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Mild behavioral impairment (MBI) has been increasingly regarded as the neurobehavioral axis of predementia risk states, but a specific investigation of its detection as a potential marker of prodromal dementia in motor neuron diseases (MNDs) is still lacking. The aims of our study were therefore to explore MBI in MNDs both at onset and over the disease course, and to evaluate its relationship with baseline and longitudinal cognitive features.Sixty MND patients with cognitive/behavioral, mood, and motor examinations were recruited and followed longitudinally for up to 15 months. Associations between baseline MBI symptoms and clinical features were tested using the Spearman correlation coefficient. Based on longitudinal data, relative deltas of variation for each cognitive measure were generated, and linear regression models were then used to evaluate the role of baseline MBI symptoms in predicting longitudinal rates of cognitive decline.At disease onset, the most impaired MBI domain was affective/emotional dysregulation, followed by impulse dyscontrol, apathy, and social inappropriateness. Greater MBI symptoms correlated with more severe baseline motor, cognitive/behavioral, and mood disturbances (p values from0.001 to 0.05). Longitudinally, the greatest decline was observed in the affective/emotional dysregulation domain, followed by impulse dyscontrol, apathy, and social inappropriateness. Greater MBI symptoms at onset were significant predictors of more severe longitudinal cognitive decline in both amyotrophic lateral sclerosis (ALS)-specific and ALS-nonspecific functions (p values from0.001 to 0.03).MBI represents a valuable clinical marker of incident cognitive decline in MNDs, and its evaluation has good potential for detecting dementia in its preclinical/prodromal phase.

Mutations in the Myelin Protein Zero gene (MPZ), encoding P0, the major structural glycoprotein of peripheral nerve myelin, are the cause of Charcot–Marie-Tooth (CMT) type 1B neuropathy, and most P0 mutations appear to act through gain-of-function mechanisms. Here, we investigated how misglycosylation, a pathomechanism encompassing several genetic disorders, may affect P0 function. Using in vitro assays, we showed that gain of glycosylation is more damaging for P0 trafficking and functionality as compared with a loss of glycosylation. Hence, we generated, via CRISPR/Cas9, a mouse model carrying the MPZD61N mutation, predicted to generate a new N-glycosylation site in P0. In humans, MPZD61N causes a severe early-onset form of CMT1B, suggesting that hyperglycosylation may interfere with myelin formation, leading to pathology. We show here that MPZD61N/+ mice develop a tremor as early as P15 which worsens with age and correlates with a significant motor impairment, reduced muscular strength and substantial alterations in neurophysiology. The pathological analysis confirmed a dysmyelinating phenotype characterized by diffuse hypomyelination and focal hypermyelination. We find that the mutant P0D61N does not cause significant endoplasmic reticulum stress, a common pathomechanism in CMT1B, but is properly trafficked to myelin where it causes myelin uncompaction. Finally, we show that myelinating dorsal root ganglia cultures from MPZD61N mice replicate some of the abnormalities seen in vivo, suggesting that they may represent a valuable tool to investigate therapeutic approaches. Collectively, our data indicate that the MPZD61N/+ mouse represents an authentic model of severe CMT1B affirming gain-of-glycosylation in P0 as a novel pathomechanism of disease.

We evaluated 13 patients affected by myasthenia gravis (MG) who had coronavirus disease 2019 (COVID-19) before vaccination and 14 myasthenic patients who contracted severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection after vaccination to evaluate factors related to different COVID-19 outcomes. We compared the two groups’ previous stability of MG and the severity of SARS-CoV-2 infection. Vaccinated and non-vaccinated patients were comparable in terms of severity of the previous MG course (mean maximum myasthenia gravis Foundation of America–MGFA–Class III) and during SARS-CoV-2 infection (mean MGFA Class II). In non-vaccinated patients, the hospitalization and severe course percentages were 61.5%, while the mortality reached 30.8%. The hospitalization, severe course, and mortality percentages in vaccinated patients were 7.1%. In deceased, non-vaccinated patients, greater myasthenia severity in the past clinical history, but not at the time of infection, was observed. Similarly, older age at MG onset and at the time of infection correlated with a more severe COVID-19 course in non-vaccinated patients (p = 0.03 and p = 0.04), but not in the group of vaccinated patients. In summary, our data support a protective role of vaccination in myasthenic patients, even if anti-CD20 therapy might be associated with a poor immune response to vaccines.

