Steroid-Responsive Encephalitis in Coronavirus Disease 2019.

Coronavirus disease 2019 (COVID-19) infection has the potential for targeting the central nervous system, and several neurological symptoms have been described in patients with severe respiratory distress. Here, we described the case of a 60-year-old patient with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection but only mild respiratory abnormalities who developed an akinetic mutism attributable to encephalitis. Magnetic resonance imaging was negative, whereas electroencephalography showed generalized theta slowing. Cerebrospinal fluid analyses during the acute stage were negative for SARS-CoV-2, positive for pleocytosis and hyperproteinorrachia, and showed increased interleukin-8 and tumor necrosis factor-α concentrations. Other infectious or autoimmune disorders were excluded. A progressive clinical improvement along with a reduction of cerebrospinal fluid parameters was observed after high-dose steroid treatment, thus arguing for an inflammatory-mediated brain involvement related to COVID-19. ANN NEUROL 2020;88:423-427.

Multi-marker algorithms based on CXCL13, IL-10, sIL-2 receptor, and ß2-microglobulin in cerebrospinal fluid to diagnose CNS lymphoma.

Tumor biopsy is essential for the definitive diagnosis of central nervous system (CNS) lymphoma. However, the biopsy procedure carries the risk of complications such as bleeding, convulsions, and infection. Cerebrospinal fluid (CSF) ß2-microglobulin (ß2-MG), soluble IL-2 receptor (sIL-2R), and interleukin-10 (IL-10) are known to be useful diagnostic biomarkers for CNS lymphoma. The C-X-C motif chemokine ligand 13 (CXCL13) was recently reported to be another useful biomarker for CNS lymphoma. The purpose of this study is to establish a diagnostic algorithm that can avoid biopsy by combining these diagnostic biomarkers. In the first, we conducted a case-control study (n = 248) demonstrating that the CSF CXCL13 concentration was significantly increased in CNS lymphoma patients compared with various other brain diseases (AUC = 0.981). We established a multi-marker diagnostic model using CSF CXCL13, IL-10, ß2-MG, and sIL-2R from the results of the case-control study and then applied the model to a prospective study (n = 104) to evaluate its utility. The multi-marker diagnostic algorithms had excellent diagnostic performance: the sensitivity, specificity, positive predictive value, and negative predictive value were 97%, 97%, 94%, and 99%, respectively. In addition, CSF CXCL13 was a prognostic biomarker for CNS lymphoma patients. Our study suggests that multi-marker algorithms are important diagnostic tools for patients with CNS lymphoma.

Beta2-microglobulin as a diagnostic marker in cerebrospinal fluid: a follow-up study.

Beta2-Microglobulin ( ß 2-m) is a low molecular weight protein occurring in all body fluids. Its concentration increases in various pathologies. Increased values in cerebrospinal fluid (CSF) are ascribed to an activation of immune system. Using immunoturbidimetry, we examined concentrations of beta2-microglobulin in cerebrospinal fluid in a large group of 6274 patients with defined neurological diseases. Cell counts, total protein, albumin, glucose, lactic acid, immunoglobulins concentrations, and isofocusing (IEF) were also evaluated. We found substantial changes of CSF ß 2-m concentrations in purulent meningitis, leptomeningeal metastasis, viral meningitis/encephalitis, and neuroborreliosis, while in multiple sclerosis these changes were not significant. Intrathecal synthesis and immune activation were present in these clinical entities. A new normative study enables better understanding of beta2-microglobulin behavior in CSF.

Multiple myeloma of the central nervous system: a clinicopathological review.

Multiple myeloma (MM) is a systemic malignancy of pathologic plasma cells that is treatable with chemotherapeutic agents and irradiation, but rarely curable. The spectrum of neurological complications of MM is diverse; however, involvement of MM in the cerebrospinal fluid and leptomeningeal infiltration is considered rare. There have been many reviews of central nervous system complications in MM but there are none on intracranial and leptomeningeal infiltration of MM. We review this here along with our clinicopathological experience and a summary of our present knowledge of this condition.

Estimation of virological and immunological parameters in subjects from South India infected with human immunodeficiency virus type 1 clade C and correlation of findings with occurrence of neurological disease.

