Background

Multiple-Sclerosis-Partners-Advancing-Technology-Health-Solutions (MSPATHS) is an international multicentre digital database that collects clinical information provided directly by patients together with standardized MRI and biomarkers.

Objectives

We identify a Benign multiple sclerosis (BMS) population using Patient-Determined-Disease-Steps (PDDS) as a proxy for EDSS. We describe its physical and non-physical characteristics, and explore the features that best discriminate BMS.

Methods

Cross-sectional study of MSPATHS patients (Feb 2019). In patients with disease duration ≥10 years, BMS was considered when PDDS score<2. We compared BMS and non-BMS in terms of (1)socio-demographic and clinical characteristics, (2)physical status (lower and upper extremity function by Neuro-QoL (LUEF-NQ) and neurological performance tests: walking speed test (WST), manual dexterity test (MDT), processing speed test (PST), contrast sensitivity test (CST)) and non-physical symptoms (anxiety, depression, fatigue, among other NQ domains), and (3)MRI (gadolinium enhancement and new T2 lesions). We built a random forest model to estimate the importance of each variable. Cohen’s d was used for descriptive statistics to categorize differences in small (d=0.2-0.5), medium (d=0.5-0.8) and large (d>0.8). A sensitivity analysis with a 1:1 matched cohort by disease duration was performed.

Results

From 15,257 patients included, 8,349 had a disease duration ≥10 years and 3,852 (46.1%) were classified as BMS. (1)BMS and non-BMS patients were similar for gender, age at disease onset and diagnosis, ethnicity, years of education and smoking status. Compared to non-BMS, BMS had small differences in disease duration (median, 17.2 (12,9-23,4) vs. 20.9 (15,1-28,8 years); d=0.39) but medium/large differences in (2)physical status (LUEF-NQ d=2.06 and 1.53, WST d=0.81, MDT d=0.97, PST d=0.82 and CST d=0.56), as well as, in all non-physical symptoms evaluated by NQ (anxiety d=0.53, depression d=0.69, fatigue d=0.84, stigma d=1.32, cognition d=0.69, social role satisfaction (SRS) d=1.11 and participation (SRP) d=1.19). (3)No differences were found on MRI activity. With 0.88 sensitivity and 0.86 specificity, LUEF-NQ was the most contributing variable for the random forest followed by stigma, SRP, WST, and SRS. The sensitivity analysis showed similar results.

Conclusions

PDDS seems to be a useful disability proxy to identify BMS when using digital technology. LUEF-NQ, stigma, SRP and SRS seem to better discriminate BMS.

Background

Rituximab (RTX) is an anti-CD20 monoclonal antibody, widely used as an off-label treatment for multiple sclerosis (MS). Despite well-known efficacy and safety, RTX regimen has not yet been standardized.

Objectives

We aimed to compare efficacy and safety data of two different rituximab doses at two large Catalan multiple sclerosis centres.

Methods

A two-centre ambispective study considering all MS patients that have received at least one RTX cycle until February 2020 was conducted. In Barcelona centre (BC), RTX regimen used was 2g intravenously (IV), at least during 3 cycles, followed by 1g every 6 months, while in Girona centre (GC), was 2g IV, at least the first cycle, followed by 500mg every 6 months. Patients were clinically followed every 6 months with lab tests, and brain MRI scans were performed at baseline and yearly thereafter. Baseline clinical, radiological and demographic characteristics were collected. Annual relapse rate (ARR), contrast-enhancing lesions (CELs) and new T2 lesions at one and third year on treatment, as well as EDSS changes at last follow-up visit, were evaluated. Also, the dynamics of CD19% lymphocytes and IG immunoglobulin (IgG) values in serum, as well as the incidence of adverse events (AE) were described.

