Value contribution of blood-based neurofilament light chain as a biomarker in multiple sclerosis using multi-criteria decision analysis.

Introduction: Multiple sclerosis (MS) is a chronic autoimmune demyelinating disease that represents a leading cause of non-traumatic disability among young and middle-aged adults. MS is characterized by neurodegeneration caused by axonal injury. Current clinical and radiological markers often lack the sensitivity and specificity required to detect inflammatory activity and neurodegeneration, highlighting the need for better approaches. After neuronal injury, neurofilament light chains (NfL) are released into the cerebrospinal fluid, and eventually into blood. Thus, blood-based NfL could be used as a potential biomarker for inflammatory activity, neurodegeneration, and treatment response in MS. The objective of this study was to determine the value contribution of blood-based NfL as a biomarker in MS in Spain using the Multi-Criteria Decision Analysis (MCDA) methodology. Materials and methods: A literature review was performed, and the results were synthesized in the evidence matrix following the criteria included in the MCDA framework. The study was conducted by a multidisciplinary group of six experts. Participants were trained in MCDA and scored the evidence matrix. Results were analyzed and discussed in a group meeting through reflective MCDA discussion methodology. Results: MS was considered a severe condition as it is associated with significant disability. There are unmet needs in MS as a disease, but also in terms of biomarkers since no blood biomarker is available in clinical practice to determine disease activity, prognostic assessment, and response to treatment. The results of the present study suggest that quantification of blood-based NfL may represent a safe option to determine inflammation, neurodegeneration, and response to treatments in clinical practice, as well as to complement data to improve the sensitivity of the diagnosis. Participants considered that blood-based NfL could result in a lower use of expensive tests such as magnetic resonance imaging scans and could provide cost-savings by avoiding ineffective treatments. Lower indirect costs could also be expected due to a lower impact of disability consequences. Overall, blood-based NfL measurement is supported by high-quality evidence. Conclusion: Based on MCDA methodology and the experience of a multidisciplinary group of six stakeholders, blood-based NfL measurement might represent a high-value-option for the management of MS in Spain.

Neurofilament light chain in the assessment of patients with multiple sclerosis.

Multiple sclerosis (MS) is an autoimmune, inflammatory, and degenerative disease of the central nervous system. Axonal degeneration is triggered by inflammation and is the pathological substrate of progressive disability in patients with MS. Therapeutic interventions can reduce inflammatory activity, thus delaying neurodegeneration and the progression of disability. Disease activity and neurodegeneration are assessed mainly through clinical evaluation and magnetic resonance imaging. These measures lack sensitivity and accuracy, so new biomarkers are necessary. Several markers have been studied and to date the most promising is neurofilament light (NfL), a component of the axonal cytoskeleton, which is released into cerebrospinal fluid (CSF) following axonal damage. In the present study, we review the current knowledge about CSF NfL determination in MS, clinically isolated syndrome, and radiologically isolated syndrome, and critically discuss how CSF NfL measurement may contribute to therapeutic decision-making in these patients.

Neurofilament light chain in the assessment of patients with multiple sclerosis / Neurofilamento de cadeia leve na avaliação de pacientes com esclerose múltipla

ABSTRACT Multiple sclerosis (MS) is an autoimmune, inflammatory, and degenerative disease of the central nervous system. Axonal degeneration is triggered by inflammation and is the pathological substrate of progressive disability in patients with MS. Therapeutic interventions can reduce inflammatory activity, thus delaying neurodegeneration and the progression of disability. Disease activity and neurodegeneration are assessed mainly through clinical evaluation and magnetic resonance imaging. These measures lack sensitivity and accuracy, so new biomarkers are necessary. Several markers have been studied and to date the most promising is neurofilament light (NfL), a component of the axonal cytoskeleton, which is released into cerebrospinal fluid (CSF) following axonal damage. In the present study, we review the current knowledge about CSF NfL determination in MS, clinically isolated syndrome, and radiologically isolated syndrome, and critically discuss how CSF NfL measurement may contribute to therapeutic decision-making in these patients.

RESUMO A esclerose múltipla (EM) é uma doença autoimune, inflamatória e degenerativa do sistema nervoso central. A degeneração axonal é deflagrada pelo processo inflamatório e é o substrato patológico da incapacidade na EM. As intervenções terapêuticas reduzem a inflamação retardando a neurodegeneração e a progressão da incapacidade. A neurodegeneração é avaliada pelo quadro clínico e pela ressonância magnética. Estas mensurações não suficientemente acuradas, havendo necessidade de novos biomarcadores. Diversos biomarcadores têm sido estudados e, até o presente, o mais promissor é o neurofilamento de cadeia leve (NfL). O mesmo é um componente do citoesqueleto que é liberado no líquido cefalorraquidiano após injúria axonal. No presente estudo nós revisamos o conhecimento atual acerca do NfL na EM, síndrome clinica isolada e síndrome radiológica isolada, discutindo criticamente como a determinação deste biomarcador pode contribuir na tomada de decisões clínicas.

