Cerebrospinal Fluid White Cell Count Research Articles

Bacterial load in cerebrospinal fluid predicts unfavourable outcome in pneumococcal meningitis: a prospective nationwide cohort study

ObjectivesThe objective of this study was to determine the role of cerebrospinal fluid (CSF) bacterial load in adults with pneumococcal meningitis. MethodsWe quantified bacterial load in CSF samples from the diagnostic lumbar puncture of adults with community-acquired pneumococcal meningitis. We also measured CSF concentrations of complement component 5a (C5a), and determined associations between bacterial load, clinical characteristics, C5a and unfavourable outcome (Glasgow Outcome Scale score <5). ResultsBacterial load was quantified in 152 CSF samples. Median age of these patients was 61 years (interquartile range [IQR] 51–68), and 69 of 152 (45%) were female. Median CSF bacterial load was 1.6 × 104 DNA copies/mL (IQR 3.4 × 103–1.2 × 105), and did not correlate with CSF white cell count nor with CSF protein concentrations. Median CSF C5a concentration was 35.8 mg/L (IQR 15.9–105.6), and was moderately correlated with CSF bacterial loads (Spearman's rho = 0.42; p < 0001). High bacterial loads were associated with development of complications, such as circulatory shock (OR per logarithmic increase: 2.4, 95% CI: 2.0–2.9; p < 0.001) and cerebrovascular complications [OR: 1.9, 95% CI: 1.6–2.3; p < 0.001]). High bacterial loads were also associated with unfavourable outcome (OR: 2.8, 95% CI: 2.4–3.3; p < 0.001) and death (OR: 3.1, 95% CI: 2.6–3.8; p < 0.001). In a multivariable regression model including age, immunocompromised state, extrameningeal infection focus, admission Glasgow Coma Scale score and CSF C5a concentration, CSF bacterial load remained an independent predictor of unfavourable outcome (adjusted OR: 2.5, 95% CI: 1.6–3.9; p < 0.001). DiscussionHigh CSF bacterial load predicts the development of complications and unfavourable outcome in adults with pneumococcal meningitis.

Systemic inflammation response index is a useful indicator in distinguishing MOGAD from AQP4-IgG-positive NMOSD.

To identify reliable immune-inflammation indicators for distinguishing myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) from anti-aquaporin-4 immunoglobulin G (AQP4-IgG)-positive neuromyelitis optica spectrum disorders (NMOSD). To assess these indicators' predictive significance in MOGAD recurrence. This study included 25 MOGAD patients, 60 AQP4-IgG-positive NMOSD patients, and 60 healthy controls (HCs). Age and gender were matched among these three groups. Participant clinical and imaging findings, expanded disability status scale (EDSS) scores, cerebrospinal fluid (CSF) information, and blood cell counts were documented. Subsequently, immune-inflammation indicators were calculated and compared among the MOGAD, AQP4-IgG-positive NMOSD, and HC groups. Furthermore, we employed ROC curve analysis to assess the predictive performance of each indicator and binary logistic regression analysis to assess potential risk factors. In MOGAD patients, systemic inflammation response index (SIRI), CSF white cell count (WCC), and CSF immunoglobulin A (IgA) levels were significantly higher than in AQP4-IgG-positive NMOSD patients (p = 0.038, p = 0.039, p = 0.021, respectively). The ROC curves showed that SIRI had a sensitivity of 0.68 and a specificity of 0.7 for distinguishing MOGAD from AQP4-IgG-positive NMOSD, with an AUC of 0.692 (95% CI: 0.567-0.818, p = 0.0054). Additionally, compared to HCs, both MOGAD and AQP4-IgG-positive NMOSD patients had higher neutrophils, neutrophil-to-lymphocyte ratio (NLR), SIRI, and systemic immune-inflammation index (SII). Eight (32%) of the 25 MOGAD patients had recurrence within 12 months. We found that the monocyte-to-lymphocyte ratio (MLR, AUC = 0.805, 95% CI = 0.616-0.994, cut-off value = 0.200, sensitivity = 0.750, specificity = 0.882) was an effective predictor of MOGAD recurrence. Binary logistic regression analysis showed that MLR below 0.200 at first admission was the only risk factor for recurrence (p = 0.005, odds ratio =22.5, 95% CI: 2.552-198.376). Elevated SIRI aids in distinguishing MOGAD from AQP4-IgG-positive NMOSD; lower MLR levels may be linked to the risk of MOGAD recurrence.

Basic CSF parameters and MRZ reaction help in differentiating MOG antibody-associated autoimmune disease versus multiple sclerosis.

