Publications by authors named "Lukas Sobisek"

20 Publications

  • Page 1 of 1

Acute Management Should Be Optimized in Patients with Less Specific Stroke Symptoms: Findings from a Retrospective Observational Study.

J Clin Med 2021 Mar 9;10(5). Epub 2021 Mar 9.

Department of Neurology, Comprehensive Stroke Center, Charles University Faculty of Medicine and University Hospital, Sokolská 581, CZ-500 05 Hradec Králové, Czech Republic.

Anterior circulation stroke (ACS) is associated with typical symptoms, while posterior circulation stroke (PCS) may cause a wide spectrum of less specific symptoms. We aim to assess the correlation between the initial presentation of acute ischemic stroke (AIS) symptoms and the treatment timeline. Using a retrospective, observational, single-center study, the set consists of 809 AIS patients treated with intravenous thrombolysis (IVT) and/or endovascular treatment (EVT). We investigate the impact of baseline clinical AIS symptoms and the affected vascular territory on recanalization times in patients treated with IVT only and EVT (±IVT). Regarding the IVT-only group, increasing the National Institutes of Health Stroke Scale (NIHSS) score on admission and speech difficulties are associated with shorter (by 1.59 ± 0.76 min per every one-point increase; = 0.036, and by 24.56 ± 8.42 min; = 0.004, respectively) and nausea/vomiting with longer (by 43.72 ± 13.13 min; = 0.001) onset-to-needle times, and vertigo with longer (by 8.58 ± 3.84 min; = 0.026) door-to-needle times (DNT). Regarding the EVT (±IVT) group, coma is associated with longer (by 22.68 ± 6.05 min; = 0.0002) DNT, anterior circulation stroke with shorter (by 47.32 ± 16.89 min; = 0.005) onset-to-groin time, and drooping of the mouth corner with shorter (by 20.79 ± 6.02 min; = 0.0006) door-to-groin time. Our results demonstrate that treatment is initiated later in strokes with less specific symptoms than in strokes with typical symptoms.
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http://dx.doi.org/10.3390/jcm10051143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7963148PMC
March 2021

Comparison of Therapies in MS Patients After the First Demyelinating Event in Real Clinical Practice in the Czech Republic: Data From the National Registry ReMuS.

Front Neurol 2020 12;11:593527. Epub 2021 Jan 12.

Department of Neurology, Faculty of Medicine and University Hospital Hradec Králové, Charles University in Prague, Hradec Králové, Czechia.

Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease of the central nervous system. Well-established drugs used for MS patients after the first demyelinating event in the Czech Republic include glatiramer acetate (GA), interferon beta-1a (IFNβ-1a), IFN beta-1b (IFNβ-1b), peginterferon beta-1a (peg-IFNβ-1a), and teriflunomide. The objective of this observational study was to compare the effectiveness of the abovementioned drugs in patients with MS who initiated their therapy after the first demyelinating event. Patients were followed for up to 2 years in real clinical practice in the Czech Republic. A total of 1,654 MS patients treated after the first demyelinating event and followed up for 2 years were enrolled. Evaluation parameters (endpoints) included the annualized relapse rate (ARR), time to next relapse, change in the Expanded Disability Status Scale (EDSS) score, and time of confirmed disease progression (CDP). When patients ended the therapy before the observational period, the reason for ending the therapy among different treatments was compared. No significant difference was found among the groups of patients treated with IFNβ-1a/1b, GA, or teriflunomide for the following parameters: time to the first relapse, change in the EDSS score, and the proportion of patients with CDP. Compared to IFNβ-1a (44 mcg), a significant increase in the percentage of relapse-free patients was found for GA, but this treatment effect was not confirmed by the validation analysis. Compared to the other drugs, there was a significant difference in the reasons for terminating GA therapy. Small differences were found among GA, IFNβ and teriflunomide therapies, with no significant impact on the final outcome after 2 years. Therefore, in clinical practice, we recommend choosing the drug based on individual potential risk from long-term therapy and on patient preferences and clinical characteristics.
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http://dx.doi.org/10.3389/fneur.2020.593527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835499PMC
January 2021

Interpretation of Brain Volume Increase in Multiple Sclerosis.

J Neuroimaging 2021 Mar 13;31(2):401-407. Epub 2020 Dec 13.

Department of Radiology, First Faculty of Medicine, Charles University and General, University Hospital in Prague, Prague, Czech Republic.

Background And Purpose: A high variability of brain MRI volume change measurement renders challenging its interpretation in multiple sclerosis (MS). Occurrence and clinical relevance of observed apparent brain volume increase (BVI) in MS patients have not been investigated yet. The objective was to quantify the prevalence and factors associated with BVI.

