Multiple Sclerosis: An Emergency Medicine-Focused Narrative Review.

BACKGROUND: Multiple sclerosis (MS) is a rare but serious condition associated with significant morbidity. OBJECTIVE: This review provides a focused assessment of MS for emergency clinicians, including the presentation, evaluation, and emergency department (ED) management based on current evidence. DISCUSSION: MS is an autoimmune disorder targeting the central nervous system (CNS), characterized by clinical relapses and radiological lesions disseminated in time and location. Patients with MS most commonly present with long tract signs (e.g., myelopathy, asymmetric spastic paraplegia, urinary dysfunction, Lhermitte's sign), optic neuritis, or brainstem syndromes (bilateral internuclear ophthalmoplegia). Cortical syndromes or multifocal presentations are less common. Radiologically isolated syndrome and clinically isolated syndrome (CIS) may or may not progress to chronic forms of MS, including relapsing remitting MS, primary progressive MS, and secondary progressive MS. The foundation of outpatient management involves disease-modifying therapy, which is typically initiated with the first signs of disease onset. Management of CIS and acute flares of MS in the ED includes corticosteroid therapy, ideally after diagnostic testing with imaging and lumbar puncture for cerebrospinal fluid analysis. Emergency clinicians should evaluate whether patients with MS are presenting with new-onset debilitating neurological symptoms to avoid unnecessary testing and admissions, but failure to appropriately diagnose CIS or MS flare is associated with increased morbidity. CONCLUSIONS: An understanding of MS can assist emergency clinicians in better diagnosing and managing this neurologically devastating disease.

Peripheral oedema as an adverse effect of treatment of secondary progressive multiple sclerosis with siponimod: A case series.

Siponimod is a sphingosine 1-phosphate receptor (S1P) modulator used to treat secondary progressive multiple sclerosis (SPMS). We report 3 SPMS patients treated with siponimod who developed new or worsening peripheral oedema soon after commencing treatment. In one case, peripheral oedema resulted in immobility. Siponimod-related peripheral oedema deserves wider recognition due to the potential for morbidity and over-investigation. Clinicians should assess for pre-existing oedema and coexisting conditions that may predispose to developing peripheral oedema prior to commencing siponimod.

Spinal Segmental Myoclonus in Primary Progressive Multiple Sclerosis.

Background: A wide variety of associated movement disorders has been described in multiple sclerosis. Phenomenology Shown: A 57-year-old woman with primary progressive multiple sclerosis developed spinal segmental myoclonus associated with focal myelitis. Educational Value: Movement disorders in multiple sclerosis are phenomenologically diverse and have varied pathophysiological mechanisms, making it essential to identify them to initiate appropriate treatment.

Virtual reality rehabilitation in patients affected by multiple sclerosis: Impact on quality of life and sexual functions.

BACKGROUND: Multiple Sclerosis (MS) can present several neurological symptoms with a progression that often leads to loss of cognitive and physical abilities. Sexual dysfunctions are frequent, although underestimated, MS symptoms significantly affecting the quality of life of these patients. The primary objective of this study was to assess the effectiveness of VR rehabilitation in enhancing the quality of life in individuals with MS. The secondary objective aimed to investigate whether the improvement in quality of life would also lead to enhanced sexual satisfaction and sexual function. MATERIALS AND METHODS: Patients diagnosed with relapsing-remitting and secondary progressive MS and attending from November 2018 to March 2020 the Rehabilitation Laboratory of IRCCS Neurolesi "Bonino Pulejo" in Messina, Italy were enrolled in this study. All patients were randomized into either the control group (CG: 35 patients) that received traditional cognitive rehabilitation (CR) or the experimental group (EG: 35) undergoing VR. RESULTS: The EG showed substantial improvements in various aspects of Multiple Sclerosis Quality of Life (MSQOL) between T0 and T1. Sexual function significantly improved, along with sexual satisfaction. Conversely, the CG achieved significant changes only in overall quality of life. Pearson's correlations highlighted the positive associations between sexual function and satisfaction, as well as with physical and mental well-being, underscoring the importance of improving sexual function as a marker of overall health. DISCUSSION: This study is meant as exploratory as it addresses a fundamental yet overlooked aspect of rehabilitation, i.e., sexual function and sexual satisfaction, which could potentially be enhanced through rehabilitation in a VR environment. Registration DOI number: DOI 10.17605/OSF.IO/NB4MJ.

Ocrelizumab in highly disabled progressive multiple sclerosis patients.

