Immunomodulators and immunosuppressants for progressive multiple sclerosis: a network meta-analysis.

BACKGROUND: In recent years a broader range of immunomodulatory and immunosuppressive treatment options have emerged for people with progressive forms of multiple sclerosis (PMS). While consensus supports these options as reducing relapses, their relative benefit and safety profiles remain unclear due to a lack of direct comparison trials. OBJECTIVES: To compare through network meta-analysis the efficacy and safety of alemtuzumab, azathioprine, cladribine, cyclophosphamide, daclizumab, dimethylfumarate, diroximel fumarate, fingolimod, fludarabine, glatiramer acetate, immunoglobulins, interferon beta 1-a and beta 1-b, interferon beta-1b (Betaferon), interferon beta-1a (Avonex, Rebif), laquinimod, leflunomide, methotrexate, minocycline, mitoxantrone, mycophenolate mofetil, natalizumab, ocrelizumab, ofatumumab, ozanimod, pegylated interferon beta-1a, ponesimod, rituximab, siponimod, corticosteroids, and teriflunomide for PMS. SEARCH METHODS: We searched CENTRAL, MEDLINE, and Embase up to August 2022, as well as ClinicalTrials.gov and the WHO ICTRP. SELECTION CRITERIA: Randomised controlled trials (RCTs) that studied one or more treatments as monotherapy, compared to placebo or to another active agent, for use in adults with PMS. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies and extracted data. We performed data synthesis by pair-wise and network meta-analysis. We assessed the certainty of the body of evidence according to GRADE. MAIN RESULTS: We included 23 studies involving a total of 10,167 participants. The most frequent (39% of studies) reason for a rating of high risk of bias was sponsor role in study authorship and data management and analysis. Other concerns were performance, attrition, and selective reporting bias, with 8.7% of studies at high risk of bias for all three of these domains. The common comparator for network analysis was placebo. Relapses over 12 months: assessed in one study (318 participants). None of the treatments assessed showed moderate or high certainty evidence compared to placebo. Relapses over 24 months: assessed in six studies (1622 participants). The number of people with clinical relapses is probably trivially reduced with rituximab (risk ratio (RR) 0.60, 95% confidence interval (CI) 0.19 to 1.95; moderate certainty evidence). None of the remaining treatments assessed showed moderate or high certainty evidence compared to placebo. Relapses over 36 months: assessed in four studies (2095 participants). The number of people with clinical relapses is probably trivially reduced with interferon beta-1b (RR 0.82, 95% CI 0.73 to 0.93; moderate certainty evidence). None of the remaining treatments assessed showed moderate or high certainty evidence compared to placebo. Disability worsening over 24 months: assessed in 11 studies (5284 participants). None of the treatments assessed showed moderate or high certainty evidence compared to placebo. Disability worsening over 36 months: assessed in five studies (2827 participants). None of the treatments assessed showed moderate or high certainty evidence compared to placebo. Serious adverse events: assessed in 15 studies (8019 participants). None of the treatments assessed showed moderate or high certainty evidence compared to placebo. Discontinuation due to adverse events: assessed in 21 studies (9981 participants). The number of people who discontinued treatment due to adverse events is trivially increased with interferon beta-1a (odds ratio (OR) 2.93, 95% CI 1.64 to 5.26; high certainty evidence). The number of people who discontinued treatment due to adverse events is probably trivially increased with rituximab (OR 4.00, 95% CI 0.84 to 19.12; moderate certainty evidence); interferon beta-1b (OR 2.98, 95% CI 1.92 to 4.61; moderate certainty evidence); immunoglobulins (OR 1.95, 95% CI 0.99 to 3.84; moderate certainty evidence); glatiramer acetate (OR 3.98, 95% CI 1.48 to 10.72; moderate certainty evidence); natalizumab (OR 1.02, 95% CI 0.55 to 1.90; moderate certainty evidence); siponimod (OR 1.53, 95% CI 0.98 to 2.38; moderate certainty evidence); fingolimod (OR 2.29, 95% CI 1.46 to 3.60; moderate certainty evidence), and ocrelizumab (OR 1.24, 95% CI 0.54 to 2.86; moderate certainty evidence). None of the remaining treatments assessed showed moderate or high certainty evidence compared to placebo. AUTHORS' CONCLUSIONS: The number of people with PMS with relapses is probably slightly reduced with rituximab at two years, and interferon beta-1b at three years, compared to placebo. Both drugs are also probably associated with a slightly higher proportion of withdrawals due to adverse events, as are immunoglobulins, glatiramer acetate, natalizumab, fingolimod, siponimod, and ocrelizumab; we have high confidence that this is the case with interferon beta-1a. We found only low or very low certainty evidence relating to disability progression for the included disease-modifying treatments compared to placebo, largely due to imprecision. We are also uncertain about the effect of interventions on serious adverse events, also because of imprecision. These findings are due in part to the short follow-up of the included RCTs, which lacked detection of less common severe adverse events. Moreover, the funding source of many included studies may have introduced bias into the results. Future research on PMS should include head-to-head rather than placebo-controlled trials, with a longer follow-up of at least three years. Given the relative rarity of PMS, controlled, non-randomised studies on large samples may usefully integrate data from pivotal RCTs. Outcomes valuable and meaningful to people with PMS should be consistently adopted and measured to permit the evaluation of relative effectiveness among treatments.

Six-minute walk test as outcome measure of fatigability in adults with spinal muscular atrophy treated with nusinersen.

