Composite Marker of Cognitive Dysfunction and Brain Atrophy is Highly Accurate in Discriminating Between Relapsing-Remitting and Secondary Progressive Multiple Sclerosis.

BACKGROUND With the advent of numerous new-generation disease-modifying drugs for multiple sclerosis (MS), the discrimination between relapsing-remitting MS (RRMS) and secondary progressive MS (SPMS) has become a problem of high importance. The aim of our study was to find a simple way to accurately discriminate between RRMS and SPMS that is applicable in clinical practice as a composite marker, using the linear measures of magnetic resonance imaging (MRI) and the results of cognitive tests. MATERIAL AND METHODS We included 88 MS patients in the study: 43 participants had RRMS and 45 had SPMS. A battery consisting of 11 tests was used to evaluate cognitive function. We used 11 linear MRI measures and 7 indexes to assess brain atrophy. RESULTS Four cognitive tests and 3 linear MRI measures were able to distinguish RRMS from SPMS with the AUC >0.8 based on ROC analysis. Multiple logistic regression models were constructed to identify the best set of cognitive and MRI markers. The model, using the Rey Auditory Verbal Learning Test (RAVLT), Digit Symbol Substitution Test (DSST), and Huckman Index, showed the highest predictive ability: AUC=0.921 (p<0.001). We constructed a simple remission-progression index from the same 3 variables, which discriminated well between RRMS and SPMS: AUC=0.920 (p<0.001), maximal Youden Index=0.702, cut-off=1.68, sensitivity=79.1%, and specificity=91.1%. CONCLUSIONS The composite remission-progression index, using the RAVLT test, DSST test, and MRI Huckman Index, is highly accurate in discriminating between RRMS and SPMS.

The BICAMS Battery for Assessment of Lithuanian-Speaking Multiple Sclerosis Patients: Relationship with Age, Education, Disease Disability, and Duration.

BACKGROUND Assessment of cognitive impairment (CI) in multiple sclerosis (MS) patients is very useful, but it requires time-consuming expert evaluation with specialized materials. The Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) was created as a brief and specific instrument for the evaluation of CI. The aims of this study were to assess the cognitive status of MS patients by using the Lithuanian version of BICAMS, to evaluate the test-retest reliability of the Lithuanian version of BICAMS, and to measure the impact of CI on disability and duration of MS. MATERIAL AND METHODS We enrolled 50 MS patients and 20 cognitively normal control subjects, matched for age, gender, and level of education. Cognitive functions were assessed by the BICAMS tests, which include the Symbol Digit Modalities Test, the Brief Visuospatial Memory Test Revised, and the California Verbal Learning Test, 2nd edition. RESULTS MS patients performed significantly worse than controls on the 3 neuropsychological tests of BICAMS (p<0.001). Younger and intellectually employed persons performed significantly better on these tests than older persons, manual workers, or unemployed persons (p<0.05). MS patients with higher disability scores tended to perform worse on the tests (p<0.05), but we found no relationship between BICAMS test scores and the duration of the disease or relapse rate (p>0.05). Test-retest reliability was excellent for all 3 subtests (r>0.8, p<0.05). CONCLUSIONS Our study shows that BICAMS is a valid and acceptable cognitive assessment tool that can be recommended for routine use in Lithuania for assessing patients with MS.

Therapeutic Plasma Exchange in Multiple Sclerosis Patients with Abolished Interferon-beta Bioavailability.