Diagnostic Value of Oligoclonal Bands in Children: A Nationwide Population-Based Cohort Study.

OBJECTIVE: We evaluated the diagnostic value of cerebrospinal fluid oligoclonal bands in individuals less than 18 years of age. METHODS: In a nationwide population-based setting, we retrieved data on 2055 children's oligoclonal band examination, including concordant cerebrospinal fluid biomarkers, during 1994 to 2017. Case ascertainment was by review of medical records and diagnostic codes. We used Fisher's exact test to explore distribution differences of oligoclonal band positivity in acquired demyelinating syndromes (ADS) before and after age 12 years and calculated the sensitivity, specificity, positive predictive value, and negative predictive value of oligoclonal bands to distinguish ADS from the other diagnostic groups. RESULTS: Median age at oligoclonal band examination was 15.2 years (range = 1.8 to 18.0), and 10% had presence of cerebrospinal fluid oligoclonal bands. Oligoclonal band positivity was the highest in ADS (52%), but it was age dependent: 21% in children with ADS before age 12 years and 68% in children aged 12 through 17 years (P < 0.0001) owing to the higher incidence of multiple sclerosis in the latter. Cerebrospinal fluid oligoclonal bands were not predictive of ADS before age 12 years compared with the other diagnostic groups. However, cerebrospinal fluid oligoclonal bands in children aged 12 through 17 years were highly predictive of ADS compared with central nervous system infections and non-ADS immune-mediated central nervous system diseases (positive predictive value: 0.89; 95% confidence interval = 0.82 to 0.94; P < 0.0001), but negative oligoclonal bands were not discriminatory (negative predictive value: P = 0.17). CONCLUSIONS: In a clinical setting, cerebrospinal fluid oligoclonal band examination may be of higher yield in children aged 12 through 17 years if there is clinical suspicion of multiple sclerosis, and in such circumstances a positive test supports a diagnosis of multiple sclerosis.

Intrathecal immunoglobulin synthesis: The potential value of an adjunct test.

BACKGROUND: Detection of cerebrospinal fluid (CSF) specific oligoclonal bands (OCB) supports the diagnosis of multiple sclerosis (MS), but the method is technically demanding and gives only qualitative information. Kappa free light chains (KFLC) quantification could represent a convenient alternative. We evaluated the diagnostic accuracy of OCB and KFLC in our cohort to further estimate the gain in diagnostic performance when combining both of them. METHODS: KFLC were measured in paired serum and CSF samples of 80 patients with MS and 50 patients with non-inflammatory neurological disorders. OCB were detected using an in-house alkaline phosphatase assay. Likelihood ratio (LR) was used to explore the benefit of the combined KFLC and OCB test. RESULTS: Sensitivity of KFLC index (≥5.3) and intrathecal KFLC fraction (≥10%) was 96% and 95% respectively, compared to 91% sensitivity of OCB assay. Specificity was 96% for intrathecal KFLC synthesis and 98% for OCB. Probability of MS in the absence of OCB was further reduced with concurrently normal KFLC index. CONCLUSIONS: Normal KFLC parameters allow confident exclusion of intrathecal inflammation, but probability of MS is greater with positive OCB. Use of KFLC as an adjunct test might be beneficial in specialized MS centers with larger pretest probability.

Intensity ratio to improve black hole assessment in multiple sclerosis.

BACKGROUND: Improved imaging methods are critical to assess neurodegeneration and remyelination in multiple sclerosis. Chronic hypointensities observed on T1-weighted brain MRI, "persistent black holes," reflect severe focal tissue damage. Present measures consist of determining persistent black holes numbers and volumes, but do not quantitate severity of individual lesions. OBJECTIVE: Develop a method to differentiate black and gray holes and estimate the severity of individual multiple sclerosis lesions using standard magnetic resonance imaging. METHODS: 38 multiple sclerosis patients contributed images. Intensities of lesions on T1-weighted scans were assessed relative to cerebrospinal fluid intensity using commercial software. Magnetization transfer imaging, diffusion tensor imaging and clinical testing were performed to assess associations with T1w intensity-based measures. RESULTS: Intensity-based assessments of T1w hypointensities were reproducible and achieved > 90% concordance with expert rater determinations of "black" and "gray" holes. Intensity ratio values correlated with magnetization transfer ratios (R = 0.473) and diffusion tensor imaging metrics (R values ranging from 0.283 to -0.531) that have been associated with demyelination and axon loss. Intensity ratio values incorporated into T1w hypointensity volumes correlated with clinical measures of cognition. CONCLUSIONS: This method of determining the degree of hypointensity within multiple sclerosis lesions can add information to conventional imaging.

