Machine learning-driven diagnosis of multiple sclerosis from whole blood transcriptomics.

Multiple sclerosis (MS) is a neurological disorder characterized by immune dysregulation. It begins with a first clinical manifestation, a clinically isolated syndrome (CIS), which evolves to definite MS in case of further clinical and/or neuroradiological episodes. Here we evaluated the diagnostic value of transcriptional alterations in MS and CIS blood by machine learning (ML). Deep sequencing of more than 200 blood RNA samples comprising CIS, MS and healthy subjects, generated transcriptomes that were analyzed by the binary classification workflow to distinguish MS from healthy subjects and the Time-To-Event pipeline to predict CIS conversion to MS along time. To identify optimal classifiers, we performed algorithm benchmarking by nested cross-validation with the train set in both pipelines and then tested models generated with the train set on an independent dataset for final validation. The binary classification model identified a blood transcriptional signature classifying definite MS from healthy subjects with 97% accuracy, indicating that MS is associated with a clear predictive transcriptional signature in blood cells. When analyzing CIS data with ML survival models, prediction power of CIS conversion to MS was about 72% when using paraclinical data and 74.3% when using blood transcriptomes, indicating that blood-based classifiers obtained at the first clinical event can efficiently predict risk of developing MS. Coupling blood transcriptomics with ML approaches enables retrieval of predictive signatures of CIS conversion and MS state, thus introducing early non-invasive approaches to MS diagnosis.

Neuroaxonal damage in natalizumab-treated MS patients: The role of JCV antibody titres.

BACKGROUND: While John Cunningham virus (JCV) is known to cause neuronal damage in progressive multifocal leukoencephalopathy (PML) among natalizumab-treated MS patients, its association with axonal loss in non-PML conditions remains unclear. METHODS: In a cohort of 128 natalizumab-treated MS patients, serum neurofilament (sNfL) levels and JCV antibody titres were measured. RESULTS: Among 128 patients (mean age = 38.4 years, 71.9% female), 51 (40%) were JCV positive. NfL levels increased by 15.3% for JCV index <0.7 (95% confidence interval [CI] = 0.963-1.381), by 18.6% for index 0.7-1.5 (95% CI = 1.009-1.394) and by 21.1% for index >1.5 (95% CI = 1.040-1.409) compared to JCV negative patients. CONCLUSION: These findings indicate a potential link between JCV burden and neuroaxonal degeneration in natalizumab-treated MS patients.

Spinal Fluid Myeloid Microvesicles Predict Disease Course in Multiple Sclerosis.

OBJECTIVE: In vivo measures of myeloid activity are promising biomarkers in multiple sclerosis. We previously demonstrated that cerebrospinal fluid (CSF) myeloid microvesicles are markers of microglial/macrophage activity and neuroinflammation in multiple sclerosis. Here, we aimed at investigating the diagnostic and prognostic value of myeloid microvesicles in a clinical setting. METHODS: Six hundred one patients discharged with a diagnosis of neuroinflammatory, neurodegenerative, or no neurological disease were enrolled. Myeloid microvesicles were measured with flow cytometry as isolectin B4-positive events in fresh CSF. Clinical, demographical, and magnetic resonance imaging (MRI) data were collected at diagnosis (all patients) and during follow-up (n = 176). RESULTS: CSF myeloid microvesicles were elevated in neuroinflammatory patients compared to the neurodegenerative and control groups. In multiple sclerosis, microvesicles were higher in patients with MRI disease activity and their concentration increased along with the number of enhancing lesions (p < 0.0001, Jonckheere-Terpstra test). CSF myeloid microvesicles were also higher in patients with higher disease activity in the month and year preceding diagnosis. Microvesicles excellently discriminated between the relapsing-remitting and control groups (receiver operator characteristic curve, area under the curve = 0.939, p < 0.0001) and between radiologically isolated syndrome and unspecific brain lesions (0.942, p < 0.0001). Furthermore, microvesicles were independent predictors of prognosis for both the relapsing-remitting and progressive groups. Microvesicles independently predicted future disease activity in relapsing-remitting patients (hazard ratio [HR] = 1.967, 95% confidence interval [CI] = 1.147-3.372), correcting for prognostic factors of standard clinical use. In the progressive group, microvesicles were independent predictors of disability accrual (HR = 10.767, 95% CI = 1.335-86.812). INTERPRETATION: Our results confirm that CSF myeloid microvesicles are a clinically meaningful biomarker of neuroinflammation and microglial/macrophage activity in vivo. These findings may support a possible use in clinical practice during diagnostic workup and prognostic assessment. ANN NEUROL 2021;90:253-265.