Several studies carried out in Western countries have demonstrated that a number of virological and immunological markers such as viral loads, cytokines, beta(2)-microglobulin, neopterin, etc., are elevated in the serum and cerebrospinal fluid (CSF) of human immunodeficiency virus (HIV)-infected individuals with neurological disease. The neurological manifestations of HIV infection noted in Indian patients is different from those reported in Western countries. Moreover, few studies have investigated the role of virological and immunological parameters with respect to the progression of HIV-1 clade C infection in India. In this study, we measured virological (HIV-1 RNA levels) and immunological parameters (CD4 cell count and inflammatory markers) in the plasma and CSF of HIV-1-infected neurologically asymptomatic and symptomatic (with opportunistic infections and/or dementia) subjects. By using clade-specific polymerase chain reaction (PCR), we ascertained that all samples used for the study were infected with HIV-1 clade C. Among the various laboratory parameters evaluated, high viral loads in the CSF, low CD4 counts, and higher levels of interleukin (IL)-1alpha, IL-6, tumor necrosis factor alpha (TNFalpha), beta(2)-microglobulin, and neopterin were noted in HIV-infected subjects with neurological disease as compared to asymptomatic subjects. These data suggest that the markers evaluated in plasma and CSF samples correlated with occurrence of neurological disease in symptomatic individuals as compared to asymptomatic HIV infected subjects.

Cerebrospinal fluid protein reactions during non-neurological surgery.

OBJECTIVE: To study changes in cerebrospinal fluid (CSF) protein markers of blood-CSF barrier integrity and immunological reactions during surgical stress. SUBJECTS AND METHODS: Thirty-five patients without neurological or psychiatric disorders undergoing knee replacements had CSF and serum samples drawn from spinal and arterial catheters before, 3 h after and the morning after surgery. RESULTS: Serum albumin decreased during surgery and CSF albumin decreased during and after surgery, and, as a consequence, the CSF/serum albumin ratio decreased significantly during the study period, especially after the intervention. In contrast, CSF concentrations of beta-2-microglobuline (beta2M) increased significantly during surgery and remained high. The CSF general marker beta-trace protein (betaTP) remained unchanged. CONCLUSIONS: Central nervous system protein reactions to a non-neurological surgical intervention include sharply decreased permeability of albumin into the CSF and signs of intrathecal inflammatory activity.

Elevated cerebrospinal fluid beta-2 microglobulin as a tumor marker in a patient with myeloma of the central nervous system.

Myeloma involvement of the nervous system is rare. Extensive literature review revealed only a few cases reported from different parts of the world. The presence of CNS symptoms and detection of plasma cells in the CSF is the usual basis of diagnosis. In addition, immunoelectrophoresis and immunofixation for detection of monoclonal protein confirm the diagnosis in some cases, while some authors used flow cytometry and cytogenetic studies on CSF. Reports of multiple myeloma also include unfavorable cytogenetic abnormalities of chromosome 13. We report a case with relapsed CNS multiple myeloma with the detection of elevated beta-2 microglobulin (beta2M) as a tumor marker in the CSF.

Beta2-microglobulin concentrations in cerebrospinal fluid correlate with neuroimaging findings in newborns with symptomatic congenital cytomegalovirus infection.