BACKGROUND: Ocrelizumab is a commonly used anti-CD20 monoclonal antibody with efficacy in the treatment of both relapsing-remitting (RRMS) and primary progressive (PPMS) multiple sclerosis. Real world use of ocrelizumab in MS patients with higher levels of motor disability requiring a walker or a wheelchair is not well characterized as these populations were excluded from initial studies. Higher levels of disability may be a barrier to treatment access. This study aimed to describe the access to, and tolerability and therapeutic outcomes of ocrelizumab in highly disabled MS patients in a real-world setting. METHODS: As part of an ongoing study of ocrelizumab treatment access, barriers, and outcomes in MS patients at the Brigham MS Center, we retrospectively reviewed all patients with an Expanded Disability Status Scale (EDSS) of 6.5 or greater at the time of ocrelizumab initiation. All patients were started on ocrelizumab by their treating providers prior to this study initiation. Patients were excluded for recent rituximab exposure, co-treatment with more than one immunosuppressant, or alternative diagnoses contributing to high EDSS. Data was collected on incidence and severity of side effects while on ocrelizumab, persistence of treatment beyond one year, and MS stabilization versus progression while on this treatment. RESULTS: Of the 1219 patients on ocrelizumab between 2017 and 2021, 113 (9.3 %) had EDSS of 6.5 or greater at the time of ocrelizumab initiation. Of the 113, 51 (45.1 %) were excluded: 6 (5.3 %) because they were duplicates or didn't receive ocrelizumab at our center, 25 (22.1 %) due to rituximab treatment in the previous year, 16 (14.2 %) due to lack of at least 1 year of follow up, and 4 (3.5 %) due to relevant comorbidities/treatment with other immunosuppressants. 62 patients were included in the final analysis. At ocrelizumab start, mean age was 62.1 +/- 8.7 years and median EDSS was 7.0 (range 6.5 to 9.5). Ocrelizumab was started in 26 of the included 62 patients (41.9 %) because of objective clinical disease worsening, in 17 (27.4 %) because of subjective worsening, in 8 (12.9 %) to prevent future progression. 32 patients (51.6 %) continued ocrelizumab throughout the study period, with average length of ocrelizumab use of 36.5 +/- 17.0 months. 29 patients (46.8 %) experienced no side effects during the study period. 29 (46.7 %) patients discontinued treatment, and of those, 9 (31.0 %) cited more than one reason for discontinuation: 17 (58.6 %) cited side effects, 12 (41.4 %) cited progression/lack of benefit, 6 (20.7 %) cited the Covid19 pandemic, and 1 (3.4 %) cited financial issues as a reason for discontinuation. Over the course of the study, 16 (25.8 %) patients had disability worsening by EDSS, 5 (8.1 %) had disability improvement, and 41 (66.1 %) remained stable, with a median end EDSS of 7.0 (range 6.5 to 9.5). Importantly, 18 patients (29.0 %) reported subjective disease stability while on ocrelizumab. CONCLUSIONS: Ocrelizumab may lead to disease stabilization in a subset of highly disabled MS patients, but possible benefits need to be carefully balanced against the incidence of adverse events in this high-risk patient population.

Dehydration associates with lower urinary tract symptoms in progressive multiple sclerosis.

BACKGROUND: Lower urinary tract symptoms (LUTS) are common in persons with progressive multiple sclerosis (pwPMS), who may consequently limit their fluid intake. We aimed to investigate the hypothesis that LUTS associate with objective evidence of inadequate hydration status in pwPMS. METHODS: In this prospective study, 55 pwPMS were studied over 2 years. A 6-monthly first-morning urine specimen was analysed for urinary osmolality and sodium as hydration markers. LUTS symptom severity in three categories (urgency, voiding and discomfort) was assessed and quantified using a questionnaire. Correlation between LUTS severity and hydration was assessed within subjects and between subjects, controlling for age. RESULTS: Some 274 urine samples with accompanying LUTS data from 55 participants were analysed. Biochemical data showed the expected loss of urine-concentrating capacity with increasing age. Inadequate hydration was observed in 47% of participants. LUTS were very common (87% reported urgency and 89% voiding symptoms). Voiding and discomfort, but not urgency severity, were correlated with hydration markers, both within and between participants. CONCLUSIONS: LUTS are very common in pwPMS, and associate with inadequate hydration. The causes and consequences of inadequate hydration in MS need further study, since (i) this will focus greater attention on LUTS management in pwPMS and (ii) dehydration has been associated with reversible cognitive dysfunction and physical underperformance.

