Perspectives on Neuromyelitis Optica Spectrum Disorders, the Narrative Medicine contribution to care.

BACKGROUND: This research aimed to investigate the experience of Neuromyelitis Optica Spectrum Disorders (NMOSD) by integrating the perspectives of patients, caregivers and clinicians through narrative-based medicine to provide new insights to improve care relationships. METHODS: The research was conducted in the second half of 2022 and involved six Italian centres treating NMOSD and targeted adult patients, their caregivers and healthcare providers to collect the three points of view of living with or caring for this rare disease, still difficult to treat despite the pharmacological options. Narratives followed a structured outline according to the time: yesterday-today-tomorrow, to capture all disease phases. RESULTS: Twenty-five patients diagnosed with NMOSD, ten caregivers and 13 healthcare providers participated in the research. Patients reported symptoms limiting their daily activities and strongly impacting their social dimension. We noticed improvements across disease duration, whilst the persistence of limitations was recurrent in patients with longer diagnoses. Caregivers' narratives mainly share experiences of their daily life changes, the burden of the caregiving role and the solutions identified, if any. Healthcare providers defined their role as a guide. CONCLUSION: Limitations in activities are prominent in the lives of people with NMOSD, along with fatigue. Family members are the weakest link in the chain and need information and support. Healthcare professionals are attentive to the helping dimension.

Identifying definite patterns of unmet needs in patients with multiple sclerosis using unsupervised machine learning.

INTRODUCTION: People with multiple sclerosis (PwMS) exhibit a spectrum of needs that extend beyond solely disease-related determinants. Investigating unmet needs from the patient perspective may address daily difficulties and optimize care. Our aim was to identify patterns of unmet needs among PwMS and their determinants. METHODS: We conducted a cross-sectional multicentre study. Data were collected through an anonymous, self-administered online form. To cluster PwMS according to their main unmet needs, we performed agglomerative hierarchical clustering algorithm. Principal component analysis (PCA) was applied to visualize cluster distribution. Pairwise comparisons were used to evaluate demographics and clinical distribution among clusters. RESULTS: Out of 1764 mailed questionnaires, we received 690 responses. Access to primary care was the main contributor to the overall unmet need burden. Four patterns were identified: cluster C1, 'information-seekers with few unmet needs'; cluster C2, 'high unmet needs'; cluster C3, 'socially and assistance-dependent'; cluster C4, 'self-sufficient with few unmet needs'. PCA identified two main components in determining the patterns: the 'public sphere' (access to information and care) and the 'private sphere' (need for assistance and social life). Older age, lower education, longer disease duration and higher disability characterized clusters with more unmet needs in the private sphere. However, demographic and clinical factors failed in explaining the four identified patterns. CONCLUSION: Our study identified four unmet need patterns among PwMS, emphasizing the importance of personalized care. While clinical and demographic factors provide some insight, additional variables warrant further investigation to fully understand unmet needs in PwMS.

Relapse-associated worsening in a real-life multiple sclerosis cohort: the role of age and pyramidal phenotype.

BACKGROUND AND PURPOSE: The overall disability in patients with relapsing-remitting multiple sclerosis is likely to be partly rather than entirely attributed to relapse. MATERIALS AND METHODS: The aim was to investigate the determinants of recovery from first relapse and relapse-associated worsening (RAW) in relapsing-remitting multiple sclerosis patients from the Italian MS Registry during a 5-year epoch from the beginning of first-line disease-modifying therapy. To determine recovery, the functional system (FS) score was used to calculate the difference between the score on the date of maximum improvement and the score before the onset of relapse. Incomplete recovery was defined as a combination of partial (1 point in one FS) and poor recovery (2 points in one FS or 1 point in two FSs or any other higher combination). RAW was indicated by a confirmed disability accumulation measured by the Expanded Disability Status Scale score confirmed 6 months after the first relapse. RESULTS: A total of 767 patients had at least one relapse within 5 years of therapy. Of these patients, 57.8% experienced incomplete recovery. Age (odds ratio [OR] 1.02, 95% confidence interval [CI] 1.01-1.04; p = 0.007) and pyramidal phenotype were associated with incomplete recovery (OR = 2.1, 95% CI 1.41-3.14; p < 0.001). RAW was recorded in 179 (23.3%) patients. Age (OR = 1.02, 95% CI 1.01-1.04; p = 0.029) and pyramidal phenotype (OR = 1.84, 95% CI 1.18-2.88; p = 0.007) were the strongest predictors in the multivariable model. CONCLUSIONS: Age and pyramidal phenotype were the strongest determinants of RAW in early disease epochs.

