Impact of COVID-19 on pregnancy and fetal outcomes in women with multiple sclerosis.

BACKGROUND: In the general population, maternal COVID-19 is associated with worse maternal and fetal outcomes. Two previous studies have assessed COVID-19 clinical outcomes in pregnant women with multiple sclerosis (MS), but there are no data about maternal and fetal outcomes. OBJECTIVES: In this multicenter study, we aimed to assess maternal and fetal outcomes in pregnant women with MS and COVID-19 infection. METHODS: We recruited pregnant patients with MS who contracted COVID-19 and were followed up in Italian and Turkish Centers, during 2020-2022. A control group was extracted from a previous Italian cohort. Associations between group (COVID-19 or healthy patients) and clinical outcomes (maternal complications, fetal malformations, and spontaneous abortion) were investigated with a weighted logistic regression where propensity score-based inverse probability of treatment weighting (IPTW) approach was applied for adjusting for difference in baseline confounders. RESULTS: In the multivariable analysis, COVID-19 during pregnancy was associated with a higher risk of maternal complications (odd ratio (OR) = 2.12; 95% confidence interval (CI) = 1.32-3.48; p = 0.002), while it was not associated with higher risk of spontaneous abortion and fetal malformations. CONCLUSION: Our data indicate that COVID-19 during pregnancy increases the risk of maternal complications, while it seems to have no significant impact on fetal outcomes.

Safety of Natalizumab infusion in multiple sclerosis patients during active SARS-CoV-2 infection.

COVID-19 pandemic represented a challenge in the management of treatments for Multiple Sclerosis (MS), such as Natalizumab (NTZ). NTZ interferes with the homing of lymphocytes into the central nervous system, reducing immune surveillance against opportunistic infection. Although NTZ efficacy starts to decline 8 weeks after the last infusion, increasing the risk of disease reactivation, evidence is lacking on the safety of reinfusion during active SARS-CoV-2 infection. We report clinical outcomes of 18 pwMS receiving NTZ retreatment during confirmed SARS-CoV-2 infection. No worsening of infection or recovery delay was observed. Our data supports the safety of NTZ redosing in these circumstances.

Identifying and managing CAR T-cell-mediated toxicities: on behalf of an Italian CAR-T multidisciplinary team.

INTRODUCTION: Chimeric antigen receptor (CAR)-T-cell therapy is a new treatment for patients with hematologic malignancies in which other therapies have failed. AREAS COVERED: The review provides an overview for recognizing and managing the most acute toxicities related to CAR-T cells. EXPERT OPINION: The development of immune-mediated toxicities is a common challenge of CAR-T therapy. The mechanism that determines this toxicity is still unclear, although an unfavorable tumor microenvironment and a pro-inflammatory state put patients at risk. The monitoring, diagnosis, and treatment of post-CAR-T toxicities must be determined and based on international guidelines and internal clinical practice. It is urgent to identify biomarkers that can identify patients at greater risk of developing complications. The adoption of consistent grading criteria is necessary to improve toxicity management strategies continually. The first-line therapy consists of supportive care and treatment with tocilizumab or corticosteroids. An early start of cytokine blockade therapies could mitigate toxicity. The plan will include cytokine release prophylaxis, a risk-adapted treatment, prevention of on-target/off-tumor effect, and a switch on/off CAR-T approach.

Myositis/Myasthenia after Pembrolizumab in a Bladder Cancer Patient with an Autoimmunity-Associated HLA: Immune-Biological Evaluation and Case Report.

Pembrolizumab (mAb to PD-1) has been recently approved for the therapy of pretreated urothelial cancer. Despite the efficacy, it is often accompanied by unpredictable and sometime severe immune-related (ir) adverse events (AEs). Here, we report the clinical and immune-biological characterization of a patient with a metastatic bladder cancer who developed myositis signs (M) and a myasthenia-like syndrome (MLS) during treatment with pembrolizumab. The patient presented an autoimmunity-associated HLA haplotype (HLA-A*02/HLA-B*08/HLA-C*07/HLA-DRB1*03) and experienced an increase in activated CD8 T-cells along the treatment. The symptomatology regressed after pembrolizumab discontinuation and a pyridostigmine and steroids-based therapy. This is the first report of concurrent M and MLS appearance in cancer patients receiving pembrolizumab. More efforts are needed to define early the risk and the clinical meaning of irAEs in this setting.

