Active T cells and humoral immune variables in blood and cerebrospinal fluid in patients after acute unilateral idiopathic optic neuritis

The active T cell rosette test - that is determination of T lymphocytes with high affinity for sheep erythrocytes after incubation at 37°C for 1 h - defines a T cell subset that has been claimed to parallel cell-mediated immunocompetence in e.g. viral diseases. In 16 patients who have had acute unilateral idiopathic optic neuritis (ON), lower percentages of active T cells were found in CSF compared to blood, irrespective if the interval between the first bout of ON and the present study was 2 months or 26 years, and irrespective of degree of mononuclear pleocytosis or humoral immune variables in CSF. The same distribution of active T cells has previously been observed in multiple sclerosis (MS). The percentages of active T cells in peripheral blood from the patients with ON were normal. Determination of active T cell does not seem to discriminate those patients with ON who are likely to develop MS. One explanation could be that ON and MS have an etiologic agent in common but that a part of patients with ON have an until now undefined competence to limit the demyelinating process.     

Prognosis of optic neuritis with special reference to cerebrospinal fluid immunoglobuhs and measles virus antibodes

Forty-eight patients with optic neuritis (ON), first seen in 1970 to 1973, were neurologically and neuroophthal mologically reexamined after 7 to 10 years. Twenty-seven patients (56%) had probable MS, and 9 (19%) had possible MS. During the attack of ON, the cerebrospinal fluid (CSF) samples and serum/CSF measles antibody ratios were studied. Twenty patients had increased relative immunoglobulin G (IgG % of total protein) in their CSF; 19 of these had probable or possible MS. However, 17 of 28 patients with a normal relative IgG value had also developed MS. CSF electrophoresis was abnormal in 20 patients with ON; reexamination showed that 19 had probable or possible MS. Sixteen of 27 patients with normal electrophoresis had also developed MS. Serum/CSF measles antibody ratio had decreased in 19 patients; 13 of these had probable MS and 3 had possible MS. Of 29 patients with a normal measles antibody ratio, 14 had probable MS and 6 had possible MS. The conclusion is that examination of the CSF in ON gives valuable prognostic information because increased relative IgG, abnormal electrophoresis, or a decreased measles antibody ratio implies a high risk of developing MS. A normal CSF does not, however, rule out the possibility of dissemination.     

Secondary lymphoid organ chemokines are elevated in the cerebrospinal fluid during central nervous system inflammation

Secondary lymphoid organ chemokines have been implicated in chronic inflammation. Their expression in the central nervous system (CNS) has not been studied. Here, levels of secondary lymphoid organ chemokines CCL19 (Exodus-3, MIP-3beta), CCL21 (Exodus-2, 6Ckine, SLC) and CXCL12 (SDF-1alpha) were analysed by ELISA in cerebrospinal fluid (CSF) and plasma from patients with multiple sclerosis (MS); acute optic neuritis (ON) with oligoclonal IgG in the CSF (i.e., first bout of MS); acute ON without oligoclonal IgG (non-MS-type ON); other inflammatory neurological diseases (OIND); and non-inflammatory neurological diseases (NIND). NIND CSF contained CCL19 and CXCL12, while CCL21 was not detected. Intrathecal production of CCL19 and CCL21 was elevated in MS, MS-type ON, and OIND, but not in non-MS-type ON. In MS, CSF levels of CCL19 weakly correlated with CSF cell counts. Intrathecal production of CXCL12 was elevated only in OIND. The role of elevated CCL19 and CCL21 in MS could be retention of mature dendritic cells (DC) in the CNS, recruitment of nai;ve T cells and activated B cells, as well as de novo formation of secondary lymphoid structures in MS plaques.     

Immune surveillance in multiple sclerosis patients treated with natalizumab

OBJECTIVE: Our objective was to test whether natalizumab, an antibody against very late activating antigen (VLA)-4, interferes with central nervous system immune surveillance as assessed by leukocyte cell numbers and cellular phenotypes in cerebrospinal fluid (CSF) and peripheral blood. METHODS: Cell numbers and cellular phenotypes in CSF and peripheral blood were analyzed in multiple sclerosis (MS) patients treated with natalizumab, untreated MS patients, and patients with other neurological disease (OND). JC virus DNA in the CSF and peripheral blood was quantified by kinetic polymerase chain reaction. RESULTS: CSF leukocyte counts, CD4(+) and CD8(+) T cells, CD19(+) B cells, and CD138(+) plasma cells were significantly lower in natalizumab-treated MS patients compared with OND patients and untreated MS patients. JC virus DNA was not detected in CSF or peripheral blood from natalizumab-treated patients. Six months after cessation of natalizumab therapy, low lymphocyte counts in the CSF persisted. The patient with the highest total leukocyte and CD4(+) and CD8(+)T-cell counts in the CSF experienced a clinical relapse. INTERPRETATION: These data suggest that natalizumab treatment results in a prolonged decrease of lymphocytes in the CSF and are consistent with the hypothesis that natalizumab impairs immune surveillance of the central nervous system.     

