Higher Cerebrospinal Fluid Concentrations Research Articles

Klebsiella pneumoniae invasive syndrome with liver, lung, and brain abscesses complicated with pulmonary fungal infection: a case report and review of the literature

BackgroundKlebsiella pneumoniae invasion syndrome (KPIS) is a severe multi-site infection that is usually caused by hypervirulent Klebsiella pneumoniae. The bacteria are relatively common in Asian diabetics and can cause organ abscesses or sepsis. When patients develop intracranial infection, the prognosis is poor. After anti-infective treatment, the Klebsiella pneumoniae-induced liver and lung abscesses and pulmonary fungal infection were relieved, but the brain abscesses worsened. Such complex and severe infection cases are rarely reported. Early identification of intracranial infection, selection of antibiotics with high concentrations in cerebrospinal fluid, and active treatment of complications such as diabetes and fungal infection are of great significance for the prognosis of patients.Case presentationA 71-year-old patient diagnosed with liver abscess in another hospital was transferred to our hospital due to a worsening condition. On day 1 (day of admission), the patient was given invasive mechanical ventilation, continuous renal replacement therapy combined with endotoxin adsorption, antimicrobial treatment with imipenem-cilastatin, and percutaneous catheter drainage for liver abscess. Metagenomic next-generation sequencing in bronchoalveolar lavage fluid indicated Klebsiella pneumoniae (K. pneumoniae), Candida albicans, and Aspergillus flavus complex, and no viruses were detected. Blood and pus cultures revealed K. pneumoniae that was sensitive to piperacillin/tazobactam. The anti-infection therapy was adjusted to piperacillin/tazobactam combined with voriconazole. On day 14, a head computed tomography (CT) scan showed no significant changes, and a chest CT scan showed absorption of multiple abscesses in both lungs. The patient was still unconscious. After the endotracheal tube was removed, cranial magnetic resonance imaging (MRI) showed multiple brain abscesses. Finally, his family gave up, and the patient was discharged and died in a local hospital.ConclusionIn cases of K. pneumoniae infection, the possibility of intracranial, liver, lung, or other site infections should be considered, and physicians should be vigilant for the occurrence of KPIS. For patients suspected of developing an intracranial infection, cerebrospinal fluid should be tested and cultured as soon as possible, a head MRI should be performed, and antibiotics with high distribution in cerebrospinal fluid should be used early. When patients are complicated with diabetes, in addition to glycemic control, vigilance for concurrent fungal infections is also needed.

Methotrexate in Combination with Orelabrutinib, Thiotepa, and Rituximab (R-MTO) Followed By Autologous Stem-Cell Transplant for Primary Central Nervous System Lymphoma Treatment