INTRODUCTION/AIMS: Fatigue (subjective perception) and fatigability (objective motor performance worsening) are relevant aspects of disability in individuals with spinal muscular atrophy (SMA). The effect of nusinersen on fatigability in SMA patients has been investigated with conflicting results. We aimed to evaluate this in adult with SMA3. METHODS: We conducted a multicenter retrospective cohort study, including adult ambulant patients with SMA3, data available on 6-minute walk test (6MWT) and Hammersmith Functional Motor Scale-Expanded (HFMSE) at baseline and at least at 6 months of treatment with nusinersen. We investigated fatigability, estimated as 10% or higher decrease in walked distance between the first and sixth minute of the 6MWT, at baseline and over the 14-month follow-up. RESULTS: Forty-eight patients (56% females) were included. The 6MWT improved after 6, 10, and 14 months of treatment (p < 0.05). Of the 27 patients who completed the entire follow-up, 37% improved (6MWT distance increase ≥30 m), 48.2% remained stable, and 14.8% worsened (6MWT distance decline ≥30 m). Fatigability was found at baseline in 26/38 (68%) patients and confirmed at subsequent time points (p < 0.05) without any significant change over the treatment period. There was no correlation between fatigability and SMN2 copy number, sex, age at disease onset, age at baseline, nor with 6MWT total distance and baseline HFMSE score. DISCUSSION: Fatigability was detected at baseline in approximately 2/3 of SMA3 walker patients, without any correlation with clinical features, included motor performance. No effect on fatigability was observed during the 14-month treatment period with nusinersen.

Critical Issues for Patients and Caregivers in Neuro-Oncology during the COVID-19 Pandemic: What We Have Learnt from an Observational Study.

OBJECTIVE: The COVID-19 pandemic affected neuro-oncological patients and their caregivers regarding tumor care and emotional functioning, including Quality of Life (QoL). This study aimed to understand how COVID-19 affected their psychological state and the relations between patients and health personnel in neuro-oncology. METHODS: A cross-sectional study was conducted on neuro-oncological patients and their caregivers. RESULTS: A total of 162 patients and 66 caregivers completed the questionnaire. Altogether, 37.5% of patients perceived a greater risk of contracting COVID-19 compared to the general population. On a 0-10 scale, the patients' tumor-related anxiety score was 5.8, and their COVID-19-related score was 4.6. The caregivers reported 7.7 and 5.5, respectively. QoL was described as at least good in 75% of both patients and caregivers; the caregivers' care burden increased in 22.7% of cases during the pandemic, with no correlation with QoL. Future perception often changed, both in patients and caregivers. In 18% of cases, the cancer treatment schedule was changed, either by patient decision or by medical decision. However, 93.5% of patients were satisfied with their overall care. CONCLUSIONS: A considerable proportion of patients and caregivers still perceived the tumor disease as more burdensome than the pandemic, and their future as more uncertain. Such data suggest the need to build a productive alliance between patients and health professionals.

Surgical and radiosurgical treatment of hypothalamic hamartoma: The Italian experience between 2011 and 2021.

OBJECTIVE: To investigate the Italian experience on the surgical and radiosurgical treatment of drug-resistant epilepsy due to hypothalamic hamartoma (HH) in the period 2011-2021 in six Italian epilepsy surgery centers, and to compare safety and efficacy profiles of the different techniques. METHODS: We collected pseudo-anonymized patient's data with at least 12 months of follow-up. Surgical outcome was defined according to Engel classification of seizure outcome. Univariate analysis was performed to assess the risk of post-operative seizures, categorized in dichotomous variable as favorable and unfavorable; explanatory variables were considered. Mann-Whitney or Chi-squared test were used to assess the presence of an association between variables (p < 0.05). RESULTS: Full presurgical and postoperative data about 42 patients from 6 epilepsy surgery centers were gathered. Engel class I was reached in the 65.8% and 66.6% of patients with gelastic and non-gelastic seizures, respectively. Other than daily non-gelastic seizures were associated with seizure freedom (p = 0.01), and the radiological type presented a trend toward significance (p = 0.12). SIGNIFICANCE: Endoscopic disconnection and laser interstitial thermal therapy are effective in the treatment of HH-related epilepsy, with a tolerable safety profile. Both gelastic and non-gelastic seizures can be treated, also in patients with a long history of seizures. PLAIN LANGUAGE SUMMARY: This study collected data about 42 patients with HH-related epilepsies. Endoscopic disconnection and laser therapy are both effective and safe in the treatment of hypothalamic hamartoma-related epilepsies.

Simulation to become a better neurosurgeon. An international prospective controlled trial: The Passion study.

Introduction: Surgical training traditionally adheres to the apprenticeship paradigm, potentially exposing trainees to an increased risk of complications stemming from their limited experience. To mitigate this risk, augmented and virtual reality have been considered, though their effectiveness is difficult to assess. Research question: The PASSION study seeks to investigate the improvement of manual dexterity following intensive training with neurosurgical simulators and to discern how surgeons' psychometric characteristics may influence their learning process and surgical performance. Material and methods: Seventy-two residents were randomized into the simulation group (SG) and control group (CG). The course spanned five days, commencing with assessment of technical skills in basic procedures within a wet-lab setting on day 1. Over the subsequent core days, the SG engaged in simulated procedures, while the CG carried out routine activities in an OR. On day 5, all residents' technical competencies were evaluated. Psychometric measures of all participants were subjected to analysis. Results: The SG demonstrated superior performance (p < 0.0001) in the brain tumour removal compared to the CG. Positive learning curves were evident in the SG across the three days of simulator-based training for all tumour removal tasks (all p-values <0.05). No significant differences were noted in other tasks, and no meaningful correlations were observed between performance and any psychometric parameters. Discussion and conclusion: A brief and intensive training regimen utilizing 3D virtual reality simulators enhances residents' microsurgical proficiency in brain tumour removal models. Simulators emerge as a viable tool to expedite the learning curve of in-training neurosurgeons.

