The effects of Transcranial Direct Current Stimulation on food craving and food intake in individuals affected by obesity and overweight: a mini review of the magnitude of the effects.

Obesity represents one of the wellness diseases concurring to increase the incidence of diabetes, cardiovascular diseases, and cancer. One of the main perpetuating factors of obesity is food craving, which is characterized by an urgent desire to eat a large and various amount of food, regardless of calories requirement or satiety signals, and it might be addressed to the alteration of the dorsolateral prefrontal cortex (DLPFC) activity. Despite most of the gold-standard therapies focus on symptom treatment only, non-invasive brain stimulation techniques such as transcranial direct current stimulation (tDCS) could help treat overeating by modulating specific neural pathways. The current systematic review was conducted to identify whether convergent evidence supporting the usefulness of tDCS to deal with food craving are present in the literature. The review was conducted by searching articles published up to January 1st 2022 on MEDLINE, Scopus and PsycInfo databases. We included studies investigating the effects of tDCS on food craving in subjects affected by overweight and obesity. According to eligibility criteria, 5 articles were included. Results showed that tDCS targeting left DLPFC with unipolar montage induced ameliorating effects on food craving. Controversial results were shown for the other studies, that might be ascribable to the use of bipolar montage, and the choice of other target areas. Further investigations including expectancy effect control, larger sample sizes and follow-up are needed to support more robust conclusions. To conclude, tDCS combined with the use of psychoeducative intervention, diet and physical activity, might represents a potential to manage food craving in individuals with overweight and obesity.

The risk of infection in patients with multiple sclerosis treated with disease-modifying therapies: A Delphi consensus statement.

The risk of infection associated with immunomodulatory or immunosuppressive disease-modifying drugs (DMDs) in patients with multiple sclerosis (MS) has been increasingly addressed in recent scientific literature. A modified Delphi consensus process was conducted to develop clinically relevant, evidence-based recommendations to assist physicians with decision-making in relation to the risks of a wide range of infections associated with different DMDs in patients with MS. The current consensus statements, developed by a panel of experts (neurologists, infectious disease specialists, a gynaecologist and a neuroradiologist), address the risk of iatrogenic infections (opportunistic infections, including herpes and cryptococcal infections, candidiasis and listeria; progressive multifocal leukoencephalopathy; human papillomavirus and urinary tract infections; respiratory tract infections and tuberculosis; hepatitis and gastrointestinal infections) in patients with MS treated with different DMDs, as well as prevention strategies and surveillance strategies for the early identification of infections. In the discussion, more recent data emerged in the literature were taken into consideration. Recommended risk reduction and management strategies for infections include screening at diagnosis and before starting a new DMD, prophylaxis where appropriate, monitoring and early diagnosis.

Switching to ocrelizumab in RRMS patients at risk of PML previously treated with extended interval dosing of natalizumab.

Discontinuation of natalizumab in patients with relapsing-remitting multiple sclerosis (RRMS) at risk of progressive multifocal leukoencephalopathy (PML) is associated with disease reactivation. Forty-two RRMS patients, who switched from an extended interval dose (EID) of natalizumab to ocrelizumab, underwent magnetic resonance imaging (MRI) and clinical monitoring during washout and after ocrelizumab starting. During the first 3 months, disease reactivation was observed in five (12%) patients; 6 months after ocrelizumab starting, no further relapses were recorded, and Expanded Disability Status Scale (EDSS) remained stable in 38 (90%) patients. In conclusion, ocrelizumab could be considered a choice to mitigate the risk of disease reactivation in patients previously treated with natalizumab-EID.

Should frequent MRI monitoring be performed in natalizumab-treated MS patients? A contribution to a recent debate.

BACKGROUND: Brain magnetic resonance imaging (MRI) is the most effective surveillance tool for the detection of asymptomatic progressive multifocal leukoencephalopathy (PML). However, the optimal frequency for routine MRI surveillance is under-investigated. OBJECTIVE: To understand whether, upon their first MRI appearance, PML lesions present a difference in volume when comparing patients who frequently underwent MRI surveillance (3/4 months) with those who were assessed at longer intervals (6/12 months) and to understand the impact of the volume of lesions on clinical outcome. METHODS: The data of patients included in the Italian PML cohort were retrospectively analysed. Patients who had all the pre-diagnostic MRI scans available (n = 37) were included. The volume of PML lesion was calculated by manually outlining the PML lesion. RESULTS: Compared with patients who underwent MRI examination at least every 4 months, patients who were assessed less frequently had a lesion of significantly higher volume (median: 2567 (883-3583) vs. 664 mm3 (392-963) p = 0.006) and suffered a higher rate of disability (median: 2.25 expanded disability status scale points (-2.5 to 8) vs. 0.5 (-1 to 2.5) p = 0.004). CONCLUSION: The positive clinical outcome of patients undergoing frequent MRI surveillance and the small volume of the PML lesion upon first appearance justify a frequent surveillance using MRI in patients at high risk of PML.

