Cerebral Spinal Fluid Protein Research Articles

Immune-related encephalitis after immune checkpoint inhibitor therapy.

Immune checkpoint inhibitors (ICI) have revolutionized cancer treatment but can trigger immune-related encephalitis. We report one of the largest case series of patients with immune-related encephalitis and review of the literature. Retrospective series of patients with immune-related encephalitis and literature review. Fourteen patients with cancer treated with ICI (50% combination therapy) developed immune-related encephalitis. Diagnostic testing revealed cerebral spinal fluid (CSF) lymphocytic pleocytosis (85%) and elevated protein (69%), abnormal brain magnetic resonance imaging(MRI) (33%) or brain FDG-PET (25%), electroencephalogram (EEG) abnormalities (30%), and autoantibodies (31%). Encephalitis treatment included: corticosteroids (86%), intravenous immunoglobulin (IVIg) (36%), plasmapheresis (7%), and rituximab (29%). There were no deaths and 12 patients had significant recovery, although long-term complications were observed. All patients discontinued ICI. Longitudinal follow-up demonstrated anti-cancer response to ICI at 3 months (85%) and 6 months post-ICI initiation (77%). A literature review identified 132 patients with immune-related encephalitis. Most were treated with PD-1 inhibitors (18% combination). Common abnormalities included elevated CSF protein (84%) or pleocytosis (77%), abnormal brain MRI (65%), or autoantibodies (47%). Nearly all were treated with corticosteroids, many required additional therapy with IVIg (26%) or rituximab (12%). Most patients had clinical improvement (81%) but a minority (10%) had a clinical relapse after completing corticosteroid taper. ICIs were resumed in 7 patients (5%), with relapse in 3. Immune-related encephalitis is treatable and improves with corticosteroids in most cases but may require additional immunosuppression. Re-emergence of encephalitis is rare and does not typically result in adverse outcomes, and this should be considered in neurological immune-related adverse event management guidelines.

Recurrent CNTN1 antibody-positive nodopathy: a case report and literature review

BackgroundContactin-1 (CNTN1) antibody-positive nodopathy is rare and exhibits distinct clinical symptoms such as tremors and ataxia. However, the mechanisms of these symptoms and the characteristics of the cerebral spinal fluid (CSF) remain unknown.Case presentationHere, we report a case of recurrent CNTN1 antibody-positive nodopathy. Initially, a 45-year-old woman experiencing numbness in the upper limbs and weakness in the lower limbs was diagnosed with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Eleven years later, her symptoms worsened, and she began to experience tremors and ataxia. Tests for serum CNTN1, GT1a, and GQ1b antibodies returned positive. Subsequently, she was diagnosed with CNTN1 antibody-positive nodopathy and underwent plasmapheresis therapy, although the treatment’s efficacy was limited. To gain a deeper understanding of the disease, we conducted a comprehensive literature review, identifying 52 cases of CNTN1 antibody-positive nodopathy to date, with a tremor prevalence of 26.9%. Additionally, we found that the average CSF protein level in CNTN1 antibody-positive nodopathy was 2.57 g/L, with 87% of patients exhibiting a CSF protein level above 1.5 g/L.ConclusionWe present a rare case of recurrent CNTN1 antibody-positive nodopathy. Our findings indicate a high prevalence of tremor (26.9%) and elevated CSF protein levels among patients with CNTN1 antibody-positive nodopathy.