Methods: We examined 366 MS patients (2,317 scans) and 44 controls (132 scans). Volumetric analysis of brain volume changes was performed by SIENA and ScanView. BVI was defined as brain volume change >0%. We compared characteristics of patients with and without BVI.

Results: BVI was found in 26.3% (from 1,951) longitudinal scans (SIENA). If BVI occurred, a probability that BVI will be repeated consecutively more than or equal to two times was 15.9%. The repeated BVI was associated with clinical disease activity in 50% of cases. BVI was associated with shorter time and lower T2 lesion volume increase between two MRI scans, and higher normalized brain volume (all P < .0001). A proportion of scans with BVI was higher when analyzed by ScanView (35.3%) and in controls (36.4% by SIENA).

Conclusions: BVI occurs in a great proportion of MR scans over short-term follow-up and is not associated with disease stabilization. Although BVI can be caused by several factors, the results indicate that measurement error may contribute to BVI in the majority of cases. Clinicians should be aware of the frequent occurrence of apparent BVI, interpret brain volume changes in MS patients with great caution, and use methods with precise quantification of brain volume changes.
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http://dx.doi.org/10.1111/jon.12816DOI Listing
March 2021

The role of the immune system and the biomarker CD3 + CD4 + CD45RA-CD62L- in the pathophysiology of migraine.

Sci Rep 2020 07 23;10(1):12277. Epub 2020 Jul 23.

Department of Neurology, Faculty of Medicine, University Hospital Hradec Králové, Charles University, Sokolská 581, Prague, Hradec Králové, 500 05, Czech Republic.

The role of the immune system as an integral component of the inflammatory response in the pathophysiology of migraine remains unclear. The aim of this study was to evaluate the differences in immune system parameters (acquired immunity parameters) in patients with episodic migraine (EM) and in healthy controls. In EM patients, we aimed to determine whether the changes found in peripheral blood parameters were related to migraine severity according to the standardised MIDAS and HIT-6 tests. Forty-nine patients with EM and 50 healthy controls were included in this study. The authors compared different lymphocyte parameters obtained by multicolor flow cytometry in the EM and control groups by performing statistical tests. The relationship between the changes in peripheral blood parameters and migraine severity in EM patients was investigated using correlation and regression analysis. EM patients showed higher values than healthy controls, especially in nine parameters: relative count of lymphocytes, relative and absolute counts of CD3 T cells, relative and absolute counts of CD8 suppressor cytotoxic T cells, relative and absolute counts of CD4 + T (terminally differentiated helper T lymphocytes), absolute count of CD8 naïve T cells, and absolute count of CD19 switched memory B cells. Among the lymphocyte parameters, CD4 + T (effector memory helper T lymphocytes) and CD8 + T (terminally differentiated cytotoxic T lymphocytes) were statistically significantly associated with HIT-6. Patients with a CD4 + T value below 15 had a high probability (90%) that the HIT-6 value would be higher than 60. The results of this study show that EM patients have changes in immune system parameters measured in the peripheral blood. Changes in the abundance of CD4 + T could be used as a biomarker for disease severity.
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http://dx.doi.org/10.1038/s41598-020-69285-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7378179PMC
July 2020

Innate Immune System and Multiple Sclerosis. Granulocyte Numbers Are Reduced in Patients Affected by Relapsing-Remitting Multiple Sclerosis during the Remission Phase.

J Clin Med 2020 May 14;9(5). Epub 2020 May 14.

Department of Neurology, Faculty of Medicine and University Hospital Hradec Králové, Charles University in Prague, Sokolská 581, 500 05 Hradec Kralove, Czech Republic.

Background: Multiple sclerosis (MS) is a neurodegenerative disease that affects the central nervous system. The cause of MS is still unknown, and the role of innate immunity is still poorly understood.

Objective: The goal of this study was to understand whether, compared to healthy controls, the elements of innate immunity are altered in the blood of MS patients in the remitting phase.

Methods: A total of 77 naïve MS patients and 50 healthy controls were included in this cohort study. Peripheral blood samples were collected and analyzed. All the calculations were performed with the statistical system R (r-project.org).

Results: The results showed that MS patients had significantly lower relative representations of granulocytes than healthy controls, while the relative representations of monocytes remained unchanged. CD64- and PD-L1-positive granulocytes exhibited a nonsignificant decreasing trend, while granulocytes with other membrane markers remained noticeably unchanged.

