Progressive Forms Of Multiple Sclerosis Research Articles

Selecting informative patients for phase 2 progressive trials in MS: Design considerations for phase 2 clinical trials in progressive MS.

While relapsing-remitting multiple sclerosis (MS) has many therapeutic options, progressive forms of MS remain largely untreatable. Phase 2 clinical trials are our main tool to advance new treatments for progressive MS. Given the complexities of progressive MS, it will likely require many phase 2 trials to improve its treatment. To conduct informative and efficient phase 2 trials, it is important that such trials are designed in a way that they can identify a successful treatment as quickly and with as few participants as possible. In this topical review, we discuss cohort selection, outcome selection, cohort enrichment, and dosing selection as strategies to optimize the efficiency of phase 2 clinical trials in progressive MS.

Disclosing the Novel Protective Mechanisms of Ocrelizumab in Multiple Sclerosis: The Role of PKC Beta and Its Down-Stream Targets.

Ocrelizumab (OCR) is a humanized anti-CD20 monoclonal antibody approved for both Relapsing and Primary Progressive forms of Multiple Sclerosis (MS) treatment. OCR is postulated to act via rapid B cell depletion; however, by analogy with other anti-CD20 agents, additional effects can be envisaged, such as on Protein Kinase C (PKC). Hence, this work aims to explore novel potential mechanisms of action of OCR in peripheral blood mononuclear cells from MS patients before and after 12 months of OCR treatment. We first assessed, up-stream, PKCβII and subsequently explored two down-stream pathways: hypoxia-inducible factor 1 alpha (HIF-1α)/vascular endothelial growth factor (VEGF), and human antigen R (HuR)/manganese-dependent superoxide dismutase (MnSOD) and heat shock proteins 70 (HSP70). At baseline, higher levels of PKCβII, HIF-1α, and VEGF were found in MS patients compared to healthy controls (HC); interestingly, the overexpression of this inflammatory cascade was counteracted by OCR treatment. Conversely, at baseline, the content of HuR, MnSOD, and HSP70 was significantly lower in MS patients compared to HC, while OCR administration induced the up-regulation of these neuroprotective pathways. These results enable us to disclose the dual positive action of OCR: anti-inflammatory and neuroprotective. Therefore, in addition to B cell depletion, the effect of OCR on these molecular cascades can contribute to counteracting disease progression.

UNLOCKING HOPE: OVERCOMING THERAPEUTIC CHALLENGES IN PROGRESSIVE MULTIPLE SCLEROSIS

Progressive forms of multiple sclerosis (MS) present significant therapeutic challenges, underscoring the pressing need for effective treatments in this domain. While relapsing-remitting MS (RRMS) transitions to secondary progressive MS (SPMS) for many patients, others experience primary progressive MS (PPMS) from the diseases onset. Despite similarities in pathophysiology and clinical progression between SPMS and PPMS, treatment options remain limited. The recent approval of ocrelizumab for PPMS marks a notable advancement, though its efficacy is modest. This retrospective study, conducted at the Neurology Department of Mohammed VI University Hospital, evaluates the tolerance and therapeutic efficacy of various treatments in progressive MS. Nineteen patient records spanning six years were analyzed, with therapeutic interventions including Fingolimod, Rituximab, cyclophosphamide-solumedrol, and ocrelizumab. Assessments utilizing the Expanded Disability Status Scale (EDSS) revealed stabilization or improvement in 15.7% of secondary progressive MS and 21% of primary progressive MS patients after 12 months of treatment. The duration of the progressive phase emerged as a key predictor of therapeutic response. Despite the approval of ocrelizumab in Morocco for PPMS, its utilization remains limited, suggesting the need for targeted studies focusing on early-stage clinical progression. Overall, this study underscores the unmet need for effective treatments in progressive MS and highlights ongoing research efforts aimed at addressing this challenge.

