Fatigue in Multiple Sclerosis: A Resting-State EEG Microstate Study.

Fatigue affects approximately 80% of people with Multiple Sclerosis (PwMS) and can impact several domains of daily life. However, the neural underpinnings of fatigue in MS are still not completely clear. The aim of our study was to investigate the spontaneous large-scale networks functioning associated with fatigue in PwMS using the EEG microstate approach with a spectral decomposition. Forty-three relapsing-remitting MS patients and twenty-four healthy controls (HCs) were recruited. All participants underwent an administration of Modified Fatigue Impact scale (MFIS) and a 15-min resting-state high-density EEG recording. We compared the microstates of healthy subjects, fatigued (F-MS) and non-fatigued (nF-MS) patients with MS; correlations with clinical and behavioral fatigue scores were also analyzed. Microstates analysis showed six templates across groups and frequencies. We found that in the F-MS emerged a significant decrease of microstate F, associated to the salience network, in the broadband and in the beta band. Moreover, the microstate B, associated to the visual network, showed a significant increase in fatigued patients than healthy subjects in broadband and beta bands. The multiple linear regression showed that the high cognitive fatigue was predicted by both an increase and decrease, respectively, in delta band microstate B and beta band microstate F. On the other hand, higher physical fatigue was predicted with lower occurrence microstate F in beta band. The current findings suggest that in MS the higher level of fatigue might be related to a maladaptive functioning of the salience and visual network.

Epidemiology and management of transient ischemic attack in Trieste district, how day hospital assessment improves outcomes: a five-year retrospective study.

BACKGROUND: Transient ischemic attack (TIA) is defined as a transient episode of neurologic dysfunction, without acute infarction or tissue injury lasting less than 24 h. Previous data suggest TIA precedes 15% of ischemic strokes, with a higher risk in the first week. Current practice guidelines advise evaluation through rapid neurological visit or admission to hospital. We provide data on TIA incidence in Trieste, and we compare three different types of assessment: day hospital (DH), stroke unit (SU), and emergency department/outpatients (ED). METHODS: This is a 5-year retrospective study of transient cerebrovascular events admitted in the University Hospital of Trieste (230.623 inhabitants), between 2016 and 2020. We calculated TIA prevalence in Trieste district's general population. Our primary endpoint is ischemic recurrences within 90 days, and we evaluate the possible association between different types of management. RESULTS: TIA incidence rate was 0.54/1000 inhabitants. In the multivariate analysis remained significantly associated with primary endpoint: ABCD2 (OR 1.625, CI 95% 1.114-2.369, p = 0.012) and DH evaluation (OR 0.260, CI 95% 0.082-0.819, p = 0.021). CONCLUSIONS: Incidence of TIA in Trieste district is in line with previous data. We demonstrate the crucial role of DH evaluation over the outpatient/ED in reducing overall mortality and recurrence rate. Prompt recognition of patients at high risk for cerebrovascular events and specialist follow-up may reduce the incidence of major vascular events and death.

COVID-19 lockdown attack on headache emergency admissions: a multidisciplinary retrospective study.

BACKGROUND: During the first COVID-19 lockdown in Italy, it was observed a reduction in emergency department (ED) attendances due to non-SARS-COV-2-related acute/chronic conditions. OBJECTIVE: To analyze the impact of the COVID-19 lockdown on patients reporting headache as the principal presenting symptom on admission to the ED of the tertiary care University Hospital of Trieste over the relevant period. METHODS: We retrospectively evaluated the frequency, features, and management of ED attendances for headache during the COVID-19 lockdown from 8 March to 31 May 2020, comparing it with the pre-lockdown period (January-February 2020) and the first 5 months of 2019. RESULTS: A reduction in ED total attendances was observed in the first 5 months of 2020 compared to the same period in 2019 (21.574 and 30.364, respectively; - 29%), in particular with respect to headache-related attendances (174 and 339 respectively; - 49%). During the COVID-19 lockdown, it was recorded a minor reduction in the ED access rate of female patients (p = 0.03), while no significant variation was detected in repeaters' prevalence, diagnostic assessment, and acute treatment. The ratio of not otherwise specified, secondary, and primary headaches (48.4%, 30.6%, and 21.0% respectively) remained unchanged during the COVID-19 lockdown, in comparison to the control periods. CONCLUSION: The COVID-19 pandemic impacted the number of ED attendances for headache but not their management and setting. Despite a reduction of accesses for headache due to the pandemic emergency, the distribution of headache subtypes and the rate of repeaters did not change.