Clinicopathological and molecular landscape of 5-year IDH-wild-type glioblastoma survivors: A multicentric retrospective study.

Five-year glioblastoma (GBM) survivors (LTS) are the minority of the isocitrate dehydrogenase (IDH)-wild-type GBM patients, and their molecular fingerprint is still largely unexplored. This multicenter retrospective study analyzed a large LTS-GBM cohort from nine Italian institutions and molecularly characterized a subgroup of patients by mutation, DNA methylation (DNAm) and copy number variation (CNV) profiling, comparing it to standard survival GBM. Mutation scan allowed the identification of pathogenic variants in most cases, showing a similar mutational spectrum in both groups, and highlighted TP53 as the most commonly mutated gene in the LTS group. We confirmed DNAm as a valuable tool for GBM classification with a diagnostic refinement by using brain tumor classifier v12.5. LTS were more heterogeneous with more cases classified as diffuse pediatric high-grade glioma subtypes and having peculiar CNVs. We observed a global higher methylation in CpG islands and in gene promoters of LTS with methylation levels of distinct gene promoters correlating with prognosis.

Efgartigimod in generalized myasthenia gravis: A real-life experience at a national reference center.

BACKGROUND AND PURPOSE: Inhibition of the neonatal Fc receptor (FcRn) for IgG is a promising new therapeutic strategy for antibody-mediated disorders. We report our real-life experience with efgartigimod (EFG) in 19 patients with generalized myasthenia gravis (gMG) along a clinical follow-up of 14 months. METHODS: EFG was administered according to the GENERATIVE protocol (consisting of a Fixed period of two treatment cycles [given 1 month apart] of four infusions at weekly intervals, followed by a Flexible period of re-cycling in case of worsening). Eight patients were positive for acetylcholine receptor antibody, four for muscle-specific tyrosine kinase antibody, and two for lipoprotein-related protein 4 antibody, and five were classified as triple negative. Efficacy of EFG was assessed by the Myasthenia Gravis Activities of Daily Living, Myasthenia Gravis Composite, and Quantitative Myasthenia Gravis scales. RESULTS: Fifty-three percent of patients needed three treatment cycles, 26% needed four, and 21% needed five along the 14-month clinical follow-up. Meaningful improvement was observed at the end of each cycle with the clinical scores adopted. EFG had a dramatic effect on disease course, as during the year before treatment eight of 19 patients (42%) were hospitalized, and 15 of 19 (79%) needed treatment with plasma exchange or immunoglobulins; three of 19 (16%) were admitted to the intensive care unit. During EFG, none of the patients was hospitalized and only one patient required plasma exchange and intravenous immunoglobulins. No major side effects or infusion-related reactions occurred. CONCLUSIONS: We observed that EFG was safe and modified significantly the course of the disease along a 14-month follow-up. Our experience strengthens the role of FcRn inhibition as an effective new tool for long-term treatment of gMG.

Immunomodulators and immunosuppressants for relapsing-remitting multiple sclerosis: a network meta-analysis.

