Routine Cerebrospinal Fluid Research Articles

A New Laboratory Workflow Integrating the Free Light Chains Kappa Quotient into Routine CSF Analysis.

We performed this cohort study to test whether further analysis of intrathecal inflammation can be omitted if the free light chain kappa (FLCκ) quotient is within the reference range in the corresponding quotient diagram. FLCκ concentrations were measured in serum and cerebrospinal fluid (CSF) samples. The intrathecal fraction (IF) of FLCκ was calculated in relation to the hyperbolic reference range. 679 patient samples were used as a discovery cohort (DC). The sensitivity and negative predictive value (NPV) of the FLCκ-IF for the detection of an intrathecal humoral immune response (CSF-specific OCB and/or IF IgG/A/M > 0%) was determined. Based on these data, a diagnostic algorithm was developed and prospectively validated in an independent validation cohort (VC, n = 278). The sensitivity of the FLCκ-IF was 98% in the DC and 97% in the VC with a corresponding NPV of 99%. The use of the FLCκ-IF as a first line analysis would have reduced the Ig and OCB analysis by 62% in the DC and 74% in the VC. The absence of a FLCκ-IF predicts the absence of a humoral intrathecal immune response with a very high NPV of 99%. Thus, integration of our proposed algorithm into routine CSF laboratory analysis could help to reduce analytical efforts.

OS11.5.A Utility of lumbar puncture (LP) and cerebrospinal fluid (CSF) profile in the diagnosis of neoplastic meningitis (NM): a retrospective cohort study and meta-analyses

Abstract Background CSF cytology remains the gold standard for diagnosing NM, but the sensitivity of this test is low (approximately 50% with one LP). Little is known about the predictive value of routine CSF and clinical findings for a positive cytology. We addressed these questions by analyzing 337 consecutive patients at our institution, and by conducting exhaustive evidence-based literature reviews and meta-analyses of relevant research. Material and Methods 337 consecutive patients at a single institution were evaluated. Of these, 210 met criteria for NM (a positive CSF cytology on at least one of four pre-treatment samples) or no NM (four consecutive negative CSF cytologies). CSF white blood cell count, glucose, protein, and lactate were collected, as well as the presence of neurological symptoms. Optimal threshold values were identified using ROC curves. Sensitivity (Sn), specificity (Sp), and likelihood ratios were calculated for each variable. Two PRISMA-compliant meta-analyses were also performed: one analyzed studies reporting the cytology results of multiple LPs, and one analyzed the frequency of abnormal CSF findings as predictors of NM. Results All published results describe outcomes in patients with known NM. These results are, therefore, strongly distorted by spectrum bias, which artificially inflates the apparent sensitivity and specificity of those outcomes. Thus, 25 studies report the yield of positive CSF cytology on the first, second, and third LP as 73%, 87%, and 94%, but also do not describe the parameters of the procedure. Our series in patients with suspected NM (the cohort most relevant to the practicing physician) reports 74%, 85%, and 92% for immediately processed, 10 mL or greater, lumbar and ventricular specimens. Similarly, while 50 studies suggested that low CSF glucose, high CSF protein, and suggestive symptoms are associated with NM, we found very poor Sn/Sp for elevated protein (61%/61%), low glucose (35%/85%), elevated lactate (35%/91%), and symptoms consistent with NM (74%/73%). Of these values, only an elevated lactate and symptoms were even marginally helpful in predicting a positive CSF cytology. No variable predicted a negative cytology, and 22.8% of patients with a positive CSF cytology had completely normal CSF findings. Conclusion Generally accepted concepts about the frequency of CSF and clinical findings in patients with suspected NM are based on biased estimates in the literature. No CSF chemistry or clinical finding reliably predicts the presence of NM, and almost a quarter of patients with cytologically proven NM have completely normal findings. In patients with positive CSF cytologies, about 73% are detected after one LP, and more than 90% after 3, but again these findings represent overestimates because of pervasive spectrum bias and differences in sample acquisition/handling. Better diagnostic techniques are desperately needed.

Longitudinal ventricular cerebrospinal fluid profile in patients with spontaneous subarachnoid hemorrhage.