Myelin oligodendrocyte glycoprotein antibody-associated autoimmune disease (MOGAD) is a rare monophasic or relapsing inflammatory demyelinating disease of the central nervous system (CNS) and can mimic multiple sclerosis (MS). The variable availability of live cell-based MOG-antibody assays and difficulties in interpreting low-positive antibody titers can complicate diagnosis. Literature on cerebrospinal fluid (CSF) profiles in MOGAD versus MS, one of the most common differential diagnoses, is scarce. We here analyzed the value of basic CSF parameters to i) distinguish different clinical MOGAD manifestations and ii) differentiate MOGAD from MS. This is retrospective, single-center analysis of clinical and laboratory data of 30 adult MOGAD patients and 189 adult patients with relapsing-remitting multiple sclerosis. Basic CSF parameters included CSF white cell count (WCC) and differentiation, CSF/serum albumin ratio (QAlb), intrathecal production of immunoglobulins, CSF-restricted oligoclonal bands (OCB) and MRZ reaction, defined as intrathecal production of IgG reactive against at least 2 of the 3 viruses measles (M), rubella (R) and varicella zoster virus (Z). MOGAD patients with myelitis were more likely to have a pleocytosis, a QAlb elevation and a higher WCC than those with optic neuritis, and, after review and combined analysis of our and published cases, they also showed a higher frequency of intrathecal IgM synthesis. Compared to MS, MOGAD patients had significantly more frequently neutrophils in CSF and WCC>30/µl, QAlb>10×10-3, as well as higher mean QAlb values, but significantly less frequently CSF plasma cells and CSF-restricted OCB. A positive MRZ reaction was present in 35.4% of MS patients but absent in all MOGAD patients. Despite these associations, the only CSF parameters with relevant positive likelihood ratios (PLR) indicating MOGAD were QAlb>10×10-3 (PLR 12.60) and absence of CSF-restricted OCB (PLR 14.32), whereas the only relevant negative likelihood ratio (NLR) was absence of positive MRZ reaction (NLR 0.00). Basic CSF parameters vary considerably in different clinical phenotypes of MOGAD, but QAlb>10×10-3 and absence of CSF-restricted OCB are highly useful to differentiate MOGAD from MS. A positive MRZ reaction is confirmed as the strongest CSF rule-out parameter in MOGAD and could be useful to complement the recently proposed diagnostic criteria.

[Analysis of the clinical characteristics of 25 cases with parenchymal neuro-Behcet's disease].

Objective: To retrospectively investigate the clinical data, radiological characteristics, treatment, and outcome of patients with parenchymal neuro-Behcet's disease (P-NBD) with particular emphasis on dizziness. Methods: This was a cross-sectional study of clinical data from 25 patients with a confirmed diagnosis of P-NBD who were admitted to the Department of Neurology of the First Medical Center of Chinese People's Liberation Army General Hospital between 2010 and 2022. The median age of the population was 37 years (range: 17-85 years). Clinical data were retrospectively analyzed, including gender, age of onset, disease duration, clinical manifestations, serum immune indicators, cerebrospinal fluid (CSF) routine biochemical and cytokine levels, cranial and spinal magnetic resonance imaging (MRI) findings, treatment, and outcome. Results: The majority of patients were male (16 cases; 64.0%), the mean age of onset was (28±14) (range: 4-58 years), and the disease course was acute or subacute. Fever was the most common clinical presentation, and the complaint of dizziness was not uncommon (8/25 patients). Analysis of serum immune indices, including complement (C3 and C4), erythrocyte sedimentation rate, interleukin-1 (IL-1), IL-6, IL-8 and tumor necrotic factor-alpha were abnormal in 80.0% of patients (20/25). Most of the 16/25 patients who underwent lumbar puncture tests had normal intracranial pressure and increased CSF white cell count and protein [median values were 44 (15-380) ×106/L and 0.73 (0.49-2.81) g/L, respectively]. Of the five patients who underwent CSF cytokine tests, four patients had abnormal results; of these, an elevated level of IL-6 was most common, followed by IL-1 and IL-8. The most common site of involvement in cranial MRI was the brainstem and basal ganglia (60.0% respectively), followed by white matter (48.0%) and the cortex (44.0%). Nine cases (36.0%) showed lesions with enhancement and six cases (24.0%) showed mass-like lesions. Three patients (12.0%) patients had lesions in the spinal cord, most frequently in the thoracic cord. All patients received immunological intervention therapy; during follow up, the majority had a favorable outcome. Conclusions: P-NBD is an autoimmune disease with multiple system involvement and diverse clinical manifestations. The symptom of dizziness is not uncommon and can be easily ignored. Early treatment with immunotherapy is important and can improve the outcome of these patients.

Differentiating neurosarcoidosis from multiple sclerosis using combined analysis of basic CSF parameters and MRZ reaction.

