Long-term treatment of SOD1 ALS with tofersen: a multicentre experience in 17 patients.

BACKGROUND: In Amyotrophic Lateral Sclerosis (ALS) patients with SOD1 mutation the intrathecal administration of tofersen slowed down the progression of disease in a controlled clinical study, but results were not statistically significant. METHODS: In this multicentre, observational study, we evaluated a cohort of 27 ALS-SOD1 patients who were treated with tofersen, focussing on 17 patients who were followed for at least 48 weeks (median period of 84 weeks, range 48-108). We compared the clinical slopes, as measured by ALSFRS-R, MRC scale and Forced Vital Capacity, during tofersen treatment with retrospective data at 1 year prior to therapy. Cerebrospinal fluid (CSF) and serum neurofilament light chains (NFL) were measured in all patients. RESULTS: Cumulative evaluation of the ALSFRS-R and MRC progression rates showed a statistically significant change during treatment with respect to the period prior to therapy (p = 0.023 and p = 0.007, respectively). The analysis of individual patients showed that nine of the seventeen patients substantially stabilized or slightly improved. Four patients deteriorated during treatment, while in the remaining patients the very slow course did not allow to identify significant changes. CSF and serum NFL concentration markedly decreased in the near totality of patients. Increased levels of white blood cells and proteins in the CSF were found in 60% of patients. Such alterations were clinically asymptomatic in all but two patients who showed an acute pure motor radiculitis, which responded to steroid therapy. CONCLUSIONS: Clinical findings and NFL analysis strongly suggest that tofersen may have a disease-modifying effect in a subset of SOD1-ALS patients.

A Knowledge-based Decision Support System for recommending safe recipes to individuals with dysphagia.

BACKGROUND: Dysphagia is a disorder that can be associated to several pathological conditions, including neuromuscular diseases, with significant impact on quality of life. Dysphagia often leads to malnutrition, as a consequence of the dietary changes made by patients or their caregivers, who may deliberately decide to reduce or avoid specific food consistencies (because they are not perceived as safe), and the lack of knowledge in how to process foods are critics. Such dietary changes often result in unbalanced nutrients intake, which can have significant consequences for frail patients. This paper presents the development of a prototypical novel ontology-based Decision Support System (DSS) to support neuromuscular patients with dysphagia (following a per-oral nutrition) and their caregivers in preparing nutritionally balanced and safe meals. METHOD: After reviewing scientific literature, we developed in collaboration with Ear-Nose-Throat (ENT) specialists, neurologists, and dieticians the DSS formalizes expert knowledge to suggest recipes that are considered safe according to patient's consistency limitations and dysphagia severity and also nutritionally well-balanced. RESULTS: The prototype can be accessed via digital applications both by physicians to generate and verify the recommendations, and by the patients and their caregivers to follow the step-by-step procedures to autonomously prepare and process one or more recipe. The system is evaluated with 9 clinicians to assess the quality of the DSS's suggested recipes and its acceptance in clinical practice. CONCLUSIONS: Preliminary results suggest a global positive outcome for the recipes inferred by the DSS and a good usability of the system.

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.

Equating norms between the ALS Cognitive Behavioral Screen (ALS-CBS™) and the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) in non-demented ALS patients.

BACKGROUND: The present study aimed at deriving equating norms to estimate scores on the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) based on those on the ALS Cognitive Behavioral Screen (ALS-CBS™) in an Italian cohort of non-demented ALS patients. METHODS: ALS-CBS™ and ECAS scores of 293 ALS patients without frontotemporal dementia were retrospectively retrieved. Concurrent validity of the ALS-CBS™ towards the ECAS was tested by covarying for demographics, disease duration and severity, presence of C9orf72 hexanucleotide repeat expansion and behavioural features. A linear-smoothing equipercentile equating (LSEE) model was employed to derive ALS-CBS™-to-ECAS cross-walks. Gaps in LSEE-based estimation were managed via a linear regression-based equating approach. Equivalence between empirical and derived ECAS scores was tested via a two-one-sided test (TOST) procedure for the dependent sample. RESULTS: The ALS-CBS™ predicted the ECAS (ß = 0.75), accounting for the vast majority of its variance (60% out of an R2 = 0.71). Consistently, a strong, one-to-one linear association between ALS-CBS™ and ECAS scores was detected (r = 0.84; R2 = 0.73). The LSEE was able to estimate conversions for the full range of the ALS-CBS™, except for raw scores equal to 1 and 6 - for whom a linear equating-based equation was derived. Empirical ECAS scores were equivalent to those derived with both methods. DISCUSSION: Italian practitioners and researchers have been herewith provided with valid, straightforward cross-walks to estimate the ECAS based on ALS-CBS™ scores in non-demented ALS patients. Conversions herewith provided will help avoid cross-sectional/longitudinal inconsistencies in test adoption within research, and possibly clinical, settings.