Co-supplementation of synbiotics and anti-inflammatory-antioxidant rich diet in patients with progressive forms of multiple sclerosis: A single-center, randomized clinical trial

BACKGROUND: The relationship between dietary modification and Multiple Sclerosis (MS)-related disability has been emphasized in several researches. AIMS: To determine whether a co-administration of anti-inflammatory-antioxidant rich diet and synbiotics might improve clinical manifestations in progressive MS patients. METHODS: The study involved 70 patients with progressive MS (primary-progressive, secondary-progressive, and progressive-relapsing) who were randomized to receive either intervention (synbiotics capsule plus an anti-inflammatory-antioxidant-rich diet) or placebo. Quality of Life (QOL), Expanded Disability Status Scale (EDSS), and depression-anxiety scores were evaluated before and after the follow-up. Analysis of covariance was performed for final analysis (SPSS v.14). RESULTS: Significant reductions were seen in EDSS (2.6±1.1 to 2.4±1.0, P < 0.001), State Anxiety Inventory (53.7±10.3 to 47.8±10.6, P < 0.001), and QOL scores after four months of intervention. No significant difference was seen across the depression severity (Δ for intervention = –2.2±5.5 vs. Δ for control = –0.6±5.7; P = 0.264). CONCLUSION: This study demonstrates that a combination of synbiotics and diet could be a promising strategy to improve severity and clinical manifestations of progressive MS.

Longitudinal quantitative assessment of TMEV-IDD-induced MS phenotypes in two inbred mouse strains using automated video tracking technology

Multiple sclerosis (MS) is a chronic disabling disease of the central nervous system affecting over 2.5 million people worldwide. Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD) is a murine model that reproduces the progressive form of MS and serves as a reference model for studying virus-induced demyelination.Certain mouse strains such as SJL are highly susceptible to this virus and serve as a prototype strain for studying TMEV infection. Other strains such as SWR are also susceptible, but their disease course following TMEV infection differs from SJL's.The quantification of motor and behavioral deficits following the induction of TMEV-IDD could help identify the differences between the two strains. Motor deficits have commonly been measured with the rotarod apparatus, but a multicomponent assessment tool has so far been lacking.For that purpose, we present a novel way of quantifying locomotor deficits, gait alterations and behavioral changes in this well-established mouse model of multiple sclerosis by employing automated video analysis technology (The PhenoTyper, Noldus Information Technology). We followed 12 SJL and 12 SWR female mice and their mock-infected counterparts over a period of 9 months following TMEV-IDD induction.We demonstrated that SJL and SWR mice both suffer significant gait alterations and reduced exploration following TMEV infection. However, SJL mice also display an earlier and more severe decline in spontaneous locomotion, especially in velocity, as well as in overall activity. Maintenance behaviors such as eating and grooming are not affected in either of the two strains. The system also showed differences in mock-infected mice from both strains, highlighting an age-related decline in spontaneous locomotion in the SJL strain, as opposed to hyperactivity in the SWR strain.Our study confirms that this automated video tracking system can reliably track the progression of TMEV-IDD for 9 months. We have also shown how this system can be utilized for longitudinal phenotyping in mice by describing useful parameters that quantify locomotion, gait and behavior.

A rapid review of differences in cerebrospinal neurofilament light levels in clinical subtypes of progressive multiple sclerosis.

