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The Multiple Sclerosis Neuropsychological Questionnaire (MSNQ) is a brief questionnaire useful for screening patients with multiple sclerosis (MS) at risk for cognitive impairment. It includes a patient self-assessment (MSNQ-p) and a section for the caregiver (informant) (MSNQ-i). This study's aim was to validate the Italian version of MSNQ and to compare MSNQ scores with Symbol Digit Modality Test (SDMT), Beck Depression Inventory (BDI), and Expanded Disability Status Scale (EDSS) score, measuring cognitive skills, mood status, and physical disability respectively. We enrolled 122 MS patients (and related caregivers) at MS center of Tor Vergata University Hospital of Rome. The final study sample consisted of 122 patients with MS (90 relapsing-remitting, 24 secondary progressive, and 8 primary progressive). Our results highlighted that MSNQ has a unidimensional factor structure. Correlational analyses found a good correlation between both versions (MSNQ-p and MSNQ-i) of the questionnaire. Both MSNQ-p and MSNQ-i were correlated with clinical variables, specifically with cognitive impairment, mood disorder, and with disability. The Italian version of MSNQ is reliable and useful as screening tool to identify MS patients at high risk of cognitive impairment., (© 2021. Fondazione Società Italiana di Neurologia.)

There are consolidated data about multiple sclerosis (MS)-dependent retinal neurodegeneration occurring in the optic disk and the macula, although it is unclear whether other retinal regions are affected. Our objective is to evaluate, for the first time, the involvement of the entire retinal posterior pole in patients diagnosed with relapsing remitting multiple sclerosis (RRMS) unaffected by optic neuritis using Spectral Domain-Optical Coherence Tomography (SD-OCT). The study protocol was approved by Tor Vergata Hospital Institutional Ethics Committee (Approval number 107/16), and conforms to the tenets of the Declaration of Helsinki. After a comprehensive neurological and ophthalmological examination, 53 untreated RRMS patients (aged 37.4 ± 10) and 53 matched controls (aged 36.11 ± 12.94) were enrolled. In addition, each patient underwent an examination of the posterior pole using the SD-OCT built-in Spectralis posterior pole scanning protocol. After segmentation, the mean thickness, as well as the thickness of the 64 single regions of interest, were calculated for each retinal layer. No statistically significant difference in terms of average retinal thickness was found between the groups. However, MS patients showed both a significantly thinner ganglion cell layer ( p < 0.001), and, although not statistically significant, a thinner inner nuclear layer ( p = 0.072) and retinal nerve fiber layer ( p = 0.074). In contrast, the retinal pigment epithelium ( p = 0.014) and photoreceptor layers p < 0.001) resulted significantly thicker in these patients. Interestingly, the analysis of the region of interest showed that neurodegeneration was non-homogeneously distributed across each layer. This is the first report that suggests a complex rearrangement that affects, layer by layer, the entire retinal posterior pole of RRMS retinas in response to the underlying neurotoxic insult.

Introduction: This study aimed to evaluate whether treatment with fingolimod (FTY) may induce functional changes on the macular pre-ganglionic retinal elements in patients affected by relapsing-remitting multiple sclerosis (RR-MS) without optic neuritis (ON)., Methods: This case-control observational and retrospective study assessed multifocal electroretinogram (mfERG) responses from 35 healthy controls (mean age 43.58 ± 5.76 years), 41 patients with RR-MS without ON (mean age 40.64 ± 4.83 years, MS-noFTY group), and from 21 patients with RR-MS without ON (mean age 42.38 ± 12.34 years) and treated with fingolimod (Gilenya®, Novartis Europharm, 0.5 mg/day) (MS-FTY group). MfERG N1 and P1 implicit times (ITs), and N1-P1 response amplitude densities (RADs) were measured from concentric rings (R) with increasing foveal eccentricity: 0-5° (R1), 5-10° (R2), 10-15° (R3), 15-20° (R4), 20-25° (R5). We considered R1 and R2 as "central macular areas" and R3, R4 and R5 as "more eccentric retinal areas". In the MS-FTY group, mfERG recordings were performed between 6 and 12 months (mean 7.2 ± 1.5 months) from the start of FTY., Results: In the MS-FTY group, the mean values of mfERG N1 and P1 ITs and RADs detected in both central macular areas (R1 and R2) and in more eccentric retinal areas (R3, R4 and R5) were not significantly different (p > 0.01) with respect to those of control and MS-noFTY groups., Conclusions: Our mfERG results suggest that the chronic use of FTY does not induce a dysfunction of pre-ganglionic retinal elements located in the 0-25° of central retina. Since FTY does not cause any retinal functional abnormality, we suggest that FTY treatment could not produce any toxic effect on pre-ganglionic retinal elements even in the absence of macular oedema., (© 2021. The Author(s).)

Background: To minimize the risk of Progressive Multifocal Leukoencephalopathy and rebound in JCV-positive multiple sclerosis (MS) patients after 24 natalizumab doses, it has been proposed to extend the administrations interval. The objective is to evaluate the EID efficacy on MRI activity compared with the standard interval dosing (SID)., Methods: Observational, multicentre, retrospective cohort study, starting from the 24th natalizumab infusion to the loss of follow-up or 2 years after baseline. Three hundred and sixteen patients were enrolled. The median dose interval (MDI) following the 24th infusion was 5 weeks, with a bimodal distribution (modes at 4 and 6 weeks). Patients were grouped into 2 categories according to the mean number of weeks between doses: <5 weeks, SID; ≥5 weeks, EID., Results: One hundred and eighty-seven patients were in the SID group (MDI = 4.5 weeks) and 129 in the EID group (MDI 6.1 weeks). The risk to develop active lesions on MRI is similar in SID and EID groups during the 6 and 12 months after the 24th natalizumab infusion, respectively 4.27% (95% CI:0.84-7.70) vs 4.71% (95% CI:0.16-9.25%) [p = 0.89] and 8.50% (95% CI:4.05-12.95) vs 6.55% (95% CI:2.11-11.00%) [p = 0.56]. The EID regimen does not appear to increase the occurrence of MRI activity during follow-up., Conclusion: There is no evidence of the reduced efficacy of natalizumab in an EID setting regarding the MRI activity. This observation supports the need for a bigger randomized study to assess the need to change the standard of the natalizumab dosing schedule, to better manage JCV-positive patients., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background and Purpose: The aim was to identify the clinical and diagnostic investigations that may help to support a diagnosis of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) in patients not fulfilling the European Federation of Neurological Societies and Peripheral Nerve Society (EFNS/PNS) electrodiagnostic criteria., Methods: The data from patients with a clinical diagnosis of CIDP included in a national database were retrospectively reviewed., Results: In all, 535 patients with a diagnosis of CIDP were included. This diagnosis fulfilled the EFNS/PNS criteria in 468 patients (87.2%) (definite in 430, probable in 33, possible in three, while two had chronic immune sensory polyradiculopathy). Sixty-seven patients had a medical history and clinical signs compatible with CIDP but electrodiagnostic studies did not fulfill the EFNS/PNS criteria for CIDP. These patients had similar clinical features and frequency of abnormal supportive criteria for the diagnosis of CIDP compared to patients fulfilling EFNS/PNS criteria. Two or more abnormal supportive criteria were present in 40 (61.2%) patients rising to 54 (80.6%) if a history of a relapsing course as a possible supportive criterion was also included. Increased cerebrospinal fluid proteins and response to immune therapy most frequently helped in supporting the diagnosis of CIDP. Response to therapy was similarly frequent in patients fulfilling or not EFNS/PNS criteria (87.3% vs. 85.9%)., Conclusions: Patients with a clinical diagnosis of CIDP had similar clinical findings, frequency of abnormal supportive criteria and response to therapy compared to patients fulfilling EFNS/PNS criteria. The presence of abnormal supportive criteria may help in supporting the diagnosis of CIDP in patients with a medical history and clinical signs compatible with this diagnosis but non-diagnostic nerve conduction studies., (© 2020 European Academy of Neurology.)