Clinimetrics of the cognitive section of the Italian ALS Cognitive Behavioral Screen (ALS-CBS™).

BACKGROUND: The present study aimed at (1) providing further validity and reliability evidence for the Italian version of the cognitive section of the ALS Cognitive Behavioral Screen (ALS-CBS™) and (2) testing its diagnostics within an Italian ALS cohort, as well as at (3) exploring its capability to discriminate patients from healthy controls (HCs). METHODS: N = 293 non-demented ALS patients were administered the cognitive sections of the ALS-CBS™ and Edinburgh Cognitive and Behavioural ALS Screen (ECAS). N = 96 HCs demographically matched with N = 96 patients were also administered the cognitive section of the ALS-CBS™. In patients, factorial and construct validity, internal reliability, and diagnostics against a defective score on the cognitive section of the ECAS were tested. Case-control discrimination was assessed via a logistic regression. RESULTS: ALS-CBS™ cognitive subscales were underpinned by a simple, unidimensional structure, internally reliable (McDonald's ω = 0.74), and mostly related with ECAS executive and fluency scores (rs = 0.54-0.71). Both raw and age- and education-adjusted scores on the cognitive section of the ALS-CBS™ accurately detected ECAS-defined cognitive impairment (AUC = 0.80 and .88, respectively), yielding optimal error-based, information-based and unitary diagnostics. A cut-off of < 15.374 was identified on adjusted scores. The test was able to discriminate patients from HCs (p < 0.001). DISCUSSION: The cognitive section of the Italian ALS-CBS™ is a valid, reliable, and diagnostically sound ALS-specific screener for detecting frontotemporal, executive-/attentive-based cognitive inefficiency in non-demented ALS patients, being also able to discriminate them from normotypical individuals.

Clinical and pathological findings in neurolymphomatosis: Preliminary association with gene expression profiles in sural nerves.

Although inflammation appears to play a role in neurolymphomatosis (NL), the mechanisms leading to degeneration in the peripheral nervous system are poorly understood. The purpose of this exploratory study was to identify molecular pathways underlying NL pathogenesis, combining clinical and neuropathological investigation with gene expression (GE) studies. We characterized the clinical and pathological features of eight patients with NL. We further analysed GE changes in sural nerve biopsies obtained from a subgroup of NL patients (n=3) and thirteen patients with inflammatory neuropathies as neuropathic controls. Based on the neuropathic symptoms and signs, NL patients were classified into three forms of neuropathy: chronic symmetrical sensorimotor polyneuropathy (SMPN, n=3), multiple mononeuropathy (MN, n=4) and acute motor-sensory axonal neuropathy (AMSAN, n=1). Predominantly diffuse malignant cells infiltration of epineurium was present in chronic SMPN, whereas endoneurial perivascular cells invasion was observed in MN. In contrast, diffuse endoneurium malignant cells localization occurred in AMSAN. We identified alterations in the expression of 1266 genes, with 115 up-regulated and 1151 down-regulated genes, which were mainly associated with ribosomal proteins (RP) and olfactory receptors (OR) signaling pathways, respectively. Among the top up-regulated genes were actin alpha 1 skeletal muscle (ACTA1) and desmin (DES). Similarly, in NL nerves ACTA1, DES and several RPs were highly expressed, associated with endothelial cells and pericytes abnormalities. Peripheral nerve involvement may be due to conversion towards a more aggressive phenotype, potentially explaining the poor prognosis. The candidate genes reported in this study may be a source of clinical biomarkers for NL.

Adults with spinal muscular atrophy: a large-scale natural history study shows gender effect on disease.

