Multiple myeloma with Echinococcus granulosus infection diagnosed by detection of oligoclonal bands: A case report.

RATIONALE: Isoelectric focusing electrophoresis (IFE) is currently recognized as the gold standard for detecting oligoclonal bands (OCBs) in cerebrospinal fluid (CSF). To the best of our knowledge, however, no study has reported on type III OCBs using IFE. In this paper, we report on a rare case of multiple myeloma (MM) with Echinococcus granulosus infection diagnosed by IFE. PATIENT CONCERNS: A 71-year-old man complained of weakness of the right lower extremity accompanied with fever (temperature range 37.8°C-38.2°C) for more than 6 months. DIAGNOSES: MM with E granulosus infection. INTERVENTIONS: The IFE results identified a unique monoclonal band, indicating that the patient may have MM in conjunction with a distinct pathogen infection. He received anthelmintic treatment and bortezomib-thalidomide-dexamethasone therapy. OUTCOMES: The patient was followed up for 15 months. During that time, his temperature returned to normal, his Medical Research Council Grading of Muscle Power scale became 5, and his vital signs stabilized. LESSONS: Detection of OCB type III indicated that the patient was diagnosed with MM accompanied by E granulosus infection. Thus, IFE of CSF may be an auxiliary diagnostic method for MM in the future.

Diagnostic accuracy of intrathecal kappa free light chains compared with OCBs in MS.

OBJECTIVE: To determine what kappa free light chain (KFLC) metric has the highest capacity to separate healthy patients from patients with MS, we evaluated the sensitivity, specificity, and the overall diagnostic accuracy of 4 different KFLC metrics. To assess the usefulness of KFLC in the diagnostics of MS, we compared the different KFLC metrics with oligoclonal bands (OCBs), the current gold standard biochemical method to demonstrate intrathecal antibody production. METHODS: CSF and plasma were collected from patients with confirmed or suspected MS, other neurological diseases, as well as symptomatic and healthy controls between May 2017 and May 2018 (n = 335) at the Department of Neurology, Karolinska University Hospital, as part of routine diagnostic workup. KFLC analysis and isoelectric focusing for the detection of oligoclonal bands (OCB) were determined and correlated with diagnosis. Receiver operating characteristic (ROC) curve analysis was used to determine accuracy. RESULTS: OCBs yielded a sensitivity of 87% and a specificity of 100%. All KFLC metrics showed a high sensitivity (89%-95%) and specificity (95%-100%). Using the optimal cutoff according to the Youden Index resulted for the KFLC intrathecal fraction in a cutoff of -0.41 with a sensitivity of 95% and a specificity of 97% and for CSF KFLC/CSF albumin with a cutoff of 1.93 × 10-3 with a sensitivity of 94% and specificity of 100%. CONCLUSION: All evaluated KFLC metrics have excellent accuracy, and both KFLC intrathecal fraction and CSF KFLC/CSF albumin are at least as good as OCB in separating patients with MS from a control group. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that CSF KFLC accurately distinguishes patients with MS from healthy controls.

Toward an automatic tool for oligoclonal band detection in cerebrospinal fluid and tears for multiple sclerosis diagnosis: lane segmentation based on a ribbon univariate open active contour.

The latest revision of multiple sclerosis diagnosis guidelines emphasizes the role of oligoclonal band detection in isoelectric focusing images of cerebrospinal fluid. Recent studies suggest tears as a promising noninvasive alternative to cerebrospinal fluid. We are developing the first automatic method for isoelectric focusing image analysis and oligoclonal band detection in cerebrospinal fluid and tear samples. The automatic analysis would provide an accurate, fast analysis and would reduce the expert-dependent variability and errors of the current visual analysis. In this paper, we describe a new effective model for the fully automated segmentation of highly distorted lanes in isoelectric focusing images. This approach is a new formulation of the classic parametric active contour problem, in which an open active contour is constrained to move from the top to the bottom of the image, and the x-axis coordinate is expressed as a function of the y-axis coordinate. The left and right edges of the lane evolved together in a ribbon-like shape so that the full width of the lane was captured reliably. The segmentation algorithm was implemented using a multiresolution approach in which the scale factor and the active contour control points were progressively increased. The lane segmentation algorithm was tested on a database of 51 isoelectric focusing images containing 419 analyzable lanes. The new model gave robust results for highly curved lanes, weak edges, and low-contrast lanes. A total of 98.8% of the lanes were perfectly segmented, and the remaining 1.2% had only minor errors. The computation time (1 s per membrane) is negligible. This method precisely defines the region of interest in each lane and thus is a major step toward the first fully automatic tool for oligoclonal band detection in isoelectric focusing images. Graphical abstract.