Objectives: To determine the prevalence of different comorbidities in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), and their impact on outcome, treatment choice and response., Methods: Using a structured questionnaire, we collected information on comorbidities from 393 patients with CIDP fulfilling the European Federation of Neurological Societies and Peripheral Nerve Society criteria included in the Italian CIDP database., Results: One or more comorbidities were reported by 294 patients (75%) and potentially influenced treatment choice in 192 (49%) leading to a less frequent use of corticosteroids. Response to treatment did not differ, however, from that in patients without comorbidities. Diabetes (14%), monoclonal gammopathy of undetermined significance (MGUS) (12%) and other immune disorders (16%) were significantly more frequent in patients with CIDP than expected in the general European population. Patients with diabetes had higher disability scores, worse quality of life and a less frequent treatment response compared with patients without diabetes. Patients with IgG-IgA or IgM MGUS had an older age at CIDP onset while patients with other immune disorders had a younger age at onset and were more frequently females. IgM MGUS was more frequent in patients with motor CIDP than in patients with typical CIDP., Conclusions: Comorbidities are frequent in patients with CIDP and in almost 50% of them have an impact on treatment choice. Diabetes, MGUS and other immune diseases are more frequent in patients with CIDP than in the general population. Only diabetes seems, however, to have an impact on disease severity and treatment response possibly reflecting in some patients a coexisting diabetic neuropathy., Competing Interests: Competing interests: PED has received travel grants to attend scientific meetings from CSL Behring and Kedrion. DC has received honoraria for lecturing from Shire, CSL Behring and Kedrion and travel grants to attend scientific meeting from Shire, Kedrion, and CSL Behring. FM reports personal fees for scientific events from CSL Behring and has received travel grants to attend scientific meetings from CSL Behring and Kedrion. RF has served on scientific advisory boards for CSL Behring and has received travel grants from Kedrion and CSL Behring to attend scientific meeting. Chiara Briani has served on scientific advisory boards for Pfizer, Alnylam, and Akcea, and has received travel grants from Kedrion and CSL Behring to attend scientific meeting. MF has served on scientific advisory boards for CSL Behring and has received travel grants from Kedrion, Baxter and CSL Behring to attend scientific meeting. SJ has received research grants from Grifols, outside this work, and travel grants from Grifols and Kedrion. Anna Mazzeo has received travel grants from Kedrion and CSL Behring to attend scientific meeting. GC has received travel grants to attend scientific meetings from CSL Behring and Kedrion. AC has received travel grants to attend scientific meetings from Kedrion. MC has received travel grants to attend scientific meetings from Kedrion. ML has received travel grants to attend scientific meetings from Kedrion. GC has received honoraria for lecturing and travel grants to attend scientific meetings from Kedrion. E Beghi reports grants from UCB-Pharma, grants from Shire, grants from EISAI, personal fees from Viropharma, grants from Italian Ministry of Health, grants from Fondazione Borgonovo, grants from Associazione IDIC 15, grants from European Union, outside the submitted work. Giuseppe Liberatore has received travel grants to attend scientific meetings from CSL Behring and Kedrion. Lucio Santoro reports personal fees for scientific events from CSL Behring and has received travel grants to attend scientific meetings from CSL Behring and Kedrion. EP has received travel grants to attend scientific meetings from CSL Behring. Eduardo Nobile Orazio reports personal fees for Advisory or Scientific Board from Kedrion, Italy, Baxter, Italy, Novartis, Switzerland, CSL-Behring, Italy, Astellas, the Netherlands, outside the submitted work and travel grants to attend Scientific Meeting from Baxter, Grifols, Kedrion, and Novartis, Italy. The other authors declare no conflict of interest., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Background Aiming to safeguard its population from COVID19 infection, Italian government provided specific advices, especially to fragile individuals such those affected by Multiple Sclerosis (MS), to respect social distancing, to arrange remote work and to use personal protective equipment (PPE). The aim of this study is to investigate real adherence to these measures among MS patients and to evaluate its impact on exposure to infection. Methods MS patients followed at the MS center of Tor Vergata University hospital, Rome, Italy were asked to complete an anonymous 35-items web-survey exploring demographics, residency, employment, social distancing habits, use of PPE, MS features and COVID19 infection data, including self-reported information about contacts with SARS-CoV-2 positive/presumed positive persons. In order to estimate adherence to social distancing and use of PPE, an overall 'Lockdown Score' (LS) on 0-10 scale was created analyzing four main domains (Working (0 - 4), Social distancing and PPE use (0 - 4), Assistance for shopping needs (0 - 2), Residency (-2 - 0)). Mean scores for several pre-defined subgroups of patients were compared using both univariable and multivariable analyses. Accuracy of the score in discriminating subjects at higher risk of coming in contact with SARS-CoV-2 positive/presumed positive individuals was calculated as the area under the receiver-operator characteristic curve (AUC). The optimal cut-off was identified and used to dichotomize LS (high/ low). Logistic regression model was applied to estimate individuals' characteristics associated with high/low LS and odds ratio of coming in contact with SARS-CoV-2 positive/presumed positive persons based on continous and dichotomised LS. Results Respondents (N = 551) had a mean(±SD) overall LS of 6.52±2.11 (Working 3.16±1.19, Social distancing and PPE use 2.69±1.33, Assistance 0.66± 0.62, Residency penalty applied in 4 cases). Female, disabled and unemployed individuals had significantly higher mean LS (p<0.05). The AUC of the LS was 0.68 (95% CI, 0.59-0.77) and the optimal LS cut-off for discrimination was 6.0. Consistently, female, disabled and unemployed individuals had higher odd of getting a high LS (≥ 6) compared to male, independent and employed (p<0.05). Odd of coming in contact with SARS-CoV-2 positive/presumed positive individuals was significantly reduced for one-unit increase in LS (0.74 (95% CI: 0.64-0.85)) and among individuals with high LS (0.37 (95% CI: 0.19-0.72)). Only one subject among respondents declared to have been diagnosed with COVID19. Conclusions MS patients, especially those with social unfavorable conditions, demonstrated good adherence to social distancing and use of protection equipment. Implementing domains, such as social assistance, may improve protection from infection. LS score is potentially able to identify subjects with behaviors at greater risk of infection, although it needs to be validated against MS population living in higher incidence areas., Competing Interests: Declaration on Competing Interest Landi D has no interests to disclose; Ponzano M has no interests to disclose; Nicoletti CG has no interests to disclose; Cecchi G has no interests to disclose; Cola G has no interests to disclose; Mataluni G has no interests to disclose; Mercuri NB has no interests to disclose; Sormani MP has no interests to disclose; Marfia GA has no interests to disclose. The study did not received funds., (Copyright © 2020. Published by Elsevier B.V.)