BACKGROUND: Natural history of spinal muscular atrophy (SMA) in adult age has not been fully elucidated yet, including factors predicting disease progression and response to treatments. Aim of this retrospective, cross-sectional study, is to investigate motor function across different ages, disease patterns and gender in adult SMA untreated patients. METHODS: Inclusion criteria were as follows: (1) clinical and molecular diagnosis of SMA2, SMA3 or SMA4 and (2) clinical assessments performed in adult age (>18 years). RESULTS: We included 64 (38.8%) females and 101 (61.2%) males (p=0.0025), among which 21 (12.7%) SMA2, 141 (85.5%) SMA3 and 3 (1.8%) SMA4. Ratio of sitters/walkers within the SMA3 subgroup was significantly (p=0.016) higher in males (46/38) than in females (19/38). Median age at onset was significantly (p=0.0071) earlier in females (3 years; range 0-16) than in males (4 years; range 0.3-28), especially in patients carrying 4 SMN2 copies. Median Hammersmith Functional Rating Scale Expanded scores were significantly (p=0.0040) lower in males (16, range 0-64) than in females (40, range 0-62); median revised upper limb module scores were not significantly (p=0.059) different between males (24, 0-38) and females (33, range 0-38), although a trend towards worse performance in males was observed. In SMA3 patients carrying three or four SMN2 copies, an effect of female sex in prolonging ambulation was statistically significant (p=0.034). CONCLUSIONS: Our data showed a relevant gender effect on SMA motor function with higher disease severity in males especially in the young adult age and in SMA3 patients.

Subacute sensory neuronopathy associated with Merkel cell carcinoma with unknown primary: a case report with literature review.

Paraneoplastic neurologic syndromes (PNSs) are a wide spectrum of neurologic diseases characterized by different clinical features, associated with a neoplasia, and triggered by an immune-mediated process. In most cases, it is possible to detect specific neuronal antibodies and the Hu protein is one of the most frequently recognized intracellular antigens in patients with PNSs. Small-cell lung cancer is the most common cancer associated with PNSs, followed by urological, gynecological and hematological malignancies. Otherwise, extra-pulmonary small-cell carcinomas, including Merkel cell carcinoma (MCC), have been rarely described as related to PNSs. In this article we report, for the first time in the published literature, a case of anti-Hu antibody-related subacute sensory neuronopathy in association with MCC.

Third cranial nerve palsy in an 88-year-old man after SARS-CoV-2 mRNA vaccination: change of injection site and type of vaccine resulted in an uneventful second dose with humoral immune response.

Vaccines for SARS-CoV-2 currently authorised by the European Medicine Agency are effective, safe and well tolerated in practice. Awareness of rare potential vaccine-related adverse effects (AEs) is important to improve their recognition, management and reporting. An 88-year-old man attended the emergency department with incomplete palsy of the right third cranial nerve 3 days after the first administration of Moderna mRNA-1273 SARS-CoV-2 vaccine. Imaging ruled out a vascular accident and a vaccine AE was hypothesised. Two weeks of oral steroids led to the patient's recovery, but without evidence of humoral immune response to vaccine. Thus, full immunisation with a dose of Pfizer mRNA-BNT162b2 SARS-CoV-2 vaccine in a different site was attempted. This was uneventful and followed by a robust antibody response. Empirical change of site and vaccine brand may represent a tailored option to obtain full immune protection in selected patients, after vaccine AEs.

Phosphorylated TDP-43 aggregates in peripheral motor nerves of patients with amyotrophic lateral sclerosis.