Conclusion: The results of this study suggest that studies of the causes of MS and its treatment should also be focused on the elements of the innate immune response.
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http://dx.doi.org/10.3390/jcm9051468DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7290702PMC
May 2020

Additive Effect of Spinal Cord Volume, Diffuse and Focal Cord Pathology on Disability in Multiple Sclerosis.

Front Neurol 2019 6;10:820. Epub 2019 Aug 6.

Department of Radiology, Charles University in Prague, 1st Faculty of Medicine and General University Hospital, Prague, Czechia.

Spinal cord (SC) pathology is strongly associated with disability in multiple sclerosis (MS). We aimed to evaluate the association between focal and diffuse SC abnormalities and spinal cord volume and to assess their contribution to physical disability in MS patients. This large sample-size cross-sectional study investigated 1,249 patients with heterogeneous MS phenotypes. Upper cervical-cord cross-sectional area (MUCCA) was calculated on an axial 3D-T2w-FatSat sequence acquired at 3T using a novel semiautomatic edge-finding tool. SC images were scored for the presence of sharply demarcated hyperintense areas (focal lesions) and homogenously increased signal intensity (diffuse changes). Patients were dichotomized according EDSS in groups with mild (EDSS up to 3.0) and moderate (EDSS ≥ 3.5) physical disability. Analysis of covariance was used to identify factors associated with dichotomized MUCCA. In binary logistic regression, the SC imaging parameters were entered in blocks to assess their individual contribution to risk of moderate disability. In order to assess the risk of combined SC damage in terms of atrophy lesional pathology on disability, secondary analysis was carried out where patients were divided into four categories (SC phenotypes) according to median dichotomized MUCCA and presence/absence of focal and/or diffuse changes. MUCCA was strongly associated with total intracranial volume, followed by presence of diffuse SC pathology, and disease duration. Compared to the reference group (normally appearing SC, MUCCA>median), patients with the most severe SC changes (SC affected with focal and/or diffuse lesions, MUCCA
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http://dx.doi.org/10.3389/fneur.2019.00820DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6691803PMC
August 2019

One-Year Results of Fixed Aflibercept Treatment Regime in Type 3 Neovascularization.

Ophthalmologica 2020 23;243(1):58-65. Epub 2019 May 23.

Department of Ophthalmology, University Vita-Salute, IRCCS Ospedale San Raffaele, Milan, Italy,

Purpose: To evaluate the effect of intravitreal aflibercept injections in treatment-naive type 3 neovascularization using a fixed treatment regime during the first year of therapy.

Methods: Fourteen eyes of 14 patients diagnosed with type 3 neovascularization were studied. All patients were treated with intravitreal aflibercept injections using a fixed treatment regime of 3 consecutive monthly dosages followed by 2-month interval injections. Results were assessed after a 12-month follow-up period. Changes of best corrected visual acuity (BCVA), central retinal thickness (CRT), central macular volume (CMV), and retinal pigment epithelium (RPE) atrophy at fundus autofluorescence and infrared reflectance images were recorded and analyzed.

Results: BCVA improved from 60.3 ± 11.7 ETDRS letters at the baseline to 70.9 ± 10.3 ETDRS letters at 12-months follow-up (p = 0.036). Also, CRT and CMV statistically improved after the treatment (from 425 ± 117 to 308 ± 117 µm [p = 0.031] and from 9.52 ± 1.90 to 8.29 ± 0.95 mm3 [p = 0.073], respectively). In 4 patients, development and progression of RPE atrophy were observed, and it was associated with the presence of serous pigment epithelium detachment at the baseline. Furthermore, the development of a fibrotic lesion eccentric to the fovea was observed in 5 patients, without significant impairment of BCVA (p = 0.290).

Conclusion: Intravitreal aflibercept administered in a fixed treatment regime during the first year of therapy may be effective for the improvement and stabilization of BCVA in eyes with type 3 neovascularization. However, RPE atrophy and subretinal/intraretinal fibrosis can develop during the treatment.
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http://dx.doi.org/10.1159/000499719DOI Listing
November 2020

CD4+/CD45RO+: A Potential Biomarker of the Clinical Response to Glatiramer Acetate.

Cells 2019 05 15;8(5). Epub 2019 May 15.

Department of Neurology, Faculty of Medicine and University Hospital Hradec Králové, Charles University in Prague, Sokolská 581, 500 05 Hradec Králové, Czech Republic.