Assessment of the treating physicians' first-hand experience with handling and satisfaction of ofatumumab therapy: findings from the PERITIA survey conducted in Europe.

BACKGROUND: Real-world evidence on experience and satisfaction of ofatumumab as a treatment option for relapsing multiple sclerosis (RMS) is limited. OBJECTIVE: To present cumulative responses from a questionnaire related to first-hand experience of treating physicians on handling and convenience of ofatumumab therapy along with concerns related to COVID-19. METHODS: PERITIA was a multicentre survey conducted to collect responses from the ASCLEPIOS I/II trial investigators from Europe via an online questionnaire. RESULTS: Forty-six physicians (Germany, n = 14; Spain, n = 12; Portugal, n = 10; Italy, n = 10) completed the survey. Overall, 43% of the physicians considered the benefit-risk ratio of ofatumumab as very good. Over 93% were in favour of ofatumumab self-administration at home and the majority (83%) believed it to be completely true that self-administration of ofatumumab eases the burden for patients in terms of time. All investigators would like to potentially use anti-CD20 therapy as a long-term strategy. Even during the COVID-19 pandemic, physicians were in favour of a self-administration of MS therapy at home over other anti-CD20 therapy infusions. CONCLUSION: European neurologists who were part of this survey considered the benefit-risk-ratio of ofatumumab as favourable and the monthly self-administered subcutaneous injections offering convenience for patients in the clinical practice.

Exposure to natalizumab throughout pregnancy: effectiveness and safety in an Italian cohort of women with multiple sclerosis.

OBJECTIVE: Assessing the risk of clinical and radiological reactivation during pregnancy and post partum in women with multiple sclerosis (MS) treated with natalizumab (NTZ) throughout pregnancy (LONG_EXP) compared with women interrupting treatment before (NO_EXP) and within >-30 days and ≤90 days from conception (SHORT_EXP), and describing newborns' outcomes. METHODS: Maternal clinical and radiological outcomes and obstetric and fetal outcomes were retrospectively collected and compared among groups (NO_EXP, SHORT_EXP, LONG_EXP). Predictors of clinical and radiological reactivation were investigated through univariable and multivariable analysis. RESULTS: 170 eligible pregnancies from 163 women referring to 29 Italian MS centres were included. Annualised relapse rate (ARR) was significantly lower in LONG_EXP (n=66, 0.02 (0.001-0.09)) compared with NO_EXP (n=31, 0.43 (0.21-0.75), p=0.002) and SHORT_EXP (n=73, 0.46 (0.30-0.66), p=0.0004) during pregnancy, and in LONG_EXP (0.12 (0.05-0.24)) compared with SHORT_EXP (0.30 (0.17-0.50), p=0.008) during post partum. Gadolinium-enhancing (Gd+) lesions were less frequent in LONG_EXP (n=6/50, 2.00%) compared with NO_EXP (n=9/21, 42.86%) and SHORT_EXP after delivery (n=17/49, 34.69%, p=0.010).Delaying NTZ resumption after delivery significantly increased the risk of relapses (OR=1.29 (95% CI 1.07 to 1.57), p=0.009) and Gd+ lesions (OR=1.49 (95% CI 1.17 to 1.89, p=0.001). Newborns' weight, length, head circumference and gestational age did not differ among groups after adjusting for confounders. Anaemia was tracked in 4/69 LONG_EXP newborns. Congenital anomaly rate was within the expected range for the untreated MS population. CONCLUSIONS: Our findings indicate that in women with MS treated with NTZ before conception, continuation of NTZ throughout pregnancy and its early resumption after delivery mitigate the risk of clinical and radiological reactivation. This approach has no major impact on newborns' outcomes.

