Cerebrospinal Fluid Oligoclonal Bands Research Articles

Demographic, Clinical, and Immunologic Features of 389 Children with Opsoclonus-Myoclonus Syndrome: A Cross-sectional Study.

Pediatric-onset opsoclonus-myoclonus syndrome (OMS) is a devastating neuroinflammatory, often paraneoplastic, disorder. The objective was to characterize demographic, clinical, and immunologic aspects in the largest cohort reported to date. Cross-sectional data were collected on 389 children in an IRB-approved, observational study at the National Pediatric Myoclonus Center. Non-parametric statistical analysis was used. OMS manifested in major racial/ethnic groups, paralleling US population densities. Median onset age was 1.5 years (1.2–2 interquartile range), inclusive of infants (14%), toddlers (61%), and youngsters (25%). The higher female sex ratio of 1.2 was already evident in toddlers. Time to diagnosis was 1.2 months (0.7–3); to treatment, 1.4 months (0.4–4). Irritability/crying dominated prodromal symptomatology (60%); overt infections in <35%. Acute cerebellar ataxia was the most common misdiagnosis; staggering appeared earliest among 10 ranked neurological signs (P < 0.0001). Some untreated youngsters had no words (33%) or sentences (73%). Remote neuroblastic tumors were detected in 50%; resection was insufficient OMS treatment (58%). Age at tumor diagnosis related to tumor type (P = 0.004) and stage (P = 0.002). A novel observation was that paraneoplastic frequency varied with patient age—not a mere function of the frequency of neuroblastoma, which was lowest in the first 6 months of life, when that of neuroblastoma without OMS was highest. The cerebrospinal fluid (CSF) leukocyte count was minimally elevated in 14% (≤11/mm3) with normal differential, and commercially screened serum autoantibodies were negative, but CSF oligoclonal bands (OCB) and B cells frequency were positive (58 and 93%). Analysis of patients presenting on immunotherapy revealed a shift in physician treatment practice patterns from monotherapy toward multi-agent immunotherapy (P < 0.001); the number of agents/sequences varied. In sum, a major clinical challenge is to increase OMS recognition, prevent initial misdiagnosis, and shorten time to diagnosis/treatment. The index of suspicion for an underlying tumor must remain high despite symptoms of infection. The disparity in onset age of neuroblastoma frequency with that of neuroblastoma with OMS warrants further studies of potential host/tumor factors. OMS neuroinflammation is best diagnosed by CSF OCB and B cells, not by routine CSF or commercial antibody studies.

Prediction of Conversion from Clinically Isolated Syndrome to Multiple Sclerosis According to Baseline Characteristics: A Prospective Study

Clinically isolated syndrome (CIS) is a clinical state that proceeds with inflammation and demyelination, suggestive of multiple sclerosis (MS) in the central nervous system in the absence of other alternative diagnoses. The purpose of this study was to determine in a prospective cohort, the predictor factors in conversion from CIS to MS on the basis of clinical, magnetic resonance (MR) imaging and cerebrospinal fluid (CSF) findings. Forty-one CIS patients were included in this study and followed up for at least two years. Clinically, polysymptomatic or sensorial involvement, good prognostic factors and complete response to pulse therapy were found to be of prognostic value in conversion to MS. A greater presence of oligoclonal bands in CSF was identified in the converted group (92.8%). In terms of localization, presence of callosal lesion (71.4%), periventricular lesion (97.1%), Gd-enhanced lesion (48.6%), black hole (54.2%) and brainstem lesion (57.1%) was statistically significant in terms of conversion to MS. A carefully performed neurological assessment of symptoms and signs, and evaluation of lesions on MR combined with CSF findings are important for identifying the risk of conversion to MS. This information may be useful when considering treatment in CIS patients instead of waiting for conversion to MS.