A multiscale assessment of bowel impairment in an Italian multiple sclerosis cohort.

Bowel dysfunctions (BD) in multiple sclerosis (MS) are under reported despite their clinical relevance. Scales usually applied do not thoroughly assess constipation and fecal incontinence. Instead, a proper qualitative and quantitative description of these symptoms might have relevant clinical and scientific consequences. The aim of this project is to study the prevalence of BD in a cohort of persons with MS (pwMS). Four-hundred and forty-seven pwMS (330 relapsing-remitting MS-RRMS and 117 progressive MS-PMS) were recruited. Three different questionnaires were administered: the neurogenic bowel dysfunction score (NBDS), the Wexner constipation scale (WexCon) and the Wexner incontinence scale (WexInc). All the scales were divided in subscores according to symptom severity. The prevalence of BD, considered as NBDS > 0, was 53.7%. Mean scores in pwMS group were as follows: NBDS 2.6 (SD 3.5), WexInc 1.1 (SD 2.4), WexCon 4.4 (SD 5.9). NBDS, WexCon and WexInc were significantly higher in PMS vs RRMS (p < 0.001), and significantly associated with disease duration, EDSS, multiple sclerosis severity score (p < 0.001), as well as with each other (p < 0.001). Our study confirms the presence of bowel dysfunctions in a large group of pwMS with a wide range of disability and their association with progressive disease phenotype and clinical disability.

How Lung Volume Recruitment Maneuvers Enhance Respiratory Function in Multiple Sclerosis Patients: A Quasi-Randomized Pilot Study.

Background and Objectives: In patients with multiple sclerosis (MS), a decrease in muscle strength can lead to limitations in pulmonary functions, potentially causing respiratory complications. To address these challenges, the lung volume recruitment (LVR) maneuver has emerged as a potential intervention. This study sought to evaluate the impact of a four-week LVR protocol on respiratory function in secondary progressive MS patients. Materials and Methods: In a quasi-randomized pre/post-controlled trial, 24 patients with secondary progressive MS were recruited. Participants aged 20-70 years with an EDSS score of 2 to 9 were alternately allocated to intervention (n = 12) or control groups (n = 12). The intervention group underwent a 4-week respiratory rehabilitation training focused on LVR, using a standardized cough machine treatment protocol twice daily. The control group received no respiratory intervention. Outcomes measured included forced vital capacity (FVC), maximal insufflation capacity (MIC), and peak cough flow (PCF), using turbine spirometry and other associated equipment. All measurements were taken at baseline (T0) and after 4 weeks (T1) by a blinded assessor. Results: For the intervention group, the mean difference pre/post-treatment in MIC (mL) was 0.45 (SD 1.13) (p = 0.02), and in MIC (%), it was 0.13 (SD 0.24) (p = 0.03). Compared to the control group (n = 10), the between-group mean difference for MIC (mL) was 0.54 (p = 0.02), and for MIC (%), it was 0.15 (p = 0.02). Conclusions: The short-term daily LVR protocol notably improved passive lung capacity, despite minimal changes in active lung capacity or cough force. The LVR maneuver offers promise for enhancing respiratory function, especially passive lung capacity, in secondary progressive MS patients. Further research should explore optimal treatment durations and frequencies for more extensive respiratory gains.

Understanding who benefits most from cognitive rehabilitation for multiple sclerosis: A secondary data analysis.

BACKGROUND: Up to 70% of people with multiple sclerosis (MS) experience cognitive difficulties. Cognitive rehabilitation is a type of therapy that helps manage cognitive problems. OBJECTIVE: The Cognitive Rehabilitation for Attention and Memory in MS (CRAMMS) trial showed some evidence of effectiveness of cognitive rehabilitation in improving cognitive function, with some participants benefitting more than others. We therefore conducted a secondary analysis of the CRAMMS data to understand who benefits most. METHODS: We grouped baseline data into four categories of possible predictors. We used regression models to identify specific factors/characteristics that could predict the likelihood that an individual will benefit from cognitive rehabilitation. RESULTS: The models predicted whether a participant improved or did not improve in neuropsychological function following cognitive rehabilitation in up to 86% of participants. Results suggest that younger participants with medium to high education, diagnosed with relapsing-remitting multiple sclerosis (RRMS) and primary-progressive multiple sclerosis (PPMS) who have not experienced any recent relapses, with mild to moderate cognitive difficulties were most likely to benefit from cognitive rehabilitation. CONCLUSION: We can predict which participants are most likely to demonstrate significant improvements in neuropsychological function following group-based cognitive rehabilitation. Clinically, this allows us to optimise limited neuropsychology resources by offering such cognitive rehabilitation to those most likely to benefit.

