OBJECTIVE:Fatigue is one of the most prevalent and debilitating symptoms in individuals with multiple sclerosis (MS). We recorded somatosensory high-frequency oscillatory (HFO) thalamocortical activity in a group of MS patients without history of optic neuritis (ON). Furthermore, we examined if, like what was previously observed in response to visual stimuli, patients exhibit diminished amplitude habituation, and whether this may further exacerbate fatigue in individuals with MS. METHODS:Twenty patients diagnosed with relapsing-remitting MS were prospectively enrolled. The MS cohorts were compared with a cohort of 20 healthy volunteers (HV). Fatigue Severity Scale (FSS) was employed to evaluate the trait levels of reported fatigue. We assessed the N20 somatosensory evoked potentials (SSEPs) parameters and N20-P25 amplitude habituation, and, following the application of a band-pass filter (450-750 Hz), we evaluated electrophysiological parameters of pre- and post-synaptic HFOs. RESULTS:The latency and amplitude of the N20 SSEP and its habituation do not exhibit significant differences between MS patients and HVs. MS patients exhibited delayed latency of negative oscillatory maximum and reduced maximum peak-to-peak amplitude of the pre-synaptic HFOs (all p < 0.01). In patients, post-synaptic HFOs showed a significant delayed latency and a trend towards a reduction in the maximal peak-to-peak amplitude. The pre-synaptic HFO latency of the negative oscillatory maximum, reflecting thalamocortical activity, shows a correlation with the FSS in MS patients (r = 0.522, p = 0.018). No significant ophthalmological anomalies were identified. CONCLUSIONS:Our data revealed a significant reduction and slowing of somatosensory thalamocortical network activity in MS patients without history of ON. Furthermore, our findings showed that fatigue levels may be affected by slowed thalamocortical activity, but not by habituation of cortical responses. SIGNIFICANCE:Our findings suggest a potential role of the thalamo-cortical network on the genesis of MS-related fatigue.

BACKGROUND AND OBJECTIVES:Antibodies to proteolipid protein-1 (PLP1-IgG), a major central myelin protein also expressed in the peripheral nervous system (PNS) as the isoform DM20, have been previously identified mostly in patients with multiple sclerosis (MS), with unclear clinical implications. However, most studies relied on nonconformational immunoassays and included few patients with non-MS CNS autoimmune demyelinating disorders (ADDs). We aimed to investigate conformational PLP1-IgG in the whole ADD spectrum. METHODS:We devised a new live cell-based assay (CBA) for PLP1-IgG and used it to test 2 cohorts (retrospective exploratory, n = 284; prospective validation, n = 824) of patients with ADDs and controls (n = 177). Patients were classified as MS, neuromyelitis optica spectrum disorders (NMOSDs), myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), and other ADDs. PLP1-IgG-positive samples were tested for IgG subclasses, DM20-IgG, and on rat brain tissue-based assay (TBA). Complement-dependent cytotoxicity (CDC) was assessed on a live CBA and antigen specificity and conformational binding through immunoadsorption/colocalization/fixation experiments. RESULTS:PLP1-IgG were found in 0 of 177 controls and 42 of 1104 patients with ADDs mainly diagnosed as other ADDs (19/42) with frequent myelitis/encephalomyelitis (14/19) and coexisting PNS involvement (13/19). Four of 19 patients with other ADDs fulfilled the seronegative NMOSD criteria. PLP1-IgG were also found in patients with MOGAD (11/42), more frequently with PNS involvement (p = 0.01), and in patients with MS (12/42), more frequently with atypical features (p < 0.001). PLP1-IgG-positive MOGAD had higher EDSS scores (p < 0.001) and PLP1-IgG-positive MS had higher severity scores (MSSS, p < 0.001) compared with those PLP1-IgG-negative. Overall, PLP1-IgG were found in 24.1% of patients with CNS+PNS-ADD, 21.2% with atypical MS, 8.3% with MOGAD, 12.0% with seronegative NMOSD, and 1.4% with typical MS. Their frequency within each diagnostic subgroup was consistent between the exploratory and validation cohorts. PLP1-IgG a) colocalized with their target on CBA-TBA, where their binding was abolished after immunoadsorption and fixation-induced conformational epitope alteration; b) mostly pertained to the IgG1/IgG3 subclass (68.3%) and were able to induce CDC; and c) coreacted with DM20 in all 12 patients with PNS involvement tested. DISCUSSION:Conformational PLP1-IgG predominantly identify patients with non-MS ADDs. They should be tested mainly in those with CNS + PNS ADD, coherently with DM20-IgG coreactivity. PLP1-IgG could also be investigated as disease modifiers and prognostic markers in MS and MOGAD. Preliminary evidence supports their pathogenic potential.

