Development of a strategy for assessing blood-brain barrier disruption using serum S100 calcium-binding protein B and neuron-specific enolase in early stage of neuroemergencies: A preliminary study.

BACKGROUND: Rapid disease progression in neuroemergencies is associated with blood-brain barrier (BBB) disruption. We investigated a less invasive strategy for assessing BBB status by evaluating S100 calcium-binding protein B (S100B) and neuron-specific enolase (NSE) at early stages of the hypoxic-ischemic brain injury (HIBI) cascade. METHODS: This retrospective study used prospectively collected data from patients with out-of-hospital cardiac arrest (August 2019-July 2021). Albumin specimens obtained from serum and cerebrospinal fluid via arterial catheter and lumbar puncture were used to measure the albumin quotient (Qa), which is widely accepted as the gold standard method for detecting BBB disruption. Serum S100B and NSE levels were measured simultaneously following the return of spontaneous circulation. We conducted linear regression to evaluate the relationship between S100B and Qa and the predictive performance of S100B for abnormal Qa. The primary study outcome was abnormal Qa (>0.007). RESULTS: Forty-one patients were enrolled; 30 showed an abnormal Qa suggestive of BBB disruption. S100B levels were significantly higher than in those with a normal Qa (0.244 µg/L [interquartile range [IQR], 0.146-0.823 vs 0.754 µg/L [IQR, 0.317-2.228], P = .03). We report a positive correlation between serum S100B and Qa (R2 = 0.110; P = .04). The area under the receiver operating characteristics curve (AUROC) evaluating the predictive performance of S100B with respect to abnormal Qa was 0.718 (95% confidence interval, 0.556-0.847). The cutoff value for S100B (with respect to BBB disruption) in the total cohort was 0.283 µg/L (sensitivity, 80.0%; specificity, 72.7%). Subgroup analyses in patients with serum neuron-specific enolase (NSE) levels of <40.8 ng/mL (excluding those with established neuronal cell injury) showed an improved correlation coefficient (R2 = 0.382; P < .01) and predictive performance (AUROC, 0.836 [95% confidence interval, 0.629-0.954]) compared with the total cohort. CONCLUSIONS: Serum S100B obtained at an early stage of the HIBI cascade is associated with abnormal Qa, suggesting BBB disruption. The predictive performance of S100B and the correlation between serum S100B and Qa can be improved using a complementary strategy (i.e., evaluations of S100B and NSE levels) that combines considerations of cell damage in astrocytes and neurons.

Blood-brain barrier disruption as a cause of various serum neuron-specific enolase cut-off values for neurological prognosis in cardiac arrest patients.

We compared the cut-off and prognostic value of serum neuron-specific enolase (NSE) between groups with and without severe blood-brain barrier (BBB) disruption to reveal that a cause of various serum NSE cut-off value for neurological prognosis is severe BBB disruption in out-of-hospital cardiac arrest (OHCA) patients underwent target temperature management (TTM). This was a prospective, single-centre study conducted from January 2019 to June 2021. Severe BBB disruption was indicated using cerebrospinal fluid-serum albumin quotient values > 0.02. The area under the receiver operating characteristic curve of serum NSE obtained on day 3 of hospitalisation to predict poor outcomes was used. In patients with poor neurologic outcomes, serum NSE in those with severe BBB disruption was higher than in those without (P = 0.006). A serum NSE cut-off value of 40.4 µg/L for poor outcomes in patients without severe BBB disruption had a sensitivity of 41.7% and a specificity of 96.0%, whereas a cut-off value of 34.6 µg/L in those with severe BBB disruption had a sensitivity of 86.4% and a specificity of 100.0%. We demonstrated that the cut-off and prognostic value of serum NSE were heterogeneous, depending on severe BBB disruption in OHCA patients treated with TTM.

Cross-Sectional Characterization of Albumin Glycation State in Cerebrospinal Fluid and Plasma from Alzheimer's Disease Patients.