OVERVIEW: In newborns with symptomatic congenital cytomegalovirus (CMV) infection, neuroimaging is the best available predictor of neurodevelopmental outcome. Cerebrospinal fluid (CSF) findings in congenital CMV infection have seldom been described. Neonates with central nervous system infections present high CSF Beta(2)-microglobulin (beta(2)-m) levels. OBJECTIVES: The objectives of this study were: (1) to determine whether CSF beta(2)-m is increased in newborns with symptomatic congenital CMV infection, and (2) to examine its correlation with neuroimaging findings. MATERIALS AND METHODS: Fourteen newborns with symptomatic congenital CMV infection admitted to La Paz Hospital from 1990 through 2004 underwent determination of CSF beta(2)-m. Ninety-three newborns, constituting the comparison group, underwent CSF beta(2)-m determination as part of a sepsis or meningo/encephalitis work-up, and at discharge had sterile cultures and normal neurological status. Neuroimaging findings were scored according to a semiquantitative system: (0) no abnormalities; (1) single punctate periventricular (PV) calcification and/or hyperechogenic areas in the thalamus and basal ganglia; (2) multiple discrete PV calcifications and/or ventriculomegaly; and (3) extensive PV calcifications and/or brain atrophy. DISCUSSION AND CONCLUSION: CSF beta(2)-m was increased in newborns with CMV infection (median 6.21 mg/L) compared with controls (1.68 mg/L) (P<.001). beta(2)-m showed a correlation with neuroimaging scores (r (s)=0.753, P=.002). beta(2)-m was higher in patients who scored 2-3 (12.83 mg/L) than in patients who scored 0-1 (5.52 mg/L) (P=.028). CSF beta(2)-m is increased in newborns with symptomatic congenital CMV infection and correlates with neuroimaging abnormalities. beta(2)-m appears to be an indicator of the severity of brain involvement in congenital CMV infection.

[CSF levels and diagnostic utility of cerebrospinal fluid beta2-microglobulin]. / Valeurs usuelles et utilité diagnostique de la beta2-microglobuline dans le liquide céphalorachidien.

CSF levels of beta2-microglobulin reflect immune activation and lymphoid cell turnover in CNS. There were proposed as a reliable marker of lymphoproliferative disorders in central nervous system in viral infections, inflammatory diseases, autoimmune diseases and malignancies. The aims of this study were to measure beta2-microglobulin on the automate Vidas of bioMérieux in 122 paired CSF and serum from control patients. We evaluated whether or not the elevated levels beta2-microglobulin in CSF can be a useful marker for diagnosis of lymphoproliferative disorders in 108 patients with neurological diseases. The concentrations of beta2-microglobulin in the CSF and sera from control patients were respectively 1.3 +/- 0.5 mg/L and 2 +/- 0.6 mg/L. The normal CSF to serum beta2-microglobulin ratio was 0.6 +/- 0.19. A CSF to serum beta2-microglobulin ratio greater than 1 was closely associated with intrathecal synthesis beta2-microglobulin in CNS lymphoproliferative disorders. Elevation of CSF beta2-microglobulin ratio is a sensitive marker of central nervous system disease activity by infiltrating lymphocytes in intracranial lymphomas (10/10) and paraneoplastic neurological syndromes (2/3).

Meningeal derived cerebrospinal fluid proteins in different forms of dementia: is a meningopathy involved in normal pressure hydrocephalus?

OBJECTIVES: In animal models and in vitro studies leptomeninges have been shown to be the origin of neurotrophic substances that support the survival and growth of neuronal cells. Because dementia is associated with neuronal loss, we investigated whether leptomeningeal dysfunction may be involved in the pathogenesis of dementia disorders. METHODS: We analysed the cerebrospinal fluid (CSF) concentrations of the leptomeningeal derived beta trace protein, beta2 microglobulin, and cystatin C. RESULTS: There was a statistically significant difference of the CSF beta trace protein levels among different groups. Patients with idiopathic normal pressure hydrocephalus (NPH) (17.5 (SD 4.3) mg/l) showed significantly lower CSF beta trace protein levels than patients with Alzheimer's disease (23.8 (6.2) mg/l), depression (24.2 (7.3) mg/l), and normal controls (25.3 (4.9) mg/l). To patients with vascular dementia (20.1 (5.6) mg/l) and frontotemporal dementia (21.9 (7.0) mg/l), the difference was not significant. There was no significant difference regarding the CSF and serum concentrations of beta2 microglobulin or cystatin C among the different groups. CONCLUSIONS: We conclude that leptomeningeal dysfunction may be involved in certain types of dementia such as NPH and that reduced CSF beta trace protein levels in patients with NPH may aid in differentiating this difficult to diagnose disorder from other syndromes such as Alzheimer's disease.

[The effect of cladribine treatment on beta-2 microglobin in the cerebrospinal fluid and serum of patients with multiple sclerosis]. / Wplyw 2-chlorodeoksyadenozyny (kladrybiny) na stezenie beta 2-mikroglobuliny w plynie mózgowo-rdzeniowym i surowicy u chorych ze stwardnieniem rozsianym.