Background: Primary central nervous system lymphoma (PCNSL) is a rare, aggressive B-cell malignancy. Despite the possibility of a cure, the prognosis remains poor. The standard treatment includes high-dose methotrexate and rituximab, followed by consolidation with either whole-brain radiation therapy or autologous stem cell transplantation (ASCT). However, there is still no clear consensus on the best treatment approach. To improve outcomes, we incorporated thiotepa chemotherapy, which has shown promising activity in inhibiting tumor growth by disrupting DNA bonds, into the regimen. Additionally, we introduced orelabrutinib, a novel and potent BTK inhibitor with high cerebrospinal fluid concentrations, which has demonstrated efficacy in treating PCNSL. In light of these findings, we conducted a clinical study to evaluate the efficacy and safety of a combination regimen of thiotepa, orelabrutinib, and methotrexate with rituximab (R-MTO) followed by autologous hematopoietic stem cell transplantation (HSCT) in patients with PCNSL. Methods: This is an ongoing, single-center, single-arm, open-label study conducted between April 2022 and July 2023. The study enrolled patients aged 18-80 years diagnosed with PCNSL. The patients received 5-8 cycles of R-MTO regimen as induction therapy, consisting of rituximab 375 mg/m 2 iv on day 0, MTX 3.5 g/m 2 iv on day1, thiotepa, 30-40 mg/m 2 on day 4 and orelabrutinib 150 mg qd po for 3 weeks per cycle). After completing the R-MTO therapy, patients were proposed to receive orelabrutinib monotherapy as maintenance treatment for up to 2 years. The efficacy was assessed by MRI/PET per the International PCNSL Collaborative Group (IPCG) criteria. Patients who did not experience disease progression subsequently underwent consolidation treatment with high-dose chemotherapy (HCT) plus ASCT. The HCT regimen involved busulfan 3.2 mg/kg on days -5, -4, thiotepa 250 mg/m 2 on days -7 and -6, cytarabine 2g/m 2 q12h on days -3 and -2, followed by reinfusion of stem cells on day 0. The primary endpoint of the study was progression-free survival (PFS) at 2 years, evaluated by intention-to-treat (ITT). Secondary endpoints included complete response (CR) rate, overall response rate (ORR), overall survival (OS) and toxicities. Results: Between April 2022 and July 2023, a total of 19 patients with PCNSL were enrolled in our study, including 16 who were newly diagnosed and had not received any prior treatment. The median age of the patients was 62 years, ranging from 31 to 72, with 9 out of 19 (47.37%) being male. By the data cutoff, all the patients had completed 4 cycles of treatment. Additionally, 8 out of 19 (42.11%) patients had completed six cycles of treatment, and 2 out of 19 (10.52%) patients had completed 7 to 8 cycles of treatment. The ORR was 94.73% (18/19), and the CR rate was 89.47% (17/19) after 4 cycles of treatment. However, one patient with a P53 mutation progressed after 2 cycles of treatment and unfortunately died 3.8 months after diagnosis. Among the six patients who underwent autologous HSCT, all of them (100%) remained in CR. One patient died due to a COVID-19 infection after 6 cycles of R-MTO and ASCT. The most common hematological adverse events associated with the R-MTO regimen were mild to moderate (grade 1-2) decreases in neutrophil count, which typically resolved within a few days. Conclusions: The R-MTO induction treatment has demonstrated notable efficacy in achieving higher response rates among patients with PCNSL, and the associated adverse events are manageable.

Altered brain dopamine metabolism is a trait marker for bipolar disorder

Pharmacological treatment, imaging, and neurochemistry studies identify altered dopamine signaling in bipolar disorder. Our previous work has shown higher concentration of homovanillic acid (HVA), the end metabolite of dopamine, in cerebrospinal fluid (CSF) from individuals with bipolar disorder compared to healthy controls. Here, we analyzed HVA concentrations from a follow-up visit in 103 adults with bipolar disorder and 57 controls from our first cohort. Further, we analyzed CSF monoamine metabolite concentrations in a second cohort of 152 adults with bipolar disorder and 55 controls. At the follow-up visit for the first cohort, HVA was higher in individuals with bipolar disorder (278 ± 102 nmol/L, p = 0.003) compared with controls (232 ± 83 nmol/L). In the second cohort, individuals with bipolar disorder had higher HVA (272 ± 97 nmol/L, p = 0.001) and lower 3-methoxy-4-hydroxyphenylglycol (MHPG, 40 ± 9 nmol/L, p = 0.002) concentrations than controls (HVA, 231 ± 71 nmol/L and MHPG, 45 ± 9 nmol/L). Baseline and follow-up measures of monoamine metabolites showed medium to high correlation to each other but did not predict course of illness. We failed to replicate the association of HVA concentration and psychotic symptoms but confirmed lower 5-hydroxyindoleacetic acid (5-HIAA) concentration in individuals treated with antidepressants. In conclusion, we confirmed high HVA concentration in CSF in patients with bipolar disorder compared to a control group. Previous work suggest that this is a feature shared with ADHD but distinct from schizophrenia and major depressive disorder. The role of increased HVA concentration in the course of illness in bipolar disorder remains unclear.

