IgM In Cerebrospinal Fluid Research Articles

Critical evaluation of the biological role of IgM in cerebrospinal fluid in inflammatory and other diseases of the nervous system

In a group of 10,156 patients with neurological diseases, the IgM level was assessed (using laser nephelometry) both in cerebrospinal fluid (CSF) and serum; concentration of other 17 protein fractions was also simultaneously determined: albumin, immunoglobulins, acute phase reactants, complement components, apolipoproteins, proteinase inhibitors and alpha1-microglobulin. Total protein, element counts and glucose level were also evaluated. In patients with normal CSF findings, only limited statistically significant correlations were demonstrated between IgM and other CSF protein fractions while, in the group of patients with pathological CSF findings, significant correlations were found between CSF(IgM) and other immunoglobulins, complement fractions and the rate of intrathecal synthesis of immunoglobulins. Correlations were also found between CSF(IgM) and CSF antithrombin-III and alpha1-microglobulin. Correlations between CSF(IgM) and CSF apolipoproteins support the theory of CNS tissue destruction whenever the concentration of CSF apolipoproteins is elevated. Our data substantially contribute to establishing the diagnosis in patients with neurological diseases; simultaneous measurement of a high number of CSF proteins is becoming inevitable for a reasonable assessment of the CSF Protein Status.

A hospital-based surveillance for Japanese encephalitis in Bali, Indonesia.

BackgroundJapanese encephalitis (JE) is presumed to be endemic throughout Asia, yet only a few cases have been reported in tropical Asian countries such as Indonesia, Malaysia and the Philippines. To estimate the true disease burden due to JE in this region, we conducted a prospective, hospital-based surveillance with a catchment population of 599,120 children less than 12 years of age in Bali, Indonesia, from July 2001 through December 2003.MethodsBalinese children presenting to any health care facility with acute viral encephalitis or aseptic meningitis were enrolled. A "confirmed" diagnosis of JE required the detection of JE virus (JEV)-specific IgM in cerebrospinal fluid, whereas a diagnosis of "probable JE" was assigned to those cases in which JEV-specific IgM was detected only in serum.ResultsIn all, 86 confirmed and 4 probable JE cases were identified. The annualized JE incidence rate was 7.1 and adjusted to 8.2 per 100,000 for children less than 10 years of age over the 2.5 consecutive years of study. Only one JE case was found among 96,920 children 10–11 years old (0.4 per 100,000). Nine children (10%) died and 33 (37%) of the survivors had neurological sequelae at discharge. JEV was transmitted in Bali year-round with 70% of cases in the rainy season.ConclusionJE incidence and case-fatality rates in Bali were comparable to those of other JE-endemic countries of Asia. Our findings contradict the common wisdom that JE is rare in tropical Asia. Hence, the geographical range of endemic JE is broader than previously described. The results of the study support the need to introduce JE vaccination into Bali.

Detection of Japanese Encephalitis (JE) Virus-Specific IgM in Cerebrospinal Fluid and Serum Samples from JE Patients

Detection of Japanese Encephalitis (JE) Virus-Specific IgM in Cerebrospinal Fluid and Serum Samples from JE Patients

Performance Characteristics of Four Immunonephelometric Assays for the Quantitative Determination of IgA and IgM in Cerebrospinal Fluid

Performance Characteristics of Four Immunonephelometric Assays for the Quantitative Determination of IgA and IgM in Cerebrospinal Fluid

Human Parvovirus B19 Infection in Multiple Sclerosis

The association of human parvovirus B19 (PVB19) infection with the development of several systemic autoimmune diseases has been confirmed in other studies. To determine if there is any association of PVB19 infection with multiple sclerosis (MS), we studied the prevalence of serum anti-PVB19 IgG and IgM by an enzyme-linked immunosorbent assay and PVB19-specific DNA in the cerebrospinal fluid (CSF) by the polymerase chain reaction method in a total of 46 patients during exacerbation or remission of MS. Anti-PVB19 IgG was detected in 65.8% of the patients’ sera. The percentage was significantly higher than that in age-matched healthy control subjects (40%; p = 0.019), but was not higher in patients with other neurological diseases (50%; p = 0.16). There was no correlation between serum anti-PVB19 IgG status and antinuclear antibodies or oligoclonal IgG bands in CSF. Serum anti-PVB19 IgM and PVB19 DNA in CSF were consistently negative in the patients during exacerbation of MS. Although MS patients may be commonly infected with PVB19, our results suggest that there is no active PVB19 infection during exacerbation of MS.