We determined albumin post-translational modifications (PTMs) by mass spectrometry (MS) in plasma and cerebrospinal fluid (CSF) from 31 Alzheimer's disease (AD) patients (with 27 samples of paired plasma-CSF from the same patients). Results were cross-sectionally compared with healthy controls. For percentage of relative intensity of glycated isoforms, plasma albumin was globally more glycated in AD patients than in healthy controls (P<0.01). MS results in plasma were confirmed by a quantitative enzymatic assay (Lucica GA-L) for albumin early-glycation detection. In CSF there were no global glycation differences detected by MS, although a different pattern of glycated isoforms was observed. Oxidized+glycated and cysteinylated+glycated isoforms were increased in both plasma and CSF of AD patients in comparison with healthy controls (P<0.001). Furthermore, AD patients showed higher glycation in plasma than in CSF (P<0.01). Our data support the role of glycation and oxidative stress in AD.

Correlation between vancomycin penetration into cerebrospinal fluid and protein concentration in cerebrospinal fluid/serum albumin ratio.

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.

Oxidative stress in the choroid plexus contributes to blood-cerebrospinal fluid barrier disruption during sepsis development.

BACKGROUND: The choroid plexus (CP), main component of blood-cerebrospinal fluid barrier (BCSFB), protects the brain from peripheral inflammation similar to the blood-brain barrier. Thus, CP is considered a critical target site of oxidative damage, which in sepsis oxidative stress is likely to be a major step in the development of brain damage. Functional alterations in CP may be associated with sepsis-induced brain injury. However, there is no description on the mechanisms associated with BCSFB disruption during sepsis development. MATERIALS AND METHODS: To test this hypothesis, we examined time-dependent oxidative stress markers in CP and permeability of BCSFB in rats submitted to polymicrobial sepsis by cecal ligation and puncture (CLP) or sham surgery (control). We assessed albumin cerebrospinal fluid/plasma concentration quotient (Qalb), an index of BCSFB dysfunction and in CP samples, the oxidative damage in lipids, proteins, antioxidant enzymes and nitrite/nitrate (N/N) concentration in 12, 24 and 48 h after CLP. RESULTS: The increase of BCSFB permeability is time-related to the increase of N/N concentration, oxidative damage to lipid and proteins, and decrease of antioxidant enzyme superoxide dismutase activity at 12 h in the CP; and decrease of catalase activity in 12 and 24 h. CONCLUSIONS: In experimental sepsis the BCSFB dysfunction occurs and oxidative stress seems to be a major step in this dysfunction.

Cerebrospinal fluid and serum levels of interleukin-8 in patients with multiple sclerosis and its correlation with Q-albumin.

INTRODUCTION: Multiple sclerosis (MS) is an inflammatory-demyelinating disease of the central nervous system (CNS). Autoimmune inflammation is common in the early stages of MS and is followed by neurodegenerative processes. The result of these changes is axon and myelin breakdown. The paraclinical examination methods are an important part of the diagnostic process. Magnetic resonance imaging of the brain and the cervical spinal cord and an examination of cerebrospinal fluid (CSF) are common paraclinical examinations. An increasing number of studies deal with CSF and serum levels of biomarkers and their role in MS. We hypothesized that the level of interleukin-8 (IL-8) could be different in MS patients than in controls. These differences may be related to damage of the blood-brain barrier (BBB). BBB damage is quantified by the quotient of albumin (Q-alb). METHODS: CSF and serum levels of IL-8 were assessed in 102 patients with newly diagnosed MS meeting McDonald's revised diagnostic criteria and in 102 subjects as a control group. We then correlated these results with Q-alb. RESULTS: Levels of IL-8 in CSF were significantly higher in MS patients than in controls (Mann-Whitney U test, p<0.0001). Serum levels of IL-8 were significantly lower in MS patients than in controls (Mann-Whitney U test, p=0.018). Spearman's correlation analysis proved a significant correlation between levels of IL-8 and Q-alb. CONCLUSION: As the etiology of MS is only partially known, research dealing with biomarkers in MS should continue. Better knowledge of etiology can provide a new perspective, especially for treatment.