Neurosarcodosis is one of the most frequent differential diagnoses of multiple sclerosis (MS) and requires central nervous system (CNS) biopsy to establish definite diagnosis according to the latest consensus diagnostic criteria. We here analyzed diagnostic values of basic cerebrospinal fluid (CSF) parameters to distinguish neurosarcoidosis from MS without CNS biopsy. We retrospectively assessed clinical, radiological and laboratory data of 27 patients with neurosarcoidosis treated at our center and compared following CSF parameters with those of 138 patients with relapsing-remitting MS: CSF white cell count (WCC), CSF/serum albumin quotient (Qalb), intrathecal production of immunoglobulins including oligoclonal bands (OCB), MRZ reaction, defined as a polyspecific intrathecal production of IgG reactive against ≥2 of 3 the viruses measles (M), rubella (R), and zoster (Z) virus, and CSF lactate levels. Additional inflammatory biomarkers in serum and/or CSF such as neopterin, soluble interleukin-2 receptor (sIL-2R) and C-reactive protein (CRP) were assessed. There was no significant difference in the frequency of CSF pleocytosis, but a CSF WCC > 30/μl was more frequent in patients with neurosarcoidosis. Compared to MS, patients with neurosarcoidosis showed more frequently an increased Qalb and CSF lactate levels as well as increased serum and CSF levels of sIL-2R, but a lower frequency of intrathecal IgG synthesis and positive MRZ reaction. Positive likelihood ratio (PLR) of single CSF parameters indicating neurosarcoidosis was highest, if (a) CSF WCC was >30/μl (PLR 7.2), (b) Qalb was >10 × 10-3 (PLR 66.4), (c) CSF-specific OCB were absent (PLR 11.5), (d) CSF lactate was elevated (PLR 23.0) or (e) sIL-2R was elevated (PLR>8.0). The combination of (a) one of three following basic CSF parameters, i.e., (a.1.) CSF WCC >30/ul, or (a.2.) QAlb >10 × 10-3, or (a.3.) absence of CSF-specific OCB, and (b) absence of positive MRZ reaction showed the best diagnostic accuracy (sensitivity and specificity each >92%; PLR 12.8 and NLR 0.08). Combined evaluation of basic CSF parameters and MRZ reaction is powerful in differentiating neurosarcoidosis from MS, with moderate to severe pleocytosis and QAlb elevation and absence of intrathecal IgG synthesis as useful rule-in parameters and positive MRZ reaction as a rule-out parameter for neurosarcoidosis.

Immune cell composition in unipolar depression: a comprehensive systematic review and meta-analysis.

Depression has been associated with inflammatory pathophysiological mechanisms, including alterations in amount of circulating immune cells. However, no meta-analysis within the past 20 years have reevaluated the circulating immune cells in blood and cerebrospinal fluid (CSF) from patients with depression compared to healthy controls. The aim of this study was to systematically evaluate the circulating immune cells in blood and CSF from patients with unipolar depression compared to healthy controls. Databases were searched up until February 12, 2021. Data-extraction was performed by two independent reviewers. 104 studies were included in the meta-analysis using fixed and random-effects models. Patients with depression had a significantly higher overall leukocyte count (35 studies; SMD, 0.46; 95% CI: 0.31-0.60, I2 = 68%), higher neutrophil count (24 studies; SMD, 0.52; 95% CI: 0.33-0.71, I2 = 77%) and higher monocyte count (27 studies; SMD, 0.32; 95% CI: 0.11-0.53, I2 = 77%) compared to healthy controls. Leukocyte counts were higher in inpatients, indicating a relation to depression severity. Furthermore, there were significant alterations in several lymphocyte subsets, including higher natural killer cells and T cell subsets. Higher neutrophil/lymphocyte ratio (11 studies; SMD = 0.24; 95% CI: 0.06-0.42, I2 = 73%), CD4/CD8 cell-ratio (26 studies; SMD = 0.14; 95% CI: 0.01-0.28, I2 = 42%) and T helper 17/T regulatory ratio (2 studies; SMD = 1.05; 95% CI: 0.15-1.95, I2 = 86%) were found in patients compared to healthy controls. CSF white cell count was higher in patients compared to controls (3 studies; SMD = 0.20; 95% CI: 0.01-0.38, I2 = 0%). There were no data for CSF cell subsets. This study suggests that there are several blood immune cell alterations in patients with unipolar depression compared to healthy controls, both in major leukocyte subsets and more specialized immune cell subsets.

Comparison of Suspected and Confirmed Internal External Ventricular Drain-Related Infections: A Prospective Multicenter United Kingdom Observational Study.

BackgroundDiagnosis of internal external ventricular drain (EVD)-related infections (iERI) is an area of diagnostic difficulty. Empiric treatment is often initiated on clinical suspicion. There is limited guidance around antimicrobial management of confirmed versus suspected iERI.MethodsData on patients requiring EVD insertion were collected from 21 neurosurgical units in the United Kingdom from 2014 to 2015. Confirmed iERI was defined as clinical suspicion of infection with positive cerebrospinal fluid (CSF) culture and/or Gram stain. Cerebrospinal fluid, blood, and clinical parameters and antimicrobial management were compared between the 2 groups. Mortality and Modified Rankin Scores were compared at 30 days post-EVD insertion.ResultsInternal EVD-related infection was suspected after 46 of 495 EVD insertions (9.3%), more common after an emergency insertion. Twenty-six of 46 were confirmed iERIs, mostly due to Staphylococci (16 of 26). When confirmed and suspected infections were compared, there were no differences in CSF white cell counts or glucose concentrations, nor peripheral blood white cell counts or C-reactive protein concentrations. The incidence of fever, meningism, and seizures was also similar, although altered consciousness was more common in people with confirmed iERI. Broad-spectrum antimicrobial usage was prevalent in both groups with no difference in median duration of therapy (10 days [interquartile range {IQR}, 7–24.5] for confirmed cases and 9.5 days [IQR, 5.75–14] for suspected, P = 0.3). Despite comparable baseline characteristics, suspected iERI was associated with lower mortality and better neurological outcomes.ConclusionsSuspected iERI could represent sterile inflammation or lower bacterial load leading to false-negative cultures. There is a need for improved microbiology diagnostics and biomarkers of bacterial infection to permit accurate discrimination and improve antimicrobial stewardship.