BackgroundTo assess the ability of the 2021 European Academy of Neurology/Peripheral Nerve Society (EAN/PNS) clinical criteria for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) to include within their classification the whole spectrum of clinical heterogeneity of the disease and to define the clinical characteristics of the unclassifiable clinical forms.MethodsThe 2021 EAN/PNS clinical criteria for CIDP were applied to 329 patients fulfilling the electrodiagnostic (and in some cases also the supportive) criteria for the diagnosis of CIDP. Clinical characteristics were reviewed for each patient not strictly fulfilling the clinical criteria (‘unclassifiable’).ResultsAt study inclusion, 124 (37.5%) patients had an unclassifiable clinical presentation, including 110 (89%) with a typical CIDP-like clinical phenotype in whom some segments of the four limbs were unaffected by weakness (‘incomplete typical CIDP’), 10 (8%) with a mild distal, symmetric, sensory or sensorimotor polyneuropathy confined to the lower limbs with cranial nerve involvement (‘cranial nerve predominant CIDP’) and 4 (1%) with a symmetric sensorimotor polyneuropathy limited to the proximal and distal areas of the lower limbs (‘paraparetic CIDP’). Eighty-one (65%) patients maintained an unclassifiable presentation during the entire disease follow-up while 13 patients progressed to typical CIDP. Patients with the unclassifiable clinical forms compared with patients with typical CIDP had a milder form of CIDP, while there was no difference in the distribution patterns of demyelination.ConclusionsA proportion of patients with CIDP do not strictly fulfil the 2021 EAN/PNS clinical criteria for diagnosis. These unclassifiable clinical phenotypes may pose diagnostic challenges and thus deserve more attention in clinical practice and research.

INTRODUCTION: Chemotherapy-induced peripheral neurotoxicity (CIPN) remains a significant toxicity in cancer survivors without preventative strategies or rehabilitation. Exercise and physical activity-based interventions have demonstrated promise in reducing existing CIPN symptoms and potentially preventing toxicity, however there is a significant gap in evidence due to the lack of quality clinical trials and appropriate outcome measures. AREAS COVERED: The authors systematically reviewed outcome measures in CIPN exercise and physical rehabilitation studies with expert panel consensus via the Peripheral Nerve Society Toxic Neuropathy Consortium to provide recommendations for future trials. Across 26 studies, 75 outcome measures were identified and grouped into 16 domains within three core areas - measures of manifestations of CIPN (e.g. symptoms/signs), measures of the impact of CIPN and other outcome measures. EXPERT OPINION: This article provides a conceptual framework for CIPN outcome measures and highlights the need for definition of a core outcome measures set. The authors provide recommendations for CIPN exercise and physical rehabilitation trial design and outcome measure selection. The development of a core outcome measure set will be critical in the search for neuroprotective and treatment approaches to support cancer survivors and to address the significant gap in the identification of effective rehabilitation and treatment options for CIPN.

Thanks to advances in gene sequencing, RYR1-related myopathy (RYR1-RM) is now known to manifest itself in vastly heterogeneous forms, whose clinical interpretation is, therefore, highly challenging. We set out to develop a novel unsupervised cluster analysis method in a large patient population. The objective was to analyze the main RYR1-related characteristics to identify distinctive features of RYR1-RM and, thus, offer more precise genotype–phenotype correlations in a group of potentially life-threatening disorders. We studied 600 patients presenting with a suspicion of inherited myopathy, who were investigated using next-generation sequencing. Among them, 73 index cases harbored variants in RYR1. In an attempt to group genetic variants and fully exploit information derived from genetic, morphological, and clinical datasets, we performed unsupervised cluster analysis in 64 probands carrying monoallelic variants. Most of the 73 patients with positive molecular diagnoses were clinically asymptomatic or pauci-symptomatic. Multimodal integration of clinical and histological data, performed using a non-metric multi-dimensional scaling analysis with k-means clustering, grouped the 64 patients into 4 clusters with distinctive patterns of clinical and morphological findings. In addressing the need for more specific genotype–phenotype correlations, we found clustering to overcome the limits of the “single-dimension” paradigm traditionally used to describe genotype–phenotype relationships.