BackgroundSpontaneous subarachnoid hemorrhage (SAH) is a severe neurological disease that frequently requires placement of external ventricular drainage (EVD). Cerebrospinal fluid (CSF) obtained via the drain is used to detect potential complications of SAH.ObjectiveThis study aimed to describe the longitudinal profile of routine CSF parameters in patients with SAH and to identify associations with neurological complications.MethodsA total of thirty-three patients with spontaneous SAH who required an EVD and had at least three consecutive CSF samples collected over a period of more than 7 days were included in this study.ResultsA median of 6 longitudinally collected CSF samples per patient were available within 1–22 days after SAH onset. Overall, red blood cells (RBC) steadily decreased over time, whereas white blood cells (WBC) and total protein (TP) increased until days 6 and 13, respectively, and decreased thereafter. The estimated decay rates of RBC, WBC, and TP were 28, 22, and 6% per day. Distinct CSF patterns over time were linked to known complications after SAH. Patients with rebleeding showed increased RBC, TP, and phagocytosing cells compared to patients without re-bleeding. For ventriculitis, an elevated cell index with a higher proportion of granulocytes was characteristic. CSF of patients with delayed cerebral ischemia showed increased RBC and WBC compared to patients without DCI. Early CSF WBC and cell index were predictive for the occurrence of DCI and ventriculitis later during the disease course. The amount of daily CSF drainage via EVD had no impact on routine CSF parameters.ConclusionLongitudinal CSF characteristics are associated with SAH-related complications.

Investigating latent syphilis in HIV treatment-experienced Ethiopians and response to therapy.

We investigated people with HIV (PWH) receiving combination antiretroviral therapy (cART) for latent syphilis infection prevalence, risk factors, treatment response, and neurosyphilis. A prospective follow-up study was conducted on PWH and latent syphilis. The cases were randomly assigned to receive either benzathine penicillin G (BPG) or doxycycline (DOXY), and the posttreatment response was evaluated after 12 and 24 months. The traditional algorithm was used for serodiagnosis, and a semi-quantitative rapid plasma reagin (RPR) test monitored disease activity and treatment effectiveness. Of the 823 participants, 64.8% were women, and the mean age was 41.7±10 years. Thirty-one (3.8%) of the participants (22 males and nine females) had latent syphilis. The risk factors were male sex (aOR = 3.14), increasing age (aOR = 1.04 per year), and cART duration (aOR = 1.01 per month). Baseline RPR titers were: ≤1:4 in 19 (61.3%), between 1:8 and 1:32 in 10 (32.2%), and >1:32 in 2 (6.4%). None of the seven cerebrospinal fluid analyses supported a neurosyphilis diagnosis. In the 12th month of treatment, 27 (87.1%) had adequate serological responses, three (9.7%) had serological nonresponse, and one (3.2%) had treatment failure. Syphilis treatment was repeated in the last four cases with the alternative drug. In terms of adequate serologic response, both therapies were comparable at the 12th month, p = 0.37. All cases responded to treatment in the 24th month. In PWH receiving cART, latent syphilis occurred more in men than women, suggesting an investigation of sexual practices and the impact of antenatal syphilis screening. Syphilis disease activity reduces in the latent stage. Therefore, the routine cerebrospinal fluid analysis contributes little to the diagnosis of asymptomatic neurosyphilis and the treatment success of latent syphilis. DOXY is an alternative to BPG, and cART improves serologic response to latent syphilis treatment.

MOG antibody‐related disorder associated with peripheral facial nerve palsy

A 44-year-old Japanese woman exhibited neurological symptoms including unsteadiness of gait, headache, hypoesthesia of the left face, and left-sided peripheral facial nerve palsy. Brain MRI revealed abnormal intensities in the hemispheres, brainstem, and corpus callosum. Although routine blood and cerebrospinal fluid studies were unremarkable, serum anti-myelin oligodendrocyte glycoprotein (MOG) antibody was positive. With two-time intravenous methylprednisolone pulse therapy, her symptoms gradually improved. We report here a rare case of a MOG antibody-related disorder with peripheral facial nerve palsy as a predominant symptom. We should be aware of this disease even in a case of peripheral facial nerve palsy.

Retrospective Evaluation of Various Serological Assays and Multiple Parameters for Optimal Diagnosis of Lyme Neuroborreliosis in a Routine Clinical Setting.