Early Predictors of 9-Year Disability in Pediatric Multiple Sclerosis.

OBJECTIVE: The purpose of this study was to assess early predictors of 9-year disability in pediatric patients with multiple sclerosis. METHODS: Clinical and magnetic resonance imaging (MRI) assessments of 123 pediatric patients with multiple sclerosis were obtained at disease onset and after 1 and 2 years. A 9-year clinical follow-up was also performed. Cox proportional hazard and multivariable regression models were used to assess independent predictors of time to first relapse and 9-year outcomes. RESULTS: Time to first relapse was predicted by optic nerve lesions (hazard ratio [HR] = 2.10, p = 0.02) and high-efficacy treatment exposure (HR = 0.31, p = 0.005). Predictors of annualized relapse rate were: at baseline, presence of cerebellar (ß = -0.15, p < 0.001), cervical cord lesions (ß = 0.16, p = 0.003), and high-efficacy treatment exposure (ß = -0.14, p = 0.01); considering also 1-year variables, number of relapses (ß = 0.14, p = 0.002), and the previous baseline predictors; considering 2-year variables, time to first relapse (2-year: ß = -0.12, p = 0.01) entered, whereas high-efficacy treatment exposure exited the model. Predictors of 9-year disability worsening were: at baseline, presence of optic nerve lesions (odds ratio [OR] = 6.45, p = 0.01); considering 1-year and 2-year variables, Expanded Disability Status Scale (EDSS) changes (1-year: OR = 26.05, p < 0.001; 2-year: OR = 16.38, p = 0.02), and ≥ 2 new T2-lesions in 2 years (2-year: OR = 4.91, p = 0.02). Predictors of higher 9-year EDSS score were: at baseline, EDSS score (ß = 0.58, p < 0.001), presence of brainstem lesions (ß = 0.31, p = 0.04), and number of cervical cord lesions (ß = 0.22, p = 0.05); considering 1-year and 2-year variables, EDSS changes (1-year: ß = 0.79, p < 0.001; 2-year: ß = 0.55, p < 0.001), and ≥ 2 new T2-lesions (1-year: ß = 0.28, p = 0.03; 2-year: ß = 0.35, p = 0.01). INTERPRETATION: A complete baseline MRI assessment and an accurate clinical and MRI monitoring during the first 2 years of disease contribute to predict 9-year prognosis in pediatric patients with multiple sclerosis. ANN NEUROL 2021;89:1011-1022.

Towards a validated definition of the clinical transition to secondary progressive multiple sclerosis: A study from the Italian MS Register.

BACKGROUND: Definitions for reliable identification of transition from relapsing-remitting multiple sclerosis (MS) to secondary progressive (SP)MS in clinical cohorts are not available. OBJECTIVES: To compare diagnostic performances of two different data-driven SPMS definitions. METHODS: Data-driven SPMS definitions based on a version of Lorscheider's algorithm (DDA) and on the EXPAND trial inclusion criteria were compared, using the neurologist's definition (ND) as gold standard, in terms of sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), Akaike information criterion (AIC) and area under the curve (AUC). RESULTS: A cohort of 10,240 MS patients with ⩾5 years of follow-up was extracted from the Italian MS Registry; 880 (8.5%) patients were classified as SPMS according to the neurologist definition, 1806 (17.6%) applying the DDA and 1134 (11.0%) with the EXPAND definition. The DDA showed greater discrimination power (AUC: 0.8 vs 0.6) and a higher sensitivity (77.1% vs 38.0%) than the EXPAND definition, with similar specificity (88.0% vs 91.5%). PPV and NPV were higher using the DDA than considering EXPAND definition (37.5% vs 29.5%; 97.6% vs 94.0%). CONCLUSION: Data-driven definitions demonstrated greater ability to capture SP transition than neurologist's definition and the global accuracy of DDA seems to be higher than the EXPAND definition.

Subclinical anterior optic pathway involvement in early multiple sclerosis and clinically isolated syndromes.