Blood-CSF-barrier dysfunction is a marker for encephalitic involvement in patients with aseptic meningitis/meningoencephalitis.

BACKGROUND: The term "aseptic meningitis" encompasses cases of meningitis with negative bacterial CSF culture, which predominantly are of viral etiology. While the clinical course is usually benign, complications such as encephalitic involvement resulting in a more severe clinical course may occur. Dysfunction of the blood-brain-barrier (BBB), which is a prerequisite for viral entry into the brain parenchyma, can be approximated using the CSF/serum albumin ratio, readily obtainable in routine CSF analysis. OBJECITVES: Analysis of CSF patterns in patients with aseptic meningitis/meningoencephalitis with a focus on BBB dysfunction as a marker for encephalitic involvement. STUDY DESIGN: Retrospective chart review of patients admitted to our hospital between 2004 and 2016 with a diagnosis of aseptic meningitis/meningoencephalitis. RESULTS: Patients with aseptic meningitis displaying clinical, MR-tomographic or electroencephalographic signs of encephalitic involvement were significantly older than patients without these features (47.4 vs. 35.5 yrs., p=0.002). In patients with meningoencephalitis, CSF analysis revealed a more severe disruption of BBB, approximated by the CSF/serum albumin ratio (p=0.002). Compromised BBB function correlated positively with length of hospitalization (p=0.007), indicative of a more severe clinical course. The number of CSF lymphocytes was found to predict the severity of the BBB disruption, which additionally was more frequently observed when herpesviridae were identified as infectious agents. CONCLUSIONS: We suggest that the CSF/serum albumin ratio as an estimate for BBB function should be attended to in the evaluation of patients with aseptic meningitis. Severe BBB dysfunction, older age and infection with herpesviridae appear to raise the risk for encephalitic involvement.

Blood-Cerebrospinal Fluid Barrier Integrity in Delirium Determined by Q-Albumin.

BACKGROUND/AIMS: Delirium is a common and serious complication in hospitalised patients and its pathophysiology is incompletely understood. We aimed to examine whether blood-cerebrospinal fluid barrier dysfunction, as measured by Q-albumin (the ratio of cerebrospinal fluid albumin to serum albumin), was associated with delirium. METHODS: In this prospective cohort study of hip fracture patients from Oslo University Hospital, Norway, serum was collected preoperatively and cerebrospinal fluid just before the onset of spinal anaesthesia. Albumin levels in serum and cerebrospinal fluid were analysed consecutively, and Q-albumin was calculated using the formula [cerebrospinal fluid albumin (mg/dl) × 1,000]/[serum albumin (mg/dl)]. Q-albumin >10.2 was used as the cut-off for blood-cerebrospinal fluid barrier dysfunction. Patients were assessed daily for delirium using the Confusion Assessment Method. RESULTS: Out of 120 patients, 69 had delirium, 22 had subsyndromal delirium, and 29 were free from delirium. The majority of patients, i.e. 106 (88%), had intact blood-cerebrospinal fluid barrier integrity, but all 14 patients with blood-cerebrospinal barrier dysfunction had delirium (n = 11) or subsyndromal delirium (n = 3). CONCLUSIONS: The results suggest that blood-cerebrospinal fluid barrier dysfunction may be relevant for delirium pathophysiology when it occurs. However, the low prevalence (16% of delirium patients) indicates that this is not a prerequisite for the development of delirium.

Upper reference limits for cerebrospinal fluid total protein and albumin quotient based on a large cohort of control patients: implications for increased clinical specificity.