Multiple ultrafast shunt failure in oncological COVID-19 pediatric patient

Introduction: Ventriculoperitoneal shunts (VPS) are one the most frequents interventions performed in Pediatric Neurosurgery, but their failure rate continues to be high. A relation between early and repeated VPS failure and the characteristics of cerebrospinal fluid (CSF) has been previously described, and there have also been reports of alterations in CSF due to coronavirus infectious disease (COVID-19).
 Case presentation: A ten-year-old girl with a low grade thalamic glioma previously treated with two partial resections, chemotherapy and proton beam radiotherapy, developed hydrocephalus with intracranial hypertension. After emergent management with external ventricular drain, a VPS shunt with a programmable valve was implanted. The patient was diagnosed of COVID-19 in between these two procedures. Afterwards, she suffered from multiple shunt complications, with several events of obstruction. Her CSF had always very high protein concentration and COVID-19 tests were persistently positive.
 Discussion: Obstruction is the main cause of VPS malfunction in children, and many studies have tried to elucidate risk factors for failure, as younger age or type of shunt. High protein concentration and cells count in CSF could influence shunt failure, but evidence is controversial. Moreover, COVID19 could also be related to such CSF alterations.
 Conclusion: Early and repeated shunt failures are a clinical problem with no clear treatment stablished. Many factors can be associated to such complications, including CSF alterations, which may also be related to COVID19. Evidence is scarce and contradictory in many aspects, and pediatric neurosurgeons have to face this problem frequently, so more studies with management recommendations are needed.

The Association between Tau Protein Level in Cerebrospinal Fluid and Cognitive Status: A Large-Scale Analysis of GAAIN Database.

Alzheimer’s disease (AD) and the associated neurodegenerative dementia have become of increasing concern in healthcare. The tau protein has been considered a key hallmark of progressive neurodegeneration. In this paper, a large-scale analysis of five datasets (more than 2500 people) from the Global Alzheimer’s Association Interactive Network (GAAIN) databases was performed to investigate the association between the level of tau protein, including total tau and phosphorylated tau (p-tau), in cerebrospinal fluid (CSF) and cognitive status. Statistically significant (or marginally significant) high total tau or p-tau concentrations in CSF were observed in dementia patients compared with healthy people in all datasets. There is also a statistically significant (or marginally significant) negative correlation between p-tau concentrations in CSF and Folstein Mini-Mental State Examination (MMSE) scores. In addition, transcriptomic data derived from mouse microglial cells showed multiple genes upregulated in Toll-like receptor signaling and Alzheimer’s disease pathways, including TNF, TLR2, IL-1β, and COX subunits, suggesting that the mechanism of action that relates p-tau and MMSE scores may be through overactivation of pro-inflammatory microglial activity by Aβ peptides, TNF-mediated hyperphosphorylation of tau, and the infectious spread of pathological tau across healthy neurons. Our results not only confirmed the association between tau protein level and cognitive status in a large population but also provided useful information for the understanding of the role of tau in neurodegeneration and the development of dementia.

Antimicrobial use in central nervous system infections.

Central nervous system (CNS) infections are associated with high rates of morbidity and mortality. The purpose of this review is to summarize current antimicrobial therapies, as well as, updates in the management of community-acquired meningitis and healthcare-associated meningitis and ventriculitis. Due to the increasing rates of multidrug resistant and extensively-drug resistant organisms, available antimicrobials are limited. Novel treatment options include newer systemic antimicrobials and antimicrobials that have previously limited data in the management of CNS infections. Although limited by retrospective data, intrathecal (IT) and intraventricular (IVT) routes of administration offer the opportunity for antimicrobials that conventionally have minimal cerebrospinal fluid (CSF) penetration to achieve high CSF concentrations while minimizing systemic exposure. Updates in the use of systemic, IT, and IVT antimicrobials offer promise as therapeutic options for CNS infections. Additional pharmacokinetic and prospective data are needed to confirm these findings.