Nabiximols and botulinum toxin injections for patients with multiple sclerosis: efficacy on spasticity and spasms in a single-centre experience.

BACKGROUND: Spasticity is a common and disabling symptom in patients with multiple sclerosis (PwMS): as highlighted by many epidemiological studies, it is often a severe and not well treated. Despite the availability of evidence-based spasticity management guidelines, there is still great variability in everyday therapeutic approach, especially for the most complex cases. METHODS: In our single-centre study, we retrospectively evaluated PwMS-treated nabiximols and botulinum toxin injections (BTI) from July 2015 to April 2019. Clinical and demographic data were collected. The severity of spasticity and spasms was recorded by modified Ashworth Scale (mAS) and Penn Spasm Frequency Scale (PSFS) at baseline and after 1 month of treatment. RESULTS: We evaluated 64 treatments for MS-related spasticity: 28 patients were treated with BTI and 36 patients with nabiximols. We found that both BTI and nabiximols are effective in reducing mAS (nabiximols, BTI: p < 0.001), PSFS frequency (nabiximols: p = 0.001, BTI: p = 0.008) and intensity (nabiximols: p = 0.001, BTI p = 0.016). No differences were found when directly comparing the efficacy of the two treatments, except for a statistical trend favouring BTI on spasms intensity (p = 0.091). Eleven patients were treated with both BTI and nabiximols, and only four patients continued both treatments. All dropouts were due to inefficacy of at least one of the two therapies. CONCLUSIONS: Our single-centre experience highlights that both BTI and nabiximols are effective in treating multiple sclerosis-related spasticity; however, BTI treatment may be more effective on spasms intensity. Combined nabiximols and BTI treatment could represent a therapeutic option for severe spasticity.

Unveiling the relationship between autonomic involvement, fatigue, and cognitive dysfunction in early relapsing-remitting multiple sclerosis.

BACKGROUND: Fatigue is a common, yet disabling, symptom in patients with multiple sclerosis (PwMS). Fatigue has shown to be associated with self-reported autonomic nervous system (ANS) symptoms, particularly for cognitive fatigue; however, the question whether ANS involvement is related to cognitive impairment has never been addressed. We performed a study to unveil the complex relationship between fatigue, ANS symptoms, and cognitive impairment. METHODS: We prospectively recruited early PwMS that were tested with Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS), State-Trait Anxiety Inventory (STAI), Beck Depression Inventory (BDI), Modified Fatigue Impact Scale (MFIS) and Composite Autonomic Symptoms Scale-31 (COMPASS-31) scale. We performed a comparison between fatigued and non-fatigued patients and between cognitive unimpaired and impaired patients. We evaluated the association of COMPASS-31, MFIS, BDI, STAI, and BICAMS scores, and the analysis was repeated for each scale's sub-scores. A multivariable analysis was performed to elucidate predictors of fatigue. RESULTS: Forty-four patients were recruited. Fatigued patients had higher COMPASS-31 total, orthostatic intolerance, secretomotor, and pupillomotor scores. No differences in fatigue and ANS symptoms were found between cognitive impaired and unimpaired patients. MFIS total score correlated with STAI state (p = 0.002) and trait (p < 0.001), BDI (p < 0.001), COMPASS-31 total (p < 0.001), orthostatic intolerance (p < 0.001), pupillomotor scores (p = 0.006). Multivariable analysis showed that BDI (p < 0.001) and COMPASS-31 (p = 0.021) predicted MFIS score. Sub-scores analysis showed that orthostatic intolerance has a relevant role in fatigue. CONCLUSION: ANS symptoms are closely related with fatigue. Orthostatic intolerance may have a predominant role. Cognitive impairment seems not to be associated with ANS symptoms.

Effects of a cooling vest with sham condition on walking capacity in heat-sensitive people with Multiple Sclerosis.

