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ObjectiveSingle cases and small series of Guillain-Barré syndrome (GBS) have been reported during the SARS-CoV-2 outbreak worldwide. We evaluated incidence and clinical features of GBS in a cohort of patients from two regions of northern Italy with the highest number of patients with COVID-19.MethodsGBS cases diagnosed in 12 referral hospitals from Lombardy and Veneto in March and April 2020 were retrospectively collected. As a control population, GBS diagnosed in March and April 2019 in the same hospitals were considered.ResultsIncidence of GBS in March and April 2020 was 0.202/100 000/month (estimated rate 2.43/100 000/year) vs 0.077/100 000/month (estimated rate 0.93/100 000/year) in the same months of 2019 with a 2.6-fold increase. Estimated incidence of GBS in COVID-19-positive patients was 47.9/100 000 and in the COVID-19-positive hospitalised patients was 236/100 000. COVID-19-positive patients with GBS, when compared with COVID-19-negative subjects, showed lower MRC sum score (26.3±18.3 vs 41.4±14.8, p=0.006), higher frequency of demyelinating subtype (76.6% vs 35.3%, p=0.011), more frequent low blood pressure (50% vs 11.8%, p=0.017) and higher rate of admission to intensive care unit (66.6% vs 17.6%, p=0.002).ConclusionsThis study shows an increased incidence of GBS during the COVID-19 outbreak in northern Italy, supporting a pathogenic link. COVID-19-associated GBS is predominantly demyelinating and seems to be more severe than non-COVID-19 GBS, although it is likely that in some patients the systemic impairment due to COVID-19 might have contributed to the severity of the whole clinical picture.

ObjectivesA few variants of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) have been described, but their frequency and evolution to typical CIDP remain unclear. To determine the frequency and characteristics of the CIDP variants, their possible evolution to typical CIDP, and treatment response.MethodsWe applied a set of diagnostic criteria to 460 patients included in a database of Italian patients with CIDP. Clinical characteristics and treatment response were reviewed for each patient. The Kaplan-Meier curve was used to estimate the progression rate from atypical to typical CIDP.ResultsAt the time of inclusion, 376 (82%) patients had a diagnosis of typical CIDP while 84 (18%) had atypical CIDP, including 34 (7%) with distal acquired demyelinating symmetric neuropathy (DADS), 17 (4%) with purely motor, 17 (4%) with Lewis-Sumner syndrome (LSS) and 16 (3.5%) with purely sensory CIDP. Based on retrospective review of the symptoms and signs present at onset and for at least 1 year, 180 (39%) patients had an initial diagnosis compatible with atypical CIDP that in 96 (53%) patients evolved to typical CIDP. Mean disease duration was longer in patients evolving to typical CIDP than in those not evolving (p=0.0016). Patients with DADS and LSS had a less frequent response to immunoglobulin than those with typical CIDP, while patients with purely motor and sensory CIDP had a similar treatment response.ConclusionsThe proportion of patients with atypical CIDP varies during the disease course. DADS and LSS have a less frequent response to intravenous immunoglobulin compared with typical CIDP, raising the possibility of a different underlying pathogenetic mechanism.

Fibromyalgia syndrome (FMS) is a complex disorder where widespread musculoskeletal pain is associated with many heterogenous symptoms ranging from affective disturbances to cognitive dysfunction and central fatigue. FMS is currently underdiagnosed and often very poorly responsive to pharmacological treatment. Pathophysiology of the disease remains still obscure even if in the last years fine structural and functional cerebral abnormalities have been identified, principally by neurophysiological and imaging studies delineating disfunctions in pain perception, processing and control systems. On such basis, recently, neurostimulation of brain areas involved in mechanism of pain processing and control (primary motor cortex: M1 and dorsolateral prefrontal cortex: DLPFC) has been explored by means of different approaches and particularly through non-invasive brain stimulation techniques (transcranial magnetic and electric stimulation: TMS and tES). Here we summarize studies on tES application in FMS. The great majority of reports, based on direct currents (transcranial direct currents stimulation: tDCS) and targeting M1, showed efficacy on pain measures and less on cognitive and affective symptoms, even if several aspects as maintenance of therapeutical effects and optimal stimulation parameters remain to be established. Differently, stimulation of DLPFC, explored in a few studies, was ineffective on pain and showed limited effects on cognitive and affective symptoms. Very recently new tES techniques as high-density tDCS (HD-tDCS), transcranial random noise stimulation (tRNS) and tDCS devices for home-based treatment have been explored in FMS with interesting even if very preliminary results opening interesting perspectives for more effective, well tolerated, cheap and easy therapeutic approaches.