BACKGROUND: Neutralizing antibodies (NAb) to interferon-beta (IFN-ß) are associated with reduced bioactivity and efficacy of IFN-ß in multiple sclerosis (MS). The myxovirus resistance protein A (MxA) gene expression is one of the most appropriate markers of biological activity of exogenous IFN-ß. We hypothesized that therapeutic plasma exchange (TPE) can restore the ability of IFN-ß to induce the MxA mRNA expression and that maintenance plasmapheresis can sustain the bioavailability of IFN-ß. MATERIAL AND METHODS: Eligible patients underwent 4 primary separate plasma exchange sessions. After the induction TPE sessions, they were transferred to maintenance plasmapheresis. Bioactivity of IFN-ß was expressed as in vivo MxA mRNA induction in whole blood using RT-qPCR. RESULTS: Six patients with low IFN-ß bioavailability detected by the MxA mRNA response were included. Four patients became biological responders after induction plasmapheresis. In 2 patients an increase of MxA mRNA expression was found, but the values persisted below the cut-off and the patients remained as "poor biological responders". The effect of maintenance plasmapheresis was transient: MxA mRNA expression values reverted to the baseline levels after 1-2 months. CONCLUSIONS: Therapeutic plasma exchange is able to restore the bioavailability of IFN-ß in the majority of studied patients, but the effect of TPE on the IFN-ß bioavailability was transient.

Belief in omens and superstitions among patients with chronic neurological disorders.

Introduction: Chronic neurological disorders may affect various cognitive processes, including religiosity or superstitious belief. We investigated whether superstitious beliefs are equally prevalent in patients with Parkinson's disease (PD), people with epilepsy (PWE), patients with multiple sclerosis (MS) and healthy controls (HCs). Methods: From late 2014 to early 2023 we conducted a cross-sectional in-person anonymous paper-based survey at the tertiary clinic of Vilnius University Hospital Santaros Klinikos among outpatients and HCs by asking them to ascribe meaning or report belief for 27 culturally adapted statements (9 omens and 18 superstitions). The sum of items that a respondent believes in was labeled the superstition index (SI). The SI was compared between groups by means of the Kruskal-Wallis (H) test and negative binomial regression modeling. A two-step cluster analysis was performed to discern different subgroups based on answers to the items of the SI. Results: There were 553 respondents who completed the questionnaire (183 PWE, 124 patients with PD, 133 with MS and 113 HCs). Complete SI scores were collected for 479 (86.6%) participants and they were lower in patients with PD (n = 96, Md = 1, IQR = 0-5.75) in comparison to those with epilepsy (n = 155, Md = 6, IQR = 1-14), MS (n = 120, Md = 4, IQR = 0-12) or HCs (n = 108, Md = 4.5, IQR = 1-10), H (3) = 26.780, p < 0.001. In a negative binomial regression model (n = 394, likelihood ratio χ2 = 35.178, p < 0.001), adjusted for sex, place of residence, income and education, female sex was the only characteristic associated with the SI (ß = 0.423, OR = 1.526, 95% CI = 1.148 to 2.028). Both female sex (ß = 0.422, OR = 1.525, 95% CI = 1.148 to 2.026) and Parkinson's disease (ß = -0.428, OR = 0.652, 95% CI = 0.432 to 0.984) were significant predictors of the SI when age was removed from the model. Two-step cluster analysis resulted in individuals with PD being grouped into "extreme non-believer," "non-believer" and "believer" rather than "non-believer" and "believer" clusters characteristic for PWE, patients with MS and HCs. Conclusion: Our study suggests that individuals with PD believe in less superstitions than patients with MS, PWE or HCs. The results of this investigation should be independently confirmed after adjusting for PD-specific variables.

Autologous hematopoietic stem cell transplantation is superior to alemtuzumab in patients with highly active relapsing multiple sclerosis and severe disability.