Assessment of Intrathecal Free Light Chain Synthesis: Comparison of Different Quantitative Methods with the Detection of Oligoclonal Free Light Chains by Isoelectric Focusing and Affinity-Mediated Immunoblotting.

OBJECTIVES: We aimed to compare various methods for free light chain (fLC) quantitation in cerebrospinal fluid (CSF) and serum and to determine whether quantitative CSF measurements could reliably predict intrathecal fLC synthesis. In addition, we wished to determine the relationship between free kappa and free lambda light chain concentrations in CSF and serum in various disease groups. METHODS: We analysed 166 paired CSF and serum samples by at least one of the following methods: turbidimetry (Freelite™, SPAPLUS), nephelometry (N Latex FLC™, BN ProSpec), and two different (commercially available and in-house developed) sandwich ELISAs. The results were compared with oligoclonal fLC detected by affinity-mediated immunoblotting after isoelectric focusing. RESULTS: Although the correlations between quantitative methods were good, both proportional and systematic differences were discerned. However, no major differences were observed in the prediction of positive oligoclonal fLC test. Surprisingly, CSF free kappa/free lambda light chain ratios were lower than those in serum in about 75% of samples with negative oligoclonal fLC test. In about a half of patients with multiple sclerosis and clinically isolated syndrome, profoundly increased free kappa/free lambda light chain ratios were found in the CSF. CONCLUSIONS: Our results show that using appropriate method-specific cut-offs, different methods of CSF fLC quantitation can be used for the prediction of intrathecal fLC synthesis. The reason for unexpectedly low free kappa/free lambda light chain ratios in normal CSFs remains to be elucidated. Whereas CSF free kappa light chain concentration is increased in most patients with multiple sclerosis and clinically isolated syndrome, CSF free lambda light chain values show large interindividual variability in these patients and should be investigated further for possible immunopathological and prognostic significance.

[Is it always useful to perform lumbar puncture for the diagnosis of multiple sclerosis? No]. / Est-il toujours utile de faire une ponction lombaire lors d'une suspicion de sclérose en plaques? Non.

In the absence of a specific test for the diagnosis of multiple sclerosis (MS), cerebrospinal fluid analysis (CSF) remains discussed. There are robust evidences which demonstrated that an early diagnosis of MS must be done, due to the availability of disease-modifying drugs that could influence the natural history of the disease. However, several arguments can be put forward to assert that CSF analysis is not useful for the diagnosis of MS and thus should not be realized in a systematic way. First, MRI remains the most sensitive and specific marker to validate dissemination in space and in time and CSF analysis is not recommended by the 2010 McDonald criteria. The second argument is related to the low sensitivity and specificity of abnormalities detected in CSF analysis to confirm the diagnosis of MS. Moreover, there is currently no evidence that the presence of oligoclonal bands could represent a surrogate marker on an individual prognostic way. Furthermore, lumbar puncture could be traumatic, may entail some infrequent risks and represents unnecessary expense. Thus, there are strong reasons to not recommend systematic CSF examination to diagnose MS.

Assessment of outcome predictors in first-episode acute myelitis: a retrospective study of 53 cases.

OBJECTIVE: To identify predictors of short- and long-term outcomes in acute myelitis (AM). DESIGN: First episodes of AM were retrospectively identified in a single institution. Information regarding demographics, clinical status, laboratory workup, magnetic resonance imaging of the spine and brain, and electrophysiological assessment was collected. Tau, 14-3-3 protein, and cystatin C levels were assessed de novo in stored cerebrospinal fluid samples. SETTING: A neurological department database. Patients Fifty-three patients with a first episode of AM. MAIN OUTCOME MEASURES: The prognostic value of all variables was analyzed for the following outcomes: recovery from the initial event, symptom recurrence, conversion to multiple sclerosis (MS), and long-term disability. RESULTS: Median follow-up was 6.2 years. Six patients (11%) remained monophasic; 5 (9%) developed recurrent myelitis; and 42 (79%) underwent conversion to MS. Sensory level absence, no sphincter involvement, abnormal magnetic resonance imaging findings in the brain, spinal cord lesions shorter than 3 vertebral segments, and abnormal somatosensory evoked potentials predicted MS conversion. Fifteen of 32 patients with pyramidal dysfunction at onset (47%) and 17 of 43 with relapses during follow-up (40%) had significant disability at the last visit compared with 2 of 21 patients without pyramidal manifestations (10%) and none of the patients without exacerbations (P = .006 and P = .02, respectively). In 11 patients with exacerbations, we observed a significant correlation between cerebrospinal fluid levels of cystatin C and the degree of neurological disability at the last visit (Spearman rho = 0.69; P = .03). CONCLUSIONS: For patients with first-episode AM, the conversion rate to MS is high. Motor dysfunction at onset and relapse occurrence are associated with worse outcome. Cerebrospinal fluid levels of cystatin C may prove useful for predicting the prognosis of such patients.

