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E P Evdoshenko - One of the best experts on this subject based on the ideXlab platform.
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neurofilament light chain and oligoclonal bands are prognostic biomarkers in radiologically Isolated Syndrome
Brain, 2018Co-Authors: Clara Matuteblanch, G S Makshakov, Vladimir Nazarov, S V Lapin, E P Evdoshenko, Luisa M Villar, Jose C Alvarezcermeno, Konrad Rejdak, Luciana Midaglia, Angela VidaljordanaAbstract:The prognostic role of cerebrospinal fluid molecular biomarkers determined in early pathogenic stages of multiple sclerosis has yet to be defined. In the present study, we aimed to investigate the prognostic value of chitinase 3 like 1 (CHI3L1), neurofilament light chain, and oligoclonal bands for conversion to Clinically Isolated Syndrome and to multiple sclerosis in 75 patients with radiologically Isolated Syndrome. Cerebrospinal fluid levels of CHI3L1 and neurofilament light chain were measured by enzyme-linked immunosorbent assay. Uni- and multivariable Cox regression models including as covariates age at diagnosis of radiologically Isolated Syndrome, number of brain lesions, sex and treatment were used to investigate associations between cerebrospinal fluid CHI3L1 and neurofilament light chain levels and time to conversion to Clinically Isolated Syndrome and multiple sclerosis. Neurofilament light chain levels and oligoclonal bands were independent risk factors for the development of Clinically Isolated Syndrome (hazard ratio = 1.02, P = 0.019, and hazard ratio = 14.7, P = 0.012, respectively) and multiple sclerosis (hazard ratio = 1.03, P = 0.003, and hazard ratio = 8.9, P = 0.046, respectively). The best cut-off to classify cerebrospinal fluid neurofilament light chain levels into high and low was 619 ng/l, and high neurofilament light chain levels were associated with a trend to shorter time to Clinically Isolated Syndrome (P = 0.079) and significant shorter time to multiple sclerosis (P = 0.017). Similarly, patients with radiologically Isolated Syndrome presenting positive oligoclonal bands converted faster to Clinically Isolated Syndrome and multiple sclerosis (P = 0.005 and P = 0.008, respectively). The effects of high neurofilament light chain levels shortening time to Clinically Isolated Syndrome and multiple sclerosis were more pronounced in radiologically Isolated Syndrome patients with ≥37 years compared to younger patients. Cerebrospinal fluid CHI3L1 levels did not influence conversion to Clinically Isolated Syndrome and multiple sclerosis in radiologically Isolated Syndrome patients. Overall, these findings suggest that cerebrospinal neurofilament light chain levels and oligoclonal bands are independent predictors of clinical conversion in patients with radiologically Isolated Syndrome. The association with a faster development of multiple sclerosis reinforces the importance of cerebrospinal fluid analysis in patients with radiologically Isolated Syndrome.
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diagnostic and prognostic value of the cerebrospinal fluid concentration of immunoglobulin free light chains in Clinically Isolated Syndrome with conversion to multiple sclerosis
PLOS ONE, 2015Co-Authors: G S Makshakov, Vladimir Nazarov, Olga Kochetova, E A Surkova, S V Lapin, E P EvdoshenkoAbstract:Background and objective In this study, we evaluated the diagnostic and prognostic significance of cerebrospinal fluid free light chains (CSF FLC) at the time of Clinically Isolated Syndrome (CIS). Methods We compared FLC-parameters at the moment of CIS in patients with conversion to multiple sclerosis (MS) after 2 years (CIS-MS), patients who remained stable both Clinically and radiologically after 2 years (CIS-nonMS), patients with non-inflammatory neurologic diseases (NIND) as a comparison group and patients with other inflammatory neurologic diseases (IND) with intrathecal oligoclonal bands (OCB) synthesis. ROC-analysis was conducted to define FLC-assay characteristics and cut-off values. We also compared FLC-concentrations in CIS patients to determine their OCB-status. A correlation analysis was performed between FLC-concentrations and the expanded disability scale score (EDSS), annualized relapse rate (ARR) and MRI-activity (i.e., number of new and gadolinium-enhancing (Gd+) lesions) in patients. Results The levels of kappa-FLC (k-FLCCSF) and lambda-FLC (λ-FLCCSF) as well as kappa- and lambda-quotients (Q-k and Q-λ) were elevated in CIS-MS compared to the CIS-nonMS and NIND groups. These levels did not differ significantly when compared with the IND group. We identified several patients with high k-FLCCSF and λ-FLCCSF in OCB-negative CIS and IND groups. The level of k-FLCCSF production was significantly higher in OCB-positive patients in the CIS-MS group compared to the CIS-nonMS group. The concentrations of k-FLCCSF and Q-k in the CIS-MS group showed significant correlation with the level of EDSS after 2 years (k-FLC: r = 0.4477,p = 0.0016; Q-k: r = 0.4621, p = 0.0016). λ-FLCCSF and Q-λ inversely correlated with the number of Gd+ lesions (CSF λ-FLC: r = -0.3698, p = 0.0223; Q-λ: r = -0.4527, p = 0.0056). Conclusion The concentration of CSF FLC predicts conversion to MS within 2 years following CIS. OCB-positive patients with an early conversion have a higher concentration of CSF-FLC. We have also shown a prognostic significance of k-FLCCSF for future EDSS-progression.
