Background: Motor rehabilitation effectiveness in progressive multiple sclerosis (PMS) remains uncertain. We assessed whether task-oriented (TO) rehabilitation, with or without non-immersive virtual reality, improves upper limb function in PMS and evaluated magnetic resonance imaging (MRI) changes related to motor performance. Methods: Eighty-one progressive multiple sclerosis patients on B-cell depleting therapy were randomized to task-oriented rehabilitation with virtual reality (TO-VR), TO rehabilitation, or passive mobilization (CG) for 8 weeks. Upper extremity performance was measured with the Nine-Hole Peg Test (9-HPT), Action Research Arm Test (ARAT), AbilHand Test (ABILHAND), and Manual Ability Measure-36 (MAM-36). Upper limb function, neurological status, and MRI were evaluated at baseline, after rehabilitation, and at 3 months. Results: Seventy-nine patients completed the study. No difference was observed in 9-HPT, but in the whole sample, ABILHAND improved post-treatment (p < 0.001), and ARAT improved on the left side (p = 0.014, false discovery rate adjusted p = 0.084). Additional gains appeared in several neurological tests. Brain volumes, morphometry, and diffusion indices were unchanged, while functional MRI showed increased connectivity post-treatment in TO-VR and TO groups, but not in CG. Connectivity changes were correlated, in particular, with clinical amelioration (ABILHAND) in both TO-VR (r = 0.54, p = 0.013) and TO groups (r = 0.50, p = 0.035). Conclusion: In PMS treated with high-efficacy therapy, TO rehabilitation, particularly when combined with VR, can improve motor function, inducing functional gains and plasticity in cerebral networks.

Background: Demyelination and remyelination are major issues for scientists dealing with myelin disorders in both clinical and research fields. Despite that, rapid, reliable and convenient tools to monitor myelin changes still lack both in central and peripheral nervous system. Given that myelin is enriched in specific lipids and proteins, it is reasonable they could represent eligible candidates as structural damage biomarkers for this characteristic membrane. Among them, we focused on sphingomyelin (SM) due to the enrichment in myelin and because it is easily measurable in different biological matrices. Objective: Depicting the roadmap to identify and validate SM dosage as a myelin biomarker useful for pre-clinical and clinical practice. Design: This study adheres to STROBE guidelines for observational cross-sectional studies on human patients and to ARRIVE guidelines for animal models. Method: Following the recommendations of the Society for CSF Analysis and Clinical Neurochemistry, we describe the stepwise process to validate SM as a myelin biomarker, starting from the optimization of the fluorescence-based assay and analytical validation in experimental models until clinical and pathological validation in biological fluids of neurological patients. Results: SM dosage monitors myelination, demyelination, remyelination and even small myelin changes associated to myelin pathology and pharmacological treatments in experimental models. SM is detectable in human biological fluids and informative of myelin damage in the CSF of neurological patients. SM dosage identifies myelin breakdown in the CSF of patients affected by Guillain-Barrè Syndrome (GBS) and Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP), identifying disease activity, axonal from demyelinating variants, and avoiding misdiagnosis. Conclusion: SM dosage displayed extremely promising real-word performances being able to identify, monitor and stage myelin pathology. Given that it is simple, inexpensive and easily adaptable to routine use in any hospital setting, it might rapidly progress to the implementation and impact on clinical outcomes.

BACKGROUND:Induction therapies for multiple sclerosis (MS), such as cladribine (CLAD), require multiple cycles to achieve full clinical effects, and the extent of immunosuppression from a single course is unclear. Fingolimod (FINGO), administered daily, provides a rapid anti-inflammatory effect, desirable for active MS. OBJECTIVES:to compare the efficacy of the first course of CLAD versus FINGO over 12 months by analyzing clinical data, brain atrophy, retinal thinning, and diffusion MRI metrics of myelin and neuroaxonal integrity in the corpus callosum. METHODS:evaluations included NEDA-3 status, percentage brain volume change (PBVC) and changes in retinal nerve fibers and MRI metrics of the corpus callosum such as Intra-Cellular Volume Fraction (ICVF) and Orientation Dispersion Index (ODI). RESULTS:we included 65 relapsing-remitting MS patients (33 on CLAD, 32 on FINGO). After 12 months, 81.8% of CLAD patients and 71.9% of FINGO patients achieved NEDA-3 (p = 0.4). PBVC <-0.4% was observed in 41.9% of CLAD and 39.2% of FINGO patients (p = 0.9). Both drugs showed similar effects on retinal thinning and ICVF and ODI of the corpus callosum. CONCLUSIONS:A single course of cladribine has comparable efficacy to daily fingolimod treatment based on clinical, OCT and advanced MRI measures.