Fatigue, a disabling symptom in many neuromuscular disorders, has been reported also in Charcot-Marie-Tooth disease (CMT). The presence of fatigue and its correlations in CMT was investigated.The Modified Fatigue Impact Scale (MFIS) was administered to CMT patients from the Italian Registry and a control group. An MFIS score38 indicated abnormal fatigue. The correlation with disease severity and clinical characteristics, the Hospital Anxiety and Depression Scale and Epworth Sleepiness Scale scores, and drug use was analysed.Data were collected from 251 CMT patients (136 women) and 57 controls. MFIS total (mean ± standard deviation 32 ± 18.3, median 33), physical (18.9 ± 9.7, 20) and psychosocial (2.9 ± 2.4, 3) scores in CMT patients were significantly higher than controls. Abnormal fatigue occurred in 36% of the patients who, compared to patients with normal scores, had more severe disease (median CMT Examination Score 9 vs. 7), more frequent use of foot orthotics (22% vs. 11%), need of support for walking (21% vs. 8%), hand disability (70% vs. 52%) and positive sensory symptoms (56% vs. 36%). Patients with abnormal fatigue had significantly increased frequency of anxiety/depression/general distress (Hospital Anxiety and Depression Scale), somnolence (Epworth Sleepiness Scale), obesity (body mass index ≥ 30) and use of anxiolytic/antidepressant or anti-inflammatory/analgesic drugs.Fatigue is a relevant symptom in CMT as 36% of our series had scores indicating abnormal fatigue. It correlated with disease severity but also with anxiety, depression, sleepiness and obesity, indicating different components in the generation of fatigue. CMT patients' management must include treatment of fatigue and of its different generators, including general distress, sleepiness and obesity.

Charcot-Marie-Tooth (CMT) disease is the most common hereditary neuropathy with an estimated prevalence of 1 person affected on 2500. Frequent symptoms include distal weakness and muscle wasting, sensory loss, reduced deep tendon reflexes, and skeletal deformities, such as hammer toes and pes cavus. CMT is a progressive disease and patients’ needs change over their lifetime. In particular, ambulation aids are increasingly needed to maintain ambulation and reduce the risk of falls. We performed a retrospective analysis of medical records from 149 patients with confirmed CMT to evaluate patients ambulation needs related to the severity of their CMT as measured by the CMT Neuropathy Score (CMTNS) and Ambulation Index (AI). Most patients required some form of orthotics (86.6%). The CMTNS and AI scores both differed significantly between patients with no orthotics compared to those who wore insoles/inserts. The CMTNS and AI also differed significantly between patients wearing insoles and those with ankle foot orthotics (AFOs). CMTNS and the AI were valid predictors of the type and choice of the orthotics. Both the CMTNS and AI can be effective tools to aid in the correct choice of orthotics in patients affected by CMT.

Charcot-Marie-Tooth (CMT) patients present mainly lower limbs disability, with slowly progressive distal muscle weakness and atrophy, but hands impairment is a relevant problem affecting the quality of life (QoL). The evaluation of the upper limb is of primary importance. Often these patients present subclinical disorders or report difficulties in manipulating objects, with little evidence in the most used outcome measures. We aim to investigate the impact of hand impairment in the perceived QoL of CMT persons and secondly whether the Disability of Arm, Shoulder and Hand (DASH) scale can be useful in assessing upper limb abilities in CMT. We recruited 23 patients with confirmed genetic diagnosis of CMT. We performed a clinical evaluation with Sollerman Hand Function Test (SHFT), Thumb Opposition Test (TOT) and CMT examination score (CMTES). We completed the clinical assessment with DASH scale and the Short form 36 (SF36) questionnaire for a subjective evaluation of upper limb disability and quality of life. All patients also underwent an instrumental evaluation with a hand-held dynamometer measuring hand grip and tripod pinch and a sensor-engineered glove test (SEGT) to evaluate finger opposition movements in a quantitative spatial-temporal way. As expected, we found significant differences between CMT and control group performances in both clinical and instrumental assessment. Concerning QoL, we found that total score of SF36 and the SF36 Physical Composite Score (PCS) correlate with all clinical and instrumental Outcome Measures (OMs), particularly with Tripod pinch strength and TOT, which are considered major determinants of manual dexterity in CMT. DASH scale correlates with most clinical and instrumental OMs. Not surprisingly, we also found a correlation with DASH work, because CMT affects young patients engaged in work activities. However, we found a low correlation with the TOT and the dynamometer suggesting that DASH may not be the best scale for remote monitoring of upper limb disorders in CMT patients. Nevertheless, the results of our study confirm the usefulness of SF36 in recognizing the impact of upper limb disability in these subjects suggesting its use even in the remote monitoring of physical functioning.