ABSTRACTLaboratory diagnosis of Lyme neuroborreliosis (LNB) is challenging, and validated diagnostic algorithms are lacking. Therefore, this retrospective cross-sectional study aimed to compare the diagnostic performance of seven commercial antibody assays for LNB diagnosis. Random forest (RF) modeling was conducted to investigate whether the diagnostic performance using the antibody assays could be improved by including several routine cerebrospinal fluid (CSF) parameters (i.e., leukocyte count, total protein, blood-CSF barrier functionality, and intrathecal total antibody synthesis), two-tier serology on serum, the CSF level of the B-cell chemokine (C-X-C motif) ligand 13 (CXCL13), and a Borrelia species PCR on CSF. In total, 156 patients were included who were classified as definite LNB (n = 10), possible LNB (n = 7), or non-LNB patient (n = 139) according to the criteria of the European Federation of Neurological Societies using a consensus strategy for intrathecal Borrelia-specific antibody synthesis. The seven antibody assays showed sensitivities ranging from 47.1% to 100% and specificities ranging from 95.7% to 100%. RF modeling demonstrated that the sensitivities of most antibody assays could be improved by including other parameters to the diagnostic repertoire for diagnosing LNB (range: 94.1% to 100%), although with slightly lower specificities (range: 92.8% to 96.4%). The most important parameters for LNB diagnosis are the detection of intrathecally produced Borrelia-specific antibodies, two-tier serology on serum, CSF-CXCL13, Reibergram classification, and pleocytosis. In conclusion, this study shows that LNB diagnosis is best supported using multiparameter analysis. Furthermore, a collaborative prospective study is proposed to investigate if a standardized diagnostic algorithm can be developed for improved LNB diagnosis.IMPORTANCE The diagnosis of LNB is established by clinical symptoms, pleocytosis, and proof of intrathecal synthesis of Borrelia-specific antibodies. Laboratory diagnosis of LNB is challenging, and validated diagnostic algorithms are lacking. Therefore, this retrospective cross-sectional study aimed to compare the diagnostic performance of seven commercial antibody assays for LNB diagnosis. Multiparameter analysis was conducted to investigate whether the diagnostic performance using the antibody assays could be improved by including several routine (CSF) parameters. The results of this study show that LNB diagnosis is best supported using the detection of intrathecally produced Borrelia-specific antibodies, two-tier serology on serum, CSF-CXCL13, Reibergram classification, and pleocytosis. Furthermore, we propose a collaborative prospective study to investigate the potential role of constructing a diagnostic algorithm using multiparameter analysis for improved LNB diagnosis.

Association of Cerebrospinal Fluid Parameters and Neurofilament Light Chain With Retinal Nerve Fiber Layer Thickness in Multiple Sclerosis.

IntroductionMultiple sclerosis (MS) pathophysiology comprises both inflammatory and neurodegenerative characteristics. Cerebrospinal fluid (CSF) analysis allows for assessment of inflammation while neurofilament light chain can indicate neuroaxonal damage. Retinal thinning is a robust prognostic biomarker for neurodegeneration in MS. To date, an association between CSF parameters upon MS diagnosis and retinal thinning has not been investigated.Aims and ObjectivesWe aimed to determine whether CSF parameters are associated with the evolution of retinal layer thinning in people with MS (pwMS).MethodsFor this longitudinal observational study, we investigated pwMS from the Vienna MS database (VMSD), who had undergone (1) a diagnostic lumbar puncture (LP) between 2015 and 2020, and (2) simultaneous optical coherence tomography (OCT) and/or (3) a follow-up OCT scan. Linear stepwise regression models were calculated with OCT parameters (peripapillary retinal nerve fiber layer [pRNFL] thickness at LP and at follow-up, annualized loss of pRNFL thickness [aLpRNFL]) as a dependent variable, and CSF parameters (white blood cell [WBC] count, total protein [CSFTP], CSF/serum albumin ratio [Qalb], intrathecal synthesis of immunoglobulins, neurofilament light chain [NfL] in both CSF and serum [CSFNfL/sNfL]) as independent variables adjusted for age, sex, and disease duration.ResultsWe analyzed 61 pwMS (median age 30.0 years [interquartile range 25.5–35.0], 57.4% female, median disease duration 1.0 month [IQR 0–2.0] before LP, median follow-up 1.9 years [IQR 1.1–3.5]). CSFNfL and sNfL measurements were available in 26 and 31 pwMS, respectively. pRNFL thickness at LP was inversely associated with the CSF WBC count (β = −0.36; 95% CI −0.51, −0.08; p = 0.008). We did not find any association between other CSF parameters, including CSFNfL, sNfL, and aLpRNFL.ConclusionsIncreased WBC count as an indicator of acute inflammation and blood-brain-barrier breakdown seems to be associated with the amount of retinal thickness already lost at the time of LP. However, neither routine CSF parameters nor a singular NfL measurement allows the prediction of future retinal thinning.