Clinical characteristics of neuromyelitis optica spectrum disorders associated with syringomyelia

Objective: To analyze the clinical characteristics of neuromyelitis optica spectrum disorders (NMOSD) associated with syringomyelia (SML). Methods: The clinical manifestations, laboratory parameters and imaging findings of 7 patients with NMOSD associated with SML during June 2008 to August 2016 from The Third Affiliated Hospital of Sun Yat-sen University were retrospectively analyzed. Results: Six patients were female and 1 was male, with ages ranging from 27-67 years, the course of the disease was 3-12 years, recurrence was 2-7 times, all the patients were cerebrospinal fluid oligoclonal bands (CSF OCB) negative, 5 patients were positive for aquaporin-4-antibody/NMO-IgG. Sensory and motor dysfunction, bowel or bladder dysfunction were the common clinical manifestation, and pain was a significant symptom. Syringomyelia was predominantly located in C4-T10, cavity length 2-6 mm, diameter 0.8-3.6 mm; 5 had lobes involvement and 6 had long segmental spinal cord involvement. Conclusions: NMOSD associated with SML had a high frequency of occurrence in female, with the clinical characteristics of limb pain, easy progression, high recurrence rate and disability rate. The anti AQP4 antibody were commonly seen in these patients. Syringomyelia was predominantly located in the lower cervical and upper thoracic spinal cord, the lobar and longitudinally extensive transverse myelitis were frequently found in patients with NMOSD associated with SML.

Cerebrospinal fluid humoral immunity in the differential diagnosis of multiple sclerosis

BackgroundThe diagnostic accuracy of cerebrospinal fluid oligoclonal bands (CSF-OCB) detected by isoelectric focusing (IEF) in patients with multiple sclerosis (MS) was evaluated in our study.MethodsThree hundred and twenty-one patients with MS and other central nervous system (CNS) immune mediated disorders were assessed (CIMD). Cerebrospinal fluid and matched serum samples were examined for the presence of OCB by IEF-IB (isoelectric focusing with immunoblotting).ResultsIsolated oligoclonal bands (ISO-OCB) were the only predictor of MS diagnosis independent of age, gender and CSF-OCB. ISO-OCB ≥ 3.5 detected by IEF yielded a sensitivity of 98% and specificity of 87% in distinguishing MS from MS mimickers.ConclusionsFor the neurologist, a score of ≥ 4 ISO-OCB supports the diagnosis of MS. On the other hand, ISO-OCB ≤3 favors CIMD. Further studies with larger population samples are warranted to confirm these findings.

Dexamethasone, Intravenous Immunoglobulin, and Rituximab Combination Immunotherapy for Pediatric Opsoclonus-Myoclonus Syndrome

BackgroundAlthough pulse-dose dexamethasone is increasingly favored for treating pediatric opsoclonus-myoclonus syndrome (OMS), and multimodal immunotherapy is associated with improved clinical response, there have been no neuroimmunologic studies of dexamethasone-based multimodal disease-modifying therapy. MethodsIn this observational retrospective study, 19 children with OMS (with or without associated neuroblastoma) underwent multibiomarker evaluation for neuroinflammation. Nine children of varying OMS severity, duration, and treatment status were treated empirically with pulse dexamethasone, intravenous immunoglobulin (IVIg), and rituximab combination immunotherapy (DEXIR-CI). Another 10 children on dexamethasone alone or with IVIg at initial evaluation only provided a comparison group. Motor severity (total score) was scored rater-blinded via videotapes using the validated OMS Evaluation Scale. ResultsDEXIR-CI was associated with a 69% reduction in group total score (P = 0.004) and was clinically well tolerated. Patients given the dexamethasone combination exhibited significantly lowered B cell frequencies in cerebrospinal fluid (−94%) and blood (−76%), normalizing the cerebrospinal fluid B cell percentage. The number of patients with positive inflammatory markers dropped 87% (P = 0.002) as did the number of markers. Cerebrospinal fluid oligoclonal bands were positive in four of nine pretreatment patients but zero of six post-treatment patients. In the comparison group, partial response to dexamethasone alone or with IVIg was associated with multiple positive markers for neuroinflammation despite an average of seven months of treatment. ConclusionsMultimechanistic dexamethasone-based combination immunotherapy increases the therapeutic armamentarium for OMS, providing a viable option for less severely affected individuals. Partial response to dexamethasone with or without IVIg is indicative of ongoing neuroinflammation and should be treated promptly and accordingly.