BIOM-52. PROTEOMIC PROFILE OF CEREBROSPINAL FLUID IN MEDULLOBLASTOMA AND THEIR RELATED EXTRACELLULAR VESICLE PROTEIN

Abstract The development of a sensitive diagnostic method for medulloblastoma (MBL), a common malignant brain tumor in children, is still a challenge. Cerebral spinal fluid (CSF) contains various substances such as soluble proteins and extracellular vesicles (EVs) and may reflect pathological changes in the central nervous system. Especially, EVs within CSF have great potential in the dynamic monitoring and intervention strategies of MBL. This study attempted to determine whether the total CSF protein selected based on proteome information distinguished from the CSF in MBL is also considered in EVs cargo proteins. CSF samples from patients with MBL (N = 44) and hydrocephalus (HC, control, N = 18) were analyzed with LC-MS. A machine-learning approach was used to identify protein biomarkers discriminating MBL CSF. The biomarker potential of the selected proteins was verified through ELISA and ROC analysis. TEM, Nanosight, and Exoview systems were used to analyze the physiological and biological characteristics of proteins in EVs from MBL CSF. Proteomic analysis revealed four elevated soluble proteins (Transketolase (TKT), SPTBN1, HSP90AA1 and NME1-NME2) in MBL CSF. Verification of the selected proteins in whole CSF confirms that TKT was significantly elevated in MBL than in HC. Importantly, the AUC value of TKT was 0.94, which was recognized as an excellent diagnostic marker. In additional TKT analysis, when MBL was divided into subtypes, Group 4 was the most significant compared to HC, and when divided into metastasis group, metastasis was more significant than non-metastatic compared to HC. Consistently, TKT was more abundant in MBL CSF EVs compared to HC CSF EVs. Our results provide insights into the relevance of the proteins in CSF to the cargo proteins reflected in EVs, while also proposing TKT in CSF EVs as an MBL diagnostic marker.

Cerebral Spinal Fluid Parameters Following CD19-Targeted Therapies in Children and Young Adults.

The presence of leukocytes in the cerebral spinal fluid (CSF) of patients with acute lymphoblastic leukemia may indicate a relapse in the central nervous system. CD19-directed immunotherapy may increase the blood-brain barrier permeability, leading to neurologic toxicity and infiltrate the CNS. We studied the CSF cell and protein content in 71 consecutive patients who received either CD19 chimeric antigen receptor T cells or blinatumomab. Responding patients had an incidence of 66% and 61% of pleocytosis following blinatumomab or chimeric antigen receptor T cells, respectively. CSF parameters did not correlate with toxicity or prior CNS disease. Routine CSF flow cytometry following immunotherapy to distinguish T-cell infiltration from CNS relapse should be considered.

Identification of cerebral spinal fluid protein biomarkers in Niemann-Pick disease, type C1

BackgroundNiemann-Pick disease, type C1 (NPC1) is an ultrarare, recessive, lethal, lysosomal disease characterized by progressive cerebellar ataxia and cognitive impairment. Although the NPC1 phenotype is heterogeneous with variable age of onset, classical NPC1 is a pediatric disorder. Currently there are no therapies approved by the FDA and therapeutics trials for NPC1 are complicated by disease rarity, heterogeneity, and the relatively slow rate of neurological decline. Thus, identification of disease relevant biomarkers is necessary to provide tools that can support drug development efforts for this devastating neurological disease.MethodsProximal extension assays (O-link® Explore 1536) were used to compare cerebrospinal fluid (CSF) samples from individuals with NPC1 enrolled in a natural history study and non-NPC1 comparison samples. Relative expression levels of 1467 proteins were determined, and candidate protein biomarkers were identified by evaluating fold-change and adjusted Kruskal–Wallis test p-values. Selected proteins were orthogonally confirmed using ELISA. To gain insight into disease progression and severity we evaluated the altered protein expression with respect to clinically relevant phenotypic aspects: NPC Neurological Severity Score (NPC1 NSS), Annual Severity Increment Score (ASIS) and age of neurological onset.ResultsThis study identified multiple proteins with altered levels in CSF from individuals with NPC1 compared to non-NPC1 samples. These included proteins previously shown to be elevated in NPC1 (NEFL, MAPT, CHIT1, CALB1) and additional proteins confirmed by orthogonal assays (PARK7, CALB2/calretinin, CHI3L1/YKL-40, MIF, CCL18 and ENO2). Correlations with clinically relevant phenotypic parameters demonstrated moderate negative (p = 0.0210, r = -0.41) and possible moderate positive (p = 0.0631, r = 0.33) correlation of CSF CALB2 levels with age of neurological onset and ASIS, respectively. CSF CHI3L1 levels showed a moderate positive (p = 0.0183, r = 0.40) correlation with the concurrent NPC1 NSS. A strong negative correlation (p = 0.0016, r = -0.648) was observed between CSF CCL18 and age of neurological onset for childhood/adolescent cases. CSF CCL18 levels also showed a strong positive correlation (p = 0.0017, r = 0.61) with ASIS.ConclusionOur study identified and validated multiple proteins in CSF from individuals with NPC1 that are candidates for further investigation in a larger cohort. These analytes may prove to be useful as supportive data in therapeutic trials.Trial registrationsNCT00344331, NCT00001721, NCT02931682.

