Biomarkers of tau phosphorylation state are associated with the clinical course of multiple sclerosis.

BACKGROUND: Mechanisms underlying neurodegeneration in multiple sclerosis (MS) remain poorly understood but mostly implicate molecular pathways that are not unique to MS. Recently detected tau seeding activity in MS brain tissues corroborates previous neuropathological reports of hyperphosphorylated tau (p-tau) accumulation in secondary and primary progressive MS (PPMS). We aimed to investigate whether aberrant tau phosphorylation can be detected in the cerebrospinal fluid (CSF) of MS patients by using novel ultrasensitive immunoassays for different p-tau biomarkers. METHODS: CSF samples of patients with MS (n = 55) and non-inflammatory neurological disorders (NIND, n = 31) were analysed with in-house Single molecule array (Simoa) assays targeting different tau phosphorylation sites (p-tau181, p-tau212, p-tau217 and p-tau231). Additionally, neurofilament light (NFL) and glial fibrillary acidic protein (GFAP) were measured with a multiplexed Simoa assay. Patients were diagnosed with clinically isolated syndrome (CIS, n = 10), relapsing-remitting MS (RRMS, n = 21) and PPMS (n = 24) according to the 2017 McDonald criteria and had MRI, EDSS and basic CSF analysis performed at the time of diagnosis. RESULTS: Patients with progressive disease course had between 1.4-fold (p-tau217) and 2.2-fold (p-tau212) higher p-tau levels than relapsing MS patients (PPMS compared with CIS + RRMS, p < 0.001 for p-tau181, p-tau212, p-tau231 and p = 0.042 for p-tau217). P-tau biomarkers were associated with disease duration (ρ=0.466-0.622, p < 0.0001), age (ρ=0.318-0.485, p < 0.02, all but p-tau217) and EDSS at diagnosis and follow-up (ρ=0.309-0.440, p < 0.02). In addition, p-tau biomarkers correlated with GFAP (ρ=0.517-0.719, p ≤ 0.0001) but not with the albumin quotient, CSF cell count or NFL. Patients with higher MRI lesion load also had higher p-tau levels p ≤ 0.01 (<10 vs. ≥ 10 lesions, all p ≤ 0.01). CONCLUSION: CSF concentrations of novel p-tau biomarkers point to a higher degree of tau phosphorylation in PPMS than in RRMS. Associations with age, disease duration and EDSS suggest this process increases with disease severity; however, replication of these results in larger cohorts is needed to further clarify the relevance of altered tau phosphorylation throughout the disease course in MS.

Psychometric evaluation of the 5-item Medication Adherence Report Scale questionnaire in persons with multiple sclerosis.

The 5-item Medication Adherence Report Scale (MARS-5) is a reliable and valid questionnaire for evaluating adherence in patients with asthma, hypertension, and diabetes. Validity has not been determined in multiple sclerosis (MS). We aimed to establish criterion validity and reliability of the MARS-5 in persons with MS (PwMS). Our prospective study included PwMS on dimethyl fumarate (DMF). PwMS self-completed the MARS-5 on the same day before baseline and follow-up brain magnetic resonance imaging (MRI) 3 and 9 months after treatment initiation and were graded as highly and medium adherent upon the 24-cut-off score, established by receiver operator curve analysis. Health outcomes were represented by relapse occurrence from the 1st DMF dispense till follow-up brain MRI and radiological progression (new T2 MRI lesions and quantitative analysis) between baseline and follow-up MRI. Criterion validity was established by association with the Proportion of Days Covered (PDC), new T2 MRI lesions, and Beliefs in Medicines questionnaire (BMQ). The reliability evaluation included internal consistency and the test-retest method. We included 40 PwMS (age 37.6 ± 9.9 years, 75% women), 34 were treatment-naive. No relapses were seen during the follow-up period but quantitative MRI analysis showed new T2 lesions in 6 PwMS. The mean (SD) MARS-5 score was 23.1 (2.5), with 24 PwMS graded as highly adherent. The higher MARS-5 score was associated with higher PDC (b = 0.027, P<0.001, 95% CI: (0.0134-0.0403)) and lower medication concerns (b = -1.25, P<0.001, 95% CI: (-1.93-(-0,579)). Lower adherence was associated with increased number (P = 0.00148) and total volume of new T2 MRI lesions (P = 0.00149). The questionnaire showed acceptable internal consistency (Cronbach α = 0.72) and moderate test-retest reliability (r = 0.62, P < 0.0001, 95% CI: 0.33-0.79). The MARS-5 was found to be valid and reliable for estimating medication adherence and predicting medication concerns in persons with MS.