: Glatiramer acetate (GA) is an effective treatment for the earliest stages of multiple sclerosis (MS)-clinically isolated syndrome (CIS) or clinically definite MS (CDMS). Objective: This study aims to determine the differences in the lymphocyte population (at baseline and the course of five years) between confirmed sustained progression (CSP) and non-CSP groups and to identify potential biomarkers among these parameters that can predict a positive response to the treatment. : Twelve male and 60 female patients were included in the study. Peripheral blood samples were collected before and five years after treatment with GA. The authors compared lymphocyte parameters between the CSP and non-CSP groups by statistical analyses. Univariate and penalized logistic regression models were fitted to identify the best lymphocyte parameters at baseline and their combination for potential biomarkers. Subsequently, the ROC analysis was used to identify cut-offs for selected parameters. : The parameter CD4+/CD45RO+ was identified as the best single potential biomarker, demonstrating the ability to identify patients with CSP. Moreover, a combination of four lymphocyte parameters at baseline, relative lymphocyte counts, CD3+/CD69+, CD4+/CD45RO+, and CD4+/CD45RA+ab, was identified as a potential composite biomarker. This combination explains 23% of the variability in CSP, which is better than the best univariate parameter when compared to CD4+/CD45RO+ at baseline. : The results suggest that other biomarkers can help monitor the conditions of patients and predict a favourable outcome.
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http://dx.doi.org/10.3390/cells8050456DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562382PMC
May 2019

Do eyes with and without optic neuritis in multiple sclerosis age equally?

Neuropsychiatr Dis Treat 2018 5;14:2281-2285. Epub 2018 Sep 5.

Center of Clinical Neuroscience, Department of Neurology, General University Hospital, 1st Faculty of Medicine, Charles University, Prague Czech Republic,

Purpose: Anterior visual pathway reflects axonal loss caused by both optic neuritis (ON) and neurodegeneration in multiple sclerosis (MS). Although the axonal injury post-ON is thought to be complete by 6 months of onset, most studies using optical coherence tomography (OCT) to evaluate retinal changes as a marker of neurodegeneration exclude eyes with a history of ON or consider them separately. The objective of this study was to assess whether the eyes post-ON (>6 months) show in later years different rate of chronic retinal changes than the fellow eyes not affected by ON.

Patients And Methods: Fifty-six patients with MS with a history of ON in one eye (ON eyes) and no ON in the fellow (FL) eye, who were followed by OCT for >2 years, were selected from a cohort of patients with MS. Paired eye analysis was performed.

Results: Mean interval post-ON at baseline was 5.65 (SD 5.05) years. Mean length of follow-up by OCT was 4.57 years. There was no statistical difference in absolute or relative thinning of retinal nerve fiber layer in peripapillary area between the ON and FL eyes.

Conclusion: This study has shown that we do not need to exclude eyes with a history of ON from longitudinal studies of neurodegeneration in MS, provided that we use data outside of the frame of acute changes post-ON. Long-term changes of peripapillary retinal nerve fiber layer in ON and FL eyes are equal.
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http://dx.doi.org/10.2147/NDT.S169638DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6130290PMC
September 2018

Lymphocyte populations and their change during five-year glatiramer acetate treatment.

Neurol Neurochir Pol 2018 Sep - Oct;52(5):587-592. Epub 2018 Aug 18.

Department of Neurology, Faculty of Medicine and University Hospital Hradec Králové, Charles University in Prague, Hradec Králové, Sokolská 581, 500 05, Czech Republic.

Background: The goal of this study was to determine the characteristics that are affected in patients treated with glatiramer acetate (GA).

Methods: A total of 113 patients were included in this study. Patients were treated with glatiramer acetate (subcutaneous injection, 20 mg, each day). Peripheral blood samples were obtained just prior to treatment as well as 5 years after GA treatment. All the calculations were performed with the statistical system R (r-project.org).

Results: After 5 years of treatment, a significant decrease was found in the absolute and relative CD3+/CD69+ counts, the absolute and relative CD69 counts, the relative CD8+/CD38+ count and the relative CD38 count. A significant increase was found in the absolute and relative CD5+/CD45RA+ counts and the absolute CD5+/CD45RO+ count after 5 years of treatment.

Conclusion: This study presents some parameters that were affected by long-term GA treatment.
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http://dx.doi.org/10.1016/j.pjnns.2018.08.001DOI Listing
June 2019

Combining clinical and magnetic resonance imaging markers enhances prediction of 12-year employment status in multiple sclerosis patients.

J Neurol Sci 2018 05 6;388:87-93. Epub 2018 Mar 6.

Department of Neurology and Center of Clinical Neuroscience, First Faculty of Medicine, Charles University and General University Hospital, Katerinska 30, 120 00 Prague, Czech Republic.

Background: Multiple sclerosis (MS) is frequently diagnosed in the most productive years of adulthood and is often associated with worsening employment status. However, reliable predictors of employment status change are lacking.

