Cerebrospinal Fluid Oligoclonal IgG Research Articles

Cerebrospinal fluid free light chain quantitation is a specific biomarker for inflammatory neurological disorders in a paediatric patient cohort.

The analysis of cerebrospinal fluid (CSF) is routinely used in the diagnostic work-up of a range of inflammatory, infective, and congenital neurological conditions. Many diagnostic tests used in this analysis have poor sensitivity; as such, we investigated the utility of CSF free light chain (FLC) analysis as an adjunct to currently used assays in a paediatric population with neurological disorders. Kappa (κ) and lambda (λ) FLC levels were quantitated in blinded CSF samples by two nephelometric platforms. Results were correlated to clinical diagnoses and classified according to inflammatory/infective or non-inflammatory pathogenesis. FLC results were also compared to currently used CSF diagnostic tests including oligoclonal bands (OCB), CSF IgG and albumin levels, and differential cell count. Of 70 samples analysed, 29 (41%) had an inflammatory or infective diagnosis and 41 (59%) presented with a range of non-inflammatory aetiologies. Thirteen patients had elevated κFLC or λFLC as detected on the IMMAGE 800, defined as greater than the detection limit of the assay (0.600 mg/L for CSF κFLC, and 0.490 mg/L for CSF λFLC), and of these 12 (92%) had an inflammatory disease (sensitivity 41.4%, specificity 97.6%). On the BN II using optimal cut-offs of 0.27 mg/L and 0.12 mg/L for CSF κFLC and λFLC respectively, 24 (34%) patients had elevated results, of which 21 (88%) had an inflammatory disease (sensitivity 72.4%, specificity 92.7%). Analysis of FLC correlated better with diagnostic classification of the diseases than OCB, cell counts and CSF IgG levels. The results of this study support the use of CSF FLC analysis in the diagnosis of paediatric neuroinflammatory conditions.

Kappa Index Versus CSF Oligoclonal Bands in Predicting Multiple Sclerosis and Infectious/Inflammatory CNS Disorders.

Background: Cerebrospinal fluid (CSF) kappa free light chains (KFLC) are gaining increasing interest as markers of intrathecal immunoglobulin synthesis. The main aim of this study was to assess the diagnostic accuracy (AUC) of the kappa index (CSF/serum KFLC divided by the CSF/serum albumin ratio) compared to CSF oligoclonal IgG bands (OCB) in predicting Multiple Sclerosis (MS) or a central nervous system infectious/inflammatory disorder (CNSID). Methods: We enrolled patients who underwent a diagnostic spinal tap throughout two years. KFLC levels were determined using a Freelite assay (Binding Site) and the turbidimetric Optilite analyzer. Results: Of 540 included patients, 223 had a CNSID, and 84 had MS. The kappa index was more sensitive (0.89 versus 0.85) and less specific (0.84 versus 0.89), with the same AUC (0.87) as OCB for MS diagnosis (optimal cut-off: 6.2). Adding patients with a single CSF IgG band to the OCB-positive group slightly increased the AUC (0.88). Likewise, the kappa index (cut-off: 3.9) was more sensitive (0.67 versus 0.50) and less specific (0.81 versus 0.97), with the same AUC (0.74) as OCB, for a CNSID diagnosis. Conclusion: The kappa index and CSF OCB have comparable diagnostic accuracies for a MS or CNSID diagnosis and supply the clinician with useful, complementary information.

Advanced MRI features in relapsing multiple sclerosis patients with and without CSF oligoclonal IgG bands

Oligoclonal IgG bands (OCB) in cerebrospinal fluid (CSF) are important in diagnosis of multiple sclerosis (MS). We evaluated the MRI features of clinically definite MS subjects with and without CSF-OCB. Relapsing MS subjects were recruited from a prospective registry in a university center. CSF-OCB were detected using isoelectric focusing and lgG-specific immunofixation. MRI metrics including brain volumes, lesion volumes and microstructural measures, were analyzed by FMRIB Software Library (FSL) and Statistical Parametric Mapping (SPM). Seventy-five subjects with relapsing MS were analyzed. Forty-four (59%) subjects had an interval MRI at around 1 year. CSF-OCB were detected in 46 (61%) subjects. The OCB-positive group had a higher proportion of cerebellar lesions than the OCB-negative group (23.9% vs. 3.4%, p = 0.057). Except for amygdala volumes which were lower in the OCB-positive group (p = 0.034), other regional brain volumes including the subcortical deep gray matter and corpus callosum were similar. The two groups also showed comparable brain atrophy rate. For DTI, the OCB-positive group showed significantly higher mean diffusivity (MD) value in perilesional normal-appearing white matter (p = 0.043). Relapsing MS patients with and without CSF-OCB shared similar MRI features regarding volumetric analyses and DTI microstructural integrity.