Retrograde cricopharyngeus dysfunction (R-CPD) is a recently recognized condition characterized by the inability to burp, typically accompanied by gurgling noises, bloating, and flatulence. Percutaneous botulinum neurotoxin (BoNT) injection into the cricopharyngeus muscle is a minimally invasive treatment with promising effects, although current evidence remains limited. In this prospective, open-label study, we evaluated the clinical effects of increasing doses (10 to 30 U) of EMG-guided unilateral BoNT injection in 67 patients with R-CPD. Symptom severity and quality of life were assessed at baseline and at 1 and 4 months post-treatment. The electromyographic (EMG) parameters of the cricopharyngeus were recorded to explore their association with symptom burden and treatment response. At a 1-month follow-up, 55.2% of patients were classified as responders (satisfaction score ≥ 6/10), with a higher rate (64.4%) observed at higher doses, particularly in female patients. Both symptom severity and quality of life improved significantly at 1 month and were sustained at 4 months. Higher cricopharyngeus EMG activity was associated with more severe symptoms and lesser treatment responses. Unilateral EMG-guided BoNT injection is a safe and effective treatment for R-CPD. Further studies should explore the potential role of electromyography in clarifying the pathophysiological aspects of R-CPD and guiding treatment.

Sigma receptors (SRs), including SR1 and SR2 subtypes, have attracted increasing interest in recent years due to their involvement in a wide range of activities, including the modulation of opioid analgesia, neuroprotection, and potential anticancer activity. In this context, haloperidol (HAL), a commonly used antipsychotic drug, also possesses SR activity and cytotoxic effects. Herein, we describe the identification of novel SR ligands, obtained by a chemical hybridization approach. There wereendowed with pan-affinity for both SR subtypes and evaluated their potential anticancer activity against SH-SY5Y and HUH-7 cancer cell lines. Through a chemical hybridization approach, we identified novel compounds (4d, 4e, 4g, and 4j) with dual affinity for SR1 and SR2 receptors. These compounds were subjected to cytotoxicity testing using a resazurin assay. The results revealed potent cytotoxic effects against both cancer cell lines, with IC50 values comparable to HAL. Interestingly, the cytotoxic potency of the novel compounds resembled that of the SR1 antagonist HAL rather than the SR2 agonist siramesine (SRM), indicating the potential role of SR1 antagonism in their mechanism of action. The further exploration of their structure-activity relationships and their evaluation in additional cancer cell lines will elucidate their therapeutic potential and may pave the way for the development of novel anticancer agents that target SRs.

Background and Purpose Early detection of peripheral nerve damage in patients with hereditary transthyretin amyloidosis (ATTRv) has become essential for the prompt initiation of effective, recently approved therapies. In our study, we propose a new variable echo time (vTE) MRI sequence as a non‐invasive method to detect nerve injury in ATTRv patients and to establish a novel potential imaging marker of neuropathy that correlates with disease severity and abnormal results of NCS. Methods In this cohort study, twenty patients with clinically confirmed ATTRv polyneuropathy (PNP) and twenty‐one healthy volunteers underwent 3 T MRI. vTE was performed on the right thigh to include the proximal tract of the sciatic nerve. The cross‐sectional area of the whole sciatic nerve, inner epineurium, and endoneurial fascicles was segmented, and the corresponding pseudo‐T2* was extrapolated from the two acquired echoes of the vTE. Results Significantly higher fascicles pT2* (p = < 0.001), total cross‐sectional area (CSA: p = 0.017) and fascicular area (p = < 0.001) were found in the ATTRv group compared to healthy controls. Fascicles pT2* also correlated with previously validated clinical outcome measures such as Polyneuropathy Disability Scoring System (PND score p = < 0. 001), Neuropathy Impairment Score (NIS p = 0.030) and NIS items related to the lower limbs, and with nerve conduction parameters, demonstrating the ability to discriminate ATTRv patients with different degrees of PNP from HC. Conclusion In conclusion, the vTE sequence provides novel and reliable imaging markers capable of detecting early nerve microstructural changes related to disease onset and severity.

ObjectiveTo investigate the frequency and clinical correlates of anti-nerve autoantibodies in an unselected series of Italian patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP)MethodsSera from 276 CIDP patients fulfilling the EFNS/PNS criteria and included in the Italian CIDP database were examined for the presence of anti-nerve autoantibodies. Results were correlated with the clinical data collected in the database.ResultsAnti-neurofascin155 (NF155) antibodies were found in 9/258 (3.5%) patients, anti-contactin1 (CNTN1) antibodies in 4/258 (1.6%) patients, and anti-contactin-associated protein1 (Caspr1) in 1/197 (0.5%) patients, while none had reactivity to gliomedin or neurofascin 186. Predominance of IgG4 isotype was present in 7of the 9 examined patients. Anti-NF155 patients more frequently had ataxia, tremor, and higher CSF protein levels than antibody-negative patients. Anti-CNTN1 patients more frequently had a GBS-like onset, pain, and ataxia and had more severe motor impairment at enrollment than antibody-negative patients. They more frequently received plasmapheresis, possibly reflecting a less satisfactory response to IVIg or steroids. IgM antibodies against one or more gangliosides were found in 6.5% of the patients (17/260) and were more frequently directed against GM1 (3.9%). They were frequently associated with a progressive course, with a multifocal sensorimotor phenotype and less frequent cranial nerve involvement and ataxia.ConclusionsAnti-paranodal and anti-ganglioside antibodies are infrequent in patients with CIDP but are associated with some typical clinical association supporting the hypothesis that CIDP might be a pathogenically heterogeneous syndrome possibly explaining the different clinical presentations.

