Seroprevalence of neuronal antibodies in diseases mimicking autoimmune encephalitis.

Detection of neuronal antibodies for autoimmune encephalitis and paraneoplastic neurological syndromes relies on commercially available cell-based assays and lineblots. However, lineblots may reveal the presence of neuronal antibodies in patients with various non-autoimmune etiologies. Herein we describe patients with non-autoimmune etiologies (cohort B) and detectable neuronal antibodies and compare them to definite cases of autoimmune encephalitis (cohort A) for differences in clinical data. All patients positive for at least one neuronal antibody were retrospectively evaluated for autoimmune encephalitis and/or paraneoplastic neurological syndrome between 2016 and 2022. 39 cases in cohort B and 23 in cohort A were identified. In cohort B, most common diagnoses were neurodegenerative disorders in 9/39 (23.1%), brain tumors in 6/39 (15.4%) while most common detected antibodies were anti-titin (N10), anti-recoverin (N11), anti-Yo (N8) and all were detected in serum only. Differential aspects between cohort A and B were CSF pleocytosis (14/23 (60.8%) vs 11/35 (31.4%), p = 0.042, respectively), MRI features suggestive of encephalitis (6/23 (26.1%) vs 0 (0%), p = 0.002, respectively) and epilepsy restricted to temporal lobes (14/23 (60.9%) vs 2/30 (6.7%), p = 0.0003, respectively). A large proportion of lineblot results were non-specific when only serum was tested and were frequently found in non-autoimmune neurological conditions.

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.

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.

Tumefactive demyelinating disorders as stroke mimics: Description of cases and systematic review of the literature.

BACKGROUND: tumefactive multiple sclerosis (TmMS) is a rare subtype of a demyelinating disease that develops over time. Cases of hyperacute presentations mimicking cerebrovascular disorders have been reported; however, detailed clinical and demographic data are lacking. METHODS: this study aimed to systematically review the literature on tumefactive demyelinating disorders presenting as strokes. After screening the PubMed, PubMed Central, and Web of Science databases, 39 articles describing 41 patients were identified, including 2 historical patients from our center. RESULTS: 23 (53.4%) patients were diagnosed with multiple sclerosis variants (vMS), 17 (39.5%) with inflammatory demyelinating variants (vInf), and 3 with tumors; however, only 43.5% of cases were verified histologically. In subgroup analysis, vMS differed from vInf in several aspects. Inflammatory cerebral spinal fluid parameters, including pleocytosis, proteinorachia was more commonly observed in vInf [11 (64.7%) vs. 1 (5.2%), P = 0.001 and 13/17 (76.4%) vs. 6/23 (31.5%), P = 0.02] than that in vMS. Neurological deterioration and fatal outcomes were more commonly observed in vInf [13/17 (76.4%) vs. 7/23 (30.4%), P = 0.003, and 11/17 (64.7%) vs. 0/23 (0%), P = 0.0001] than that in vMS. CONCLUSIONS: Clinicodemographic data might aid in recognizing different subtypes of TmMS and warrant consideration of unconventional therapies because outcomes may be poor in the vInf of TmMS.

Rapid and sustained B-cell depletion with subcutaneous ofatumumab in relapsing multiple sclerosis: APLIOS, a randomized phase-2 study.

BACKGROUND: Ofatumumab, the first fully human anti-CD20 monoclonal antibody, is approved in several countries for relapsing multiple sclerosis (RMS). OBJECTIVE: To demonstrate the bioequivalence of ofatumumab administered by an autoinjector versus a pre-filled syringe (PFS) and to explore the effect of ofatumumab on B-cell depletion. METHODS: APLIOS (NCT03560739) is a 12-week, open-label, parallel-group, phase-2 study in patients with RMS receiving subcutaneous ofatumumab 20 mg every 4 weeks (q4w) (from Week 4, after initial doses on Days 1, 7, and 14). Patients were randomized 10:10:1:1 to autoinjector or PFS in the abdomen, or autoinjector or PFS in the thigh, respectively. Bioequivalence was determined by area under the curve (AUCτ) and maximum plasma concentration (Cmax) for Weeks 8-12. B-cell depletion and safety/tolerability were assessed. RESULTS: A total of 256 patients contributed to the bioequivalence analyses (autoinjector-abdomen, n = 128; PFS-abdomen, n = 128). Abdominal ofatumumab pharmacokinetic exposure was bioequivalent for autoinjector and PFS (geometric mean AUCτ, 487.7 vs 474.1 h × µg/mL (ratio 1.03); Cmax, 1.409 vs 1.409 µg/mL (ratio 1.00)). B-cell counts (median cells/µL) depleted rapidly in all groups from 214.0 (baseline) to 2.0 (Day 14). Ofatumumab was well tolerated. CONCLUSION: Ofatumumab 20 mg q4w self-administered subcutaneously via autoinjector is bioequivalent to PFS administration and provides rapid B-cell depletion.

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.

Distinctive Pattern of Cognitive Disorders During Multiple Sclerosis Relapse and Recovery Based on Computerized CANTAB Tests.

Background: Cognition may be affected at least as seriously as physical function during multiple sclerosis (MS) relapse, however MS relapse related cognitive disorders are still underdiagnosed and poorly characterized. The limited number of paper-pencil tests were used for assessment, and nevertheless, some significant changes were found. Unlike the paper-pencil tests, computerized batteries and tests are more sensitive and highly standardized, produce instant scoring and can minimize the learning and practice effects on follow-up. We investigated the cognition during MS relapse with the Cambridge Neuropsychological Test Automated Battery (CANTAB), which has shown sensitivity to cognitive dysfunction across different clinical groups, including patients with MS. Objective: The objective of the study was to assess the cognitive functions with CANTAB battery in MS patients during relapse, in stable MS patients, and healthy controls, and to establish the timing and pattern of cognitive recovery after relapse. Methods: Sixty relapsing, thirty stable MS patients, and thirty controls were assessed with CANTAB. The relapse group was assessed during multiple sclerosis relapse and 1 and 3 months after the first assessment. Results: The score of the difficult task of spatial planning was worse in MS relapse group than in MS stable group (p < 0.05). The scores of medium difficulty tasks of spatial planning, episodic visual recall and working memory were worse in the relapse group than in the control group (p < 0.05), while in stable MS and control groups, the scores of these tasks didn't differ. The most significant improvement of speed of response, spatial planning, episodic visual recall memory and spatial working memory, was established at 1 month after the first assessment, additional improvement of spatial planning and working memory was observed at 3 months after the first assessment. Conclusions: The results of this study indicate that cognitive function is affected during MS relapse. The difficult task of CANTAB battery, which assesses the spatial planning, showed MS relapse related cognitive dysfunction. The changes in scores of episodic visual recall and working memory may be related to MS relapse. A significant improvement in the speed of response, spatial planning, episodic visual recall and working memory was established at 1 month after MS relapse. The additional improvement in spatial planning for the most difficult task and working memory was observed at 3 months after MS relapse. It may be possible that the practice effect had the impact on the improvement of cognitive scores that was noted in relapsing MS patients.

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.

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.

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.