Longitudinally extensive transverse myelitis associated with intrathecal synthesis of oligoclonal immunoglobulin G and with vitamin B12 deficiency

The differential diagnosis of transverse myelitis (TM) is a challenging clinical problem due to a wide range of diseases, the pattern of which may include TM. Comorbidity is also a highly relevant problem in the development of inflammatory myelopathies. The described clinical case demonstrates difficulties in the nosological diagnosis in case of monophasic TM concurrent with its several probable causes. An examination of a female patient with longitudinally extensive TM and a history of two cerebral ischemic strokes also revealed the reduced levels of vitamin B12 in serum and oligoclonal IgG in cerebrospinal fluid. A CNS lesion is regarded as a possible interaction of two typical pathological processes: inflammation and thrombogenesis. In this case vitamin B12 deficiency could predispose to the initiation and maintenance of the above mechanisms. The specific features of formulation of a diagnosis in patients with such multifactorial conditions are considered.

Cerebrospinal fluid oligoclonal IgG bands in Japanese patients with clinically isolated syndrome

Cerebrospinal fluid oligoclonal IgG bands in Japanese patients with clinically isolated syndrome

Prevalence of cerebrospinal fluid oligoclonal IgG bands in Greek patients with clinically isolated syndrome and multiple sclerosis

Lower prevalence of cerebrospinal fluid oligoclonal IgG bands (IgG-OCBs) has been reported in multiple sclerosis (MS) patients from Southern Europe compared to other western countries. ObjectivesWe aimed to determine the prevalence of CSF OCBs in Greek MS patients and to examine their relation with some selected clinical and demographical features. MethodsIncluded patients fulfilled the 2005 McDonald criteria for definite MS (CDMS) or clinically isolated syndrome (CIS) and had a spinal tap performed between 2006 and 2010. Paired CSF and plasma samples were analyzed using isoelectric focusing followed by IgG-specific immunofixation. A pattern of two or more bands present only in the CSF was defined as positive. OCB status was correlated with age at disease onset, initial symptomatology, relapse rate, disease subtype, disease duration, medication, EDSS score and MSSS. ResultsOf the 231 included patients (53.2% with CDMS and 48.6% with CIS) 67.5% had OCBs. The prevalence of positive patterns did not differ between CIS and CDMS patients (67.6% vs. 67.5%, respectively). OCB-positive patients were younger than OCB-negative patients (35.2±10.3 vs. 38.7±11.8 years respectively, p=0.022) and had more frequently cervical spinal cord lesions (x2=7.08, p=0.008). No difference was observed between the two subgroups in the other studied disease parameters. ConclusionDespite the lower frequency of positive IgG-OCB patterns in our patients, both subgroups were mostly similar with regard to their clinical and demographic characteristics suggesting that the OCB status lacks prognostic significance in MS.

Cerebrospinal fluid oligoclonal IgG bands in multiple sclerosis: what does it mean?

ultiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). Presence of plaques is the main pathological feature of MS, occurring in myelinated axons within the CNS (brain and spi-nal cord). MS is classified as relapsing-remitting MS (RRMS) characterized by attacks, whose symptoms occur so suddenly with subsequent partial or complete recovery; primary-progressive MS (PPMS) with progressive symptoms accumulated over time; and sec-ondary-progressive MS (SPMS), after the initial form of RRMS. The most common type of MS is the relapsing-remitting (when attacks may sequelae or not)

OLIGOCLONAL IgG AND MEASLES ANTIBODY IN CSF OF MULTIPLE SCLEROSIS PATIENTS

Cerebrospinal fluid (CSF) was obtained from 50 neurological patients, 26 of whom suffered from multiple sclerosis (MS). Agar gel electrophoresis and determination of anti-measles antibody titre were performed on the CSF samples. The frequency of elevated measles antibody titre was higher among the MS patients than among the patients with other neurological diseases. Furthermore, oligoclonal IgG in CSF occurred more often among the MS patients than among the other neurological patients. An association between high measles antibody titre and the presence of oligoclonal IgG was observed in CSF from both the MS patients and the patients with other neurological diseases. However, the nature of the correlation between occurrence of oligoclonal IgG and high measles antibody titre remains to be explained.