Cognitive function in primary and secondary progressive multiple sclerosis: A multiparametric magnetic resonance imaging study.

BACKGROUND AND PURPOSE: The differences in cognitive function between primary progressive and secondary progressive multiple sclerosis (MS) remain unclear. We compared cognitive performance between primary progressive multiple sclerosis (PPMS) and secondary progressive multiple sclerosis (SPMS), and explored the structural and functional magnetic resonance imaging (MRI) correlates of their cognitive functions. METHODS: Seventy-five healthy controls and 183 MS patients (60 PPMS and 123 SPMS) underwent 3.0-T MRI. MS patients were administered the Brief Repeatable Battery of Neuropsychological Tests; cognitive domain z-scores were calculated and then averaged to obtain a measure of global cognition. Using hierarchical linear regression analysis, the contribution of lesion volumes, normalized brain volumes, white matter (WM) fractional anisotropy (FA) and mean diffusivity abnormalities, and resting state (RS) functional connectivity (FC) alterations to global cognition in PPMS and SPMS was investigated. RESULTS: PPMS and SPMS had similar z-scores in all investigated cognitive domains. Poor global cognitive function was associated with decreased FA of the medial lemniscus (ΔR 2 = 0.11, p = 0.011) and lower normalized gray matter volume (ΔR 2 = 0.29, p < 0.001) in PPMS, and with decreased FA of the fornix (ΔR 2 = 0.35, p < 0.001) and lower normalized WM volume (ΔR 2 = 0.05; p = 0.034) in SPMS. CONCLUSIONS: PPMS and SPMS had similar neuropsychological performance. Cognitive dysfunction in PPMS and SPMS was related to distinct patterns of structural MRI abnormalities and involvement of different WM tracts, whereas RS FC alterations did not contribute to explaining their global cognitive functioning.

Long non-coding RNAs BACE1-AS and BC200 in multiple sclerosis and their relation to cognitive function: A gene expression analysis.

Cognitive impairment is a common and debilitating feature of multiple sclerosis (MS), and the dysregulation of synaptic plasticity is one of its direct causes. Long non-coding RNAs (lncRNAs) have been shown to play a role in synaptic plasticity, but their role in cognitive impairment in MS has not been fully explored. In this study, using quantitative real-time PCR, we examined the relative expression of two specific lncRNAs, BACE1-AS and BC200, in the serum of two cohorts of MS patients with and without cognitive impairment. Both lncRNAs were overexpressed in both cognitively impaired and non-cognitively impaired MS patients, with consistently higher levels in the cohort with cognitive impairment. We also found a strong positive correlation between the expression levels of these two lncRNAs. Notably, BACE1-AS was consistently higher in the remitting cases of both relapsing-remitting MS (RRMS) and secondary progressive MS (SPMS) groups than in the respective relapse cases of the same subtype, with the SPMS-Remitting group of cognitively impaired MS patients showing the highest expression of BACE1-AS among all MS groups. Additionally, we observed that the primary progressive MS (PPMS) group had the highest expression of BC200 in both cohorts of MS. Furthermore, we developed a model called Neuro_Lnc-2, which showed better diagnostic performance than either BACE1-AS or BC200 alone in predicting MS. Our findings suggest that these two lncRNAs may have a significant impact on the pathogenesis of the progressive types of MS and on the cognitive function of the patients. Future research is required to confirm these findings.

The impact of cognitive impairment on disease burden in Chinese patients with multiple sclerosis: A model simulation study.