Medication persistence among people with multiple sclerosis in Slovenia treated with dimethyl fumarate.

Objective: Multiple sclerosis is a chronic, demyelinating inflammatory disease of the central nervous system. Medication persistence is defined as an interval between the initiation and last dose of the applied medication and presents a useful surrogate marker of a stable disease course. This observational study aimed to evaluate medication persistence and discontinuation reasons in Slovenian people with multiple sclerosis treated with dimethyl fumarate.Methods: Our retrospective cohort study evaluated people with relapsing-remitting multiple sclerosis treated with dimethyl fumarate as an initial monotherapy or switched from injectable disease-modifying therapy medication between 2014 and 2021. Medication dispenses were extracted from the Slovenian National Institute of Public Health Outpatient Medication Database. The medication persistence criterion was based on the treatment gap. Patients exceeding a 60-day gap were considered nonpersistent. The median time to discontinuation was assessed using survival analyses. Considering discontinuation reasons, patients were further divided into safety and inefficacy groups. Due to the high probability of adverse effects, patients exceeding a 60-day gap were included in the safety group, but definite discontinuation reason remains unknown. The impact of covariates was evaluated by Cox regression.Results: A total of 269 patients were included (183 women, mean age 37 years). During the 7-year follow-up period, 123 (45.7%) patients discontinued treatment. The median time to discontinuation was 5.6 years. After 1, 2, and 5 years of treatment, 84%, 77%, and 57% of patients were found to be persistent, respectively. All patients older than 30 years (p = 0.0013) and among them, those in the inefficacy group (p = 0.037) were more likely to be persistent.Conclusions: The results of our study proved a high persistence rate among our patients. The most frequent discontinuation reason was gastrointestinal adverse effects. Medication persistence requires interventions in younger patients with an unstable disease course.

Cladribine tablets in people with relapsing multiple sclerosis: A real-world multicentric study from southeast European MS centers.

BACKGROUND: Cladribine is an oral disease-modifying drug authorized by the European Medicine Agency for the treatment of highly active relapsing multiple sclerosis (MS). OBJECTIVES: To provide real-world evidence of cladribine's effectiveness and safety in people with MS (pwMS). METHODS: A retrospective observational multi-center, multi-national study of pwMS who were started on cladribine tablets in ten centers from five European countries. RESULTS: We identified 320 pwMS treated with cladribine tablets. The most common comorbidities were arterial hypertension and depression. Three patients had resolved hepatitis B infection, while eight had positive Quantiferon test prior to cladribine commencement. There were six pwMS who had malignant diseases, but all were non-active. During year 1, 91.6% pwMS did not have EDSS worsening, 86.9% were relapse-free and 72.9% did not have MRI activity. During the second year, 90.2% did not experience EDSS worsening, 86.5% were relapse-free and 75.5% did not have MRI activity. NEDA-3 was present in 58.0% pwMS in year 1 and in 54.2% in year 2. In a multivariable logistic regression model age positively predicted NEDA-3 in year 1. The most common adverse events were infections and skin-related adverse events. Lymphopenia was noted in 54.7% of pwMS at month 2 and in 35.0% at month 6. Two pwMS had a newly discovered malignant disease, one breast cancer, and one melanoma, during the first year of treatment. CONCLUSION: Our real-world data on the effectiveness and safety of cladribine tablets are comparable to the pivotal study and other real-world data with no new safety signals.