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serum neurofilament light chain levels are increased in patients with a Clinically Isolated Syndrome
Journal of Neurology Neurosurgery and Psychiatry, 2015Co-Authors: Giulio Disanto, E P Evdoshenko, Vittorio Martinelli, Rocco Adiutori, Ruth Dobson, Gloria Dalla Costa, Tessel F Runia, Eric Thouvenot, Maria Trojano, Niklas NorgrenAbstract:Background Neurofilament light chain (NfL) represents a promising biomarker for axonal injury. We present the first exploratory study on serum NfL in patients with a Clinically Isolated Syndrome (CIS) and healthy controls. Methods We investigated serum NfL levels in 100 patients with CIS with a short conversion interval to Clinically definite multiple sclerosis (MS) (fast converters (FC), median (IQR) conversion time: 110 days (79–139)); 98 patients with non-converting CIS (non-converters (NC), follow-up: 6.5 years (5.3–7.9)); and 92 healthy controls. Results NfL levels were higher in FC (24.1 pg/mL (13.5–51.8)) and NC (19.3 pg/mL (13.6–35.2)) than in healthy controls (7.9 pg/mL (5.6–17.2)) (OR=5.85; 95% CI 2.63 to 13.02; p=1.5×10 −5 and OR=7.03; 95% CI 2.85 to 17.34; p=2.3×10 −5 , respectively). When grouping FC and NC, increased serum NfL concentration was also associated with increasing numbers of T2 hyperintense MRI lesions (OR=2.36; 95% CI 1.21 to 4.59; p=0.011), gadolinium-enhancing lesions (OR=2.69; 95% CI 1.13 to 6.41; p=0.026) and higher disability scores (OR=2.54; 95% CI 1.21 to 5.31; p=0.013) at CIS diagnosis. Conclusions If replicated in future studies, serum NfL may represent a reliable and easily accessible biomarker of early axonal damage in CIS and MS.
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DIAGNOSTIC AND PROGNOSTIC SIGNIFICANCE OF INTRATHECAL SYNTHESIS OF IMMUNOGLOBULIN FREE LIGHT CHAINS IN MULTIPLE SCLEROSIS
SPb RAACI, 2015Co-Authors: V. D. Nazarov, G S Makshakov, E A Surkova, S V Lapin, E P Evdoshenko, Areg A. TotolianAbstract:Increased intrathecal synthesis and oligoclonal banding of immunoglobulins (Ig) in cerebrospinal fluid (CSF) are major immunological findings in multiple sclerosis. Free light chains are fragments of Ig molecules that are produced in parallel to oligoclonal Ig, and their production reflects total Ig synthesis within central nervous system. Assessment of intrathecal kappaand lambda free light chain production within CNS compartment will help to improve diagnosis and prediction of outcomes in multiple sclerosis. Concentrations of kappa and lambda free light chains and clonality of immunoglobulin pattern synthesis were studied in paired CSF and serum samples of 151 patients, including 92 patients with multiple sclerosis, and 33 patients with Clinically Isolated Syndrome which later was transformed into the definite multiple sclerosis. A control group consisted of 26 patients with other inflammatory diseases of central nervous system. Several Ig parameters have been determined in the patients, i.e., Ig clonality in CSF; concentrations of free light chains (both kappaand lambda-) in CSF; as well as their indexes and ratios. It was established that synthesis of kappa free light chains were significantly elevated in patients with multiple sclerosis. Moreover, the amounts of free light Ig chains in patients with positive oligoclonality test were significantly higher than in cases without intrathecal oligoclonal synthesis. With respect to diagnostic significance, the kappa quotient proved the best available option for diagnosis of multiple sclerosis. Its combination with Ig oligoclonality assays caused a decrease in false-negative diagnostics by 42%. Diagnostic benefit of the kappa quotient could be also confirmed by the data of ROC analysis. Also concentration of lambda free light chains in cerebrospinal fluid showed a negative correlation with conversion terms of Clinically Isolated Syndrome to evident multiple sclerosis. Therefore, the indexes of free Ig light chains enables more precise diagnostics, like as more efficient severity evaluation of multiple sclerosis
Frederik Barkhof - One of the best experts on this subject based on the ideXlab platform.