Results

A total of 303 patients (249 at BC and 54 at GC) were included. Main reason to start RTX was clinical progression plus inflammatory activity (clinical, radiological or both) (45.8% BC vs 79.6% GC). No differences on age at RTX onset, gender and disease duration were found between both centres. At baseline, mean ARR was 0.37±0.6 (BC) vs. 0.33±0.5 (GC); median EDSS was 5.5 (1-9.0) (BC) vs. 6.0 (1-8.0) (GC); and proportion of MRI with CELs was 32.4% (BC) vs. 42.6% (GC). ARR decrease to 0.05 (87.5%, p<0.001) for BC vs. 0.03 (90.3%, p=0.018) for GC at first year, and to 0.08 (88.3%, p=0.016) vs. 0 (100%, p=0.172) at third year. Considering only progressive MS phenotypes, 79.4% vs. 71.4% of patients remained stable or improved the EDSS. Regarding MRI findings, percentages of patients with CELs and new T2 lesions (BC vs GC) were 2.7% vs. 8% and 19% vs. 16% at one year; and 0% vs. 0% and 12% vs. 0% at third year. AE incidence was higher at BC during the first year (14.8% vs 4.1%). No difference in the dynamics of CD19% lymphocytes was found, while IgG values decreased significantly in the BC cohort throughout the first 3 years.

Conclusions

In the treatment of multiple sclerosis, low doses of rituximab seem to offer similar effectiveness with better safety profile than high doses.

Background

Superficial siderosis (SS) is a rare disease caused by hemosiderin deposition in central nervous system and typically leads to neurological dysfunction and progressive irreversible symptoms. Multiple Sclerosis is most common demyelinating disease which usually courses with relapses and remissions but some patients can have a progressive course. Progression in MS patients is defined as a worsening of functional systems over one year.

We are presenting MS patient since 1994 who developed in last three years a progressive ataxia which was initially attributed to MS progression, nevertheless MRI showed hypointensities on cerebellum that led us to diagnose SS. Recognizing this entity is important because it could be a cause of pseudo progression in MS patients.

Objectives

We want to disclose the superficial siderosis as an unusual cause of pseudo-progression in patients affected by multiple sclerosis.

Methods

A 63 year-old woman with history of relapsing-remitting MS (RRMS) treated with Glatiramer acetate. She was stable until 2017, but since then she started to notice clumsiness of her both hands and difficulties to walk. She even had some falls because of unsteady gait.

Her Expanded Disability Status Scale (EDSS) passed from 2.0 to 4.5 due to worsening of cerebellar functional system and the using of a cane for walking. Over next three years she had progressive impairment of gait and coordination of all limbs. Sensorineural hearing loss of unknown cause was also diagnosed during this time. On last neurological examination she presented mild cerebellar dysarthria, moderate ataxia of all limbs, ataxic gait and need to walk with bilateral support. Other signs of the neurological examination were mild decrease of vibration and brisk reflexes on lower extremities. Currently her EDSS is 6.5

A cerebellar relapse was ruled out as cause of her symptoms because of progressive course, no recovery after steroids and no evidence of new T2 lesions on cerebellum. A RRMS turning into SPMS was initially accepted as responsible of her worsening.

Results

A comprehensive approach was performed, as there was an almost exclusive deterioration of the cerebellar functional system. So, a new brain MRI was requested and hemosiderin effect was seen along cerebellar folias. This finding was the key to diagnose superficial siderosis.

A neuroaxis MRI evaluation was done and there was no evidence of SS in other parts of CNS nor evidence of chronic bleeding that causes SS on cerebellum.

We proposed to initiate treatment with Deferiprone but the patient rejected to take it after we exposed lack of clear effectiveness. She is still being treated with Glatiramer acetate for MS.

Conclusions

Superficial siderosis can be a mimic of progression in patients affected by multiple sclerosis, that is why we recommend to take into account this entity in those patients with progressive worsening of walking secondary to exclusive affectation of cerebellar functional system.

Background

Primary progressive multiple sclerosis (PPMS) is a clinical subtype of MS characterized by the progressive accumulation of disability from onset. It is diagnosed in approximately 15% of people with multiple sclerosis (MS).

microRNAs (miRNAs) are small non-coding RNA molecules that participate in the regulation of gene expression. Their role in different diseases, including MS, is being studied.

Current disease-modifying therapies for MS as well as miRNA studies mainly focus on relapsing-remitting MS (RRMS), the most common subtype.

Objectives

The aim of this study was to identify and validate a differential profile of circulating miRNAs in PPMS patients compared to RRMS and controls with other neurological disease (OND) subjects in order to increase our knowledge of the biological processes involved in the different forms of the disease.