The expense of sending cerebrospinal fluid for analysis on all lumbar punctures in pediatric acute lymphoblastic leukemia patients.

Central nervous system (CNS) relapse in pediatric acute lymphoblastic leukemia (ALL) patients is uncommon. The cerebrospinal fluid (CSF) of patients with ALL is routinely sampled at each intrathecal chemotherapy treatment to screen for CNS relapse. The analysis of CSF is both time consuming and resource intensive and must be completed approximately 20 times per patient throughout treatment. Our objective was to examine the expense of routine screening on all CSF samples for CNS relapse in ALL patients, and to identify if CNS relapse can be detected clinically. We identified all patients diagnosed with ALL at the Children's Hospital of Eastern Ontario (CHEO) between January 2001 and June 2021. We collected the total number of CSF samples in these patients and the number of CSF samples positive for CNS relapse. An in-depth chart review on the patients who relapsed in the CNS was completed to identify symptoms at relapse. Over the study period, 351 patients were diagnosed with ALL and underwent a total of 6515 lumbar punctures (LPs), each of which examined the CSF. The cost of CSF sample analysis is $14.32 (Canadian dollars [CDN]); thus, the total cost for the study sample was $93,294.80 (CDN). There were 14 CNS relapses and although symptoms including headache, vomiting, and fatigue were common, two patients were asymptomatic at relapse. Given the marginal cost of routine CSF screening and the lack of specific and sensitive symptoms for CNS relapse, we conclude that the routine practice of sending all CSF samples for analysis of CNS relapse in ALL patients is relatively inexpensive and beneficial.

Blood amyloid and tau biomarkers as predictors of cerebrospinal fluid profiles

IntroductionBlood biomarkers represent a major advance for improving the management, diagnosis, and monitoring of Alzheimer's disease (AD). However, their context of use in relation to routine cerebrospinal fluid (CSF) analysis for the quantification of amyloid peptides and tau proteins remains to be determined.MethodsWe studied in two independent cohorts, the performance of blood biomarkers in detecting “nonpathological” (A−/T−/N−), amyloid (A+) or neurodegenerative (T+ /N+) CSF profiles.ResultsPlasma Aβ1–42/Aβ1–40 ratio and phosphorylated tau (p-tau(181)) were independent and complementary predictors of the different CSF profile and in particular of the nonpathological (A−/T−/N−) profile with a sensitivity and specificity close to 85%. These performances and the corresponding biomarker thresholds were significantly different from those related to AD detection.ConclusionThe use of blood biomarkers to identify patients who may benefit from secondary CSF testing represents an attractive stratification strategy in the clinical management of patients visiting memory clinics. This could reduce the need for lumbar puncture and foreshadow the use of blood testing on larger populations.

Cerebrospinal fluid findings in COVID-19: a multicenter study of 150 lumbar punctures in 127 patients

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

Role and Relevance of Cerebrospinal Fluid Cells in Diagnostics and Research: State-of-the-Art and Underutilized Opportunities.

Cerebrospinal fluid (CSF) has recently experienced a revival in diagnostics and research. However, little progress has been made regarding CSF cell analysis. For almost a century, CSF cell count and cytomorphological examination have been central diagnostic parameters, with CSF pleocytosis as a hallmark finding of neuroinflammation and cytology offering valuable clues regarding infectious, autoimmune, and malignant aetiologies. A great deal of information, however, remains unattended as modern immune phenotyping technologies have not yet been broadly incorporated into routine CSF analysis. This is a serious deficit considering the central role of CSF cells as effectors in central nervous system (CNS) immune defence and autoimmune CNS processes, and the diagnostic challenges posed by clinically overlapping infectious and immune-mediated CNS diseases. Here, we summarize historical, specimen-intrinsic, methodological, and technical issues determining the state-of-the-art diagnostics of CSF cells and outline future perspectives for this underutilized window into meningeal and CNS immunity.