Multiple biomarkers improve the prediction of multiple sclerosis in clinically isolated syndromes

Since its introduction, MRI had a major impact on the early and more precise diagnosis of multiple sclerosis (MS), and the 2010 diagnostic criteria even allow a diagnosis to be made just after a single attack if stringent MRI criteria are met. Several other clinical and paraclinical markers have been reported to be associated with an increased risk of MS independently of MRI in patients with clinically isolated syndromes (CIS), but the incremental usefulness of adding them to the current criteria has not been evaluated. In this study, we determined whether multiple biomarkers improved the prediction of MS in patients with CIS in a real-world clinical practice. This was a retrospective study involving patients with CIS admitted to our department between 2000 and 2013. We evaluated baseline clinical, MRI, neurophysiological, and cerebrospinal fluid (CSF) data. During follow-up (median, 7.2years), 127 of 243 participants (mean age, 31.6years) developed MS. Cox proportional-hazards models adjusted for established MRI criteria, age at onset, number of T1 lesions, and presence of CSF oligoclonal bands significantly predicted the risk of developing MS at 2 and 5years. The use of multiple biomarkers led to 29% net reclassification improvement at 2years (P<.001) and 30% at 5years (P<.001). The simultaneous addition of several biomarkers significantly improved the risk stratification for MS in patients with CIS beyond that of a model based only on established MRI criteria.

Myelin-specific multiple sclerosis antibodies cause complement-dependent oligodendrocyte loss and demyelination

Intrathecal immunoglobulin G (IgG) synthesis, cerebrospinal fluid (CSF) oligoclonal IgG bands and lesional IgG deposition are seminal features of multiple sclerosis (MS) disease pathology. Both the specific targets and pathogenic effects of MS antibodies remain poorly characterized. We produced IgG1 monoclonal recombinant antibodies (rAbs) from clonally-expanded plasmablasts recovered from MS patient CSF. Among these were a subset of myelin-specific MS rAbs. We examined their immunoreactivity to mouse organotypic cerebellar slices by live binding and evaluated tissue injury in the presence and absence of human complement. Demyelination, glial and neuronal viability, and complement pathway activation were assayed by immunofluorescence microscopy and compared to the effects of an aquaporin-4 water channel (AQP4)-specific rAb derived from a neuromyelitis optica (NMO) patient. MS myelin-specific rAbs bound to discrete surface domains on oligodendrocyte processes and myelinating axons. Myelin-specific MS rAbs initiated complement-dependent cytotoxicity to oligodendrocytes and induced rapid demyelination. Demyelination was accompanied by increased microglia activation; however, the morphology and survival of astrocytes, oligodendrocyte progenitors and neurons remained unaffected. In contrast, NMO AQP4-specific rAb initiated complement-dependent astrocyte damage, followed by sequential loss of oligodendrocytes, demyelination, microglia activation and neuronal death. Myelin-specific MS antibodies cause oligodendrocyte loss and demyelination in organotypic cerebellar slices, which are distinct from AQP4-targeted pathology, and display seminal features of active MS lesions. Myelin-specific antibodies may play an active role in MS lesion formation through complement-dependent mechanisms.