Background: Rituximab, an anti-CD20 monoclonal antibody leading to B lymphocyte depletion, is increasingly used as an off-label treatment option for multiple sclerosis (MS)., Objective: To investigate the effectiveness and safety of rituximab in relapsing-remitting (RR) and progressive MS., Methods: This is a multicenter, retrospective study on consecutive MS patients treated off-label with rituximab in 22 Italian and 1 Swiss MS centers. Relapse rate, time to first relapse, Expanded Disability Status Scale (EDSS) progression, incidence of adverse events, and radiological outcomes from 2009 to 2019 were analyzed., Results: A total of 355/451 enrolled subjects had at least one follow-up visit and were included in the outcome analysis. Annualized relapse rate significantly decreases after rituximab initiation versus the pre-rituximab start year in RRMS (from 0.86 to 0.09, p  < .0001) and in secondary-progressive (SP) MS (from 0.34 to 0.06, p  < .0001) and had a slight decrease in primary-progressive (PP) MS patients (from 0.12 to 0.07, p  = 0.45). After 3 years from rituximab start, the proportion of patients with a confirmed EDSS progression was 14.6% in the RRMS group, 24.7% in the SPMS group, and 41.5% in the PPMS group. No major safety concerns arose., Conclusion: Consistently with other observational studies, our data show effectiveness of rituximab in reducing disease activity in patients with MS.

A few observational studies and randomized trials suggest that exercise and rehabilitation may improve activity limitation and quality of life (QoL) in patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), but the impact of other modifiable factors on the severity of the disease is not well understood. Using a structured questionnaire, we collected data on lifestyle and dietary habits of the patients included in the Italian CIDP database to investigate the possible influence of modifiable lifestyle factors on disability and QoL. Questionnaire data were available for 323 patients. The effect of lifestyle and dietary exposures on impairment, disability and QoL was evaluated using logistic regression models, adjusting for age, sex, disease duration, physical activity and smoking. Physical activity was associated with lower sensory impairment by the ISS scale, less disability by the INCAT and RODS scale and a better QoL in all the domains of EURO-QoL scale with the exception of anxiety/depression. None of the other parameters had an impact on these scales. This study adds evidence to the possible role of physical activity in improving symptom severity, disability and QoL in patients with CIDP. None of the other environmental factors investigated appeared to have an impact on the severity and health perception of CIDP.

Objective: Cladribine tablets were tested against placebo in randomized controlled trials (RCTs). In this study, the effectiveness of cladribine vs other approved drugs in patients with relapsing-remitting MS (RRMS) was compared by matching RCT to observational data., Methods: Data from the pivotal trial assessing cladribine tablets vs placebo (CLARITY) were propensity score matched to data from the Italian multicenter database i-MuST. This database included 3,150 patients diagnosed between 2010 and 2018 at 24 Italian MS centers who started a disease-modifying drug. The annualized relapse rate (ARR) over 2 years from treatment start and the 24-week confirmed disability progression were compared between patients treated with cladribine and other approved drugs (interferon, glatiramer acetate, fingolimod, natalizumab, and dimethyl fumarate), with comparisons with placebo as a reference. Treatment effects were estimated by the inverse probability weighting negative binomial regression model for ARR and Cox model for disability progression. The treatment effect has also been evaluated according to baseline disease activity., Results: All weighted baseline characteristics were well balanced between groups. All drugs tested had an effect vs placebo close to that detected in the RCT. Patients treated with cladribine had a significantly lower ARR compared with interferon (relapse ratio [RR] = 0.48; p < 0.001), glatiramer acetate (RR = 0.49; p < 0.001), and dimethyl fumarate (RR = 0.6; p = 0.001); a similar ARR to that with fingolimod (RR = 0.74; p = 0.24); and a significantly higher ARR than natalizumab (RR = 2.13; p = 0.014), confirming results obtained by indirect treatment comparisons from RCTs (network meta-analyses). The relative effect of cladribine tablets 10 mg (cumulative dose 3.5 mg/kg over 2 years) was higher in patients with high disease activity vs all treatments except fingolimod and natalizumab. Effects on disability progression were largely nonsignificant, probably due to lack of power for such analysis., Conclusion: In patients with RRMS, cladribine tablets showed lower ARR compared with matched patients who started interferon, glatiramer acetate, or dimethyl fumarate; was similar to fingolimod; and was higher than natalizumab. The beneficial effect of cladribine tablets was generally amplified in the subgroup of patients with high disease activity., Classification of Evidence: This study provides Class III evidence that for patients with RRMS, cladribine-treated patients had lower ARR compared with interferon, glatiramer acetate, or dimethyl fumarate; similar ARR compared with fingolimod; and higher ARR compared with natalizumab., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: The approval of an increasing number of disease modifying drugs for the treatment of Multiple Sclerosis (MS) creates new challenges for patients and clinicians on the first treatment choice. The main aim of this study was to assess factors impacting first therapy choice in a large Italian MS cohort., Methods: Newly diagnosed relapsing-remitting (RR) MS patients (2010-2018) followed in 24 Italian MS centres were included in the study. We evaluated the association of baseline demographics, clinical and MRI characteristics to the first treatment choice by logistic regression models applied to pre-defined binary alternatives: dimethyl fumarate vs injectables (interferon and glatiramer acetate), teriflunomide vs injectables, fingolimod vs dimethyl fumarate and fingolimod vs natalizumab., Results: We enrolled 3025 patients in the period between January 2010 and June 2018. Relapses in the previous year (OR = 2.75; p = 0.001), presence of spinal cord lesions (OR = 1.80; p = 0.002) and higher number (>9) of T2 lesions on the baseline brain MRI scan (OR = 1.65; p = 0.022) were the factors associated to dimethyl fumarate choice as first therapy vs an injectable drug. Older age (OR = 1.06; p < 0.001), male sex (OR = 2.29; p = 0.001) and higher EDSS (OR = 1.36; p < 0.001) were the factors associated with the choice of teriflunomide vs injectables. In more recent years, dimethyl fumarate (OR = 3.23; p < 0.001) and teriflunomide (OR = 2.53; p < 0.001) were chosen more frequently than injectables therapies. The main determinant for the choice of fingolimod as compared with dimethyl fumarate was a higher EDSS (OR = 1.56; p = 0.001), while there was a weak association with a longer disease duration (p = 0.068) and a longer time from onset to diagnosis (p = 0.085). Compared to fingolimod, natalizumab was preferred in patients with a younger age (OR = 0.95; p = 0.003) and higher EDSS (OR = 1.45; p = 0.007) and a shorter disease duration (OR = 0.52; p = 0.076)., Conclusion: Many factors guided therapeutic decision for our Italian cohort of MS patients; they are mainly related to MS disease activity, baseline EDSS, disease duration and age., Competing Interests: Deckaration of Competing Interest None, (Copyright © 2020 Elsevier B.V. All rights reserved.)