Intrathecal synthesis of immunoglobulin G in vascular dementia

Serum and CSF from 53 vascular dementia (VD) patients and 50 controls were analysed to investigate the possibility of an intrathecal synthesis of IgG, defined as an elevated IgG index (greater than or equal to 7) and/or presence of oligoclonal IgG in cerebrospinal fluid (CSF), but not in serum. Five (9%) patients and no controls exhibited an intrathecal synthesis of IgG. The IgG index increased with the degree of dementia (p less than 0.05). It was positively related to presence/absence of hypertension (p less than 0.05) and correlated positively with diastolic blood pressure (p less than 0.05). The findings suggest that immunological factors might be involved in the pathogenesis of VD.

Agarose isoelectric focusing, antiserum immunofixation and silver staining for detection of oligoclonal bands in unconcentrated cerebrospinal fluid

Unconcentrated cerebrospinal fluid (CSF) and corresponding serum from 30 patients with multiple sclerosis (MS), 30 with other neurological disease and 30 controls suffering from tension headache or psychoneurosis, were examined for oligoclonal IgG bands by initial separation employing agarose isoelectric focusing (AIF) followed by a modified procedure of immunofixation with monospecific antiserum and silver staining. This method is specific for demonstration of IgG and has a limit for detection of 0.4 microgram of IgG. Comparing the results with those obtained by AIF followed by capillary blotting to nitrocellulose membrane, double antibody peroxidase labeling and avidin-biotin amplification, both methods revealed similar frequencies of positive findings for oligoclonal IgG bands in the three patient groups. AIF followed by antiserum immunofixation and silver staining is a simple, sensitive and specific method for detection of oligoclonal IgG in unconcentrated CSF.

Neurosyphilis révélée par une atteinte multiple des nerfs crâniens : apport de l’imagerie par résonance magnétique nucléaire

Introduction We report the magnetic resonance imaging (MRI) findings in a case of neurosyphilis revealed by the involvement of two cranial nerves. Case report A 41-year-old man developed a right cochleovestibular and left trigeminal neuropathy, associated with high serum titers of VDRL and TPHA, high titers of TPHA in the cerebrospinal fluid (CSF) and several CSF oligoclonal IgG bands. On MRI, hypertrophy and gadolinium contrast enhancement of these cranial nerves were associated with several supratentorial cortical nodules surrounded by marked cerebral edema, corresponding to syphilitic gummas. One of these cortical nodules was biopsied. Microscopic examination showed lesions of meningoencephalitis with necrosis and granulomatous vasculitis. After penicillin therapy, the serum VDRL titers and the MRI abnormalities disappeared, a partial clinical recovery was observed and a significant reduction of the serum TPHA titers was found. Discussion Such MRI abnormalities are not specific and can be observed in various tumoral, auto-immune and infectious diseases. They can also mimic neurofibromatosis type II. Cranial nerve involvements in neurosyphilis can result from nerve inflammation in basal meningitis, nerve ischemia in meningovasculitis or from compression by an adjacent gumma. In our case, the cranial neuropathy was related to a mixed meningovascular and parenchymatous form of neurosyphilis.

CSF analysis in patients with sporadic CJD and other transmissible spongiform encephalopathies

Patients with suspected Creutzfeldt-Jakob disease (CJD) often have routine cerebrospinal fluid (CSF) analysis performed to exclude treatable inflammatory conditions; however, little information is available about the range of results obtained for CSF tests in patients with sporadic CJD and other transmissible spongiform encephalopathies (TSE). Data from 450 patients with sporadic CJD and 47 patients with other TSEs were collected as part of an EC-supported multinational study. Raised white cell counts of >5 cells/microl were found in three of 298 patients with sporadic CJD, with two cell counts of 7 cells/microl and one of 20 cells/microl. Total protein concentrations of >0.9 g/l were found in five of 438 patients with sporadic CJD, although none had a concentration of >1 g/l. CSF oligoclonal IgG was detected in eight of 182 sporadic CJD patients. Of the patients with other TSEs, six had elevated cell counts ranging from 6 to 14 cells/microl but none had total protein concentrations of >0.9 g/l and one patient had detectable oligoclonal IgG. None of the patients with sporadic CJD or other TSEs had abnormalities in all three tests.