Multiple sclerosis (MS) is the most frequent demyelinating disease of the central nervous system (CNS). Lymphocytes seem to play a crucial role in the pathogenesis of the disorder. They are rich in, among others, beta-2Microglobulin (beta 2M)--a low molecular weight protein located extracellularly and associated with class 1 antigens of the major histocompatibility complex. beta-2M is considered as a marker for disease activity in immune disorders. Its precise role in pathology remains still unknown, but there is evidence that it may be involved in lymphocyte activation. Cladribine (2-chloro-2-deoxyadenosine, 2-CDA) is a potent lymphocytotoxic agent under investigation in the treatment in MS patients, earlier used in hairy-cell-leukemia therapy. Previous studies in MS populations showed beta 2-microglobulin to be moderately increased. Suspecting that beta 2M levels might indicate inflammatory events in CNS we determined CSF-beta 2M and serum beta 2M concentration in patients with relapsing-remitting MS (n = 15) before and after cladribine treatment as well as in a control group diagnosed as tension type headache (n = 10). There was a significant decrease in the CSF and sera beta 2M level in MS patients after cladribine treatment, associated with a slight but significant clinical improvement measured by Kurtzke's Expanded Disability Status Scale. We conclude that beta 2M is a sensitive marker of the CDA influence on the immune system in MS patients; however, increase in CSF and sera beta 2M is not specific as there was no statistically significant difference between MS and control patients.

Cerebrospinal fluid beta2-microglobulin, monocyte chemotactic protein-1, and soluble tumour necrosis factor alpha receptors before and after treatment with lamivudine plus zidovudine or stavudine.

CSF levels of beta2-microglobulin (b2m), monocyte chemotactic protein-1 (MCP-1), soluble tumor necrosis factor receptors (sTNFRs), and HIV-1 RNA were determined in 16 neurologically asymptomatic HIV-1 infected patients before and 12 weeks after treatment with lamivudine plus zidovudine or stavudine. b2m levels were significantly higher in patients (1.7 mg/l) compared with controls (0.8 mg/l) (P < 0.001), and decreased to 1.1 mg/l during treatment (P = 0.001). MCP-1 levels were low, and did not change during treatment. Levels of sTNFR type I were elevated in patients (0.92 ng/ml) compared to controls (0.30 ng/ml) (P = 0.03), but did not change during treatment. Levels of sTNFR type II were below the limit of detection in most patients and controls. In conclusion, CSF levels of b2m and HIV-I RNA, but not sTNFRs or MCP-1, are candidate surrogate markers of treatment efficacy in early CNS infection.

[Diagnostic and prognostic significance of some laboratory indices of cerebrospinal fluid in multiple myeloma]. / Diagnosticheskoe i prognosticheskoe znachenie nekotorykh laboratornykh pokazatelei spinnomozgovoi zhidkosti u bol'nykh mnozhestvennoi mielomoi.

beta 2-microglobulin (beta 2-m) and certain other characteristics of liquor have been followed in the course of multiple myeloma (MM) versus severity of the disease and its response to chemotherapy, to establish the diagnostic and prognostic value of these indices. Lymphocytes and plasma cells were found in most of 17 patients under study, who were resistant to chemotherapy and relapsed; they revealed regular rise in liquor pressure and cytosis. Similarly, raised concentrations of beta 2-m were registered. However, there was no correlation between blood serum-beta 2-m levels and that in cerebrospinal fluid (CSF) nor between CSF-beta 2-m concentration, on the one hand, and such parameters as CSF-total protein, blood serum-beta 2-m and pathologic cytosis, on the other. In advanced MM, CSF-beta 2-m levels were, as a rule, abnormally higher. Our data suggest that, in addition to assaying CSF-total protein, severity of cytosis and liquor pressure as well as morphological identification of detected cells, beta 2-m levels be followed in the course of the disease in MM patients, to make therapeutic correction possible. Moreover, CSF-beta 2-m level dynamics can be used as another factor of prognosis.