Lack of specific T- and B-cell clonal expansions in multiple sclerosis patients with progressive multifocal leukoencephalopathy.

Progressive multifocal leukoencephalopathy (PML) is a rare, potentially devastating myelin-degrading disease caused by the JC virus. PML occurs preferentially in patients with compromised immune system, but has been also observed in multiple sclerosis (MS) patients treated with disease-modifying drugs. We characterized T and B cells in 5 MS patients that developed PML, 4 during natalizumab therapy and one after alemtuzumab treatment, and in treated patients who did not develop the disease. Results revealed that: i) thymic and bone marrow output was impaired in 4 out 5 patients at the time of PML development; ii) T-cell repertoire was restricted; iii) clonally expanded T cells were present in all patients. However, common usage or pairings of T-cell receptor beta variable or joining genes, specific clonotypes or obvious "public" T-cell response were not detected at the moment of PML onset. Similarly, common restrictions were not found in the immunoglobulin heavy chain repertoire. The data indicate that no JCV-related specific T- and B-cell expansions were mounted at the time of PML. The current results enhance our understanding of JC virus infection and PML, and should be taken into account when choosing targeted therapies.

Four cases of natalizumab-related PML: a less severe course in extended interval dosing?

BACKGROUND: Progressive multifocal leukoencephalopathy (PML) is a severe adverse event of natalizumab (NTZ). The administration of NTZ with extended interval dosing (EID) has been proposed as a strategy to potentially reduce the incidence of PML while maintaining its therapeutic efficacy. METHODS: In the current paper, we describe 4 cases of NTZ-PML in EID included in the Italian PML cohort. RESULTS: The patients developed PML after at least 38 NTZ infusions. Their John Cunningham virus (JCv) index was > 1.5, and patients had not previously used immunosuppressant. Two patients were asymptomatic at PML onset, while two had mild motor impairment of the right hand and anomia, respectively. All of them had undetectable viral load but one (37 JCv copies/ml). In all patients, MRI revealed unilobar lesions with deferred contrast enhancement suggestive of immune reconstitution. The clinical course ended with a favorable clinical outcome (ΔEDSS up to 1). CONCLUSIONS: Although PML in EID seems to occur less frequently than in conventional dosing regimen, strict monitoring of high-risk patients contributed to the indolent course observed in the four described cases, characterized by a prolonged pre-symptomatic phase, paucisymptomatic onset, low JCv load, less severe functional impairment during immune reconstitution, and a mild disability burden.

Early diagnosis of progressive multifocal leucoencephalopathy: longitudinal lesion evolution.

OBJECTIVE: Early diagnosis of natalizumab-related progressive multifocal leucoencephalopathy (NTZ-PML) in multiple sclerosis has been deemed a major priority by the regulatory agencies but has yet to become a reality. The current paper aims to: (1) investigate whether patients with NTZ-PML pass through a prolonged presymptomatic phase with MRI abnormalities, (2) estimate the longitudinal PML lesion volume increase during the presymptomatic phase and (3) estimate the presymptomatic phase length and its impact on therapy duration as a risk stratification parameter. METHODS: All Italian patients who developed NTZ-PML between 2009 and 2018 were included. The data of patients with available prediagnostic MRI were analysed (n=41). Detailed clinical and neuroradiological information was available for each participant. RESULTS: (1) PML lesions were detectable in the presymptomatic phase in 32/41 (78%) patients; (ii) the lesion volume increased by 62.8 % for each month spent in the prediagnostic phase; (3) the prediagnostic phase length was 150.8±74.9 days; (4) PML MRI features were detectable before the 24th month of therapy in 31.7 % of patients in our cohort. CONCLUSIONS: Considering the latency of PML clinical manifestation, the presymptomatic phase length supports the usefulness of MRI surveillance every 3-4 months. Early diagnosis could prompt a better outcome for patients due to the relationship between lesion volume and JC virus infection. The insight from this study might also have an impact on risk stratification algorithms, as therapy duration as a parameter of stratification appears to need reassessment.

Mental Insanity Assessment of Pedophilia: The Importance of the Trans-Disciplinary Approach. Reflections on Two Cases.

