples, was mainly mild (median, 19 cells/μl; range 6-380), and frequently included neutrophils, eosinophils, activated lymphocytes, and/or plasma cells. Albumin CSF/serum ratios, total protein and CSF L-lactate levels correlated significantly with disease activity as well as with the length of the spinal cord lesions in patients with acute myelitis. CSF findings differed significantly between patients with acute myelitis and patients with acute optic neuritis at the time of LP. Pleocytosis and blood CSF barrier dysfunction were also present during remission in some patients, possibly indicating sustained subclinical disease activity., Conclusion: AQP4-Ab positive NMOSD is characterized by CSF features that are distinct from those in MS. Our findings are important for the differential diagnosis of MS and NMOSD and add to our understanding of the immunopathogenesis of this devastating condition., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Background: Chemotherapeutic effects in leptomeningeal carcinomatosis (LC) vary widely between patients, presumably in part because drug elimination from cerebrospinal fluid (CSF) differs between individuals. An individual dosing, adapted to elimination, may improve treatment efficacy., Objective: To discuss the feasibility of easily accessible elimination parameters for an individual dosing of chemotherapy in LC., Materials and Methods: The elimination of intrathecally applied methotrexate (Mtx) was tested in 14 LC patients and compared to the literature data. Plasma drug levels and CSF albumin levels are suggested as elimination parameters., Results and Discussion: Mtx disappeared from CSF and appeared in plasma with an expected wide variation (interindividual range of coefficients of variation (CV) of CSF Mtx levels 158-189%, intraindividual range of CV of plasma Mtx levels 35-64%). Our data together with reported data suggest that plasma Mtx levels mirror closely the Mtx elimination from CSF. The levels of CSF albumin and of plasma Mtx at defined sample times correlated negatively (r=-0.7), which reflects their largely common elimination from CSF., Conclusion: Both parameters seem appropriate to describe the Mtx elimination from CSF. They should allow to individually adapt Mtx dosing towards an improvement of Mtx availability in CSF and of treatment efficacy.

Objectives: To estimate the mean influence of the main determinants of the cerebrospinal fluid (CSF) concentration of albumin and plasma-derived immunoglobulin G (IgG)., Methods: Correlations of serum and CSF concentrations of albumin and IgG and assumptions of the mode of action of the determinants (plasma concentration, barrier permeability, and CSF flow) are used to quantify the determinants' influences in a sample of 1700 patients., Results: We estimated in patients with normal CSF albumin that the serum concentrations of albumin and IgG explained 3.3% and 23% of the variation of the respective CSF concentrations, whereas the barrier permeability accounted for 41.9% and 22.2%, and CSF flow for 54.8%. In patients with pathologic CSF albumin concentration, the serum concentrations were estimated to explain 0.2% and 8.2% of the variation of the respective CSF concentrations, the barrier permeability 19.7% and 11.7%, and CSF flow 80.1%., Conclusions: CSF flow had the strongest mean influence, especially at elevated CSF albumin levels. The serum concentrations and barrier permeabilities of albumin and IgG influenced the respective CSF concentrations quite differently, which should be due to the different physicochemical properties of the two molecules. Mean influences from large patient samples, as explored here, can give only an overview. Understanding the determinants in individuals will need further specific measurements, especially of CSF flow.

Neuronal damage seems to be a major source of disability in multiple sclerosis (MS) patients and at present magnetic resonance imaging (MRI) is a sensitive method to evaluate lesion and disease activity. We studied the potential correlation between changes in MS patients' disability after relapse, the degree of T1 lesion hypointensity on MRI in vivo and neuronal apoptosis induced by cerebrospinal fluid (CSF) on neuron cultures. In this study, we included 24 MS patients with relapsing disease. Clinical recovery from relapse was measured by the Expanded Disability Status Scale (EDSS). T1-weighted MRI studies were done according to established standards and neuronal apoptosis was induced by treatment of neuronal cultures with CSF from patients while relapsing. Recovery after relapse is inversely correlated with neuronal apoptosis (r=-0.725, p<0.0001). A correlation was found between T1 lesion hypointensity and a poor recovery from relapse (r=0.656, p=0.0005) and such hypointensity correlated strongly with neuronal apoptosis (r=-0.779, p<0.0001). CSF from all patients with hypointense T1 lesions caused significantly increased neuronal apoptosis, whereas all CSF that did not induced such effects corresponded to patients without T1 lesions. The recovery from an acute MS relapse is significantly worse in patients with hypointense T1 lesions in MRI and in those whose CSF damaged neurons on cultures in vitro, phenomena that closely correlated each other.