Pure/predominant upper motor neuron (pUMN) and lower motor neuron (pLMN) diseases have significantly better prognosis compared to amyotrophic lateral sclerosis (ALS), but their early differentiation is often challenging. We therefore tested whether a multimodal characterization approach embedding clinical, cognitive/behavioral, genetic, and neurophysiological data may improve the differentiation of pUMN and pLMN from ALS already by the time of diagnosis. Dunn’s and chi-squared tests were used to compare data from 41 ALS, 34 pLMN, and 19 pUMN cases with diagnoses confirmed throughout a 2-year observation period. Area under the curve (AUC) analyses were implemented to identify the finest tools for phenotypes discrimination. Relative to ALS, pLMN showed greater lower limbs weakness, lower UMN burden, and progression rate (p < 0.001–0.04). PUMN showed a greater frequency of lower limbs onset, higher UMN burden, lower ALSFRS-r and MRC progression rates (p < 0.001–0.03), and greater ulnar compound muscle action potential (CMAP) amplitude and tibial central motor conduction time (CMCT) (p = 0.05–0.03). The UMN progression rate was the finest measure to identify pLMN cases (AUC = 90%), while the MRC progression rate was the finest tool to identify pUMN (AUC = 82%). Detailed clinical and neurophysiological examinations may significantly improve MNDs differentiation, facilitating prognosis estimation and ameliorating stratification strategies for clinical trials enrollment.

SPTLC1-related disorder is a late onset sensory-autonomic neuropathy associated with perturbed sphingolipid homeostasis which can be improved by supplementation with the serine palmitoyl-CoA transferase (SPT) substrate, l-serine. Recently, a juvenile form of motor neuron disease has been linked to SPTLC1 variants. Variants affecting the p.S331 residue of SPTLC1 cause a distinct phenotype, whose pathogenic basis has not been established. This study aims to define the neuropathological and biochemical consequences of the SPTLC1 p.S331 variant, and test response to l-serine in this specific genotype.We report clinical and neurophysiological characterisation of two unrelated children carrying distinct p.S331 SPTLC1 variants. The neuropathology was investigated by analysis of sural nerve and skin innervation. To clarify the biochemical consequences of the p.S331 variant, we performed sphingolipidomic profiling of serum and skin fibroblasts. We also tested the effect of l-serine supplementation in skin fibroblasts of patients with p.S331 mutations.In both patients, we recognised an early onset phenotype with prevalent progressive motor neuron disease. Neuropathology showed severe damage to the sensory and autonomic systems. Sphingolipidomic analysis showed the coexistence of neurotoxic deoxy-sphingolipids with an excess of canonical products of the SPT enzyme. l-serine supplementation in patient fibroblasts reduced production of toxic 1-deoxysphingolipids but further increased the overproduction of sphingolipids.Our findings suggest that p.S331 SPTLC1 variants lead to an overlap phenotype combining features of sensory and motor neuropathies, thus proposing a continuum in the spectrum of SPTLC1-related disorders. l-serine supplementation in these patients may be detrimental.

Introduction Electrophysiological diagnosis of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) may be challenging. Thus, with the aim ofproviding some practical advice in electrophysiological approach to a patient with suspected CIDP, we analyzed electrophysiological data from 499 patients enrolled inthe Italian CIDP Database. Methods We calculated the rate of each demyelinating feature, the rate of demyelinating features per nerve, the diagnostic rate for upper andlower limb nerves, and, using a ROC curve analysis, the diagnostic accuracy of each couple of nerves and each demyelinating feature, for every CIDP subtype.Moreover, we compared the electrophysiological data of definite and probable CIDP patients with those of possible and not-fulfilling CIDP patients, and by a logisticregression analysis, we estimated the odds ratio (OR) to make an electrophysiological diagnosis of definite or probable CIDP. Results The ulnar nerve had the highestrate of demyelinating features and, when tested bilaterally, had the highest diagnostic accuracy except for DADS in which peroneal nerves were the most informative.In possible and not-fulfilling CIDP patients, a lower number of nerves and proximal temporal dispersion (TD) measurements had been performed compared to definiteand probable CIDP patients. Importantly, OR for each tested motor nerve and each TD measurement was 1.59 and 1.33, respectively. Conclusion Our findingsdemonstrated that the diagnosis of CIDP may be missed due to inadequate or incomplete electrophysiological examination or interpretation. At the same time, thesedata taken together could be useful to draw a thoughtful electrophysiological approach to patients suspected of CIDP.