Methods

miRNAs were extracted from serum and cerebrospinal fluid (CSF) from a cohort of 111 patients (49 PPMS, 35 RRMS and 27 OND). In the identification phase, samples were analyzed using TaqMan OpenArray Human Advanced MicroRNA panels and in the validation phase, the quantification of the miRNAs was performed by qPCR. Differential expression was analyzed using the Kruskal-Wallis test with the normalized value of miRNAs.

Results

In the identification phase, 10 miRNAs showed differential expression in serum between some of the groups; while in CSF, miR-143-3p presented differential expression in PPMS group (p= 0.009), and let-7b-5p and miR-451a showed a tendency to be deregulated.

In serum samples, the validation phase showed miR-20a-5p overexpression in PPMS compared to controls, and miR-26a-5p among the forms of MS (p= 0.002 and p= 0.036, respectively). On the other hand, miR-142-5p was differentially expressed in RRMS compared to OND (p= 0.036).

In CSF, let-7b-5p and miR-143-3p presented significantly reduced levels in PPMS forms compared to OND (p= 0.029 and p= 0.039, respectively).

Conclusions

miR-20a-5p, miR-26a-5p, let-7b-5p and miR-143-3p present deregulation in PPMS versus RRMS and OND, indicating that they are involved in the pathophysiological mechanisms of PPMS forms. Further studies will be necessary to determine the role of these miRNAs in the development of the different forms of the disease.

Background

Some studies have shown a more aggressive clinical course in multiple sclerosis (MS) patients of North African origin residing in Europe. It has been established that some genetic and environmental factors interact in a complex way by means of epigenetics to produce the pathology and the symptoms in MS. One of these epigenetic mechanisms is microRNAs (miRNAs), small non-coding RNA molecules that participate in the regulation of gene expression.

Objectives

The objective of this study was to identify the existence of a differential profile of circulating cerebrospinal fluid (CSF) miRNAs between individuals with MS based on their ethnic origin.

Methods

A cohort of 20 individuals was studied: 10 European origin (MS-E) and 10 North African origin individuals (MS-NA). MS-NA individuals were subclassified according to migration age (before or after 15 years old).

216 miRNAs were analyzed in CSF using TaqMan OpenArray Human Advanced MicroRNA panels. Differential expression of the normalized value of each miRNA was studied using the U Mann-Whitney test.

Results

When comparing the expression of miRNAs in CSF between MS-E and MS-NA, overexpression of miR-335-5p and miR-653-3p was observed in MS-NA (p= 0.008 and p= 0.027, respectively). Furthermore, two other miRNAs (miR-143-3p and miR-20a-5p) showed a tendency to be deregulated.

A sub-analysis was performed in which MS-NA was divided according to the age of migration. miR-145-5p, miR-150-5p and miR-653-3p showed significant differences between some of the 3 groups. Specifically, miR-150-5p, previously related to inflammation and MS in CSF, showed very low levels in MS-NA that migrated older than 15 years of age.

Conclusions

The results show the presence of a differential expression in miRNAs between MS patients according to their ethnic origin. In patients of North African origin who migrated at an early age, an overexpression of miRNAs clearly related to inflammation is observed.

Background

BACKGROUND:

Cerebrospinal fluid (CSF) studies are necessary in neurological diseases, but the use of healthy controls (HC) is limited due to the ethical issues and difficulty in obtaining them. Usually, the control group corresponds to patients with other neurological diseases (OND).

Objectives

OBJECTIVES:

The main objective of this study was to evaluate the role of the control group in detecting altered miRNAs in multiple sclerosis (MS).

Methods

METHODS:

A panel of 216 CSF-specific miRNAs were analyzed using TaqMan Open Array Human Advanced MicroRNA in a cohort of 38 patients (16 primary progressive forms – PPMS, 9 HC, 13 OND).

HC corresponds to neurologically healthy patients with hip/knee impairment undergoing surgical intervention that requires spinal anaesthesia.

The pathologies presented by OND were: 6 individuals of vascular origin, 3 migraines, 1 conversion syndrome, 1 dementia, 1 dizziness, 1 cerebellar syndrome of non-inflammatory/infectious origin.