Systemic and central nervous system metabolic alterations in Alzheimer\u2019s disease

BackgroundMetabolic alterations, related to cerebral glucose metabolism, brain insulin resistance, and age-induced mitochondrial dysfunction, play an important role in Alzheimer’s disease (AD) on both the systemic and central nervous system level. To study the extent and significance of these alterations in AD, quantitative metabolomics was applied to plasma and cerebrospinal fluid (CSF) from clinically well-characterized AD patients and cognitively healthy control subjects. The observed metabolic alterations were associated with core pathological processes of AD to investigate their relation with amyloid pathology and tau-related neurodegeneration.MethodsIn a case-control study of clinical and biomarker-confirmed AD patients (n = 40) and cognitively healthy controls without cerebral AD pathology (n = 34) with paired plasma and CSF samples, we performed metabolic profiling, i.e., untargeted metabolomics and targeted quantification. Targeted quantification focused on identified deregulated pathways highlighted in the untargeted assay, i.e. the TCA cycle, and its anaplerotic pathways, as well as the neuroactive tryptophan and kynurenine pathway.ResultsConcentrations of several TCA cycle and beta-oxidation intermediates were higher in plasma of AD patients, whilst amino acid concentrations were significantly lower. Similar alterations in these energy metabolism intermediates were observed in CSF, together with higher concentrations of creatinine, which were strongly correlated with blood-brain barrier permeability. Alterations of several amino acids were associated with CSF Amyloidβ1–42. The tryptophan catabolites, kynurenic acid and quinolinic acid, showed significantly higher concentrations in CSF of AD patients, which, together with other tryptophan pathway intermediates, were correlated with either CSF Amyloidβ1–42, or tau and phosphorylated Tau-181.ConclusionsThis study revealed AD-associated systemic dysregulation of nutrient sensing and oxidation and CNS-specific alterations in the neuroactive tryptophan pathway and (phospho)creatine degradation. The specific association of amino acids and tryptophan catabolites with AD CSF biomarkers suggests a close relationship with core AD pathology.Our findings warrant validation in independent, larger cohort studies as well as further investigation of factors such as gender and APOE genotype, as well as of other groups, such as preclinical AD, to identify metabolic alterations as potential intervention targets.

Dimethyl fumarate decreases neurofilament light chain in CSF and blood of treatment naïve relapsing MS patients

ObjectivesIn a prospective phase IV trial of the first-line oral treatment dimethyl fumarate (DMF), we examined dynamics of neurofilament light (NFL) chain in serum, plasma and cerebrospinal fluid (CSF) samples...

Mass spectrometry‐based method for quantification of nimodipine and glutamate in cerebrospinal fluid. Pilot study with patients after aneurysmal subarachnoid haemorrhage

Delayed cerebral ischaemia is an important cause of morbidity and mortality after aneurysmal subarachnoid haemorrhage (aSAH). Nimodipine is the only drug approved by the FDA for improving outcome after aSAH. Clinically, however, there are no specific values of this drug in cerebrospinal fluid (CSF) during aSAH treatment that could be associated to outcome improvement. Furthermore, the neurotransmitter glutamate acts as a secondary marker for brain injury. The aim was to establish a method to measure nimodipine and glutamate concentrations simultaneously in CSF of patients after aSAH. From June 2017 to June 2018, we prospectively collected clinical data of patients with aSAH admitted to our neurointensive care unit. All included patients received nimodipine orally (60mg every 4hours). Patients, who developed clinical vasospasm during their in-hospital stay, underwent intra-arterial application of nimodipine (IAN), followed by angiographic control. A method using high-performance liquid chromatography coupled with mass spectrometric analysis (LC-MS/MS) was established for quantification of both analytes in CSF. In 15 (60%) of 25 patients, nimodipine and glutamate concentrations were measured. After IAN for treatment of vasospasms, CSF nimodipine concentrations were slightly higher than in patients who received nimodipine only orally (0.60±0.27ng/mL vs 0.48±0.18ng/mL). Patients developing vasospasm exhibited higher glutamate concentrations than patients without vasospasm (188.84ng/mL vs136.07ng/mL). The developed method allowed the simultaneous quantification of nimodipine and glutamate in CSF. Furthermore, we demonstrated that IAN resulted in higher concentrations in CSF, when compared to oral application only.