Patients with multiple sclerosis on long-term injectable therapies may suffer from the so-called "needle fatigue", i.e., a waning commitment to continue with the prescribed injectable treatment. Therefore, alternative treatment strategies to enhance patients' adherence are warranted. In this independent, multicentre post-marketing study, we sought to directly compare switching to either teriflunomide (TFN), dimethyl fumarate (DMF), or pegylated interferon (PEG) on treatment persistence and time to first relapse over a 12-month follow-up. We analyzed a total of 621 patients who were free of relapses and gadolinium-enhancing lesions in the year prior to switching to DMF (n = 265), TFN (n = 160), or PEG (n = 196). Time to discontinuation and time to first relapse were explored in the whole population by Cox regression models adjusted for baseline variables and after a 1:1:1 ratio propensity score (PS)-based matching procedure. Treatment discontinuation was more frequent after switching to PEG (28.6%) than DMF (14.7%; hazard ratio [HR] = 0.25, p < 0.001) and TFN (16.9%; HR = 0.27, p < 0.001). We found similar results even in the re-sampled cohort of 222 patients (74 per group) derived by the PS-based matching procedure. The highest discontinuation rate observed in PEG recipient was mainly due to poor tolerability (p = 0.005) and pregnancy planning (p = 0.04). The low number of patients who relapsed over the 12-month follow-up (25 out of 621, approximately 4%) prevented any analysis on the short-term risk of relapse. This real-world study suggests that oral drugs are a better switching option than low-frequency interferon for promoting the short-term treatment persistence in stable patients who do not tolerate injectable drugs.

Objectives: The efficacy and safety of high-dose intravenous immunoglobulin (IVIG) in treatment-resistant diabetic painful polyneuropathy (DPN) were assessed., Design: This was a randomized, double-blind, placebo-controlled, multicenter trial (EudraCT 2010-023883-42)., Setting: This trial was conducted at eight sites in Italy with a neurology specialist level of care., Subjects: Twenty-six diabetic patients with DPN who reported baseline severity of pain >60 units (mm) on a VAS scale at enrollment and were resistant to antidepressants and antiepileptic drugs were enrolled; 23 were randomized (11 in the IVIG arm and 12 in the placebo arm). All patients completed the study and were evaluated. All patients were Caucasian, 15 were male, and 21 had a diagnosis of type II diabetes., Methods: IVIG (0.4 g/kg/d) or placebo was given for five consecutive days. Pain intensity (visual analog scale, Neuropathic Pain Symptom Inventory) and quality of life (36-Item Short-Form Health Survey, Clinical/Patient Global Impression of Change questionnaires) assessments were performed at visits: baseline, start of therapy (one week later), end of therapy (five days later), and follow-up (four and eight weeks later)., Results: The study achieved its prespecified primary end point of ≥50% pain reduction at four weeks after IVIG, achieved in seven of 11 patients (63.6%) in the IVIG group vs zero of 12 in the placebo group (P = 0.0013). Only two adverse events were reported during the study: one patient in the treatment arm reported a mild "dermatitis psoriasiform," whereas one patient from the placebo group reported a mild "influenza.", Conclusions: Treatment with IVIG at the dose given was efficacious and safe for patients with DPN resistant to standard therapies., (© 2020 American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background and Purpose: The role of lifestyle and dietary habits and antecedent events has not been clearly identified in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP)., Methods: Information was collected about modifiable environmental factors and antecedent infections and vaccinations in patients with CIDP included in an Italian CIDP Database. Only patients who reported not having changed their diet or the lifestyle habits investigated in the study after the appearance of CIDP were included. The partners of patients with CIDP were chosen as controls. Gender-matched analysis was performed with randomly selected controls with a 1:1 ratio of patients and controls., Results: Dietary and lifestyle data of 323 patients and 266 controls were available. A total of 195 cases and 195 sex-matched controls were used in the analysis. Patients eating rice at least three times per week or eating fish at least once per week appeared to be at decreased risk of acquiring CIDP. Data on antecedent events were collected in 411 patients. Antecedent events within 1-42 days before CIDP onset were reported by 15.5% of the patients, including infections in 12% and vaccinations in 1.5%. Patients with CIDP and antecedent infections more often had an acute onset of CIDP and cranial nerve involvement than those without these antecedent events., Conclusions: The results of this preliminary study seem to indicate that some dietary habits may influence the risk of CIDP and that antecedent infections may have an impact on the onset and clinical presentation of the disease., (© European Academy of Neurology 2019.)

Extending the natalizumab interval after the 24th administration could reduce the risk of progressive multifocal leukoencephalopathy (PML). The objective is to evaluate the noninferiority of the efficacy of an extended interval dosing (EID) compared with the standard interval dosing (SID) of natalizumab. It is an observational, multicenter (14 Italian centers), retrospective cohort study, starting from the 24th natalizumab infusion to the loss of follow-up or 2 years after baseline. Patients were grouped in 2 categories according to the mean number of weeks between doses: < 5 weeks, SID; ≥ 5 weeks, EID. Three hundred and sixty patients were enrolled. Median dose interval (MDI) following 24th infusion was 4.7 weeks, with a bimodal distribution (modes at 4 and 6 weeks). Two hundred and sixteen patients were in the SID group (MDI = 4.3 weeks) and 144 in the EID group (MDI 6.2 weeks). Annualized relapse rate was 0.060 (95% CI = 0.033-0.087) in the SID group and 0.039 (95% CI = 0.017-0.063) in the EID group. The non-inferiority of EID versus SID was satisfied. In conclusion, there is no evidence of a reduced efficacy of natalizumab in an EID setting. This observation confirms previous results and together with the emerging evidence of a reduced risk of PML associated to an EID, supports the need of a randomized study to assess the need to change the standard of the natalizumab dosing schedule.