Efficacy of urine reagent strips for analysis of cerebrospinal fluid cellularity and biochemical parameters

Background: Meningitis is a severe infection affecting the central nervous system requiring early management to prevent debilitating consequences and death. Detection of meningitis can be done by the analysis of cerebrospinal fluid cellularity and biochemistry (glucose and protein concentration). Urine reagent strips can be used to assess these variables and reach to the diagnosis of meningitis early, thereby, reducing the delay in the initiation of its treatment. Aims and Objectives: The current study aimed to determine the efficacy of urine reagent strips for the analysis of CSF. Materials and Methods: The current prospective study was done in a tertiary care center in Rewa, M.P., on 100 cerebral spinal fluid (CSF) samples obtained from the children suspected of meningitis, which were, then, analyzed by both the conventional methods of CSF analysis (including routine biochemical and microscopic analysis) the index test, utilizing the Combur-10 urine reagent strips for the estimation of CSF cell, protein, and glucose. These results were, then, correlated to calculate the diagnostic utility of urine reagent strips for the rapid diagnosis of meningitis. Results: The sensitivity, specificity, and diagnostic accuracy of urine reagent strips for the detection of cell count >10/cumm were 81.81%, 98.21%, and 91%, respectively, and 78.57%, 81.25%, and 79% for detection of protein >30 mg/dL. Reagent strips showed a sensitivity and specificity of 96.85% and 79.41% for the detection of glucose levels <50 mg/dL. The two methods showed an almost perfect degree of agreement for the detection of leucocytes with Cohen’s kappa value of 0.86. Conclusion: Reagent strips can be a helpful bedside screening test for the detection of meningitis and also in resource-limited settings.

Association of Circulating T Follicular Helper Cells With Idiopathic Optic Neuritis and Neuromyelitis Optica Spectrum Disorders.

Background: T follicular helper cells (Tfh cells) play an important role in activating B lymphocytes and may associate with idiopathic Optic Neuritis (ON) and Neuromyelitis Optica Spectrum Disorders (NMOSD).Objective: This study aimed to examine the potential role of Tfh cells in pathogenesis of idiopathic ON and NMOSD.Methods: Circulating CD4+CXCR5+ and CD4+CXCR5+PD-1+ cells in 46 idiopathic ON and 68 NMOSD patients as well as 28 healthy controls were examined by flow cytometry before treatment. Serum AQP4 antibody, Expended Disability Status Scale (EDSS) and Visual Outcome Scale (VOS) were detected before and after treatment.Results: The percentages of circulating CD4+CXCR5+ and CD4+CXCR5+PD-1+Tfh cells in CD4+ cells (%) were significantly increased in idiopathic ON and NMOSD compared with those of healthy controls (p < 0.01). No significant difference of Tfh cells in blood and cerebral spinal fluid (CSF) was found between ON and NMOSD patients. The percentages of CSF, CD4+, CXCR5+, and CD4+CXCR5+PD-1+ cells in CD4+ cells (%) were positively correlated with those of the blood (r = 0.5781, r = 0.6079, p = 0.0076, and p = 0.0045, respectively). EDSS scores of NMOSD group were higher than those of ON group and the time course of NMOSD patients was longer than that of ON patients (p < 0.01). After methylprednisolone treatment, both EDSS and VOS scores were significantly decreased at discharge compared with before treatment (p < 0.01). There was no significant correlation among Tfh cell percentages in CD4+ cells, CSF leukocytes, CSF protein, annual recurrence rate, EDSS and VOS scores between two groups (p > 0.05).Conclusion: The Circulating T follicular helper cells were increased in both idiopathic ON and NMOSD.