A 60 plus-year-old male was charged with pedophilia for forcing a child to touch him inappropriately near a primary school fence. In another case, a 70 plus-year-old male was charged with pedophilia for intimately touching a boy in a cinema. What led them to manifest this socially-inappropriate and legally-relevant behavior? Is there an explanation for the sexually-related behavioral changes emerging late in life of these two men? Indeed, a common point exists between the two men: both were found to suffer from highly-disabling neurological conditions, known to have a potential effect on social behavior. Specifically, a large right frontoparietal meningioma was found to have important influence on the first man's cognition and control inhibition, whereas frontotemporal dementia prevented the second man from understanding the moral disvalue of his sexually-inappropriate behavior and controlling his sexual impulses. In the current presentation, particular emphasis is placed on the logical reasoning supporting the conclusions that both the pedophiles should be considered not guilty by reason of insanity. Furthermore, experimental methods have been used to explore both cases, which rely on the existence of cognitive models for the phenomena under study, the integration of insights offered by different disciplines and the application of a variety of tools and approaches that follow the "convergence of evidence" principle, which could be safely used in court to support a mental insanity claim. Here, we describe how the use of the experimental method could become useful to reduce the uncertainty in mental insanity assessments. The use of a transdisciplinary, scientifically-grounded approach can help to change the way legal phenomena are interpreted. For instance, when assessing mental insanity, consultants should not only investigate the eventual existence of a diagnosis, but should assess the cognitive/affective abilities that are necessary to understand our own behavior and emotions as well as those of others. The criteria for responsibility should be symptoms-based and not diagnosis-based. Since pedophilia is among the most hideous behaviors condemned by society, a more comprehensive and transdisciplinary approach is recommended in court.

To do or not to do? plasma exchange and timing of steroid administration in progressive multifocal leukoencephalopathy.

OBJECTIVE: To retrospectively analyze the effect of plasma exchange (PLEX; yes = PLEX+ , no = PLEX- ) and steroids administration timing (prophylactically [proST] or therapeutically [therST]) on the longitudinal clinical course of patients with natalizumab-related progressive multifocal leukoencephalopathy (PML) and full-blown immune reconstitution inflammatory syndrome (PML-IRIS). METHODS: Clinical and radiological data of 42 Italian patients with PML were analyzed. Patient's data are available until 12 months after PML diagnosis. PLEX and steroids treatment as time-dependent covariates were entered in: (1) a Cox model to investigate their impact on full-blown PML-IRIS latency; (2) an analysis of variance ANOVA to investigate their impact on IRIS duration; and (3) a linear mixed model to assess their impact on the longitudinal clinical course (measured by means of Expanded Disability Status Scale [EDSS]). RESULTS: Treatment with PLEX was not associated to PML-IRIS latency (hazard ratio [HR] = 1.05; p = 0.92), but once IRIS emerged, its duration was significantly longer in patients who underwent PLEX (101 vs 54 days in PLEX+ and PLEX- patients; p = 0.028). Receiving proST versus therST was not associated to IRIS latency (HR = 0.67; p = 0.39) or duration (p = 0.95). Patients who underwent proST had a significantly higher EDSS increase during PML (0.09 EDSS points per month; p = 0.04) as compared to those who had therST. INTERPRETATION: This study highlights that: (1) caution on the use of PLEX should be considered as the current data do not support a beneficial effect of PLEX and (2) caution on the early use of steroids is suggested because their prophylactic use to prevent full-blown PML-IRIS seems to negatively impact on the longitudinal disability course. Ann Neurol 2017;82:697-705.

Age as a risk factor for early onset of natalizumab-related progressive multifocal leukoencephalopathy.

Progressive multifocal leukoencephalopathy (PML) is a rare but potentially fatal opportunistic infection that arises almost exclusively in immunocompromised patients or in those treated with monoclonal antibodies, especially natalizumab. Here, we aimed at exploring if age at treatment start affects the time to onset of natalizumab-related PML. PubMed was searched for the terms "natalizumab and progressive multifocal leukoencephalopathy" in articles published from January 2005 to March 2017. We collected information on each identified PML case, including demographic and clinical variables at natalizumab start and at PML onset. The number of natalizumab infusions until PML onset was investigated in time-to-event analyses. We identified 238 cases who developed PML after a median number of 33 natalizumab infusions (range 6 to 103). Risk factors for an earlier onset of natalizumab-related PML were prior immunosuppressant exposure (hazard ratio [HR] = 1.43, p = 0.017) and older age at treatment start (HR = 1.02, p = 0.016). In particular, patients older than 50 years had a more than doubled-increased risk for an earlier PML onset (HR = 2.11, p = 0.006). Our findings suggest that the age at natalizumab start may represent a risk factor for an earlier PML onset, thus claiming further investigations about the interplay between immunosenescence and MS treatments.

Is maraviroc useful in multiple sclerosis patients with natalizumab-related progressive multifocal leukoencephalopathy?