Cerebrospinal fluid levels of brain specific proteins in optic neuritis

This study evaluates levels of cerebrospinal fluid (CSF) brain-specific proteins (BSP) in subjects with optic neuritis (ON) who are at high risk of progression to multiple sclerosis (MS). Forty-one subjects had acute ON and 17 subjects with other neurological diseases (OND) served as controls. Twenty-one subjects with ON had white matter lesions on magnetic resonance imaging (MRI) and intrathecal synthesis of oligoclonal IgG bands (OB) consistent with being at high risk of progression to MS; eight of whom later were diagnosed with clinically definite MS (CDMS). Levels of S100B, ferritin and two neurofilament heavy chain phosphoforms (NfH(SM134) and NfH(SM135)) were analysed using ELISA technique. A putative index of 'axonal health' was expressed as a ratio of NfH(SM134) to NfH(S135). NfH(SM134) and the NfH(SM134:SM135) were significantly elevated in subjects with ON compared to controls. No significant differences in levels of CSF BSP were seen between ON subjects with CDMS plus those at high risk of progression to MS and ON subjects with normal MRI and negative CSF analysis. In conclusion, there is evidence of axonal damage in subjects who present with ON, which is independent of the diagnosis of CDMS.     

Lymphocyte subpopulations in the blood and cerebrospinal fluid of multiple sclerosis patients in active disease

Lymphocyte subpopulations (total T cells, active T cells and B cells) were simultaneously analyzed in peripheral blood and CSF of MS patients. All patients were in active disease, 3 to 4 weeks after first signs of disease activation appeared. Per cent levels and absolute numbers of examined lymphocyte subpopulations in the blood of MS patients were significantly lower than in healthy controls. In MS, the level of active T lymphocytes was lower in CSF than in peripheral blood. The results support our earlier observations relating to the role of active T lymphocytes in the clinical course of disease.     

CSF cells in multiple sclerosis: monoclonal antibody analysis and relationship to peripheral blood T-cell subsets

Mononuclear cells were analyzed in CSF and blood of 102 patients with MS. In CSF, the majority (78%) of cells were T lymphocytes (T3+), and the ratio of inducer (T4+) to suppressor/cytotoxic (T8+) cells was 2:1. No characteristic alterations in CSF phenotypes could be related to changes in circulating T8 cells or to disease activity. In a group of 75 patients, CSF cell count was higher in patients with low numbers of circulating T8 cells than in those with normal T8 cells. Thus, decreases in suppressor cells in the blood of MS patients are associated with CSF pleocytosis but not with fluctuations in the ratio of different subsets in CSF. Furthermore, large numbers of T8 cells are not sequestered in CSF when these cells are decreased in peripheral blood.     

Magnetic resonance imaging, evoked responses and cerebrospinal fluid findings in a follow-up study of children with optic neuritis

Fourteen patients with previous optic neuritis (ON) in childhood were examined by magnetic resonance (MR) imaging from two months to 14 years after the onset of symptoms. Five patients had a single monosymptomatic course of ON but 7 developed multiple sclerosis (MS); 2 had another demyelinating disease. Eight patients had high signal intensity areas in the T2 weighted images compatible with MS plaques in MR scan; 2 with monosymptomatic ON, 5 with MS and one with another demyelinating disease. The plaques were periventricular or in the optic radiation. The plaques could already be seen during the first symptoms of ON. All 7 MS patients had abnormal visual evoked response, 3/4 abnormal somatosensory evoked response and 5/6 intrathecal immunoglobulin production, when examined at onset of optic neuritis or at follow-up. All patients except one, with lesions in MR, had either oligoclonal CSF antibodies or Dr2 HLA antigen. We suggest that MR is a very sensitive test showing MR abnormalities in children with ON. It is an important tool in the early assessment of MS.     