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2010. Resting state networks change in Clinically Isolated Syndrome
2020Co-Authors: Frederik Barkhof, Hanneke E Hulst, Menno M Schoonheim, Ernesto J Sanz-arigita, Stephen M Smith, Jeroen J G Geurts, Stefan D RoosendaalAbstract:Task-functional magnetic resonance imaging studies have shown that early cortical recruitment exists in multiple sclerosis, which can partly explain the discrepancy between conventional magnetic resonance imaging and clinical disability. The study of the brain 'at rest' may provide additional information, because task-induced metabolic changes are relatively small compared to the energy use of the resting brain. We therefore questioned whether functional changes exist at rest in the early phase of multiple sclerosis, and addressed this question by a network analysis of no-task functional magnetic resonance imaging data. Fourteen patients with symptoms suggestive of multiple sclerosis (Clinically Isolated Syndrome), 31 patients with relapsing remitting multiple sclerosis and 41 healthy controls were included. Resting state functional magnetic resonance imaging data were brought to standard space using non-linear registration, and further analysed using multi-subject independent component analysis and individual time-course regression. Eight meaningful resting state networks were identified in our subjects and compared between the three groups with non-parametric permutation testing, using threshold-free cluster enhancement to correct for multiple comparisons. Additionally, quantitative measures of structural damage were obtained. Grey and white matter volumes, normalized for head size, were measured for each subject. White matter integrity was investigated with diffusion tensor measures that were compared between groups voxel-wise using tract-based spatial statistics. Patients with Clinically Isolated Syndrome showed increased synchronization in six of the eight resting state networks, including the default mode network and sensorimotor network, compared to controls or relapsing remitting patients. No significant decreases were found in patients with Clinically Isolated Syndrome. No significant resting state synchronization differences were found between relapsing remitting patients and controls. Normalized grey matter volume was decreased and white matter diffusivity measures were abnormal in relapsing remitting patients compared to controls, whereas no atrophy or diffusivity changes were found for the Clinically Isolated Syndrome group. Thus, early synchronization changes are found in patients with Clinically Isolated Syndrome that are suggestive of cortical reorganization of resting state networks. These changes are lost in patients with relapsing remitting multiple sclerosis with increasing brain damage, indicating that cortical reorganization of resting state networks is an early and finite phenomenon in multiple sclerosis
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MRI-based prediction of conversion from Clinically Isolated Syndrome to Clinically definite multiple sclerosis using SVM and lesion geometry
Brain Imaging and Behavior, 2019Co-Authors: Kerstin Bendfeldt, Viktor Wottschel, Hugo Vrenken, Bernd Taschler, Laura Gaetano, Philip Madoerin, Pascal Kuster, Nicole Mueller-lenke, Michael Amann, Frederik BarkhofAbstract:Neuroanatomical pattern classification using support vector machines (SVMs) has shown promising results in classifying Multiple Sclerosis (MS) patients based on individual structural magnetic resonance images (MRI). To determine whether pattern classification using SVMs facilitates predicting conversion to Clinically definite multiple sclerosis (CDMS) from Clinically Isolated Syndrome (CIS). We used baseline MRI data from 364 patients with CIS, randomised to interferon beta-1b or placebo. Non-linear SVMs and 10-fold cross-validation were applied to predict converters/non-converters (175/189) at two years follow-up based on clinical and demographic data, lesion-specific quantitative geometric features and grey-matter-to-whole-brain volume ratios. We applied linear SVM analysis and leave-one-out cross-validation to subgroups of converters ( n = 25) and non-converters ( n = 44) based on cortical grey matter segmentations. Highest prediction accuracies of 70.4% ( p = 8e-5) were reached with a combination of lesion-specific geometric (image-based) and demographic/clinical features. Cortical grey matter was informative for the placebo group (acc.: 64.6%, p = 0.002) but not for the interferon group. Classification based on demographic/clinical covariates only resulted in an accuracy of 56% ( p = 0.05). Overall, lesion geometry was more informative in the interferon group, EDSS and sex were more important for the placebo cohort. Alongside standard demographic and clinical measures, both lesion geometry and grey matter based information can aid prediction of conversion to CDMS.