Medication adherence and health outcomes in persons with multiple sclerosis treated with dimethyl fumarate.

BACKGROUND: Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system that particularly affects people in their 30s. Oral disease-modifying therapy (DMT) offers a simple dosage form, good efficacy and safety. Dimethyl fumarate (DMF) is a frequently prescribed oral DMT medication worldwide. The aim of this study was to evaluate the impact of medication adherence on health outcomes in Slovenian persons with MS treated with DMF. METHODS: Our retrospective cohort study included persons with relapsing-remitting MS on DMF treatment. The medication adherence was evaluated by AdhereR software package using the proportion of days covered (PDC) measure. The threshold was set at 90%. Health outcomes after treatment initiation were represented by relapse occurrence, disability progression and occurrence of active (new T2 and T1/Gadolinium (Gd) enhancing) lesions between first two outpatient visits and first two brain magnetic resonance imaging (MRI), respectively. For each health outcome a separate multivariable regression model was built. RESULTS: The study included 164 patients. Their mean age (SD) was 36.7 (8.8) years, and the majority of patients were women (114 or 70%). Eighty-one patients were treatment naive. The mean (SD) PDC value was 0.942 (0.08) and 82% of patients were considered adherent above the 90% threshold. Older age (OR 1.06 per one year, P = 0.017, 95% CI (1.01-1.11)) and treatment naivety (OR 3.93, P = 0.004, 95% CI (1.64-10.4)) were related to higher adherence. In the 6-year follow-up period after DMF treatment initiation, 33 patients experienced a relapse. Among those, 19 required an emergency visit. Sixteen patients had a 1-point disability progression on the Expanded Disability Status Scale (EDSS) score between two consecutive outpatient visits. Thirty-seven patients were found to have active lesions between first and second brain MRI. Medication adherence showed no impact on relapse occurrence or disability progression. Lower medication adherence (10% lower PDC) was associated with higher occurrence of active lesions (OR 1.25, P=0.038, 95% CI: 1.01-1.56). Higher disability prior to DMF initiation was related to a higher risk for relapse occurrence and EDSS progression. CONCLUSION: Our study showed high medication adherence among Slovenian persons with relapse-remitting MS on DMF treatment. Higher adherence was associated with lower incidence of the radiological progression of MS. Interventions for improving medication adherence should be intended for younger patients with higher disability prior treatment with DMF and those switching from alternative DMTs.

Treatment with Cladribine Tablets Beyond Year 4: A Position Statement by Southeast European Multiple Sclerosis Centers.

Based on the results of the pivotal CLARITY study, cladribine tablets were approved for use in the European Union in 2017 as a high-efficacy therapy for highly active relapsing-remitting multiple sclerosis (MS). Cladribine tablets are used as an induction therapy: half of the total dose is given in year 1 and the other half in year 2. In the CLARITY Extension trials, repeating the dose routinely in years 3 and 4, was not associated with significantly improved disease control. However, there is very limited evidence on how to manage people with MS (pwMS) beyond year 4, which is increasingly important because more and more patients are now ≥ 4 years after cladribine treatment. Overall, postapproval data show that treatment with two cladribine cycles effectively controls disease activity in the long term. However, there is general agreement that some pwMS with suboptimal response could benefit from retreatment. This study reviews the practical aspects of using cladribine tablets, summarizes the evidence from clinical trials and real-world studies on the safety and efficacy of cladribine, and proposes a treatment algorithm developed by expert consensus for pwMS previously treated with cladribine. In brief, we propose that additional courses of cladribine tablets should be considered in patients with minimal (no relapses, 1-2 new lesions) or moderate (1 relapse, 3-4 new lesions) disease activity, while significant disease activity (> 1 relapse, > 3 new lesions) or progression should warrant a switch to another high-efficacy treatment (HET). More evidence is needed to improve the treatment guidelines for pwMS who previously received cladribine.