BACKGROUND:Cerebrospinal fluid (CSF) oligoclonal IgM bands (OCMBs) have been suggested as prognostic biomarkers in MS, but serum OCMBs meaning is still uncertain. OBJECTIVES:We aimed to assess frequency and clinical relevance of all OCMB patterns. METHODS:In this retrospective cohort study, 136 paired sera-CSF from consecutive persons with MS (pwMS) were tested in 2 centers for OCMBs using isoelectric focusing-immunoblotting. Active disease was defined as clinical or radiological relapse occurring during two-year follow-up. Predictors of active disease were analyzed with logistic regressions and Kaplan-Meier survival curves. RESULTS:OCMBs were found in 6.6 % of pwMS as unique-to-CSF (pattern #2), and in 20.6 % as identical in serum-CSF (pattern #4), without between-cohort difference. Active disease was more frequent in those with pattern #2 (88.9 %) and #4 (64.3 %) than in those OCMB-negative (33.3 %, p < 0.001). In multivariate analysis, pattern #2 (OR: 15.9; 95 % CI [1.8-136]), and pattern #4 (OR: 3.3 95 % CI [1.3-8.3]) were independent predictors of active disease. In survival analysis, pattern #2 (p < 0.001) and #4 (p = 0.017) predicted radiological relapses. CONCLUSIONS:Our data confirm that CSF OCMB marks poor prognosis in MS. However, both OCMB pattern #4 and pattern #2, with different strength prediction, might be useful to stratify pwMS deserving more aggressive treatments, although the stratification could be achieved in the near future with more standardized and easily measurable biomarkers (e.g., serum neurofilaments).

We studied the detection of Treponema pallidum (TP)-IgM antibodies in the serum of 69 patients treated for syphilis. The persistence of TP-IgM antibodies in serum for more than 3 years was the only clue to suspect an active infection and, therefore, to investigate a central nervous system involvement.

Background: Treatment with fingolimod for multiple sclerosis (MS) reduces the efficacy of COVID-19 vaccina-tion. The aim of this exploratory study was to evaluate whether main lymphocyte subsets and demographic features correlated to the subsequent increase in anti-SARS-CoV2 antibodies following the third dose of COVID-19 vaccination in fingolimod-treated MS patients.Methods: This was a prospective single-center observational exploratory study including a subgroup of adult patients with MS (pwMS) in treatment with fingolimod who underwent COVID-19 vaccination. The association of anti-SARS-CoV2 antibody levels (reported as the Log10 of the difference between the post and pre third dose levels) with the total number and percentage of CD3+ T and CD19+ B was assessed by a linear regression model adjusted for age and sex.Results: We found that peripheral blood CD19+ B lymphocytes before the third dose of vaccination in pwMS treated with fingolimod predict the subsequent increase of anti-SARS-CoV2 antibodies.Conclusion: This work suggests that evaluating the percentage of CD19+ B cells may be important to identify patients at risk of not producing SARS-CoV-2 antibodies, with possible reduced protection from COVID-19.

During SARS-CoV-2 pandemic, we adopted a personalized delayed protocol for ocrelizumab infusions in Relapsing Remitting Multiple Sclerosis (RRMS) patients according to the national recommendations. Out of the 83 RRMS patients whose infusion was scheduled between March and December 2020, 56 patients experienced a delay in treatment based on MS severity and SARS-CoV2 infection risk profile. In most cases, the immunophenotype was performed monthly to guide re-infusions. Specifically, B CD19 + cells repopulation rate was monitored. Mean infusion delay was 103,1 [SD 40,6] days, and none of the patients presented relapses or active disease at MRI at the end of the observation period. Treatment naïve status and the interval between immunophenotyping and the last ocrelizumab infusion were predictors of earlier B CD19 + cells repopulation. Two patients contracted SARS-CoV2 with complete recovery. Definitive data about Sars-Cov2 vaccine efficacy in patients treated with ocrelizumab are still lacking. Our findings suggest that a personalized treatment with a delayed infusion schedule does not compromise ocrelizumab short-term efficacy and may help to lengthen the therapeutic window for an effective response to SARS-CoV2 vaccine.

Vanishing White Matter Disease (VWMD) is a rare autosomal recessive leukoencephalopathy . The classical presentation is characterized by a severe cerebellar ataxia, spasticity, neurological deterioration with a chronic progressive course and episodes of acute neurological deterioration after stress conditions. We report a 52-year-old man with VWMD and atypical features who manifested two major events of transient aphasia eleven years apart with complete recovery in 48 hours. No cognitive decline was present. Brain MRI revealed typical aspects of VWMD including diffuse leukoencephalopathy with relative sparing of U-fibers. We identified the presence of c.592G>A (p.Glu198Lys) and c.1360 C>T (p.Pro454Ser) mutations in EIF2B5.

To assess in-vivo prevalence of LME in relapsing-remitting MS (RRMS) and to evaluate its association with cerebrospinal fluid (CSF) markers.

ObjectiveTo investigate prevalence of EMG patterns underlying hypertonia in multiple sclerosis (MS) and whether these patterns indicate different levels of spinal excitability.MethodsWe investigated the EMG activity recorded from 108 hypertonic muscles of 59 consecutive MS patients. To investigate spastic dystonia (SD), we looked for the presence of EMG activity in muscles in a resting position. To investigate dynamic stretch reflex (DSR) and static stretch reflex (SSR), we looked for the presence of EMG activity in response to a manually performed passive stretch of the muscle.ResultsDSR was evoked in 104 muscles. In 51 muscles, DSR was the sole EMG activity. This pattern corresponds to the classical notion of spasticity, and was predominant in extensors. In contrast, SSR was detected in 48 muscles – predominantly in flexors. SD was observed in 28 muscles, showing even distribution in flexor and extensor muscles. Only in the flexors, SSR was associated with a larger DSR compared to spasticity.ConclusionsThese findings likely depend on the central effects of both flexor and extensor spindle afferents on the homonymous spinal motor neurons.SignificanceImproving our capacity to assess spinal excitability in MS patients.