Cerebrospinal fluid abnormalities in first- and multi-episode schizophrenia-spectrum disorders: impact of clinical and demographical variables

Multiple lines of evidence indicate that immunological and inflammatory alterations contribute at least in a subgroup to the pathophysiology of schizophrenia. In this retrospective chart review, we investigated whether clinical factors contribute to altered cerebrospinal fluid (CSF) findings in schizophrenia-spectrum disorders. Clinical data from electronic medical records of patients with psychotic disorders (ICD-10: F20-F29) who received routine CSF diagnostics at the Department of Psychiatry and Psychotherapy, LMU Munich, Germany, were included. Chi² tests for dichotomous outcomes and independent t tests for continuous outcomes were used to compare differences between groups. A total of 331 patients were included in the analyses (43.2% female and 56.8% male). The mean age was 37.67 years (±15.58). The mean duration of illness was 71.96 months (±102.59). In all, 40% (128/320) were first-episode psychosis (FEP) patients and 60% (192/320) were multi-episode psychosis (MEP) patients. Elevated CSF protein levels were found in 19.8% and elevated CSF/serum albumin ratios (QAlb) in 29.4% of the cases. Pleocytosis was found in 6.1% of patients. MEP patients showed significantly higher mean QAlb compared with FEP patients (t(304.57) = −2.75, p = 0.006), which did not remain significant after correcting for age. QAlb elevation occurred more frequently in men (X2(1) = 14.76, p = <0.001). For treatment resistance, family history, and cMRI alterations, no significant differences in CSF-related outcomes were detected. Our work extends other retrospective cohorts confirming a relevant degree of CSF alterations in schizophrenia-spectrum disorders and shows the difficulty to relate these alterations to clinical and disease course trajectories. More research is needed to develop treatment response predictors from CSF analyses.

Wykorzystanie Panelu FilmArray® Meningitis/Encephalitis w diagnostyce zakażeń ośrodkowego układu nerwowego u dzieci

Acute infection of the central nervous system (CNS) is a serious diagnostic and therapeutic problem. It is a potentially life-threatening condition, therefore any suspected central nervous system infection requires urgent diagnosis. The etiology of CNS infection is diverse and depends on many elements. Cerebrospinal fluid (CSF) examination confirms the infection of the CNS and identifies the causative agent. The available diagnostic methods have their limitations. Molecular tests, including the use of comprehensive molecular panels, such as Film Array Meningitis/Encephalitis, facilitate the precise diagnosis of the etiological factor, but they cannot and should not replace routine CSF tests, but should complement them.

Development and analytical characterization of novel tau Simoa assays targeting full‐length tau in CSF and mid‐tau in CSF and plasma

AbstractBackgroundBiofluid markers of neurodegeneration and neural injury have great potential to elucidate disease mechanisms and accelerate development of experimental therapeutics. Cerebrospinal fluid (CSF) tau and phosphorylated tau are established biomarkers for AD, while plasma (N‐terminal) tau and phosphorylated tau (p‐tau) are being evaluated as complementary markers in a more accessible biofluid.Tau is present in CSF and plasma in both full‐length and truncated forms, with great interest in characterizing and advancing these different forms as biomarkers to support clinical development. To contribute to the emerging research on tau fragments as biomarker, novel ultra‐sensitive immunoassays were developed targeting low‐abundant, non‐truncated full‐length (FL) tau in CSF and a mid‐region tau fragment in CSF and plasma.MethodSimoa assays were developed using monoclonal antibodies (mAbs) targeting mid‐region tau epitopes or epitopes on full‐length tau.Resulting assays were qualified and partially validated for analytical performance parameters: measuring range, specificity, repeatability, reproducibility and parallelism were assessed. Reagent and analyte stability were investigated by assessing hold time and freeze/thaw (F/T) stability. Paired clinical routine CSF and plasma samples were analysed (20 controls and 20 AD based upon CSF Aβ1‐42, t‐tau and p‐tau(T181) profile).ResultFL‐ and mid‐tau Simoa assays were analytically characterized, upscaled to bulk volumes and partially validated. Both assays had acceptable repeatability and reproducibility (%CV &lt;20%) for plasma and/or CSF. Parallelism was within acceptance criteria (ACC of 75‐125%; %CV &lt;20%) for FL‐tau in 4 CSF samples and for mid‐tau in 4 CSF and 4 plasma samples. Analyte stability was demonstrated up to 5 F/T cycles and for a hold‐time of 24h at 21°C with a %CV&lt;20%. Testing of clinical samples showed an increased CSF FL‐ (p&lt;0.005) and mid‐Tau (p&lt;0.0001) concentration in AD versus controls, whereas plasma mid‐tau did not increase.ConclusionA novel CSF assay for full length tau and a novel CSF/plasma assay for the mid‐tau fragment was developed, qualified and partially validated. The generated data indicated well‐performing tau assays available as RUO kits in pre‐clinical and clinical use in drug development programs.