Fatigue is an extremely common symptom in in people with multiple sclerosis (PwMS) and has a severe impact on quality of life. The purpose of the present study was to verify whether fatigue in PwMS is associated with a selective covert attention impairment, as measured by event-related potentials and to assess whether it is more associated with an impairment of top-down or bottom-up attentional control. Twenty-two PwMS and fatigue-MSF, 17 without fatigue-MSnF and 35 healthy volunteers underwent a three-stimulus P300 novelty task that elicits both the P3a and the P3b components. P3b latency was comparable between groups, but PwMS, independently from the presence of fatigue displayed significantly greater P3b amplitudes. P3a latency was significantly prolonged in MSF alone, while P3a amplitude in MSnF group was greater than controls. MSF were able to categorize the task-relevant target stimulus but the orienting response to a novel salient stimulus was delayed, indicating an impairment in bottom-up attentional control mechanism related to ventral attention network. Fatigue is selectively associated with a covert attentional deficit related to the ability to reallocate attentional resources to salient stimuli, a crucial function of adaptive decision-making behaviour.

In this research, Beta naphtha oxy acetate (BNOA) was used as the guest anion, and Zirconium-aluminum 7075 layered double hydroxide (Zr-AA7075-LDH) was employed as the inorganic host, to create an organic–inorganic nanohybrid nanocomposite using the co-precipitation process. At a BNOA concentration of 0.08 M and a Zr/AA7075, R = 2 M ratio, a stable nanohybrid nanocomposite was produced. The formation of a Zr-AA7075-BNOA nanocomposite, wherein the nitrate ion interlayer gap in layered double hydroxide grew from 8.8 to 19.6 Å, demonstrates the successful intercalation of Beta naphtha oxy acetate into these spaces. Moreover, it was discovered that the Brunauer-Emmett-Teller surface area for Zr-AA7075-LDH and Zr-AA7075-BNOA nanocomposites rose from 4.23 to 45.84 m2 g−1. The generated nanocomposite is a mesoporous material with a BJH mean pore diameter of199 Å. CHNS analysis of the sample revealed that the Zr-AA7075- Beta naphtha oxy acetate nanocomposite material is 37.4% (w/w) depend on the carbon content. Pseudo-second order kinetics took over after 200 min of BNOA deintercalation from the Zr-AA7075 lamella being driven by zeroth and first order kinetics. It appears that the organic acid herbicide BNOA can be manufactured using layered double hydroxide as a carrier, as shown by the study's findings.

Computational modeling of soft tissue deformation is a fundamental issue for engineering assistive medical procedures. However, existing methods are not suitable for online clinical scenes as these methods are not efficient due to high computational cost and complexity.A new Weighted Skinning and Cubature Integrated (WSC-integrated) order reduction method is proposed for dynamic modeling of soft tissue deformation. The presented method includes two integrated-based schemes for construction of sub-space and estimation of internal elastic forces: a weighted skinning integrated scheme and a cubature integrated scheme. The weighted skinning integrated scheme derived from handle-based reduced order method is adopted to construct a reduced-order sub-space, in which dynamics of soft tissue are governed by low-order system equations. The cubature integrated scheme is adopted to estimate internal elastic forces of soft tissue. The proposed method relies on integration schemes both in sub-space construction and internal forces estimation instead of precomputation of soft tissue deformation snapshots, making it possible to achieve efficient computation of soft tissue deformation.Compared to a finite element method in full-space for computing soft tissue deformation, the proposed method has a relative root mean square error for strain–stress and volumetric responses is 4.27 % and 3.11 %, respectively, and for rotation-moment and volumetric responses is 2.15 % and 2.63 %, respectively. The computation time of the proposed method achieve significant improvement (ranges from 37× to 54× ) with proper choice of sample handles and elements. Simulation of left ventricle dynamics based on the proposed method takes (21.81 ms) approximately 1/43 amount of computation time of the finite element method during online stage, and difference between their results is negligible (with relative root mean square error of 2.4 %).The simulation results and comparison validated that the proposed method presents higher computational efficiency and comparable accuracy to the finite element method in full-space. The high degree of computational efficiency and accuracy of the proposed method makes it suitable for online clinical scenes.