BACKGROUND: Different therapeutic strategies are available for the treatment of people with relapsing-remitting multiple sclerosis (RRMS), including immunomodulators, immunosuppressants and biological agents. Although each one of these therapies reduces relapse frequency and slows disability accumulation compared to no treatment, their relative benefit remains unclear. This is an update of a Cochrane review published in 2015. OBJECTIVES: To compare the efficacy and safety, through network meta-analysis, of interferon beta-1b, interferon beta-1a, glatiramer acetate, natalizumab, mitoxantrone, fingolimod, teriflunomide, dimethyl fumarate, alemtuzumab, pegylated interferon beta-1a, daclizumab, laquinimod, azathioprine, immunoglobulins, cladribine, cyclophosphamide, diroximel fumarate, fludarabine, interferon beta 1-a and beta 1-b, leflunomide, methotrexate, minocycline, mycophenolate mofetil, ofatumumab, ozanimod, ponesimod, rituximab, siponimod and steroids for the treatment of people with RRMS. SEARCH METHODS: CENTRAL, MEDLINE, Embase, and two trials registers were searched on 21 September 2021 together with reference checking, citation searching and contact with study authors to identify additional studies. A top-up search was conducted on 8 August 2022. SELECTION CRITERIA: Randomised controlled trials (RCTs) that studied one or more of the available immunomodulators and immunosuppressants as monotherapy in comparison to placebo or to another active agent, in adults with RRMS. DATA COLLECTION AND ANALYSIS: Two authors independently selected studies and extracted data. We considered both direct and indirect evidence and performed data synthesis by pairwise and network meta-analysis. Certainty of the evidence was assessed by the GRADE approach. MAIN RESULTS: We included 50 studies involving 36,541 participants (68.6% female and 31.4% male). Median treatment duration was 24 months, and 25 (50%) studies were placebo-controlled. Considering the risk of bias, the most frequent concern was related to the role of the sponsor in the authorship of the study report or in data management and analysis, for which we judged 68% of the studies were at high risk of other bias. The other frequent concerns were performance bias (34% judged as having high risk) and attrition bias (32% judged as having high risk). Placebo was used as the common comparator for network analysis. Relapses over 12 months: data were provided in 18 studies (9310 participants). Natalizumab results in a large reduction of people with relapses at 12 months (RR 0.52, 95% CI 0.43 to 0.63; high-certainty evidence). Fingolimod (RR 0.48, 95% CI 0.39 to 0.57; moderate-certainty evidence), daclizumab (RR 0.55, 95% CI 0.42 to 0.73; moderate-certainty evidence), and immunoglobulins (RR 0.60, 95% CI 0.47 to 0.79; moderate-certainty evidence) probably result in a large reduction of people with relapses at 12 months. Relapses over 24 months: data were reported in 28 studies (19,869 participants). Cladribine (RR 0.53, 95% CI 0.44 to 0.64; high-certainty evidence), alemtuzumab (RR 0.57, 95% CI 0.47 to 0.68; high-certainty evidence) and natalizumab (RR 0.56, 95% CI 0.48 to 0.65; high-certainty evidence) result in a large decrease of people with relapses at 24 months. Fingolimod (RR 0.54, 95% CI 0.48 to 0.60; moderate-certainty evidence), dimethyl fumarate (RR 0.62, 95% CI 0.55 to 0.70; moderate-certainty evidence), and ponesimod (RR 0.58, 95% CI 0.48 to 0.70; moderate-certainty evidence) probably result in a large decrease of people with relapses at 24 months. Glatiramer acetate (RR 0.84, 95%, CI 0.76 to 0.93; moderate-certainty evidence) and interferon beta-1a (Avonex, Rebif) (RR 0.84, 95% CI 0.78 to 0.91; moderate-certainty evidence) probably moderately decrease people with relapses at 24 months. Relapses over 36 months findings were available from five studies (3087 participants). None of the treatments assessed showed moderate- or high-certainty evidence compared to placebo. Disability worsening over 24 months was assessed in 31 studies (24,303 participants). Natalizumab probably results in a large reduction of disability worsening (RR 0.59, 95% CI 0.46 to 0.75; moderate-certainty evidence) at 24 months. Disability worsening over 36 months was assessed in three studies (2684 participants) but none of the studies used placebo as the comparator. Treatment discontinuation due to adverse events data were available from 43 studies (35,410 participants). Alemtuzumab probably results in a slight reduction of treatment discontinuation due to adverse events (OR 0.39, 95% CI 0.19 to 0.79; moderate-certainty evidence). Daclizumab (OR 2.55, 95% CI 1.40 to 4.63; moderate-certainty evidence), fingolimod (OR 1.84, 95% CI 1.31 to 2.57; moderate-certainty evidence), teriflunomide (OR 1.82, 95% CI 1.19 to 2.79; moderate-certainty evidence), interferon beta-1a (OR 1.48, 95% CI 0.99 to 2.20; moderate-certainty evidence), laquinimod (OR 1.49, 95 % CI 1.00 to 2.15; moderate-certainty evidence), natalizumab (OR 1.57, 95% CI 0.81 to 3.05), and glatiramer acetate (OR 1.48, 95% CI 1.01 to 2.14; moderate-certainty evidence) probably result in a slight increase in the number of people who discontinue treatment due to adverse events. Serious adverse events (SAEs) were reported in 35 studies (33,998 participants). There was probably a trivial reduction in SAEs amongst people with RRMS treated with interferon beta-1b as compared to placebo (OR 0.92, 95% CI 0.55 to 1.54; moderate-certainty evidence). AUTHORS' CONCLUSIONS: We are highly confident that, compared to placebo, two-year treatment with natalizumab, cladribine, or alemtuzumab decreases relapses more than with other DMTs. We are moderately confident that a two-year treatment with natalizumab may slow disability progression. Compared to those on placebo, people with RRMS treated with most of the assessed DMTs showed a higher frequency of treatment discontinuation due to AEs: we are moderately confident that this could happen with fingolimod, teriflunomide, interferon beta-1a, laquinimod, natalizumab and daclizumab, while our certainty with other DMTs is lower. We are also moderately certain that treatment with alemtuzumab is associated with fewer discontinuations due to adverse events than placebo, and moderately certain that interferon beta-1b probably results in a slight reduction in people who experience serious adverse events, but our certainty with regard to other DMTs is lower. Insufficient evidence is available to evaluate the efficacy and safety of DMTs in a longer term than two years, and this is a relevant issue for a chronic condition like MS that develops over decades. More than half of the included studies were sponsored by pharmaceutical companies and this may have influenced their results. Further studies should focus on direct comparison between active agents, with follow-up of at least three years, and assess other patient-relevant outcomes, such as quality of life and cognitive status, with particular focus on the impact of sex/gender on treatment effects.

Use, tolerability, benefits and side effects of orthotic devices in Charcot-Marie-Tooth disease.

BACKGROUND: Shoe inserts, orthopaedic shoes, ankle-foot orthoses (AFOs) are important devices in Charcot-Marie-Tooth disease (CMT) management, but data about use, benefits and tolerance are scanty. METHODS: We administered to Italian CMT Registry patients an online ad hoc questionnaire investigating use, complications and perceived benefit/tolerability/emotional distress of shoe inserts, orthopaedic shoes, AFOs and other orthoses/aids. Patients were also asked to fill in the Quebec User Evaluation of Satisfaction with assistive Technology questionnaire, rating satisfaction with currently used AFO and related services. RESULTS: We analysed answers from 266 CMT patients. Seventy per cent of subjects were prescribed lower limb orthoses, but 19% did not used them. Overall, 39% of subjects wore shoe inserts, 18% orthopaedic shoes and 23% AFOs. Frequency of abandonment was high: 24% for shoe inserts, 28% for orthopaedic shoes and 31% for AFOs. Complications were reported by 59% of patients and were more frequently related to AFOs (69%). AFO users experienced greater emotional distress and reduced tolerability as compared with shoe inserts (p<0.001) and orthopaedic shoes (p=0.003 and p=0.045, respectively). Disease severity, degree of foot weakness, customisation and timing for customisation were determinant factors in AFOs' tolerability. Quality of professional and follow-up services were perceived issues. CONCLUSIONS: The majority of CMT patients is prescribed shoe inserts, orthopaedic shoes and/or AFOs. Although perceived benefits and tolerability are rather good, there is a high rate of complications, potentially inappropriate prescriptions and considerable emotional distress, which reduce the use of AFOs. A rational, patient-oriented and multidisciplinary approach to orthoses prescription must be encouraged.