Objective: To identify early clinical and brain magnetic resonance imaging (MRI) markers of employment status worsening in MS patients at 12-year follow-up.

Methods: A total of 145 patients with early relapsing-remitting MS from the original Avonex-Steroids-Azathioprine (ASA) study were included in this prospective, longitudinal, observational cohort study. Cox models were conducted to identify MRI and clinical predictors (at baseline and during the first 12 months) of worsening employment status (patients either (1) working full-time or part-time with no limitations due to MS and retaining this status during the course of the study, or (2) patients working full-time or part-time with no limitations due to MS and switching to being unemployed or working part-time due to MS).

Results: In univariate analysis, brain parenchymal fraction, T1 and T2 lesion volume were the best MRI predictors of worsening employment status over the 12-year follow-up period. MS duration at baseline (hazard ratio (HR) = 1.10, 95% confidence interval (CI) 1.03-1.18; p = 0.040) was the only significant clinical predictor. Having one extra milliliter of T1 lesion volume was associated with a 53% greater risk of worsening employment status (HR = 1.53, 95% CI 1.16-2.02; p = 0.018). A brain parenchymal fraction decrease of 1% increased the risk of worsening employment status by 22% (HR = 0.78, 95% CI 0.65-0.95; p = 0.034).

Conclusion: Brain atrophy and lesion load were significant predictors of worsening employment status in MS patients. Using a combination of clinical and MRI markers may improve the early prediction of an employment status change over long-term follow-up.
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http://dx.doi.org/10.1016/j.jns.2018.02.045DOI Listing
May 2018

The Role of High-Frequency MRI Monitoring in the Detection of Brain Atrophy in Multiple Sclerosis.

J Neuroimaging 2018 05 27;28(3):328-337. Epub 2018 Feb 27.

Department of Radiodiagnostic, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic.

Background And Purpose: A relatively high intraindividual variability of longitudinal magnetic resonance imaging (MRI) of brain volume loss (BVL) measurements over time renders challenging its application to individual multiple sclerosis (MS) patients. Objective of this study was to investigate if high-frequency brain MRI monitoring affects identification of pathological BVL in an individual patient.

Methods: One hundred fifty-seven relapsing-remitting MS patients had seven MRI scans over 12 months follow-up. All 1,585 MRI scans were performed on the same 1.5T scanner using an identical scanning protocol. Volumetric analysis was performed by ScanView and SIENA software. Linear regression analysis was used for estimation of annualized BVL, with a cutoff greater than .4% defined as pathological. We compared proportions of patients with pathological BVL obtained by analysis of different number of MRI time-points.

Results: An analysis of seven MRI scans (months 0, 2, 4, 6, 8, 10, and 12) showed pathological BVL in 105 (65%) of patients. When three MRI scans were included (months 0, 6, and 12), we found 10 (6.4%) false negative and 9 (5.7%) false positive results compared with the analysis of seven MRI scans, used as a reference for assessment of pathological BVL. Analysis of two MRI time-points (months 0 and 12) showed 10 (6.4%) false negative and 13 (8.3%) false positive results compared with analysis of seven MRI time-points. Change in the accuracy of pathological BVL between results obtained by analysis of seven and two time-points was 14.7%.

Conclusions: High-frequency MRI monitoring may have a considerable effect on improving the precision of precisely identifying pathological BVL in individual patients. However, limitations in translation to clinical practice remain.
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http://dx.doi.org/10.1111/jon.12505DOI Listing
May 2018

Cognitive clinico-radiological paradox in early stages of multiple sclerosis.

Ann Clin Transl Neurol 2018 01 15;5(1):81-91. Epub 2017 Dec 15.

Department of Radiodiagnostic First Faculty of Medicine Charles University and General University Hospital in Prague Prague Czech Republic.

Objective: To investigate whether the strength of the association between magnetic resonance imaging (MRI) metrics and cognitive outcomes differs between various multiple sclerosis subpopulations.

Methods: A total of 1052 patients were included in this large cross-sectional study. Brain MRI (T1 and T2 lesion volume and brain parenchymal fraction) and neuropsychological assessment (Brief International Cognitive Assessment for Multiple Sclerosis and Paced Auditory Serial Addition Test) were performed.