Optical coherence tomography (OCT) is gaining increasing relevance in the assessment of patients with multiple sclerosis. Converging evidence point to the view that neuro-retinal changes, in eyes without acute optic neuritis, reflect inflammatory and neurodegenerative processes taking place throughout the CNS. The present study aims at exploring the usefulness of OCT as a marker of inflammation and disease burden in the earliest phases of the disease. Thus, a cohort of 150 consecutive patients underwent clinical, neurophysiological and brain MRI assessment as well as lumbar puncture as part of their diagnostic workup for a neurological episode suggestive of inflammatory CNS disorder; among those 32 patients had another previous misdiagnosed episode. For the present study, patients also received a visual pathway assessment (OCT, visual evoked potentials, visual acuity), measurement of CSF inflammatory markers (17 cytokines-chemokines, extracellular vesicles of myeloid origin), and dosage of plasma neurofilaments. Subclinical optic nerve involvement is frequently found in clinically isolated syndromes by visual evoked potentials (19.2%). OCT reveals ganglion cell layer asymmetries in 6.8% of patients; retinal fibre layer asymmetries, despite being more frequent (17.8%), display poor specificity. The presence of subclinical involvement is associated with a greater disease burden. Second, ganglion cell layer thinning reflects the severity of disease involvement even beyond the anterior optic pathway. In fact, the ganglion cell layer in eyes without evidence of subclinical optic involvement is correlated with Expanded Disability Status Scale, low contrast visual acuity, disease duration, brain lesion load, presence of gadolinium enhancing lesions, abnormalities along motor and somatosensory evoked potentials, and frequency of CSF-specific oligoclonal bands. Third, the inner nuclear layer thickens in a post-acute (1.1-3.7 months) phase after a relapse, and this phenomenon is counteracted by steroid treatment. Likewise, a longitudinal analysis on 65 patients shows that this swelling is transient and returns to normal values after 1 year follow-up. Notwithstanding, the clinical, MRI, serological and CSF markers of disease activity considered in the study are strictly associated with one another, but none of them are associated with the inner nuclear layer. Our findings challenge the current hypothesis that the inner nuclear layer is an acute phase marker of inflammatory activity. The present study suggests that instrumental evidence of subclinical optic nerve involvement is associated with a greater disease burden in clinically isolated syndrome. Neuro-retinal changes are present since the earliest phases of the disease and yield important information regarding the neurodegenerative and inflammatory processes occurring in the CNS.

Early evidence of disease activity during fingolimod predicts medium-term inefficacy in relapsing-remitting multiple sclerosis.

BACKGROUND: Fingolimod (FTY) is an effective second-line drug for relapsing-remitting multiple sclerosis, with ~50% patients showing no evidence of disease activity (NEDA) after 2 years. Nonetheless, the early identification of non-responders is extremely important, to promptly address them to more aggressive drugs. OBJECTIVES: This cohort study evaluates FTY medium-term effectiveness, searching for early markers of treatment failure. PATIENTS AND METHODS: Three hundred eighty patients starting FTY were enrolled and classified according to NEDA and time to first relapse criteria at 4-year follow-up. Logistic and Cox regression analyses were applied to identify early predictors of non-response. RESULTS: At 4 years, 65.6% of patients were free from relapses and 35.4% had NEDA. Female gender was associated with a higher risk of non-response. Moreover, evidence of clinical and/or magnetic resonance imaging (MRI) activity during the first year of treatment was highly predictive of disease activity in the follow-up: the positive predictive value for non-response was 0.74 for the presence of ⩾1 relapse, 0.73 for the presence of ⩾1 active MRI lesion, and 0.83 for the presence of both clinical and MRI activity. CONCLUSIONS: FTY effectiveness persists at medium-term follow-up; a close monitoring during the first year of treatment is warranted to early identify non-responders requiring treatment optimization.

Serum neurofilaments increase at progressive multifocal leukoencephalopathy onset in natalizumab-treated multiple sclerosis patients.

This study analyzed serum neurofilament light chains (NfL) in 2 European cohorts of 312 multiple sclerosis (MS) patients to investigate whether NfL are biomarkers of progressive multifocal leukoencephalopathy (PML) during natalizumab treatment. The cohort comprised 25 PML, 136 natalizumab-treated, and 151 untreated MS patients. Patients subsequently developing PML had similar NfL to other natalizumab-treated MS patients. At PML onset, NfL were 10-fold higher than in the pre-PML condition and in natalizumab-treated or untreated MS patients, and NfL continued to increase until onset of immune reconstitution inflammatory syndrome. The results suggest that in natalizumab-treated patients, NfL may represent an early and accessible marker of PML. Ann Neurol 2019;85:606-610.

Effectiveness of fingolimod in real-world relapsing-remitting multiple sclerosis Italian patients: the GENIUS study.