Results

RESULTS:

miR-1260a, miR-320a, and let-7c-5p showed differential expression, or a trend, in PPMS versus HC (p = 0.005; p = 0.021; p = 0.088, respectively). When making the same comparison with OND these significances were lost.

When analyzing deregulated miRNAs function, it was observed that let-7c-5p and miR-320a are involved in cerebral ischaemic and neurodegenerative disorders.

Conclusions

CONCLUSIONS:

Choosing the control group is crucial to identify altered miRNAs in a specific condition. If the objective is to identify metabolic pathways involved in a certain process, HC will be necessary since OND controls can share the altered pathways. On the other hand, when the objective is to identify biomarkers, the incorporation of OND into the analysis will be of great value to differentiate pathologies.

Background

Neuromyelitis optica spectrum disorders (NMOSD) are mostly relapsing autoimmune inflammatory disorders of the central nervous system. Hallmark features of NMOSD include acute attacks of bilateral or rapidly sequential optic neuritis or transverse myelitis. Attacks most often occur over days, with variable degrees of recovery over weeks to months

Other suggestive symptoms include episodes of intractable nausea, vomiting, hiccups, excessive daytime somnolence or narcolepsy, reversible posterior leukoencephalopathy syndrome, neuroendocrine disorders, and seizures

The discovery of AQP-4 antibodies supposed a breakthrough for understanding NMOSD. Recently, MOG antibodies have been also related to this entity. However, about 10-50% of NMOSD patients are still seronegative. These patients are a heterogeneous subgroup that may be associated with other autoantibodies

Objectives

To identify main clinical and radiological characteristics

To recognize differences between seropositive and seronegative NMOSD patients

To evaluate safety and effectiveness of Rituximab

Methods

We presented 12 patients diagnosed of NMOSD according revised consensus criteria published in 2015 at Unit of Neuroimmunology and Multiple Sclerosis Unit of Girona, Spain

The data were collected during the course of clinical care. We focused on medical history, neurologic symptoms, MRI features, CSF findings

Rituximab response was assessed using the annualized relapse rate (ARR)

Results

Disease-onset form: optic neuritis 7 (58,3%) 1 of them had bilateral optic neuritis; myelitis 4 (33,3%); brainstem syndrome 1 (8,3%)

Abnormal laboratory findings: 2 patients had positivity for lupus anticoagulant, 1 for TPO-Ab and 1 for ANAs

8 patients were seronegative NMOSD

6 patients (50%) had cognitive impairment

CSF findings: 8 patients had CSF abnormalities include pleocytosis and elevated protein levels. Oligoclonal bands were positive in 4 patients

4 patients were positive for antibodies: AQP-4= 2 / MOG= 2

MRI findings: 4 patients had brain MRI abnormalities that matched with NMOSD pattern, rest of patients had normal or unspecific MRI. Longitudinally extensive spinal cord lesions were observed in 7 patients. Cervical and thoracic segments were most affected

4 patients had positivity for other antibodies. 3 of them are seronegative NMOSD

Of 4 seropositive patients, 3 had cognitive impairment

Of 4 patients with presence of CSF oligoclonal bands, 3 were seronegative NMOSD

ARR before Rituximab: 1,25 and ARR after Rituximab: 0,27

No patient had serious adverse events after Rituximab treatment. Rituximab was discontinued in 1 patient due to an allergic reaction

Conclusions

Seronegative NMOSD has a prevalence up to 60% and it could be related with presence of other serum antibodies and with positivity for CSF oligoclonal bands

Cognitive impairment is frequent in NMOSD and can be more prevalent in seropositive patients

Rituximab is safe and effective to reduce ARR

Background

Memory impairment affects more than 50% of patients with multiple sclerosis (MS), strongly impacting their life quality. Previous studies have suggested a correlation between functional hippocampal alterations and episodic memory impairments in MS. Nevertheless, these studies are rarely focused on preclinical nor initial stages of the disease, essential to develop targeted interventions to prevent or delay memory impairment in MS.

Objectives

To investigate episodic memory performance and hippocampal functional connectivity abnormalities in the preclinical and initial stages of MS.