Common and uncommon neurological manifestations of neuroborreliosis leading to hospitalization

BackgroundNeuroborreliosis represents a relevant infectious disease and can cause a variety of neurological manifestations. Different stages and syndromes are described and atypical symptoms can result in diagnostic delay or misdiagnosis. The aim of this retrospective study was to define the pivotal neurological deficits in patients with neuroborreliosis that were the reason for admission in a hospital.MethodsWe retrospectively evaluated data of patients with neuroborreliosis. Only patients who fulfilled the diagnostic criteria of an intrathecal antibody production against Borrelia burgdorferi were included in the study.ResultsSixty-eight patients were identified with neuroborreliosis. Cranial nerve palsy was the most frequent deficit (50%) which caused admission to a hospital followed by painful radiculitis (25%), encephalitis (12%), myelitis (7%), and meningitis/headache (6%). In patients with a combination of deficits, back pain was the first symptom, followed by headache, and finally by cranial nerve palsy. Indeed, signs of meningitis were often found in patients with neuroborreliosis, but usually did not cause admission to a hospital. Unusual cases included patients with sudden onset paresis that were initially misdiagnosed as stroke and one patient with acute delirium. Cerebrospinal fluid (CSF) analysis revealed typical changes including elevated CSF cell count in all but one patient, a blood-CSF barrier dysfunction (87%), CSF oligoclonal bands (90%), and quantitative intrathecal synthesis of immunoglobulins (IgM in 74%, IgG in 47%, and IgA in 32% patients). Importantly, 6% of patients did not show Borrelia specific antibodies in the blood.ConclusionIn conclusion, the majority of patients presented with typical neurological deficits. However, unusual cases such as acute delirium indicate that neuroborreliosis has to be considered in a wide spectrum of neurological diseases. CSF analysis is essential for a reliable diagnosis of neuroborreliosis.

Acquired Demyelinating Syndromes in Children

Collectively, pediatric acquired demyelinating syndromes encompass a diverse clinical spectrum and include disorders such as multiple sclerosis (MS), acute disseminated encephalomyelitis, acute transverse myelitis, optic neuritis, and neuromyelitis optica spectrum disorders (NMOSDs). Acquired demyelination may occur as a monophasic illness or represent chronic demyelinating disease (such as MS or NMOSD) and thus prompt identification and classification is essential for proper treatment and guidance. As such, approximately 3% of all patients affected by MS experience their first attack during childhood. In general, one quarter of children diagnosed with an acute demyelinating syndrome will be ultimately confirmed to have MS. The likelihood that an incident demyelinating attack represents the first attack of MS is increased in adolescents, females, patients with positive cerebrospinal fluid oligoclonal bands, and those with clinically silent T2 bright and T1 hypointense lesions on brain magnetic resonance imaging at onset. Early therapeutic intervention for MS and NMOSD is recommended to reduce relapses, modify relapse severity, and, it is hoped, limit future disability and reduce demyelination-related central nervous system injury. Of particular clinical relevance in children, there are many mimics of demyelinating disease that must be considered.

Blood Biomarkers as Outcome Measures in Inflammatory Neurologic Diseases.

Multiple sclerosis (MS) is an autoimmune demyelinating disorder of the central nervous system. Only a few biomarkers are available in MS clinical practice, such as cerebrospinal fluid oligoclonal bands and immunoglobulin index, serum anti-aquaporin 4 antibodies, and serum anti-John Cunningham virus antibodies. Thus, there is a significant unmet need for biomarkers to assess prognosis, response to therapy, or potential treatment complications. Here we describe emerging biomarkers that are in development, focusing on those from peripheral blood. There are several limitations in the process of discovery and validation of a good biomarker, such as the pathophysiological complexity of MS and the technical difficulties in globally standardizing methods for sampling, processing, and conserving biological specimens. In spite of these limitations, ongoing international collaborations allow the exploration of many interesting molecules and markers to validate diagnostic, prognostic, and therapeutic-response biomarkers.

Clinical Features of Patients with Multiple Sclerosis and Neuromyelitis Optica Spectrum Disorders.