Multiple sclerosis (MS) is divided into three clinical phenotypes: relapsing-remitting MS (RRMS), secondary progressive MS (SPMS), and primary progressive MS (PPMS). It is unknown to what extent SPMS and PPMS pathophysiology share inflammatory or neurodegenerative pathological processes. Cerebrospinal (CSF) neurofilament light (NfL) has been broadly studied in different MS phenotypes and is a candidate biomarker for comparing MS subtypes. Are CSF NfL levels different among clinical subtypes of progressive MS? A search strategy identifying original research investigating fluid neurodegenerative biomarkers in progressive forms of MS between 2010 and 2022 was applied to Medline. Identified articles underwent title and abstract screen and full text review against pre-specified criteria. Data abstraction was limited to studies that measured NfL levels in the CSF. Reported statistical comparisons of NfL levels between clinical phenotypes were abstracted qualitatively. 18 studies that focused on investigating direct comparisons of CSF NfL from people with MS were included in the final report. We found NfL levels were typically reported to be higher in relapsing and progressive MS compared to healthy controls. Notably, higher NfL levels were not clearly associated with progressive MS subtypes when compared to relapsing MS, and there was no observed difference in NfL levels between PPMS and SPMS in articles that separately assessed these phenotypes. CSF NfL levels distinguish individuals with MS from healthy controls but do not differentiate MS subtypes. Broad biological phenotyping is needed to overcome limitations of current clinical phenotyping and improve biomarker translatability to decision-making in the clinic.

Povezanost bola sa brzinom hoda i funkcionalnom sposobnošću kod pacijenata obolelih od progresivnih formi multiple skleroze

Introduction/Aim: In progressive forms of MS, the frequency of pain increases as the disease progresses affecting patients' functional abilities and making the disease much more complex. We conducted a cross-sectional study to examine the association of pain with walking speed and functional abilities in patients who suffer from progressive forms of multiple sclerosis. Material and methods: The cross-sectional study was conducted at the Clinic for rehabilitation "Dr Miroslav Zotović" in the period from January 2020 to May 2023. The research included 55 patients with PPMS and SPMS consecutively admitted to this Clinic for rehabilitation. Demographic and socio-epidemiological data and disease-related data were collected from all the patients. Pain intensity was assessed using Numeric Rating Scale (NRS). Since all patients experienced spasticity, pain was also assessed using the Pain/Discomfort (PD) subscale of the Multiple Sclerosis Spasticity Scale 88 (MSSS-88). The subjective perception of gait impairment was assessed using a subscale of the same questionnaire, MSSS 88, related to walking, namely the Walk (WL). Walking speed was measured by The Timed 25 Foot Walk (T25FW). The functional assessment and all questionnaires were completed in the morning hours over a 24-hour period from the day patients were admitted to rehabilitation. Results: There is a significant strong correlation between WL and P/D (rho=0. 770; p<0.001) and between WL and NRS (rho=0. 825 p<0.001). There is a statistically significant moderate negative correlation between T25FW and NRS pain (p<0.001). There is no statistically significant correlation between T25FW and pain intensity measured by PD (p=0.033). There is a statistically significant correlation between EDSS and pain intensity (NRS p=0.002; PD p=0.006) either. Conclusion: The results of this research indicated a significant negative impact of pain on walking speed and functional disability.

Possibilities of magnetic resonance morphometry and laboratory biomarkers in studying the progression of multiple sclerosis

To show that magnetic resonance morphometry and laboratory biomarkers are promising methods for early detection of progressive forms of multiple sclerosis (MS). Eighty-one patients with MS were examined, magnetic resonance morphometry was performed in all of them, 60 patients were analyzed for neurofilament light chains (sNFL), phosphorylated neurofilament heavy chains (spNFH) and glial fibrillary protein (sGFAP) in serum by enzyme-linked immunosorbent assay. Brain volumes were negatively correlated with disease duration, EDSS score, 25-foot walk test score and 9-ring test and positively correlated with the Symbol-Numeric Test and the Montreal Cognitive Assessment. Patients with progressive types of MS (PMS) had smaller volumes of brain gray matter, cerebellar white matter, occipital lobes, caudate nucleus, hippocampus, pallidum, thalamus, and contiguous nucleus. A CSF volume greater than 15.06% could suggest progression (CI 54.79-91%) with a sensitivity of 77.78% and specificity of 70.18%. When patients were on DMT, they had larger thalamic volumes (median 1.09% [1.6; 1.16] vs 1.04% [0.95; 1.14]; p=0.02) and smaller CSF volumes (13.86±2.87% vs. 15.55±3.49%; p=0.03). The levels of sNFL and spNFH were not increased in PMS and during exacerbations, and the low obtained values of sNFL suggest poor sensitivity of the method. There were trends (p=0.374) towards higher sGFAP in patients with PRS (median 3.2 ng/mL [1.85; 4.6] compared to remitting MS (2.05 ng/mL [1.29; 4.52]). The results demonstrate the differences in brain volumes in patients with different types of MS and emphasize the importance of long-term follow-up to better assess disease progression.