BACKGROUND: Despite the recent advances in the understanding of natalizumab (NTZ) related progressive multifocal leukoencephalopathy (PML) and its associated immune reconstitution inflammatory syndrome (PML-IRIS), the therapeutic options are still under investigated. In this context, the beneficial use of maraviroc is still an anecdotal observation. OBJECTIVE: To evaluate the impact of maraviroc in modifying the course of PML preventing IRIS or blunting IRIS manifestations. METHODS: Three patients with NTZ PML included in the Italian dataset of PML were treated with maraviroc. Their longitudinal clinical and radiological course was described in detail. RESULTS: The three patients were characterized by a steady clinical worsening not controlled by maraviroc. All the three patients manifested PML-IRIS, which emerged, respectively, at 62, 64 and 90days post NTZ withdrawal. This is in accordance with the data of the Italian dataset. Clinical and radiological stabilization of PML-IRIS occurred only after corticosteroids administration. CONCLUSION: In these three cases, maraviroc did not show any clear effect in modulating the clinical course of PML preventing IRIS. Moreover, once PML-IRIS emerged, the clinical stabilization was achieved only with the use of corticosteroids. Thus, the use of maraviroc should be regarded with extreme caution due the potential adverse events associated with its use.

No evidence of beneficial effects of plasmapheresis in natalizumab-associated PML.

OBJECTIVE: To examine retrospectively the effects of plasmapheresis (PLEX) on the survival and clinical outcomes of patients with multiple sclerosis (MS) and natalizumab (NTZ)-associated progressive multifocal leukoencephalopathy (PML). METHODS: The medical literature was searched for the terms natalizumab and progressive multifocal leukoencephalopathy. A total of 193 international and 34 Italian NTZ-PML cases were included. Clinical outcome was determined by comparing the patients' clinical status at PML diagnosis with status after PML resolution. The effects on survival and clinical outcome of PLEX, sex, age, country, pre-PML Expanded Disability Status Scale score, NTZ infusion number, prior immunosuppressant exposure, PML symptoms, PML lesion location at diagnosis, CSF JC virus status and copies, additional PML treatments and steroids, and PML immune reconstitution inflammatory syndrome (IRIS) development were investigated with both univariate and multivariate analyses. RESULTS: A total of 219 NTZ-PML cases were analyzed, and 184 (84%) underwent PLEX, which did not reduce the mortality risk or the likelihood of poor vs favorable outcomes. Country was predictive of mortality and poor outcome, while PML-IRIS development was predictive of poor outcome. CONCLUSIONS: PLEX did not improve the survival or clinical outcomes of Italian or international patients with MS and NTZ-PML, suggesting that this treatment should be performed cautiously in the future. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for patients with NTZ-PML, PLEX does not improve survival. The study lacks the statistical precision to exclude an important benefit or harm of PLEX.

Natalizumab-Related Progressive Multifocal Leukoencephalopathy in Multiple Sclerosis: Findings from an Italian Independent Registry.

BACKGROUND: The monoclonal antibody natalizumab (NTZ) is a highly effective treatment for patients with multiple sclerosis (MS). However, this drug is associated with increased risk of developing Progressive Multifocal Leukoencephalopathy (PML), an opportunistic infection of central nervous system (CNS) caused by the John Cunningham polyomavirus (JCV). OBJECTIVE: To describe the 12-month clinical course of 39 patients with MS (28 women, 11 men) who developed NTZ-related PML after a mean exposure of 39 infusions. METHODS: An Italian independent collaborative repository initiative collected and analyzed socio-demographic, clinical, magnetic resonance imaging (MRI) data and number of JCV-DNA copies detected on cerebrospinal fluid (CSF) samples of patients diagnosed as affected by NTZ-related PML. The evolution of disability, measured by the Expanded Disability Status Scale, was assessed at NTZ start, at PML diagnosis and after 2, 6 and 12 months from PML diagnosis. The effect of clinical and paraclinical characteristics at PML diagnosis on the final outcome was also investigated. RESULTS: Ten patients (25.6%) were diagnosed before 24 NTZ infusions. In six cases (15.4%) the PML suspect was made on the basis of highly suggestive MRI findings in absence of any detectable change of clinical conditions (asymptomatic PML). In patients with symptomatic PML, the diagnosis was quicker for those who presented with cognitive symptoms (n = 12) rather than for those with other neurological pictures (n = 21) (p = 0.003). Three patients (7.7%) died during the 12-month observation period, resulting in a survival rate of 92.3%. Asymptomatic PML, more localized brain involvement and gadolinium-enhancement detected at MRI, as well as lower viral load were associated with a better disability outcome (p-values<0.01). CONCLUSION: Our findings support that early PML diagnosis, limited CNS involvement and initial signs of immune restoration are associated with a better outcome and higher survival rate, and confirm the utility of MRI as a surveillance tool for NTZ-treated patients.