Diagnosis of central nervous system (CNS) involvement in sleeping sickness is crucial in order to give an appropriate treatment regimen. Neurological symptoms occur late, therefore field diagnosis is based on white blood cell count, total protein concentration and presence of trypanosomes in cerebrospinal fluid (CSF). More sensitive and specific parameters are now available. Blood-CSF barrier (B-CSFB) dysfunction, intrathecal total and specific immunoglobulin synthesis were evaluated in 95 patients with and without obvious meningoencephalitis, and compared to field criteria.B-CSFB dysfunction is a rather late event in the course of CNS involvement and correlates with the presence of trypanosomes, neurological signs and intrathecal polyspecific and specific immune response. IgM intrathecal response and particularly IgM antibody index are early markers of CNS invasion. We showed that 29% of patients with CSF abnormalities but without trypanosome detection in the field had no neuro-immunological response. In contrast, patients with normal CSF according to field diagnosis showed an intrathecal immune response in 31% of the cases.Field diagnosis can therefore fail to determine neurological involvement but can also provide false positive results. Improved criteria including B-CSFB dysfunction and IgM detection are needed in order to provide an adapted treatment regimen.

Cerebrospinal fluid (CSF) analysis is a basic tool for diagnosis of neurological diseases. Knowledge regarding blood-CSF barrier function (molecular flux/CSF flow theory) and neuroimmunology is reviewed to aid understanding and evaluation of CSF data. Disease-related immunoglobulin patterns (IgG, IgA, IgM with reference to albumin) are described in CSF/serum quotient diagrams with the hyperbolic reference range for blood-derived protein fractions in CSF. Clinical relevance of complementary analyses (cytology, PCR, oligoclonal IgG, antibody detection and brain-derived proteins) is briefly discussed. Integrated CSF data reports are shown with numerical and graphical data representation, reference range-related interpretation and diagnosis-related comments. The principles and rationale of general CSF analysis reported in this review should enable the reader to accurately interpret CSF data profiles, and to plan a proper evaluation of new brain- or blood-derived analytes in CSF.

Paired serum and cerebrospinal fluid (CSF) specimens from 17 patients with Behçet's disease and central nervous system (CNS) involvement (neuro-Behçet's syndrome; NB) were studied for beta(2)-microglobulin (beta(2)MG) and albumin, using ELISA and single radial immunodiffusion, respectively. We also studied 29 patients with non-inflammatory neurological diseases for comparison. All of CSF beta(2)MG, serum beta(2)MG, Q albumin (an indicator of blood-brain barrier function), and CSF beta(2)MG index (an indicator of intrathecal beta(2)MG synthesis) were significantly elevated in patients with NB compared with the control patients. There were no significant differences in these parameters between 11 patients with chronic NB and six patients with acute NB. In nine patients with NB, CSF beta(2)MG and Q albumin were significantly decreased when the CNS manifestations were improved by successful treatment, whereas CSF beta(2)MG index and serum beta(2)MG were not significantly changed. The results indicate that the elevation of CSF beta(2)MG, which results from the transudation of serum beta(2)MG as well as the increased intrathecal synthesis presumably by infiltrating lymphocytes, is a good marker of CNS disease activity of NB. The data, however, also suggest that the intrathecal synthesis of beta(2)MG might not parallel to the CNS disease activity of NB, most likely due to the recovery of constitutive physiological intrathecal synthesis of beta(2)MG in spite of the withdrawal of pathological beta(2)MG synthesis at times of treatment-associated improvement.