Disability assessment using Google Maps.

OBJECTIVES: To evaluate the concordance between Google Maps® application (GM®) and clinical practice measurements of ambulatory function (e.g., Ambulation Score (AS) and respective Expanded Disability Status Scale (EDSS)) in people with multiple sclerosis (pwMS). MATERIALS AND METHODS: This is a cross-sectional multicenter study. AS and EDSS were calculated using GM® and routine clinical methods; the correspondence between the two methods was assessed. A multinomial logistic model is investigated which demographic (age, sex) and clinical features (e.g., disease subtype, fatigue, depression) might have influenced discrepancies between the two methods. RESULTS: Two hundred forty-three pwMS were included; discrepancies in AS and in EDDS assessments between GM® and routine clinical methods were found in 81/243 (33.3%) and 74/243 (30.4%) pwMS, respectively. Progressive phenotype (odds ratio [OR] = 2.8; 95% confidence interval [CI] 1.1-7.11, p = 0.03), worse fatigue (OR = 1.03; 95% CI 1.01-1.06, p = 0.01), and more severe depression (OR = 1.1; 95% CI 1.04-1.17, p = 0.002) were associated with discrepancies between GM® and routine clinical scoring. CONCLUSION: GM® could easily be used in a real-life clinical setting to calculate the AS and the related EDSS scores. GM® should be considered for validation in further clinical studies.

Perceived stress and social support in a large population of people with multiple sclerosis recruited online through the COVID-19 pandemic.

BACKGROUND AND PURPOSE: The COVID-19 emergency may cause post-traumatic stress disorder (PTSD), and with regard to people with MS (pwMS) chronic exposure to a wide range of challenging life events has been shown to be correlated with worsening of neurological symptoms, increased lesion burden on brain magnetic resonance imaging and relapses. The aim was to investigate perceived stress, depression, perceived social support, habits and behaviour changes in pwMS through COVID-19 in comparison to a control group. METHODS: A web-based survey was posted on SMsocialnetwork.com to investigate perceived stress (using the Perceived Stress Scale), depression (with Patient Health Questionnaire 2) and perceived social support (using Social Provision Scale 10 item) in pwMS and a control group through the COVID-19 pandemic. A secondary group of people with migraine was investigated. RESULTS: In all, 1286 answers from 612 pwMS and 674 control people were included in the final analysis. The answers from 318 people with migraine were included for a secondary analysis. A higher proportion of pwMS were depressed (43.1% vs. 23.1%; p < 0.001), had a high level of perceived stress (58% vs. 39.8%; p < 0.001) and felt significantly less social support (median 33 vs. 35; Q1-Q3 28-36 vs. 32-37; p < 0.001) compared to the control group. A higher percentage of people with migraine were depressed (50% vs. 43%, p = 0.04) compared to pwMS. CONCLUSIONS: Considering the negative impact that prolonged stress may have on clinical and radiological disease activity of pwMS, and bearing in mind that a beneficial effect has been demonstrated and achieved with stress management, it is suggested to promote stress control in these patients during the COVID-19 pandemic.

COVID-19 pandemic and mental distress in multiple sclerosis: Implications for clinical management.