HUMORAL IMMUNITY IN PATIENTS WITH MULTIPLE SCLEROSIS

Introduction. More than 1 million people in the world suffer from multiple sclerosis (MS). The etiology of MS remains not fully understood. The main role in the pathogenesis of MS belongs to the combination of chronic inflammation and neurodegenerative processes, in the genesis of which autoimmune processes play a significant role. Progress in studying the mechanisms of the pathological process of demyelinating diseases has been achieved mainly thanks to immunological research. One of the manifestations of activation of humoral immunity in MS is increased synthesis of immunoglobulins in brain tissue and cerebrospinal fluid
 The aim of the study. To study the state of humoral immunity in multiple sclerosis patients with different types of disease course
 Research methods. 68 patients with a verified diagnosis of multiple sclerosis (MS) based on the MacDonald et al criteria aged 19 to 65 years (37 women, 29 men) were examined. The primary progressive type of the course was established in 19 patients, the secondary-progressive - in 3, the remitting-relapsing type of the course - in 26 patients. The control group consisted of 80 practically healthy male volunteers aged 25-45 years.
 The concentration of immunoglobulins A, G, M in blood serum was determined by the Mancini method (1965). The content of circulating immune complexes (CIC) in blood serum was determined by the method of precipitation in polyethylene glycol.
 Results and discussion. The highest content of Ig A was observed in the group of patients with primary progressive form of MS, which was 3.7 times higher than normal values and 1.2 times higher than in the general group of MS patients. In the group of patients with the secondary progressive form of MS, the content of Ig A was 3.1 times higher than in the control group and 1.2 times lower than in the group with the primary progressive form. In the group of patients with relapsing-remitting form of MS, there was an increase in the level of Ig A three times relative to the normal indicator, and a decrease (by 1.2 times) relative to the level in the group with a primary progressive form of MS.
 The content of Ig M in the blood serum of patients with MS exceeded the norm by 5 times. In the group with the primary progressive form of MS, the level of Ig M was 3.5 times higher than the level in the control group and 1.5 times lower than the level in the group of patients with MS. In patients with secondary progressive form of MS, the content of Ig M was 2.6 times higher than the norm, but 1.3 times lower than the level in the group with primary progressive form of MS and 1.9 times lower than in the group of patients with MS. In patients with the relapsing-remitting form of MS, the level of Ig M was: 4.6 times higher than the level in the control group and 1.7 times higher than the content in patients with the secondary-progressive form of MS, and also 1.3 times higher, than in the group with the primary progressive form.
 In all groups of patients with MS with different types of the course of the disease, the most pronounced increase in the level of Ig G was noted.
 The highest level of CIC was recorded in the general group of patients with MS and in the group with secondary progressive form of MS.
 Conclusions. An imbalance of the humoral link of immunity was observed in patients with multiple sclerosis. A probable increase in the concentration of Ig A in the blood serum of patients with multiple sclerosis indicates the presence of infection of the mucous membranes, which is especially pronounced in patients with the primary progressive form of multiple sclerosis. A significant increase in the content of Ig G in the blood serum of patients with multiple sclerosis indicates a chronic course of the process, which is especially evident in the relapsing-relapsing form of multiple sclerosis. An increased concentration of IgM in the blood serum of patients with multiple sclerosis may indicate an exacerbation of the course of chronic inflammation, especially in the case of relapsing-remitting multiple sclerosis. The detected fluctuations of the average content of CIC in the blood serum of patients with multiple sclerosis did not go beyond the physiological norm.