Background:Neuromyelitis optica spectrum disorder (NMOSD) was long believed to be an aggressive form of multiple sclerosis (MS). This study aimed to describe the clinical features of patients with MS and NMOSD to assist in differential diagnoses in clinical practice.Methods:Data including the patients’ serum and cerebrospinal fluid (CSF) tests, image findings, and clinical information from 175 patients with MS or NMOSD at Xuanwu Hospital, Capital Medical University from November 2012 to May 2014 were collected and analyzed retrospectively. An enzyme-linked immunosorbent assay was performed to detect the myelin oligodendrocyte glycoprotein (MOG) autoantibodies in CSF and serum. Cell-based assays were used to detect aquaporin-4-antibody (AQP4-Ab). The Chi-square test was used to compare the categorical variables. Wilcoxon rank sum test was performed to analyze the continuous variables.Results:Totally 85 MS patients (49%) and 90 NMOSD patients (51%) were enrolled, including 124 (71%) women and 51 (29%) men. Fewer MS patients (6%) had autoimmune diseases compared to NMOSD (19%) (χ2 = 6.9, P < 0.01). Patients with NMOSD had higher Expanded Disability Status Scale scores (3.5 [3]) than MS group (2 [2]) (Z = −3.69, P < 0.01). The CSF levels of white cell count and protein in both two groups were slightly elevated than the normal range, without significant difference between each other. Positivity of serum AQP4-Ab in NMOSD patients was higher than that in MS patients (MS: 0, NMOSD: 67%; χ2 = 63.9, P < 0.01). Oligoclonal bands in CSF among NMOSD patients were remarkably lower than that among MS (MS: 59%, NMOSD: 20%; χ2 = 25.7, P < 0.01). No significant difference of MOG autoantibodies was found between the two groups.Conclusion:The different CSF features combined with clinical, magnetic resonance imaging, and serum characteristics between Chinese patients with MS and NMOSD could assist in the differential diagnosis.

The correlation factor analysis for conversion of clinically isolated syndrome to multiple sclerosis and neuromyelitis optica

To analyze the features of patients who converted from clinically isolated syndrome (CIS) to multiple sclerosis (MS) and neuromyelitis optica (NMO) and explore the correlated factors. A total of 151 patients admitted in our unit as CIS from January 2009 to December 2014 were enrolled in the study. All patients were divided into the following four groups by locations of the initial lesion, which were the spinal cord, the optic nerve, the brain stem and the multifocal lesions. Data were collected at the baseline including demographics, expanded disability status scale (EDSS) score, site of CIS, presence or absence of cerebrospinal fluid (CSF) oligoclonal bands (OB) and serum aquaporin-4 antibody (AQP4-Ab), evoked potential (EP) and MRI lesions. The conversion rates from CIS to clinically definite MS or NMO were calculated and the correlated factors were explored. With a mean follow-up period of (44.11±17.62)months, 46/151(30.5%) patients converted to MS, 28/151 (18.5%) to definite NMO and 66/151 patients(43.7%)remained as CIS. Other patients were converted to optic neuritis(4/151), one-time transverse myelitis(3/151), acute disseminated encephalomyelitis (1/151) and Balo concentric sclerosis(3/151) . The EDSS score was significantly higher in patients converted to NMO than those converted to MS (P=0.003). The initial manifestation of optic neuritis significantly correlated with the conversion to NMO (P=0.000), while the initial manifestation of CIS with multifocal lesions significantly correlated with the conversion to MS (P=0.000). Neither the isolated BAEP (P=0.703), VEP (P=0.076), SEP (P=0.915) nor the combination of two (P=0.546)or three (P=1.000) of the above parameters could help to distinguish the conversion to MS or NMO. More patients with positive CSF-OB converted to MS (P=0.001), while more patients with positive serum AQP4-Ab converted to NMO (P=0.001). More patients were serum AQP4-Ab positive in those converted to NMO than those converted to MS (P=0.000). Lesions longer than three vertebral segments were dominant in patients converted to NMO (P=0.000). The logistic regression analysis revealed that factors correlated with conversion from CIS to MS were the initial CIS manifestation of multifocal lesions (OR=4.775, P=0.002), positive CSF-OB (OR=7.794, P=0.002) and VEP abnormality (OR=7.251, P=0.001). Factors correlated with conversion from CIS to NMO were female in gender (OR=12.536, P=0.019), positive serum AQP4-Ab (OR=36.410, P=0.002), lesions longer than three vertebral segments (OR=93.602, P=0.001), abnormal VEP and SEP (OR=18.448, P=0.002; OR=12.731, P=0.016). Factors correlated with the conversion from CIS to MS are initial CIS manifestation of multifocal lesions, positive CSF-OB and abnormal VEP, while those correlated with the conversion from CIS to NMO are female in gender, positive serum AQP4-Ab, initial CIS manifestation with optic nerve, lesions involved more than three vertebral segments and abnormal VEP and SEP.