Serum Immunoglobulin G Level and Neutrophils to Lymphocytes Ratio Associated with the Prognosis of Neuromyelitis Optica Spectrum Disorder.

To investigate the factors related to the prognosis of Neuromyelitis Optica Spectrum Disorder (NMOSD) in cerebrospinal fluid and peripheral blood examination. In this study, we enrolled 111 patients who were admitted to the First Affiliated Hospital of Zhengzhou University between January 2016 and January 2018 and diagnosed with NMOSD. The patients were divided into the relapse group (n = 48) and remission group (n = 67). Before treatment, all the patients underwent a routine Cerebrospinal Fluid (CSF) and peripheral blood test on the second morning of admission. The association between laboratory data and disease prognosis was evaluated. The immunoglobulin G (IgG) level in the serum showed a strong correlation with the relapse of patients, especially in the aquaporin-4-Antibody (AQP4-Ab) positive group (p < 0.01). A high level of serum IgG concentration was associated with the relapse of NMOSD, especially in the anti-AQP4 positive group. The area under the Receiver Operating Characteristic (ROC) curve of serum IgG level was 0.888 (p<0.001, 95%CI: 0.808-0.968). The ratio of Neutrophils to Lymphocytes (NLR) was associated with the disability degree of NMOSD patients in 3 years. The NLR value was a linear correlation with final Expanded Disability Status Scale (EDSS) scores; patients with a high level of NLR value presented an increased degree of disability in the following three years (R2 = 0.053, p= 0.015). The serum IgG level and NLR of first-attack patients were correlated with the prognosis of NMOSD.

Metagenomic Next Generation Sequencing in the Detection of Pathogens in Cerebrospinal Fluid of Patients After Alternative Donor Transplantation: A Feasibility Analysis.

Central nervous system (CNS) complications can occur in 9%–15% of patients after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The clinical manifestations of the CNS complications are non-specific, with most of them being disturbances of consciousness, convulsions, headaches, fever, and epilepsy, making it difficult to infer the cause of the complications based on clinical manifestations. We retrospectively analyzed the sensitivity and feasibility of metagenomic next generation sequencing (mNGS) in the diagnosis of CNS infections after allo-HSCT. Lumbar punctures were performed on 20 patients with CNS symptoms after receiving alternative donor HSCT(AD-HSCT) at the Affiliated Cancer Hospital of Zhengzhou University from February 2019 to December 2020, and their cerebrospinal fluid (CSF) was collected. The mNGS technique was used to detect pathogens in the CSF. Routine CSF testing, biochemical analyses, G experiments, GM experiments, ink staining, acid-fast staining, and bacterial cultures were carried out, and quantitative PCR (qPCR) tests were used to detect cytomegalovirus (CMV), Epstein-Barr virus (EBV), BK polyomavirus (BKPyV), and human alphaherpesvirus (HHV). A total of 29 tests were performed with 21 of them being positive. Of the five negative patients, three were diagnosed with a posterior reversible encephalopathy syndrome, one as having transplantation-associated thrombotic microangiopathy, and one with transient seizure caused by hypertension. Fifteen patients tested positive, of which four had single infections and eleven had mixed infections. Five cases of fungal infections, six cases of bacterial infections, and 13 cases of viral infections were detected. Among the 13 cases of viral infections, ten cases were CMV(HHV-5); three were BKPyV; two were Torque teno virus (TTV); Two were HHV-1,two were EBV(HHV4), and one each of HpyV5 and HHV-6B. Thirteen patients tested positive for virus while the qPCR detection method of 6 identical specimens were below the minimum detection limit(<1×103 U/ml). The mNGS technique is highly sensitive, and it can be used to diagnose CNS infections after allo-HSCT.