Aberrant immunity in the central nervous system in relation to disease progression in HAM/TSP.

The immunological status of the central nervous systems of 19 patients with HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) was distinct from that of 6 asymptomatic HTLV-I carriers. Cross-sectional analysis of the time course of disease-related abnormalities in the cerebrospinal fluid (CSF) showed that activated B cell function was a feature in relatively early HAM/TSP patients in whom duration of the disease was less than 5 to 6 years. During this period many patients experienced notable neurological deterioration. By contrast, an increase in CD8+CD11a+ cytotoxic T lymphocytes along with elevated beta 2-microglobulin levels in the CSF was a consistent finding in early as well as late patients with more than a 10-year history of the illness. In light of the generally progressive course of this disorder, the mode of immunity related to the pathogenesis of HAM/TSP may be different according to the stages of the disease.

Cultured leptomeningeal cells secrete cerebrospinal fluid proteins.

To extrapolate the function of the leptomeninges, we examined the profile of the proteins secreted from the cultured leptomeningeal cells prepared from 1-2-day-old rats. In sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis of the medium conditioned with the cultured cells, 20-25 differentially distinctive protein bands were noted. Through several chromatographic procedures (Sephadex G-75, Mono Q, and 7C8-300), altogether 18 proteins were purified to homogeneity, and the partial amino acid sequence of each protein was determined. Homology search revealed that the major proteins included prostaglandin-D-synthase or beta-trace protein, insulin-like growth factor (IGF)-II, IGF-binding protein-2, apolipoprotein E, beta 2-microglobulin, cystatin C, transferrin, peptidyl-prolyl cis-trans isomerase or cyclophilin C, secreted protein acidic and rich in cysteine, ubiquitin, lysozyme C, extracellular superoxide dismutase, and collagen alpha-1 (III). Most of these proteins are known to be the major brain-derived protein constituents of CSF and are thought to play important roles in certain biological events in the brain. Considering the morphological features, the present findings suggest the importance of the leptomeninges as an origin of such proteins in CSF.

Elevation of cerebrospinal fluid soluble CD27 levels in patients with meningeal localization of lymphoid malignancies.

Diagnosis of meningeal localization of lymphoid malignancies by means of cytologic examination of the cerebrospinal fluid (CSF) can be difficult. Thus far no reliable CSF tumor markers have been identified. CD27 is a transmembrane disulfide-linked 55-kD homodimer present on most peripheral blood T cells and on a subset of B cells. CD27 is also expressed on human malignant B cells and high levels of soluble CD27 can be present in the serum of patients with B-cell malignancies. The aim of this study is to determine prospectively the diagnostic value of CSF sCD27 as a tumor marker in patients with meningeal localization of lymphoid malignancies. CSF sCD27 levels were determined by sandwich enzyme-linked immunosorbent assay. The optimal cut-off value using receiver operator characteristics curves was found to be 10 U/mL. sCD27 levels were normal in all 50 control patients (lumbar disc protrusion) and in 39 of 40 samples obtained from patients with either solid tumors or acute myeloid leukemia. Of 104 CSF samples from 70 children with acute lymphoblastic leukemia (ALL) or non-Hodgkin's lymphoma (NHL) undergoing routine central nervous system (CNS) staging, sCD27 was false positive and false negative in only one sample each. In 70 samples from 45 patients suspected of meningeal localization of ALL or NHL, the sCD27 test had an excellent sensitivity (100%) and specificity (82%). In 7 patients with positive CSF studied longitudinally, sCD27 levels correlated very well with remission and relapse. sCD27 levels were not nonspecifically increased by the administration of cytostatic drugs. Finally, sCD27 was also elevated in the 4 patients studied with primary central nervous system lymphoma (PCNSL). CSF sCD27 is a promising tumor marker in patients with either meningeal localization of lymphoid malignancies or PCNSL, and can be useful in the differential diagnosis of CNS involvement by either lymphoid malignancies or solid tumors.

Cerebrospinal fluid beta 2-microglobulin in neonates with central nervous system infections.