BACKGROUND AND PURPOSE: In multiple sclerosis (MS), disease-related factors and dysfunctional coping might favor the development of mental distress induced by COVID-19 containment measures. Aim of this study was exploring the relationship between disability, coping strategies, daily life reorganization and neuropsychiatric symptoms in an Italian MS population during the COVID-19 lockdown, in order to identify potentially modifiable factors that could inform clinical management of mental distress in people with MS. METHODS: We explored the relationship between mental distress, disability and coping strategies in the Italian MS population under lockdown. Structural equation modeling was applied to information collected via web survey to identify modifiable factors that could account for mental distress. RESULTS: A total of 845 participants (497 with MS and 348 controls) were included in the study. The MS group had higher scores than the control group for depression (p = 0.005), but not for anxiety, emotional dyscontrol or sleep disturbances. The structural equation modeling explained 74% of the variance observed in depression score. Within the model, three latent factors were characterized from measured variables: motor disability and cognitive dysfunction contributed to disability (ß = 0.509 and ß = 0.836; p < 0.001); positive attitude and exercise contributed to active attitude (ß = 0.386 and ß = 0.297; p < 0.001); and avoidance, social support and watching television contributed to passive attitude (ß = 0.301, ß = 0.243 and ß = 0.212; p < 0.001). With regard to the relationship between latent factors and their influence on depression, disability contributed to passive attitude (ß = 0.855; p < 0.001), while both passive and active attitude significantly influenced depression (ß = 0.729 and ß = -0.456; p < 0.001). CONCLUSION: As a practical implication of our model, favoring exercise would enhance active attitude and its positive impact on mental well-being while, at the same time, reducing the negative impact of disability on depression, representing a valuable tool in facing COVID-19-related mental distress.

Long-term fingolimod treatment in two pediatric patients with multiple sclerosis.

Data suggest that patients with pediatric-onset multiple sclerosis (POMS) should initiate treatment with a disease-modifying therapy early to slow progression. The PARADIGMS trial demonstrated that oral fingolimod reduced the annual rate of relapse by 82% compared with intramuscular interferon beta-1a in children with POMS. The PARADIGMS study had a follow-up of 2 years, but no data are available about the safety and efficacy of fingolimod for longer periods in children with POMS. Here we present two cases of children with POMS who achieved sustained clinical benefit from treatment with fingolimod for more than 2 years. The first patient, an 11-year-old male, who participate in the PARADIGMS study, was treatment naïve at the time of fingolimod initiation. His clinical condition remained stable over 5 years of treatment, with no relapses and no radiological lesion progression. The second patient was a female who initiated fingolimod at the age of 12 years, 2 years after her POMS diagnosis and after an 8-month trial of interferon beta-1a. The patient had experienced two relapses during interferon beta-1a but had no relapses in more than 2 years of treatment with fingolimod, and her MRI scans showed no new or active lesions. These data show that prolonged treatment with fingolimod can be safe and effective during long-term treatment as first- or second-line therapy in children with POMS.

Effects of 2-year treatment with dimethyl fumarate on cognition and functional impairment in patients with relapsing remitting multiple sclerosis.

BACKGROUND: A significant proportion of patients with multiple sclerosis (MS) show cognitive impairment. OBJECTIVE: To evaluate the effect of 2-year treatment with oral dimethyl fumarate (DMF) on cognition in relapsing remitting MS (RRMS). METHODS: In this prospective single-arm study RRMS patients treated with DMF underwent a wide battery of tests, including an extensive neuropsychological evaluation, clinical and patient-reported outcomes (PROs) and quality of life (QoL). Primary endpoints were the proportion of patients with cognitive impairment at baseline and of patients with cognitive worsening over 2 years. RESULTS: Overall, 217 patients (74.2% females, mean age 37.3 years) receiving DMF were recruited, and 156 (67.2%) completed the study. Of the 49 patients with cognitive impairment at baseline, 34 had 2-year data: 15 (44.1%) patients worsened and 19 (55.9%) did not. The cognitive impairment index improved in one third of patients at 2 years. Less than 20% of patients had relapses at 2 years (annualized relapse rate: 0.190). Few patients had disability progression. PROs (fatigue, depression, impairment in work/social activities), QoL, and most of neuropsychological tests significantly improved vs. baseline. CONCLUSION: The 2-year treatment with DMF was associated with slowing of cognitive impairment and with significant improvements in QoL and psychosocial function.

The Effects of Concurrent Resistance and Aerobic Exercise Training on Functional Status in Patients with Multiple Sclerosis.