First studies on the interactions of the C-terminal cystatin C fragment 85–94 with Cu(II) ions

The hypothesis connecting dyshomeostasis of selected metal ions in the brain with increased probability of the development of severe neurodegenerative diseases is gaining increasing attention. The mechanisms of metal toxicity can be studied using different methodologies. One of the approaches is based on peptides as mimetics of the metal binding sites in proteins. In our studies, we have focused on human cystatin C (hCC) as one of the proteins involved in neurodegeneration. Physiologically, it is an important inhibitor of cysteine proteases and modulator of many physiological and pathological states. Native hCC is present at particularly high concentrations in cerebrospinal fluid (CSF) and was shown to possess both neurodegenerative and neuroprotective propensities. We have studied the copper(II) binding to its C-terminal fragment containing two histidine residues as potential site(s) for metal coordination. Our data indicate that the hCC fragment is fully capable of effective metal binding. Moreover, two potential metal binding sites can be proposed for the studied ligand. At the physiological range of pH formation of two types of complexes was observed: with imidazole and one/two amide donors in the coordination sphere of the metal ion and the final species characterized by the 4N-type of coordination.

Potential Diagnostic Value of Red Blood Cells α-Synuclein Heteroaggregates in Alzheimer's Disease.

A plethora of complex misfolded protein combinations have been found in Alzheimer disease (AD) brains besides the classical pathological hallmarks. Recently, α-synuclein (α-syn) and its heterocomplexes with amyloid-β (Aβ) and tau have been suggested to be involved in the pathophysiological processes of neurodegenerative diseases. These pathological features are not limited to the brain, but can be also found in peripheral fluids. In this respect, red blood cells (RBCs) have been suggested as a good model to investigate the biochemical alterations of neurodegeneration. Our aim is to find whether RBC concentrations of α-syn and its heterocomplexes (i.e., α-syn/Aβ and α-syn/tau) were different in AD patients compared with healthy controls (HC). The levels of homo- and heteroaggregates of α-syn, Aβ and tau, were analyzed in a cohort of AD patients at early stage either with dementia or prodromal symptoms (N = 39) and age-matched healthy controls (N = 39). All AD patients received a biomarker-based diagnosis (low cerebrospinal fluid levels of Aβ peptide combined with high cerebrospinal fluid concentrations of total tau and/or phospho-tau proteins; alternatively, a positivity to cerebral amyloid-PET scan). Our results showed lower concentrations of α-syn and its heterocomplexes (i.e., α-syn/Aβ and α-syn/tau) in RBCs of AD patients with respect to HC. RBC α-syn/Aβ as well as RBC α-syn/tau heterodimers discriminated AD participants from HC with fair accuracy, whereas RBC α-syn concentrations differentiated poorly the two groups. Although additional investigations are required, these data suggest α-syn heteroaggregates in RBCs as potential tool in the diagnostic work-up of early AD diagnosis.

Pharmacokinetics and pharmacodynamics of antibiotics in central nervous system infections.

The barriers surrounding the central nervous system (CNS) together with the emergence of multiresistant pathogens pose a therapeutic challenge for the effective treatment of CNS infections. In addition to vancomycin, colistin and aminoglycosides, classically used for intrathecal injection, drug concentrations in cerebrospinal fluid after intrathecal injection of daptomycin and tigecyclin were recently studied. The entry of antiinfectives into the CNS compartments is determined by the physicochemical properties of the drug and by conditions in the host. The most important drug properties are lipophilicity at a neutral pH, molecular mass and drug binding to serum proteins. In clinical practice, active transport is of importance only for some drugs. In recent years, intrathecal injection of antiinfectives in addition to systemic therapy has regained attention as a means to achieve high cerebrospinal fluid concentrations. The classification of antibacterials and antifungals into time-dependent and concentration-dependent compounds is also valid for the CNS compartments.