Adverse effects of immunotherapies for multiple sclerosis: a network meta-analysis.

BACKGROUND: Multiple sclerosis (MS) is a chronic disease of the central nervous system that affects mainly young adults (two to three times more frequently in women than in men) and causes significant disability after onset. Although it is accepted that immunotherapies for people with MS decrease disease activity, uncertainty regarding their relative safety remains. OBJECTIVES: To compare adverse effects of immunotherapies for people with MS or clinically isolated syndrome (CIS), and to rank these treatments according to their relative risks of adverse effects through network meta-analyses (NMAs). SEARCH METHODS: We searched CENTRAL, PubMed, Embase, two other databases and trials registers up to March 2022, together with reference checking and citation searching to identify additional studies. SELECTION CRITERIA: We included participants 18 years of age or older with a diagnosis of MS or CIS, according to any accepted diagnostic criteria, who were included in randomized controlled trials (RCTs) that examined one or more of the agents used in MS or CIS, and compared them versus placebo or another active agent. We excluded RCTs in which a drug regimen was compared with a different regimen of the same drug without another active agent or placebo as a control arm. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods for data extraction and pairwise meta-analyses. For NMAs, we used the netmeta suite of commands in R to fit random-effects NMAs assuming a common between-study variance. We used the CINeMA platform to GRADE the certainty of the body of evidence in NMAs. We considered a relative risk (RR) of 1.5 as a non-inferiority safety threshold compared to placebo. We assessed the certainty of evidence for primary outcomes within the NMA according to GRADE, as very low, low, moderate or high. MAIN RESULTS: This NMA included 123 trials with 57,682 participants. Serious adverse events (SAEs) Reporting of SAEs was available from 84 studies including 5696 (11%) events in 51,833 (89.9%) participants out of 57,682 participants in all studies. Based on the absolute frequency of SAEs, our non-inferiority threshold (up to a 50% increased risk) meant that no more than 1 in 18 additional people would have a SAE compared to placebo. Low-certainty evidence suggested that three drugs may decrease SAEs compared to placebo (relative risk [RR], 95% confidence interval [CI]): interferon beta-1a (Avonex) (0.78, 0.66 to 0.94); dimethyl fumarate (0.79, 0.67 to 0.93), and glatiramer acetate (0.84, 0.72 to 0.98). Several drugs met our non-inferiority criterion versus placebo: moderate-certainty evidence for teriflunomide (1.08, 0.88 to 1.31); low-certainty evidence for ocrelizumab (0.85, 0.67 to 1.07), ozanimod (0.88, 0.59 to 1.33), interferon beta-1b (0.94, 0.78 to 1.12), interferon beta-1a (Rebif) (0.96, 0.80 to 1.15), natalizumab (0.97, 0.79 to 1.19), fingolimod (1.05, 0.92 to 1.20) and laquinimod (1.06, 0.83 to 1.34); very low-certainty evidence for daclizumab (0.83, 0.68 to 1.02). Non-inferiority with placebo was not met due to imprecision for the other drugs: low-certainty evidence for cladribine (1.10, 0.79 to 1.52), siponimod (1.20, 0.95 to 1.51), ofatumumab (1.26, 0.88 to 1.79) and rituximab (1.01, 0.67 to 1.52); very low-certainty evidence for immunoglobulins (1.05, 0.33 to 3.32), diroximel fumarate (1.05, 0.23 to 4.69), peg-interferon beta-1a (1.07, 0.66 to 1.74), alemtuzumab (1.16, 0.85 to 1.60), interferons (1.62, 0.21 to 12.72) and azathioprine (3.62, 0.76 to 17.19). Withdrawals due to adverse events Reporting of withdrawals due to AEs was available from 105 studies (85.4%) including 3537 (6.39%) events in 55,320 (95.9%) patients out of 57,682 patients in all studies. Based on the absolute frequency of withdrawals, our non-inferiority threshold (up to a 50% increased risk) meant that no more than 1 in 31 additional people would withdraw compared to placebo. No drug reduced withdrawals due to adverse events when compared with placebo. There was very low-certainty evidence (meaning that estimates are not reliable) that two drugs met our non-inferiority criterion versus placebo, assuming an upper 95% CI RR limit of 1.5: diroximel fumarate (0.38, 0.11 to 1.27) and alemtuzumab (0.63, 0.33 to 1.19). Non-inferiority with placebo was not met due to imprecision for the following drugs: low-certainty evidence for ofatumumab (1.50, 0.87 to 2.59); very low-certainty evidence for methotrexate (0.94, 0.02 to 46.70), corticosteroids (1.05, 0.16 to 7.14), ozanimod (1.06, 0.58 to 1.93), natalizumab (1.20, 0.77 to 1.85), ocrelizumab (1.32, 0.81 to 2.14), dimethyl fumarate (1.34, 0.96 to 1.86), siponimod (1.63, 0.96 to 2.79), rituximab (1.63, 0.53 to 5.00), cladribine (1.80, 0.89 to 3.62), mitoxantrone (2.11, 0.50 to 8.87), interferons (3.47, 0.95 to 12.72), and cyclophosphamide (3.86, 0.45 to 33.50). Eleven drugs may have increased withdrawals due to adverse events compared with placebo: low-certainty evidence for teriflunomide (1.37, 1.01 to 1.85), glatiramer acetate (1.76, 1.36 to 2.26), fingolimod (1.79, 1.40 to 2.28), interferon beta-1a (Rebif) (2.15, 1.58 to 2.93), daclizumab (2.19, 1.31 to 3.65) and interferon beta-1b (2.59, 1.87 to 3.77); very low-certainty evidence for laquinimod (1.42, 1.01 to 2.00), interferon beta-1a (Avonex) (1.54, 1.13 to 2.10), immunoglobulins (1.87, 1.01 to 3.45), peg-interferon beta-1a (3.46, 1.44 to 8.33) and azathioprine (6.95, 2.57 to 18.78); however, very low-certainty evidence is unreliable. Sensitivity analyses including only studies with low attrition bias, drug dose above the group median, or only patients with relapsing remitting MS or CIS, and subgroup analyses by prior disease-modifying treatments did not change these figures. Rankings No drug yielded consistent P scores in the upper quartile of the probability of being better than others for primary and secondary outcomes. AUTHORS' CONCLUSIONS: We found mostly low and very low-certainty evidence that drugs used to treat MS may not increase SAEs, but may increase withdrawals compared with placebo. The results suggest that there is no important difference in the occurrence of SAEs between first- and second-line drugs and between oral, injectable, or infused drugs, compared with placebo. Our review, along with other work in the literature, confirms poor-quality reporting of adverse events from RCTs of interventions. At the least, future studies should follow the CONSORT recommendations about reporting harm-related issues. To address adverse effects, future systematic reviews should also include non-randomized studies.