Results: Weak correlations between cognitive domains and MRI measures were observed in younger patients (age≤30 years; absolute Spearman's rho = 0.05-0.21), with short disease duration (<2 years; rho = 0.01-0.21), low Expanded Disability Status Scale [EDSS] (≤1.5; rho = 0.08-0.18), low T2 lesion volume (lowest quartile; <0.59 mL; rho = 0.01-0.20), and high brain parenchymal fraction (highest quartile; >86.66; rho = 0.01-0.16). Stronger correlations between cognitive domains and MRI measures were observed in older patients (age>50 years; rho = 0.24-0.50), with longer disease duration (>15 years; rho = 0.26-0.53), higher EDSS (≥5.0; rho = 0.23-0.39), greater T2 lesion volume (highest quartile; >5.33 mL; rho = 0.16-0.32), and lower brain parenchymal fraction (lowest quartile; <83.71; rho = 0.13-0.46). The majority of these observed results were confirmed by significant interactions (≤0.01) using continuous variables.

Interpretation: The association between structural brain damage and functional cognitive impairment is substantially weaker in multiple sclerosis patients with a low disease burden. Therefore, disease stage should be taken into consideration when interpreting associations between structural and cognitive measures in clinical trials, research studies, and clinical practice.
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http://dx.doi.org/10.1002/acn3.512DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5771324PMC
January 2018

Pathological cut-offs of global and regional brain volume loss in multiple sclerosis.

Mult Scler 2019 04 16;25(4):541-553. Epub 2017 Nov 16.

Department of Neurology and Center of Clinical Neuroscience, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic.

Background: Volumetric MRI surrogate markers of disease progression are lacking.

Objective: To establish cut-off values of brain volume loss able to discriminate between healthy controls and MS patients.

Methods: In total, 386 patients after first demyelinating event suggestive of MS (CIS), 964 relapsing-remitting MS (RRMS) patients, 63 secondary-progressive MS (SPMS) patients and 58 healthy controls were included in this longitudinal study. A total of 11,438 MRI scans performed on the same MRI scanner with the same protocol were analysed. Annualised percentage changes of whole brain, grey matter, thalamus and corpus callosum volumes were estimated. We investigated cut-offs able to discriminate between healthy controls and MS patients.

Results: At a predefined specificity of 90%, the annualised percentage change cut-off of corpus callosum volume (-0.57%) was able to distinguish between healthy controls and patients with the highest sensitivity (51% in CIS, 48% in RRMS and 42% in SPMS patients). Lower sensitivities (22%-49%) were found for cut-offs of whole brain, grey matter and thalamic volume loss. Among CIS and RRMS patients, cut-offs were associated with greater accumulation of disability.

Conclusion: We identified cut-offs of annualised global and regional brain volume loss rates able to discriminate between healthy controls and MS patients.
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http://dx.doi.org/10.1177/1352458517742739DOI Listing
April 2019

Towards personalized therapy for multiple sclerosis: prediction of individual treatment response.

Brain 2017 Sep;140(9):2426-2443

Flinders Medical Centre, Flinders Drive, Adelaide, 5042, Australia.

Timely initiation of effective therapy is crucial for preventing disability in multiple sclerosis; however, treatment response varies greatly among patients. Comprehensive predictive models of individual treatment response are lacking. Our aims were: (i) to develop predictive algorithms for individual treatment response using demographic, clinical and paraclinical predictors in patients with multiple sclerosis; and (ii) to evaluate accuracy, and internal and external validity of these algorithms. This study evaluated 27 demographic, clinical and paraclinical predictors of individual response to seven disease-modifying therapies in MSBase, a large global cohort study. Treatment response was analysed separately for disability progression, disability regression, relapse frequency, conversion to secondary progressive disease, change in the cumulative disease burden, and the probability of treatment discontinuation. Multivariable survival and generalized linear models were used, together with the principal component analysis to reduce model dimensionality and prevent overparameterization. Accuracy of the individual prediction was tested and its internal validity was evaluated in a separate, non-overlapping cohort. External validity was evaluated in a geographically distinct cohort, the Swedish Multiple Sclerosis Registry. In the training cohort (n = 8513), the most prominent modifiers of treatment response comprised age, disease duration, disease course, previous relapse activity, disability, predominant relapse phenotype and previous therapy. Importantly, the magnitude and direction of the associations varied among therapies and disease outcomes. Higher probability of disability progression during treatment with injectable therapies was predominantly associated with a greater disability at treatment start and the previous therapy. For fingolimod, natalizumab or mitoxantrone, it was mainly associated with lower pretreatment relapse activity. The probability of disability regression was predominantly associated with pre-baseline disability, therapy and relapse activity. Relapse incidence was associated with pretreatment relapse activity, age and relapsing disease course, with the strength of these associations varying among therapies. Accuracy and internal validity (n = 1196) of the resulting predictive models was high (>80%) for relapse incidence during the first year and for disability outcomes, moderate for relapse incidence in Years 2-4 and for the change in the cumulative disease burden, and low for conversion to secondary progressive disease and treatment discontinuation. External validation showed similar results, demonstrating high external validity for disability and relapse outcomes, moderate external validity for cumulative disease burden and low external validity for conversion to secondary progressive disease and treatment discontinuation. We conclude that demographic, clinical and paraclinical information helps predict individual response to disease-modifying therapies at the time of their commencement.
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http://dx.doi.org/10.1093/brain/awx185DOI Listing
September 2017

A Novel Semiautomated Pipeline to Measure Brain Atrophy and Lesion Burden in Multiple Sclerosis: A Long-Term Comparative Study.