Insights into the mechanism of cystatin C oligomer and amyloid formation and its interaction with β-amyloid

Cystatin C (CysC) is a versatile and ubiquitously-expressed member of the cysteine protease inhibitor family that is present at notably high concentrations in cerebrospinal fluid. Under mildly denaturing conditions, CysC forms inactive domain-swapped dimers. A destabilizing mutation, L68Q, increases the rate of domain-swapping and causes a fatal amyloid disease, hereditary cystatin C amyloid angiopathy. Wild-type (wt) CysC will also aggregate into amyloid fibrils under some conditions. Propagated domain-swapping has been proposed as the mechanism by which CysC fibrils grow. We present evidence that a CysC mutant, V57N, stabilized against domain-swapping, readily forms fibrils, contradicting the propagated domain-swapping hypothesis. Furthermore, in physiological buffer, wt CysC can form oligomers without undergoing domain-swapping. These non-swapped oligomers are identical in secondary structure to CysC monomers and completely retain protease inhibitory activity. However, unlike monomers or dimers, the oligomers bind fluorescent dyes that indicate they have characteristics of pre-amyloid aggregates. Although these oligomers appear to be a pre-amyloid assembly, they are slower than CysC monomers to form fibrils. Fibrillation of CysC therefore likely initiates from the monomer and does not require domain-swapping. The non-swapped oligomers likely represent a dead-end offshoot of the amyloid pathway and must dissociate to monomers prior to rearranging to amyloid fibrils. These prefibrillar CysC oligomers were potent inhibitors of aggregation of the Alzheimer's-related peptide, β-amyloid. This result illustrates an example where heterotypic interactions between pre-amyloid oligomers prevent the homotypic interactions that would lead to mature amyloid fibrils.

Biomarkers for the Early Detection and Progression of Alzheimer's Disease.

The recent failures of potential disease-modifying drugs for Alzheimer's disease (AD) may reflect the fact that the enrolled participants in clinical trials are already too advanced to derive a clinical benefit. Thus, well-validated biomarkers for the early detection and accurate diagnosis of the preclinical stages of AD will be crucial for therapeutic advancement. The combinatorial use of biomarkers derived from biological fluids, such as cerebrospinal fluid (CSF), with advanced molecular imaging and neuropsychological testing may eventually achieve the diagnostic sensitivity and specificity necessary to identify people in the earliest stages of the disease when drug modification is most likely possible. In this regard, positive amyloid or tau tracer retention on positron emission tomography imaging, low CSF concentrations of the amyloid-β 1-42 peptide, high CSF concentrations in total tau and phospho-tau, mesial temporal lobe atrophy on magnetic resonance imaging, and temporoparietal/precuneus hypometabolism or hypoperfusion on 18F-fluorodeoxyglucose positron emission tomography have all emerged as biomarkers for the progression to AD. However, the ultimate AD biomarker panel will likely involve the inclusion of novel CSF and blood biomarkers more precisely associated with confirmed pathophysiologic mechanisms to improve its reliability for detecting preclinical AD. This review highlights advancements in biological fluid and imaging biomarkers that are moving the field towards achieving the goal of a preclinical detection of AD.

Duloxetine enters the brain – But why is it not found in the cerebrospinal fluid

BackgroundAntidepressants enter the brain to reach their site of action in a different extent. However, there has been no study to date about duloxetine's ability to enter the brain and cerebrospinal fluid. Aim of this study was to measure blood and cerebrospinal fluid concentrations of duloxetine and to account for the distribution between the two compartments. MethodsConcentrations of duloxetine were measured in blood serum and cerebrospinal fluid of 19 patients treated with daily doses of 30–120mg. Daily doses were correlated with serum and cerebrospinal fluid concentrations and serum concentrations were correlated with concentrations in cerebrospinal fluid. ResultsSerum concentrations of duloxetine showed a moderate but significant correlation with the applied daily dose, r=+0.473, p=0.04. Duloxetine concentrations in the cerebrospinal fluid above the designated limit of quantification of 2.0ng/mL were only found in three of the 19 patients. Conclusions and limitationsContrasting to own preceding studies on venlafaxine, mirtazapine and citalopram with comparably high concentrations in cerebrospinal fluid, the here presented findings indicate that duloxetine shows a very different distribution pattern. Very low concentrations in the cerebrospinal fluid may be due to the fact that the drug crosses the blood–cerebrospinal fluid barrier much worse than other antidepressants do, suggesting a low ability of duloxetine to enter the brain. Alternatively, low drug concentrations may be interpreted in a sense of a missing residence time in cerebrospinal fluid due to active transport mechanisms out of this environment either back into the bloodstream or into the brain.