BACKGROUND: Cognitive impairment (CI) is prevalent in Chinese patients with relapsing-remitting multiple sclerosis (RRMS). METHODS: A decision analytic model was constructed to simulate Chinese patients with newly diagnosed RRMS and their matched control cohort without MS for the risks of developing CI, developing secondary progressive MS (SPMS), and mortality. Both English and Chinese bibliographic databases were searched for evidence to estimate model inputs. Base case analysis and sensitivity analysis were conducted for the point estimations and uncertainty of the measured burden outcomes. RESULTS: Model simulations estimated that the lifetime cumulative risk of CI in newly diagnosed RRMS patients was 85.2%. Relative to the matched control cohort, newly diagnosed RRMS patients were associated with a lower life expectancy (33.2 years vs. 41.7 years, difference: -8.5 years), lower quality-adjusted life years (QALY) (18.4 QALY vs. 38.4 QALY, difference: -19.9 QALY), and higher lifetime medical costs (¥613,883 vs. ¥202,726, difference: ¥411,157) and indirect costs (¥1,099,021 vs. ¥94,612, difference: ¥1,004,410). Patients who developed CI accounted for at least half of the measured burden. The disease burden outcomes were mainly driven by the risk of developing CI, progression risk from RRMS to SPMS, hazard ratios of mortality associated with CI relative to no CI, utility of patients with RRMS, annual relapse risk, and annual costs of personal care. CONCLUSION: Most Chinese patients with newly diagnosed RRMS are likely to develop CI in their lifetime, and such patients that develop CI could significantly contribute to the disease burden of RRMS.

Profiling cognitive-motor interference in a large sample of persons with progressive multiple sclerosis and impaired processing speed: results from the CogEx study.

BACKGROUND: Performing cognitive-motor dual tasks (DTs) may result in reduced walking speed and cognitive performance. The effect in persons with progressive multiple sclerosis (pwPMS) having cognitive dysfunction is unknown. OBJECTIVE: To profile DT-performance during walking in cognitively impaired pwPMS and examine DT-performance by disability level. METHODS: Secondary analyses were conducted on baseline data from the CogEx-study. Participants, enrolled with Symbol Digit Modalities Test 1.282 standard deviations below normative value, performed a cognitive single task ([ST], alternating alphabet), motor ST (walking) and DT (both). Outcomes were number of correct answers on the alternating alphabet task, walking speed, and DT-cost (DTC: decline in performance relative to the ST). Outcomes were compared between EDSS subgroups (≤ 4, 4.5-5.5, ≥ 6). Spearman correlations were conducted between the DTCmotor with clinical measures. Adjusted significance level was 0.01. RESULTS: Overall, participants (n = 307) walked slower and had fewer correct answers on the DT versus ST (both p < 0.001), with a DTCmotor of 15.8% and DTCcognitive of 2.7%. All three subgroups walked slower during the DT versus ST, with DTCmotor different from zero (p's < 0.001). Only the EDSS ≥ 6 group had fewer correct answers on the DT versus ST (p < 0.001), but the DTCcognitive did not differ from zero for any of the groups (p ≥ 0.039). CONCLUSION: Dual tasking substantially affects walking performance in cognitively impaired pwPMS, to a similar degree for EDSS subgroups.

[A case of primary progressive multiple sclerosis with improvement in cognitive impairment by anti-CD20 monoclonal antibody therapy].

The patient was a 44-year-old man who developed cognitive impairment beginning at the age of 35 years that gradually worsened. The cognitive impairment led to a difficult social life, and he retired from his company. After hospitalization and workup, he was diagnosed with primary progressive multiple sclerosis (PPMS) that presented only with cognitive impairment for 10 years. Since he had multiple predictive factors for poor prognosis, anti-CD20 monoclonal antibody therapy was implemented. Cognitive impairment and cerebral blood flow SPECT findings improved, and he returned to a social life 3 months later. Anti-CD20 monoclonal antibody therapy was effective in improving cognitive impairment in a case of an advanced stage of PPMS.

Case Report: Recurrent Severe Uveitis Secondary to Primary Progressive Multiple Sclerosis Responsive to Ocrelizumab.

PURPOSE: To report a case of severe, recurrent bilateral panuveitis secondary to primary progressive multiple sclerosis responsive to ocrelizumab infusions. OBSERVATION: We describe the clinical progression of a 40 year old female who presented with a 3-week history of insidious bilateral visual loss that was clinically consistent with panuveitis. A diagnosis of multiple sclerosis was established with serial magnetic resonance imaging (MRI) that coincided with focal neurological events separated by time. There was initially good response to high dose oral prednisolone; however, the patient would have recurrent uveitis each time the dose was weaned. Under guidance of neurology, we had initiated treatment with ocrelizumab with stability of ocular inflammation for the past 24 months. CONCLUSION: Six-monthly 600mg ocrelizumab infusions may be effective as a steroid sparing option for patients with severe, recurrent bilateral panuveitis secondary to primary progressive multiple sclerosis.

Limb apraxia in individuals with multiple sclerosis: Is there a role of semi-immersive virtual reality in treating the Cinderella of neuropsychology?