Migraine is a highly disabling disease characterized by recurrent pain. Despite an intensive effort, mechanisms of migraine pathophysiology still represent an unsolved issue. Evidence from both animal and human studies suggests that migraine is characterized by hyperresponsivity or hyperexcitability of sensory cortices, especially the visual cortex. This phenomenon, in turn, may affect multisensory processing. Indeed, migraineurs present with an abnormal, reduced, perception of the Sound-induced Flash Illusion (SiFI), a crossmodal illusion that relies on optimal integration of visual and auditory stimuli by the occipital visual cortex. Decreasing visual cortical excitability with transcranial direct current stimulation (tDCS) can increase the SiFI in healthy subjects. Moving away from these issues, we applied cathodal tDCS over the visual cortex of migraineurs, with and without aura, in order to decrease cortical excitability and thus physiologically restoring the perception of a reliable SiFI. Differently from our expectations, tDCS was unable to reliably modulate SiFI in migraine. The chronic, relatively excessive, visual cortex hyperexcitability, featuring the migraineur brain, may render tDCS ineffective for restoring multisensory processing in this disease.

Background The offset analgesia phenomenon refers to the disproportionately large decrease in the perceived pain following a slight decrease in intensity of a noxious heat stimulus. It is considered an expression of the activation of the endogenous pain-modulation system. The main aim of this study was to examine pain processing using the offset analgesia paradigm in subjects with interictal episodic migraine compared to those with non-ictal chronic migraine. Additionally, as secondary outcome measures, we aimed to: (1) explore fluctuations in the endogenous pain modulation system throughout the migraine cycle by including small subgroups of episodic migraine patients in different migraine phases, and (2) compare different subgroups of non-ictal chronic migraine patients with or without medication overuse headache (MOH). Methods A total of 68 subjects with episodic migraine (different subjects were evaluated during the interictal, preictal, ictal, or postictal phase), 34 with non-ictal chronic migraine with or without MOH, and 30 healthy controls were enrolled. Participants underwent six trials involving constant temperature and stimulus offset applied to the forehead, with pain responses measured using a continuous analogue-to-digital converter of VAS. Results The offset analgesia phenomenon was recorded predominantly during the postictal phase among the population of episodic migraine patients, as well as in healthy subjects. Offset analgesia was generally absent in interictal episodic migraine subjects and in subjects with chronic migraine with MOH, though some individual variability was observed. A paradoxical increase in pain facilitation was observed in most preictal and ictal episodic migraine subjects, as well as in chronic migraine subjects without MOH. The severity of offset analgesia impairment correlated with scores on the Allodynia Symptom Checklist and the Numeric Pain Rating Scale, which assessed average headache intensity during untreated migraine attacks. Conclusions Episodic and chronic migraine patients exhibit disrupted top-down pain modulation pathways, with more significant alterations in chronic migraine without MOH. Additionally, we provide preliminary evidence that cyclical changes in the endogenous pain modulation system could contribute to migraine recurrence in episodic migraine sufferers. However, given the small subgroups of interictal patients evaluated in different migraine phases and the cross-sectional study design, these findings should be interpreted with caution and confirmed by future longitudinal studies with larger sample sizes.

In this study, we investigate the effects of high-frequency repetitive transcranial magnetic stimulation (rTMS) applied over the left upper limb primary motor cortex (M1) on the offset analgesia (OA) phenomenon, a measure of endogenous pain modulation. In particular, we aim to determine whether rTMS influences OA differently in the forearm region, corresponding to the stimulated cortical area, compared to the trigeminal region. Twenty-two healthy volunteers underwent three experimental sessions: a baseline session without stimulation, an active rTMS session, and a sham rTMS session. Quantitative sensory testing (QST) paradigms, including warm and cold detection thresholds, heat pain threshold corresponding to a visual analogue scale (VAS) score of approximately 50–60 out of 100 (Pain50–60), and constant and offset trials, were assessed in both the forearm and trigeminal regions. The results revealed that active rTMS significantly enhanced the OA phenomenon in the forearm during the late phase, while no significant effects were observed in the trigeminal region. These findings suggest that rTMS may modulate central pain mechanisms in a body region-specific manner, potentially linked to the somatotopic organization of M1. This study points to possible mechanisms of action of rTMS for pain relief, highlighting the importance of region-specific effects in chronic pain treatment. Further research is needed to investigate the underlying mechanisms and clinical applicability of rTMS in patients with chronic pain conditions, especially when OA is compromised.