Evidence for potential involvement of pro-inflammatory adipokines in the pathogenesis of idiopathic intracranial hypertension.

Background Although specific role players are currently unknown, contribution of inflammatory mediators has been suggested in the pathophysiology of idiopathic intracranial hypertension (IIH), which is a disease more prevalent in obese female individuals of childbearing age. We aimed to investigate the levels of adipokines and cytokines to demonstrate possible markers for inflammation that participate in IIH pathophysiology and their association with clinical features of IIH. Methods IIH patients, diagnosed according to the revised criteria, and age-, gender- and body mass index (BMI)-matched healthy controls were enrolled in this study. Serum samples were evaluated for insulin-like growth factor 1, insulin, nesfatin, adiponectin, interleukin (IL)-1β, IL-6, IL-8, leptin, plasminogen activator inhibitor type-1, resistin, tumour necrosis factor-alpha (TNF-α) and monocyte chemotactic protein 1 via enzyme-linked immunosorbent assay or multiplex immunoassays. Results IL-1β level was significantly higher ( p = 0.012), and IL-8 and TNF-α levels were significantly lower in the IIH group ( p < 0.001 and p = 0.008, respectively) compared to the control group. There were no correlations between the cytokine/adipokine levels and age, BMI, disease duration, and cerebrospinal fluid oligoclonal bands. There were also no significant differences in cytokine and adipokine levels between IIH patients regarding visual impairment. However, statistically significant differences were found between IIH patients with relapse versus healthy controls regarding IL-1β ( p = 0.007), IL-8 ( p = 0.001) and TNF-α ( p = 0.017) levels. Other investigated cytokines and adipokines showed no significant alterations in IIH patients investigated in the remission period. Conclusion Altered serum levels of IL-1β, IL-8 and TNF-α seem to be associated with IIH pathogenesis, and these cytokines may be used as prognostic markers in IIH to predict relapse.

Evidence of cerebrospinal fluid abnormalities in patients with depressive syndromes

BackgroundDepression is the most prevalent psychiatric disease. In addition to primary, idiopathic depression, there are multiple secondary organic forms. However, distinguishing the two can be difficult, information about cerebrospinal fluid (CSF) basic findings in patients with depressive syndromes is sparse. Therefore, we investigated CSF alterations in so far the largest sample of patients with depressive syndromes. We hypothesized that increased prevalence of CSF pleocytosis, blood-brain-barrier (BBB) dysfunction, and oligoclonal bands (OCBs) would be observed as possible markers of underlying immunological processes. MethodsFrom January 2006 until October 2013, we performed CSF basic diagnostics in 125 patients with depressive syndromes. We also performed serum and CSF autoantibody measurements, cerebral magnetic resonance imaging (cMRI) and electroencephalography (EEG). ResultsFour % of the patients displayed increased CSF white blood cell counts (WBC), 46.4% had increased protein concentrations, and 19.4% had pathological albumin quotients. OCBs in the CSF were detected in 6.5%. Overall, CSF basic diagnostics were abnormal in 56%. Including instrument-based diagnostics, we found alterations in 80.8% of patients. Suicidal tendencies correlated with an increased WBC count (r=0.276, p=0.002). LimitationsIn this open, uncontrolled study, we investigated mainly CSF samples of depressive patients with signs of organic features. Therefore, the study cohort is not representative of idiopathic depression. ConclusionsThe main findings of this study are the high rates of pathological (although mainly unspecific) CSF findings. We discuss the findings regarding possible immunological mechanisms and the vascular depression hypothesis. If these findings are associated with low-level inflammation of the central nervous system, new treatment alternatives could be considered. More and better controlled research is necessary.