Bad Tests Die Slowly: The Myelin Basic Protein Example.

BACKGROUND: Our national reference laboratory sought to improve stewardship for multiple sclerosis (MS) testing, which included orders for myelin basic protein (MBP) and oligoclonal bands (OCB). From 2011 to 2012, we performed 2 interventions for MS testing: one gentle-strength intervention of a publication designed to educate others about the lack of utility for MBP results and a second medium-strength intervention that included removal of MBP from the panel of MS tests. The ordering trends and practice variation were examined for OCB and MBP to retrospectively observe the effect of the interventions. METHODS: Data from clients within academic and community hospitals were examined (n = 1710 clients). Ordering patterns for OCB and MBP were investigated from 2008 to 2018 by calculating the %OCB: %OCB = (OCB)/(OCB + MBP). Practice variation was examined by comparing the distribution of clients with different %OCB statistics before and after the interventions in 5-year blocks (2008-2012 vs 2014-2018). RESULTS: From 2000 to 2011, the %OCB was approximately 50%, but gradually increased to 67% in 2018. For practice variation, analysis of the distribution of clients by %OCB also demonstrated a shift toward clients favoring OCB alone vs OCB + MBP for MS testing for the later time period of 2014-2018. CONCLUSION: Our 2 interventions had a measurable, beneficial effect on ordering trends for MS testing over a 10-year period at a single reference laboratory. However, given that MBP has questionable clinical utility, stronger interventions are likely needed to bring about larger changes in ordering behavior.

Cerebrospinal fluid analysis and the determination of oligoclonal bands.

This document presents the guidelines for the cerebrospinal fluid (CSF) analysis and the determination of oligoclonal bands (OCBs) as pivotal tests in neuroinflammatory pathologies of the central nervous system. The guidelines have been developed following a consensus process built on questionnaire-based surveys, internet contacts, and discussions at workshops of the sponsoring Italian Association of Neuroimmunology (AINI) congresses. Essential clinical information on the pathologies in which the CSF analysis is indicated, and, particularly, on those characterized by the presence of OCBs in the intrathecal compartment, indications and limits of CSF analysis and OCB determination, instructions for result interpretation, and agreed laboratory protocols (Appendix) are reported for the communicative community of neurologists and clinical pathologists.

Tear analysis as a tool to detect oligoclonal bands in radiologically isolated syndrome.

BACKGROUND: Although radiologically isolated syndrome (RIS) is a newly defined entity, incidental findings of T2 hypersignals on brain MRI can lead to misdiagnosis or useless investigations. The detection of oligoclonal bands (OCBs) in cerebrospinal fluid (CSF) is a major indicator that helps in diagnosis of subclinical inflammatory disease of the central nervous system, but lumbar puncture still remains an invasive option. METHODS: We have prospectively included patients with RIS, have compared the results of CSF and tear OCB detection by isoelectric focusing (IEF) and assessed concordance between OCB detection in tears and in CSF. Tears were collected using a Schirmer strip. RESULTS: In 45 recruited RIS patients, OCBs were detected in CSF for 55% (25/45) and in tears for 50% (21/42) of samples. CONCLUSIONS: We suggest that tear OCB detection may replace CSF OCB detection as a diagnostic tool in patients with RIS and be useful in follow-up.

The presence of oligoclonal IgG bands in human CSF during the course of neurological diseases.