Identification of Epstein-Barr virus proteins as putative targets of the immune response in multiple sclerosis

MS is a chronic inflammatory and demyelinating disease of the CNS with as yet unknown etiology. A hallmark of this disease is the occurrence of oligoclonal IgG antibodies in the cerebrospinal fluid (CSF). To assess the specificity of these antibodies, we screened protein expression arrays containing 37,000 tagged proteins. The 2 most frequent MS-specific reactivities were further mapped to identify the underlying high-affinity epitopes. In both cases, we identified peptide sequences derived from EBV proteins expressed in latently infected cells. Immunoreactivities to these EBV proteins, BRRF2 and EBNA-1, were significantly higher in the serum and CSF of MS patients than in those of control donors. Oligoclonal CSF IgG from MS patients specifically bound both EBV proteins. Also, CD8(+) T cell responses to latent EBV proteins were higher in MS patients than in controls. In summary, these findings demonstrate an increased immune response to EBV in MS patients, which suggests that the virus plays an important role in the pathogenesis of disease.

Detection of Oligoclonal Immunoglobulins in Cerebrospinal Fluid by an Immunofixation-Peroxidase Method

The detection of intrathecal synthesis of immunoglobulins is used in the diagnosis of multiple sclerosis (MS). We tested the semiautomated immunofixation-peroxidase (IFPOD) technique, which uses high-resolution agarose gel electrophoresis (HRAGE) directly followed by immunofixation with a peroxidase-labeled anti-IgG antiserum to detect oligoclonal immunoglobulins in cerebrospinal fluid (CSF). We analyzed 230 consecutive matched serum/CSF pairs that arrived in the laboratory over a 6-month period with both IFPOD and our routine techniques, immunofixation electrophoresis (IFE) and HRAGE. For IFPOD, CSF samples were not concentrated before testing. Among the 230 samples were 12 clinically definite MS, 33 clinically probable, and 20 clinically possible MS samples. IFPOD and HRAGE + IFE each detected oligoclonal IgG in CSF in 10, 16, and 7 cases of these respective groups. For clinically definite MS, sensitivity and specificity (95% confidence intervals) were, respectively, 83% (51-97%) and 79% (73-84%). The IFPOD technique performs comparably to other analytical methods, without the requirement for sample concentration, and may represent an attractive alternative in testing for intrathecal immunoglobulin synthesis.

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.

Oligoclonal IgG in the Cerebrospinal Fluid from Patients with Neurologic Diseases in Kuwait: An Isoelectric Focusing Study

Cerebrospinal fluid (CSF) and serum IgG from 139 inpatients were analyzed for the detection of oligoclonal banding by isoelectric focusing on agarose (AIEF) with immunoperoxide staining. All of the patients had been admitted to one of the three major hospitals dealing with neurological diseases in Kuwait (Ibn Sina, Mubarak Al-Kabeer and Al-Amiri Hospitals). Of the 139 patients, 23 had oligoclonal bands in the CSF, 9 had evidence of intrathecal synthesis of IgG (bands in CSF but not in parallel serum), and 9 had evidence of systemic immune stimulation (oligoclonal bands in the CSF and in parallel serum). In 5 cases, serum was not available for an appropriate interpretation. Patients with intrathecal synthesis of IgG had demyelinating diseases and infections of the central nervous system (CNS). Patients with systemic immune response had infections, connective tissue disorders and malignancy. In cases with positive oligoclonal IgG in CSF, the diagnosis of diseases not associated with immune response within the CNS may be excluded. Our results compare favorably with already published sensitivity of AIEF and further recommend this method as a useful adjunct in the diagnosis of neurologic disease.

The significance of brain magnetic resonance imaging abnormalities at presentation with clinically isolated syndromes suggestive of multiple sclerosis. A 5-year follow-up study.