Why do we so rarely recognise and treat the primary progressive form of multiple sclerosis?

The primary progressive form of multiple sclerosis is characterised by a systematic increase in disability from the onset of the disease, usually without overlapping relapses. It is estimated that it accounts for 10–15% of all cases of multiple sclerosis, occurs with similar frequency in both sexes, and its symptoms appear at an older age, usually after 40. The initial manifestation usually consists of pyramidal symptoms and myelopathy. The most typical symptoms include progressive gait and sphincter function impairment. Symptoms of cerebellar syndrome, truncal syndromes, as well as visual and cognitive disturbances are less common. The clinical course with characteristic symptomatology resulting from the location of the changes primarily in the spinal cord, followed by the occurrence of initial symptoms, means that this form of multiple sclerosis requires careful differential diagnosis. It should be differentiated primarily from diseases causing lower limb paresis (myelopathy associated with vitamin B12 deficiency, amyotrophic lateral sclerosis, spinal cerebellar ataxia, neuromyelitis optica spectrum disorder, Wernicke’s encephalopathy, Lyme disease, and spinal cord tumours). The diagnosis of primary progressive multiple sclerosis should be guided by the current 2017 McDonald diagnostic criteria. Understanding these criteria and being aware of the differences from the most common relapsing-remitting form of multiple sclerosis can be helpful in speeding up the diagnosis and implementing effective treatment. Even though new treatment options have emerged in recent years, primary progressive multiple sclerosis is still little known and too rarely recognised.

OPERA and ORATORIO – how the world has been changed by “music”

Multiple sclerosis is a chronic autoimmune disease that progresses over time, leading to disability. The condition is still incurable, but available therapies are increasingly effective. Ocrelizumab is the first anti-CD20 monoclonal antibody approved for the treatment of relapsing-remitting and primary progressive forms of multiple sclerosis. In the article, based on the results of the OPERA and ORATORIO clinical trials, their extensions, and post-hoc and meta-analyses, the evidence for long-term high effectiveness of the molecule is presented. Aspects including the control of relapses (annual relapse rate and time to relapse), delay in the occurrence of confirmed disability, probability to achieve disability improvement, need to use a wheelchair and loss of upper limb mobility, as well as radiological activity (gadolinium-enhancing lesions, new T2 lesions, brain atrophy), are assessed. An additional advantage of the OPERA studies is that almost similar results, acquired with identical protocols in a different patient populations, were achieved. Moreover, the effects of therapy did not wear off over time. Based on these findings, ocrelizumab can be regarded as a highly effective therapy in multiple sclerosis, with the highest (48%) NEDA-3 index (no evidence of disease activity) and the greatest potential for delaying the onset of confirmed disability. The presented studies also confirm the benefit of introducing the drug in multiple sclerosis therapy as early as possible.

Multiple sclerosis and seizures: A retrospective observational study in a multiple sclerosis autoimmunity center of excellence