Objective: To assess the prevalence and isotypes of anti-nodal/paranodal antibodies to nodal/paranodal proteins in a large chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) cohort, compare clinical features in seronegative vs seropositive patients, and gather evidence of their isotype-specific pathogenic role., Methods: Antibodies to neurofascin-155 (Nfasc155), neurofascin-140/186 (Nfasc140/186), contactin-1 (CNTN1), and contactin-associated protein 1 (Caspr1) were detected with ELISA and/or cell-based assay. Antibody pathogenicity was tested by immunohistochemistry on skin biopsy, intraneural injection, and cell aggregation assay., Results: Of 342 patients with CIDP, 19 (5.5%) had antibodies against Nfasc155 (n = 9), Nfasc140/186 and Nfasc155 (n = 1), CNTN1 (n = 3), and Caspr1 (n = 6). Antibodies were absent from healthy and disease controls, including neuropathies of different causes, and were mostly detected in patients with European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) definite CIDP (n = 18). Predominant antibody isotypes were immunoglobulin G (IgG)4 (n = 13), IgG3 (n = 2), IgG1 (n = 2), or undetectable (n = 2). IgG4 antibody-associated phenotypes included onset before 30 years, severe neuropathy, subacute onset, tremor, sensory ataxia, and poor response to intravenous immunoglobulin (IVIG). Immunosuppressive treatments, including rituximab, cyclophosphamide, and methotrexate, proved effective if started early in IVIG-resistant IgG4-seropositive cases. Five patients with an IgG1, IgG3, or undetectable isotype showed clinical features indistinguishable from seronegative patients, including good response to IVIG. IgG4 autoantibodies were associated with morphological changes at paranodes in patients' skin biopsies. We also provided preliminary evidence from a single patient about the pathogenicity of anti-Caspr1 IgG4, showing their ability to penetrate paranodal regions and disrupt the integrity of the Nfasc155/CNTN1/Caspr1 complex., Conclusions: Our findings confirm previous data on the tight clinico-serological correlation between antibodies to nodal/paranodal proteins and CIDP. Despite the low prevalence, testing for their presence and isotype could ultimately be part of the diagnostic workup in suspected inflammatory demyelinating neuropathy to improve diagnostic accuracy and guide treatment., Classification of Evidence: This study provides Class III evidence that antibodies to nodal/paranodal proteins identify patients with CIDP (sensitivity 6%, specificity 100%)., (Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: Dimethyl fumarate (DMF) exerts anti-inflammatory effects in multiple sclerosis by activating the Nrf2 antioxidant pathway, which is also stimulated by acetylcholine via alpha-7 nicotinic acetylcholine receptors. In animal models, Nrf2 potentiates cholinergic synaptic plasticity., Objective: The aim of this study was to test whether treatment with DMF modulates cholinergic pathways in relapsing-remitting multiple sclerosis (RRMS)., Methods: Patients starting DMF (20) or IFN-β 1a (20) and healthy subjects (20) were enrolled. Short-latency afferent inhibition (SAI), which is a transcranial stimulation measure of central cholinergic transmission, was recorded in patients and controls at baseline and, in patients only, after 6 months of treatment. Patients treated with DMF also underwent autonomic function testing to further explore peripheral and central cholinergic tone., Results: At baseline, SAI was similar in patients and in controls (p = 0.983). Treatment with DMF significantly increased SAI (p = 0.01), while IFNβ had no effect (p = 0.80). In the cold face test, DMF treatment also increased reflex bradycardia (p = 0.013), and reduced diastolic blood pressure variation (p = 0.010), further indicating its ability to stimulate cholinergic transmission., Conclusions: Treatment of MS patients with DMF results in increased cholinergic stimulation, with possible implications for neuroinflammation and neuroprotection.

Objective: To evaluate disease activity according to rituximab (RTX) induction and maintenance regimens in a multicenter real-life dataset of NMOSD patients., Methods: This is an observational-retrospective multicentre study including patients with NMOSD treated with RTX in 21 Italian and 1 Swiss centers. Demographics, relapse rate and adverse events over the follow-up were summarized taking into account induction strategy (two-1 g infusions at a 15-day interval (IND-A) vs. 375 mg/m2/week infusions for one month (IND-B)) and maintenance therapy (regimen A (M-A) with fixed time-points infusions vs. regimen B (M-B) based on cytofluorimetric driven reinfusion regimens, the least further subdivided according to CD19+ B cells (M-B1) or CD27+ memory B cells (M-B2) monitoring)., Results: 131 subjects were enrolled, 127 patients completed the induction regimen and 119 patients had at least one follow-up visit and were included in the outcome analysis. Median follow-up was 1.7 years (range 0.1-11.6). Annualized relapse rate (ARR) was 1.7 in the year before RTX start and decreased to 0.19 during the follow-up. Both ARR and Time to first relapse (TTFR) analysis showed a trend toward an increased disease activity for IND-B and M-A. No patients with MT-B2 experienced relapses during the follow-up. Number of relapses in the year before RTX initiation and having received a previous treatment were significantly associated with higher ARR and reduced TTFR in the multivariate analysis., Interpretation: We confirm RTX efficacy in NMOSD patients. Use of specific induction and maintenance protocols is warranted in order to foster RTX efficacy and to reduce costs and side effects., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: With many options now available, first therapy choice is challenging in multiple sclerosis (MS) and depends mainly on neurologist and patient preferences., Objectives: To identify prognostic factors for early switch after first therapy choice., Methods: Newly diagnosed relapsing-remitting MS patients from 24 Italian centers were included. We evaluated the association of baseline demographics, clinical, and magnetic resonance imaging (MRI) data to the switch probability for lack of efficacy or intolerance/safety with a multivariate Cox analysis and estimated switch rates by competing risks models., Results: We enrolled 3025 patients. The overall switch frequency was 48% after 3 years. Switch risk for lack of efficacy was lower with fingolimod (hazard ratio (HR) = 0.50; p  = 0.009), natalizumab (HR = 0.13; p  < 0.001), dimethyl-fumarate (HR = 0.60; p  = 0.037), teriflunomide (HR = 0.21; p  = 0.031) as compared to interferons. Younger age (HR = 0.96; p  < 0.001), diagnosis delay (HR = 1.23; p  = 0.021), higher baseline Expanded Disability Status Scale (HR = 1.17; p  = 0.001), and spinal cord lesions (HR = 1.46; p  = 0.001) were independently associated with higher inefficacy switch rates. We found lower switch for intolerance/safety with glatiramer acetate (HR = 0.61; p  = 0.001), fingolimod (HR = 0.35; p  = 0.002), and dimethyl-fumarate (HR = 0.57; p  = 0.022) as compared to interferons, while it increased with natalizumab (HR = 1.43; p  = 0.022). Comorbidities were associated with intolerance switch (HR = 1.28; p  = 0.047)., Conclusion: Several factors are associated with higher switch risk in patients starting a first-line therapy and could be integrated in the decision-making process of first treatment choice.