Transverse myelitis following COVID-19: Insights from a multi-center study and systematic literature review.

INTRODUCTION: We aimed to provide insights into transverse myelitis (TM) following COVID-19 by analyzing cases treated at tertiary care neurology centers and a systemic review of the literature. METHODS: The retrospective observational multi-center study was conducted at the four university neurology departments in Croatia, Slovenia, Serbia, and Austria. We searched for acute myelitis cases that occurred during or after COVID-19. A systemic review of the literature on COVID-19 and transverse myelitis was performed. RESULTS: We identified 76 persons with TM associated with COVID-19, 13 from the multi-center study and 63 from the literature review. Most of the participants (55.6%) had an intermediate latency, 25.4% had short and 19% long latency from COVID-19 symptoms to TM. The clinical presentation consisted of the typical TM signs. More than half of the participants had inflammatory changes in the CSF, with rare patients having intrathecal OCB synthesis and positive serology for anti-MOG or anti-AQP4 antibodies. Persons with autonomic symptoms and CSF pleocytosis were significantly more common to have an intermediate latency of 8 to 21 days from COVID-19 to TM (p = 0.005 and p = 0.003; respectively). According to logistic regression analysis, only participants with lesions evident on spinal cord MRI compared to normal spinal cord MRI had reduced risks for poor recovery. >80% of participants were treated with a combination of corticosteroids and intravenous immunoglobulins or plasma exchange with 73% having incomplete recovery. CONCLUSION: Our study further characterizes clinical, laboratory, and MRI features, as well as treatment of TM associated with COVID-19.

Sudomotor dysfunction in people with neuromyelitis optica spectrum disorders.

BACKGROUND AND PURPOSE: The aim was to determine the extent of sudomotor dysfunction in people with neuromyelitis optica spectrum disorder (pwNMOSD) and to compare findings with a historical cohort of people with relapsing-remitting multiple sclerosis (pwRRMS). METHODS: Forty-eight pwNMOSD were enrolled from four clinical centers. All participants completed the Composite Autonomic Symptom Score 31 to screen for symptoms of sudomotor dysfunction. Sudomotor function was assessed using the quantitative sudomotor axon reflex test. The results were compared with a historical cohort of 35 pwRRMS matched for age, sex and disease duration. RESULTS: Symptoms of sudomotor dysfunction, defined by a score in the Composite Autonomic Symptom Score 31 secretomotor domain >0, were present in 26 (54%) of pwNMOSD. The quantitative sudomotor axon reflex test confirmed a sudomotor dysfunction in 25 (52.1%) of pwNMOSD; in 14 of them (29.2%) sudomotor dysfunction was moderate or severe. No difference was observed between pwNMOSD and pwRRMS in any of the studied parameters. However, symptomatic sudomotor dysfunction was more frequent in pwNMOSD (n = 8, 22.9%) compared to pwRRMS (n = 1, 3%; p = 0.028). In a multivariable logistic regression analysis, statistically significant predictors for symptomatic sudomotor failure were age and diagnosis of neuromyelitis optica spectrum disorder. CONCLUSIONS: Sudomotor dysfunction is common in pwNMOSD and more often symptomatic compared to pwRRMS.

Pulmonary embolism in patients with multiple sclerosis treated with teriflunomide: A series of three cases.

Teriflunomide is an oral disease modifying therapy for patients with relapsing remitting multiple sclerosis. It is moderately effective while having a favourable safety profile with liver toxicity being the major concern. We present a series of three patients who developed pulmonary embolism within two years of initiation of teriflunomide treatment. They had stable multiple sclerosis with low level of disability, with immobility presenting a negligible risk for the development of pulmonary embolism. The estimated prevalence of pulmonary embolism in our cohort is 2.8%. Thus, we believe additional attention to the general risk factors for PE is warranted before teriflunomide is introduced to patients with multiple sclerosis.