PURPOSE: Heat sensitivity is a common contraindication in people with Multiple Sclerosis (pwMS), and physical fatigue is one of the most frequently reported symptoms that can affect quality of life. Increases in body temperature may exacerbate fatigue and heat-related symptoms. Decreasing body temperature via cooling devices may mitigate disease symptoms and improve physical abilities and quality of life. This study evaluates the effects of a cooling vest with sham condition on walking capacity using a commercially-available cooling vest specifically designed for pwMS. METHODS: A counter-balanced, cross-over design was used to assess the effects of a cooling vest (CryoVest Comfort, CryoInnov, France) (COLD) from a menthol-induced sham condition (CON) on ground walking time to exhaustion (Tex, s) and distance at exhaustion (Dex, m) in ambulatory pwMS. Secondary outcomes were heart rate (HR, bpm), thermal sensation (Tsens), skin chest (Tchest) and back (Tback) temperature. RESULTS: Ten females with Multiple Sclerosis (59 ± 9 years, EDSS 3.0-5.5) participated to the study. During COLD, pwMS walked significantly longer (1896 ± 602 vs. 1399 ± 404 s, p < 0.001) and farther (1879 ± 539 vs. 1302 ± 318 m, p < 0.001) than CON. Importantly, Tsens and HR at exhaustion were not significantly different between conditions, although Tchest (- 2.7 ± 1.8 °C, p < 0.01) and Tback (- 3.9 ± 1.8 °C, p < 0.001) were lower at volitional fatigue during COLD. CONCLUSION: The lightweight cooling vest improved total walking time and distance in heat-sensitive pwMS. These physiological improvements were likely due to feeling perceptually cooler in the COLD trial, compared to the corresponding point of fatigue in the CON condition.

Microstates in multiple sclerosis: an electrophysiological signature of altered large-scale networks functioning?

Multiple sclerosis has a highly variable course and disabling symptoms even in absence of associated imaging data. This clinical-radiological paradox has motivated functional studies with particular attention to the resting-state networks by functional MRI. The EEG microstates analysis might offer advantages to study the spontaneous fluctuations of brain activity. This analysis investigates configurations of voltage maps that remain stable for 80-120 ms, termed microstates. The aim of our study was to investigate the temporal dynamic of microstates in patients with multiple sclerosis, without reported cognitive difficulties, and their possible correlations with clinical and neuropsychological parameters. We enrolled fifty relapsing-remitting multiple sclerosis patients and 24 healthy subjects, matched for age and sex. Demographic and clinical data were collected. All participants underwent to high-density EEG in resting-state and analyzed 15 min free artefact segments. Microstates analysis consisted in two processes: segmentation, to identify specific templates, and back-fitting, to quantify their temporal dynamic. A neuropsychological assessment was performed by the Brief International Cognitive Assessment for Multiple Sclerosis. Repeated measures two-way ANOVA was run to compare microstates parameters of patients versus controls. To evaluate association between clinical, neuropsychological and microstates data, we performed Pearsons' correlation and stepwise multiple linear regression to estimate possible predictions. The alpha value was set to 0.05. We found six templates computed across all subjects. Significant differences were found in most of the parameters (global explained variance, time coverage, occurrence) for the microstate Class A (P < 0.001), B (P < 0.001), D (P < 0.001), E (P < 0.001) and F (P < 0.001). In particular, an increase of temporal dynamic of Class A, B and E and a decrease of Class D and F were observed. A significant positive association of disease duration with the mean duration of Class A was found. Eight percent of patients with multiple sclerosis were found cognitive impaired, and the multiple linear regression analysis showed a strong prediction of Symbol Digit Modalities Test score by global explained variance of Class A. The EEG microstate analysis in patients with multiple sclerosis, without overt cognitive impairment, showed an increased temporal dynamic of the sensory-related microstates (Class A and B), a reduced presence of the cognitive-related microstates (Class D and F), and a higher activation of a microstate (Class E) associated to the default mode network. These findings might represent an electrophysiological signature of brain reorganization in multiple sclerosis. Moreover, the association between Symbol Digit Modalities Test and Class A may suggest a possible marker of overt cognitive dysfunctions.