The role of infection and vaccination in the genesis of optic neuritis and multiple sclerosis in children

This article describes the association between previous infection and/or vaccination and the development of optic neuritis (ON) in 18 children. Ten of these children subsequently developed clinically definite multiple sclerosis (MS), while in 8 patients a clinically definite etiology could not be confirmed. Vaccination preceded the first ON attack in 6 patients, all but one of whom subsequently developed MS. It also preceded subsequent demyelinating events in 6 patients. Ten of the patients had a bacterial or viral infection within the 2 weeks prior to the first symptoms of ON. Intrathecal antibody synthesis against 2 or more viruses could be shown in 5 out of 8 patients studied; 5 out of 6 patients had oligoclonal antibodies in CSF and 12 out of 16 patients a high IgG index. Neither intrathecal antibody synthesis against 2 or more viruses nor elevated IgG indexes could be found in the control patients. Measles and mumps occurred at a significantly later age in the children who subsequently developed MS than in the control children, and these patients had significantly more events that might have impaired the blood-brain barrier than the controls. These results indicate that immunological events leading to MS may be triggered during childhood. Vaccination and infection often precede ON in childhood. Intrathecal viral antibody production can occur already in childhood at the time of the first symptoms of MS.     

多发性硬化患者外周血和脑脊液淋巴细胞亚群的观察

用碱性磷酸酶抗酸酶法检查了４６例多发性硬化活动期患者外周血和脑脊液的淋巴细胞亚群。结果显示：活动期ＭＳ者外周血ＣＤ＾＋４，ＣＤ＾＋９细胞较对照组减少，ＣＤ＾＋２５细胞，ＣＤ＾＋４／ＣＤ＾＋８比值较对照组升高。ＣＳＦ中ＣＤ＾４，ＣＤ＾＋２５细胞，ＣＤ＾＋４／ＣＤ＾＋８比值较对照组升高，ＣＤ＾＋８细胞降低，且ＣＳＦ中淋巴亚群均高于自身外周血中的相应细胞。     

Analysis of lymphocyte subpopulations in cerebrospinal fluid and peripheral blood in patients with multiple sclerosis and inflammatory diseases of the nervous system

We analysed different subsets of lymphocytes from peripheral blood (PB) and cerebrospinal fluid (CSF) by flow cytometry in order to determinate alterations in patients with multiple sclerosis (MS) in acute relapse and viral inflammatory neurological disease (IND). We found increased levels of adhesion molecules (LFA-1 and β₁ integrin) in the CSF of patients with MS and IND compared to NIND. CD4 ⁺/CD8 ⁺ ratio was significantly higher in CSF of MS as compared with all groups analysed and compared with PB. We detected a significantly higher expression of the interleukin-2 receptor in PB of MS patients when compared with other groups. In patients with IND a significant higher expression of the interleukin-2 receptor was found in the CSF compared with MS and NIND. Our findings indicate that the activation of T lymphocytes primarily occurs in the peripheral immune compartment in MS and the increase of adhesion molecules in CSF is related to inflammatory disorders and not only to MS.     

Mononuclear cell types in cerebrospinal fluid and blood of patients with multiple sclerosis. Quantitation by immunoenzyme microassay with panel of monoclonal antibodies

Phenotypic distribution of mononuclear cells in cerebrospinal fluid (CSF) and peripheral blood from patients with multiple sclerosis (MS) and, for reference, patients with acute aseptic meningoencephalitis (AM), and in blood only from healthy controls, was studied with an immunoenzymatic microassay enabling analysis even in the presence of a normal CSF cell count. In MS, increased CD5+ (pan-T) cell proportion in CSF compared with blood was not reflected by changes of CD4+ or CD8+ cells, while in AM, an increase of CD4+ cells was registered. Therefore, a population of CD5+, CD4-, and CD8- cells may be anticipated to exist in CSF of patients with MS. Numbers of OKB7+, OKM1+, or HLA-DR+ cells did not distinguish between MS and AM. Proliferating cells expressing transferrin receptors (OKT9+ cells) were generally few or absent in CSF and not useful as a marker of disease activity in either MS or AM.     

INTERFERON IN the SERUM and CEREBROSPINAL FLUID IN PATIENTS WITH MULTIPLE SCLEROSIS and OTHER NEUROLOGICAL DISORDERS

The presence of interferon (IF) was investigated in serum and cerebrospinal fluid (CSF) from neurological patients. Significant titres of IF were found both in the serum and in the CSF in about half of the patients suffering from acute encephalitis and from multiple sclerosis (MS), but not in patients suffering from various non-inflammatory disorders in the central nervous system (CNS) or in the peripheral nervous system (PNS), and not in the serum of healthy blood donors. Significant IF titres in the CSF were regularly associated with significant titres in the serum, but the converse was not true. Interferon levels were not correlated to cell counts in the CSF; nor to concentration of IgG and albumin in serum and CSF; nor to presence of electrophoretically oligoclonal IgG patterns; nor to hemagglutinating and gel-precipitation antibodies against measles. IF levels were lower in the serum of patients having reduced serum/CSF ratios for measles antibody than those with normal ratios. The data may indicate that MS is linked to factors which induce IF production in the CNS.     