Loss of balance and walking ability are two of the primary impairments in multiple sclerosis (MS), which leads to loss of autonomy, increased fatigue perception, and disease severity in patients. Physical activity has been shown to ameliorate MS functional impairments, but there is limited evidence of synergistic efficacy of exercise training interventions that have both a resistance and aerobic focus in these patients. We evaluated the effect of a 12-wk combined training intervention (resistance and aerobic exercise) on balance, walking ability, fatigue perception, quality of life, and severity of disease in patients with MS. The combined training was well tolerated by the patients and improved the quality of life of the patients as also reflected in the improvement in walking and balance ability as well as reduced depression, fatigue, and severity of disease. The results of this study confirm the beneficial effects of physical activity in patients with MS and support the use of a combination of resistance and aerobic exercise training to achieve functional and psychological therapeutic outcomes.

Neuromuscular Electrical Stimulation Does Not Influence Spinal Excitability in Multiple Sclerosis Patients.

(1) Background: Neuromuscular electrical stimulation (NMES) has beneficial effects on physical functions in Multiple sclerosis (MS) patients. However, the neurophysiological mechanisms underlying these functional improvements are still unclear. This study aims at comparing acute responses in spinal excitability, as measured by soleus Hoffmann reflex (H-reflex), between MS patients and healthy individuals, under three experimental conditions involving the ankle planta flexor muscles: (1) passive NMES (pNMES); (2) NMES superimposed onto isometric voluntary contraction (NMES+); and (3) isometric voluntary contraction (ISO). (2) Methods: In total, 20 MS patients (MS) and 20 healthy individuals as the control group (CG) took part in a single experimental session. Under each condition, participants performed 15 repetitions of 6 s at 20% of maximal voluntary isometric contraction, with 6 s of recovery between repetitions. Before and after each condition, H-reflex amplitudes were recorded. (3) Results: In MS, H-reflex amplitude did not change under any experimental condition (ISO: p = 0.506; pNMES: p = 0.068; NMES+: p = 0.126). In CG, H-reflex amplitude significantly increased under NMES+ (p = 0.01), decreased under pNMES (p < 0.000) and was unaltered under ISO (p = 0.829). (4) Conclusions: The different H-reflex responses between MS and CG might reflect a reduced ability of MS patients in modulating spinal excitability.

Ocrelizumab and ofatumumab comparison: an Italian real-world propensity score matched study.

BACKGROUND: The management of Multiple Sclerosis (MS) has undergone transformative evolution with the introduction of high-efficacy disease-modifying therapies (DMTs), specifically anti-CD20 monoclonal antibodies, such as ocrelizumab (OCR) and ofatumumab (OFA). MATERIALS AND METHODS: This is an independent retrospective cohort study in Relapsing MS (RMS) patients followed at eight Italian MS centers who initiated treatment with OCR or OFA in the participating centers and with at least 12 months on therapy. A generalized linear regression model inverse probability of treatment weight (IPTW) PS-adjusted was performed to evaluate the relationship between annualized relapse rate (ARR) and treatment groups. No evidence of disease activity-NEDA-3 at 12-month score was also collected. Safety profile of the investigated DMTs was recorded. RESULTS: A total cohort of 396 RMS patients fulfilled the required criteria and were enrolled in the study. Out of them, 216 had a prescription of OCR and 180 of OFA. The mean follow-up was 13.2 ± 1.9 months. The estimated means for ARR did not show differences between the two groups, 0.059 for patients on OCR and 0.038 for patients on OFA (p = 0.185). The generalized regression model IPTW PS-adjusted did not reveal differences between patients on OCR and OFA (ExpBOFA 0.974, 95%CI 934-1.015, p = 0.207). NEDA-3 at 12 months was experienced by 199(92.1%) patients on OCR and 170(94.4%) patients on OFA (p = 0.368). Generally, both therapies exhibit good tolerability. CONCLUSIONS: The treatment with OCR and OFA resulted in comparable control of disease activity with good safety profile. Our results need further validation in larger multicentre studies with long-term follow-up.

ChatGPT vs. neurologists: a cross-sectional study investigating preference, satisfaction ratings and perceived empathy in responses among people living with multiple sclerosis.