Objectives: A 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., Methods: We 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., Results: At 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., Conclusions: The 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., Competing Interests: Competing interests: EN-O reports personal fees for Advisory or Scientific Board from Kedrion, Italy, Baxter, Italy, Novartis, Switzerland, CSL Behring, Italy, Astellas, the Netherlands, outside the submitted work and travel grants to attend scientific meeting from Baxter, Grifols, Kedrion and Novartis, Italy. PED has received travel grants to attend scientific meetings from CSL Behring and Kedrion. GLib has received travel grants to attend scientific meetings from CSL Behring and Kedrion. DC has received honoraria for lecturing from Shire, CSL Behring and Kedrion and travel grants to attend scientific meeting from Shire, Kedrion and CSL Behring. EP has received travel grants to attend scientific meetings from CSL Behring. RF has served on scientific advisory boards for CSL Behring and has received travel grants from Kedrion and CSL Behring to attend scientific meeting. MC has received travel grants to attend scientific meetings from Kedrion. AM has received travel grants from Kedrion and CSL Behring to attend scientific meeting. CB has served on scientific advisory boards for Pfizer and has received travel grants from Kedrion and CSL Behring to attend scientific meeting. GC has received travel grants to attend scientific meetings from CSL Behring and Kedrion. BF has received travel grants to attend scientific meetings from CSL Behring and liberal contribution from CSL Behring for the neuromuscular diseases centre, outside the submitted work. EB reports grants from UCB-Pharma, grants from Shire, grants from EISAI, personal fees from Viropharma, grants from Italian Ministry of Health, grants from Fondazione Borgonovo, grants from Associazione IDIC 15, grants from European Union, outside the submitted work. AC has received travel grants to attend scientific meetings from Kedrion. ML has received honoraria for scientific board from Pfeizer and Alnylam and travel grants from Grifols and Kedrion to attend scientific meeting. LS reports personal fees for scientific events from CSL Behring and has received travel grants to attend scientific meetings from CSL Behring and Kedrion. FM reports personal fees for scientific events from CSL Behring and has received travel grants to attend scientific meetings from CSL Behring and Kedrion. GC has received honoraria for lecturing and travel grants to attend scientific meetings from Kedrion. MF has served on scientific advisory boards for CSL Behring and has received travel grants from Kedrion, Baxter and CSL Behring to attend scientific meeting. SJ has received research grants from Grifols, outside this work, and travel grants from Grifols and Kedrion., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To investigate clinical and radiological outcomes of women with relapsing-remitting multiple sclerosis (RRMS) undergoing abortion., Methods: An independent, multicentre retrospective study was conducted collecting data from eight Italian MS centres. We compared the preconception and postabortion annualised relapse rate (ARR) and number of Gadolinium enhancing (Gd+) lesions, by analyses of covariance. Variables associated with postabortion clinical and MRI activity were investigated using Poisson regression models; each abortion was considered as a statistical unit., Results: From 1995 to 2017, we observed 188 abortions (17 elective) in 153 women with RRMS. Abortions occurred after a mean time of 9.5 (4.4) weeks from estimated conception date. In 86 events out of 188, conception happened during treatment with disease modifying drugs. The mean postabortion ARR (0.63±0.74) was significantly increased (p=0.037) compared with the preconception year (0.50±0.71) as well as the postabortion mean number of new Gd+ lesions (0.77±1.40 vs 0.39±1.04; p=0.004). Higher likelihood of relapses was predicted by higher preconception ARR, discontinuation of preconception treatment and elective abortion; the occurrence of new Gd+ lesions was associated with higher preconception number of active lesions, discontinuation of preconception treatment, shorter length of pregnancy maintenance and elective abortion., Conclusions: Abortion was associated with clinical and radiological inflammatory rebound remarkably in the first 12 months postevent. Deregulated proinflammatory processes arising at the early stages of pregnancy might play a role both in MS reactivation and abortion. Women with MS should be counselled about these risks of abortion and followed up accordingly., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2018. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: It has been already confirmed that retinal neurodegeneration has a predictive value in the development of microvascular alterations in diabetic retinopathy. However, no data are available on the association between neuroretinal dysfunction and peripheral motor unit loss. Our study, therefore, was aimed at investigating the hypothesis that retinal neurodegeneration could be considered an early marker of diabetic peripheral neuropathy (DPN)., Methods: 20 T1DM patients with no symptoms/signs of peripheral polyneuropathy, without DR or with very mild nonproliferative DR, and 14 healthy controls (C) age- and gender-matched were enrolled. The following electrophysiological tests were performed: standard nerve conduction studies (NCS) and incremental motor unit number estimation (MUNE) from the abductor hallux (AH) and abductor digiti minimi (ADM). Neuroretinal function was studied by multifocal electroretinogram (MfERG) recordings, measuring response amplitude density (RAD) and implicit time (IT) from rings and sectors of superior (S)/inferior (I)/temporal (T)/nasal (N) macular sectors up to 10 degrees of foveal eccentricity., Results: MfERG RADs from rings and sectors were significantly reduced in T1DM ( p < 0.05) vs. C. ADM MUNE and AH MUNE were significantly decreased in T1DM ( p = 0.039 and p < 0.0001, respectively) vs. C. A positive correlation between mean MfERG RADs from the central 5 degrees of the four (S, I, T, and N) macular sectors and lower limb motor unit number ( r = 0.50, p = 0.041; r = 0.64, p = 0.005; r = 0.64, p = 0.006; and r = 0.61, p = 0.010, respectively) was observed in T1DM patients. No abnormalities of NCS were found in any subject., Conclusions: The motor unit loss on the one hand and neuroretinal dysfunction on the other hand are already present in T1DM patients without DPN. The relationship between neuroretinal dysfunction and motor unit decline supports the hypothesis that neuroretina may represent a potential "window" to track the early neurogenic damage in diabetes.