The analysis of cerebrospinal fluid (CSF) is an important tool for the diagnosis of neurological diseases. However, there is limited knowledge about the representativity of a single oligoclonal band (OCB) analysis for a neurological disease during its clinical course. In this study, we analyzed the presence of OCB in the CSF of patients who underwent lumbar puncture more than once. We retrospectively analyzed anonymized data from serial 17,002 CSF analyses done in the CSF laboratory of the Department of Neurology, University Hospital Zurich. We included cases with documented diagnosis in whom OCB were determined more than once. We included 144 patients. The median time span between the first and second OCB analysis was 274 days (range, 1-3,533 days). The result of the second OCB analysis was identical in 109 cases, and different in 35 (24 %). Twenty-five patients acquired and ten patients lost OCB over time. Three of 24 MS patients did not show OCB at the first CSF analysis, but in the second. In the entire group, newly occurring OCB were often associated with new symptoms or occurred after the acute phase of CNS infectious diseases, supposedly as a consequence of the immune reaction. A loss of OCB was often associated with remissions from diseases, e.g., during effective treatment. In patients with neurological diseases, both initially positive and negative OCB results may change over time, which often parallels the clinical condition. Such variability must be taken into account for the interpretation of OCB results.

Intrathecal synthesis in particular types of multiple sclerosis.

AIM: The aim of this study was to determine whether there were any differences in intrathecal synthesis of immunoglobulin G (IgG) (IgG index) and number of oligoclonal bands (OCB) among particular types of multiple sclerosis (MS). METHODS: 120 cerebrospinal fluid (CSF) samples were examined from 29 clinically isolated syndrome (CIS) patients and 91 MS patients (77 patients with relapsing-remitting MS (RR), 6 patients with primary progressive course of the disease (PP) and 8 patients in secondary progression (SP)); mean age = 42 years (range = 18 to 70 years). Albumin and IgG in serum and CSF was evaluated using nephelometry; an albumin quotient (CSF albumin/serum albumin), an IgG quotient (CSF IgG/serum IgG) and an IgG index (IgG quotient / albumin quotient) were then calculated. OCB were assessed using isoelectric focusing (IEF) on agarose gel, followed by immunoblotting. All patients were evaluated using the Kurtzke Expanded Disability Status Scale (EDSS). RESULTS: No statistically significant differences between the IgG index and OC bands relative to particular types of MS were found. Further, there were no significant correlations between EDSS values and intrathecal synthesis (IgG index: QIgG / Qalbumin) and OC bands. CONCLUSION: No difference in intrathecal synthesis (IgG index) and the number of OCB between different types of MS was confirmed.

Clinical significance of the appearance of abnormal protein band in patients with multiple myeloma.

Multiple myeloma (MM) is characterized by clonal expansion of malignant bone marrow cells producing a unique monoclonal immunoglobulin. The appearance of abnormal protein band (APB) in MM has been reported during follow-up. We aimed to evaluate the clinical characteristics and outcomes of patients with APB in a single center cohort. A total of 377 consecutive MM patients were treated at the Asan Medical Center between January 2002 and December 2012. We compared clinical characteristics and survival outcome between those with and without APB. Of the 377 patients, 34 (9 %) experienced APB. They comprised 18.2 % (27/148) of patients treated with autologous stem cell transplantation (ASCT) and 3.1 % (7/229) of those not receiving ASCT. APB occurred after a median of 7.9 months (range, 2.2-95.7 months) from diagnosis. Immunoglobulin isotypes at diagnosis were as follows: IgG (n = 10), IgA (n = 8), IgD (n = 5), free κ (n = 4), and free λ (n = 7). Nine patients experienced a second APB. With a median follow-up of 54.1 months, the median overall survival (OS) has not been reached in patients with APB and was 38.3 months in patients without (P < 0.001). Multivariate analysis indicated that the development of APB was a significant favorable prognostic factor for OS (hazard ratio 0.21; 95 % confidence interval 0.08-0.52). Serum ß2-microglobulin, albumin, creatinine, and ASCT were also independent prognostic factors for OS. Further investigation is required to establish the mechanisms underlying APB in MM.

Quantification of intraocular IFNgamma and IgG in cataract and diabetes.

The anterior eye chamber is called the immunologically privileged place. The inflammatory disturbances in the interior of the eye chamber are characterised primarly by the changes of the IFN-gamma, IgG and IL-4 concentration and appearance of the oligoclonal IgG. In type I diabetes, there are antibodies to the beta cells of the pancreas, IgG class (among others such as antiretinal antibodies) and they are also found in preretinal membranes of diabetics. In type II there are IgG antibodies to insulin receptors.