Advances in biomarker research in multiple sclerosis.

Development of novel biomarkers in multiple sclerosis (MS), needed to assess long-term prognosis, develop personalised treatment plans and facilitate earlier diagnosis, has so far been limited since potential candidates have often lacked specificity, reproducibility and accessibility. Despite considerable academic endeavour over many years, the only robust markers commonly utilised in current practice remain MRI and cerebrospinal fluid (CSF) oligoclonal bands, both of which provide limited essential prognostic information. More recently a number of alternative potential biomarkers have been proposed including chitinase-3 like 1 and neurofilament light chains both of which are based on analysis of CSF but have so far failed to be applied in clinical practice. In this month’s journal club, we examine three recent papers investigating biomarkers in MS. The first study uses a candidate approach assessing serum B cell-activating factor (BAFF) in relation to treatment response and disease course. The second study applies a broad proteomics approach to assess extremes of disease outcome. The third study looks at genetic variants in patients on disease modifying treatments (DMT) to identify markers predictive of treatment response. These three approaches highlight the collaborative effort and extensive biobank resources required for biomarker discovery in this field.

Cerebrospinal fluid chitinase-3-like 2 and chitotriosidase are potential prognostic biomarkers in early multiple sclerosis.

The role of chitinases and chitinase-like proteins in multiple sclerosis (MS) is currently unknown; however, cerebrospinal fluid (CSF) levels of chitinase 3-like 1 (CHI3L1) predict prognosis in early MS. Whether this applies to other chitinases and chitinase-like proteins is yet to be established. Our objective was to investigate the potential of chitinase 3-like 2 (CHI3L2) and chitotriosidase as prognostic biomarkers in optic neuritis (ON) as the first demyelinating episode and to evaluate the ability of CHI3L2 to predict long-term MS risk and disability. In a prospective cohort of 73 patients with ON as a first demyelinating episode and 26 age-matched healthy controls levels of CHI3L2 and chitotriosidase in CSF were explored by enzyme-linked immunosorbent assay. Associations with magnetic resonance imaging white matter lesions, CSF oligoclonal bands, immunoglobulin G index and leukocyte count were investigated. Long-term MS risk and disability (Expanded Disability Status Scale, Multiple Sclerosis Functional Composite components) were examined in a retrospective cohort of 78 patients with ON as the first demyelinating episode (mean follow-up 14 years). The predictive ability of CHI3L2 was compared with CHI3L1. Cerebrospinal fluid levels of CHI3L2 and chitotriosidase were significantly elevated in patients with ON and were associated with MS risk measures. CHI3L2 levels predicted MS development after ON (hazard ratio 1.95, P = 0.00039, Cox regression) and cognitive impairment by the Paced Auditory Serial Addition Test (P = 0.0357, linear regression) at follow-up. In a multivariate analysis of MS risk, CHI3L2 performed better than CHI3L1. CHI3L2 and chitotriosidase are promising biomarkers in patients with a first demyelinating episode. Our findings thus support a role for these proteins as biomarkers in early MS.

Higher frequency of brain abnormalities in neuromyelitis optica spectrum disorder patients without primary Sjögren's syndrome.