Background: In the early phases of relapsing-remitting multiple sclerosis (RR-MS), a clear correlation between brain lesion load and clinical disability is often lacking, originating the so-called clinico-radiological paradox. Different factors may contribute to such discrepancy. In particular, synaptic plasticity may reduce the clinical expression of brain damage producing enduring enhancement of synaptic strength largely dependent on neurotrophin-induced protein synthesis. Cytokines released by the immune cells during acute inflammation can alter synaptic transmission and plasticity possibly influencing the clinical course of MS. In addition, immune cells may promote brain repair during the post-acute phases, by secreting different growth factors involved in neuronal and oligodendroglial cell survival. Platelet-derived growth factor (PDGF) is a neurotrophic factor that could be particularly involved in clinical recovery. Indeed, PDGF promotes long-term potentiation of synaptic activity in vitro and in MS and could therefore represent a key factor improving the clinical compensation of new brain lesions. The aim of the present study is to explore whether cerebrospinal fluid (CSF) PDGF concentrations at the time of diagnosis may influence the clinical course of RR-MS., Methods: At the time of diagnosis, we measured in 100 consecutive early MS patients the CSF concentrations of PDGF, of the main pro- and anti-inflammatory cytokines, and of reliable markers of neuronal damage. Clinical and radiological parameters of disease activity were prospectively collected during follow-up., Results: CSF PDGF levels were positively correlated with prolonged relapse-free survival. Radiological markers of disease activity, biochemical markers of neuronal damage, and clinical parameters of disease progression were instead not influenced by PDGF concentrations. Higher CSF PDGF levels were associated with an anti-inflammatory milieu within the central nervous system., Conclusions: Our results suggest that PDGF could promote a more prolonged relapse-free period during the course of RR-MS, without influencing inflammation reactivation and inflammation-driven neuronal damage and likely enhancing adaptive plasticity.

We describe a case of a 25-year-old male with a diagnosis of acute disseminated encephalomyelitis (ADEM) following infection with Campylobacter jejuni, which is implicated in various human pathologies regarding the central nervous system (CNS) with acute course like Guillain-Barré syndrome (GBS), Miller-Fisher syndrome (MFS), Bickerstaff's brainstem encephalitis (BEE), acute transverse myelitis (ATM) as well as ADEM. These conditions are caused by cross-reactivity between Campylobacter's epitopes and cells of the CNS that causes an immunomediated inflammatory demyelination of the CNS. In the acute phase, magnetic resonance (MR) can detect pathologic signal intensity at the CNS with areas of pathologic contrast enhancement at cortical and spinal white matter that normalize over time or can be stable. These findings can be associated with edema in parts of the CNS. The lesions typically appear at different times during the disease course and also can have a different evolution. Our purpose therefore was to describe the clinical course and MR findings of this case and perform a critical review of the literature.

Aims: To investigate the independent effect on depression of painless diabetic polyneuropathy, painful diabetic polyneuropathy, and general and diabetes-related comorbidities., Methods: In 181 patients, the presence of painless diabetic polyneuropathy, painful diabetic polyneuropathy, comorbidities and depression was assessed using the Michigan Neuropathy Screening Instrument Questionnaire, the Michigan Diabetic Neuropathy Score, nerve conduction studies, the Douleur Neuropathique en 4 Questions, the Charlson Comorbidity Index and the Beck Depression Inventory-II., Results: In all, 46 patients met the criteria of confirmed painless diabetic polyneuropathy and 25 of painful diabetic polyneuropathy. Beck Depression Inventory-II scores indicative of mild-moderate-severe depression were reached in 36 patients (19.7%). In a multiple logistic regression analysis (including age, sex, body mass index, being unemployed, duration, haemoglobin A1c, insulin treatment, systolic blood pressure, nephropathy, retinopathy, Charlson Comorbidity Index and painful diabetic polyneuropathy), female sex (odds ratio: 5.9, p = 0.005) and painful diabetic polyneuropathy (odds ratio: 4.6, p = 0.038) were the only independent predictors of depression. Multiple regression analysis, including Douleur Neuropathique en 4 Questions and Michigan Diabetic Neuropathy Score instead of painful diabetic polyneuropathy, showed that Douleur Neuropathique en 4 Questions, in addition to female sex, was a significant predictor of depressive symptoms severity (p =0.005)., Conclusion: Painful diabetic polyneuropathy is a greater determinant of depression than other diabetes-related complications and comorbidities. Painful symptoms enhance depression severity more than objective insensitivity., (© The Author(s) 2016.)

Background: Inflammation triggers secondary neurodegeneration in multiple sclerosis (MS)., Objectives: It is unclear whether classical anti-inflammatory cytokines have the potential to interfere with synaptic transmission and neuronal survival in MS., Methods: Correlation analyses between cerebrospinal fluid (CSF) contents of anti-inflammatory cytokines and molecular, imaging, clinical, and neurophysiological measures of neuronal alterations were performed., Results: Our data suggest that interleukin-13 (IL-13) plays a neuroprotective role in MS brains. We found, in fact, that the levels of IL-13 in the CSF of MS patients were correlated with the contents of amyloid-β(1-42). Correlations were also found between IL-13 and imaging indexes of axonal and neuronal integrity, such as the retinal nerve fibre layer thickness and the macular volume evaluated by optical coherence tomography. Furthermore, the levels of IL-13 were related to better performance in the low-contrast acuity test and Multiple Sclerosis Functional Composite scoring. Finally, by means of transcranial magnetic stimulation, we have shown that GABAA-mediated cortical inhibition was more pronounced in patients with high IL-13 levels in the CSF, as expected for a neuroprotective, anti-excitotoxic effect., Conclusions: The present correlation study provides some evidence for the involvement of IL-13 in the modulation of neuronal integrity and synaptic function in patients with MS.

Cognitive dysfunction is of frequent observation in multiple sclerosis (MS). It is associated with gray matter pathology, brain atrophy, and altered connectivity, and recent evidence showed that acute inflammation can exacerbate mental deficits independently of the primary functional system involved. In this study, we measured cerebrospinal fluid (CSF) levels of amyloid-β(1-42) and τ protein in MS and in clinically isolated syndrome patients, as both proteins have been associated with cognitive decline in Alzheimer's disease (AD). In AD, amyloid-β(1-42) accumulates in the brain as insoluble extracellular plaques, possibly explaining why soluble amyloid-β(1-42) is reduced in the CSF of these patients. In our sample of MS patients, amyloid-β(1-42) levels were significantly lower in patients cognitively impaired (CI) and were inversely correlated with the number of Gadolinium-enhancing (Gd+) lesions at the magnetic resonance imaging (MRI). Positive correlations between amyloid-β(1-42) levels and measures of attention and concentration were also found. Furthermore, abnormal neuroplasticity of the cerebral cortex, explored with θ burst stimulation (TBS), was observed in CI patients, and a positive correlation was found between amyloid-β(1-42) CSF contents and the magnitude of long-term potentiation-like effects induced by TBS. No correlation was conversely found between τ protein concentrations and MRI findings, cognitive parameters, and TBS effects in these patients. Together, our results indicate that in MS, central inflammation is able to alter amyloid-β metabolism by reducing its concentration in the CSF and leading to impairment of synaptic plasticity and cognitive function.