Plasminogen in cerebrospinal fluid originates from circulating blood.

BackgroundPlasminogen activation is a ubiquitous source of fibrinolytic and proteolytic activity. Besides its role in prevention of thrombosis, plasminogen is involved in inflammatory reactions in the central nervous system. Plasminogen has been detected in the cerebrospinal fluid (CSF) of patients with inflammatory diseases; however, its origin remains controversial, as the blood–CSF barrier may restrict its diffusion from blood.MethodsWe investigated the origin of plasminogen in CSF using Alexa Fluor 488–labelled rat plasminogen injected into rats with systemic inflammation and blood–CSF barrier dysfunction provoked by lipopolysaccharide (LPS). Near-infrared fluorescence imaging and immunohistochemistry fluorescence microscopy were used to identify plasminogen in brain structures, its concentration and functionality were determined by Western blotting and a chromogenic substrate assay, respectively. In parallel, plasminogen was investigated in CSF from patients with Guillain-Barré syndrome (n = 15), multiple sclerosis (n = 19) and noninflammatory neurological diseases (n = 8).ResultsEndogenous rat plasminogen was detected in higher amounts in the CSF and urine of LPS-treated animals as compared to controls. In LPS-primed rats, circulating Alexa Fluor 488–labelled rat plasminogen was abundantly localized in the choroid plexus, CSF and urine. Plasminogen in human CSF was higher in Guillain-Barré syndrome (median = 1.28 ng/μl (interquartile range (IQR) = 0.66 to 1.59)) as compared to multiple sclerosis (median = 0.3 ng/μl (IQR = 0.16 to 0.61)) and to noninflammatory neurological diseases (median = 0.27 ng/μl (IQR = 0.18 to 0.35)).ConclusionsOur findings demonstrate that plasminogen is transported from circulating blood into the CSF of rats via the choroid plexus during inflammation. Our data suggest that a similar mechanism may explain the high CSF concentrations of plasminogen detected in patients with inflammation-derived CSF barrier impairment.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-014-0154-y) contains supplementary material, which is available to authorized users.

Central nervous system penetration of oxycodone after intravenous and epidural administration

BackgroundDespite being increasingly used for pain management, only two studies, with controversial results, have evaluated the epidural use of oxycodone. MethodsTwenty-four women, aged 26–64 yr, undergoing elective gynaecological surgery were enrolled in this randomized, double-blinded, parallel group study. The subjects were administered either i.v. oxycodone and epidural placebo (IV group; n=12) or epidural oxycodone and i.v. placebo (EPI group; n=12) after operation. Oxycodone was administered as a single dose of 0.1 mg kg−1. An epidural catheter for drug administration was placed at T12/L1 and a spinal catheter for cerebrospinal fluid (CSF) sampling at L3/4. Plasma and CSF were frequently collected for the analysis of oxycodone and its major metabolites. The primary outcomes were the peak concentration (Cmax), time to peak concentration (Tmax), and the exposure (AUClast) of oxycodone in CSF and plasma. The secondary outcome was the analgesic efficacy, measured as the total dose of rescue fentanyl during the first four postoperative hours. ResultsIn the EPI group, the median oxycodone Cmax and AUClast in the CSF were 320- and 120-fold higher, respectively, compared with the IV group. The total dose of rescue fentanyl was significantly lower in the EPI group (seven subjects needed 16 doses) than in the IV group [12 subjects needed 71 doses (P=0.001)]. No serious or unexpected adverse events were reported. ConclusionsEpidural oxycodone provides much higher CSF concentrations and possibly better analgesic efficacy than does i.v. oxycodone. Clinical trial registrationEudraCT reference number: 2011-000125-76.