Respiratory function in a large cohort of treatment-naïve adult spinal muscular atrophy patients: a cross-sectional study.

Due to poor data in literature, we aimed to investigate the respiratory function in a large cohort of naïve Italian adult (≥18 years) SMA patients in a multi-centric cross-sectional study. The following respiratory parameters were considered: forced vital capacity (FVC), forced expiratory volume in one second (FEV1) and need for non-invasive ventilation (NIV). We included 145 treatment-naïve adult patients (SMA2=18, SMA3=125; SMA4=2), 58 females (40 %), with median age at evaluation of 37 years (range 18-72). Fifty-six (37 %) and 41 (31 %) patients had abnormal (<80 %) values of FVC and FEV1, respectively. Fourteen (14 %) patients needed NIV, started at median age of 21 (range 4-68). Motor function, measured by Hammersmith Functional Motor Scale Expanded and Revised Upper Limb Module as well as SMA2, loss of walking ability, surgery for scoliosis, use of NIV, and cough assisting device (CAD) were all significantly associated to lower FVC and FEV1 values, while no association with age at baseline, disease duration, gender or 6 min walking test was observed, except for a correlation between FVC and age in SMA3 walkers (p < 0.05). In conclusion, respiratory function in adult SMA patients is relatively frequently impaired, substantially stable, and significantly correlated with motor function and disease severity.

Microvascular decompression for trigeminal neuralgia: a single-center experience with 516 cases, including 32 patients with multiple sclerosis.

BACKGROUND AND OBJECTIVES: To evaluate the effectiveness and long-term pain relief of microvascular decompression (MVD) for "typical" trigeminal neuralgia (TN), including patients affected by multiple sclerosis (MS). METHODS: Between January 2011 and December 2022, 516 consecutive patients presenting with trigeminal neuralgia and a diagnosed neurovascular conflict at MRI underwent microvascular decompression surgery in our neurosurgery department. Ten surgeons with different ages and experiences performed the surgical procedures. Pain improvement, re-operation rate, and complication rates were retrospectively collected and analyzed. RESULTS: 516 patients were included (214 males 302 females, ranging from 12 to 87 years), including 32 patients with multiple sclerosis. Neurovascular compression was found in all cases during surgery. Barrow Neurological Institute pain intensity scale with a score of I was achieved in 404 patients (78,29%), a score II or III was obtained in 100 cases (19,37%) and a score of IV and V in 12 patients (2,32%). In the multiple sclerosis subset of patients, a BNI score of I was achieved in 21/32 (65.62%). The pain recurrence rate of our series was 15.11%. The follow-up for all patients was at least of 13 months, with a mean follow-up of 41.93 months (± 17.75 months, range 13-91 months). Neither intraoperative mortality nor major intra-operative complications occurred in the analyzed series. The re-operation rate was 12.98%. Thermorhizotomy, percutaneous balloon compression, cyber-knife radiosurgery, or new MVD were the surgical techniques utilized for re-operations. CONCLUSIONS: MVD may be considered an effective and safe surgical technique for TN, and in patients affected by multiple sclerosis, it may be proposed even if a less favorable outcome has to be expected with respect to classic TN patients. Larger studies focusing on the relation of multiple sclerosis with neurovascular compression are required.

Daytime sleepiness and sleep quality in Charcot-Marie-Tooth disease.