Phosphorylated TDP-43 (pTDP-43) aggregates in the cytoplasm of motor neurons and neuroglia in the brain are one of the pathological hallmarks of amyotrophic lateral sclerosis. Although the axons exceed the total volume of motor neuron soma by several orders of magnitude, systematic studies investigating the presence and distribution of pTDP-43 aggregates within motor nerves are still lacking. The aim of this study is to define the TDP-43/pTDP-43 pathology in diagnostic motor nerve biopsies performed on a large cohort of patients presenting with a lower motor neuron syndrome and to assess whether this might be a discriminating tissue biomarker for amyotrophic lateral sclerosis and non-amyotrophic lateral sclerosis cases. We retrospectively evaluated 102 lower motor neuron syndrome patients referred to our centre for a diagnostic motor nerve biopsy. Histopathological criteria of motor neuron disease and motor neuropathy were applied by two independent evaluators, who were blind to clinical data. TDP-43 and pTDP-43 were evaluated by immunohistochemistry, and results compared to final clinical diagnosis. We detected significant differences between amyotrophic lateral sclerosis and non-amyotrophic lateral sclerosis cases in pTDP-43 expression in myelinated fibres: axonal accumulation was detected in 98.2% of patients with amyotrophic lateral sclerosis versus 30.4% of non-amyotrophic lateral sclerosis samples (P < 0.0001), while concomitant positive staining in Schwan cell cytoplasm was found in 70.2% of patients with amyotrophic lateral sclerosis versus 17.4% of patients who did not have amyotrophic lateral sclerosis (P < 0.001). Importantly, we were also able to detect pTDP-43 aggregates in amyotrophic lateral sclerosis cases displaying normal features at standard histopathological analysis. Our findings demonstrated that a specific pTDP-43 signature is present in the peripheral nervous system of patients with amyotrophic lateral sclerosis, and could be exploited as a specific, accessible tissue biomarker. The detection of pTDP-43 aggregates within motor nerves of living patients with amyotrophic lateral sclerosis, occurring before axonal degeneration, suggests that this is an early event that may contribute to amyotrophic lateral sclerosis pathogenesis.

Standardization of the Italian ALS-CBS™ Caregiver Behavioral Questionnaire.

Background: The present investigation aimed at testing the psychometrics and diagnostics of the Italian version of the Caregiver Behavioral Questionnaire (CBQ) from the ALS Cognitive Behavioral Screen (ALS-CBS™), as well as its case-control discrimination, in a cohort of non-demented patients with ALS. Methods: The caregivers of N = 265 non-demented patients with ALS and N = 99 healthy controls (HCs) were administered the CBQ and the Edinburgh Cognitive and Behavioural ALS Screen-Carer Interview (ECAS-CI). For N = 98 patients, an in-depth behavioural/psychopathological assessment via the Frontal Behavioural Inventory (FBI), the Dimensional Apathy Scale (DAS), the State and Trait Anxiety Inventory-Form Y (STAI-Y), and the Beck Depression Inventory (BDI) was also available. Factorial and construct validity, internal reliability, and diagnostics against an abnormal ECAS-CI score were tested in patients. Case-control discrimination was explored through logistic regression. Results: The CBQ was internally reliable (McDonald's ω = 0.90) and underpinned by a simple, unidimensional structure; it converged with ECAS-CI, FBI, and DAS scores and diverged from STAI-Y and BDI ones. A cutoff of ≤ 33 accurately detected abnormal ECAS-CI scores (AUC = 0.85), yielding optimal error- and information-based diagnostics. The CBQ was independent of demographic and disease-related variables and discriminated patients from HCs (p < 0.001). Discussion: The Italian version of the CBQ from the ALS-CBS™ is a valid, reliable, diagnostically sound, and feasible screener for detecting frontotemporal-like behavioural changes in non-demented patients with ALS. Its adoption is thus recommended within clinical practice and research in the view of providing preliminary information on whether the administration of more extensive behavioural instruments is needed.

Normal structure and pathological features in peripheral neuropathies.

Normal nerve architecture is basic to a complete understanding of nerve pathology. Here, normal components of the nerve are illustrated, including myelinated and non-myelinated nerve fibres, stromal elements, and vascular components. These are relevant because the differential diagnosis of neuropathy depends on the pathological processes affecting axon, myelin, interstitial space, and blood vessels. Thus, we present a description of the general pathological characteristics for the diagnosis of peripheral nerve disorders.

Nusinersen safety and effects on motor function in adult spinal muscular atrophy type 2 and 3.