Cerebrospinal Fluid Pathologies in Schizophrenia-Spectrum Disorder-A Retrospective Chart Review.

The role of inflammatory processes in the etiology of schizophrenia is increasingly being investigated. A link between psychosis and inflammation measured with different biomarkers has been reported in the literature and needs to be further explored. To investigate the presence of inflammatory biomarkers in first-episode psychosis (FEP) we analyzed the largest available FEP cohort to date regarding routine CSF and blood diagnostics. We report a retrospective analysis of clinical data from all inpatients that were admitted to our tertiary care hospital with a ICD-10 diagnosis of F2x (schizophrenia-spectrum) between January 1, 2008 and August 1, 2018 and underwent a lumbar puncture. A total of n = 314 FEP patients were included in our sample. 42.7% patients (134/314) showed cerebrospinal fluid (CSF) alterations. Oligoclonal bands in the CSF were present in 21.8% of patients (67/307) with 12.4% (27/217) of patients presenting OCBs type 2 or 3. 15.8% (49/310) of our cohort revealed signs of blood-brain-barrier (BBB) dysfunction with increased albumin ratios. Mean serum CRP levels were 2.4 mg/l (SD = 9.5). CRP elevation was present in 116/280 cases (41.4%). This large retrospective analysis on FEP cohort greatly enriches the clinical data available on this population and contributes to the discussion around inflammation in psychosis. Of note, even though several inflammatory alterations were found both in CSF and in blood tests, we found no evidence for a significant relationship between peripheral inflammation and inflammatory CSF. Furthermore, no significant relationship between CSF alterations and peripheral inflammation measured with CRP could be established.

Cerebrospinal Fluid and Clinical Profiles in Adult Type 2-3 Spinal Muscular Atrophy Patients Treated with Nusinersen: An 18-Month Single-Centre Experience.

Background and ObjectivesNusinersen was approved as the first disease-modifying therapy in spinal muscular atrophy (SMA). Our aim was to analyse therapy-related changes in cerebrospinal fluid (CSF) and serum parameters of adult type 2–3 SMA and to correlate biochemical data with motor functional status.MethodsNine adult SMA type 2–3 patients and ten control subjects without neurodegenerative diseases were included in our single-centre study. Cross-sectional analysis of CSF routine parameters, CSF neurofilament light chain, CSF Tau, CSF phospho-Tau and serum creatinine was performed between SMA patients at baseline (T0) and control subjects. The above-mentioned fluid parameters were longitudinally analysed in the SMA cohort after loading dose (T1) and after four maintenance doses (T2, T3, T4, T5). Hammersmith Functional Motor Scale Expanded (HFMSE), Revised Upper Limb Module (RULM) and the 6-minute walking test (6MWT) were used to evaluate motor outcomes.ResultsImprovements in HFMSE, RULM and 6MWT were observed only after the loading dose of nusinersen. No significant differences in routine CSF parameters and CSF markers of neurodegeneration were found between SMA patients and control subjects. Serum creatinine levels were significantly lower in SMA patients than in control subjects. CSF/serum albumin ratio (Qalb) significantly increased from T0 to each time point, without any further increase after the maintenance doses. Persistent systemic oligoclonal bands (OCBs) were found in five patients from baseline. Three more patients developed persistent systemic OCBs from T1; one patient showed intrathecal OCBSs from baseline to T5. Markers of neurodegeneration did not change during the follow-up and did not correlate with motor scores at baseline and at each timepoint. Serum creatinine levels significantly correlated with HFMSE and RULM at each time point.ConclusionsThe increase of the Qalb values and the development of systemic OCBs in some SMA patients could be due to repeated lumbar puncture and to the immunogenic effect of nusinersen. On the other hand, the presence of OCBs in serum and/or CSF at baseline should be further investigated. Furthermore, biomarkers of neurodegeneration did not play a prognostic role in our cohort of adult SMA patients.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40261-021-01071-0.