J Neuroimaging 2017 11 2;27(6):620-629. Epub 2017 May 2.

Department of Neurology, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY.

Background And Purpose: Lesion burden and brain volume changes are frequent end points in research but nowadays are becoming important in the clinical practice of multiple sclerosis (MS). The objective of this study was to investigate the correlation between magnetic resonance imaging (MRI) measures obtained by in-house developed ScanView software and commonly used volumetric techniques for assessment of T2 lesion and whole brain volumes and their changes.

Methods: Together 3,340 MRI scans from 209 patients after first demyelinating event suggestive of MS, 181 relapsing-remitting MS patients and 43 controls were analyzed. The average number of MRI scans and follow-up duration was 8.2 and 6.5 years, respectively. All MRI scans were performed in a single center but independently analyzed in two neuroimaging centers. Volumetric analysis by ScanView software was applied in Prague. Commonly used techniques, such as SIENA, SIENAX, and Jim software, were applied in Buffalo. Correlations between MRI measures were evaluated using correlation coefficients. Intraindividual variability of longitudinal MRI data was estimated by mean squared error.

Results: The associations of the cross-sectional and longitudinal MRI measures between commonly used techniques and ScanView were significant (r/rho = .83-.95). The associations of cross-sectional MRI measures were stronger (r/rho = .90-.95) compared with longitudinal ones (r = .83). Standardized intraindividual variability of whole brain % volume change was greater in ScanView compared with SIENA (mean squared error .32 vs. .21; P < .001).

Conclusions: We found relatively strong correlations of cross-sectional and longitudinal data obtained by both techniques. However, SIENA showed lower intraindividual variability than the ScanView method in measuring whole brain volume loss over time.
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http://dx.doi.org/10.1111/jon.12445DOI Listing
November 2017

Serum lipid profile changes predict neurodegeneration in interferon-β1a-treated multiple sclerosis patients.

J Lipid Res 2017 02 6;58(2):403-411. Epub 2016 Dec 6.

Department of Pharmaceutical Sciences, State University of New York, Buffalo, NY

The purpose of this work was to determine whether changes in cholesterol profiles after interferon-β (IFN-β)1a treatment initiation following the first demyelinating event suggestive of multiple sclerosis are associated with clinical and MRI outcomes over 4 years. A group of 131 patients (age: 27.9 ± 7.8 years, 63% female) with serial 3-monthly clinical and 12-monthly MRI follow-ups over 4 years were investigated. Serum cholesterol profiles, including total cholesterol (TC), HDL cholesterol (HDL-C), and LDL cholesterol (LDL-C) were obtained at baseline, 1 month, 3 months, and every 6 months thereafter. IFN-β1a initiation caused rapid decreases in serum HDL-C, LDL-C, and TC within 1 month of IFN-β1a initiation (all P < 0.001) that returned slowly toward baseline. In predictive mixed model analyses, greater percent decreases in HDL-C after 3 months of IFN-β1a treatment initiation were associated with less brain atrophy over the 4 year time course, as assessed by percent brain volume change (P < 0.001), percent gray matter volume change (P < 0.001), and percent lateral ventricle volume change (P = 0.005). Decreases in cholesterol biomarkers following IFN-β1a treatment are associated with brain atrophy outcomes over 4 years. Pharmacological interventions targeting lipid homeostasis may be clinically beneficial for disrupting neurodegenerative processes.
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http://dx.doi.org/10.1194/jlr.M072751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5282956PMC
February 2017

Quantification of Gait Abnormalities in Healthy-Looking Multiple Sclerosis Patients (with Expanded Disability Status Scale 0-1.5).

Eur Neurol 2016 6;76(3-4):99-104. Epub 2016 Aug 6.

Department of Neurology and Centre of Clinical Neuroscience, First School of Medicine and General University Hospital, Charles University in Prague, Prague, Czech Republic.