BACKGROUND: Limb apraxia is an acquired cognitive-motor disorder characterized by spatial and temporal disorganization of limb movements, negatively affecting the quality of life of patients, including those with multiple sclerosis (MS). Although recent studies have shown the potential role of VR in increasing cognitive and motor functions, only a few studies have been carried out on the rehabilitation of upper limb apraxia. Hence, our study aims to evaluate the potential efficacy of VR training to improve upper limb ideomotor apraxia in patients with MS. METHODS: One hundred and six patients, affected by secondary progressive MS, who attended our Robotic and Behavioral Neurorehabilitation Service from March 2019 to February 2020, were enrolled in this study and randomly divided into two groups: the control group (CG: 53 patients) performed traditional therapy whereas the experimental group (EG:53 patients) received training using semi-immersive VR. All patients underwent the same amount of cognitive training, 3 times a week for 8 weeks. They were submitted to a specific neuropsychological assessment before (T0) and after the rehabilitation treatment (T1). RESULTS: The VR training led to a significant improvement in global cognitive functions, with regard to constructive and ideomotor apraxia. On the contrary, the CG achieved significant improvements only in ideomotor apraxia. Moreover, only in the EG, we observed an improvement in the mood at the end of training. CONCLUSION: The present study demonstrates that VR rehabilitation can be an effective tool for the treatment of apraxia, which is a neuropsychological problem often underestimated in MS patients. Further studies with long-term follow-up periods are needed to confirm the effect of this promising approach.

Serum NfL but not GFAP predicts cognitive decline in active progressive multiple sclerosis patients.

BACKGROUND: Cognitive decline is inadequately captured by the standard neurological examination. Serum neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP) are biomarkers of neuronal damage and astrocytic reactivity that may offer an accessible measure of the multiple sclerosis (MS) pathology linked to cognitive decline. OBJECTIVE: To investigate the association of sNfL and sGFAP with cognitive decline in MS patients at high risk for progressive pathology. METHODS: We included 94 MS patients with sustained Expanded Disability Status Score (EDSS) ⩾ 3, available serum samples and cognitive assessment performed by symbol digit modalities test (SDMT) over a median of 3.1 years. The visit for sGFAP/sNfL quantification was at confirmed EDSS ⩾ 3. Linear regression analysis on log-transformed sGFAP/sNfL assessed the association with current and future SDMT. Analyses were adjusted for age, sex, EDSS, treatment group, and recent relapse. RESULTS: sNfL was significantly associated with concurrent SDMT (adjusted change in mean SDMT = -4.5; 95% confidence interval (CI): -8.7, -0.2; p = 0.039) and predicted decline in SDMT (adjusted change in slope: -1.14; 95% CI: -1.83, -0.44; p = 0.001), particularly in active patients. sGFAP was not associated with concurrent or future SDMT. CONCLUSIONS: Higher levels of sNfL were associated with cognitive impairment and predicted cognitive decline in MS patients at high risk for having an underlying progressive pathology.

Emotional Recognition and Its Relation to Cognition, Mood and Fatigue in Relapsing-Remitting and Secondary Progressive Multiple Sclerosis.

(1) Background: Emotional recognition (ER), the ability to read into others' minds and recognize others' emotional states, is important in social environment adaptation. Recently it has been found that ER difficulties affect patients with multiple sclerosis (pMS) and relate to different gray matter atrophy patterns from secondary progressive (SP-pMS) and relapsing-remitting (RR-pMS). The aim of this study was to compare the performances of the two MS phenotypes on the Reading the Mind in the Eyes test (RMEt) and other cognitive, mood and fatigue measures. We also examined associations between performance on the RMEt and cognitive, mood and fatigue variables. (2) Methods: A total of 43 pMS (27RR-pMS/16SP-pMS) underwent a clinical assessment, the RMEt, the cognitive battery, and completed mood and fatigue questionnaires. Both groups' performances on the RMEt were then correlated with all these measures. (3) Results: the RMEt scores of RR-pMS were significantly correlated with the impairment degree in some cognitive scores. SP-pMS scores correlated mainly with fatigue, anxiety, anger and depression. (4) Conclusions: ER performances relate to cognitive aspects in RR-pMS, whereas mainly to mood outcomes in the SP-pMS group. We can hypothesize that deficits in ER are a further sign of disease progression. Our data support the different roles of cognitive and emotional deficits related to different disease courses and lesional correlates.