BACKGROUND: Fingolimod is the first oral agent approved for treatment of relapsing-remitting multiple sclerosis (RRMS). We aimed to evaluate fingolimod effectiveness in a real-world sample of RRMS patients. METHODS: A retrospective, multicentre study in patients treated with fingolimod, whom clinical and radiological data were collected in the 2 years preceding and following the initiation of fingolimod. RESULTS: Out of 414 patients, 56.8% received prior first-line injectable disease-modifying therapies, 25.4% were previously treated with natalizumab, 1.2% with immunosuppressant agents, and 16.7% were treatment naive. The annualized relapse rate decreased by 65% in the first year and by 70% after two years of treatment. Age ≤ 40 years, ≥ 1 relapse in the 24 months before fingolimod initiation and previous treatment with natalizumab were risk factors for relapses. Overall, 67.9% patients had no evidence of disease activity (NEDA-3) after 1 year and 54.6% after 2 years of treatment. A higher proportion of naïve (81.2% in 1 year and 66.7% after 2 years) or first-line injected patients (70.2% and 56.6%) achieved NEDA-3 than those previously treated with natalizumab (54.3% and 42.9%). CONCLUSIONS: Fingolimod appeared to be effective in naive patients and after first-line treatment failure in reducing risk of relapse and disease activity throughout the 2-year follow-up.

Assessing the role of innovative therapeutic paradigm on multiple sclerosis treatment response.

OBJECTIVE: Within the last decade, many changes have been made to the management of patients with multiple sclerosis (MS). The aim of our study was to investigate the global impact of all these changes on the disease's course. MATERIALS AND METHODS: This single-centre study was carried out on patients with multiple sclerosis (pwMS) who started treatment with first-line disease-modifying therapies. We have compared three large cohorts of patients with MS diagnosis, for three consecutive periods within July 2001, August 2001-December 2005, and January 2006-September 2011. RESULTS: A total of 1068 relapsing-remitting pwMS cases were included. Patients in the last cohort began treatment earlier (P < 0.0001), started more frequent treatment with high-dose interferon beta or glatiramer acetate (P < 0.0001), and had experienced a more frequent treatment escalation strategy (P = 0.004) than patients in other cohorts. The multivariate analysis adjusted for baseline characteristics showed that pwMS of the last cohort had a high probability of showing no evidence of disease activity (NEDA3) at 4 years (OR 3.22, 95% CIs 1.89-5.47; P < 0.0001). These results were confirmed in a propensity score analysis. CONCLUSIONS: Our study showed an improvement over the last 15 years in the treatment response; this observation can be associated to a paradigm shift in MS treatment strategies.

Clinical deterioration due to co-occurrence of multiple sclerosis and glioblastoma: report of two cases.

Clinical worsening during the course of multiple sclerosis (MS) might be secondary to not only an incomplete recovery after relapses, to progressive accumulation of deficits, but also to other etiologies, different from MS. This report discusses the cases of two MS patients showing a gradual and progressive deterioration of locomotor and cognitive functions which were due to the co-occurrence of MS and glioblastoma. Additional investigations (especially magnetic resonance imaging) are strongly recommended to exclude concomitant pathologies in MS patients suffering from new neurological symptoms over weeks to months, without remission, or an unexpected rapid and progressive accumulation of disability.

Recurrence of disease activity after repeated Natalizumab withdrawals.

Natalizumab (NTZ) is extremely effective in reducing disease activity in multiple sclerosis (MS) patients but its long-term use is associated with the risk of progressive multifocal leukoencephalopathy (PML). Thus, many patients discontinue NTZ and, after drug withdrawal, most of them face disease reactivation despite immunomodulant (IMD) start. The aim of this study was to evaluate the efficacy of different therapeutic strategies in preventing post-NTZ disease recurrence in a small cohort of patients that underwent repeated NTZ courses. 15 patients underwent two distinct NTZ discontinuations and started IMD after first withdrawal and a second line therapy (mainly fingolimod, FTY) after the second one. They were followed with periodic clinical and neuroradiological evaluations. All patients showed disease reactivation after first withdrawal and 13 out of 15 relapsed after the second one. In both the occasions annualized relapse rate (ARR) significantly increased as compared to on-treatment period (from 0.03 to 1.5 and from 0.26 to 1.71) with no differences between the two NTZ-free periods. Likewise, the mean number of Gd enhancing lesions increased both times to similar values (3.1 and 2.9). Median time to disease recurrence was comparable (4.7 and 5.7 months, p = 0.57). This study demonstrated recurrence of disease activity after two distinct NTZ discontinuations despite the treatment with IMD or more aggressive therapy, when used according to recent safety recommendations. Therefore, we need different therapeutic strategies to cope with the risk of post-NTZ disease recurrence and a "bridging strategy" with an earlier switch to second line drugs should be taken into account.