[Biomarkers in multiple sclerosis]. / Biomarcadores en esclerosis múltiple.

Multiple sclerosis is the most frequent disabling neurological disease in young adults. Its development includes independent processes of inflammation, demyelination, neurodegeneration, gliosis and repair, which are responsible for the heterogeneity and individual variability in the expression of the disease, its prognosis and response to treatment. As part of personalised medicine, the progress made in the search for new biomarkers has identified promising candidates that may be useful for the early diagnosis of the disease, for detecting prognostic and developmental profiles of the disease, and for monitoring the response to treatment. Unfortunately, few of them have been validated adequately, which prevents them from being applied in clinical practice. In view of the latest findings, the experts recommend orienting research in another direction, not so much towards the discovery of new molecules or imaging techniques, but instead towards a clinical validation of these markers, with the aim of fostering translational research. This review offers an update on the information about the biomarkers in multiple sclerosis that have currently been validated and are thus potential candidates, as well as looking at their value in the diagnosis, prognosis, evaluation of the development of the disability caused by the disease and the response to therapy.

Reibergram and oligoclonal bands in diagnosis of multiple sclerosis.

INTRODUCTION: In this study authors have analyzed the correlation between the IgG immunoglobulins in cerebrospinal fluid and the findings of oligoclonal bands on gel. Immunoglobulin IgG in cerebrospinal fluid (CSF) can be detected in neurological diseasses (infections and inflammatory neurological diseases and in demyelinating diseases, like multiple sclerosis (MS)). Quantitative IgG in CSF can be expressed by different formulae Reiber (Reiber and Felgenhauer 1987), Tourtellotte (Tourtellotte 1970), Schuller (Schuller and Sagar 1983) and IgG Index (Link and Tibbling 1977). In this study we used Reibergram. Qualitative CSF IgG can be measured by electrophoresis and isoelectric focusing (IEF). We used IEF for analysig CSF and seum because of its higher sensitivity. AIMS OF THE STUDY: To determine the correlation of immunoglobulins IgG positivity in CSF with the finding of oligoclonal bands on the gel. MATERIAL AND METHODS: The retrospective study based on data processed in OJ Clinical Immunology KCUS. Patients were suspicious of multiple sclerosis according to clinical findings and magnetic resonance imaging. All CSF and serum samples were processed by nephelometry, isoelectric focusing on the gel. Statistical analysis of intrathecal synthesis was also performed according to Reibergram. RESULTS: Analyses were performed on 76 samples of cerebrospinal fluid and serum of patients from neurological clinic, suspected of multiple sclerosis. We received following results: 42 samples tested had type 1.25 samples tested showed type 2.3 samples had type 3.5 samples had type 4.1 sample had a fifth type. When we compare these results with values obtained by intrathecal synthesis of which is determined by Reibergram we obtained the following values: 16 samples had intrathecal synthesis of 20%-60%, 9 samples had a negative value of intrathecal synthesis of 10% or less. DISCUSSION AND CONCLUSION: For most patients with established MS we found intrathecal humoral response, type two, and the number and arrangement of IgG bands generally does not change during the disease, because they reflect long-term non-specific immune stimulation rather than a specific immune response that during infectious disease changes (quantitatively and qualitatively).

Comparison of two methods for the detection of oligoclonal bands in a large number of clinically isolated syndrome and multiple sclerosis patients.

OBJECTIVE: A novel oligoclonal band (OB) assay which consists of isoelectric focusing (IEF) and IgG immunodetection by alkaline phosphatase-labeled anti IgG antibody was reported to be very sensitive. It also accurately predicted conversion to MS in patients with CIS. The aim of our study was to compare sensitivity of a novel and the standard procedure with peroxidase immunodetection in a large number of CIS and MS patients. METHODS: OB were determined in serum and CSF samples in 161 patients (104 females), 47 with CIS and 114 with MS with median age 38 years (range 19-68) using both methods. RESULTS: Eighty-three percent of patients had CSF OB with the standard and 89% with the novel method. Median number of OB was 5 (range 0-17) with the peroxidase and 8 (range 0-18) with the alkaline phosphatase method; p = 0.001. Twenty-one percent of patients had ≥ 10 OB with the standard and 37% with the novel method of the detection; p = 0.021. Subjective impression of band clarity showed that 20% of patients had sharper and stronger bands when the peroxidase and 65% when the alkaline phosphatase method was used; p<0.0001. CONCLUSION: The alkaline phosphatase method is more sensitive than the peroxidase method and at the same time cheaper, easy to perform and less time consuming.