BACKGROUND: Determination of cerebrospinal fluid (CSF) total protein (TP) as well as of CSF/serum albumin quotient (Qalb) is part of the routine CSF work-up. However, currently used upper reference limits (URL) are not well validated leading to over-reporting of blood-CSF barrier dysfunction in approximately 15% of patients without neurological disease. The objective of this study was to determine age-related URL for CSF TP and Qalb in a cohort of control patients. METHODS: A total of 332 paired CSF and serum samples of patients without objective clinical and paraclinical findings of a neurological disease were analyzed for CSF TP and Qalb. CSF TP was measured by spectrophotometry and albumin in CSF and serum by nephelometry. RESULTS: CSF TP concentration and Qalb significantly correlated with age. In subjects at the age of 18-70 years, median CSF TP ranged from 320 to 460 mg/L and URL defined as the 95th percentile were 530-690 mg/L. Median Qalb ranged from 4.1 to 6.1 and URL from 8.7 up to 11.0. For URL of Qalb we calculated the following formula: age/25+8. CONCLUSIONS: Age-dependent URL for CSF TP and Qalb are presented here in a large cohort of control patients. They are higher than those currently recommended and this probably explains why isolated blood-CSF barrier dysfunction has been apparently over-reported. These new URL might be considered in a future revision of CSF guidelines.

Cellular specificity of the blood-CSF barrier for albumin transfer across the choroid plexus epithelium.

To maintain the precise internal milieu of the mammalian central nervous system, well-controlled transfer of molecules from periphery into brain is required. Recently the soluble and cell-surface albumin-binding glycoprotein SPARC (secreted protein acidic and rich in cysteine) has been implicated in albumin transport into developing brain, however the exact mechanism remains unknown. We postulate that SPARC is a docking site for albumin, mediating its uptake and transfer by choroid plexus epithelial cells from blood into cerebrospinal fluid (CSF). We used in vivo physiological measurements of transfer of endogenous (mouse) and exogenous (human) albumins, in situ Proximity Ligation Assay (in situ PLA), and qRT-PCR experiments to examine the cellular mechanism mediating protein transfer across the blood-CSF interface. We report that at all developmental stages mouse albumin and SPARC gave positive signals with in situ PLAs in plasma, CSF and within individual plexus cells suggesting a possible molecular interaction. In contrast, in situ PLA experiments in brain sections from mice injected with human albumin showed positive signals for human albumin in the vascular compartment that were only rarely identifiable within choroid plexus cells and only at older ages. Concentrations of both endogenous mouse albumin and exogenous (intraperitoneally injected) human albumin were estimated in plasma and CSF and expressed as CSF/plasma concentration ratios. Human albumin was not transferred through the mouse blood-CSF barrier to the same extent as endogenous mouse albumin, confirming results from in situ PLA. During postnatal development Sparc gene expression was higher in early postnatal ages than in the adult and changed in response to altered levels of albumin in blood plasma in a differential and developmentally regulated manner. Here we propose a possible cellular route and mechanism by which albumin is transferred from blood into CSF across a sub-population of specialised choroid plexus epithelial cells.

Blood-cerebrospinal fluid barrier dysfunction in patients with bipolar disorder in relation to antipsychotic treatment.

Blood-cerebrospinal barrier (BCB) dysfunction has previously been shown in subjects with schizophrenia and depressed patients with attempted suicide. Bipolar disorder (BPD) shares clinical features with both these disorders, but it is unknown if the integrity of the BCB is altered also in BPD. To assess if BCB function in BPD we surveyed 134 mood-stabilized BPD patients and 86 healthy controls. Serum and cerebrospinal fluid (CSF) samples were collected and analyzed for albumin concentration by immunonephelometry. CSF/serum albumin ratio, an established measure of BCB function, was significantly elevated in BPD patients as compared to controls. After stratifying patients according to diagnostic subtype, BPD I patients had the highest CSF/serum albumin ratios. Moreover, BPD patients on antipsychotic treatment had higher CSF/serum albumin ratio than BPD patients on other treatments. When excluding BPD patients on antipsychotic treatment the difference in CSF/serum albumin ratio between the BPD and control groups disappeared. In conclusion, antipsychotic treatment in BPD is associated with elevated CSF/serum albumin ratio, tentatively as a sign of impaired BCB function. Whether this elevation is caused by antipsychotic treatment or is associated with a certain subtype of BPD, requiring antipsychotic treatment, remains to be determined.

Multi-wavelength spectrophotometric analysis for detection of xanthochromia in cerebrospinal fluid and accuracy for the diagnosis of subarachnoid hemorrhage.