Effectiveness and safety of alemtuzumab in the treatment of active relapsing-remitting multiple sclerosis: a multicenter, observational study.

OBJECTIVE: So far, a limited number of real-world evidence studies about the effectiveness and safety of alemtuzumab (ALM) have been published, some of them with a relatively small number of included patients. We aimed to study the efficacy and safety of ALM in real-world clinical practice in two MS centers in Slovenia and Croatia. METHODS: This was a retrospective chart review of 71 consecutive patients with relapsing-remitting MS who were treated with ALM from 2015 till 2018. The following data were collected: gender, age at disease onset, disease duration at ALM initiation, previous disease modifying therapy, number of relapses, active MRI lesions, and EDSS in the year prior to ALM initiation and every year of follow-up. RESULTS: All patients completed the standard dosing schedule and were followed for a mean time of 3.2±1.1 years after the initiation of treatment. Complete data for the 2 years after treatment (relapses, EDSS, and MRI) were available for 48 patients, of which 14 (29.2%) achieved NEDA. Clinical NEDA was achieved in 38 out of 63 participants (60.3%). In year 1, 24 out of 57 (42.1%) patients achieved NEDA. In year 2, 26 out of 41 (63.4%) patients achieved NEDA. Lower EDSS prior to starting ALM was the only independent predictor of NEDA in a multivariable model. Adverse events occurred in 58 participants (84.1%), with no new safety signals identified. CONCLUSION: According to the data from our cohort of early active RRMS patients we conclude ALM efficacy remains high in the real-world clinical practice.

Intravenous immunoglobulins for the prevention of postpartum relapses in multiple sclerosis.

OBJECTIVES: To evaluate the effect of intravenous immunoglobulins (IVIG) on prevention of postpartum relapses in women with relapsing-remitting multiple sclerosis (RRMS). METHODS: This was a retrospective study performed in Ljubljana, Slovenia where the practice for all pregnant women with RRMS is to receive IVIG after the delivery (10 g monthly, during first 6 months after delivery) and in Zagreb, Croatia where no such practice exists. The following data were collected: date of delivery, maternal age at delivery, year of the RRMS diagnosis, EDSS, disease modifying therapy prior to pregnancy, relapses in the year prior, during and in the period of one year after pregnancy. RESULTS: Data on 132 pregnancies from 112 women (mean age at delivery 31.70±4.10, average disease duration 6.34±4.33) were analyzed. There was no association between the IVIG treatment and annualized relapse rate one year after the delivery (0.27 vs 0.38, rate ratio 1.409, 95% CI 0.764-2.598, p = 0.272). No risk factors for the postpartum relapse were identified (age at delivery, duration of RRMS, EDSS prior pregnancy, disease modifying therapy prior pregnancy, relapses in the year prior pregnancy, IVIG). CONCLUSION: This study provides no evidence of benefit for postpartum administration of IVIG in women with RRMS.

Visual but not verbal working memory interferes with balance in patients after optic neuritis suggestive of multiple sclerosis.