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disrupted module efficiency of structural and functional brain connectomes in Clinically Isolated Syndrome and multiple sclerosis
Frontiers in Human Neuroscience, 2018Co-Authors: Yaou Liu, Frederik Barkhof, Yunyun Duan, Huiqing Dong, Ni ShuAbstract:Recent studies have demonstrated disrupted topological organization of brain connectome in multiple sclerosis (MS). However, whether the communication efficiency between different functional systems is affected in the early stage of MS remained largely unknown. In this study, we constructed the structural connectivity (SC) and functional connectivity (FC) networks in 41 patients with Clinically Isolated Syndrome (CIS), 32 MS patients and 35 healthy controls (HC) based on diffusion and resting-state functional MRI. To quantify the communication efficiency within and between different functional systems, we proposed two measures called intra- and inter-module efficiency. Based on the module parcellation of functional backbone network, the intra- and inter-module efficiency of SC and FC networks was calculated for each participant. For the SC network, CIS showed decreased inter-module efficiency between the sensory-motor network (SMN), the visual network (VN), the default-mode network (DMN) and the fronto-parietal network (FPN) compared with HC, while MS showed more widespread decreased module efficiency both within and between modules relative to HC and CIS. For the FC network, no differences were found between CIS and HC, and a decreased inter-module efficiency between SMN and FPN and between VN and FPN was identified in MS, compared with HC and CIS. Moreover, both intra- and inter-module efficiency of SC network were correlated with the disability and cognitive scores in MS. Therefore, our results demonstrated early SC changes between modules in CIS, and more widespread SC alterations and inter-module FC changes were observed in MS, which were further associated with cognitive impairment and physical disability.
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Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria
The Lancet Neurology, 2018Co-Authors: Alan J. Thompson, Brenda L. Banwell, Timothy Coetzee, William M Carroll, Jorge Correale, Franz Fazekas, Frederik Barkhof, Massimo FilippiAbstract:The 2010 McDonald criteria for the diagnosis of multiple sclerosis are widely used in research and clinical practice. Scientific advances in the past 7 years suggest that they might no longer provide the most up-to-date guidance for clinicians and researchers. The International Panel on Diagnosis of Multiple Sclerosis reviewed the 2010 McDonald criteria and recommended revisions. The 2017 McDonald criteria continue to apply primarily to patients experiencing a typical Clinically Isolated Syndrome, define what is needed to fulfil dissemination in time and space of lesions in the CNS, and stress the need for no better explanation for the presentation. The following changes were made: in patients with a typical Clinically Isolated Syndrome and clinical or MRI demonstration of dissemination in space, the presence of CSF-specific oligoclonal bands allows a diagnosis of multiple sclerosis; symptomatic lesions can be used to demonstrate dissemination in space or time in patients with supratentorial, infratentorial, or spinal cord Syndrome; and cortical lesions can be used to demonstrate dissemination in space. Research to further refine the criteria should focus on optic nerve involvement, validation in diverse populations, and incorporation of advanced imaging, neurophysiological, and body fluid markers.
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Prediction of a multiple sclerosis diagnosis in patients with Clinically Isolated Syndrome using the 2016 MAGNIMS and 2010 McDonald criteria: a retrospective study.
The Lancet. Neurology, 2017Co-Authors: Massimo Filippi, Frederik Barkhof, Olga Ciccarelli, Jette L. Frederiksen, Paolo Preziosa, Alessandro Meani, Sarlota Mesaros, Alex Rovira, Christian Enzinger, Claudio GasperiniAbstract:Summary Background In 2016, the Magnetic Resonance Imaging in Multiple Sclerosis (MAGNIMS) network proposed modifications to the MRI criteria to define dissemination in space (DIS) and time (DIT) for the diagnosis of multiple sclerosis in patients with Clinically Isolated Syndrome (CIS). Changes to the DIS definition included removal of the distinction between symptomatic and asymptomatic lesions, increasing the number of lesions needed to define periventricular involvement to three, combining cortical and juxtacortical lesions, and inclusion of optic nerve evaluation. For DIT, removal of the distinction between symptomatic and asymptomatic lesions was suggested. We compared the performance of the 2010 McDonald and 2016 MAGNIMS criteria for multiple sclerosis diagnosis in a large multicentre cohort of patients with CIS to provide evidence to guide revisions of multiple sclerosis diagnostic criteria. Methods Brain and spinal cord MRI and optic nerve assessments from patients with typical CIS suggestive of multiple sclerosis done less than 3 months from clinical onset in eight European multiple sclerosis centres were included in this retrospective study. Eligible patients were 16–60 years, and had a first CIS suggestive of CNS demyelination and typical of relapsing-remitting multiple sclerosis, a complete