A 5-year follow-up study was performed on 89 patients who had undergone brain magnetic resonance imaging (MRI) at presentation with an acute clinically isolated syndrome of the optic nerves, brainstem or spinal cord of a type suggestive of multiple sclerosis. At presentation, MRI was abnormal, revealing one or more asymptomatic cerebral white matter lesions in 57 (64%), and was normal in 32 (36%). At follow-up, progression to clinically definite multiple sclerosis had occurred in 37 out of 57 (65%) with an abnormal MRI and one out of 32 (3%) with normal MRI. Human leucocyte antigen (HLA) typing was performed in 70 patients and cerebrospinal fluid (CSF) was examined at presentation in 36. The presence of HLA-DR2 antigen or cerebrospinal fluid oligoclonal IgG bands were both associated with a significantly increased risk of progression to multiple sclerosis, but MRI was much more powerful in predicting outcome. The presence of four or more MRI lesions at presentation was associated with a higher rate of progression to multiple sclerosis, more frequent development of moderate or severe disabilities and a greater number of new MRI lesions at follow-up. The results indicate that brain MRI at presentation with a clinically isolated syndrome suggestive of multiple sclerosis is a powerful predictor of the clinical course over the next 5 years. This observation, combined with an ability to detect other sometimes treatable disorders which can also cause such syndromes, suggests that MRI is the investigation of choice in evaluating this group of patients.

Effect of treatment on oligoclonal IgG bands and intrathecal IgG synthesis in sequential cerebrospinal fluid and serum from patients with subacute sclerosing panencephalitis

Oligoclonal IgG bands were analyzed in matching pairs of cerebrospinal fluid (CSF) and serum from 12 subacute sclerosing panencephalitis (SSPE) patients, using isoelectric focusing and immunofixation. Each patient was given isoprinosine, and four of the 12 patients were given alpha-interferon in addition. Two to 4 serial CSF and serum samples were collected from each SSPE patient during periods ranging from 1 to 16 months. In 3 SSPE patients in a small number of new oligoclonal bands were seen in the follow-up CSF samples. In the other 9 SSPE patients there was no change in CSF band patterns between initial and follow-up specimens. Band patterns in serum remained unchanged between initial and follow-up samples. Although all 12 SSPE cases had higher IgG indices and increased rate of intra blood-brain barrier (BBB) IgG synthesis in comparison to patients with other neurological diseases, the values did not significantly differ between the first and follow-up specimens. We conclude that treatment of SSPE patients with isoprinosine or with isoprisonine and alpha-interferon had no significant effect on the CSF oligoclonal band profiles or IgG synthesis within the central nervous system.

Paramyxovirus SV5 and multiple sclerosis

Multiple sclerosis is commonly associated with a local humoral immune response within the central nervous system. A hallmark of this intrathecal response is the presence of electrophoretically demonstrable oligoclonal bands of IgG in the cerebrospinal fluid (CSF) of up to 95% of patients. Observations indicating that a major part of the CSF IgG in some patients may represent antibodies to SV5, a simian virus closely related to human parainfluenza type 2 virus, were recently reported by Goswami et al. We have studied thirty patients with multiple sclerosis, but although we find intrathecal synthesis of IgG antibodies reacting with SV5 in seven of these, the antibodies were not associated with oligoclonal CSF IgG bands and could in each case be explained as potentially cross-reacting antibodies to other paramyxoviruses known to be human pathogens. We have therefore been unable to confirm that SV5 may be a major intrathecal immunogen in multiple sclerosis.

The long march of the cerebrospinal fluid profile indicative of clinical definite multiple sclerosis; and still marching

Much progress has been made, especially in the last two decades, in laboratory aids to diagnosis and to follow the course of patients with multiple sclerosis (MS). The cerebrospinal fluid (CSF) profile indicative of MS, though not pathognomonic of MS, is present in almost every case of clinical definite MS in a chronic progressive phase (probably also true for early MS). The cardinal aspect of the profile is intra-blood-brain barrier (BBB) IgG synthesis which can be qualitatively detected by determining unique CSF oligoclonal IgG bands and quantitated by rate formula, mg/day. We believe that intra-BBB IgG synthesis is caused by a persistent antigen, most likely a virus, possibly measles. A number of issues about the profile are proposed and opportunities are presented to resolve them.