Cerebrospinal fluid cell count variability is a major confounding factor in external ventricular drain-associated infection surveillance diagnostics: a prospective observational study

BackgroundExternal ventricular drain (EVD)-related infections (EVDIs) are feared complications that are difficult to rapidly and correctly diagnose, which can lead to unnecessary treatment with broad-spectrum antibiotics. No readily available diagnostic parameters have been identified to reliably predict or identify EVDIs. Moreover, intraventricular hemorrhage is common and affect cerebrospinal fluid (CSF) cellularity. The relationship between leukocytes and erythrocytes is often used to identify suspected infection and triggers the use of antibiotics pending results of cultures, which may take days. Cell count based surveillance diagnostics assumes a homogeneous distribution of cells in the CSF. Given the intraventricular sedimentation of erythrocytes on computed tomography scans this assumption may be erroneous and could affect diagnostics.AimsTo evaluate the consistency of cell counts in serially sampled CSF from EVDs, with and without patient repositioning, to assess the effect on infection diagnostics.MethodsWe performed a prospective single-center study where routine CSF sampling was followed by a second sample after 10 min, allocated around a standard patient repositioning, or not. Changes in absolute and pairwise cell counts and ratios were analyzed, including mixed regression models.ResultsData from 51 patients and 162 paired samples were analyzed. We observed substantial changes in CSF cellularity as the result of both resampling and repositioning, with repositioning found to be an independent predictor of bidirectional cellular change. Glucose and lactate levels were affected, however clinically non-significant. No positive CSF cultures were seen during the study. Thirty percent (30%) of patients changed suspected EVDI status, as defined by the cell component of local and national guidelines, when resampling after repositioning.ConclusionsCSF cell counts are not consistent and are affected by patient movement suggesting a heterogeneity in the intraventricular space. The relationship between leukocytes and erythrocytes was less affected than absolute changes. Importantly, cell changes are found to increase with increased cellularity, often leading to changes in suspected EVDI status. Faster and more precise diagnostics are needed, and methods such as emerging next generation sequencing techniques my provide tools to more timely and accurately guide antibiotic treatment.Trial Registration NCT04736407, Clinicaltrials.gov, retrospectively registered 2nd February 2021.

Routine cerebrospinal fluid parameters as biomarkers in first-episode psychosis: A prospective observational study

In recent years, multiple studies have investigated the role of biomarkers in first-episode psychosis (FEP) to facilitate early diagnosis, disease stratification, therapeutic choice and outcome prediction. Few studies have focused on cerebrospinal fluid (CSF) investigations. In this prospective observational study, 95 FEP inpatients were followed up for one year. A lumbar puncture was performed at index admission (baseline) to study the CSF parameters (glucose, total proteins, lactate dehydrogenase [LDH], and pleocytosis). At the baseline visit, the clinical assessment included prodromal (psychotic and non-psychotic) symptoms before the psychotic outbreak and psychopathology at admission. The SCID-I was administered to obtain a clinical diagnosis at baseline and at 12 months. The relationship between prodromal and psychopathology symptoms at the baseline visit was tested with multiple linear regression. Multinomial logistic regression was also used to explore the association between CSF biomarkers and longitudinal diagnoses at follow-up (schizophrenia/schizoaffective disorder vs unipolar/bipolar depression vs other psychoses). Higher CSF glucose was associated with depressive (Standardized beta = 0.27, p = 0.041) and disorganized/concrete symptoms (Standardized beta = 0.33, p = 0.023) and lower CSF LDH was associated with prodromal symptoms (Standardized beta = −0.25, p = 0.042). Lower LDH concentrations were also associated with social withdrawal (r = −0.342, p = 0.001). CSF glucose was a predictor of the long-term diagnosis (lower CSF concentrations were associated with schizophrenia or schizoaffective disorder diagnoses [OR = 0.88, CI95%: 0.77–0.99). Our study suggests that CSF biomarkers that involve bioenergetic systems are associated with prodromal symptoms and the phenotype of psychotic disorders during the early stages of the disease.