Optic Nerve Demyelination in IgG4 Anti-Neurofascin 155 Antibody-Positive Combined Central and Peripheral Demyelination Syndrome.

Optic nerve demyelination is one of the clinical features of combined central and peripheral demyelination (CCPD), an entity with heterogenous immunopathogenesis and clinical characteristics, overlapping between multiple sclerosis (MS) and chronic inflammatory demyelinating polyneuropathy (CIDP). Of interest, earlier studies among patients with CIDP prior to discovery of antibodies against paranodal protein neurofascin 155 (anti–NF 155) also reported optic nerve dysfunction. We aimed to evaluate optic nerve demyelination among anti–NF 155 CIDP patients. We studied 2 patients with anti–NF 155 CIDP using visual-evoked potentials (VEP) and optical coherence tomography (OCT). Both patients had distal acquired demyelinating symmetric (DADS) subtype CIDP. Other common features were prominent sensory ataxia, hand tremors, significantly elevated cerebral spinal fluid protein, high titre anti–NF 155 antibodies and poor response to corticosteroid and intravenous immunoglobulin (IVIg). No central nervous system neuroradiological abnormality detected. Both had normal visual acuity and colour vision, but one had subclinical right relative afferent pupillary defect (RAPD). VEP of both showed bilateral prolonged P100 latencies. OCT for patient with RAPD demonstrated moderate to severe retinal nerve fibre layer (RNFL) thinning. Identification of optic nerve demyelination among subclinical CIDP with anti–NF 155 antibodies expanded the spectrum of demyelination within the subset of CCPD.

341. Clinical and Laboratory Data in Patients with Viral and Bacterial Meningitis in Conjunction with FilmArray Meningitis/Encephalitis Panel Use: A Multi-Site Retrospective Cohort Study

BackgroundThe ability to quickly recognize and diagnose meningitis is a critical component in its management. The use of the FilmArray Meningitis/Encephalitis (ME) panel has made pathogen identification easier and faster. Although literature exists regarding clinical and laboratory data in patients with bacterial meningitis, less is known about the characteristics of viral meningitis caused by viruses detected by the ME panel This study aims to compare differences in clinical and laboratory characteristics between viral and bacterial meningitis identified by the ME panel.MethodsWe conducted a multisite retrospective review of pediatric patients with cerebral spinal fluid (CSF) positive for viral or bacterial organisms from January 2015 - February 2019. Demographic, clinical, and lab characteristics were extracted from medical records. Frequencies and percentages are used to explain descriptive data. Fisher’s exact test was used for categorical data. The Mann-Whitney test was used for continuous data.ResultsFour hundred thirty-eight patients were included in the analysis with baseline characteristics found in Table 1. Among these, 345 and 93 patients tested positive for viral and bacterial organisms respectively. Viral organisms identified are presented in Figure 1. Patients with bacterial organisms were more likely to have a history of prematurity, a prior neurosurgical procedure, neurological symptoms at presentation, neurological complications, and death within 30 days of admission. The median serum white blood cell (WBC) count, C-reactive protein (CRP), procalcitonin, CSF WBC count, CSF neutrophil percentage, and CSF protein were significantly higher in patients with bacterial organisms compared to viral organisms (Table 2).Table 1: Baseline Characteristics of the Study Population Figure 1: Viral organisms identified. Table 2: Comparison of Laboratory Data by CSF Pathogen Group ConclusionPatients positive for bacterial meningitis were more likely to have higher markers of infection compared to patients with viral organisms. Patients with bacterial organisms were also more likely to have death within 30 days of admission and neurological symptoms and subsequent complications, although the small number of patients limits these conclusions. These findings may help clinicians utilize clinical and laboratory data in conjunction with a ME panel result.Disclosures All Authors: No reported disclosures

BIOM-53. DIFFUSION MR IMAGING DERIVED APPARENT DIFFUSION COEFFICIENT AS A POTENTIAL BIOMARKER OF CLINICAL OUTCOME IN RECURRENT CENTRAL NERVOUS SYSTEM LYMPHOMA