BACKGROUND: Cerebrospinal fluid (CSF) was examined for bilirubin, an important indicator for diagnosis of subarachnoid hemorrhage (SAH). METHODS: A multi-wavelength (340, 415, and 460 nm) spectrophotometric assay was developed for the quantitative measurement of bilirubin in CSF, enabling the mathematical correction for absorbance of hemoglobin and proteins. Bilirubin and hemoglobin results were correlated to HPLC and a standard colorimetric assay, respectively. A subset of samples was sent for an absorbance reading at 450 nm following baseline correction. The multi-wavelength bilirubin assay was validated on 70 patients with confirmed SAH and 70 patients with neurologic symptoms who ruled out for SAH. RESULTS: The multi-wavelength spectrophometric assay demonstrated no interferences due to proteins (albumin) up to 30 g/l or oxyhemoglobin up to 260 mg/l. The assay limit of detection was 0.2 mg/l, linear to 20 mg/l, and CVs ranged from 1 to 6% at bilirubin concentrations of 0.84 and 2.1mg/l. The spectrophotometric assay correlated to HPLC and the colorimetric assay for bilirubin and hemoglobin, respectively. Results also correlated to the absorbance method (with removal of samples with high hemoglobin and proteins). The area under the ROC curve for diagnosis of SAH was 0.971 and 0.954 for the HPLC and spectrophotometric assay, respectively. At a cutoff of 0.2mg/l, the clinical specificity was 100% for both assays, and the clinical sensitivity was 94.3% and 88.6% for SAH for the HPLC and spectrophotometric asays, respectively. CONCLUSIONS: The multi-wavelength spectrophotometric assay is an objective alternative to visual inspection, HPLC, and absorbance for CSF bilirubin.

Albumin heterogeneity in low-abundance fluids. The case of urine and cerebro-spinal fluid.

BACKGROUND: Serum albumin is a micro-heterogeneous protein composed of at least 40 isoforms. Its heterogeneity is even more pronounced in biological fluids other than serum, the major being urine and cerebrospinal fluid. Modification 'in situ' and/or selectivity of biological barriers, such as in the kidney, determines the final composition of albumin and may help in definition of inflammatory states. SCOPE OF REVIEW: This review focuses on various aspects of albumin heterogeneity in low 'abundance fluids' and highlights the potential source of information in diseases. MAJOR CONCLUSIONS: The electrical charge of the protein in urine and CSF is modified but with an opposite change and depending on clinical conditions. In normal urine, the bulk of albumin is more anionic than in serum for the presence of ten times more fatty acids that introduce equivalent anionic charges and modify hydrophobicity of the protein. At the same time, urinary albumin is more glycosylated compared to the serum homolog. Finally, albumin fragments can be detected in urine in patients with proteinuria. For albumin in CSF, we lack information relative to normal conditions since ethical problems do not allow normal CSF to be studied. In multiple sclerosis, the albumin charge in CSF is more cationic than in serum, this change possibly involving structural anomalies or small molecules bindings. GENERAL SIGNIFICANCE: Massively fatty albumin could be toxic for tubular cells and be eliminated on this basis. Renal handling of glycosylated albumin can alter the normal equilibrium of filtration/reabsorption and trigger mechanisms leading to glomerulosclerosis and tubulo-interstitial fibrosis. This article is part of a Special Issue entitled Serum Albumin.

Blood-brain barrier disruption is more severe in neuromyelitis optica than in multiple sclerosis and correlates with clinical disability.

OBJECTIVES: This study evaluated blood-brain barrier (BBB) integrity, using blood and cerebrospinal fluid (CSF) markers, and assessed the practicality of these markers in the differential diagnosis of neuromyelitis optica (NMO) and multiple sclerosis (MS). METHODS: This was a retrospective observational study of consecutive patients presenting with acute phase NMO or MS (first attack or relapse). Haematological tests (including antiaquaporin-4 antibody levels) and CSF parameters (using primary component analyses) were undertaken; the correlation between BBB permeability and disease severity (by Expanded Disability Status Scale [EDSS] score) was examined. RESULTS: Levels of several markers of BBB permeability were higher in patients with NMO (n=21) than in those with MS (n=52). The CSF:serum albumin ratio (AR) was the one of the main differentiators of NMO and MS. Additionally, there was a significant correlation between AR and clinical severity for NMO but not for MS. CONCLUSIONS: Markers of BBB permeability were significantly higher in NMO patients than in MS patients. AR was the best marker for differentiating NMO and MS. Thus, measurement of BBB disruption markers (such as AR) might help to differentiate the diagnosis of NMO and MS in acute clinical settings.