Data regarding effectiveness and safety of ocrelizumab in the post-marking setting are lacking. The aim of our study was to provide effectiveness and safety data of ocrelizumab treatment in patients with relapsing–remitting (RR-) and progressive multiple sclerosis (PMS) and to evaluate clinical and immunological predictors of early treatment response. In this single-center prospective observational study, we investigated effectiveness outcomes (time-to-confirmed disability worsening, time-to-first relapse, time-to-first evidence of MRI activity and time-to-first evidence of disease activity), clinical and immunological predictors of early treatment response, and incidence of adverse events (AEs). One hundred and fifty-three subjects were included (93 RRMS; 84 females). Median follow-up was 1.9 (1.3–2.7). At 2-year follow-up (FU), disability worsening-free survival were 90.5%, 64.7%, and 68.8% for RRMS, primary-progressive MS (PPMS), and secondary-progressive MS (SPMS) patients, respectively. At 2-year FU, 67.1%, 72.7%, and 81.3% of patients with RRMS, PPMS, and SPMS were free of MRI activity, with NEDA-3 percentages of 62.1%, 54.6%, and 55.1%, respectively. Lower baseline EDSS was independently associated with a reduced risk of disability worsening (HR(95%CI) = 1.45(1.05–2.00), p = 0.024) and previous treatment exposure was independently associated with increased probability of radiological activity (HR = 2.53(1.05–6.10), p = 0.039). At 6-month FU, CD8 + cell decrease was less pronounced in patients with inflammatory activity (p = 0.022). Six patients (3.9%) discontinued ocrelizumab due to severe AEs. Our findings suggest that ocrelizumab is an effective treatment in real-world patients with RRMS and PMS, with a manageable safety profile. Better outcomes were observed in treatment-naïve patients and in patients with a low baseline disability level. Depletion of CD8 + cells could underlie early therapeutic effects of ocrelizumab.

Recently, during the pandemic infection of the novel SARS-CoV-2, some cases of Guillan-Barre Syndrome (GBS) have been reported. The aim of this work is to report the natural history of patients with GBS, both COVID and not-COVID related, hospitalized in Liguria region, during lock down period, in order to assess clinical features of both groups and possible managements pitfalls due to pandemic emergency. Fifteen GBS patients were admitted to the Hospitals of Liguria, from February 15th to May 3rd 2020, six with SARS-CoV-2 infection and nine without infection. In COVID-19 related GBS five patients presented with classical GBS and one with variant. Two patients presented neurologic symptoms during or shortly after the viral syndrome, suggesting the pattern of a para-infectious profile. Multi-organ involvement, delay in the diagnosis, incomplete work up and start of therapy, were registered in 50% of cases with a GBS-Disability scale >= 4 at follow-up evaluation. In not-COVID-19 related GBS, main problem was diagnostic delay. In three patients the first neurological observation took place after a mean of 33,6 days. Moreover, five patients went to emergency room after an average of 30 days since the onset of neurological symptoms because of fear of contagion. In conclusion, not only SARS-CoV-2 infection can cause GBS, but it can also, due to effects of pandemic on the health organization, affect the outcome of patients with not COVID-19 related GBS.

OBJECTIVE:To validate sphingomyelin (SM) dosage in the cerebrospinal fluid (CSF) of patients affected by chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and Guillain-Barré syndrome (GBS) as a reliably assessable biomarker. METHODS:We prospectively enrolled 184 patients from six Italian referral centres, in whom CSF SM levels were quantified by a fluorescence-based assay optimised and patented in our laboratory. RESULTS:We confirmed increased levels of SM in the CSF of patients affected by typical CIDP (n=35), atypical CIDP (n=18) and acute inflammatory demyelinating polyradiculoneuropathy, AIDP (n=12) compared with patients affected by non-demyelinating neurological diseases, used as controls (n=85) (p<0.0001, p=0.0065 and p<0.0001, respectively). In patients with CIDP classified for disease stage, SM was higher in active CIDP compared with both controls and stable CIDP (p<0.0001), applying for a selective tool to treatment tailoring or withdrawal. SM was also increased in AIDP compared with axonal GBS, discerning the demyelinating from axonal variant of the disease. SM did not correlate with CSF protein levels, stratifying patients independently from commonly used CSF indexes, and displaying high specificity to avoid potential misdiagnosis. Finally, SM correlated with the main clinical scores and some neurophysiological parameters in patients with CIDP and AIDP. CONCLUSIONS:CSF SM is a diagnostic and staging wet biomarker for acquired demyelinating neuropathies and may effectively improve the management of patients affected by GBS and CIDP.