Beta 2-microglobulin (beta 2m) determination in CSF of 72 neonates who underwent a spinal tap as part of a sepsis or meningo-encephalitis workup was performed to evaluate the usefulness of this test in the diagnosis of CNS infections. Beta 2m was measured by enzyme immunoassay. Sixty neonates had sterile culture and normal neurological status at discharge. Twelve infants had CNS infections: 8 bacterial meningitis, 3 TORCH infections (T = toxoplasmosis, O = others, R = rubella, C = cytomegalovirus and H = herpes simplex) and 1 viral meningitis. Neonates with CNS infection exhibited significantly higher CSF beta 2m levels compared to neonates with sterile culture (6.24 +/- 2.66 vs 1.74 +/- 0.5 mg/l; P < 0.0001). CSF beta 2m levels did not correlate with the white cell count, total protein concentration or glucose level in CSF. When serum and CSF levels were measured simultaneously, the CSF beta 2m level was significantly higher than the corresponding serum level in patients with CNS infection (6.98 +/- 2.5 vs 3.2 +/- 0.25 mg/l; P < 0.01). Sensitivity, specificity, and predictive values were estimated for different cut-off points. The best operational diagnostic cut-off value was 2.25 mg/l. Receiver operating characteristic curve analysis showed an appropriate trade-off between specificity and sensitivity and indicated that CSF beta 2m was accurate in distinguishing between neonates with and without CNS infection. Conclusion. CSF beta 2m may be a useful ancillary tool in neonates when CNS infection is suspected.

Proteinergic profiles in cerebrospinal fluid from alcoholic subjects.

Minute amounts of cerebrospinal fluid samples from alcoholics were subjected to separation by HPLC-molecular sieving, combined with multispectral UV analysis of the acquired data. A significant difference in the protein/polypeptide pattern within the molecular weight range of 7-10 kDa has been observed between samples, taken directly after detoxification and 2 weeks later. Spectral analysis of the results suggests that the components are of peptidergic nature. On the other hand, albumin content did not differ significantly, suggesting that the blood-brain barrier was not affected. An enzyme marker, dynorphin converting enzyme, remained unchanged in both groups.

[Determination of beta 2-microglobulin in the serum and cerebrospinal fluid using radial immunodiffusion (comparison with the Elisa Pharmacia method)]. / Stanovení beta 2-mikroglobulinu v séru a likvoru metodou radiální imunodifuze. (Srovnání s referencní metodou Elisa Pharmacia)

The authors elaborated a method of radial immunodiffusion for assessment of beta 2-microglobulin serum and cerebrospinal fluid levels in patients. The method is based on a modified procedure of staining and decolouration. The antibody produced by USOL Co. which was used for the purpose was not modified. Comparison of 90 sera and 27 cerebrospinal fluid samples where also the reference method ELISA Pharmacia was used revealed almost absolute agreement, the correlation coefficient was 0.98. The method is used for clinical monitoring in patients with myelomas and renal insufficiencies.

Relationship of cerebrospinal fluid immune activation associated factors to HIV encephalitis.

OBJECTIVES AND DESIGN: Because macrophages are the predominant immune cell and the predominant infected cell in the brains of patients with HIV encephalitis, we studied macrophage and immune activation-associated factors in the cerebrospinal fluid (CSF) from 39 autopsied AIDS cases for whom complete neuropathologic evaluation of the brain was available. RESULTS: CSF HIV p24 antigen was present in less than one-third of cases (11 out of 39). Less than half of the autopsies with moderate to severe parenchymal infection by HIV had high levels of CSF p24, although all autopsies with elevated levels of HIV p24 had moderate to severe HIV encephalitis. Elevated levels of cytokines, beta 2-microglobulin, neopterin, and quinolinic acid were observed. CONCLUSIONS: Although many of the CSF findings showed a strong correlation with each other, none showed a strong correlation with the severity of HIV infection of the brain itself. The absence of a close association between CSF abnormalities and HIV encephalitis could reflect the abundance of complicating opportunistic infections in these terminally ill patients or the inadequacy of CSF as a marker of basal ganglia involvement in HIV encephalitis. These findings complicate interpretation of clinical studies of CSF in patients with AIDS where neuropathologic evaluation is unavailable.