neurological examination, a baseline brain and spinal cord MRI scan obtained less than 3 months from clinical onset, and a follow-up brain scan obtained less than 12 months from CIS onset. We recorded occurrence of a second clinical attack (Clinically definite multiple sclerosis) at months 36 and 60. We evaluated MRI criteria performance for DIS, DIT, and DIS plus DIT with a time-dependent receiver operating characteristic curve analysis. Findings Between June 16, 1995, and Jan 27, 2017, 571 patients with CIS were screened, of whom 368 met all study inclusion criteria. At the last evaluation (median 50·0 months [IQR 27·0–78·4]), 189 (51%) of 368 patients developed Clinically definite multiple sclerosis. At 36 months, the two DIS criteria showed high sensitivity (2010 McDonald 0·91 [95% CI 0·85–0·94] and 2016 MAGNIMS 0·93 [0·88–0·96]), similar specificity (0·33 [0·25–0·42] and 0·32 [0·24–0·41]), and similar area under the curve values (AUC; 0·62 [0·57–0·67] and 0·63 [0·58–0·67]). Performance was not affected by inclusion of symptomatic lesions (sensitivity 0·92 [0·87–0·96], specificity 0·31 [0·23–0·40], AUC 0·62 [0·57–0·66]) or cortical lesions (sensitivity 0·92 [0·87–0·95], specificity 0·32 [0·24–0·41], AUC 0·62 [0·57–0·67]). Requirement of three periventricular lesions resulted in slightly lower sensitivity (0·85 [0·78–0·90], slightly higher specificity (0·40 [0·32–0·50], and similar AUC (0·63 [0·57–0·68]). Inclusion of optic nerve evaluation resulted in similar sensitivity (0·92 [0·87–0·96]), and slightly lower specificity (0·26 [0·18–0·34]) and AUC (0·59 [0·55–0·64]). AUC values were also similar for DIT (2010 McDonald 0·61 [0·55–0·67] and 2016 MAGNIMS 0·61 [0·55–0·66]) and DIS plus DIT (0·62 [0·56–0·67] and 0·64 [0·58–0·69]). Interpretation The 2016 MAGNIMS criteria showed similar accuracy to the 2010 McDonald criteria in predicting the development of Clinically definite multiple sclerosis. Inclusion of symptomatic lesions is expected to simplify the clinical use of MRI criteria without reducing accuracy, and our findings suggest that needing three lesions to define periventricular involvement might slightly increase specificity, suggesting that these two factors could be considered during further revisions of multiple sclerosis diagnostic criteria. Funding UK MS Society, National Institute for Health Research University College London Hospitals Biomedical Research Centre, Dutch MS Research Foundation.
G S Makshakov - One of the best experts on this subject based on the ideXlab platform.
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neurofilament light chain and oligoclonal bands are prognostic biomarkers in radiologically Isolated Syndrome
Brain, 2018Co-Authors: Clara Matuteblanch, G S Makshakov, Vladimir Nazarov, S V Lapin, E P Evdoshenko, Luisa M Villar, Jose C Alvarezcermeno, Konrad Rejdak, Luciana Midaglia, Angela VidaljordanaAbstract:The prognostic role of cerebrospinal fluid molecular biomarkers determined in early pathogenic stages of multiple sclerosis has yet to be defined. In the present study, we aimed to investigate the prognostic value of chitinase 3 like 1 (CHI3L1), neurofilament light chain, and oligoclonal bands for conversion to Clinically Isolated Syndrome and to multiple sclerosis in 75 patients with radiologically Isolated Syndrome. Cerebrospinal fluid levels of CHI3L1 and neurofilament light chain were measured by enzyme-linked immunosorbent assay. Uni- and multivariable Cox regression models including as covariates age at diagnosis of radiologically Isolated Syndrome, number of brain lesions, sex and treatment were used to investigate associations between cerebrospinal fluid CHI3L1 and neurofilament light chain levels and time to conversion to Clinically Isolated Syndrome and multiple sclerosis. Neurofilament light chain levels and oligoclonal bands were independent risk factors for the development of Clinically Isolated Syndrome (hazard ratio = 1.02, P = 0.019, and hazard ratio = 14.7, P = 0.012, respectively) and multiple sclerosis (hazard ratio = 1.03, P = 0.003, and hazard ratio = 8.9, P = 0.046, respectively). The best cut-off to classify cerebrospinal fluid neurofilament light chain levels into high and low was 619 ng/l, and high neurofilament light chain levels were associated with a trend to shorter time to Clinically Isolated Syndrome (P = 0.079) and significant shorter time to multiple sclerosis (P = 0.017). Similarly, patients with radiologically Isolated Syndrome presenting positive oligoclonal bands converted faster to Clinically Isolated Syndrome and multiple sclerosis (P = 0.005 and P = 0.008, respectively). The effects of high neurofilament light chain levels shortening time to Clinically Isolated Syndrome and multiple sclerosis were more pronounced in radiologically Isolated Syndrome patients with ≥37 years compared to younger patients. Cerebrospinal fluid CHI3L1 levels did not influence conversion to Clinically Isolated Syndrome and multiple sclerosis in radiologically Isolated Syndrome patients. Overall, these findings suggest that cerebrospinal neurofilament light chain levels and oligoclonal bands are independent predictors of clinical conversion in patients with radiologically Isolated Syndrome. The association with a faster development of multiple sclerosis reinforces the importance of cerebrospinal fluid analysis in patients with radiologically Isolated Syndrome.