CSF abnormalities can be predicted by VEP and MRI pathology in the examination of optic neuritis

Optic neuritis (ON) is linked to multiple sclerosis (MS). The presence of white matter lesions on cerebral magnetic resonance imaging (MRI) predicts the risk of MS after ON with considerable accuracy. Oligoclonal bands (OCB) are present in 95?% of MS patients, and a lumbar puncture can also be valuable in the evaluation of patients with ON. We analyzed CSF findings in patients referred with ON in the context of MRI and visual evoked potential (VEP) pathology. We assessed the possible contributory role of a lumbar puncture and weigh this against disadvantages of the procedure. Between February 2003 and November 2011, 505 patients were referred by ophthalmologists to the Clinic of Optic Neuritis, Glostrup Hospital, University of Copenhagen. None had MS prior to referral. A total of 437 were included in the study, and all underwent MRI, a lumbar puncture and VEP. Patients with other organic causes of their symptoms and patients with >3?months between onset and tests were excluded. All files were reviewed retrospectively. CSF leukocytes and the IgG index were elevated in 33 and 41?%, respectively, and OCBs were detected in 61?% of patients. CSF abnormalities correlated strongly with VEP and MRI (p?<?0.0001). Patients with normal VEP and MRI had a 96?% probability of a normal lumbar puncture. The contributory role of a lumbar puncture in the evaluation of ON seems negligible when patients have a normal VEP and MRI. We suggest that all patients should be evaluated with VEP and MRI before deciding on a lumbar puncture.     

Inflammatory cytokines in CSF in bacterial meningitis: association with altered blood flow velocities in basal cerebral arteries.

OBJECTIVE--To investigate the association between release of humoral inflammatory mediators in CSF and blood and alterations of cerebral blood flow in patients with bacterial meningitis. METHODS--Immunomodulatory (interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6), and tumour necrosis factor-alpha (TNF alpha)) and vasoactive (thromboxane A, prostacyclin, endothelin-1) molecules of probable or confirmed leucocyte origin were determined in CSF and venous blood from 20 patients with bacterial meningitis, and matched control subjects. Their concentrations were related to the presence of increased blood flow velocities in the middle cerebral arteries, as recorded by transcranial Doppler sonography. RESULTS--Concentrations of proinflammatory cytokines and prostacyclin and leucocyte counts were significantly increased in meningitis, but concentrations of the vasoconstrictors thromboxane and endothelin-1 were not. Patients with high blood flow velocities ( > 140 cm/s) had significantly increased concentrations of IL-1 beta and IL-6 and raised cell counts in CSF. CONCLUSION--The increases of key mediators of inflammation and immunoactivation and of leucocyte count in the CSF of patients with high cerebral blood flow velocities suggest a role of excessive compartmentalised host defence in pathogenesis of disorders of cerebral blood flow in bacterial meningitis.     

Lymphocyte subpopulations in human cerebrospinal fluid.

Lymphocyte subpopulations in both human cerebrospinal fluid and peripheral blood were identified and compared by rosette techniques. In patients without neuroaxial disease, the percent distribution of Fc receptor and T-lymphocytes reflected peripheral blood values, although there was a significantly higher percentage of T cells in normal CSF. Alterations in lymphocyte cerebrospinal fluid populations were observed in various systemic and neurologic diseases.     

Terminal component of complement C9 in CSF and plasma of patients with MS and aseptic meningitis

A sensitive sandwich ELISA was applied to the measurement of the terminal component of complement C9 in CSF and plasma from 40 tension headache patients (reference group), 33 affected by clinically definite MS and 10 by aseptic meningitis. The levels of C9 in plasma were increased in aseptic meningitis. The determinations of CSF/plasma C9 ratio and C9 index, equal to (CSF C9/plasma C9): (CSF albumin/plasma albumin), thus accounting for changes of plasma C9 levels as well as damaged blood brain barrier, documented the existence of local consumption of C9 in aseptic meningitis. In contrast, only borderline alterations were evident in MS. The results indicate that local consumption of total C9 in CSF is an additional variable reflecting an acute inflammation within the CNS, but not demonstrable in MS, a chronic inflammatory CNS disorder.     