Identification of oxidized serum albumin in the cerebrospinal fluid of ischaemic stroke patients.

BACKGROUND AND PURPOSE: Extensive evidence has shown that oxidative stress mediates neuronal death in animal models of hypoxic-ischaemia. Brain biomarkers of oxidative stress need to be identified in order to better understand and treat brain damage in human stroke patients. The present study was conducted to identify potential target proteins of oxidative stress in the cerebrospinal fluid (CSF) of stroke patients with acute ischaemic brain injury. METHODS: We performed two-dimensional polyacrylamide gel electrophoresis to separate protein samples obtained from the CSF of control and stroke patients. To determine protein oxidation levels, oxyblot was then used to detect protein carbonyls that were determined by formation of a stable 2,4-dinitrophenylhydrazine (DNP) product using an anti-DNP antibody. RESULTS: We found that oxidation of serum albumin was increased in the CSF from stroke patients as well as rats who underwent permanent middle cerebral artery occlusion (6.5%, 23%, respectively). In stroke patients, oxidized albumin levels correlated to neurologic indications. CONCLUSIONS: The present study suggests that oxidized albumin in CSF can be utilized as an oxidative stress marker in human stroke patients.

Cardiopulmonary bypass increases permeability of the blood-cerebrospinal fluid barrier.

BACKGROUND: The integrity of the blood-cerebrospinal fluid (CSF) barrier during cardiopulmonary bypass (CPB) with hypothermic circulatory arrest (HCA) has not been systematically studied, especially in children. We tested the hypothesis that the blood-CSF barrier is disrupted by CPB. METHODS: The study randomized 25 piglets (mean weight, 11 kg) to five groups (5 per group): anesthesia alone (control); CPB at 37 degrees C with full-flow (FF); CPB at 25 degrees C with very low flow (LF); and HCA at 15 degrees C and 25 degrees C. pH-stat strategy was applied during CPB. An epidural catheter was inserted into the cisterna magna for collection of CSF. CSF and blood samples were collected at seven points: after induction of anesthesia (baseline), at 10, 50 and 115 minutes after start of CPB, just before the end of CPB, and at 30 and 120 minutes after CPB. Albumin levels in CSF and plasma were measured to assess blood-CSF barrier integrity and the albumin ratio (CSF/plasma) was calculated (Q(Alb)). RESULTS: In both HCA groups, the Q(Alb) was significantly higher than in the control and 37 degrees C FF groups (all p < 0.05), whereas Q(Alb) in the 37 degrees C group was not significantly different vs control. CONCLUSIONS: The blood-CSF barrier is impaired by CPB with 1 hour of 15 degrees C or 25 degrees C HCA. Further investigations are needed to understand the behavior of the blood-CSF barrier during CPB and its role in neuroprotection.

Paediatric and adult multiple sclerosis: age-related differences and time course of the neuroimmunological response in cerebrospinal fluid.