BACKGROUND:The disease-modifying therapies (DMTs) largely used in multiple sclerosis (MS) may result in higher infectious risk. OBJECTIVE:We aimed to investigate the infectious risk in DMT-treated MS patients. METHODS:MS patients were evaluated for infectious risk before starting, switching or during DMT. RESULTS:In this three-year observational cohort study 174 MS patients were enrolled. Among them, 18 patients were anti-HBc + and 19 patients were QuantiFERON®-TB Gold In-Tube (QFT)  +  . No patients with anti-HBc + showed a detectable HBV-DNA and all started DMT. Among QTB + patients, 17 latent TB infections (LTBIs) and 2 active TB infections (TBIs) were identified. After one month of LTBI prophylaxis or TB treatment, respectively, all patients started DMTs.Overall, 149 started DMTs. During DMTs, one ocrelizumab-treated patient with anti-HBc + developed HBV reactivation and six patients (3 on natalizumab, 2 on ocrelizumab and 1 on IFN-β) showed reactivation of HSV-1, with detectable plasma DNA. Finally, 1 cladribine-treated patient experienced VZV reactivation. All the reactivations of latent infections have been successfully treated. CONCLUSION:Screening of infectious diseases in DMT candidate MS patients helps to mitigate the infectious risk. During DMTs, a regular assessment of infectious risk allows to avoid discontinuing MS therapy and guarantees a higher degree of safety.

BACKGROUND AND PURPOSE:Stroke-associated pneumonia (SAP) affects 10 to 38% of patients in the acute phase of stroke. Stroke patients diagnosed with dysphagia have an 11-fold higher risk of developing SAP. Thus, identifying dysphagic patients through a highly accurate screening tool might be crucial in reducing the incidence of SAP. We present a case-control study designed to evaluate efficacy in reducing the risk of SAP between two swallowing screening tools, the classic water swallow test (WST) and a recently validated tool such as the GLOBE-3S (the Sapienza GLObal Bedside Evaluation of Swallowing after Stroke), which is a highly sensitive swallowing screening tool particularly accurate in detecting silent aspiration as well.METHODS:We analyzed the occurrence of dysphagia in 100 acute stroke patients distributed in two groups: half were screened with WST and the other half with GLOBE-3S.RESULTS:Dysphagia was diagnosed in 28 patients. The main result is that, among patients who passed the dysphagia screenings, none of those screened with the GLOBE-3S method developed pneumonia compared to 31.82% in the WST group. Discriminant function analysis (DFA) showed that NIH Stroke Scale (NIHSS) score and the dysphagia screening method (i.e., GLOBE-3S vs. WST) were the two main factors in the SAP's predicting model and the only significant ones per se.CONCLUSIONS:The new GLOBE-3S screening test can reduce the risk of SAP compared to WST.

We aim to define the infectious risk in DMT-treated MS patients with approaches tailored to individual patients.

Background: Italy was one of the first affected countries by coronavirus disease 2019 (COVID-19) pandemic. Public health measures like quarantine or national lockdown were adopted, with negative psychological and clinical effects on patients with chronic diseases. To investigate the impact of lockdown on patients with multiple sclerosis (MS), we developed a 36 items self-report questionnaire. Methods: Questionnaires were emailed to 120 patients with MS and 100 with chronic migraine (CM) as a control group, matched for age, sex, and education. The questionnaire was divided into five domains, evaluating concerns about 1) MS and therapy during COVID-19 pandemic, 2) personal and family caregiving, 3) working activities, 4) general and disease-related emotions during the lockdown, 5) future expectations concerning health status, social life, and working activity. Results: patients with MS had higher scores than those with CM in domains 4 and 5, investigating respectively general and disease-related emotions and future expectations (p= 0.05 and 0.02 respectively). About half of the patients with MS expressed some concern about the need to continue their therapy during the pandemic compared to people with CM (p= 0.0002). Conclusions: Covid-19 pandemic had a more negative impact on psychological status of patients with MS compared with those with CM

Background and aims Most patients with multiple sclerosis presenting with a relapsing-remitting disease course at diagnosis transition to secondary progressive multiple sclerosis (SPMS) 1-2 decades after onset. SPMS is characterized by predominant neurodegeneration and atrophy. These pathogenic hallmarks result in unsatisfactory treatment response in SPMS patients. Therefore, early diagnosis of SPMS is necessary for prompt treatment decisions. The aim of this review was to assess neurophysiological and fluid biomarkers that have the potential to monitor disease progression and support early SPMS diagnosis. Methods We performed a systematic review of studies that analyzed the role of neurophysiological techniques and fluid biomarkers in supporting SPMS diagnosis using the preferred reporting items for systematic reviews and meta-analyses statement. Results From our initial search, we selected 24 relevant articles on neurophysiological biomarkers and 55 articles on fluid biomarkers. Conclusion To date, no neurophysiological or fluid biomarker is sufficiently validated to support the early diagnosis of SPMS. Neurophysiological measurements, including short interval intracortical inhibition and somatosensory temporal discrimination threshold, and the neurofilament light chain fluid biomarker seem to be the most promising. Cross-sectional studies on an adequate number of patients followed by longitudinal studies are needed to confirm the diagnostic and prognostic value of these biomarkers. A combination of neurophysiological and fluid biomarkers may be more sensitive in detecting SPMS conversion.