OBJECTIVE: To assess the differences of treatment outcomes regarding disease activity in patients with highly active relapsing multiple sclerosis (RMS), treated with autologous hematopoietic stem cell transplantation (HSCT) or alemtuzumab (ATZ). METHODS: Open-label prospective single-center observational cohort study, enrolling patients with highly active RMS for treatment with ATZ or HSCT between 2014 and 2021. RESULTS: A total of 50 patients (31/50 (62 %) in HSCT vs 19/50 (38 %) in ATZ group) were included. There were no significant differences in relapse rate, MRI activity or disability worsening between the two study groups during the first two years after treatment onset. However, at 3 to 5 years follow-up, HSCT was superior to ATZ in all the aforementioned aspects. Kaplan-Meier analysis at 5 years post treatment revealed superiority of HSCT in relapse rate (69.6 % vs 95.7 %, p = 0.027), MRI activity (54.5 % vs 75.1 %, p = 0.038) and disability worsening (57.1 % vs 90.9 %, p =  0.031). CONCLUSIONS: ATZ may halt disability progression early in the course of highly active RMS, but the disability starts accumulating later, while in HSCT patients disability improvement is consistent both 3 and 5 years after treatment onset.

Chronotypes and their relationship with depression, anxiety, and fatigue among patients with multiple sclerosis in Vilnius, Lithuania.

Background: Approximately half of patients with multiple sclerosis (PWMS) experience sleep disorders or changes in the circadian rhythm, that may further promote the pathogenesis of multiple sclerosis. As the prevalence of chronotypes among PWMS remains unclear, we aimed to evaluate the prevalence of chronotypes among Lithuanian PWMS; to assess the relationship of chronotypes with depression, anxiety, and fatigue symptoms; and to compare these results with those of healthy controls. Methods: We enrolled 101 PWMS and 100 healthy controls. We included 130 (64.7%) and 71 (35.3%) women and men, respectively. The median age of all respondents was 39 [interquartile range (IQR) 20.75] years. Participants were assessed using general questionnaire, Horne-Östberg Morningness-Eveningness Questionnaire (MEQ), Hospital Anxiety and Depression Scale (HADS), and Shortened Fatigue Questionnaire (SFQ). Chronotypes were identified based on the total MEQ score. Results: The average MEQ scores of the PWMS and control groups were 54 (IQR 15.0) and 53.5 (IQR 13), respectively, which indicated the intermediate chronotype. There was no significant between-group difference in the prevalence of chronotypes (p = 0.893). In both groups, individuals with moderate evening and intermediate chronotypes showed higher average HADS depression scores (p = 0.022). Further, in both groups, the individuals with the evening chronotype showed the highest average HADS anxiety scores (p = 0.001). The PWMS group had a higher average SFQ score than the control group (p < 0.001). High SFQ scores were more common among PWMS who had the intermediate (p < 0.001) and morning chronotypes (p = 0.011). The fatigue level was higher among healthy individuals with the evening chronotype (p < 0.001). Conclusion: The most common chronotype for PWMS and healthy controls was the intermediate chronotype. Further, in both groups, higher HADS depression and anxiety scores were associated with the evening chronotype. Fatigue was more commonly found in healthy controls with the evening, and in PWMS - with intermediate and morning chronotypes.

Cognitive Decline in Multiple Sclerosis Is Related to the Progression of Retinal Atrophy and Presence of Oligoclonal Bands: A 5-Year Follow-Up Study.

Background: Brain atrophy, which is associated with cognitive impairment and retinal nerve fiber layer (RNFL) atrophy, is the main biomarker of neurodegeneration in multiple sclerosis (MS). However, data on the relationship between inflammatory markers, such as oligoclonal bands (OCBs) in the cerebrospinal fluid (CSF), and cognition, RNFL atrophy, and brain atrophy are scarce. The aim of this study was to assess the influence of RNFL thickness, brain atrophy markers, intrathecal OCBs, and the immunoglobulin G (IgG) index on cognitive decline over a 5-year period in patients with MS. Methods: This prospective, single-center, observational cohort study included 49 patients with relapsing MS followed up over 5 years. At baseline, the patients underwent brain magnetic resonance imaging (MRI). Cognitive evaluation was performed using the Brief International Cognitive Assessment for MS (BICAMS), and RNFL thickness was assessed using optical coherence tomography (OCT). OCBs and IgG levels in the CSF were evaluated at baseline. The BICAMS, OCT, and MRI findings were re-evaluated after 5 years. Results: A significant reduction in information processing speed, visual learning, temporal RNFL thickness, the Huckman index, and third ventricle mean diameter was found in all 49 patients with relapsing MS over the observation period (p < 0.05). Of the patients, 63.3% had positive OCBs and 59.2% had elevated IgG indices. The atrophy of the temporal segment and papillomacular bundle and the presence of OCBs were significantly related to a decline in information processing speed in these patients (p < 0.05). However, brain atrophy markers were not found to be significant on the general linear models. Conclusions: RNFL atrophy and the presence of OCBs were related to cognitive decline in patients with MS over a 5-year follow-up period, thereby suggesting their utility as potential biomarkers of cognitive decline in MS.