Real world experience with teriflunomide in multiple sclerosis: the TER-Italy study.

OBJECTIVE: To identify baseline factors associated with disease activity in patients with relapsing-remitting multiple sclerosis (RRMS) under teriflunomide treatment. METHODS: This was an independent, multi-centre, retrospective post-marketing study. We analysed data of 1,507 patients who started teriflunomide since October 2014 and were regularly followed in 28 Centres in Italy. We reported the proportions of patients who discontinued treatment (after excluding 32 lost to follow-up) and who experienced clinical disease activity, i.e., relapse(s) and/or confirmed disability worsening, as assessed by the Expanded Disability Status Scale (EDSS). Decision tree-based analysis was performed to identify baseline factors associated with clinical disease activity during teriflunomide treatment. RESULTS: At database lock (September 2020), approximately 29% of patients (430 out of 1,475) discontinued teriflunomide because of disease activity (~ 46%), adverse events (~ 37%), poor tolerability (~ 15%), pregnancy planning (~ 2%). Approximately 28% of patients experienced disease activity over a median follow-up of 2.75 years: ~ 9% had relapses but not disability worsening; ~ 13% had isolated disability worsening; ~ 6% had both relapses and disability worsening. The most important baseline factor associated with disease activity (especially disability worsening) was an EDSS > 4.0 (p < 0.001). In patients with moderate disability level (EDSS 2.0-4.0), disease activity occurred more frequently in case of ≥ 1 pre-treatment relapses (p = 0.025). In patients with milder disability level (EDSS < 2.0), disease activity occurred more frequently after previous exposure to ≥ 2 disease-modifying treatments (p = 0.007). CONCLUSIONS: Our study suggests a place-in-therapy for teriflunomide in naïve patients with mild disability level or in those who switched their initial treatment for poor tolerability. Adverse events related with teriflunomide were consistent with literature data, without any new safety concern.

Cryptogenic cerebral venous thrombosis in a multiple-sclerosis-patient treated with Alemtuzumab.

Alemtuzumab is a highly effective treatment for relapsing-remitting multiple sclerosis (MS). Its molecular target is CD 52, a GPI-anchored protein. Herein, we describe the case of a 40-year-old man with MS treated with alemtuzumab, who developed cerebral sinus thrombosis. In the literature, alemtuzumab was associated with venous thrombosis, attributed to a paroxysmal nocturnal hemoglobinuria (PNH)-like mechanism. In our case, no PNH clones were detected. Other common causes of cerebral venous thrombosis, like infections and thrombophilia, were excluded, thus the pathogenic mechanism remains obscure.

Sexual Function in Young Individuals With Multiple Sclerosis: Does Disability Matter?

INTRODUCTION: Studies on the prevalence of sexual dysfunction (SD) in multiple sclerosis (MS) have shown that 40% to 80% of women and 50% to 90% of men have had sexual complaints. Sexual function is often disregarded during consultation with healthcare professionals, and SD is frequently underdiagnosed. The aim of this study was to investigate the prevalence of SD and its relationship to sociodemographic and disease-related factors, with regard to disability state, in a hospital cohort of MS patients, by using a semistructured interview. METHODS: Of 130 screened outpatients, 87 met the inclusion criteria and completed the study. The mean age of the participants was 39.3 ± 8.3 years, with a disease duration of 8.3 ± 5.4 years and a mean Expanded Disability Status Scale (EDSS) score of 2.04 ± 0.19. Sexual function was evaluated by means of a semistructured interview, investigating a patient's 3 main life areas: sociodemographic information, illness perception, and sexuality. RESULTS: Approximately 70% of the patients complained at least 1 SD (decreased libido, erectile dysfunction, premature or retarded ejaculation, painful penetration), and 22% of them reported the disorder as frequent. The disease duration was associated with lower satisfaction in sexual function, and lack of sexual interest was the most common problem having a negative correlation with EDSS. CONCLUSIONS: Healthcare professionals involved in MS, should assess patients for SD. Further studies should be fostered to better quantify SD etiology, the degree of sexual impairment, and its impact on patients' quality of life to "overcome" this problem.