Approach to discriminate subgroups in multiple sclerosis with cerebrospinal fluid (CSF) basic inflammation indices and TNF-α, IL-1β, IL-6, IL-8

Lumbar CSF and serum pairs of untreated multiple sclerosis patients (MS; n=47) were analyzed on admission. On average, higher CSF leukocyte (lymphocyte and monocyte) counts, IgG index, CSF IgG contents, but not of TNF-α, IL-1β, IL-6, IL-8 in CSF and serum, were revealed in all MS or patients with long disease course (LO-MS) compared with controls. In primary progressive MS (PP-MS) cell counts were low, but IgG contents were high, when compared to relapsing-remitting MS (RR-MS). In clinically probable MS (CP-MS) both contents were low, in clinically definite MS (CD-MS) high. Spearman’s correlation with the four monokines and the basic indices in CSF revealed activation patterns known for microglia/macrophages in the four MS subgroups, for astrocytes in CP-MS and RR-MS, for CSF lymphocytes in CP-MS and PP-MS, for cells of blood–brain barrier (BBB) in CP-MS, for intrathecal IgG synthesis in PP-MS and for lymphocyte transfer in CD-MS. Correlations between CSF and serum parameters indicated CNS disease processes to be associated with systemic processes of inflammation (acute, chronic) in CD-MS, RR-MS, and PP-MS in different ways. CSF IgG content, IgG index and systemic markers of inflammation correlated with overall disability scores in LO-MS; increasing levels may indicate a bad outcome.     

Serum and cerebrospinal fluid nitrite and nitrate levels in relapsing-remitting and secondary progressive multiple sclerosis patients

Nitric oxide (NO) has been implicated in immune mediated cellular cytotoxicity and inflammatory processes including multiple sclerosis (MS). We aimed to assess NO production in MS patients and to delineate its involvement in different stages. The stable end-products of NO; nitrite(NO₂⁻) and nitrate(NO₃⁻) were analysed both in serum and CSF (cerebrospinal fluid) of patients with MS and non-inflammatory neurological diseases. Nitrite levels were quantified by calorimetric assay based on the Griess reaction. Nitrate levels were examined spectrophotometrically. MS patients exhibited significantly increased serum and CSF levels of NO₂⁻+NO₃⁻ compared with the control subjects. CSF NO₂⁻+NO₃⁻ levels were raised significantly in MS patients with both relapsing remitting (RR) and secondary progressive (SP) course. There was no significant difference between RR and SP MS patients with regard to NO metabolites. No significant correlation was found between NO metabolites and disability score, disease progression index, MRI (magnetic resonance imaging) activity and development of cortical atrophy on MRI. This study provides further evidence for excessive NO production both in CSF and peripheral blood of MS patients. Excessive CSF NO₂⁻+NO₃⁻ levels being more increased than the levels in sera supports pathological inflammatory process within CNS (central nervous system) in both stages of MS. Another implication for the role of NO and INOS inhibitors in the treatment of MS patients with both RR and SP courses was also suggested.     

Clinical, MRI, CSF and electrophysiological findings in different stages of multiple sclerosis

Effective therapy in the earliest stages of multiple sclerosis (MS) demands early correct diagnosis. Retrospective analysis included 130 patients (90 women) with a median age of 35.5 years, median duration of the disease of 2 years and median EDSS score of 3.0. Twenty-seven patients had clinically isolated syndrome (CIS) suggestive of MS, 66 relapsing-remitting (RR) MS, 19 secondary progressive (SP) MS and 18 primary progressive (PP) MS. The predominant symptoms were sensory in 52% of the patients with CIS compared to 27% in patients with RRMS, whereas they were more often motor in patients with PPMS. Patients with CIS had higher CSF cell counts than patients diagnosed in later stages of the disease and oligoclonal bands were found in 89% of all patients without statistically significant differences between the subgroups. Prolonged latencies of visual evoked potentials (VEP) were found in only 29% of patients with CIS compared to 66% in RRMS, 75% in SPMS and 65% of PPMS patients. Fifty-six percent of patients with CIS, 88% with RRMS, 74% with SPMS and 78% of patients with PPMS fulfilled modified the Barkhof et al. MRI criteria at the time of diagnosis. Patients in early MS often present with sensory symptoms. Brain MRI can be inconclusive in over 40% of patients with CIS but the elevated CSF cell count and positive oligoclonal bands are helpful in establishing the diagnosis of CIS suggestive of MS. In later stages of the disease the combination of clinical features, MRI, prolonged VEP latencies and positive CSF oligoclonal bands secures the correct diagnosis.