Methods

Cross-sectional study of 50 subjects: 30 healthy controls and 20 patients with clinical and radiological isolated syndrome (CIS/RIS) (n=13 and 7, respectively). Episodic memory capabilities were assessed with a modified version of Rey Auditory Verbal Learning Test (RAVLTm): introduction of two recognition trials in the five learning trials. Moreover, participants underwent a magnetic resonance imaging session on which resting-state sequences were acquired. Regression models were used to evaluate between-group differences in memory capabilities. Two-sample t-tests models were used to assess whole-brain differences in the seed-based functional connectivity (FC) of the bilateral hippocampus. All analysis were controlled for gender, age, educational level and presence of anxiety and/or depressive symptoms.

Results

No between-group differences emerged in the sum of the words of the learning trials (p=0.164), the delayed recall trial (p=0.193) nor the three recognition trials as measured by discriminability index (d’) (p=0.775, p=0.954, p=0.395, respectively) and Criterion Level (C) (p=0.860, p=0.864, p=0.858, respectively). Nevertheless, compared to controls, CIS/RIS showed higher FC in the hippocampi-right angular gyrus network (t= 5.18, p<0.001).

Conclusions

Prior any sign of episodic memory dysfunction in preclinical and initial stages of MS, higher FC in the hippocampi-right angular gyrus are detected. These findings could be explained as compensatory mechanism used by CIS/RIS to achieve the same performance in episodic memory task as healthy controls. At the same time, such FC increase could be an early sign of future episodic memory problems.

Background

Memory impairment is commonly found in multiple sclerosis (MS), presented in between 40 to 75% of patients. It is accepted that hippocampus plays a critical role in memory function therefore studying this brain structure is crucial to understand the nature of memory deficits. However, there is a lack of knowledge regarding how functional connectivity changes in memory-related brain regions, such as the hippocampus, exist between MS subtypes.

Objectives

To investigate hippocampal resting-state functional connectivity changes between MS subtypes and healthy controls, and associations with the presence of total white matter (WM) lesions.

Methods

30 healthy controls and 78 MS patients (34 relapsing-remitting (RRMS)), 24 primary or secondary progressive subtypes (PMS) and 20 clinical or radiological isolated syndrome (CIS/RIS)) underwent a magnetic resonance imaging session. Univariate ANOVA models in SPM12 were used to assess whole-brain differences in the seed-based functional connectivity (FC) of the bilateral hippocampus, between controls and MS subtypes. Regression models then assessed whether the FC strength in the identified hippocampal networks showed a significant association with total WM lesions.

Results

Mean total WM lesion volume was different among MS subtypes (F=18.493; p<0.001), with PMS showing the highest lesioned volume (16.32±14.09ml), followed by RRMS (8.93±9.46ml) and CIS/RIS (2.07±2.67ml). Compared to controls, both the PMS and RRMS showed lower FC in the hippocampi-right middle frontal gyrus network, while RRMS additionally showed lower FC with the rostral anterior cingulate cortex. Conversely, CIS/RIS showed higher FC in the hippocampi-right angular gyrus network. The lower FC in the hippocampi-right middle frontal gyrus network in PMS and RRMS was also significant compared with CIS/RIS, with PMS additionally showing lower FC in the hippocampi-dorsomedial frontal cortex. Finally, RRMS showed lower FC in the hippocampi-left insula network when directly compared to PMS. The strength of FC in the hippocampi-dorsomedial prefrontal cortex network was negatively associated with the total WM lesion volume (R²= 0.085, F= 6.76, p= 0.011) across the MS patients.

Conclusions

Hippocampal FC differences exist depending on MS subtypes, and the highest presence of total WM lesions impacts the FC with medial prefrontal cortex regions. Future studies are necessary to link such hippocampal changes with specific memory impairment.

Background

There are different treatments used for multiple sclerosis. Observational data generates evidence about what are the efficacy, safety, tolerance, adherence and management of these drugs in real world.

Objectives

To describe the experience with the use of teriflunomide in a specialized multiple sclerosis (MS) unit from September 2015 to May 2020

Methods

Epidemiological analysis of MS patients treated with teriflunomide from September 2015 to May 2020 in a specialized MS unit, together with the reasons to start and to stop with the treatment and the clinical evolution of the patients.