Plasma Complement 3 and Complement 4 Are Promising Biomarkers for Distinguishing NMOSD From MOGAD and Are Associated With the Blood-Brain-Barrier Disruption in NMOSD.

Background and ObjectiveNeuromyelitis optica spectrum disorders (NMOSD) and myelin oligodendrocyte glycoprotein antibody (MOG-IgG) associated disease (MOGAD) are autoimmune inflammatory demyelinating diseases of the central nervous system (CNS). As the clinical features of NMOSD are similar to MOGAD, diagnostic confusion exists between the two diseases. To better discriminate NMOSD from MOGAD, we investigated whether the plasma levels of complement 3 (C3) and complement 4 (C4) are different in NMOSD and MOGAD during the acute attacks of the diseases. We sought to determine whether C3 or C4 has an influence on the features of NMOSD.MethodsIn this observational study, data from 73 aquaporin-4 antibodies (AQP4-IgG) positive NMOSD patients and 22 MOG-IgG positive MOGAD patients were collected retrospectively. Demographics, clinical characteristics, plasma parameters, and cerebrospinal fluid (CSF) findings will be analyzed for comparability between the two groups. Immunoglobulin-G (IgG) and albumin were measured in both plasma and CSF. Plasma levels of C3 and C4 were measured and compared between the NMOSD, MOGAD, and 42 healthy controls (HC). The correlations between plasma C3, C4, and NMOSD clinical parameters were analyzed.ResultsThe ages of onset were later in the AQP4-IgG positive NMOSD group and females predominated, which differed from the MOGAD group, whose ages were younger and with a slight male preponderance. The AQP4-IgG positive NMOSD patients presented with the clinical symptoms of optic neuritis (ON) and transverse myelitis (TM), whereas encephalitis symptoms were more prevalent in MOGAD patients. CSF analysis shows that slight but not significantly higher white cell count (WCC) and protein were observed in the MOGAD group than in the AQP4-IgG positive NMOSD group. The plasma levels of IgG in MOGAD patients are significantly lower (p = 0.027) than in NMOSD patients. On the contrary, the plasma levels of albumin in MOGAD were higher than in NMOSD, which reached statistical significance (p = 0.039). Both the plasma C3 and C4 levels in the NMOSD group were significantly lower than in MOGAD and HC. The receiver operating characteristic (ROC) curve of the prediction model comprises C3 and C4 to distinguish NMOSD from MOGAD [area under the curve (AUC): 0.731, 0.645], which are considered to have discriminatory values. The results of Spearman’s analysis revealed that there was a significant positive correlation between the plasma C3 and the CSF WCC (r = 0.383, p = 0.040). There was an inverse correlation between plasma C4 and plasma IgG (r = -0.244, p = 0.038). Plasma C3 or C4 was significantly positively correlated with CSF albumin and Q-Alb, which is considered a measure of blood-brain barrier (BBB) disruption.ConclusionDuring the acute phase of NMOSD and MOGAD, plasma C3 and C4 may become potential biomarkers for distinguishing the two diseases and reflecting the NMOSD BBB damage.

MOG encephalomyelitis after vaccination against severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2): case report and comprehensive review of the literature

BackgroundIn around 20% of cases, myelin oligodendrocyte glycoprotein (MOG) immunoglobulin (IgG)-associated encephalomyelitis (MOG-EM; also termed MOG antibody-associated disease, MOGAD) first occurs in a postinfectious or postvaccinal setting.ObjectiveTo report a case of MOG-EM with onset after vaccination with the Pfizer BioNTech COVID-19 mRNA vaccine BNT162b2 (Comirnaty®) and to provide a comprehensive review of the epidemiological, clinical, radiological, electrophysiological and laboratory features as well as treatment outcomes of all published patients with SARS-CoV-2 vaccination-associated new-onset MOG-EM.MethodsCase report and review of the literature.ResultsIn our patient, MOG-IgG-positive (serum 1:1000, mainly IgG1 and IgG2; CSF 1:2; MOG-specific antibody index < 4) unilateral optic neuritis (ON) occurred 10 days after booster vaccination with BNT162b2, which had been preceded by two immunizations with the vector-based Oxford AstraZeneca vaccine ChAdOx1-S/ChAdOx1-nCoV-19 (AZD1222). High-dose steroid treatment with oral tapering resulted in complete recovery. Overall, 20 cases of SARS-CoV2 vaccination-associated MOG-EM were analysed (median age at onset 43.5 years, range 28–68; female to male ratio = 1:1.2). All cases occurred in adults and almost all after immunization with ChAdOx1-S/ChAdOx1 nCoV-19 (median interval 13 days, range 7–32), mostly after the first dose. In 70% of patients, more than one CNS region (spinal cord, brainstem, supratentorial brain, optic nerve) was affected at onset, in contrast to a much lower rate in conventional MOG-EM in adults, in which isolated ON is predominant at onset and ADEM-like phenotypes are rare. The cerebrospinal fluid white cell count (WCC) exceeded 100 cells/μl in 5/14 (36%) patients with available data (median peak WCC 58 cells/μl in those with pleocytosis; range 6–720). Severe disease with tetraparesis, paraplegia, functional blindness, brainstem involvement and/or bladder/bowel dysfunction and a high lesion load was common, and treatment escalation with plasma exchange (N = 9) and/or prolonged IVMP therapy was required in 50% of cases. Complete or partial recovery was achieved in the majority of patients, but residual symptoms were significant in some. MOG-IgG remained detectable in 7/7 cases after 3 or 6 months.ConclusionsMOG-EM with postvaccinal onset was mostly observed after vaccination with ChAdOx1-S/ChAdOx1 nCoV-19. Attack severity was often high at onset. Escalation of immunotherapy was frequently required. MOG-IgG persisted in the long term.