Neutropenia complicating anti-CD20 treatment in patients with multiple sclerosis: A retrospective case series and a systematic review of reported cases.

BACKGROUND: Neutropenia is an infrequent complication of treatment with CD20 depleting agents and may require the administration of granulocyte-colony stimulating factors (G-CSF), which have been associated with an increased relapse risk in patients with multiple sclerosis (PwMS). The management of this side effect is still matter of debate. METHODS: Aim of this study is to evaluate the clinical features and the management of neutropenia occurring in anti-CD20 treated PwMS through a single-center case series and a systematic review of the literature, performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. RESULTS: A total of 19 patients were included (3 from our clinical experience, 16 from the systematic review). Median age was 38 years-old (25-69) and nearly 70% were female, most of these patients had already received a median of 3 (0-4) previous treatments. Neutropenia occurred in 11 patients treated with ocrelizumab and 8 with rituximab, after a median of 2 (1-7) infusions and 9.5 (1-42) months from the first infusion. Most of these patients had late-onset neutropenia, that occurred after a median time of 90 days (2-156). About 70% of patients were symptomatic and most were treated with G-CSF or antibiotics. No relapses after G-CSF were reported. In those who did not suspend anti-CD20 (68.8%), neutropenia reoccurred in 18.2% of cases. Finally, switching between rituximab and ocrelizumab seem not to affect the occurrence of neutropenia. CONCLUSION: Our data provides practical evidence regarding the occurrence and the management of neutropenia during treatment with anti-CD20 in PwMS.

Lymphopenia during treatment with dimethyl fumarate in patients with multiple sclerosis: Prevalence, predicting factors and clinical outcomes.

BACKGROUND: Lymphopenia is a common side effect of treatment with dimethyl fumarate (DMF) in patients with multiple sclerosis (PwMS). Prevalence and predictive factors of this side effect are still uncertain, because literature has provided discrepant results and it is still a matter of debate if lymphopenia is associated with a better treatment outcome. METHODS: We retrospectively recruited PwMS treated for at least one month with DMF and collected clinical, demographic data and absolute lymphocyte count (ALC) during follow-up. Lymphopenia was graded according to CTCAE. Patients according to the grade in lymphopenia (all grades) and severe lymphopenia (grade II-IV). To evaluate predictors of lymphopenia, we compared characteristics of patients with/without lymphopenia and patients with/without severe lymphopenia. A logistic binary regression was performed to elucidate any predictive factor of lymphopenia and severe lymphopenia. Area under the curve (AUC) was calculated to evaluate sensibility and specificity of predictors. We analyzed treatment outcome with NEDA-3 status at 1- and 2-years. RESULTS: 98 of 105 patients treated with DMF were included. 46.9% developed lymphopenia, 27.6% severe lymphopenia. Lymphopenia was associated with basal ALC (p<0.001, AUC=0.786), treatment duration (p = 0.01, AUC=0.685),% of reduction at third month (p = 0.001, AUC=0.616) Severe lymphopenia was associated with basal ALC (p = 0.003, AUC=0.750).NEDA-3 status at 1-year (n = 66) and at 2-year (n = 44) did not differ in patients with/without lymphopenia (p = 0.059; p = 0.583) or with/without severe lymphopenia (p = 1.02; p = 0.169). CONCLUSION: Lymphopenia is a common side effect of DMF and basal ALC predicts its development. Lymphopenia is not associated with the achievement of NEDA-3 status.

Hiccups, severe vomiting and longitudinally extensive transverse myelitis in a patient with prostatic adenocarcinoma and Aquaporin-4 antibodies.

Neuromyelitis optica spectrum disorder (NMOSD) is not defined as a classical paraneoplastic neurological syndrome, however there are growing evidences that NMOSD may be rarely associated with cancer. Older (>45 years old) male patients with longitudinally extensive transverse myelitis (LETM) or patients with "area postrema" syndrome (intractable vomiting and hiccups) at onset are at higher risk for neoplasm-associated NMOSD. We report the case of 79-years old man who developed, a month after radiotherapy for prostatic adenocarcinoma, an area postrema syndrome rapidly followed by a LETM involving the whole spinal cord (from C2 to the conus). Aquaporin-4-IgG antibodies were positive in serum.