Simultaneous expression of Borrelia OspA and OspC and IgM response in cerebrospinal fluid in early neurologic Lyme disease.

Lyme disease is the major tick-borne disease, caused by Borrelia burgdorferi (Bb). Neurological involvement is common in all stages. In vivo expression of Bb antigens (Ags) and the immune response to them has not been well investigated in the cerebrospinal fluid (CSF). Upregulation of outer surface protein (Osp) C and concomitant downregulation of OspA before tick inoculation of the spirochete has been reported in skin and blood in animals. CSF OspA Ag in early disease suggests otherwise in CSF. Early Ag expression and IgM response in human CSF was investigated here. Paired CSF and serum was collected from 16 early, predominantly erythema migrans Lyme disease patients with neurologic problems, 13 late Lyme disease patients, and 19 other neurologic disease (OND) controls. Samples were examined for IgM reactivity to recombinant Bb-specific Osps using ELISA and immunoblot. Of 12 early Lyme disease patients with neurologic involvement with both CSF and serum IgM against OspC, 7 (58%) had IgM to OspA (n = 5) or OspB (n = 2) that was restricted to the CSF, not serum. Overall, 12 of 16 (75%) of these early Lyme disease patients with neurologic involvement had CSF and serum IgM against OspC. Only 3 of 13 (23%) late Lyme disease patients and none of 19 OND controls had CSF IgM directed against OspC. In conclusion, in CSF, OspC and OspA can be coexpressed, and IgM response to them occurs in early Lyme disease patients with neurologic involvement. This biologic finding may also provide a discriminating marker for CNS infection in Lyme disease.

High levels of cerebrospinal fluid IgM binding to myelin basic protein are associated with early benign course in multiple sclerosis

We assessed human myelin basic protein (MBP) binding IgM levels in the CSF. MBP is the most studied putative antigen in multiple sclerosis (MS) and immune responses directed against it may be involved in the demyelination process. We also correlated these levels with EDSS score and other parameters of disease progression and prognosis, both at the time of CSF analysis and during follow-up. CSF IgM anti-MBP levels were assayed by measuring total IgM levels with solid-phase ELISA in CSF samples from 66 patients with relapsing–remitting MS, 11 subjects without neurological diseases, 20 patients with non-inflammatory neurological diseases and 7 patients with lymphocytic meningitis, before and after immunoabsorption with human MBP. Confirmation of IgM binding specificity was performed by immunoblotting of positive CSF samples onto MBP coated-nitrocellulose sheets. Clinical evaluation (disability score, number and time of attacks) was performed during a mean follow-up of 2.7±1.1 years. 23 of 66 relapsing–remitting MS patients (33.8%) had elevated IgM anti-MBP levels. In this patient subgroup, IgM anti-MBP levels correlated with the IgM index ( r=0.71; P=0.0001), but not with CSF/serum albumin ( r=0.08; P=0.72). In the first year of follow-up, patients with low IgM anti-MBP suffered from more numerous attacks than those with elevated levels (0.86±0.63 versus 0.43±0.58; P=0.017). Patients with high IgM binding to MBP had a first attack during follow-up in a significantly higher time than those with low binding (28.87±4.7 versus 17±2.6 months, respectively; P=0.005) and reached a decrease of 0.5 EDSS point significantly faster than those with low IgM (16.17±1.2 versus 29.7±2.6 months, respectively; P=0.0002). A similar significant finding was observed when the time to reach low disability score (EDSS≤2.0) was analyzed (10.7±2 versus 25.7±3.3 months, respectively; P=0.014). These findings demonstrate that in a subgroup of MS patients, elevated CSF levels of IgM anti-MBP are associated with early favorable course and therefore suggest that IgM binding to MBP could be a possible prognostic marker in relapsing–remitting MS to select early MS patients for future trials.