PurposeThe prevalence of epilepsy in patients with multiple sclerosis (MS) is three to six times the prevalence in the general population. Mechanisms resulting in increased seizure risk are not fully understood. Our objective is to characterize patients with MS and epilepsy regarding timing of diagnoses, MS and seizure (SZ) type, EEG findings suggesting cortical dysfunction, frequency of status epilepticus (SE), and seizure freedom. MethodsThis was a single center retrospective study. Cases were obtained via DataDirect via the University of Michigan electronic medical record from January 1, 2006 through October, 12, 2016. The University of Michigan Health System is a large academic institute with a tertiary referral center and an Autoimmunity Center of Excellence. Patients were included if chart listed one or more of the top 62 epilepsy, and one or more of the top 2 MS, most frequently entered ICD9 and ICD10 codes. Patients with alternative epilepsy etiology were excluded. 74 of 361 patients were included. We collected information regarding demographics, MS and SZ type, age at diagnosis, imaging, EEG, seizure freedom, medications, and SE. ResultsWe found a high percentage of patients with SE. Most patients with imaging had multiple lesions at seizure onset. 27/54 of patients with EEG data showed electrographic evidence of cortical dysfunction. 6/8 of EEGs in PPMS showed features consistent with cortical dysfunction, followed by 9/17 in SPMS and 11/23 in RRMS. 7/8 of patients with PPMS showed EEG evidence of temporal lobe dysfunction. ConclusionTime of seizure onset relative to MS diagnosis varied with MS type suggesting distinct pathophysiology. EEG results correspond with reports of increased cortical damage and temporal dysfunction in PPMS, but are unique as a functional modality (EEG) as indicator of gray matter dysfunction. EEG findings differed in RRMS and progressive MS suggesting possibility of supportive diagnostic marker. Our data suggests higher risk of SE in progressive MS and diminished rate of seizure freedom for MS patients with SE. We conclude that early treatment with antiseizure medication would be beneficial for MS patients with SE and with progressive MS forms and SZ, in agreement with previous studies.

Claims-based algorithm to estimate the Expanded Disability Status Scale for multiple sclerosis in a German health insurance fund: a validation study using patient medical records.

The Expanded Disability Status Scale (EDSS) quantifies disability and measures disease progression in multiple sclerosis (MS), however is not available in administrative claims databases. To develop a claims-based algorithm for deriving EDSS and validate it against a clinical dataset capturing true EDSS values from medical records. We built a unique linked dataset combining claims data from the German AOK PLUS sickness fund and medical records from the Multiple Sclerosis Management System 3D (MSDS3D). Data were deterministically linked based on insurance numbers. We used 69 MS-related diagnostic indicators recorded with ICD-10-GM codes within 3 months before and after recorded true EDSS measures to estimate a claims-based EDSS proxy (pEDSS). Predictive performance of the pEDSS was assessed as an eight-fold (EDSS 1.0-7.0, ≥8.0), three-fold (EDSS 1.0-3.0, 4.0-5.0, ≥6.0), and binary classifier (EDSS <6.0, ≥6.0). For each classifier, predictive performance measures were determined, and overall performance was summarized using a macro F1-score. Finally, we implemented the algorithm to determine pEDSS among an overall cohort of patients with MS in AOK PLUS, who were alive and insured 12 months prior to and after index diagnosis. We recruited 100 people with MS insured by AOK PLUS who had ≥1 EDSS measure in MSDS3D between 01/10/2015 and 30/06/2019 (620 measurements overall). Patients had a mean rescaled EDSS of 3.2 and pEDSS of 3.0. The pEDSS deviated from the true EDSS by 1.2 points, resulting in a mean squared error of prediction of 2.6. For the eight-fold classifier, the macro F1-score of 0.25 indicated low overall predictive performance. Broader severity groupings were better performing, with the three-fold and binary classifiers for severe disability achieving a F1-score of 0.68 and 0.84, respectively. In the overall AOK PLUS cohort (3,756 patients, 71.9% female, mean 51.9 years), older patients, patients with progressive forms of MS and those with higher comorbidity burden showed higher pEDSS. Generally, EDSS was underestimated by the algorithm as mild-to-moderate symptoms were poorly captured in claims across all functional systems. While the proxy-based approach using claims data may not allow for granular description of MS disability, broader severity groupings show good predictive performance.

Use of interferons in secondary progressive forms of multiple sclerosis. Efficacy, safety and quality of life of patients treated with these therapies

Use of interferons in secondary progressive forms of multiple sclerosis. Efficacy, safety and quality of life of patients treated with these therapies

Biological aging in multiple sclerosis.