BACKGROUND: Sleep abnormalities have been reported in Charcot-Marie-Tooth disease (CMT), but data are scanty. We investigated their presence and correlation in a large CMT patients' series. METHODS: Epworth Sleepiness Scale (ESS) and Pittsburgh Sleep Quality Index (PSQI) were administered to CMT patients of the Italian registry and controls. ESS score > 10 indicated abnormal daytime somnolence, PSQI score > 5 bad sleep quality. We analyzed correlation with disease severity and characteristics, Hospital Anxiety and Depression Scale (HADS), Modified Fatigue Impact Scale (MFIS), Body Mass Index, drug use. RESULTS: ESS and PSQI questionnaires were filled by 257 and 253 CMT patients, respectively, and 58 controls. Median PSQI score was higher in CMT patients than controls (6 vs 4, p = 0.006), with no difference for ESS score. Abnormal somnolence and poor sleep quality occurred in 23% and 56% of patients; such patients had more frequently anxiety/depression, abnormal fatigue, and positive sensory symptoms than those with normal ESS/PSQI. Moreover, patients with PSQI score > 5 had more severe disease (median CMT Examination Score, CMTES, 8 vs 6, p = 0.006) and more frequent use of anxiolytic/antidepressant drugs (29% vs 7%, p < 0.001). CONCLUSIONS: Bad sleep quality and daytime sleepiness are frequent in CMT and correlated with anxiety, depression and fatigue, confirming that different components affect sleep. Sleep disorders, such as sleep apnea and restless leg syndrome, not specifically investigated here, are other factors known to impact on sleep quality and somnolence. CMT patients' management must include sleep behavior assessment and evaluation of its correlated factors, including general distress and fatigue.

Clinical spectrum and frequency of Charcot-Marie-Tooth disease in Italy: Data from the National CMT Registry.

BACKGROUND AND PURPOSE: Data are reported from the Italian CMT Registry. METHODS: The Italian CMT Registry is a dual registry where the patient registers and chooses a reference center where the attending clinician collects a minimal dataset of information and administers the Charcot-Marie-Tooth (CMT) Examination/Neuropathy Score. Entered data are encrypted. RESULTS: Overall, 1012 patients had registered (535 females) and 711 had received a genetic diagnosis. Demyelinating CMT (65.3%) was more common than axonal CMT2 (24.6%) and intermediate CMT (9.0%). The PMP22 duplication was the most frequent mutation (45.2%), followed by variants in GJB1 and MPZ (both ~10%) and MFN2 (3.3%) genes. A relatively high mutation rate in some "rare" genes (HSPB1 1.6%, NEFL 1.5%, SH3TC2 1.5%) and the presence of multiple mutation clusters across Italy was observed. CMT4A was the most disabling type, followed by CMT4C and CMT1E. Disease progression rate differed depending on the CMT subtype. Foot deformities and walking difficulties were the main features. Shoe inserts and orthotic aids were used by almost one-half of all patients. Scoliosis was present in 20% of patients, especially in CMT4C. Recessive forms had more frequently walking delay, walking support need and wheelchair use. Hip dysplasia occurred in early-onset CMT. CONCLUSIONS: The Italian CMT Registry has proven to be a powerful data source to collect information about epidemiology and genetic distribution, clinical features and disease progression of CMT in Italy and is a useful tool for recruiting patients in forthcoming clinical trials.

Nabiximols oromucosal spray in patients with multiple sclerosis-related bladder dysfunction: A prospective study.

BACKGROUND: Spasticity and urinary disturbances can profoundly impact the daily lives of persons with multiple sclerosis (pwMS). Cannabis has been associated with improvement in sphincteric disturbances. To our knowledge, few studies have evaluated the effect of nabiximols oromucosal spray (Sativex®) on urinary disturbances by instrumental methods. OBJECTIVES: This longitudinal study was conducted to assess the effect of nabiximols oromucosal spray on urinary disturbances by clinical and urodynamic evaluation in pwMS. MATERIALS AND METHODS: Neurological, spasticity, and quality of life (QoL) assessments were performed before (T0), and at one (T1) and six (T6) months after the start of nabiximols treatment. At these same time points, patients were assessed for urinary disturbances by the International Prostatic Symptoms Score (IPSS) and a urodynamic test evaluating maximum detrusor pressure (Pdet), bladder filling capacity (CCmax), uninhibited detrusor contractions (UDC), bladder volume at first desire (BVFD), post-void residual volume (PVR) and voluntary abdominal pressure (PA). RESULTS: Of 31 pwMS enrolled in the study, 25 reached T1 and 18 reached T6. Mean IPSS total score, its subscores, and IPSS QoL decreased significantly from T0 to T6 (p = 0.000), with no differences according to sex, age, MS type, disease duration and disability at baseline. Pdet improved significantly from T0 to T6 (p = 0.0171), and CCmax changed only marginally (p = 0.0494); results were similar in patient subgroups naïve to or previously exposed to urological treatment. All patients with overactive bladder showed improvement in their urodynamic assessment based on significant reduction of Pdet (p = 0.0138). In patients with mainly hypotonic bladder, mean Pdet decreased from T0 to T6 without reaching statistical significance; most urodynamic parameters showed a trend to improve. Mean numerical scale scores for MS spasticity, and for spasms, pain and tremors, decreased significantly from T0 to T6. The mean 'physical health composite' score of the MS Quality of Life-54 questionnaire increased significantly from T0 to T6 (p = 0.0126). DISCUSSION AND CONCLUSION: Our data suggest that nabiximols has an appreciable effect on ameliorating subjective perception of urinary disturbances and appears to have a positive effect on objective urodynamic parameters, particularly in patients with hyperactive bladder.

Corrigendum: PMCA-based detection of prions in the olfactory mucosa of patients with sporadic Creutzfeldt-Jakob disease.

[This corrects the article DOI: 10.3389/fnagi.2022.848991.].

Are Thalamic Intrinsic Lesions Operable? No-Man's Land Revisited by the Analysis of a Large Retrospective, Mono-Institutional, Cohort.