Spinal cord tumor versus transverse myelitis.

BACKGROUND CONTEXT: Longitudinally extensive transverse myelitis (LETM) is one of the defining features of neuromyelitis optica (NMO). Despite the well-established criteria, clinical and paraclinical features, the disease is often misdiagnosed and erroneously treated. PURPOSE: We report on a case of LETM in a patient with spatially limited NMO spectrum disorder that was misdiagnosed as spinal cord tumor and underwent spinal cord biopsy. STUDY DESIGN: A 43-year-old female patient is described. METHODS: The patient developed spastic tetraparesis over 1 week. Spinal cord magnetic resonance imaging (MRI) revealed LETM, and she was treated with steroids and recovered. Nine months later, her condition worsened and repeat spinal cord MRI was interpreted as a large intramedullary tumor in the cervical region with irregular postcontrast enhancement. Biopsy revealed demyelination. Cerebrospinal fluid (CSF) analysis revealed positive oligoclonal IgG bands, and serum was positive for NMO-IgG antibody. RESULTS: The patient was diagnosed with spatially limited NMO spectrum disorder, treated with plasma exchange, high-dose corticosteroids, and cyclophosphamide, and with good recovery. CONCLUSIONS: The factors favoring inflammatory LETM are acute or subacute onset of clinical symptoms, positive oligoclonal bands in the CSF, positive NMO-IgG or other antibodies, and brain MRI showing demyelinating lesions. Postcontrast axial MRI sequences of the spinal cord can also be helpful. In doubtful situations, a trial of therapy and follow-up MRI a month later might be a more prudent approach if the patient is not rapidly deteriorating.

Utility of oligoclonal IgG band detection for MS diagnosis in daily clinical practice.

An early and accurate diagnosis of multiple sclerosis (MS) is very important, since it allows early treatment initiation, which reduces the activity of the disease. Oligoclonal IgG band (OCGB) detection is a good ancillary tool for MS diagnosis. However, it was argued that its usefulness was limited by the high interlaboratory variability. In the last years, different techniques for OCGB detection have appeared. We performed a blinded aleatorized multicenter study in 19 Spanish hospitals to assess the accuracy and reproducibility of OCGB detection in this new scenario. We studied cerebrospinal fluid (CSF) and serum samples from 114 neurological patients. Every hospital contributed to the study with triplicated pairs of CSF and serum samples of six patients and analyzed 18 different samples. Global analysis rendered a sensitivity of 92.1%, a specificity of 95.1% and a Kappa value of 0.81. This shows that current techniques for OCGB detection have good accuracy and a high interlaboratory reproducibility and thus, represent a good tool for MS diagnosis. When we analyzed separately the different techniques used for OCGB detection, the highest concordance was observed in western blot with alkaline phosphatase detection (kappa=0.91). This indicates that high sensitivity techniques improve the reproducibility of this assay.

Cerebrospinal BAFF and Epstein-Barr virus-specific oligoclonal bands in multiple sclerosis and other inflammatory demyelinating neurological diseases.

We measured circulating serum and cerebrospinal fluid (CSF) concentrations of B lymphocyte activating factor of the tumour necrosis factor superfamily (BAFF), and determined total and Epstein-Barr virus (EBV)-specific oligoclonal IgG bands (OCBs) in 43 patients with multiple sclerosis (MS), 23 patients with other inflammatory demyelinating neurological diseases, and 20 patients with non-inflammatory neurological diseases. Serum and CSF BAFF concentrations did not differ in the three studied groups. In MS, the highest BAFF concentrations were found in the CSF samples with more than 6 OCBs (233.1 ± 129.5 vs 79.2 ± 51.6 pg/mL in the samples with less than 7 OCBs, p<0.0001). Irrespectively from BAFF levels, EBV-specific OCBs were detected in MS and in the other non-inflammatory and inflammatory demyelinating neurological diseases, with a similar frequency, and as a 'mirror pattern' in 30 of 33 EBV-specific OCB-positive cases (p<0.0001). These results indicate that circulating CSF BAFF concentrations cannot help differentiate MS from other inflammatory demyelinating neurological diseases, but positively associates with the qualitative expression of elevated intrathecal IgG production in MS, and that the oligoclonal EBV-specific antibody response, when present, is mostly systemic in all the studied neurological patients, and not preferentially restricted to MS.