Background: Gait impairment is a common symptom in multiple sclerosis (MS) patients, but there is a lack of evidence about gait performance in the group of MS patients with no apparent disability. The aim of our study was to evaluate gait characteristics in MS patients with no apparent impairment of walking and with an Expanded Disability Status Scale (EDSS 0-1.5), and to determine whether any abnormalities are detectable by common clinical tests.

Methods: This was an observational study of 64 MS patients with an EDSS 0-1.5 and 47 age- and sex-matched healthy controls. We measured their performance in the timed 25-foot walk test (T25FWT) and the 2-minute walk test (2MWT). The spatiotemporal parameters of gait were measured using a GAITRite instrument.

Results: MS patients with no apparent disability (EDSS 0-1.5) performed worse in T25FWT and 2MWT than normal controls. During the self-selected walking speed test on GAITRite, MS patients had a prolonged double support phase, and during the fast walking speed test, they had lower cadence and decreased step length.
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http://dx.doi.org/10.1159/000448091DOI Listing
September 2017

Is no evidence of disease activity an achievable goal in MS patients on intramuscular interferon beta-1a treatment over long-term follow-up?

Mult Scler 2017 Feb 11;23(2):242-252. Epub 2016 Jul 11.

Department of Neurology and Center of Clinical Neuroscience, First Faculty of Medicine and General University Hospital, Charles University in Prague, Prague, Czech Republic.

Background: No evidence of disease activity (NEDA) has been proposed as a new treatment goal in multiple sclerosis (MS). NEDA-3 status is defined as the absence of magnetic resonance imaging (MRI; new/enlarging/enhancing lesions and increased whole brain volume loss in NEDA-4) and clinical disease activity.

Objectives: To investigate the persistence of NEDA status over long-term follow-up in MS patients treated with weekly intramuscular interferon beta-1a.

Methods: We included 192 patients after the first demyelinating event suggestive of MS, that is, clinically isolated syndrome (CIS) and 162 relapsing-remitting MS (RRMS) patients.

Results: NEDA-3 status was observed in 40.1% of CIS and 20.4% of RRMS patients after 1 year. After 4 years, 10.1% of CIS patients had NEDA-3 status. After 10 years, none of the RRMS patients had NEDA-3 status. Only 4.6% of CIS and 1.0% of RRMS patients maintained NEDA-4 status after 4 years. Loss of NEDA-3 status after the first year was associated with a higher risk of disability progression (hazard ratio (HR) = 2.3-4.0; p = 0.005-0.03) over 6 years.

Conclusions: Despite intramuscular interferon beta-1a treatment, loss of NEDA status occurred in the vast majority of individuals. Loss of NEDA status during the first year was associated with disability progression over long-term follow-up; however, specificity for individual patient was low.
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http://dx.doi.org/10.1177/1352458516650525DOI Listing
February 2017

Combining clinical and magnetic resonance imaging markers enhances prediction of 12-year disability in multiple sclerosis.

Mult Scler 2017 01 11;23(1):51-61. Epub 2016 Jul 11.

Department of Neurology and Center of Clinical Neuroscience, First Faculty of Medicine and General University Hospital, Charles University, Prague, Czech Republic.

Background: Disease progression and treatment efficacy vary among individuals with multiple sclerosis. Reliable predictors of individual disease outcomes are lacking.

Objective: To examine the accuracy of the early prediction of 12-year disability outcomes using clinical and magnetic resonance imaging (MRI) parameters.

Methods: A total of 177 patients from the original Avonex-Steroids-Azathioprine study were included. Participants underwent 3-month clinical follow-ups. Cox models were used to model the associations between clinical and MRI markers at baseline or after 12 months with sustained disability progression (SDP) over the 12-year observation period.

Results: At baseline, T2 lesion number, T1 and T2 lesion volumes, corpus callosum (CC), and thalamic fraction were the best predictors of SDP (hazard ratio (HR) = 1.7-4.6; p ⩽ 0.001-0.012). At 12 months, Expanded Disability Status Scale (EDSS) and its change, number of new or enlarging T2 lesions, and CC volume % change were the best predictors of SDP over the follow-up (HR = 1.7-3.5; p ⩽  0.001-0.017). A composite score was generated from a subset of the best predictors of SDP. Scores of ⩾4 had greater specificity (90%-100%) and were associated with greater cumulative risk of SDP (HR = 3.2-21.6; p < 0.001) compared to the individual predictors.

Conclusion: The combination of established MRI and clinical indices with MRI volumetric predictors improves the prediction of SDP over long-term follow-up and may provide valuable information for therapeutic decisions.
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http://dx.doi.org/10.1177/1352458516642314DOI Listing
January 2017