Abstract BACKGROUND Studies have shown that diffusion-weighted imaging (DWI) derived apparent diffusion coefficient (ADC) measurements inversely correlate with tumor cell density and may have prognostic value in newly-diagnosed CNS lymphoma patients. This study characterizes ADC measurements in a relapsed/refractory CNS lymphoma population and describes the potential prognostic value of ADC measurements in these patients. METHODS ADC measurements were assessed in immunocompetent patients enrolled on a prospective clinical trial studying ibrutinib-based treatment in recurrent/refractory CNS lymphoma (NCT02315326; 42 treated with single agent ibrutinib and 15 with an ibrutinib containing combination). Measurements were normalized to values contralateral to the lesion to generate an ADC measurement ratio. Imaging and clinical variables were correlated with treatment response. High-quality lesions were defined as areas with clear delineation from preserved brain parenchyma ≥ 10mm in maximal transverse dimension. Cerebral spinal fluid (CSF) was collected at time of MR imaging in all patients. RESULTS Thirty-nine out of 57 patients had lesions with measurable ADC of which 17 (44%) were high-quality ADC lesions. The median ADCmean ratio was 0.909 (range 0.497–1.444). There was no association between ADC ratios and tumor volume, CSF cell count, or CSF protein. The high-quality lesions had a median ADCmean ratio of 0.774 (range 0.497–1.051). These patients with a high ADCmean ratio (≥ 0.774) had increased rates of partial and complete responses (p=0.057) as well as a longer progression free survival (PFS; median not reached) compared to those with low ADCmean ratios (&amp;lt; 0.774; median PFS=1.5 months, p=0.016). CONCLUSION ADC ratios in the recurrent CNS population do not correlate with tumor size, cell count, or protein in the CSF. In high-quality DWI measurements, ADC might be a prognostic marker in relapsed/refractory CNS lymphoma patients treated with ibrutinib.

DIAGNOSTIC YIELD OF LUMBAR PUNCTURE IN CRITICALLY ILL MEDICAL ICU PATIENTS WITH ALTERED MENTAL STATUS: A RETROSPECTIVE COHORT STUDY

SESSION TITLE: Critical Care Posters SESSION TYPE: Original Investigation Posters PRESENTED ON: October 18-21, 2020 PURPOSE: ICU-acquired delirium frequently complicates critical illness with the elderly and those with pre-existing neurocognitive disorders at greatest risk. Primary central nervous system (CNS) diseases frequently present similarly to ICU-acquired delirium. Whether to perform lumbar puncture (LP) in all cases of diagnostic uncertainty remains unknown. Previous retrospective studies of hospitalized patients have shown that nosocomial meningitis is rare. In these cohorts, LP yield depended on indication and timing of the procedure and pretest probability of neurological disease processes. These studies are largely descriptive and are hampered by small sample sizes. The aims of this study were to establish the diagnostic yield of LP among the critically ill and to determine therapeutic efficacy i.e. how often management changed based on LP results. METHODS: This retrospective cohort study examined patients admitted to a medical ICU service from 2012 to 2018 at a tertiary academic center. Patients were included if they had altered mental status (or synonymous term) documented and underwent LP in the medical ICU.We gathered clinical variables including patient demographics, duration of hospitalization and ICU stay prior to LP, and duration of index ICU admission. We also collected patient variables such as immunocompromised status, underlying CNS disorders, and receipt of EEG, vasopressors, sedatives, or antimicrobials. LP-specific variables included indication and cerebral spinal fluid (CSF) analyses.The primary outcome was LP diagnostic yield as defined by CSF pleocytosis, elevated CSF protein, positive cytology, or microbiological evidence of infection. The secondary outcome of interest was the therapeutic efficacy on a Likert scale of 1-5 which was subsequently dichotomized.We performed chi-square analyses for individual variables and multivariable logistic regression of all variables. To assess the reliability of therapeutic efficacy, a second reviewer rated a subset of cases on the same Likert scale. RESULTS: We identified 104 records of patients who met inclusion criteria. While 48% of LPs yielded a "positive result” (50/104), only 16% (17/104) demonstrated abnormal cytology (3 cases) or evidence of CNS infection (14 cases). Moreover, only 13% (14/104) of LPs had therapeutic efficacy.In both chi-square and multivariate logistic regression analyses, we did not identify any variables that were significantly associated with diagnostic yield or therapeutic efficacy of LP. Cohen's kappa was 0.64 for dichotomized ratings of therapeutic efficacy (2 reviewers, 40 charts), indicating modest to strong agreement. CONCLUSIONS: Diagnostic yield and therapeutic efficacy of LP were low among critically ill medical ICU patients and likely cannot be predicted from clinical variables alone. CLINICAL IMPLICATIONS: Physicians must rely on clinical judgement to determine the necessity of LP in medical ICU patients. DISCLOSURES: No relevant relationships by Paul Bergl, source=Web Response No relevant relationships by Rahul Nanchal, source=Web Response No relevant relationships by Meghan Nothem, source=Web Response No relevant relationships by Alan Salazar, source=Web Response No relevant relationships by Shama Sharwani, source=Web Response