Laser nephelometry (LN) is a rapid and very sensitive method for simultaneous determination of albumin, immunoglobulins, C3c and C4 in diluted serum and paired cerebrospinal fluid (CSF) samples. It is very useful in routine analyses. Determination of C3c and C4 covers classical as well as alternative pathways of complement activation. In CSF, they are mostly derived from and related to serum values. Under physiological conditions, the addition of intrathecal C4 synthesis is likely. The incidence of complement activation within CSF is also influenced by the method of choice (native molecules, activation products and complexes, inhibitors) and the mode of interpretation of results according to the functional state of the blood-brain barrier (BBB). Calculation of indexes and the modified Reiber's graph method are valid means of detection of complement activation within CSF. Complement activation within CSF was confirmed in 36% (111/302) of neurological patients examined; in 55% (48/87) of patients with inflammatory and demyelinating diseases, in 40% (37/94) of patients with CNS infections and complications, in 33% (4/12) of patients with motor neuron diseases, in 27% (11/40) of patients with spinal cord compression and sequelae, in 25% (8/32) of patients with neoplastic disease, and in 17% (6/37) of patients with cerebrovascular accidents.

Cerebrospinal fluid and serum levels of albumin, immunoglobulin G and alpha 2-macroglobulin were determined by laser nephelometer in various pathological conditions: Guillain-Barré syndrome amyotrophic lateral sclerosis, lumbar disc herniation. These proteins are different due to their molecular weight, spacial conformation, CSF and serum concentrations and their CSF/serum quotient reflects the status of the blood-brain barrier. In the subjects group comparisons, albumin quotient and IgG quotient show a significant differentiations. The linear regression of albumin quotient compared to alpha 2-macroglobulin quotient behaves differently in the individual groups. The protein CSF/serum quotients are helpful in distinguishing the causes of alterations in the blood-brain barrier.

Cerebrospinal fluid (CSF) from patients suffering from senile dementia (SD) and multiinfarct dementia (MID) was fractionated into CSF-specific and antigenically serum-like proteins, using affinity chromatography with antihuman serum antibodies. The samples were isoelectric focused. Protein patterns were compared to similarly treated CSF from patients suffering from transient ischemic attacks (TIA), or normal volunteers. Characteristic changes were found in the CSF-specific protein pattern from SD patients.

Plasma and cerebrospinal fluid (CSF) from 20 patients with Alzheimer's dementia or senile dementia of Alzheimer type (AD/SDAT), 23 with multi-infarct dementia (MID) and 16 controls were assayed for their content of immunoglobulins (Ig) and albumin (Alb). The concentrations of IgG and Alb were used to analyze the blood-CSF barrier function in the respective group. MID patients had significantly (P less than 0.001) elevated plasma IgG levels compared to controls and AD/SDAT patients. CSF concentration of Alb was significantly higher in MID (P less than 0.01) and AD/SDAT (P less than 0.05) patients compared to the controls. Concentration of CSF IgG was significantly (P less than 0.05) lower in AD/SDAT patients compared to the MID patients; no significant differences were found when CSF concentrations of IgG of demented patients were compared to controls. These findings may indicate a blood-CSF barrier dysfunction especially in cases with MID with significantly (P less than 0.001) elevated values of transudation. Also these findings indicate a non-specific and/or specific binding of IgG in CNS tissue and/or vessel walls in both forms of dementia on the basis of low IgG ratios compared to proportionally higher Alb ratios. There were no signs of local synthesis of IgG in CNS in either group of demented patients.

The lead content of cerebrospinal fluid (CSF) was found to be significantly elevated in 12 patients with amyotrophic lateral sclerosis, when compared to 28 control subjects having non-degenerative neurological disorders. The difference could not be explained as being merely secondary to blood-CSF barrier damage. A hypothetical model of the pathogenesis of the disease is advanced and the results are discussed in relation to this model.

Polyacrylamide-gel disc electrophoresis has been applied to the fractionation of CSF samples obtained from 2m control subjects (range of age 16 to 77 yr, mean 41.0 yr) and from 157 patients with various neurological diseases, with the purpose of evaluating the diagnostic significance of separated protein bands. It was found that the immunoglobulins, with some exceptions, were fractionated in the G-zone which was defined as an area between the origin and 0.57 in terms of relative migration based on transferrin (RT). Fourty-four percent of the whole Bence Jones protein bands which were examined were detected in the area of RT 0.70-0.90. The normal values of CSF protein fractions were (means+/-SD):Pre-alb-zone, 10.97+/-2.31%; Alb-zone, 40.74+/-5.72%; A1-zone, 5.25+/-0.72%; A2-zone, 8.23+/-1.24%; B1-zone, 10.82+/-2.18%. B2-zone, 7.94+/-1.93%; G-zone, 16.05+/-2.49%. The following significant results were obtained: (1) When the total protein concentration (TP) of CSF is increased: the percentage of the Pre-alb-zone is lowered and that of the A1- and G-zones is increased in diseases such as neurosyphilis, infectious meningitis, brain tumour, multiple sclerosis, intervertebral disc protrusion and cerebral infarction. The A2-zone was diminished in cerebral infarction, and a similar change was seen in brain tumour with in addition a decrease of the B2-zone; (2) When the TP was normal: the percentage of the G-zone was increased in multiple sclerosis, brain tumour and intervertebral disc protrusion. In the latter 2 disorders the A1-zone also increased. This fraction also increased in the cases of cerebral infarction, whose mean age was, however, much higher than that of the control subjects.