We investigate common pathophysiology in paediatric and adult multiple sclerosis (MS) by comparison of cerebrospinal fluid (CSF) data. We compared cerebrospinal fluid (CSF) data from eight patient groups with onset of MS at 7 to 29 years (n = 184). A new statistics program allows sensitive detection, quantifies the mean amount of intrathecal Ig synthesis in groups based on the 96% reference range of 4100 non-inflammatory controls, corrects for age-related increase of blood-derived albumin and immunoglobulins in CSF, and presents graphical data interpretation in Reibergrams. Already at onset of MS before puberty (< or =10 years) the frequency of intrathecal IgG synthesis (oligoclonal IgG) was 100% like in adults with 98%, but the amount of intrathecal IgG increases twofold during puberty. Intrathecal IgM synthesis is most frequent before and during puberty (in 57-67% of patients) compared with 41% in adults. The amount of intrathecal IgM synthesis before puberty is only 30% of that in adults. IgG and IgM Index are biased evaluations not suitable for characterizing age-related dynamics. A twofold age-related increase of the albumin quotient, Q(Alb), as a measure of the blood-CSF barrier function, represents normal physiological growth. Cell counts in CSF are low. The pre-puberty gender ratio is about 1:1. Intrathecal antibodies against measles, rubella and/or varicella zoster virus are detected in 73% of patients before puberty compared with 89% of adults. Individual paediatric patients (n = 17), with sequential punctures over 2-5 years, show constant quantities of intrathecal IgM and specific antibodies. In conclusion, paediatric MS already at first clinical manifestation shows the complete, neuroimmunological data pattern in CSF, i.e. inflammatory signs are not gradually evolving. Paediatric and adult MS differ quantitatively but not qualitatively in neuroimmunological patterns which does not allow for discrimination between 'early' and 'late' onset MS. CSF analysis may help to discriminate between acute and mono-symptomatic chronic inflammatory disease already at earliest clinical manifestation.

Glossopharyngeal neuralgia as onset of multiple sclerosis.

OBJECTIVES AND METHODS: Glossopharyngeal neuralgia is a painful condition, affecting the ninth cranial nerve, rarely described in the course of multiple sclerosis. Here we describe a case of multiple sclerosis presenting with glossopharyngeal neuralgia. RESULTS AND DISCUSSION: We suggest the presence of demyelinating areas at the nerve root entry zone as principal trigger mechanism.

Effect of acute inflammatory brain injury on accumulation of morphine and morphine 3- and 6-glucuronide in the human brain.

OBJECTIVE: In animals, central nervous system inflammation increases drug accumulation in the brain partly due to a loss of central nervous system drug efflux transporter function at the blood-brain barrier. To determine whether a similar loss of active drug efflux occurs in humans after acute inflammatory brain injury. DESIGN: Observational human pharmacokinetic study. SETTING: Medical-surgical-neurosurgical intensive care unit at a university-affiliated, Canadian tertiary care center. PATIENTS: Patients with acute inflammatory brain injury, including subarachnoid hemorrhage (n = 10), intracerebral and/or intraventricular hemorrhage (n = 4), or closed head trauma (n = 2) who received morphine intravenously after being fitted with cerebrospinal fluid ventriculostomy and peripheral arterial catheters. INTERVENTIONS: We correlated the cerebrospinal fluid distribution of morphine, morphine-3-glucuronide, and morphine-6-glucuronide with the cerebrospinal fluid and plasma concentration of the proinflammatory cytokine interleukin-6 and the passive marker of blood-brain barrier permeability, albumin. MEASUREMENTS AND MAIN RESULTS: Acute brain injury produced a robust inflammatory response in the central nervous system as reflected by the elevated concentration of interleukin-6 in cerebrospinal fluid. Penetration of morphine metabolites into the central nervous system increased in proportion to the neuroinflammatory response as demonstrated by the positive correlation between cerebrospinal fluid interleukin-6 exposure and the area under the curve cerebrospinal fluid/plasma ratio for morphine-3-glucuronide (r = .49, p < .001) and morphine-6-glucuronide (r = .51, p < .001). In contrast, distribution of morphine into the brain was not linked with cerebrospinal fluid interleukin-6 exposure (r = .073, p = .54). Albumin concentrations in plasma and cerebrospinal fluid were consistently in the normal range, indicating that the physical integrity of the blood-brain barrier was likely undisturbed. CONCLUSIONS: Our results suggest that central nervous system inflammation following acute brain injury may selectively inhibit the activity of specific drug efflux transporters within the blood-brain barrier. This finding may have significant implications for patients with neuroinflammatory conditions when administered centrally acting drugs normally excluded from the brain by such transporters.