The role of robotic gait training coupled with virtual reality in boosting the rehabilitative outcomes in patients with multiple sclerosis.

Motor impairment is the most common symptom in multiple sclerosis (MS). Thus, a variety of new rehabilitative strategies, including robotic gait training, have been implemented, showing their effectiveness. The aim of our study was to investigate whether an intensive robotic gait training, preceding a traditional rehabilitative treatment, could be useful in improving and potentiating motor performance in MS patients. Forty-five patients, who fulfilled the inclusion criteria, were enrolled in this study and randomized into either the control group (CG) or the experimental group (EG). A complete clinical evaluation, including the Expanded Disability Severity Scale, the Functional Independence Measure, the Hamilton Rating Scale for Depression, the time up and go test (TUG), and the Tinetti balance scale, was performed at baseline (T0), after 6 week (T1), at the end of rehabilitative training (T2), and 1 month later (T3). A significant improvement was observed in the EG for all the outcome measures, whereas the CG showed an improvement only in TUG. In contrast, from T1 to T2, only CG significantly improved in all outcomes, whereas the EG had an improvement only regarding TUG. From T2 to T3, no significant differences in Functional Independence Measure scores emerged for both the groups, but a significant worsening in Tinetti balance scale and TUG was observed for the CG and in TUG for the EG. Our study provides evidence that robotic rehabilitationn coupled with two-dimensional virtual reality may be a valuable tool in promoting functional recovery in patients with MS.

The role of Sativex in robotic rehabilitation in individuals with multiple sclerosis: Rationale, study design, and methodology.

INTRODUCTION: Currently, none of the available multiple sclerosis (MS) disease-modifying medications has been shown to stop or reverse gait disability. Recently, the nabiximols has been tested for the treatment of spasticity and walking impairment in MS. Nabiximols (trade name Sativex) is an oromucosal spray formulation containing 1:1 fixed ratio of delta-9-tetrahydrocannabinol and cannabidiol derived from cloned Cannabis sativa L. plant. METHOD AND ANALYSIS: A single-center, prospective, parallel design, single-blind trial will be conducted at the IRCCS Neurolesi "Bonino-Pulejo" (Italy) involving MS patients affected by spasticity and undergoing a Robotic Rehabilitation training. The aim of the study is to clarify the role of Sativex coupled to a robotic neurehabilitation training in MS patients in improving motor outcomes, by means of clinical, kinematic, and neurophysiological measures. Patients will be randomly divided in 2 groups: one taking only an oral antispastic drug and the other with Sativex in add-on. After 1 month, we will evaluate the response to Sativex (responder patients' amelioration >20% at MRS score) enrolling into the study the first 20 patients with a good response to Sativex, whereas other 20 no-responder individuals will continue their antispastic drug. All the 40 subjects, were divided into 2 groups (A: Sativex + Lokomat Training, and B: other antispastic+Lokomat Training), will perform a neurorobotic-assisted gait training (each session will last at least 45 minutes, 3 times per week, for a total of 20 sessions). All the patients will undergo a complete physical and neurological examination at baseline, at the end of the robotic training (T1), and 30 days after the end of the neurorehabilitation training (T2).

Relationship between Interferon Beta-1A Administration and Intracranial Vascular Tone Regulation in Patients with Relapsing-Remitting Multiple Sclerosis: A Pilot Study.

Interferon beta (IFN-ß) therapy is one of the most commonly prescribed immunomodulatory therapies in relapsing-remitting multiple sclerosis (RRMS). A reversible cerebral vasoconstriction syndrome (RCVS), associated with IFN-ß use, has been recently described. For this reason, we tested the effect of once a week intramuscular administration of IFN-ß-1A on the function of cerebral vessels in a cohort of RRMS patients. Using transcranial Doppler (TCD) ultrasound, we measured the mean blood flow velocity (MFV) in intracranial vessels 10 h after IFN-ß administration. Measurements showed a significant increase in MFV compared to the baseline values in some vessels.

Does the radiologically isolated syndrome exist? A dual-task cost pilot study.