Albumin and IgG have been determined in the serum and cerebrospinal fluid (CSF) of 64 patients affected by Alzheimer's disease and senile dementia of Alzheimer type (SDAT/AD), 17 multi-infarct dementia (MID) patients and 52 controls. The concentrations of albumin and IgG in the serum and CSF have been taken into account to evaluate the integrity of the blood-brain barrier (BBB) and the occurrence of intrathecal immunological activation in demented patients. Clear-cut signs of BBB damage have been shown only in the group of patients affected by MID, whilst none of the two groups of patients displayed signs of immunological activation, expressed by an increase in IgG index, nor abnormally low CSF/serum ratios for IgG, previously suggested as expressive of a "consumption" of IgG by the brain parenchyma.

The cerebrospinal fluid and serum proteins from 32 healthy individuals have been examined by isoelectric focusing in a pH-gradient from 3.5--11.0. Seventeen normal proteins have been identified by means of crossed immunoelectrofocusing. The pI-values of the main fractions of these proteins have been determined. On crossed immunoelectrofocusing microheterogeneity was observed for all of the proteins except haemopexin, gamma-trace protein of CSF and prealbumin of serum. Differences between serum and CSF were observed for 6 of the proteins. Prealbumin of CSF had a lower pI-value than in serum and showed partial immunological identity with prealbumin of serum. Transferrin of CSF included several components with lower sialic acid contents than in serum. The conversion of C'3-complement from beta-1-C to beta 1-A was slower in CSF than in serum. Qualitative differences between CSF and serum were also noticed for alpha2-macroglobulin and haptoglobin. IgM was not detected in CSF. In CSF the gamma-trace protein was found on isoelectric focusing in one third of the subjects. Two subjects had 2 close tau-fractions and another two had one unidentified band in the anodal IgG-area. The gamma-trace protein did not show any proteolytic activity, nor any resemblance in charge to 4 basic enzymes or with the histones tested.

Cerebrospinal fluid (CSF) was studied in 2 cases of Devic's syndrome (DS). In one of these cases autopsy was carried out. The main CSF feature in DS is the association of blood-brain barrier damage and intrathecal IgG synthesis. These findings are in keeping with our neuropathological observation of diffuse central nervous system vasculitis and leptomeningitis. As a whole, our CSF and neuropathological findings in DS are consistently different from those in multiple sclerosis.

128 cerebrospinal fluid samples were obtained. About 5 mul of each of the samples was subjected unconcentrated to agar gel electrophoresis. The remaining 44 of these samples were concentrated and the concentrates were electrophoresed. The proteins were stained. Analysis of the relative mobilities of the peaks makes two conclusions possible: the albumin in cerebrospinal fluid has the same electrophoretic mobility as purified serum albumin. The tau-protein possibly arises from transferrin by proteolytic breakdown, some products (such as the classical tau-protein) being less unstable than others (the intermediate peaks).

To assess signs of immunoactivation within the central nervous system in myasthenia gravis (MG) we examined the cerebrospinal fluid (CSF) of 44 MG patients for certain immunological parameters. Altogether 73% of the patients had some protein and/or cellular abnormality in their CSF. 22 (50%) out of 44 patients had a lymphoid reaction, i.e. a pathologically elevated proportion of enlarged lymphoid cells, in their CSF. In 15 (37.5%) out of 40 patients an enrichment of anti-acetylcholine receptor antibodies in the CSF was observed in relation to serum antibodies. Our findings suggest involvement of the central nervous system in many myasthenia gravis patients.