P1112: TREATING BING-NEEL SYNDROME USING A TAILORED APPROACH: EXPERIENCE OF A SPECIALIST NEUROHAEMATOLOGY CLINIC

Background: Bing-Neel syndrome (BNS) is a rare complication of lymphoplasmacytic lymphoma (LPL) comprising LPL infiltration in the central nervous system (CNS). Clinical and radiological features are diverse; the diagnosis is confirmed by cerebrospinal fluid (CSF) analysis using immunological and molecular techniques. Rarely, a tissue biopsy is required. The pattern of presentation including systemic involvement and CSF features inform treatment strategies, which include CNS-penetrating therapies. Aims: To evaluate the diagnostic characteristics of patients with BNS and their influence on therapy. Methods: Data from patients referred between 2011-2021 for management of BNS to our academic neurohaematology centre were retrospectively reviewed. Those with imaging features alone or where it was not possible to distinguish from high-grade transformation were excluded. Results: Thirty-five patients (22 male, 13 female) were identified. Median age at diagnosis of BNS was 65 years (range 48-85). All patients were symptomatic. In 12 patients (34%) BNS was the de novo presentation of the IgM-related disorder, of which 3 (25%) had no detectable bone marrow (BM) infiltration of LPL at diagnosis. Approximately half (17; 49%) had previously received therapy for LPL; median time to BNS diagnosis in these was 49 months (range 3-125). At BNS diagnosis, BM involvement with LPL ranged from 0-95%. More than half (14/26; 54%) had ≤10% infiltrate and almost a fifth (4/26) >60%. All patients had leptomeningeal involvement and 8 (23%) additionally had parenchymal CNS disease. The majority had kappa light-chain predominance: IgMκ (n=26), non-IgMκ (n=5), IgMλ (n=3), one unknown. The BNS diagnosis was made on CSF analysis (n=28; 80%), leptomeningeal tissue biopsy (n=3; 9%) where CSF was non-informative, or by expert opinion based on supportive clinical, radiological and non-definitive CSF features (n=4; 11%). Of those with a diagnosis based on CSF studies, B-cell clonality was confirmed by flow cytometry (27/28; 96%), MYD88L265P mutation (18/28; 64%) and immunoglobulin gene rearrangement (12/28; 43%). In 22 samples with a full dataset, median CSF white cell count was 25/ul (1-233), CSF protein 1.69g/l (0.35-6), CSF IgM 9.49mg/l (1.07-61.5). The majority were treated with intensive regimens (rituximab, methotrexate (MTX), cytarabine (ARA-C) ± thiotepa/idarubicin; n=30) due to the presence of CNS disease bulk and clinical need, and less commonly ibrutinib (n=3), bendamustine-rituximab (BR, n=1); one patient had intrathecal therapy (MTX, ARA-C) at the height of the COVID pandemic. Of those who received 2 cycles of intensive chemotherapy, 3 had ≥4 cycles followed by BCNU/thiotepa autologous stem cell transplant; 10 proceeded to ‘consolidation’ (indefinite) ibrutinib to limit intensive chemotherapy or tackle systemic disease. At a median follow up of 26 months (range 1-121), median survival was not reached; 2-year overall survival was 91% (95% CI 74-97). Three patients died during treatment (1 invasive fungal infection post COVID-19 during ibrutinib consolidation post MTX/ARA-C based therapy) and 2 during MTX-ARA-C based therapy; 7 patients relapsed or progressed and were treated with ibrutinib: 1 relapsed after ibrutinib use, 1 patient was intolerant of ibrutinib and switched to BR. Image:Summary/Conclusion: Our cohort confirms that BNS may present with leptomeningeal disease and/or parenchymal disease, de novo and without systemic disease. Overall outcomes are excellent with intensive regimens, consolidated with or followed by ibrutinib; however, there are treatment-related toxicities emphasising the need for a tailored approach.

Cerebrospinal fluid white cell count to red cell count ratio as a predictor of ventriculitis in patients with external ventricular drains.

External ventricular drain (EVD) associated ventriculitis is a complication of EVD placement associated with significant morbidity and mortality. Gold-standard for EVD associated bacterial ventriculitis diagnosis involves cerebrospinal fluid (CSF) sampling from the EVD with microscopy, culture and sensitivity testing. The ratio of white blood cells to red blood cells has anecdotally been considered a predictive factor in diagnosing EVD associated ventriculitis, however no study has been done demonstrating this. A retrospective cross-sectional study was designed to assess whether the ratio of CSF white blood cells to red blood cells could be used to diagnose EVD associated ventriculitis. Data was collected for all patients undergoing EVD insertion at a major neurosurgical unit in Sydney, Australia. A receiver operator characteristics (ROC) curve was used to determine if this ratio was useful, and Youden's index was calculated to determine the appropriate cut-off point. This sample of n=157 consecutive patients a total of 29 patients were diagnosed with ventriculitis. The area under the ROC curve was significant (0.706, P <0.001), and Youden's index demonstrated an appropriate cut-off point was a ratio of 1:106. CSF parameters have long been considered predictive of EVD associated ventriculitis. We demonstrated that using a component of routine testing it is possible to accurately predict a ventriculitis diagnosis. As the ratio is used, it enables discrimination in a raised white blood cell count due to local trauma with interventricular bleeding. CSF white blood cell to red blood cell ratio is an appropriate diagnostic test for ventriculitis.