What Is in the Literature.

What is in the Literature focuses on peripheral neuropathies with new and practical information related to the diagnosis, treatment, and management. Diagnostic and treatment guidelines are available for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) but not all clinicians follow them resulting in erroneous diagnoses and prolonged treatment. Secondary axonal loss in CIDP causes increased connective tissue in muscle. Antibodies to proteins at the node of Ranvier are found in a small percentage of patients with CIDP. The differential diagnosis for CIDP-like neuropathies includes amyloid neuropathy and POEMS (polyneuropathy, organomegaly, endocrinopathy, M-protein, skin changes) and amyloidosis. Upper limits for cerebral spinal fluid protein are 0.45 g/L and cell count <10/µL, but both may be too low. Hyperactive reflexes may occur in Guillain-Barré syndrome and should not exclude the diagnosis. In severely affected Guillain-Barré syndrome patients, a second dose of intravenous immune globulin within 4 weeks of onset is not likely to be effective.

Increased Intracranial Pressure Without Hydrocephalus Associated With Spinal Cord Tumor: Literature Review.

Spinal cord tumors (SCTs) may rarely cause increased intracranial pressure without hydrocephalus (IICPWH). A review of the English literature published after 1970 revealed 29 cases of IICPWH secondary to SCT. The following data were acquired: demographics, tumor characteristics, ophthalmic and neurological manifestations, and cerebral spinal fluid (CSF) features. We summarize the existing literature regarding various theories of pathophysiology, spinal imaging recommendations, and treatment modalities used in managing such patients. Patients with papilledema who also have neurological signs or symptoms of myelopathy or elevated CSF protein particularly in the setting of an atypical demographic for pseudotumor cerebri should raise a suspicion for a spinal tumor and prompt further investigation with a spinal MRI.

Antiepileptic drugs for acute encephalitic patients presented with seizure

ObjectiveThe aim of this study was to clarify the pattern and efficacy of antiepileptic drugs (AEDs) in acute encephalitis and discuss how long AEDs should be used after the acute phase. MethodsPatients with acute encephalitis who presented with seizure were enrolled. The clinical features were systematically gathered, and the information about AEDs and seizures was obtained by a clinical follow-up and (or) a telephone interview based on a structured form. ResultsA total of 327 patients were enrolled, and the mean follow-up period was 63.8 (14–123) months. The risk of seizure relapse was estimated as 43.6% five years after the acute phase and the first three months was the peak time for relapse. Univariate analysis showed that status epilepticus, more than one seizure, cerebral spinal fluid protein level, abnormal MRI finding, temporal lobe involvement, and epileptiform discharge were related to seizure relapse. But only more than one seizure (OR = 2.80 (95% CI 1.29–6.09), p = 0.009) and temporal lobe involvement (5.34 (2.68–10.64), p < 0.001) remain predictive on multivariate regression analysis. For patients with only one seizure and no temporal lobe involvement, the risk of seizure relapse was similar between those with or without AED (2/29 vs. 4/28, p = 0.423). For the rest, the risks of relapse were similar among those who took sodium valproate and levetiracetam. SignificanceFor patients with only one seizure and no temporal lobe involvement, AEDs may not be strictly needed. The first three months after acute phase was the peak time for relapse and AEDs may should be used during this period. Both sodium valproate and levetiracetam could be selected.