BACKGROUND: Subtle cognitive deficits are present in almost half of the patients with clinically isolated syndrome (CIS) suggestive of multiple sclerosis (MS). Similarly, subtle balance deficits can be detected at the earliest stages of the disease. To assess cognitive-motor interference (CMI) in nondisabled CIS patients, we studied postural performance using dual task paradigm in CIS patients presenting with optic neuritis. METHODS: We prospectively included 20 patients with visual acuity of 0.8 or more within the 3 months from unilateral ON. We also included 20 age, weight, height and education matched healthy subjects. Baseline cognitive performance of the patients was assessed using neuropsychological tests. Balance was studied by posturography (Po) and center of pressure (CoP) measures (maximal medio-lateral, maximal antero-posterior amplitudes, maximal CoP velocity and total CoP path. CMI between static balance and WM was investigated using a dual-task paradigm in three conditions: Po alone, Po+Brooks' visual working memory (WM) task and Po+2-back verbal WM task. RESULTS: The two most commonly affected cognitive domains in the patients were attention (52% of the patients) and executive functions (45% of the patients). Static balance as measured by higher maximal CoP velocity while standing alone (p = 0.02) was impaired in patients. Significantly lower maximal m-l CoP amplitude (p = 0.01) and total CoP path (p = 0.004) in the Po + Brooks' task condition compared to Po alone were observed in the group of ON patients but not in healthy subjects. The cost of dualtasking was highest in the ON patients under Po + Brooks' task (p = 0.04 for the total CoP path parameter). CONCLUSION: Static balance and cognition are impaired in the earliest MS. CMI between static balance and working memory is higher in the patients and while loading visual working memory. Dual-task paradigms should be used in rehabilitation programmes for patients at the very beginning of the disease.

Hypometric anticipatory postural adjustments in dystonia are not affected by deep brain stimulation of globus pallidus internus.

BACKGROUND: Dystonia is a movement disorder with patterned, directional, and often sustained muscle contractions that produce abnormal postures or repetitive movements. Deep brain stimulation (DBS) of the globus pallidus internus (GPi) is an effective and safe treatment for medically refractory dystonia. However, recent studies reported gait problems, gait freezing and falls in patients treated with DBS. Because these symptoms may point to deficient gait initiation processes, we systematically assessed the anticipatory postural adjustments (APAs) prior to stepping in dystonia patients with GPi-DBS. METHODS: Thirteen patients with focal/segmental dystonia under GPi-DBS and twelve healthy control subjects were included in the study. Data were collected using pressure sensitive sensors and APAs were studied by centre of pressure measures. We compared APAs of both groups and analysed the influence of GPi-DBS on APAs in patients. RESULTS: Medio-lateral and antero-posterior COP displacements, total COP path, maximal APA velocity and 1st step length were all smaller in patients for both ON (p=0.006, p=0.018, p=0.002, p=0.016, p=0.04) and OFF (p=0.001, p=0.01, p=0.001, p=0.03, p=0.024) condition compared to healthy subjects. GPi-DBS did not change APA parameters in patients. CONCLUSIONS: Observations that APAs are impaired in dystonia and are at the same time not affected by the stimulation current are compatible with the assumption that APAs and dystonic symptoms may rely on distinct networks, possibly within the same cortical and basal ganglia structures. With no effect of stimulation on APAs it is unlikely that this would be a mechanism of impaired balance in the patients after the surgery.

Postural stability under globus pallidus internus stimulation for dystonia.

OBJECTIVE: Deep brain stimulation of the globus pallidus internus (GPi-DBS) is an efficient and safe treatment for medically refractory dystonia. However, recent studies reported gait problems, falls and bradykinesia in patients after the DBS procedure. The aim of this study was to quantify the effect of GPi-DBS on postural performance in patients with cranio-cervical dystonia. METHODS: Thirteen patients with focal/segmental dystonia and GPi-DBS participated in the study. We performed two postural tests (pull test and push and release test) in on- and off-stimulation conditions and recorded the movements of the patients with inertial sensors. RESULTS: Under stimulation patients exhibited a higher number of steps (p=0.015), reduced first step length (p=0.011) and lower stepping velocity (p=0.001), compared to off stimulation. We observed a higher number of steps in the push and release test compared to the pull test (p=0.038). The interaction between stimulation condition and test type was significant (p=0.027). CONCLUSIONS: The velocity and amplitude of postural reactions are compromised by GPi-DBS in patients with cranio-cervical dystonia. SIGNIFICANCE: This information corresponds to patient's reports of falls and postural instability after GPi-DBS. Pre-operatively, patients should be informed about the possibility of the occurrence of such phenomena.