Simultaneous performance of motor and cognitive tasks may compete for common brain network resources in aging or patients with some neurological diseases, suggesting the occurrence of a cognitive-motor interference. While this phenomenon has been well described for multiple sclerosis (MS) patients, it never has been tested on asymptomatic subject with magnetic resonance imaging (MRI) findings suggestive of demyelinating disease (i.e., radiologically isolated syndrome: RIS). In this pilot study, 10 RIS subjects and 10 sex/age-matched healthy controls were tested by means of static posturography under eyes opened (single-task trial) and while performing two different cognitive tasks (semantic modified word list generation for first dual-task trial and phonemic semantic modified word list generation for second dual-task trial), to estimate the dual-task cost (DTC) of standing balance. In our sample, under cognitive interference (without any substantial differences between semantic and phonemic modified word list generation), the RIS group showed significance differences in CoP (center of pressure) total sway area, ellipse eccentricity, CoP sway path length, CoP median sway velocity along the AP (anteroposterior) axis and along the ML (mediolateral) axis, reflecting a higher negative DTC respect to healthy subjects (which have simply shown a statistical trend, failing to reach a significance, in some trials). The phenomenon of cognitive-motor interference might be unmasked by a dual-task posturography in RIS subjects, too. We hypothesize that this approach could be useful to early reveal the presence of a demyelinating disease and to reach a MS diagnosis in subjects otherwise classified as RIS.

Robotic gait training in multiple sclerosis rehabilitation: Can virtual reality make the difference? Findings from a randomized controlled trial.

Gait, coordination, and balance may be severely compromised in patients with multiple sclerosis (MS), with considerable consequences on the patient's daily living activities, psychological status and quality of life. For this reason, MS patients may benefit from robotic-rehabilitation and virtual reality training sessions. Aim of the present study was to assess the efficacy of robot-assisted gait training (RAGT) equipped with virtual reality (VR) system in MS patients with walking disabilities (EDSS 4.0 to 5.5) as compared to RAGT without VR. We enrolled 40 patients (randomized into two groups) undergoing forty RAGT±VR sessions over eight weeks. All the patients were assessed at baseline and at the end of the treatment by using specific scales. Effect sizes were very small and non-significant between the groups for Berg Balance Scale (-0.019, CI95% -2.403 to 2.365) and TUG (-0.064, 95%CI -0.408 to 0.536) favoring RAGT+VR. Effects were moderate-to-large and significant for positive attitude (-0.505, 95%CI -3.615 to 2.604) and problem-solving (-0.905, 95%CI -2.113 to 0.302) sub-items of Coping Orientation to Problem Experienced, thus largely favoring RAGT+VR. Our findings show that RAGT combined with VR is an effective therapeutic option in MS patients with walking disability as compared to RAGT without VR. We may hypothesize that VR may strengthen RAGT thanks to the entrainment of different brain areas involved in motor panning and learning.

Multiple sclerosis and amyotrophic lateral sclerosis: a human leukocyte antigen challenge.

Multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS) are two different central nervous system pathology that, according to the most accredited hypotheses, recognize a different etiopathogenesis. The simultaneous occurrence of MS and ALS is quite unusual. To our knowledge, only three cases have been so far described by clinical, laboratory, and post-mortem studies. We report four new cases of this peculiar combination that have been observed and are herein described, included their human leukocyte antigen (HLA) profile studies. On the basis that three out of four patients in our case series presented HLA-B*18:01A, we may hypothesize that this antigen could play a role in developing both diseases.

Cognitive processess and cognitive reserve in multiple sclerosis.

Multiple Sclerosis (MS) is characterized by motor, cognitive, and neuropsychiatric symptoms, which can occur independently. While MS is traditionally considered an inflammatory disease of the white matter, degeneration of gray matter is increasingly recognized as an important contributor to the progressive cognitive decline. A protective factor against the progression of cognitive dysfunction in MS could be the cognitive reserve, defined as resistance to brain dysfunction. Aim of the present study is to evaluate the role of cognitive reserve for different aspects of cognitive dysfunction of patients with MS. We found that patients with MS and lower cognitive reserve have poorer neuropsychological performance and slower information speed processing. These findings support the notion that intellectual reserve may protect some aspects of cognitive function in patients with MS.

Fatigue in patients with multiple sclerosis: from movement preparation to motor execution.