Association between APOE4 and biomarkers in cerebral adrenoleukodystrophy

Cerebral adrenoleukodystrophy (cALD) is an inflammatory neurodegenerative disease associated with mutation of the ABCD1 gene. Proteomic analysis of cerebral spinal fluid (CSF) from young males with active cALD revealed markers of inflammation including APOE4. APOE4 genotype has been associated with an inferior prognosis following acute and chronic neurologic injury. We assessed APOE4 inheritance among 83 consecutive young males with cALD prior to hematopoietic cell transplant and its association with markers of cerebral disease. The allele frequency of APOE4 was not significantly different from that of the general population at 17%. Young males with cALD that were APOE4 carriers had similar CSF protein and chitotriosidase activity to that of non-carriers. In contrast, APOE4 carriers had an increased burden of cerebral disease involvement as determined by MRI severity score (10.5 vs 7.0 points, p = 0.01), higher gadolinium intensity score (2.0 vs 1.3 points, p = 0.007), inferior neurologic function (neurologic function score 2.4 vs 1.0, p = 0.001), and elevated CSF MMP2 levels compared to that of non-carriers (13168 vs 9472 pg/mL, p = 0.01). These are the first data showing that APOE4 is associated with increased severity of cerebral disease in cALD and suggest it may be a modifier of disease.

Preconditioning in the Rhesus Macaque Induces a Proteomic Signature Following Cerebral Ischemia that Is Associated with Neuroprotection.

Each year, thousands of patients are at risk of cerebral ischemic injury, due to iatrogenic responses to surgical procedures. Prophylactic treatment of these patients as standard care could minimize potential neurological complications. We have shown that protection of brain tissue, in a non-human primate model of cerebral ischemic injury, is possible through pharmacological preconditioning using the immune activator D192935. We postulate that preconditioning with D192935 results in neuroprotective reprogramming that is evident in the brain following experimentally induced cerebral ischemia. We performed quantitative proteomic analysis of cerebral spinal fluid (CSF) collected post-stroke from our previously published efficacy study to determine whether CSF protein profiles correlated with induced protection. Four groups of animals were examined: naïve animals (no treatment or stroke); animals treated with vehicle prior to stroke; D192935 treated and stroked animals, further delineated into two groups, ones that were protected (small infarcts) and those that were not protected (large infarcts). We found that distinct protein clusters defined the protected and non-protected animal groups, with a 16-member cluster of proteins induced exclusively in D192935 protected animals. Seventy percent of the proteins induced in the protected animals have functions that would enhance neuroprotection and tissue repair, including several members associated with M2 macrophages, a macrophage phenotype shown to contribute to neuroprotection and repair during ischemic injury. These studies highlight the translational importance of CSF biomarkers in defining mechanism and monitoring responses to treatment in development of stroke therapeutics.

Treatment of Autoimmune Glial Fibrillary Acidic Protein Astrocytopathy: Follow-Up in 7 Cases

Objective: The aim of this work was to report an autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy with long-term follow-up in 7 patients. Methods: Antibodies were detected by indirect immunofluorescence assay and patient data were analyzed retrospectively. Results: Seven patients (4 female, 3 male) with ≥1 year follow-up were included. All patients had positive GFAP antibodies in their cerebral spinal fluid (CSF). Their median age at disease onset was 56 years (range 27-69) and the median disease duration was 1 year (range 1-4). In the initial attack, all patients received intravenous methylprednisolone (IVMP) followed by oral steroids, which were tapered. Six patients received intravenous immunoglobulin (IVIg). One patient had no response to IVIg and IVMP. Four patients received immunosuppressive agents. Five patients underwent the second lumbar puncture after treatment. CSF white blood cell counts, protein levels, and antibody titers were significantly decreased. CSF protein levels correlated positively with the Expanded Disability Status Scale score, which was elevated at each lumbar puncture. Four patients experienced relapse. To date, 6 patients had a bad prognosis, of which 2 died. Conclusions: Some patients with GFAP astrocytopathy experienced a poor response to treatment although they received steroids and immunosuppressive agents.