MRI criteria in MS patients with negative and positive oligoclonal bands: equal fulfillment of Barkhof's criteria but different lesion patterns.

In multiple sclerosis (MS) more than 95% of the patients have positive oligoclonal bands (OCB) in the cerebrospinal fluid (CSF). Previous studies have reported differences between patients with and without OCB mainly with regard to clinical parameters such as age, gender, disease duration, and clinical severity. However, several MRI characteristics have also been hypothesized to be distinct, and a varying lesion load in OCB-negative and -positive patients is proposed. In this study, we aimed to evaluate whether Barkhof's diagnostic MRI criteria are unequally frequently fulfilled in OCB-negative and -positive MS patients. We screened our database for all OCB-negative MS patients who had (1) been treated with the diagnosis of a clinical definite relapsing-remitting MS in our institution as well as (2) undergone CSF analysis and MR brain imaging during hospital stay between January 2004 and December 2007. Eleven OCB-negative patients were identified who fulfilled these criteria. In a second step, we carefully matched each of them to two OCB-positive controls according to age, gender, EDSS, and disease duration. The separate analysis of the several parameters of Barkhof's criteria revealed a less frequent prevalence of infratentorial (3/11 vs. 18/22; P = 0.005) and a more frequent occurrence of juxtacortical lesions (10/11 vs. 10/22; P = 0.022) in OCB-negative as compared to OCB-positive patients. The overall fulfillment of the Barkhof criteria did not differ in OCB-negative and -positive patients (7/11 vs. 16/22; P = 0.696). Further analyses of MRI findings between OCB-negative and -positive MS patients might contribute to a better pathophysiological understanding of the genesis and evidence of OCB in the CSF of MS patients.

HLA-DRB115 and cerebrospinal-fluid-specific oligoclonal immunoglobulin G bands lower age at attainment of important disease milestones in multiple sclerosis.

Carriage of HLA-DRB1*15 is the most important genetic risk factor in multiple sclerosis (MS), while CSF-specific oligoclonal immunoglobulin G bands (OCB) constitute the most sensitive biochemical marker for diagnosing MS. We demonstrated in an earlier study the interdependence of HLA-DRB1 genotype and OCB status; the effect of these phenotypic features on MS prognosis remains controversial, however. We investigated by survival analysis the impact of each variable on age at two important MS milestones: onset of clinical symptoms and an Expanded Disability Status Scale (EDSS) score of 6.0. Both carriage of HLA-DRB1*15 and the presence of OCB hastened attainment of EDSS 6.0.

Clinical and diagnostic management of toxoplasmosis in the immunocompromised patient.

With the advent of the highly active antiretroviral therapy (HAART), the natural course of HIV infection has markedly changed and opportunistic infections including toxoplasmosis have declined and modified in presentation, outcome and incidence. However, TE is a major cause of morbidity and mortality especially in resource-poor settings but also a common neurological complication in some countries despite the availability of HAART and effective prophylaxis. In most cases toxoplasmosis occurs in brain and toxoplasmic encephalitis (TE) is the most common presentation of toxoplasmosis in immunocompromised patients with or without AIDS. The need of a definitive diagnosis is substantial because other brain diseases could share similar findings. Rapid and specific diagnosis is thus crucial as early treatment may improve the clinical outcome. Classical serological diagnosis is often inconclusive as immunodeficient individuals fail to produce significant titres of specific antibodies. Polymerase chain reaction (PCR) has a high diagnostic value in the acute disease, but like many 'in-house' PCR assays, suffers from lack of standardization and variable performance according to the laboratory. Molecular diagnosis of toxoplasmosis can be improved by performing real-time PCR protocols. This article summarises the clinical manifestations, diagnostic procedures and management strategies for this condition.