Intrathecal IgM, IgA and IgG antibody response in tick-borne encephalitis. Long-term follow-up related to clinical course and outcome

Background: Tick-borne encephalitis (TBE) of western subtype causes long-term morbidity and is considered a health problem in Scandinavia, eastern and central parts of Europe and Russia. The pathophysiology is not fully elucidated. As TBE RNA is rarely demonstrable in cerebrospinal fluid (CSF) the kinetics of the CSF antibody response to the disease has attracted attention. Objectives: To investigate the intrathecal TBE-specific antibody response and to correlate its intensity and persistence to the clinical course. To compare indirect, commercially-based ELISA methods indexed against albumin ratio or IgG ratio with the capture ELISA method for the establishment of CSF response. Study design: The specific IgM, IgG and IgA antibody responses in serum and CSF were analysed in 69 Swedish patients included in a prospective study of TBE from the acute phase up to 11 – 13 months after onset. Results: Antibody response by all three classes was demonstrable in serum and CSF. All methods were useful, but capture technique was the most sensitive and results were easiest to interpret. Peak IgM activity was seen early during the disease and persisted after 6 weeks. Maximum IgG levels were encountered in late convalescent samples (median 6 weeks). Intrathecal antibody production was demonstrable in nearly all patients: in 41% days 0–6, in 97% days 7–19, in 98% days 21–61 and—at lower levels—in 84% of the patients after 1 year ( 50 52 of CSF-serum sampled in the interval 11–61 days). Day 9 after onset, patients with dominating encephalitic symptoms showed significantly lower intrathecal IgM activity. The persistence of serum and CSF antibodies did not correlate to severity of disease. Conclusions: Capture IgM and IgG assays were superior to indirect ELISA. Low early CSF IgM response correlated to encephalitic symptoms, otherwise the intensity and duration of intrathecal antibody response were of limited value for the prediction of clinical course and long-term outcome.

Viral etiology of acute childhood encephalitis in Beijing diagnosed by analysis of single samples.

To understand the viral etiology of acute childhood encephalitis in Beijing. Ninety-seven Chinese children (between 7 months and 13 years of age) with acute encephalitis were retrospectively investigated. They were treated in Beijing Children's Hospital between June, 1991, and October, 1994. Different serologic methods (immunofluorescence assay, enzyme-linked immunosorbent assay, solid phase reverse immunosorbent test) were used for detection of IgM antibody to enteroviruses, herpesviruses, mumps, measles, rubella and Japanese encephalitis virus. The viral DNA of six herpesviruses was detected by polymerase chain reaction. Viral etiology was identified in 35 of 97 (36.0%) cases. The most frequently identified pathogens were enteroviruses (15; 15.4%), followed by mumps (7; 7.2%), rubella (6; 6.1%), Japanese encephalitis virus (5; 5.1%), human herpesvirus 6 (2; 2.0%), herpes simplex virus (2; 2.0%) and Epstein-Barr virus (1; 1.0%). IgM antibody in cerebrospinal fluid was detected for enterovirus, mumps and rubella viruses. Enteroviruses were the most frequent viral pathogens of acute childhood encephalitis in Beijing. Detection of IgM in cerebrospinal fluid may be useful for diagnosis in certain cases of viral encephalitis.

External quality assessment in clinical neurochemistry: survey of analysis for cerebrospinal fluid (CSF) proteins based on CSF/serum quotients

Participants (230) from Germany and 20 laboratories in 11 European countries took part in a newly designed cerebrospinal fluid (CSF) survey distributed by INSTAND. Conventional proficiency testing for albumin, IgG, IgA, and IgM in CSF and serum, for total protein in CSF, and for oligoclonal IgG in CSF and serum was combined with evaluation and interpretation of CSF/serum quotients in quotient diagrams. The correct detection of a blood-CSF barrier dysfunction and the pattern of intrathecal immunoglobulin synthesis was judged. The accuracy of CSF/serum quotients and their clinically relevant interpretation was given first priority as a new concept in quality assessment. The main result of the surveys was to confirm that CSF/serum quotients of proteins represent method-independent values approaching the quality of reference values. This finding has consequences for internal quality control of CSF analysis and for accreditation bodies. The sensitivity of the methods for quantifying IgA and IgM in CSF and for detecting oligoclonal IgG fractions is discussed.