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diagnostic and prognostic value of the cerebrospinal fluid concentration of immunoglobulin free light chains in Clinically Isolated Syndrome with conversion to multiple sclerosis
PLOS ONE, 2015Co-Authors: G S Makshakov, Vladimir Nazarov, Olga Kochetova, E A Surkova, S V Lapin, E P EvdoshenkoAbstract:Background and objective In this study, we evaluated the diagnostic and prognostic significance of cerebrospinal fluid free light chains (CSF FLC) at the time of Clinically Isolated Syndrome (CIS). Methods We compared FLC-parameters at the moment of CIS in patients with conversion to multiple sclerosis (MS) after 2 years (CIS-MS), patients who remained stable both Clinically and radiologically after 2 years (CIS-nonMS), patients with non-inflammatory neurologic diseases (NIND) as a comparison group and patients with other inflammatory neurologic diseases (IND) with intrathecal oligoclonal bands (OCB) synthesis. ROC-analysis was conducted to define FLC-assay characteristics and cut-off values. We also compared FLC-concentrations in CIS patients to determine their OCB-status. A correlation analysis was performed between FLC-concentrations and the expanded disability scale score (EDSS), annualized relapse rate (ARR) and MRI-activity (i.e., number of new and gadolinium-enhancing (Gd+) lesions) in patients. Results The levels of kappa-FLC (k-FLCCSF) and lambda-FLC (λ-FLCCSF) as well as kappa- and lambda-quotients (Q-k and Q-λ) were elevated in CIS-MS compared to the CIS-nonMS and NIND groups. These levels did not differ significantly when compared with the IND group. We identified several patients with high k-FLCCSF and λ-FLCCSF in OCB-negative CIS and IND groups. The level of k-FLCCSF production was significantly higher in OCB-positive patients in the CIS-MS group compared to the CIS-nonMS group. The concentrations of k-FLCCSF and Q-k in the CIS-MS group showed significant correlation with the level of EDSS after 2 years (k-FLC: r = 0.4477,p = 0.0016; Q-k: r = 0.4621, p = 0.0016). λ-FLCCSF and Q-λ inversely correlated with the number of Gd+ lesions (CSF λ-FLC: r = -0.3698, p = 0.0223; Q-λ: r = -0.4527, p = 0.0056). Conclusion The concentration of CSF FLC predicts conversion to MS within 2 years following CIS. OCB-positive patients with an early conversion have a higher concentration of CSF-FLC. We have also shown a prognostic significance of k-FLCCSF for future EDSS-progression.
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DIAGNOSTIC AND PROGNOSTIC SIGNIFICANCE OF INTRATHECAL SYNTHESIS OF IMMUNOGLOBULIN FREE LIGHT CHAINS IN MULTIPLE SCLEROSIS
SPb RAACI, 2015Co-Authors: V. D. Nazarov, G S Makshakov, E A Surkova, S V Lapin, E P Evdoshenko, Areg A. TotolianAbstract:Increased intrathecal synthesis and oligoclonal banding of immunoglobulins (Ig) in cerebrospinal fluid (CSF) are major immunological findings in multiple sclerosis. Free light chains are fragments of Ig molecules that are produced in parallel to oligoclonal Ig, and their production reflects total Ig synthesis within central nervous system. Assessment of intrathecal kappaand lambda free light chain production within CNS compartment will help to improve diagnosis and prediction of outcomes in multiple sclerosis. Concentrations of kappa and lambda free light chains and clonality of immunoglobulin pattern synthesis were studied in paired CSF and serum samples of 151 patients, including 92 patients with multiple sclerosis, and 33 patients with Clinically Isolated Syndrome which later was transformed into the definite multiple sclerosis. A control group consisted of 26 patients with other inflammatory diseases of central nervous system. Several Ig parameters have been determined in the patients, i.e., Ig clonality in CSF; concentrations of free light chains (both kappaand lambda-) in CSF; as well as their indexes and ratios. It was established that synthesis of kappa free light chains were significantly elevated in patients with multiple sclerosis. Moreover, the amounts of free light Ig chains in patients with positive oligoclonality test were significantly higher than in cases without intrathecal oligoclonal synthesis. With respect to diagnostic significance, the kappa quotient proved the best available option for diagnosis of multiple sclerosis. Its combination with Ig oligoclonality assays caused a decrease in false-negative diagnostics by 42%. Diagnostic benefit of the kappa quotient could be also confirmed by the data of ROC analysis. Also concentration of lambda free light chains in cerebrospinal fluid showed a negative correlation with conversion terms of Clinically Isolated Syndrome to evident multiple sclerosis. Therefore, the indexes of free Ig light chains enables more precise diagnostics, like as more efficient severity evaluation of multiple sclerosis
Richard A L Macdonell - One of the best experts on this subject based on the ideXlab platform.