Elevated CSF free kappa light chains correlate with disability prognosis in multiple sclerosis.

Elevated CSF free kappa light chains (FKLCs) may predict disability in multiple sclerosis (MS). We reviewed records of 57 patients with MS with 15-year median follow-up for correlations of disability and CSF FKLCs. Levels > or = 1.53 microg/mL predicted progression to need for ambulatory assistance during follow-up (specificity 87.5%, positive predictive value 88.9%) or within 10 years (specificity 78.6%, positive predictive value 66.7%).

[Role of isoelectric focusing of cerebrospinal fluid immunoglobulin G in the early biological assessment of multiple sclerosis]. / Apport de la focalisation isoélectrique des immunoglobulines G du liquide céphalorachidien dans le bilan biologique précoce de la sclérose en plaques.

A retrospective study was carried out at the Neurological and Neurosurgical Hospital of Lyon in order to evaluate the interest of detecting IgG oligoclonal bands by isoelectric focusing with IgG immunorevelation for the early diagnosis of multiple sclerosis (MS). Patients have been grouped according to their disorders: multiple sclerosis (281 cases), definite (182 cases) and possible (99 cases), others inflammatory neurological diseases (63 cases), various non-inflammatory neurological disorders (180 cases) and indefined neurological disorders (664 cases). The following examinations were performed: CSF cell count and cytology after concentration and cytocentrifugation, CSF and serum determination of albumin and IgG with CSF/serum ratios, agarose gel electrophoresis and isoelectric focusing of oligoclonal IgG. The technique used was isoelectric focusing using agarose gel, transfer onto PVDF membrane and then IgG immunorevelation with biotinylated anti-human IgG antibodies. Isoelectric focusing with IgG immunorevelation is the most sensitive (94%) and specific (96%) technique. Isoelectric focusing with immune detection can be recommended as the most efficient test (gold standard) for the detection of chronic CNS inflammation.

[Neurophysiological assessment in patients with clinically defined multiple sclerosis with special reference to P300 wave study]. / Evaluación neurofisiológica en pacientes con esclerosis múltiple clínica definida con especial referencia al estudio de la onda P300.

INTRODUCTION: In the cognitive sphere, alterations have been found in up to 65% of patients with multiple sclerosis (MS). Study of the P300 wave is a positive component of long latency related to cognitive function: amplitude with attention, and latency with the ability to process information. OBJECTIVE: To assess a study of the P300 wave in a group of patients with MS. PATIENTS AND METHODS: The P300 wave was studied in 26 patients, 22 women and 4 men, with definite clinical MS (on criteria of Poser et al), with normal motor and sensory conduction velocity studies. All patients had a battery of multi-modal evoked potentials (MEP), nuclear magnetic resonance imaging and immunological study of the cerebrospinal fluid. Seventeen patients had the exacerbation-remission (ER) and nine the primary progressive (PP) clinical forms of the disorder. RESULTS: The most markedly altered MEP were the visual and somatosensory evoked potentials (SSEP) of the patients with MS. When the types of clinical course were compared, the SSEP were statistically significant in the PP form, which may be explained by the greater spinal involvement of these patients. Comparative analysis of the P300 wave was done for 26 healthy patients of similar age and sex to that of the patients, and significant differences were found in P300 latency and amplitude between the MS and control groups. The patients who had had the disease for longer had significantly greater anomalies in the P300 waves. CONCLUSION: Study of the evolution of the P300 wave, which is cheap and easy to do, may be valuable in the evolutional assessment of cognitive changes in patients with MS.

A decision analytic approach to the role of visual evoked response and cerebrospinal fluid abnormalities in the management of singular spinal sclerosis.

With the use of Bayesian decision analytic techniques we assess the role of visual evoked response (VER) and cerebrospinal fluid (CSF) examinations in the investigation of patients with suspected singular spinal sclerosis. An abnormal VER increases the probability of multiple sclerosis by 50%. An associated CSF abnormality does not affect this probability. In a setting of a negative VER, CSF abnormalities increase the probability of multiple sclerosis by 27%. On currently available data, VER should therefore be the primary investigation in patients with suspected singular spinal sclerosis. If the result is abnormal myelography may be omitted. CSF examinations are only useful if VER facilities are not available.