OBJECTIVE: To retrospectively investigate safety and efficacy of nusinersen in a large cohort of adult Italian patients with spinal muscular atrophy (SMA). METHODS: Inclusion criteria were: (1) clinical and molecular diagnosis of SMA2 or SMA3; (2) nusinersen treatment started in adult age (>18 years); (3) clinical data available at least at baseline (T0-beginning of treatment) and 6 months (T6). RESULTS: We included 116 patients (13 SMA2 and 103 SMA3) with median age at first administration of 34 years (range 18-72). The Hammersmith Functional Rating Scale Expanded (HFMSE) in patients with SMA3 increased significantly from baseline to T6 (median change +1 point, p<0.0001), T10 (+2, p<0.0001) and T14 (+3, p<0.0001). HFMSE changes were independently significant in SMA3 sitter and walker subgroups. The Revised Upper Limb Module (RULM) in SMA3 significantly improved between T0 and T14 (median +0.5, p=0.012), with most of the benefit observed in sitters (+2, p=0.018). Conversely, patients with SMA2 had no significant changes of median HFMSE and RULM between T0 and the following time points, although a trend for improvement of RULM was observed in those with some residual baseline function. The rate of patients showing clinically meaningful improvements (as defined during clinical trials) increased from 53% to 69% from T6 to T14. CONCLUSIONS: Our data provide further evidence of nusinersen safety and efficacy in adult SMA2 and SMA3, with the latter appearing to be cumulative over time. In patients with extremely advanced disease, effects on residual motor function are less clear.

From pathogenesis to personalized treatments of neuropathies in hematological malignancies.

The peripheral nervous system may be involved at any stage in the course of several hematological diseases, the most common being monoclonal gammopathies (of undetermined significance or malignant) or lymphomas. The underlying pathogenic mechanisms are different and therapies aim at targeting the dangerous either B-cell or plasma cell clones. Recently, high-throughput technologies, and next-generation sequencing have increased our knowledge of hematological diseases pathogenesis by the identification of somatic mutation affecting pivotal signaling pathways. Accordingly, new target therapies are used that may also be borrowed for treatment of neuropathies in hematological diseases.

Antibodies to neurofascin, contactin-1, and contactin-associated protein 1 in CIDP: Clinical relevance of IgG isotype.

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%).

Limitations in daily activities and general perception of quality of life: Long term follow-up in patients with anti-myelin-glycoprotein antibody polyneuropathy.

In this study, we assessed the modifications over time of daily activities and quality of life (QoL) in 32 subjects with anti-myelin-glycoprotein (MAG) antibody neuropathy. A widespread panel including clinical scores and patient-reported questionnaires, in compliance of the terms by the International Classification of Functioning, Disability, and Health (ICF) of the World Health Organization (WHO), was employed at enrollment (T0) and at follow-up evaluation (T1) after a mean interval of 15.4 ± 5.7 months. The Sensory Modality Sum score (SMS) at four limbs showed a significant worsening over time (mean score 27.2 ± 3.9 at T0 vs 25.7 ± 3 at T1 at upper limbs, P = .03; 20.5 ± 4.8 at T0 vs 18.6 ± 5.9 at T1 at lower limbs, P = .04). The Visual Analogue Scale (VAS) for pain significantly worsened at upper limbs at T1 (mean values 0.84 ± 1.95 at T0 vs 1.78 ± 2.6 at T1, P = .03). All the other tests did not show significant differences between T0 and T1. In the subgroup who underwent rituximab (15/32 treated before T0, 3/32 patients treated between T0 and T1 with median interval of 1 year), no significant differences were observed between T0 and T1. Despite the quite long follow-up, statistical significance was not achieved either for the limited number of patients or for the lack of sensitive outcome measures. In our cohort, the significant worsening of the SMS and VAS after a median of 14 months can be considered as a reliable expression of the natural history of the disease, and suggest that these scales might represent possible outcome measures in anti-MAG antibody neuropathy.

Assessing seasonal dynamics of Guillain-Barré syndrome with search engine query data.