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internal jugular and vertebral vein volume flow in patients with Clinically Isolated Syndrome or mild multiple sclerosis and healthy controls results from a prospective sonographer blinded study
Phlebology, 2014Co-Authors: Brian R Chambers, Jayne Chambers, Heather Cameron, Leonid Churilov, Richard A L MacdonellAbstract:Objectives & Methods:We evaluated internal jugular vein and vertebral vein volume flow using ultrasound, in patients with Clinically Isolated Syndrome or mild multiple sclerosis and controls, to determine whether volume flow was different between the two groups.Results:In patients and controls, internal jugular vein volume flow increased from superior to inferior segments, consistent with recruitment from collateral veins. Internal jugular vein and vertebral vein volume flow were greater on the right in supine and sitting positions. Internal jugular vein volume flow was higher in the supine posture. Vertebral vein volume flow was higher in the sitting posture. Regression analyses of cube root transformed volume flow data, adjusted for supine/sitting, right/left and internal jugular vein/vertebral vein, revealed no significant difference in volume flow in patients compared to controls.Conclusions:Our findings further refute the concept of venous obstruction as a causal factor in the pathogenesis of multipl...
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internal jugular and vertebral vein volume flow in patients with Clinically Isolated Syndrome or mild multiple sclerosis and healthy controls results from a prospective sonographer blinded study
Phlebology, 2014Co-Authors: Brian R Chambers, Jayne Chambers, Heather Cameron, Leonid Churilov, Richard A L MacdonellAbstract:Objectives & Methods:We evaluated internal jugular vein and vertebral vein volume flow using ultrasound, in patients with Clinically Isolated Syndrome or mild multiple sclerosis and controls, to de...
S V Lapin - One of the best experts on this subject based on the ideXlab platform.
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neurofilament light chain and oligoclonal bands are prognostic biomarkers in radiologically Isolated Syndrome
Brain, 2018Co-Authors: Clara Matuteblanch, G S Makshakov, Vladimir Nazarov, S V Lapin, E P Evdoshenko, Luisa M Villar, Jose C Alvarezcermeno, Konrad Rejdak, Luciana Midaglia, Angela VidaljordanaAbstract:The prognostic role of cerebrospinal fluid molecular biomarkers determined in early pathogenic stages of multiple sclerosis has yet to be defined. In the present study, we aimed to investigate the prognostic value of chitinase 3 like 1 (CHI3L1), neurofilament light chain, and oligoclonal bands for conversion to Clinically Isolated Syndrome and to multiple sclerosis in 75 patients with radiologically Isolated Syndrome. Cerebrospinal fluid levels of CHI3L1 and neurofilament light chain were measured by enzyme-linked immunosorbent assay. Uni- and multivariable Cox regression models including as covariates age at diagnosis of radiologically Isolated Syndrome, number of brain lesions, sex and treatment were used to investigate associations between cerebrospinal fluid CHI3L1 and neurofilament light chain levels and time to conversion to Clinically Isolated Syndrome and multiple sclerosis. Neurofilament light chain levels and oligoclonal bands were independent risk factors for the development of Clinically Isolated Syndrome (hazard ratio = 1.02, P = 0.019, and hazard ratio = 14.7, P = 0.012, respectively) and multiple sclerosis (hazard ratio = 1.03, P = 0.003, and hazard ratio = 8.9, P = 0.046, respectively). The best cut-off to classify cerebrospinal fluid neurofilament light chain levels into high and low was 619 ng/l, and high neurofilament light chain levels were associated with a trend to shorter time to Clinically Isolated Syndrome (P = 0.079) and significant shorter time to multiple sclerosis (P = 0.017). Similarly, patients with radiologically Isolated Syndrome presenting positive oligoclonal bands converted faster to Clinically Isolated Syndrome and multiple sclerosis (P = 0.005 and P = 0.008, respectively). The effects of high neurofilament light chain levels shortening time to Clinically Isolated Syndrome and multiple sclerosis were more pronounced in radiologically Isolated Syndrome patients with ≥37 years compared to younger patients. Cerebrospinal fluid CHI3L1 levels did not influence conversion to Clinically Isolated Syndrome and multiple sclerosis in radiologically Isolated Syndrome patients. Overall, these findings suggest that cerebrospinal neurofilament light chain levels and oligoclonal bands are independent predictors of clinical conversion in patients with radiologically Isolated Syndrome. The association with a faster development of multiple sclerosis reinforces the importance of cerebrospinal fluid analysis in patients with radiologically Isolated Syndrome.