Improved Formulae for the Judgement of Intrathecal Produced IgA and IgM in the Presence of Blood CSF Barrier Damage

In order to discriminate between transsudated and intrathecally produced IgA and IgM in patients with blood cerebrospinal fluid (CSF) barrier (BCB) damage, we developed extended indices (IgA-EI and IgM-EI) for these immunoglobulins according to the general formula for extended index of a component X in CSF: X-EI = (CSF-X/serum-X)/(CSF-albumin/serum-albumin)a where a is a parameter specific for X. For IgA parameter a was found to be 1.15 and for IgM 1.9. A preliminary evaluation of IgA-EI and IgM-EI indicated lower false positive rates as compared to CSF IgA and IgM concentrations as well as 'conventional' IgA and IgM indices in cases with BCB damage, and essentially the same rates as for the hyperbolic formulae of Reiber and Felgenhauer. The importance of reliable sampling and analytical technique for IgM in CSF is discussed.

HIV-1 specificity of cerebrospinal fluid and serum IgG, IgM, and IgG1-G4 antibodies in relation to clinical disease

The reactivities of intrathecal and serum IgG and IgM, and IgG1–4 subclass antibodies to various HIV-1 proteins were assessed by immunoblotting at various stages of HIV-1 infection. All patients were examined neurologically including CT and/or MRI, and with HIV-1-specific and nonspecific tests of the cerebrospinal fluid (CSF). In early infection, the occurrence of anti-gag antibodies in both CSF and serum was higher than that of anti-pol antibodies among all IgG subclasses ( P < 0.05). Also in late infection, anti-gag IgG1 response was most frequent ( P < 0.04), while anti-gag IgG3 and IgG4 reactivities predominated over similar anti-pol antibodies ( P < 0.05, respectively). Of anti-pol reactivities, in the CSF of subjects at early infection anti-p32 IgG and IgG1 antibodies were more frequent than in patients at late stages ( P < 0.015). In late infection, however, the occurrence of anti-p64 IgM and IgG2–4 antibodies of both CSF and serum was higher than at early stages ( P = 0.014). Regarding anti-env response, in patients with advanced infection, the CSF and serum IgG subclass reactivity against gp120 was restricted to IgG1. The CSF of individual patients with HIV encephalopathy showed a higher or similar occurrence of polyisotypic anti-gag and anti-pol IgG3 antibodies than corresponding serum. These results indicate association between declining frequency of anti-pol p32 and anti-env gp120 antibodies and severity of HIV-1 disease. On the other hand, the higher occurrence of anti-pol p64 IgM and IgG2-G4 antibodies in both CSF and serum of patients at late infection, indicate active systemic and intrathecal viral replication. Such reactivity of the CSF, in the absence of increased blood-brain barrier permeability, is suggestive of HIV-1 infection the CNS.

IgM antibody to Treponema pallidum in cerebrospinal fluid of infants with congenital syphilis.