Caffeine is the most commonly self-administered psychoactive substance worldwide. At usual doses, the effects of caffeine on vigilance, attention, mood and arousal largely depend on the modulation of central adenosine receptors. The present review article describes the action of caffeine within the striatum, to provide a possible molecular mechanism at the basis of the psychomotor and reinforcing properties of this pharmacological agent. The striatum is in fact a subcortical area involved in sensorimotor, cognitive, and emotional processes, and recent experimental findings showed that chronic caffeine consumption enhances the sensitivity of striatal GABAergic synapses to the stimulation of cannabinoid CB1 receptors. The endocannabinoid system is involved in the psychoactive effects of many compounds, and adenosine A2A receptors (the main receptor target of caffeine) elicit a permissive effect towards CB1 receptors, thus suggesting that A2A-CB1 receptor interaction plays a major role in the generation and maintenance of caffeine reinforcing behavior. Aim of this review is to describe the effects of caffeine on striatal neurotransmission with special reference to the modulation of the endocannabinoid system.

The endogenous cannabinoid system is involved in the regulation of the central reward pathway. Running wheel and sucrose consumption have rewarding and reinforcing properties in rodents, and share many neurochemical and behavioral characteristics with drug addiction. In this study, we investigated whether running wheel or sucrose consumption altered the sensitivity of striatal synapses to the activation of cannabinoid CB1 receptors. We found that cannabinoid CB1 receptor-mediated presynaptic control of striatal inhibitory postsynaptic currents was remarkably potentiated after these environmental manipulations. In contrast, the sensitivity of glutamate synapses to CB1 receptor stimulation was unaltered, as well as that of GABA synapses to the stimulation of presynaptic GABAB receptors. The sensitization of cannabinoid CB1 receptor-mediated responses was slowly reversible after the discontinuation of running wheel or sucrose consumption, and was also detectable following the mobilization of endocannabinoids by metabotropic glutamate receptor 5 stimulation. Finally, we found that the upregulation of cannabinoid transmission induced by wheel running or sucrose had a crucial role in the protective effects of these environmental manipulations against the motor and synaptic consequences of stress.

Voluntary exercise is beneficial in models of primarily neurodegenerative disorders. Whether exercise also affects inflammatory neurodegeneration is unknown. In the present study, we evaluated the clinical, synaptic and neuropathological effects of voluntary wheel running in mice with myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis. Exercising EAE mice exhibited less severe neurological deficits compared to control EAE animals. The sensitivity of striatal GABA synapses to the stimulation of cannabinoid CB1 receptors was dramatically downregulated following EAE induction, and was rescued by exercise in EAE mice with access to a running wheel. Finally, we found that exercise was able to contrast dendritic spine loss induced by EAE in striatal neurons, although the degree of inflammatory response was similar in the two experimental groups. Our work suggests that life style and experiences can impact the clinical course of inflammatory neurodegenerative diseases by affecting their synaptic bases.

The endocannabinoid system (ECS) plays a fundamental role in the regulation of synaptic transmission. Exposure to stressful events triggers synaptic adaptations in many brain areas. The activity of the ECS in stress-responsive neural circuits suggests that it may be involved in the behavioral responses and synaptic effects typical of stress. In this review, we discuss evidence demonstrating that striatal ECS is modulated by stress. Chronic stress exposure alters endocannabinoid levels, cannabinoid CB1 receptor binding and cannabinoid CB1 receptor-mediated control of inhibitory synaptic transmission in the striatum. Recent studies have shown that impairment of endocannabinoid signalling is associated with inability to adapt to chronic stress and to the development of maladaptive behaviors. The ECS represents a novel potential pharmacological target to treat stress-associated neuropsychiatric conditions.

Caffeine, the psychoactive ingredient of coffee and of many soft drinks, is frequently abused by humans especially during stressful live events. The endocannabinoid system is involved in the central effects of many psychoactive compounds and of stress. Whether caffeine alters the cannabinoid system and interferes with stress-induced synaptic alterations is however unknown. We have studied electrophysiologically the sensitivity of cannabinoid receptors modulating synaptic transmission in the striatum of mice exposed to caffeine in their drinking solution. Chronic caffeine assumption sensitized GABAergic synapses to the presynaptic effect of cannabinoid CB1 receptor stimulation by exo- and endocannabinoids. Caffeine was conversely unable to affect the sensitivity of cannabinoid receptors modulating glutamate transmission. The synaptic effects of caffeine were slowly reversible after its removal from the drinking solution. Furthermore, although exposure to caffeine for only 24h did not produce measurable changes of the sensitivity of cannabinoid CB1 receptors, it was able to contrast the down-regulation of CB1 receptor-mediated responses after social defeat stress. Our data suggest that the cannabinoid system is implicated in the psychoactive properties of caffeine and in the ability of caffeine to reduce the pathological consequences of stress.

Recent findings proposed that the cerebellum and the striatum, key structures in motor control, are more interconnected than commonly believed, and that the cerebellum may influence striatal activity. In the present study, the possible changes of synaptic transmission in the striatum of hemicerebellectomized rats have been investigated. Neurophysiological recordings showed a significant facilitation of glutamate transmission in the contralateral striatum occurring early following hemicerebellectomy. This process of synaptic adaptation appears to be relevant for the compensation of cerebellar deficits. Accordingly, pharmacological blockade of glutamate N-methyl-d-aspartate (NMDA) receptors with MK-801 prevented the rearrangement of excitatory synapses in the striatum and interfered with the recovery from motor disturbances in rats with cerebellar lesions. Hemicerebellectomy also perturbed gamma-aminobutyric acid (GABA) transmission in contralateral but not ipsilateral striatum. The present findings advance the role of striatal excitatory transmission in the compensation of cerebellar deficits, providing support to the notion that adaptations of striatal function exert a role in the recovery of cerebellar symptoms.

Altered glutamate transmission in the striatum has been proposed to play a critical role in the pathophysiology of Huntington's disease (HD), a genetic disorder associated with impaired activity of the mitochondrial complex II (succinate dehydrogenase, SD). In the present study, we recorded spontaneous (sEPSCs) and miniature excitatory postsynaptic currents (mEPSCs) from striatal neurons of both toxic (systemic administration of 3-nitropropionic acid in rats) and genetic models of HD (R6/2 transgenic mice). In both models, we found a significant down-regulation of glutamate transmission, suggesting that reduced synaptic excitation of the input structure of the basal ganglia represents a physiological correlate of HD.