Quantitative body symmetry assessment during neurological examination.

BACKGROUND: A lack of movement coordination characterized by the undershoot or overshoot of the intended location with the hand, arm, or leg is often found in individuals with multiple sclerosis (MS). Standardized as Finger-to-Nose (FNT) and The Heel-to-Shin (HST) tests are the most frequently used tests for qualitative examination of upper and lower body coordination. Inertial sensors facilitate in performing quantitative motion analysis and by estimating body symmetry more accurately assess coordination lesion and imbalance. OBJECTIVES: To assess the body symmetry of upper and lower limbs quantitatively, and to find the best body symmetry indices to discriminate MS from healthy individuals (CO). METHODS: 28 MS patients and 23 CO participated in the study. Spatiotemporal parameters obtained from six Inertial Measurement Units (IMUs) were placed on the upper and lower extremities during FNT and HST tests. All data were analyzed using statistical methods in MATLAB. RESULTS: Asymmetry indices of temporal parameters showed a significant increase in upper body and lower body asymmetry of MS compared to CO. However, CO have a greater kinematic asymmetry compared to MS. CONCLUSION: Temporal parameters are the most sensitive to body asymmetry evaluation. However, range of motion is completely inappropriate if it is calculated for one movement cycle.

Incidence rate and sex ratio in multiple sclerosis in Lithuania.

OBJECTIVES: To determine the temporal changes in incidence rates of multiple sclerosis (MS) over the past 15 years in Lithuania with prediction up to 2020, and to estimate female-to-male sex ratio and its changes among MS patients. MATERIALS AND METHODS: We conducted a descriptive incidence study. The crude incidence rates (CIR) were calculated using 15-year period, sex, age-groups, and the number of newly registered MS patients. Standardized incidence rates (SIR) were calculated using European standard in order to evaluate the influence of resident structure changes on incidence of MS during the last 15 years. The data were processed using Minitab set to estimate a linear trend model for the temporal changes of 16 parameters. RESULTS: The data showed a substantial growth of the incidence rate of MS in Lithuania during the period of 2001-2015. In 2001, MS was diagnosed to 162 new individuals, whereas 343 new cases of MS were diagnosed in 2015. During 2001-2015, the incidence of MS was on average 6.5 (95% CI 5.70-7.30) cases per 100,000 residents, and 4.9 (95% CI 4.46-5.34) and 8.1 (5.86-9.34) for 100,000 male and female, respectively. Female-to-male sex ratio in MS in Lithuania had a tendency to increase over the period. Females were affected from 1.5 to 2 times more often than males. CONCLUSIONS: In 2020, the incidence rate of MS is estimated to reach 13 cases per 100,000 persons and females are expected to be diagnosed with MS two times more often than males.

Cognition During and After Multiple Sclerosis Relapse as Assessed With the Brief International Cognitive Assessment for Multiple Sclerosis.