To characterize the neonatal IgG and IgM response to specific Treponema pallidum antigens in the cerebrospinal fluid (CSF) of infants with congenital syphilis. Cross-sectional survey. Newborn nursery and neonatal intensive care unit of a county hospital in Dallas, Tex. Twenty-one infants born to mothers with reactive serologic tests for syphilis were enrolled. Group 1 consisted of six infants with clinical and laboratory evidence of congenital syphilis; group 2, six asymptomatic infants born to mothers with untreated syphilis; and group 3, nine asymptomatic infants whose mothers were treated for syphilis before delivery. Random sample. Immunoblotting was used to examine the IgM and IgG reactivities of neonatal serum and CSF against T pallidum antigens. Among serum samples of all group 1 infants, a specific IgM response to T pallidum antigens with apparent molecular masses of 47, 45, and 17 kd was observed. Cerebrospinal fluid IgM reactivity to a 47-kd antigen of T pallidum was seen in four group 1 infants. Serum samples from two group 2 and three group 3 infants demonstrated IgM reactivity against the 47-kd antigen and, in some cases, against the 45-kd antigen of T pallidum. None of 15 group 2 and 3 infants had a positive CSF IgM immunoblot result. The IgG reactivity in CSF was similar in the three groups and was directed against T pallidum antigens with apparent molecular masses of 72, 59, 47, 45, 42, 37, 34, 17, and 15 kd. A specific IgM response to T pallidum antigens, particularly the 47-kd antigen, was detected in the CSF of some infants with clinical and laboratory evidence of congenital syphilis. The potential usefulness of this test for the diagnosis of congenital neurosyphilis merits further study.

Cerebrospinal Fluid Interleukins, Immunoglobulins, and Fibronectin in Neuroborreliosis

Intrathecal synthesis of IgM and IgG, oligoclonal immunoglobulin bands, and the levels of fibronectin, soluble interleukin 2 receptor, interleukin 6, and tumor necrosis factor alpha were investigated with the use of enzyme-linked immunosorbent assay in 46 paired cerebrospinal fluid and serum samples from 32 patients with meningopolyradiculoneuritis due to Borrelia burgdorferi (Lyme borreliosis stage 2). Cerebrospinal fluid and serum interleukin 6, although not specific for neuroborreliosis, were good indicators of disease activity, while the serum soluble interleukin 2 receptor level was only mildly elevated. Tumor necrosis factor alpha was never detected in cerebrospinal fluid or serum specimens, and cerebrospinal fluid IgM, IgM index, and cerebrospinal fluid IgM/cerebrospinal fluid IgG ratios were significantly higher than in all other neuroimmunologic disorders evaluated and may be valuable diagnostic indicators for neuroborreliosis. The estimation of intrathecally synthesized IgG and IgM fractions for the differential diagnosis of neuroimmunologic disorders did not add to IgG and IgM index calculations.

Japanese Encephalitis in Southeastern Nepal: Clinical Aspects in the 1986 Epidemic

A multi disciplinary team furthered the collaborative study of acute encephalitis in southeastern Nepal during a major epidemic which occurred in the monsoon period of 1986. Viral studies of serum and cerebro-spinal fluid (CSF) confirmed Japanese Encephalitis Virus (JEV) as the causative agent. Analysis of epidemiologic data suggests recent introduction of the virus to the regional population. Children accounted for the majority of all hospital admissions and had a markedly lower fatality rate from the infection than adults. Unfavourable prognostic indicators identified include a reduced conscious level on admission to hospital and a low serum or CSF IgM response to JEV.

INTRATHECAL IMMUNOGLOBULIN M SYNTHESIS IN MULTIPLE SCLEROSIS&lt;subtitle&gt;RELATIONSHIP WITH CLINICAL AND CEREBROSPINAL FLUID PARAMETERS&lt;/subtitle&gt;

Intrathecal IgM synthesis was assessed through the detection of oligoclonal bands in cerebrospinal fluid (CSF) and through calculation of IgM index values and total CSF IgM amounts. Intrathecal production of IgM was then evaluated along with other CSF parameters and clinical variables in 150 patients with multiple sclerosis (MS). Intrathecal production of IgM was detected in 55% of patients and was found to correlate with disease activity, manifesting as a recent relapse, as well as the total number of relapses. An inverse correlation was found between CSF oligoclonal IgM and both the time interval between the last relapse and lumbar puncture, and duration of the disease process. It also correlated with the number of leucocytes, free kappa and lambda light chain bands in CSF. No correlation was found between intrathecal IgM synthesis and degree of disability (Kurtzke scale), disease progression index (Poser scale), or total cerebral plaque burden (detected by enhanced CT and MRI scans). Oligoclonal IgM bands were found to be more specific for active disease process than either IgM index or total CSF IgM amount. It is concluded that intrathecal synthesis of IgM, as detected by CSF oligoclonal bands, is a useful parameter in monitoring disease relapse activity in MS.