Thalamic gliomas represent a heterogeneous subset of deep-seated lesions for which surgical removal is advocated, although clear prognostic factors linked to advantages in performance status or overall survival are still lacking. We reviewed our Institutional Cancer Registry, identifying patients who underwent surgery for thalamic gliomas between 2006 and 2020. Associations between possible prognostic factors such as tumor volume, grade, the extent of resection and performance status (PS), and overall survival (OS) were evaluated using univariate and multivariate survival analyses. We found 56 patients: 31 underwent surgery, and 25 underwent biopsy. Compared to biopsy, surgery resulted positively associated with an increase in the OS (hazard ratio, HR, at multivariate analysis 0.30, 95% confidence interval, CI, 0.12-0.75). Considering the extent of resection (EOR), obtaining GTR/STR appeared to offer an OS advantage in high-grade gliomas (HGG) patients submitted to surgical resection if compared to biopsy, although we did not find statistical significance at multivariate analysis (HR 0.53, 95% CI 0.17-1.59). Patients with a stable 3-month KPS after surgery demonstrated to have a better prognosis in terms of OS if compared to biopsy (multivariate HR 0.17, 95% CI, 0.05-0.59). Age and histological grades were found to be prognostic factors for this condition (p = 0.04 and p = 0.004, respectively, chi-square test). Considering the entire cohort, p53 positivity (univariate HR 2.21, 95% CI 1.01-4.82) and ATRX positivity (univariate HR 2.69, 95% CI 0.92-7.83) resulted associated with a worse prognosis in terms of OS. In this work, we demonstrated that surgery aimed at tumor resection might offer a stronger survival advantage when a stable 3-month KPS after surgery is achieved.

Hypofractionated Radiosurgery for Large or in Critical-Site Intracranial Meningioma: Results of a Phase 2 Prospective Study.

PURPOSE: Radiosurgery is a well-known, safe, and effective technique used in the treatment of intracranial meningiomas. However, single-fraction radiosurgery can lead to high toxicity rates when large-volume or critically located lesions are targeted. Multisession-also called hypofractionated-radiosurgery (hypo-RS) might overcome these limitations. Accordingly, we carried out a prospective phase 2 trial, aiming to establish whether a fractionated RS schedule of 25 Gy in 5 fractions would be safe and effective in treating large (≥ 3 cm) and/or critically located (<3 mm from critical structures) grade 1 intracranial meningiomas. The main aim was to evaluate the safety of hypo-RS in terms of absence of adverse events. The secondary aim was to evaluate tumor response in terms of local control, defined as stability or reduction of lesion volume. METHODS AND MATERIALS: We prospectively enrolled patients with diagnoses of grade 1 meningiomas, large size and/or critically located lesions, either histologically diagnosed or imaging defined. Additional inclusion criteria were signed informed consent, an age of ≥18 years, and Karnofsky Performance Status ≥70. RESULTS: Between 2011 and 2016, 178 patients were consecutively enrolled. The median follow-up was 53 months (range, 4-101 months). Overall, the toxicity rate was 12.7% (21 of 166 patients). At a 5-year minimum follow-up, the patients' toxicity rates were 11.7 % (9 of 77 patients). Symptom evaluation at both 3-year and last follow-up showed an improvement in most of the patients. Five-year local tumor control was 97% (95% confidence interval, 92%-99%). CONCLUSIONS: Hypo-RS schedule of 25 Gy in 5 fractions is a well-tolerated option in the treatment of large-volume and/or critically located benign meningiomas. Early results suggest favorable local control, although longer-term follow-up is needed.

A new study protocol for in-vivo assessment of tumor diagnosis and microscopic tumor infiltration at the resection cavity in central nervous system tumors by a new miniature confocal endomicroscope (CONVIVO system).

BACKGROUND: Confocal laser technology has been recently suggested as a promising method to obtain near real-time intraoperative histological data. We recently demonstrated the accuracy of a newly designed confocal endomiscroscope (CONVIVO) in offering an intraoperative diagnosis during high-grade gliomas (HGGs) removal in an ex vivo study. With this work we aim to perform a standardized, prospective and blinded-to-histological section study for evaluating the potentiality of CONVIVO in offering in-vivo data regarding histological diagnosis and presence of tumor at margins during resection of central nervous system (CNS) tumors. METHODS: This prospective, observational, standardized, blinded-to-histological section, clinical trial was approved by the institutional review board in Carlo Besta Neurologic Institute IRCCS Foundation in Milan and is expected to last 24 months. 75 patients will be included, with at least 53 of them being HGGs based on the statistical sample size calculation. Main objectives will be the assessing of the concordance of tumor diagnoses between CONVIVO images and frozen section at the center of all tumor subtypes and the evaluation of the accuracy of CONVIVO in the identification of tumor tissue at the margins, compared to standard histology. For this purpose, "virtual biopsies" and physical biopsies will be performed directly on patient tumor tissue and surrounding brain parenchima during tumor resection, comparing the results of CONVIVO analysis and frozen and histological sections. RESULTS: Despite promising preliminary data on ex vivo usefulness of CLE machines are emerging in literature, still few studies are available when looking at in vivo potentiality of CONVIVO. At this regard, this study will be the first work where a standardized, prospective, and blinded-to-histological section CONVIVO analysis will be performed in an in-vivo setting in neuro-oncological surgery. CONCLUSIONS: We hypothesize that this new technique may have a role in offering data regarding presence of tumor tissue, eventually giving an intraoperative diagnosis in neuro-oncological surgery, rendering more fluid the decision-making process in the operating room. Furthermore, the result of this study will provide a solid base for further expanding the clinical applications of confocal machines in neurosurgery.