BACKGROUND: The neural mechanisms underlying fatigue in multiple sclerosis (MS) are still poorly understood. Cortico-cortical and cortico-subcortical circuitry abnormalities may play a central role in its pathogenesis. Our previous studies suggest that central fatigue may be related to an impairment of volition drive during movement preparation. OBJECTIVE: We further explored the central mechanisms of fatigue at the premovement level in MS patients during a sustained motor task. METHODS: In MS patients with (MS-F) and without (MS-NF) fatigue and age-matched healthy controls, we evaluated the motor cortex excitability and the premovement facilitation (PMF) through transcranial magnetic stimulation before and after 5min of sequenced finger-tapping movements at a fixed frequency of 2Hz. RESULTS: In MS-F patients, the number of correct sequences performed and the ability to keep a fixed movement rate during the 5-min motor task were significantly decreased in comparison to the normal controls and MS-NF patients. Also, in MS-F patients, post-exercise PMF was significantly decreased. The PMF abnormalities were highly correlated with the performance decay. CONCLUSIONS: PMF may be considered as a kind of servo-mechanism which could play a crucial role during sustained motor task in order to prevent motor performance disruption and to avoid motor exhaustion.

Is central fatigue in multiple sclerosis a disorder of movement preparation?

We tested the hypothesis that fatigue in MS is related to a dysfunction in cortical areas involved in movement preparation. Thirty-three patients with clinically definite MS (16 with fatigue MS-F, 17 without fatigue MS-NF) and a relapsing-remitting course, matched for disease severity and duration, disability scores and level of depression were enrolled. They underwent a combined assessment with magnetic resonance imaging (MRI) and transcranial magnetic stimulation (TMS) and, for the electrophysiological study, were compared with 12 healthy controls. MRI was used to assess regional and total lesion-load volume (LL) on T1- and T2-weighted sequences and total brain volume on T1-weighted sequences. With TMS we tested central motor conduction time, short intracortical inhibition (SICI) and facilitation (ICF), pre-movement facilitation related to a simple reaction time paradigm and the effect of short trains of 5-Hz repetitive TMS (rTMS). No significant differences were found in total and regional LL between MS-F and MS-NF, except for a significant increase in frontal lobe LL in MS-F. Neurophysiological assessment did not disclose any difference of SICI and ICF among the three groups. The significant increase of MEP size produced by 5 Hz rTMS in controls was absent in both MS-NF and MS-F. MS-F lacked pre-movement facilitation compared with MS-NF and controls. The lack of pre-movement facilitation and the increased frontal lobe lesion load were significantly correlated to the FSS score, suggesting that central fatigue in MS is probably due to a dysfunction of cortical motor areas involved in movement preparation.

Multicenter case-control study on restless legs syndrome in multiple sclerosis: the REMS study.

STUDY OBJECTIVES: To verify the existence of a symptomatic form of restless legs syndrome (RLS) secondary to multiple sclerosis (MS) and to identify possible associated risk factors. DESIGN: Prospective, multicenter, case-control epidemiologic survey. SETTINGS: Twenty sleep centers certified by the Italian Association of Sleep Medicine. PATIENTS: Eight hundred and sixty-one patients affected by MS and 649 control subjects. INTERVENTIONS: N/A. MEASURES AND RESULTS: Data regarding demographic and clinical factors, presence and severity of RLS, the results of hematologic tests, and visual analysis of cerebrospinal magnetic resonance imaging studies were collected. The prevalence of RLS was 19% in MS and 4.2% in control subjects, with a risk to be affected by RLS of 5.4 (95%confidence interval: 3.56-8.26) times greater for patients with MS than for control subjects. In patients with MS, the following risk factors for RLS were significant: older age; longer MS duration; the primary progressive MS form; higher global, pyramidal, and sensory disability; and the presence of leg jerks before sleep onset. Patients with MS and RLS more often had sleep complaints and a higher intake of hypnotic medications than patients with MS without RLS. RLS associated with MS was more severe than that of control subjects. CONCLUSIONS: RLS is significantly associated with MS, especially in patients with severe pyramidal and sensory disability. These results strengthen the idea that the inflammatory damage correlated with MS may induce a secondary form of RLS. As it does in idiopathic cases, RLS has a significant impact on sleep quality in patients with MS; therefore, it should be always searched for, particularly in the presence of insomnia unresponsive to treatment with common hypnotic drugs.