Solid-phase immunofluorometric assay for quantification of CSF immunoglobulins: Determination of normal reference values

Because a highly sensitive method is required to quantify low concentrations of immunoglobulin (Ig) classes in cerebrospinal fluid (CSF), there have been a few papers reporting normal values of CSF IgG, IgA and IgM determined in the same samples. Enzyme immunoassay (EIA) is most frequently used, but has such drawbacks as susceptibility of enzyme to inhibition and denaturation and the requirement for additional incubation with a substrate. Therefore, solid-phase immunofluorometric assay was evaluated for quantification of CSF IgG, IgA and IgM in the nanogram range. We found this to be rapid and reproducible. The mean (SD) values of normal CSF samples obtained from 22 subjects with tension headache were 23.9 (7.6) μg/ml for IgG, 2.00 (0.90) μg/ml for IgA and 197 (87) ng/ml for IgM. The normal mean (SD) values of indexes were 0.51 (0.10) for IgG, 0.25 (0.05) for IgA and 0.044 (0.017) for IgM. These values agreed quite well with those determined by EIA. The values of CSF albumin correlated significantly with those of CSF IgG or IgA, but did not with those of CSF IgM. Levels of each of the three Ig classes in CSF and serum were significantly correlated. When CSF serum ratio was introduced, a significant correlation between the albumin ratio and each Ig ratio was found. These results suggest that the Ig content of normal CSF may depend upon that of serum and upon the characteristics of the Ig molecule.

Intrathecal synthesis of IgM in neurological diseases: A comparison between detection of oligoclonal bands and quantitative estimation

Immunoglobulin (Ig) M concentration in cerebrospinal fluid (CSF) was measured in 30 reference subjects to determine reference ranges which were up to 0.41 mg/l for CSF IgM, 0.06 for IgM index, and 9 × 10 −4 mg/l for the Reiber empirical formula. Intrathecal IgM synthesis was then studied in 159 patients with different neurological diseases both by detecting CSF oligoclonal IgM bands and by determining the IgM index and Reiber's intrathecal IgM production values. At the same time, the state of blood-CSF barrier was evaluated in all patients by CSF polyacrylamide gel electrophoresis and by CSF/serum albumin ratio. Oligoclonal IgM bands were present mainly in patients with intrathecal humoral immune response, e.g. multiple sclerosis, other inflammatory nervous diseases, and infections of the central nervous system. Quantitative IgM ratios were, however, elevated in conditions not associated with local humoral immune response. Furthermore, quantitative ratios were elevated in patients with damaged blood-CSF barriers. Oligoclonal IgM bands are thus considered to be the most useful tool in detecting intrathecal synthesis of IgM.

Laboratory diagnosis of japanese encephalitis using monoclonal antibodies and correlation of findings with the outcome

Detection of virus, viral antigen, and class-specific antibody was carried out in cerebrospinal fluid (CSF) and sera of 27 children with Japanese encephalitis. The diagnosis could be confirmed in 78.57% of cases (22/27) by demonstration of virus-specific IgM in CSF (15/22), viral antigen in CSF (5/22), or by virus isolation (2/22). Absence of virus specific IgM in CSF was associated with a fatal outcome (P = 0.05).

Kappa/Lambda Ratios In IgG, IgA and IgM of Cerebrospinal Fluid and of Sera in Patients with Multiple Sclerosis

Kappa/lambda (kappa/lambda) ratios of each immunoglobulin, i.e. IgG, IgA and IgM in cerebrospinal fluid (CSF) and in sera of patients with multiple sclerosis (MS) were analysed by sandwich enzyme linked immunosorbent assay. In CSF kappa/lambda ratios of IgG of MS patients were significantly (p less than 0.05) higher than those of normal controls, whereas the values of IgA and IgM did not differ significantly from those of normal controls. In sera kappa/lambda ratios of IgG, IgA and IgM did not differ significantly from those of normal controls. Our results suggest that in MS patients abnormal kappa/lambda ratios are also restricted to IgG components in CSF, as oligoclonal IgG bands are.