Results

112 patients (70% women, 30% men) were treated with teriflunomide from September 2015 to May 2020. The mean age was 42 years (range 21-68 years). Teriflunomide was the first MS treatment in >50% of cases and the others had been treated with other MS treatments with moderate efficacy, mainly interferons and glatiramer acetate. During this period, the drug was discontinued in 38 patients (34%): 27 patients for disease activity (relapses or new brain o spinal core lesions), 5 for adverse events, 4 for developing a progressive form of the disease, 2 for pregnancy desire, 1 for personal decision. There have been no severe adverse events. 3 patients had severe diarrhea and 2 peripheral neuropathy. 5 patients had significant hair fragility that was treated but did not cause discontinuation of teriflunomide.

Conclusions

Teriflunomide is an optimal, suitable and effective drug for relapsing-remitting with known and mild-to-moderate adverse events.

Background

Multiple sclerosis (MS) can cause progressive walking impairment that contributes to disability and reduced quality of life. Dalfampridine, a voltage-dependent potassium channel blocker, has been shown to improve walking in patients with MS, as demonstrated by an increase in walking speed.

Dalfampridine is approved as symptomatic treatment of impaired mobility in MS patients. Recently, it has been published dalfampridine could have an effect on other functional systems (FS) not directly related to ambulation.

Objectives

To demonstrate the dalfampridine effect on different FS.

To identify wether the impact on the different FS stabilizes the EDSS.

To establish correlations between different scales used to measure dalfampridine effectiveness and FS scores.

Methods

We collected 22 patients diagnosed of either relapsing-remitting, secondary progressive or primary progressive MS according Mc Donald´s criteria 2010 responsers to dalfampridine for at least one year.

Dalfampridine effectiveness was evaluated by Timed 25 foot-walk (T25-FW), Timed Up and GO (TUG), and Two minutes walk test (2MWT).

EDSS was performed every 3 months.

Median, interquartile ranges and p values were evaluated by Friedman test.

Results

- The mean of follow-up was 19,5 months (13 - 26)

- Outcomes on functional systems were:

Visual functions: at start treatment 0,0 (0.0 - 1.0); at 12 months 0,0 (0.0 - 0.0); at last visit: 0,0 (0.0 - 0.0) p= 0,069

Brainstem functions: at start treatment 0,0 (0.0 - 2.0); at 12 months 0,0 (0.0 - 2.0); at last visit: 0,0 (0.0 - 2.0) p= 0,368

Pyramidal functions: at start treatment 3,0 (2.0 - 3.0); at 12 months 3,0 (2.0 - 3.0); at last visit: 3,0 (2.0 - 3.0) p= 1,000

Cerebellar functions: at start treatment 2,0 (2.0 - 3.0); at 12 months 2,0 (1.0 - 2.0); at last visit: 2,0 (1.0 - 2.0) p= 0,670

Sensory functions: at start treatment 2,0 (2.0 - 3.0); at 12 months 2,0 (2.0 - 3.0); at last visit: 2,0 (2.0 - 3.0) p= 0,867

Bowel and Bladder functions: at start treatment 1,0 (0.0 - 1.0); at 12 months 1,0 (1.0 - 1.0); at last visit: 1,0 (1.0 - 1.0) p= 1,000

Cerebral functions: at start treatment 1,0 (0.0 - 2.0); at 12 months 0,0 (0.0 - 0.0); at last visit: 0,0 (0.0 - 0.0) p= 0,005

Ambulation score: at start treatment 6,0 (2.0 - 7.0); at 12 months 6,0 (3.0 - 7.0); at last visit: 6,0 (5.0 - 8.0) p= 0,323

- The EDSS mean at the start of dalfampridine was 5,61 (4.0 - 6.5), at 12 months 5,5 (3.5 - 7.0) p= 0,339 and at the last visit 5,45 (2.0 - 7.0) p= 0,441.

- There was a negative correlation between sphincter and sensory functions and 2MWT.

Conclusions

We could obtain a relevant effect of dalfampridine on cerebral functions measured over more than a year. Nonetheless, we can not conclude if this outcome is directly related with an effect over cognition or it is related with improvement of fatigue and depression.

EDSS remained stable over more than a year in dalfampridine responsers.

We can not explain why patients who are responsers to dalfampridine had worsening of sphincter and sensory functions at the same time.