Background and purpose Dysphagia occurs in up to 50% of all patients with acute stroke. There is debate regarding which is the most effective screening tool in identifying aspiration in patients with acute stroke. We assessed the accuracy of the Sapienza Global Bedside Evaluation of Swallowing after Stroke ( GLOBE ‐3S), which combines the Toronto Bedside Swallowing Screening Test ( TOR ‐ BSST ©) with oxygen desaturation and laryngeal elevation measurement during swallowing. Methods We prospectively enrolled consecutive patients with stroke within 72 h of symptom onset. All patients with stroke firstly underwent a standard neurological examination, then the GLOBE ‐3S evaluation and finally the fiberoptic endoscopic evaluation of swallowing ( FEES ). Two different assessors, a neurologist and a speech pathologist, blind to both the clinical data and each other's evaluation, administered the GLOBE ‐3S and FEES examination. We assessed the accuracy of the GLOBE ‐3S in detecting post‐stroke swallow impairment with aspiration using the FEES as the standard. Results We enrolled 50 patients with acute stroke, 28 of whom (56%) had swallowing impairment with aspiration at FEES evaluation. A total of 33 patients (66%) failed the GLOBE ‐3S evaluation. The GLOBE ‐3S reached a sensitivity of 100% and a specificity of 77.3% (negative predictive value, 100%; positive likelihood ratio, 4.34). The median time required for the GLOBE ‐3S to be performed was 297 s. Conclusions GLOBE ‐3S is quick to perform at the bedside and can accurately identify aspiration in patients with acute stroke. By including the measurement of laryngeal elevation and monitoring of oxygen desaturation, it could represent a highly sensitive instrument to avoid the misdiagnosis of silent aspirators.

ObjectivesTo study the effects of a standard acute medication withdrawal program on short-term cortical plasticity mechanisms in patients with medication overuse headache (MOH).MethodsThirteen patients with MOH and 16 healthy volunteers underwent repetitive transcranial magnetic stimulation (rTMS) over the left motor cortex; in patients with MOH, recordings were performed before and after a 3-week medication withdrawal program. Ten trains of 10 stimuli each (120% resting motor threshold) were delivered at 1Hz or 5Hz in two separate sessions in a randomised order. Motor evoked potential (MEP) amplitudes were measured from the right first dorsal interosseous muscle and the slope of the linear regression line from the first to the tenth stimuli was calculated for each participant.ResultsAll subjects exhibited MEP amplitude inhibition in response to 1Hz rTMS. Alternatively, the 5-Hz trains of rTMS inhibited rather than potentiated MEP amplitudes in patients with MOH. The physiological potentiating effect of 5Hz rTMS on MEP amplitudes was restored after drug withdrawal and in proportion with the percentage reduction in monthly headache days in patients with MOH.ConclusionsThe results suggest that acute medication withdrawal normalises brain responses in patients with MOH. Clinical improvements after medication withdrawal may reflect the reversal of neurophysiological dysfunction. Accordingly, medication withdrawal should be offered to patients with MOH as early as possible in order to prevent the development of more pronounced alterations in brain plasticity.

Objective To study the effects of trains of repetitive transcranial magnetic stimulation (rTMS) over the motor cortex in patients with chronic migraine (CM) with or without medication overuse (MOH). Subjects and methods Thirty-two patients (CM [n=16]; MOH [n=16]) and 16 healthy volunteers (HVs) underwent rTMS recording. Ten trains of 10 stimuli each (120% resting motor threshold) were applied over the left motor cortex at 1Hz or 5Hz in random order. The amplitude of motor evoked potential (MEP) was evaluated from electromyographic recording in the first dorsal interosseous muscle. The slope of the linear regression line for the 10 stimuli for each participant was calculated using normalized data. Results rTMS-1Hz had a normal depressive effect on MEP amplitude in all groups. rTMS-5Hz depressed instead of potentiating MEP amplitudes in MOH patients, with a significantly different response from that in HVs and CM patients. The slope of the linear regression of MEP amplitudes was negatively correlated with pain intensity in CM patients, and with the duration of overuse headache in MOH patients. Conclusions This different plastic behaviour suggests that MOH and CM, despite exhibiting a similar clinical phenotype, have different neurophysiological learning processes, probably related to different pathophysiological mechanisms of migraine chronification.