BACKGROUND: ChatGPT is an open-source natural language processing software that replies to users' queries. We conducted a cross-sectional study to assess people living with Multiple Sclerosis' (PwMS) preferences, satisfaction, and empathy toward two alternate responses to four frequently-asked questions, one authored by a group of neurologists, the other by ChatGPT. METHODS: An online form was sent through digital communication platforms. PwMS were blind to the author of each response and were asked to express their preference for each alternate response to the four questions. The overall satisfaction was assessed using a Likert scale (1-5); the Consultation and Relational Empathy scale was employed to assess perceived empathy. RESULTS: We included 1133 PwMS (age, 45.26 ± 11.50 years; females, 68.49%). ChatGPT's responses showed significantly higher empathy scores (Coeff = 1.38; 95% CI = 0.65, 2.11; p > z < 0.01), when compared with neurologists' responses. No association was found between ChatGPT' responses and mean satisfaction (Coeff = 0.03; 95% CI = - 0.01, 0.07; p = 0.157). College graduate, when compared with high school education responder, had significantly lower likelihood to prefer ChatGPT response (IRR = 0.87; 95% CI = 0.79, 0.95; p < 0.01). CONCLUSIONS: ChatGPT-authored responses provided higher empathy than neurologists. Although AI holds potential, physicians should prepare to interact with increasingly digitized patients and guide them on responsible AI use. Future development should consider tailoring AIs' responses to individual characteristics. Within the progressive digitalization of the population, ChatGPT could emerge as a helpful support in healthcare management rather than an alternative.

Sexual Dysfunction in People with Multiple Sclerosis: The Role of Disease Severity, Illness Perception, and Depression.

Despite being a common issue in people with multiple sclerosis (pwMS), sexual dysfunction is still underinvestigated. This work aims to assess the potential determinants of sexual dysfunction in pwMS by considering its relationship with disease severity (in terms of global disability), illness perception, and depressive symptoms. In this multicenter study, 1010 pwMS responded to an online survey. A serial mediation model considering negative illness perception and depressive symptoms as mediators of the relationship between disease severity and sexual dysfunction was conducted using the SPSS PROCESS Macro with bias-corrected bootstrapping (5000 samples). Disease severity exerts an indirect effect on sexual dysfunction via illness perception, both independently and through depressive symptoms. However, the results indicated that illness perception plays a more crucial role in sexual dysfunction in pwMS with mild disability than in pwMS with moderate-severe disability. This study suggests that higher disability increases its magnitude by enhancing negative illness perception, that, in turn, affects sexual dysfunction both directly and through depressive symptoms, especially in pwMS with mild disability. Modulating the effect of illness perception by favoring adaptive coping strategies might represent a valid approach to mitigate sexual dysfunction symptoms in MS.

MRI-based analysis of the natalizumab therapeutic window in multiple sclerosis.

The recommended natalizumab dosage is 300 mg every 4 weeks. We evaluated radiological activity at various times from the last natalizumab infusion by examining 386 magnetic resonance imaging (MRI) scans from 166 natalizumab-treated patients with relapsing-remitting MS. Of 113 scans performed >4 weeks after last natalizumab infusion, 26 were active (i.e. had ≥1 contrast-enhancing lesions). Risk of radiological activity increased by 1.34 fold for each week of delay with respect to the recommended 4-week dosing interval, compared with schedule-adherent patients (p<0.0001). Our data suggest that an increased MRI activity ≥7 weeks from the last infusion of natalizumab should be considered in cases of therapy discontinuation.

Escalation to natalizumab or switching among immunomodulators in relapsing multiple sclerosis.