Neuromyelitis optica spectrum disorder often co-exists with primary Sjögren's syndrome. We compared the clinical features of 16 neuromyelitis optica spectrum disorder patients with (n = 6) or without primary Sjögren's syndrome (n = 10). All patients underwent extensive clinical, laboratory, and MRI evaluations. There were no statistical differences in demographics or first neurological involvement at onset between neuromyelitis optica spectrum disorder patients with and without primary Sjögren's syndrome. The laboratory findings of cerebrospinal fluid oligoclonal banding, serum C-reactive protein, antinuclear autoantibody, anti-Sjögren's-syndrome-related antigen A antibodies, anti-Sjögren's-syndrome-related antigen B antibodies, and anti-Sm antibodies were significantly higher in patients with primary Sjögren's syndrome than those without. Anti-aquaporin 4 antibodies were detectable in 67% (4/6) of patients with primary Sjögren's syndrome and in 60% (6/10) of patients without primary Sjögren's syndrome. More brain abnormalities were observed in patients without primary Sjögren's syndrome than in those with primary Sjögren's syndrome. Segments lesions (> 3 centrum) were noted in 50% (5/10) of patients without primary Sjögren's syndrome and in 67% (4/6) of patients with primary Sjögren's syndrome. These findings indicate that the clinical characteristics of neuromyelitis optica spectrum disorder patients with and without primary Sjögren's syndrome are similar. However, neuromyelitis optica spectrum disorder patients without primary Sjögren's syndrome have a high frequency of brain abnormalities.

Antibodies produced by clonally expanded plasma cells in multiple sclerosis cerebrospinal fluid cause demyelination of spinal cord explants.

B cells are implicated in the etiology of multiple sclerosis (MS). Intrathecal IgG synthesis, cerebrospinal fluid (CSF) oligoclonal bands and lesional IgG deposition suggest a role for antibody-mediated pathology. We examined the binding of IgG1 monoclonal recombinant antibodies (rAbs) derived from MS patient CSF expanded B cell clones to central nervous system (CNS) tissue. MS rAbs displaying CNS binding to mouse and human CNS tissue were further tested for their ability to induce complement-mediated tissue injury in ex vivo spinal cord explant cultures. The staining of CNS tissue, primary human astrocytes and human neurons revealed a measurable bias in MS rAb binding to antigens preferentially expressed on astrocytes and neurons. MS rAbs that recognize myelin-enriched antigens were rarely detected. Both myelin-specific and some astrocyte/neuronal-specific MS rAbs caused significant myelin loss and astrocyte activation when applied to spinal cord explant cultures in the presence of complement. Overall, the intrathecal B cell response in multiple sclerosis binds to both glial and neuronal targets and produces demyelination in spinal cord explant cultures implicating intrathecal IgG in MS pathogenesis.

Laboratory performance on reporting monoclonal gammopathy during cerebrospinal fluid oligoclonal banding analysis

Laboratory performance on reporting monoclonal gammopathy during cerebrospinal fluid oligoclonal banding analysis

Use of multiple biomarkers to improve the prediction of multiple sclerosis in patients with clinically isolated syndromes

Background: The early identification of patients at high risk of Clinically Definite Multiple Sclerosis (CDMS) represents the main purpose of diagnostic criteria and of clinicians in everyday clinical practice. Objective: To investigate whether the incorporation of different biomarkers in a model with established MRI criteria improves the prediction of MS. Methods: We evaluated baseline clinical data as well as MRI, multimodal evoked potentials and cerebrospinal fluid (CSF) data of patients with a first demyelinating episode. We used discrimination and calibration characteristics and reclassification of risk categories to assess incremental utility of different biomarkers for CDMS prediction. Results: During follow-up (median 7.2 years), 127 of the 243 participants in our study (mean age 31.6 years) developed a second clinical attack (CDMS). In Cox proportional-hazards models adjusted for established MRI criteria, age at onset, number of T1 lesions and presence of CSF oligoclonal bands significantly predicted the risk of developing MS within 2 and 5 years. The C-statistic increased significantly when the three biomarkers were incorporated into a model with established MRI criteria, both at 2 years (C-statistic with biomarkers vs. without biomarkers, 0.74 vs. 0.69) and at 5 years (0.66 vs. 0.70). The use of multiple biomarkers led to a 29% net-reclassification improvement at 2 years (p < 0.001) and 30% at 5 years (p < 0.001). Conclusions: The simultaneous addition of several biomarkers improves the risk stratification for MS in patients with clinically isolated syndromes beyond that of a model that is based only on MRI criteria.