Neuroinflammatory Biomarkers in Cerebrospinal Fluid From 106 Patients With Recent-Onset Depression Compared With 106 Individually Matched Healthy Control Subjects

BackgroundNeuroinflammation has been linked to depression; however, neuroinflammatory biomarkers in the cerebrospinal fluid (CSF) have not previously been thoroughly investigated in a large group of patients with recent-onset depression compared with healthy control subjects. MethodsWe conducted an individually matched case-control study comparing patients with recent-onset depression (ICD-10: F32) to control subjects. Primary outcomes were CSF white cell count (WCC), CSF-to-serum albumin ratio, CSF total protein, and immunoglobulin G (IgG) index. Secondary outcomes were CSF WCC differential count and CSF neutrophil-to-lymphocyte, CSF-to-serum IgG, and CSF-to-plasma glucose ratios. Linear models adjusting for sex and age were applied. ResultsWe included 106 patients with recent-onset depression (84.0% outpatients) and 106 healthy control subjects. Patients had 18% higher CSF WCC relative to control subjects (relative mean difference [MD]: 1.18; 95% CI: 1.02–1.40; p = .025). CSF WCC differed with depression symptomatology (p = .034), and patients with severe depression (n = 29) had 43% higher CSF WCC relative to control subjects (MD: 1.43; 95% CI: 1.13–1.80, p = .003). Two (1.9%) patients and no controls (0.0%) had CSF WCC above the normal range (>5 × 106/L). No significant differences between groups were observed regarding CSF-to-serum albumin ratio (MD: 1.07; 95% CI: 0.97–1.18; p = .191), CSF total protein (MD: 1.01; 95% CI: 0.94–1.09; p = .775), or IgG index (MD: 1.05; 95% CI: 0.97–1.15; p = .235). Regarding secondary outcomes, the proportion of CSF neutrophils was lower among patients (MD: 0.22; 95% CI: 0.08–0.59; p = .003) relative to control subjects, whereas the remaining outcomes were not significantly different (all p > .06). ConclusionsPatients had higher CSF WCC relative to control subjects, indicating increased neuroimmunologic activation, particularly for severe depression.

Value of cerebrospinal fluid white cell count and protein level in predicting leptomeningeal involvement by systemic aggressive B‐cell lymphoma

Diagnostic cerebrospinal fluid (CSF) analysis for patients with newly diagnosed aggressive B-cell lymphoma at risk of secondary central nervous system involvement typically includes multiparametric flow cytometry (MFC), cytology (CC), white cell count (WCC) and total protein. The strength of relationships between MFC results and the remaining variables has been disputed in small studies. We explored these relationships in a large homogeneous cohort of patient samples, aiming to establish the relationship between WCC and protein level and MFC results. Adult patients with aggressive B-cell lymphoma at risk of CNS involvement who underwent staging CSF analysis by MFC were identified retrospectively from institutional electronic records between October 2011 and December 2020. Three hundred and seventy eight samples, including 45 (11.9%) MFC+ samples, were analysed. The relative sensitivity of CC for MFC positivity was 0.38, with PPV of 0.68. Significantly higher median WCC (p<.001) and protein levels (p=.011) were seen in MFC+ vs. MFC- samples. MFC+CC+ (vs. MFC+CC- samples) demonstrated higher median neoplastic events and neoplastic cell concentration. WCC ≥36×106 /L and protein ≥1.12g/L cut-off values demonstrated the highest PPVs for MFC positivity (0.67 and 0.88, respectively). Statistically significant associations exist between elevated WCC and protein and MFC positivity, and selected WCC and protein cut-off values have PPVs comparable to that of cytological assessment. Whilst routine WCC and protein analysis may be unnecessary, WCC/protein values above these levels could be regarded as reasonable evidence of CSF involvement in the appropriate setting.

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.

Neuroimmunological investigations of cerebrospinal fluid in patients with recent onset depression \u2013 a study protocol