Multiple sclerosis (MS) is most likely to adopt a progressive clinical course during middle age or beyond, and the number of older adults with MS is steadily increasing. Developing new strategies to manage progressive forms of MS, which do not respond to currently available disease-modifying therapies (DMTs), will require a deeper understanding of the mechanisms by which biological aging interacts with pathogenic pathways to propel disability accumulation. In experimental autoimmune encephalomyelitis (EAE), a widely used preclinical mouse model of MS, middle-aged animals experience a more severe and protracted clinical course than their younger counterparts. This exacerbated disease course is accompanied by persistent neuroinflammation. Clinical studies of age-related biomarkers, such as telomere length, senescence markers, and DNA methylation, suggest that biological aging is accelerated in people with MS compared with age- and sex-matched healthy controls. Furthermore, distinguishing biological age from chronological may afford more precision in determining aging effects in MS. Here we review the current literature on aging biology and its impact on MS pathogenesis. Future research on this topic may lead to the development of novel biomarkers and senotherapy agents that slow neurological decline in people with progressive MS by targeting relevant aging-related pathways.

Self-reports by persons with multiple sclerosis are an adequate surrogate for healthcare provider data on disease-modifying therapy and multiple sclerosis type

IntroductionSelf-reports are a valuable and cost-effective method of data collection, though they can be influenced by bias. Limited evidence exists on the quality of self-reports by persons with multiple sclerosis (pwMS), particularly since more potent disease-modifying therapies (DMTs) have been introduced. This study aimed to assess the reliability and validity of self-reported DMT use and multiple sclerosis (MS) type in the Swiss Multiple Sclerosis Registry (SMSR) by comparing self-reports with reimbursement approval requests from the Swiss Association for Joint Tasks of Health Insurers. MethodsThe self-reported and reimbursement approval data were linked using privacy-preserving methods based on information available in both databases, i.e., date of birth, canton of residence, sex, and year of MS diagnosis. The SMSR baseline questionnaire data was utilized for the main analysis, while the SMSR follow-up survey data was utilized for the sensitivity analysis. For both analyses, we compared self-reported data with reimbursement approval data that corresponded to the respective periods of the SMSR data collection. Thus, the main analysis included the entirety of the data over the six-year period, while the sensitivity analysis captured a more recent snapshot of the data. To assess reliability, we estimated agreement using Cohen's kappa, and for validity, we estimated accuracy parameters using reimbursement approvals as the reference standard. Univariable and multivariable logistic regression models were employed to investigate factors associated with discordance between self-reports and reimbursement approvals in the main analysis. ResultsThe main analysis included 446 participants, and the sensitivity analysis included 193 participants. The agreement between self-reported and reimbursement approval data for medication use was near-perfect in both analyses (κ = 0.87, 95% confidence interval (CI) 0.85, 0.90 and κ = 0.82, 95% CI 0.76, 0.88). However, the agreement between self-reported and reimbursement approval-documented MS types ranged from fair to moderate (κ = 0.37, 95% CI 0.25, 0.48 to κ = 0.61, 95% CI 0.46, 0.77). The accuracy estimates for self-reported DMT use were generally high (≥ 0.80) with narrow CIs, except for less frequently reported drugs. While the sensitivity and specificity for RRMS were high, there was a notable possibility of false-negative self-reports for RRMS (NPV = 0.33, 95% CI 0.22, 0.45), and false-positive reports for SPMS (PPV = 0.36, 95% CI 0.21, 0.54). Multivariable logistic regression models showed that age (OR = 1.07, 95% CI 1.04, 1.10 per year) and education level (OR = 0.27, 95% CI 0.11, 0.65) were associated with discordance in reported and documented MS types, whereas possession of Swiss citizenship (OR = 0.32, 95% CI 0.14, 0.72) was associated with discordance in DMT use. ConclusionSelf-reported DMT use in pwMS is a reliable and valid information source, with near-perfect agreement and high accuracy. Self-reported MS types showed fair to moderate agreement and varying accuracy, likely reflecting the complexity of diagnosing progressive forms of MS and access to DMTs. In population-based MS research, self-reports of MS types, and particularly DMT use, can serve as a suitable surrogate for healthcare provider data.