Introduction The trigeminal autonomic cephalagias (TACs) are short-lasting unilateral headaches associated with autonomic features. Even if coexistence of different ipsilateral TACs in the same patient has been previously reported in few papers, the simultaneous occurrence of contralateral TACs is not described previously. Case description A 50 years old working man complained, at the end of his cluster period, a new TAC, fitting the criteria for probable paroxysmal hemicrania. The dramatic improvement of this last cephalalgia with indomethacin treatment confirmed the diagnosis. Discussion, evaluation and conclusion There is a clear overlap in clinical diagnosis between cluster headache (CH) and paroxysmal hemicrania (PH) and similarities are somewhat greater than differences. The originality of this report is the coexistence of contralateral TACs in the same patients at the same moment. According neuroimaging studies, CH hypothalamic activation occurs ipsilateral to the side of the headache while in PH hypothalamic activation occurs contralateral to the side of headache. It could be suggested that a continuous hypothalamic activation give a maladaptive plasticity recruiting closed neuronal aggregates responsible for the developing of PH after a long period of CH, confirming the central origin of both CH and PH. Further studies need to confirm this hypothesis.

O028. Thalamo-cortical network changes during the migraine cycle: insights from MRI-based microstructural and functional resting-state network correlation analysis Gianluca Coppola, Antonio Di Renzo, Emanuele Tinelli, Chiara Lepre, Elisa Iacovelli, Cherubino Di Lorenzo, Giorgio Di Lorenzo, Vincenzo Parisi, Mariano Serrao, Flavia Pauri, Giancarlo Fiermonte, Claudio Colonnese, Jean Schoenen, Francesco Pierelli

Neurophysiological investigations have demonstrated that there are unique fluctuations in the migraine brain functional activity between the ictal and interictal periods. Here we investigated the possibility that there are fluctuations over time also in whole brain morphometry of patients affected by episodic migraine without aura (MO). Twenty-four patients with untreated MO underwent 3T MRI scans during ( n = 10) or between attacks ( n = 14) and were compared to a group of 15 healthy volunteers (HVs). We then performed voxel-based-morphometry (VBM) analysis of structural T1-weighted MRI scans to determine if changes in brain structure were observed over the course of the migraine cycle. Interictally, MO patients had a significantly lower gray matter (GM) density within the right inferior parietal lobule, right temporal inferior gyrus, right superior temporal gyrus, and left temporal pole than did HVs. Ictally, GM density increased within the left temporal pole, bilateral insula, and right lenticular nuclei, but no areas exhibited decreased GM density. These morphometric GM changes between ictal and interictal phases suggest that abnormal structural plasticity may be an important mechanism of migraine pathology. Given the functional neuroanatomy of these areas, our findings suggest that migraine is a condition associated with global dysfunction of multisensory integration and memory processing.

Background Neurophysiological investigations have demonstrated that there are distinctive fluctuations in the brain’ se lectric signals between the ictal and interictal periods of recurrent migraine. Whether structural plasticity of the brain is also an important feature of episodic migraine remains unresolved. Aim We therefore investigated the possibility that there are fluctuations over time in whole brain grey matter morphometry of patients affected by episodic migraine without aura (MO). Method Twenty-four patients with untreated MO underwent MRI scans (3-Tesla Siemens Verio) during (n = 10) or between attacks (n = 14) and were compared to a group of 15 healthy volunteers (HV). We then performed voxelbased-morphometry (VBM) analysis of structural T1-weighted MRI scans to determine if changes in brain structure were observed over the course of the migraine cycle. Results During the interictal phase, MO patients had a significantly lower grey matter (GM) density within the right inferior parietal lobule, right temporal inferior gyrus, right superior temporal gyrus, and left temporal pole than did HV. During attacks, GM density increased within the left temporal pole, bilateral insula, and right lenticular nuclei, but no areas exhibited decreased GM density. Conclusion The morphometric GM changes between ictal and interictal phases reported in the present study suggest that abnormal structural plasticity may be an important mechanism of migraine pathology. Given the functional neuroanatomy of these areas, our findings suggest that migraine is a condition associated with global dysfunction of multisensory integration and memory processing. No conflict of interest.