BackgroundA proinflammatory response has been suggested to be involved in the pathophysiology of depression in a subgroup of patients. However, comprehensive largescale studies on neuroimmunological investigations of the cerebrospinal fluid (CSF) are lacking and no largescale longitudinal CSF studies comparing patients with depression to healthy controls currently exist.MethodsA longitudinal case-control study including at least 100 patients with first time depression (ICD-10: F32) within the past year with ongoing symptoms and at least 100 sex and age matched healthy controls with collection of CSF, blood, and fecal samples. All individuals will be evaluated by neurological examination including neurological soft signs, interviewed for psychopathology assessment and have symptomatology evaluated by relevant rating scales. Level of functioning and quality of life will be evaluated by a panel of interview questions and rating scales, and cognitive function assessed by a relevant test battery. In addition, a large number of potential confounders will be registered (BMI, smoking status, current medication etc.). Primary outcomes: CSF white cell count, CSF/serum albumin ratio, CSF total protein levels, IgG index, CSF levels of IL-6 and IL-8, and the prevalence of any CNS-reactive autoantibody in CSF and/or blood. Secondary outcomes: exploratory analyses of a wide range of neuroimmunological markers and specific autoantibodies. Power calculations are computed for all primary outcomes based on previous CSF studies including patients with depression and healthy controls.DiscussionThis study will represent the hitherto largest investigation of CSF in patients with recent onset depression compared to healthy controls. We expect to elucidate neuroimmunological alterations in individuals with depression and characterize an immunological profile paving the way for the development of effective treatments based on biomarkers.Trial registrationThe study is approved by The Regional Committee on Health Research Ethics (Capital Region, j.no: H-16030985) and The Danish Data Protection Agency (j.no: RHP-2016-020, I-Suite no.: 04945).

Clinical Predictors of Encephalitis in UK Adults – A Multi-Centre Prospective Observational Cohort Study

Background: Encephalitis, brain inflammation and swelling, most often caused by an infection or the body’s immune defences, can have devastating consequences, especially if diagnosed late. We looked for clinical predictors of different types of encephalitis to help clinicians consider earlier treatment. Methods: We conducted a multicentre prospective observational cohort study (ENCEPH-UK) of adults (> 16 years) with suspected encephalitis at 31 UK hospitals. We evaluated clinical features and investigated for infectious and autoimmune causes. Findings: 341 patients were enrolled between December 2012 and December 2015 and followed up for 12 months. 233 had encephalitis, of whom 65 (28%) had herpes simplex virus (HSV), 38 (16%) had confirmed or probable autoimmune encephalitis, and 87 (37%) had no cause found. The median time from admission to 1st dose of aciclovir for those with HSV was 14 hours (IQR 5-50); time to 1st dose of immunosuppressant for the autoimmune group was 125 hours (IQR 45-250). Compared to non-HSV encephalitis, patients with HSV more often had fever, lower serum sodium and lacked a rash. Those with probable or confirmed autoimmune encephalitis were more likely to be female, have abnormal movements, normal serum sodium levels and a cerebrospinal fluid white cell count < 20 cells x106/L, but they were less likely to have a febrile illness. Interpretation: Initiation of treatment for autoimmune encephalitis is delayed considerably compared with HSV encephalitis. Clinical features can help identify patients with autoimmune disease and could be used to initiate earlier presumptive therapy. Clinical Trial Registration Details: Funding Information: National Institute for Health Research, UK. Declaration of Interests: None to declare. Ethics Approval Statement: The study protocols were approved by participating sites and the National Research Ethics Service (now part of the Health Research Authority) East Midlands Nottingham 1 committee (reference 11/EM/0442). Written consent for entry into the study was obtained from patients or an accompanying relative.

The utility of cerebrospinal fluid white cell count during the prognostic assessment for cryptococcal meningitis patients: a retrospective study

BackgroundThe incidence of cryptococcal meningitis (CM) has gradually increased in recent years. Cerebrospinal fluid (CSF) cytology and cell count are very important for CM on etiology diagnosis and assessment of disease status and therapeutic response. However, the clinical significance of CSF white cell count (WCC) in CM patients is not fully understood. Using longitudinal data of CSF WCC and its relationship with clinical outcomes in CM patients, we aimed to elucidate the clinical significance of this test.MethodsWe retrospectively analyzed the medical records of 150 CM patients admitted to our hospital between January 2008 and December 2018.ResultsCM patients with lower baseline CSF WCC, CSF protein concentration or CD4/CD8 ratio, and those with altered mentation or HIV coinfection were more likely to have poor clinical outcome (P<0.05). CM patients with triple therapy during the induction period presented with a better clinical outcome (P<0.05). Baseline CSF WCC had a moderate positive correlation with peripheral CD4+ T lymphocyte count (r = 0.738, P < 0.001) and CD4+ T lymphocyte percentage (r = 0.616, P < 0.001). The best cut-off value to predict a poor clinical outcome was 40 cells/μL during baseline CSF WCC. The predictive model incorporating longitudinal data of CSF WCC had better sensitivity, specificity, and accuracy than a model incorporating only baseline CSF WCC data.ConclusionsOur results indicated that baseline CSF WCC and changes in CSF WCC over time could be used to assess the prognosis of CM patients.