Autologous bone marrow transplantation for the treatment of multiple sclerosis.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system and represents one of the leading causes of neurologic disability in young adults. Current treatments for MS have shown limited efficacy in patients with either a progressive or an aggressive disease course. Hematopoietic stem cell transplantation (HSCT) has been proposed to control or even cure refractory cases of MS. Indeed, HSCT is able to temporarily eradicate the autoreactive cells and to reset the aberrant immune response to self-antigens. In the last decade, owing to the growing experience in selecting the most appropriate patients to transplant and the recent advances in chemotherapeutic and support regimens, the transplant-related mortality of autologous HSCT in MS patients dropped down to 1,3 % and the progression-free survival ranges from 47 % to 100 %. Altogether, these data support autologous HSCT as a possible second-line therapy for refractory MS.

Neural stem cell transplantation in patients with progressive multiple sclerosis: an open-label, phase 1 study.

Innovative pro-regenerative treatment strategies for progressive multiple sclerosis (PMS), combining neuroprotection and immunomodulation, represent an unmet need. Neural precursor cells (NPCs) transplanted in animal models of multiple sclerosis have shown preclinical efficacy by promoting neuroprotection and remyelination by releasing molecules sustaining trophic support and neural plasticity. Here we present the results of STEMS, a prospective, therapeutic exploratory, non-randomized, open-label, single-dose-finding phase 1 clinical trial ( NCT03269071 , EudraCT 2016-002020-86), performed at San Raffaele Hospital in Milan, Italy, evaluating the feasibility, safety and tolerability of intrathecally transplanted human fetal NPCs (hfNPCs) in 12 patients with PMS (with evidence of disease progression, Expanded Disability Status Scale ≥6.5, age 18-55 years, disease duration 2-20 years, without any alternative approved therapy). The safety primary outcome was reached, with no severe adverse reactions related to hfNPCs at 2-year follow-up, clearly demonstrating that hfNPC therapy in PMS is feasible, safe and tolerable. Exploratory secondary analyses showed a lower rate of brain atrophy in patients receiving the highest dosage of hfNPCs and increased cerebrospinal fluid levels of anti-inflammatory and neuroprotective molecules. Although preliminary, these results support the rationale and value of future clinical studies with the highest dose of hfNPCs in a larger cohort of patients.

Bilateral intracavernous carotid artery occlusion caused by invasive lymphocytic hypophysitis.

Lymphocytic hypophysitis is a rarely recognized disease that is characterized by inflammatory infiltration and destruction of the pituitary gland. The etiology of lymphocytic hypophysitis is still unclear, but an autoimmune pathogenesis has been advocated. In fact, histopathologic specimens reveal a diffuse infiltration of the hypophysis by CD3(+)CD4(+) T cells and CD20(+) plasma cells, and antipituitary antibodies are usually found in sera of affected patients. Although previous cases were found to be correlated only to pregnancy and the postpartum period, recent reports in men and women (without association with pregnancy) suggest a possibly higher prevalence of disease. We present the case of a 55-year-old woman affected by an unusually aggressive form of lymphocytic hypophysitis that infiltrated both cavernous sinuses causing bilateral internal carotid artery occlusion and acute ischemic stroke. Diagnosis was achieved with both a biopsy specimen of the pituitary gland and the detection of antipituitary antibodies. The prompt administration of steroid therapy was effective to obtain regression and stabilization of the disease, but both carotid arteries remained permanently occluded. The natural history of lymphocytic hypophysitis is unpredictable. It usually has a benign evolution, but in exceptional cases the inflammatory process may extend beyond the pituitary gland and infiltrate the surrounding structures. These extremely serious consequences highlight the importance of early diagnosis and treatment of this otherwise curable disease.

Early use of fingolimod is associated with better clinical outcomes in relapsing-remitting multiple sclerosis patients.