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diagnostic and prognostic value of the cerebrospinal fluid concentration of immunoglobulin free light chains in Clinically Isolated Syndrome with conversion to multiple sclerosis
PLOS ONE, 2015Co-Authors: G S Makshakov, Vladimir Nazarov, Olga Kochetova, E A Surkova, S V Lapin, E P EvdoshenkoAbstract:Background and objective In this study, we evaluated the diagnostic and prognostic significance of cerebrospinal fluid free light chains (CSF FLC) at the time of Clinically Isolated Syndrome (CIS). Methods We compared FLC-parameters at the moment of CIS in patients with conversion to multiple sclerosis (MS) after 2 years (CIS-MS), patients who remained stable both Clinically and radiologically after 2 years (CIS-nonMS), patients with non-inflammatory neurologic diseases (NIND) as a comparison group and patients with other inflammatory neurologic diseases (IND) with intrathecal oligoclonal bands (OCB) synthesis. ROC-analysis was conducted to define FLC-assay characteristics and cut-off values. We also compared FLC-concentrations in CIS patients to determine their OCB-status. A correlation analysis was performed between FLC-concentrations and the expanded disability scale score (EDSS), annualized relapse rate (ARR) and MRI-activity (i.e., number of new and gadolinium-enhancing (Gd+) lesions) in patients. Results The levels of kappa-FLC (k-FLCCSF) and lambda-FLC (λ-FLCCSF) as well as kappa- and lambda-quotients (Q-k and Q-λ) were elevated in CIS-MS compared to the CIS-nonMS and NIND groups. These levels did not differ significantly when compared with the IND group. We identified several patients with high k-FLCCSF and λ-FLCCSF in OCB-negative CIS and IND groups. The level of k-FLCCSF production was significantly higher in OCB-positive patients in the CIS-MS group compared to the CIS-nonMS group. The concentrations of k-FLCCSF and Q-k in the CIS-MS group showed significant correlation with the level of EDSS after 2 years (k-FLC: r = 0.4477,p = 0.0016; Q-k: r = 0.4621, p = 0.0016). λ-FLCCSF and Q-λ inversely correlated with the number of Gd+ lesions (CSF λ-FLC: r = -0.3698, p = 0.0223; Q-λ: r = -0.4527, p = 0.0056). Conclusion The concentration of CSF FLC predicts conversion to MS within 2 years following CIS. OCB-positive patients with an early conversion have a higher concentration of CSF-FLC. We have also shown a prognostic significance of k-FLCCSF for future EDSS-progression.
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DIAGNOSTIC AND PROGNOSTIC SIGNIFICANCE OF INTRATHECAL SYNTHESIS OF IMMUNOGLOBULIN FREE LIGHT CHAINS IN MULTIPLE SCLEROSIS
SPb RAACI, 2015Co-Authors: V. D. Nazarov, G S Makshakov, E A Surkova, S V Lapin, E P Evdoshenko, Areg A. TotolianAbstract:Increased intrathecal synthesis and oligoclonal banding of immunoglobulins (Ig) in cerebrospinal fluid (CSF) are major immunological findings in multiple sclerosis. Free light chains are fragments of Ig molecules that are produced in parallel to oligoclonal Ig, and their production reflects total Ig synthesis within central nervous system. Assessment of intrathecal kappaand lambda free light chain production within CNS compartment will help to improve diagnosis and prediction of outcomes in multiple sclerosis. Concentrations of kappa and lambda free light chains and clonality of immunoglobulin pattern synthesis were studied in paired CSF and serum samples of 151 patients, including 92 patients with multiple sclerosis, and 33 patients with Clinically Isolated Syndrome which later was transformed into the definite multiple sclerosis. A control group consisted of 26 patients with other inflammatory diseases of central nervous system. Several Ig parameters have been determined in the patients, i.e., Ig clonality in CSF; concentrations of free light chains (both kappaand lambda-) in CSF; as well as their indexes and ratios. It was established that synthesis of kappa free light chains were significantly elevated in patients with multiple sclerosis. Moreover, the amounts of free light Ig chains in patients with positive oligoclonality test were significantly higher than in cases without intrathecal oligoclonal synthesis. With respect to diagnostic significance, the kappa quotient proved the best available option for diagnosis of multiple sclerosis. Its combination with Ig oligoclonality assays caused a decrease in false-negative diagnostics by 42%. Diagnostic benefit of the kappa quotient could be also confirmed by the data of ROC analysis. Also concentration of lambda free light chains in cerebrospinal fluid showed a negative correlation with conversion terms of Clinically Isolated Syndrome to evident multiple sclerosis. Therefore, the indexes of free Ig light chains enables more precise diagnostics, like as more efficient severity evaluation of multiple sclerosis