Resveratrol is Neuroprotective and Improves Cognition in Pentylenetetrazole-kindling Model of Epilepsy in Rats.

S100B protein in serum and cerebral spinal fluid is increasingly used as a biochemical marker in early examinations after seizure to assess brain damage. Resveratrol, a nonflavonoid polyphenol, has been identified as a potent antiepileptic agent. However, a potential association between epilepsy with S100B protein in the cerebral spinal fluid and the sera of animal models lacks investigation. In this study, we evaluated the effects of resveratrol on behaviour and S100B protein levels in cerebral spinal fluid and serum in a rat model of chronic epilepsy induced via pentylenetetrazole kindling. By Morris water maze experiment analysis, we found that recovery of cognitive function in the resveratrol group (15 mg/kg/day), was significantly better than that of either the untreated or the vehicle groups. Further Nissl staining revealed that resveratrol significantly reduced pentylenetetrazole-induced death of neurons in the CA1 and CA3 regions of the hippocampus. Moreover, S100B protein levels in the cerebral spinal fluid and serum of rats treated with resveratrol were significantly reduced compared with the untreated and vehicle groups. These novel findings suggest an important mechanism of resveratrol and contribute to the treatment of epilepsy.

Mass spectrometric analysis of rat cerebrospinal fluid proteins following exposure to the neurotoxicant carbonyl sulfide.

Using a proteomic-based approach we have investigated possible altered expression of a range of cerebral spinal fluid (CSF) proteins following exposure to the neurotoxicant carbonyl sulfide (COS). CSF is ideal for the investigation of markers of brain injury or disease since it is secreted from several central nervous system structures and changes in the CSF composition may reflect brain insult and many pathological processes. Animals were placed in exposure chambers and were exposed to 0 ppm or 500 ppm COS for 1, 2 or 3 days, 6 h per day. After the last inhalation exposure, 50-70 μL CSF sample was obtained by lumbar puncture. CSF samples were analyzed by electrospray ionization mass spectrometry (ESI-MS) on either a Premier quadrupole time-of-flight (QTOF) or an Agilent 6340 ion trap and by matrix-assisted laser desorption/ionization (MALDI)-MS on a 4800 MALDI-TOF/TOF analyzer. The dynamic range of abundance of the identified proteins spanned over more than three orders of magnitude. The four most abundant proteins identified (albumin, cystatin C, serotransferrin, transthyretin) are major proteins that are present in both CSF and blood at high levels but the fifth most abundant protein identified (prostaglandin H2D isomerase) is the second most abundant protein in human CSF and is secreted and synthesized in the rat central nervous system. No significant differences were observed between COS-treated CSF samples and the control CSF samples because of blood contamination. Quantitative MS protein analyses of rat CSF is limited by the low sample volumes that can practicably be obtained from rats and the low protein concentrations in rat CSF. Results of this work suggest a clear need for CSF collection that would minimize blood contamination. Published in 2014. This article is a U.S. Government work and is in the public domain in the USA.

POEMS syndrome – A case report revealing a complex evolving diagnosis

Key Clinical MessageDescription of POEMS syndrome (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal gammopathy, Skin changes) goes back to 1938 when a patient with sensorimotor peripheral neuropathy, hyperpigmemntation, solitary plasmacytoma, and elevated cerebral spinal fluid protein was reported. Since then, numerous other cases of this condition have been described by various authors including one that followed the first case 18 years later about two patients. Even though this rare condition still remains an oddity in diagnosis calling for clinicians to have a high index of suspicion due to its manifestation with varied clinical features. We present a case of POEMS syndrome that started as an episode of transient ischemic attack (TIA) and elevated levels of digestive enzymes not previously reported.