There is some evidence that cognition may be impaired during multiple sclerosis (MS) relapse. The aims of this study were to assess the cognitive status with the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) in MS patients during relapse, in stable patients, and in healthy controls; to evaluate cognitive changes up to 3 months after relapse; and to estimate the impact of different factors on cognition after relapse. BICAMS was performed in 60 relapsing, 30 stable patients and 30 controls. Relapsing MS patients were assessed during relapse and one and three months after relapse. SDMT score was lower in relapsing than in stable patients. The mean scores of all BICAMS tests were higher one month after relapse than during relapse (p < 0.001). SDMT score after relapse improved in younger patients, who had more severe relapse (p < 0.05). BVMT-R score improved more in men, in patients with biologically active interferon-beta, in patients treated with methylprednisolone and in patients who were rehabilitated (p < 0.05). CVLT-II score improved in women and in patients with shorter relapse (p < 0.05). A neuropsychological assessment, like the evaluation of physical disability, is important during relapse. BICAMS may be suitable for a quick and effective assessment of cognition during relapse.

Quantitative assessment of upper extremities motor function in multiple sclerosis.

BACKGROUND: Upper extremity (UE) motor function deficits are commonly noted in multiple sclerosis (MS) patients and assessing it is challenging because of the lack of consensus regarding its definition. Instrumented biomechanical analysis of upper extremity movements can quantify coordination with different spatiotemporal measures and facilitate disability rating in MS patients. OBJECTIVE: To identify objective quantitative parameters for more accurate evaluation of UE disability and relate it to existing clinical scores. METHODS: Thirty-four MS patients and 24 healthy controls (CG) performed a finger-to-nose test as fast as possible and, in addition, clinical evaluation kinematic parameters of UE were measured by using inertial sensors. RESULTS: Generally, a higher disability score was associated with an increase of several temporal parameters, like slower task performance. The time taken to touch their nose was longer when the task was fulfilled with eyes closed. Time to peak angular velocity significantly changed in MS patients (EDSS > 5.0). The inter-joint coordination significantly decreases in MS patients (EDSS 3.0-5.5). Spatial parameters indicated that maximal ROM changes were in elbow flexion. CONCLUSIONS: Our findings have revealed that spatiotemporal parameters are related to the UE motor function and MS disability level. Moreover, they facilitate clinical rating by supporting clinical decisions with quantitative data.

Detection of aquaporin-4 antibodies for patients with CNS inflammatory demyelinating diseases other than typical MS in Lithuania.

OBJECTIVES: Neuromyelitis optica (NMO) is frequently associated with aquaporin-4 autoantibodies (AQP4-Ab); however, studies of NMO in Lithuania are lacking. Therefore, the main objective of our study is to assess positivity for AQP4-Ab in patients presenting with inflammatory demyelinating central nervous system (CNS) diseases other than typical multiple sclerosis (MS) in Lithuania. MATERIALS AND METHODS: Data were collected from the two largest University hospitals in Lithuania. During the study period, there were 121 newly diagnosed typical MS cases, which were included in the MS registry database. After excluding these typical MS cases, we analyzed the remaining 29 cases of other CNS inflammatory demyelinating diseases, including atypical MS (n = 14), acute transverse myelitis, TM (n = 8), acute disseminated encephalomyelitis, ADEM (n = 3), clinically isolated syndrome, CIS (n = 2), atypical optic neuritis, ON (n = 1), and NMO (n = 1). We assessed positivity for AQP4-Ab for the 29 patients and evaluated clinical, laboratory, and instrumental differences between AQP4-Ab seropositive and AQP4-Ab seronegative patient groups. RESULTS: AQP4-Ab test was positive for three (10.3%) patients in our study, with initial diagnoses of atypical MS (n = 2) and ADEM (n = 1). One study patient was AQP4-Ab negative despite being previously clinically diagnosed with NMO. There were no significant clinical, laboratory, or instrumental differences between the groups of AQP4-Ab positive (3 [10.3%]) and negative (26 [89.7%]) patients. CONCLUSIONS: AQP4-Ab test was positive for one-tenth of patients with CNS inflammatory demyelinating diseases other than typical MS in our study. AQP4-Ab testing is highly recommended for patients presenting with not only TM and ON but also an atypical course of MS and ADEM.