Impact of comorbid primary headache on neurological function of patients with multiple sclerosis

Multiple Sclerosis (MS) is a progressive disease affecting the working population. Due to the demyelination process, patients have motor, sensory and cognitive impairments. Often patients with MS complain of headaches. Comorbid primary headache accompanies more than half of patients with MS. The aim of our study was to reveal the relationship between the presence of primary comorbid headache and the progression of MS. For this purpose, the Expanded Disability Status Scale (EDSS), motor testing for 25-Foot Walk Test (25FWT), 9-Hole Peg Test (9HPT) were used. International Classification of Headache - 3 (ICHD-3) scale was used for differential diagnosis of headache types. The obtained data were compared among patients with different types of MS: Relapsing-Remitting (RRMS); primary and secondary progressive, which was combined into Progressive forms of MS (PMS). 130 patients with MS were studied, among whom patients with RRMS prevailed (n=98), primary comorbid headache was found in 56.2% (n=73). Among patients with MS, migraine prevailed (p=0.015), in particular, the most cases were found in patients with RRMS. Among patients with PMS, tension headache prevailed (p&lt;0.05). The 9HPT and 25FWT scores did not differ significantly between the groups with and without primary comorbid headache, however, according to the confidence intervals, the EDSS score exceeded the score in the group of patients with comorbid headache. It was found that patients with comorbid migraine performed the motor test faster than patients with tension type headache. Therefore, it can be concluded that comorbid primary headache may have an impact on motor function indicators among MS patients and requires further investigation to determine the role of comorbid headache in the patterns of initial MS symptoms. Keywords: central nervous system, demyelination, migraine, tension type headache, motor function, comorbidity.

Prospects of treatment of progressive forms of multiple sclerosis by transplantation of stem cells (review)

Prospects of treatment of progressive forms of multiple sclerosis by transplantation of stem cells (review)

NfL and GFAP in serum are associated with microstructural brain damage in progressive multiple sclerosis.

The potential of neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) as biomarkers of disease activity and severity in progressive forms of multiple sclerosis (MS) is unclear. To investigate the relationship between serum concentrations of NfL, GFAP, and magnetic resonance imaging (MRI) in progressive MS. Serum concentrations of NfL and GFAP were measured in 32 healthy controls and 32 patients with progressive MS from whom clinical and MRI data including diffusion tensor imaging (DTI) were obtained during three years of follow-up. Serum concentrations of NfL and GFAP at follow-up were higher in progressive MS patients than in healthy controls and serum NfL correlated with the EDSS score. Decreasing fractional anisotropy (FA) in normal-appearing white matter (NAWM) correlated with worsening EDSS scores and higher serum NfL. Higher serum NfL and increasing T2 lesion volume correlated with worsening paced autitory serial addition test scores. In multivariable regression analyses with serum GFAP and NfL as independent factors and DTI measures of NAWM as dependent factors, we showed that high serum NfL at follow-up was independently associated with decreasing FA and increasing MD in NAWM. Moreover, we found that high serum GFAP was independently associated with decreasing MD in NAWM and with decreasing MD and increasing FA in cortical gray matter. Serum concentrations of NfL and GFAP are increased in progressive MS and are associated with distinct microstructural changes in NAWM and CGM.

Wobbly hedgehog syndrome- a progressive neurodegenerative disease

Wobbly hedgehog syndrome (WHS) has been long considered to be a myelin disease primarily affecting the four-toed hedgehog. In this study, we have shown for the first time that demyelination is accompanied by extensive remyelination in WHS. However, remyelination is not enough to compensate for the axonal degeneration and neuronal loss, resulting in a progressive neurodegenerative disease reminiscent of progressive forms of multiple sclerosis (MS) in humans. Thus, understanding the pathological features of WHS may shed light on the disease progression in progressive MS and ultimately help to develop therapeutic strategies for both diseases.