Phase 1–2 Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS

BackgroundTofersen is an antisense oligonucleotide that mediates the degradation of superoxide dismutase 1 (SOD1) messenger RNA to reduce SOD1 protein synthesis. Intrathecal administration of tofersen is being studied for the treatment of amyotrophic lateral sclerosis (ALS) due to SOD1 mutations.MethodsWe conducted a phase 1–2 ascending-dose trial evaluating tofersen in adults with ALS due to SOD1 mutations. In each dose cohort (20, 40, 60, or 100 mg), participants were randomly assigned in a 3:1 ratio to receive five doses of tofersen or placebo, administered intrathecally for 12 weeks. The primary outcomes were safety and pharmacokinetics. The secondary outcome was the change from baseline in the cerebrospinal fluid (CSF) SOD1 concentration at day 85. Clinical function and vital capacity were measured.ResultsA total of 50 participants underwent randomization and were included in the analyses; 48 participants received all five planned doses. Lumbar puncture–related adverse events were observed in most participants. Elevations in CSF white-cell count and protein were reported as adverse events in 4 and 5 participants, respectively, who received tofersen. Among participants who received tofersen, one died from pulmonary embolus on day 137, and one from respiratory failure on day 152; one participant in the placebo group died from respiratory failure on day 52. The difference at day 85 in the change from baseline in the CSF SOD1 concentration between the tofersen groups and the placebo group was 2 percentage points (95% confidence interval [CI], −18 to 27) for the 20-mg dose, −25 percentage points (95% CI, −40 to −5) for the 40-mg dose, −19 percentage points (95% CI, −35 to 2) for the 60-mg dose, and −33 percentage points (95% CI, −47 to −16) for the 100-mg dose.ConclusionsIn adults with ALS due to SOD1 mutations, CSF SOD1 concentrations decreased at the highest concentration of tofersen administered intrathecally over a period of 12 weeks. CSF pleocytosis occurred in some participants receiving tofersen. Lumbar puncture–related adverse events were observed in most participants. (Funded by Biogen; ClinicalTrials.gov number, NCT02623699; EudraCT number, 2015-004098-33.)

Drug-induced meningitis: A review of the literature and comparison with an historical cohort of viral meningitis cases

Drug-induced aseptic meningitis (DIAM) is potentially insufficiently considered by clinician, being of rare etiology, with there being no previously published exhaustive study describing its clinical and biological features. Two independent academic clinicians searched all the case reports of DIAM from 1995 until 15th April, 2017. The search was limited to studies performed in humans, published in English or French. Clinical and biological data of subjects were compared with those of patients with documented viral meningitis. One hundred and fifty-one case reports fulfilled our inclusion criteria. Non-steroidal anti-inflammatory drugs were the commonest drug cause of AM n=49, followed by antibiotics n=46, biotherapy n=19 and finally immunomodulators n=15. The clinical and biological presentation of DIAM varies according to the causative etiological drug, especially with respect to the interval between exposure and presentation and cerebrospinal fluid (CSF) pleiocytosis. Clinical symptoms associated with meningitis were more prevalent in viral meningitis than in DIAM, except for fever and signs of encephalitis. Cerebrospinal fluid examination in DIAM reveals an increased CSF white cell count and an increased proportion of neutrophils and protein, compared with viral meningitis. We present an extensive review of the DIAM case reports, and highlight their clinical and biological characteristics according to the drugs involved. While comparing for the first time their characteristics with those of viral meningitis, this review hopes in facilitate earlier diagnosis and management of DIAM in clinical practice.

Mortality in adult patients with culture-positive and culture-negative meningitis in the Botswana national meningitis survey: a prevalent cohort study

SummaryBackgroundCNS infections are a leading cause of HIV-related deaths in sub-Saharan Africa, but causes and outcomes are poorly defined. We aimed to determine mortality and predictors of mortality in adults evaluated for meningitis in Botswana, which has an estimated 23% HIV prevalence among adults.MethodsIn this prevalent cohort study, patient records from 2004–15 were sampled from the Botswana national meningitis survey, a nationwide audit of all cerebrospinal fluid (CSF) laboratory records from patients receiving a lumbar puncture for evaluation of meningitis. Data from all patients with culture-confirmed pneumococcal and tuberculous meningitis, and all patients with culture-negative meningitis with CSF white cell count (WCC) above 20 cells per μL were included in our analyses, in addition to a random selection of patients with culture-negative CSF and CSF WCC of up to 20 cells per μL. We used patient national identification numbers to link CSF laboratory records from the national meningitis survey to patient vital registry and HIV databases. Univariable and multivariable Cox proportional hazards models were used to evaluate clinical and laboratory predictors of mortality.FindingsWe included data from 238 patients with culture-confirmed pneumococcal meningitis, 48 with culture-confirmed tuberculous meningitis, and 2900 with culture-negative CSF (including 1691 with CSF WCC of up to 20 cells per μL and 1209 with CSF WCC above 20 cells per μL). Median age was 37 years (IQR 31–46), 1605 (50%) of 3184 patients were male, 2188 (72%) of 3023 patients with registry linkage had documentation of HIV infection, and median CD4 count was 139 cells per μL (IQR 63–271). 10-week and 1-year mortality was 47% (112 of 238) and 49% (117 of 238) for pneumococcal meningitis, 46% (22 of 48) and 56% (27 of 48) for tuberculous meningitis, and 41% (1181 of 2900) and 49% (1408 of 2900) for culture-negative patients. When the analysis of patients with culture-negative CSF was restricted to those with known HIV infection, WCC (0–20 cells per μL vs >20 cells per μL) was not predictive of mortality (average hazard ratio 0·93, 95% CI 0·80–1·09).InterpretationMortality from pneumococcal, tuberculous, and culture-negative meningitis was high in this setting of high HIV prevalence. There is an urgent need for improved access to diagnostics, to better define aetiologies and develop novel diagnostic tools and treatment algorithms.FundingNational Institutes of Health, President's Emergency Plan for AIDS Relief, National Institute for Health Research.