OBJECTIVE: To evaluate whether an escalation approach was more effective in suppressing clinical and magnetic resonance imaging (MRI) activity than switching among immunomodulators in relapsing-remitting multiple sclerosis (RRMS) patients. METHODS: In this post-marketing, prospective, observational study in two Italian multiple sclerosis (MS) centres, a total of 285 RRMS patients who failed a first-line treatment with interferon beta (IFNß) or glatiramer acetate (GA) were considered. Patients were subdivided according to the strategy adopted after the failure (defined as the occurrence of ≥2 relapses or 1 relapse with residual disability): the switching (SWI) group, i.e. those switched among different IFNß formulations, or from IFNß to GA and vice versa; and the escalating (ESC) group, i.e. those escalated to natalizumab. Proportions of patients free from different types of disease activity (relapses, sustained disability progression, new active lesions on MRI, or a combination of them) were calculated at 12 and 24 months. Since patients were not randomized to treatment group, propensity score (PS)-adjusted Cox regression models were built to control for several potential confounders. RESULTS: At 12 months there were no differences between the two groups in proportions of patients free from relapse, disability progression, MRI activity, and combined activity. After 24 months we observed greater proportions of patients in the ESC than SWI group free from relapse (p < 0.0001), disability progression (p = 0.0045), MRI activity (p = 0.0003), and combined activity (p < 0.0001). PS-adjusted models confirmed these findings, with hazard ratios ranging from 0.38 to 0.56 favours the ESC group. CONCLUSION: We suggest that an escalation to natalizumab is more effective than switching among immunomodulators in RRMS patients who failed a first-line treatment.

Are Neurophysiological Biomarkers Able to Discriminate Multiple Sclerosis Clinical Subtypes?

Secondary progressive multiple sclerosis (SPMS) subtype is retrospectively diagnosed, and biomarkers of the SPMS are not available. We aimed to identify possible neurophysiological markers exploring grey matter structures that could be used in clinical practice to better identify SPMS. Fifty-five people with MS and 31 healthy controls underwent a transcranial magnetic stimulation protocol to test intracortical interneuron excitability in the primary motor cortex and somatosensory temporal discrimination threshold (STDT) to test sensory function encoded in cortical and deep grey matter nuclei. A logistic regression model was used to identify a combined neurophysiological index associated with the SP subtype. We observed that short intracortical inhibition (SICI) and STDT were the only variables that differentiated the RR from the SP subtype. The logistic regression model provided a formula to compute the probability of a subject being assigned to an SP subtype based on age and combined SICI and STDT values. While only STDT correlated with disability level at baseline evaluation, both SICI and STDT were associated with disability at follow-up. SICI and STDT abnormalities reflect age-dependent grey matter neurodegenerative processes that likely play a role in SPMS pathophysiology and may represent easily accessible neurophysiological biomarkers for the SPMS subtype.

Predictors of Cladribine Effectiveness and Safety in Multiple Sclerosis: A Real-World, Multicenter, 2-Year Follow-Up Study.

INTRODUCTION: Cladribine administration has been approved for the treatment of relapsing-remitting multiple sclerosis (MS) in 2017; thus, data on cladribine in a real-world setting are still emerging. METHODS: We report on cladribine effectiveness, safety profile, and treatment response predictors in 243 patients with MS followed at eight tertiary MS centers. Study outcomes were: (1) No Evidence of Disease Activity-3 (NEDA-3) status and its components (absence of clinical relapses, MRI activity, and sustained disability worsening); (2) development of grade III/IV lymphopenia. The relationship between baseline features and the selected outcomes was tested via multivariate logistic models. RESULTS: Of the 243 subjects included in the study (66.5% female, age 34.2 ± 10 years, disease duration 6.6 ± 9.6 years), 64% showed NEDA-3 at median follow-up (22 months). Patients with higher number of previous treatments had lower probability to retain NEDA-3 [odds ratio (OR) 0.64, 95% confidence interval (CI) 0.41-0.98, p = 0.04] and were more prone to experience clinical relapses (OR 1.6, 95% CI 1-2.6, p = 0.04). The presence of active lesions at baseline was associated with follow-up magnetic resonance imaging (MRI) activity (OR 1.92, 95% CI 1.04-3.55, p = 0.04). Patients with higher rate of relapses in the year prior to cladribine start were at higher risk of developing sustained disability worsening (OR 2.95% CI 1-4.2, p = 0.04). Lymphopenia grade III/IV over the follow-up was associated with baseline lymphocyte count (OR 0.998, 95% CI 0.997-0.999, p = 0.01). CONCLUSION: In this large cohort, we confirm previous data about cladribine effectiveness on disease activity and disability worsening and provide information on response predictors that might inform therapeutic choices.