BACKGROUND AND OBJECTIVE: In previous studies, data deriving from Google Trends showed promising correlation with disease incidence trends assessed with public health control systems. The aim of this work is to use search engine query data to investigate seasonal dynamics in Guillain-Barré syndrome (GBS) in the USA. METHODS: Average Google monthly search volumes for GBS from 2008 to 2017 were analysed for the USA overall and on regional base with generalized estimating equation models. Association with monthly historical temperature variations was tested. RESULTS: Monthly search volume for GBS displayed the greatest positive anomaly for October, clustering with September and November. Region-wide analysis confirmed this pattern and showed secondary spring (Feb/Apr) subpeaks in Pacific and Midwest. Association of GBS search volume with month-to-month temperature variations showed J-shaped relationship, with the highest peak occurring in months with greatest temperature falls, and subpeak in months with sharpest temperature rises. CONCLUSIONS: This study represents the first approach in investigating digital epidemiology of GBS and establishing possible links with traditional epidemiology. Cold season GBS peak has been observed by some traditional studies; hypothetical pathogenic relationship with infectious antecedents is supported from finding GBS peaks clustering with greatest temperature change. Further studies are needed to compare these findings to traditional public health approaches.

An update on the diagnosis and management of the polyneuropathy of POEMS syndrome.

POEMS syndrome is a rare, chronic, disabling paraneoplastic disorder characterized by peripheral neuropathy, organomegaly, endocrinopathy, monoclonal plasma cells disorder and skin changes. Diagnosis relies on the fulfillment of a set of clinical criteria of which polyneuropathy and a monoclonal plasma cell dyscrasia are early and essential features. Treatment may be either local or systemic and is aimed at the monoclonal plasma cell disorder. Our knowledge of the pathogenesis underlying the POEMS syndrome has advanced greatly over the past years, favoring an important progression in the recognition and management of this disorder. Here, we discuss the recent literature that has advanced our knowledge of the pathogenesis and clinical management of the polyneuropathy in POEMS syndrome.

Functioning and quality of life in patients with neuropathy associated with anti-MAG antibodies.

Although anti-myelin-associated glycoprotein (MAG) antibody neuropathy is reported as a slowly progressive disease, it can lead to significant disability and impairment of health-related quality of life (HR-QoL) and social participation. The aim of this cross-sectional study was to evaluate the functioning and HR-QoL determinants in 67 patients with anti-MAG neuropathy in terms of the International Classification of Functioning, Disability, and Health (ICF). Evaluations included: Medical Research Council (MRC) sum score, Sensory Modality Sum score (SMS), Berg balance scale (BBS), Fatigue Severity Scale (FSS), Visual Analogue Scale (VAS) for pain, 9-Hole Peg Test (9-HPT), 6-min Walk Distance (6MWD), Impact on Participation and Autonomy (IPA) and the physical component score (PCS) and mental component score (MCS) of the short-form-36 health status scale (SF-36) HR-QoL measure. In the regression models, 6MWD was the most reliable predictor of PCS, explaining the 52% of its variance, while the strongest determinants of 6MWD were BBS and FSS, explaining the 41% of its variance. Consistently, VAS and BBS were good predictor of PCS, explaining together 54% of its variance. FSS was the most reliable determinant of MCS, explaining 25% of its variance. SMS and MRC were not QoL determinants. The results of our study suggest that 6MWD and FSS might be considered as potential meaningful outcome measures in future clinical trials. Furthermore, neurorehabilitation interventions aimed at improving balance and walking performance, fatigue management, and specific pain relief therapy should be considered to ameliorate participation in social life and HR-QoL in anti-MAG neuropathy patients.

Proteomic expression profile of injured rat peripheral nerves revealed biological networks and processes associated with nerve regeneration.

Peripheral nerve regeneration is regulated through the coordinated spatio-temporal activation of multiple cellular pathways. In this work, an integrated proteomics and bioinformatics approach was employed to identify differentially expressed proteins at the injury-site of rat sciatic nerve at 20 days after damage. By a label-free liquid chromatography mass-spectrometry (LC-MS/MS) approach, we identified 201 differentially proteins that were assigned to specific canonical and disease and function pathways. These include proteins involved in cytoskeleton signaling and remodeling, acute phase response, and cellular metabolism. Metabolic proteins were significantly modulated after nerve injury to support a specific metabolic demand. In particular, we identified a group of proteins involved in lipid uptake and lipid storage metabolism. Immunofluorescent staining for acyl-CoA diacylglycerol acyltransferase 1 (DGAT1) and DAGT2 expression provided evidence for the expression and localization of these two isoforms in Schwann cells at the injury site in the sciatic nerve. This further supports a specific local regulation of lipid metabolism in peripheral nerve after damage.