BACKGROUND: Multiple sclerosis (MS) is a chronic autoimmune disease with huge heterogeneity in terms of clinical course, disease severity and treatment response. The need for a tailored treatment approach has emerged over the last few years. The present observational study aims to assess fingolimod (FTY) effectiveness in RRMS patients, stratifying them according to the disease-modifying treatments used before FTY, to identify subjects who could benefit more from this treatment. METHODS: We prospectively included 554 RRMS patients who started FTY at San Raffaele Hospital between 2012 and 2018. We classified them into three categories according to previous treatments: naïve patients, subjects previously treated with first-line drugs, and patients previously treated with second-line drugs. We compared disease activity during a 2-years follow-up using No-Evidence-of-Disease-Activity (NEDA-3) and Time-To-First-Relapse (TTFR) outcomes, applying logistic and Cox proportional hazard regression respectively. RESULTS: The proportion of patients who maintained NEDA-3 status was higher in the naïve group despite a higher level of baseline disease activity (naïve versus first-line p = 0.025, naïve versus second-line p < 0.001). In the multivariable analyses, patients switching to FTY from first- and second-line treatments showed a higher risk of disease reactivation (p = 0.041, OR = 1.86 and p = 0.002, OR = 2.92, respectively) and a shorter TTFR (p = 0.017, HR = 4.35 and p = 0.001, HR = 8.19, respectively). CONCLUSION: Naïve patients showed a better response to FTY compared to patients switching to FTY from other drugs. Our findings support the early use of FTY in patients with active MS.

Atrioventricular block after fingolimod resumption: a consequence of sphingosine-1-phosphate axis alteration due to COVID-19?

During the COVID-19 pandemic, concerns raised regarding the use of immunosuppressants in multiple sclerosis, even if current data do not support an increased risk of infection. Although fingolimod can be temporarily suspended during COVID-19, the benefit-risk balance of suspension can be challenging. Till now, no adverse events have been described after the resumption of fingolimod, following a previous discontinuation. We report the occurrence of atrioventricular block following fingolimod restart. Fingolimod acts on sphingosine-1-phosphate-axis, a pathway that is altered with COVID-19 and hypoxic conditions. Herein we discuss how these metabolic changes may have influenced fingolimod pharmacology leading to a cardiac event.

Dynamic Functional Connectivity in the Main Clinical Phenotypes of Multiple Sclerosis.

Introduction: Dynamic functional connectivity (dFC) allows capturing recurring patterns (states) of interaction among functional networks. In this study, we investigated resting state (RS) dFC abnormalities across the different clinical phenotypes of multiple sclerosis (MS) and assessed their correlation with motor and cognitive performances. Methods: RS functional magnetic resonance imaging (fMRI) and 3D T1-weighted MRI data were acquired from 128 MS patients (69 relapsing-remitting [RR] MS, 34 secondary progressive [SP] MS, and 25 primary progressive [PP] MS) and 40 healthy controls (HC). RS fMRI data underwent independent component analysis and sliding-window correlations, to identify recurring dFC states and between-group dFC differences in the main networks. Results: dFC identified three recurring connectivity states: State 1 (frequency of appearance during fMRI acquisition = 57%, low dFC strength), State 2 (frequency = 19%, middle-high dFC strength), and State 3 (frequency = 24%, high sensorimotor and visual dFC strength). Compared to HC, MS (as a whole), RRMS, and PPMS patients exhibited lower State1/State 3 dFC (p = 0.0001, corrected) between sensorimotor, cerebellar, and cognitive networks, and some dFC increments (p = 0.001-0.05, uncorrected) in sensorimotor, visual, default-mode, and frontal/attention networks in States 2 and 3. Similar results were observed in SPMS versus RRMS patients. In MS, dFC decrease in sensorimotor, default-mode, and frontal/attention networks was correlated with worse motor and cognitive performances. Conclusions: MS patients exhibited overall lower dFC, and marginally higher dFC in sensorimotor/cognitive networks in the less-frequent middle/high-connected States. dFC abnormalities became more severe in progressive MS and correlated with motor and cognitive impairment, suggesting the presence of maladaptive mechanisms concomitant with accumulation of damage. Impact statement This is the first study exploring reorganization of dynamic functional connectivity in patients with multiple sclerosis (MS) across the main clinical phenotypes of the disease. Here, we demonstrated abnormalities of connectivity dynamism, which were present at all disease stages, but became more severe in progressive MS and correlated with worse motor and cognitive performances. These findings suggested that progressive MS patients might experience a maladaptive neuronal response to transient loss of dynamic coordination and flexibility among sensory and cognitive brain regions, leading to the progression of clinical impairment.