Identification of human cerebrospinal fluid proteins and their distribution in an in vitro microdialysis sampling system

A qualitative study is presented on how proteins from a complex biological sample are distributed in a microdialysis sample system. A comparison between proteins identified in the human ventricular cerebrospinal fluid (CSF) sample, the collected dialysate and the proteins adsorbed onto the membrane was conducted. The microdialysis experiment was performed in vitro at 37°C for the duration of 24h. Thereafter, the membranes were removed from the catheter and the adsorbed proteins were tryptically digested using the on-surface enzymatic digestion (oSED) protocol. The CSF samples and the dialysates were digested using a standard in-solution trypsin digestion protocol. In the final phase, the samples were analysed using nano-liquid chromatography in combination with tandem mass spectrometry. In the four sample compartments analysed (CSF start, Membrane, Dialysate, CSF end) a total of 134 different proteins were found. However, most of the identified proteins (n=87) were uniquely found in one sample compartment only. Common CSF proteins such as albumin, apolipoproteins and cystatin C together with plasma proteins such as hemoglobin and fibrinogen were among the 11 proteins that were found in all samples. These proteins are present in high concentrations in CSF, which means that they effectively block out the detection signal of less abundant proteins. Therefore, only 25% of the proteins adsorbed onto the membrane were detected in the CSF compared with the dialysate that shared 44% of its proteins with the CSF. The proteins adsorbed onto the membrane were significantly more hydrophobic, had a lower instability index and more thermostable compared to the proteins in the CSF and the dialysate. The results suggest that proteins adsorbed onto the microdialysis membranes may escape detection because they are prevented from passing the membrane into the dialysate. Thus, the membrane needs to be examined after sample collection in order to better verify the protein content in the original sample. This is particularly important when searching for new protein biomarkers for neurodegenerative diseases.

English

Enterobacte r species are increasingly a cause of nosocomial meningitis among neurosurgery patients, but risk factors for these infections are not well defined. It was found that external cerebrospinal fluid (CSF) drainage devices, isolation of Enterobacter species from a non-CSF culture, prolonged administration of antimicrobial drugs before the diagnosis of meningitis that were inactive in vitro against Enterobacter species, immunosuppression and advanced age are also independent risk factors for Enterobacter Meningitis. Despite favourable treatment outcomes, EM is a serious infection associated with Enterobacter species colonization or infection at other surgical sites, with selective antimicrobial pressure, and with invasive CNS devices. The treatment is difficult because of inability of many of the antibiotics that are active against these bacteria to achieve adequate concentration in CSF. However third generation cephalosporins are active against gram negative bacilli and also achieved high concentration in CSF.

Cerebrospinal fluid concentration of gefitinib and erlotinib in patients with non-small cell lung cancer

Several cases have been reported in which central nervous system (CNS) metastases of non-small cell lung cancer (NSCLC) resistant to gefitinib were improved by erlotinib. However, there has been no study in which cerebrospinal fluid (CSF) concentrations of gefitinib and erlotinib are directly compared. Thus, we aimed to compare them. We examined 15 Japanese patients with NSCLC and CNS metastases with epidermal growth factor receptor gene mutations who received CSF examinations during epidermal growth factor receptor-tyrosine kinase inhibitors treatment (250 mg daily gefitinib or 150 mg daily erlotinib). Plasma and CSF concentrations were determined using high-performance liquid chromatography with tandem mass spectrometry. The concentration and penetration rate of gefitinib (mean ± standard deviation) in the CSF were 3.7 ± 1.9 ng/mL (8.2 ± 4.3 nM) and 1.13 ± 0.36 %, respectively. The concentration and penetration rate of erlotinib in the CSF were 28.7 ± 16.8 ng/mL (66.9 ± 39.0 nM) and 2.77 ± 0.45 %, respectively. The CSF concentration and penetration rate of erlotinib were significantly higher than those of gefitinib (P = 0.0008 and <0.0001, respectively). The CNS response rates of patients with erlotinib treatment were preferentially (but not significantly) higher than those with gefitinib treatment. (1/3 vs. 4/7, respectively). Leptomeningeal metastases in one patient, which were refractory to gefitinib, dramatically responded to erlotinib. This study suggested that higher CSF concentration could be achieved with erlotinib and that erlotinib could be more effective for the treatment for CNS metastases, especially leptomeningeal metastases, than gefitinib.