After extensive evaluation, one-third of patients affected by polyneuropathy remain undiagnosed and are labelled as having chronic idiopathic axonal polyneuropathy, which refers to a sensory or sensory-motor, axonal, slowly progressive neuropathy of unknown origin. Since a sensory neuropathy/neuronopathy is identified in all patients with genetically confirmed RFC1 cerebellar ataxia, neuropathy, vestibular areflexia syndrome, we speculated that RFC1 expansions could underlie a fraction of idiopathic sensory neuropathies also diagnosed as chronic idiopathic axonal polyneuropathy. We retrospectively identified 225 patients diagnosed with chronic idiopathic axonal polyneuropathy (125 sensory neuropathy, 100 sensory-motor neuropathy) from our general neuropathy clinics in Italy and the UK. All patients underwent full neurological evaluation and a blood sample was collected for RFC1 testing. Biallelic RFC1 expansions were identified in 43 patients (34%) with sensory neuropathy and in none with sensory-motor neuropathy. Forty-two per cent of RFC1-positive patients had isolated sensory neuropathy or sensory neuropathy with chronic cough, while vestibular and/or cerebellar involvement, often subclinical, were identified at examination in 58%. Although the sensory ganglia are the primary pathological target of the disease, the sensory impairment was typically worse distally and symmetric, while gait and limb ataxia were absent in two-thirds of the cases. Sensory amplitudes were either globally absent (26%) or reduced in a length-dependent (30%) or non-length dependent pattern (44%). A quarter of RFC1-positive patients had previously received an alternative diagnosis, including Sjögren’s syndrome, sensory chronic inflammatory demyelinating polyneuropathy and paraneoplastic neuropathy, while three cases had been treated with immune therapies., Currò et al. investigate the prevalence of RFC1 expansions in a cohort of patients with chronic idiopathic axonal polyneuropathy. RFC1 expansions were found in 34% of patients with sensory neuropathy, but in none with sensory-motor neuropathy. Clinical features and diagnostic clues that should lead to suspicion of RFC1 neuropathy are discussed.

Guillain–Barré syndrome (GBS) is an autoimmune neurological disorder often preceded by viral illnesses or, more rarely, vaccinations. We report on a unique combination of postcoronavirus disease 2019 (COVID-19) vaccine GBS that occurred months after a parainfectious COVID-19–related GBS. Shortly after manifesting COVID-19 symptoms, a 57-year-old man developed diplopia, right-side facial weakness, and gait instability that, together with electrophysiology and cerebrospinal fluid examinations, led to a diagnosis of post-COVID-19 GBS. The involvement of cranial nerves and IgM seropositivity for ganglioside GD1b were noteworthy. COVID-19 pneumonia, flaccid tetraparesis, and autonomic dysfunction prompted his admission to ICU. He recovered after therapy with intravenous immunoglobulins (IVIg). Six months later, GBS recurred shortly after the first dose of the Pfizer/BioNTech vaccine. Again, the GBS diagnosis was confirmed by cerebrospinal fluid and electrophysiology studies. IgM seropositivity extended to multiple gangliosides, namely for GM3/4, GD1a/b, and GT1b IgM. An IVIg course prompted complete recovery. This case adds to other previously reported observations suggesting a possible causal link between SARS-CoV-2 and GBS. Molecular mimicry and anti-idiotype antibodies might be the underlying mechanisms. Future COVID-19 vaccinations/revaccinations in patients with previous para-/post-COVID-19 GBS deserve a reappraisal, especially if they are seropositive for ganglioside antibodies.

Background There is little information about neuropsychiatric comorbidities in Charcot-Marie-Tooth disease (CMT). We assessed frequency of anxiety, depression, and general distress in CMT. Methods We administered online the Hospital Anxiety-Depression Scale (HADS) to CMT patients of the Italian registry and controls. HADS-A and HADS-D scores ≥ 11 defined the presence of anxiety/depression and HADS total score (HADS-T) ≥ 22 of general distress. We analysed correlation with disease severity and clinical characteristics, use of anxiolytics/antidepressants and analgesic/anti-inflammatory drugs. Results We collected data from 252 CMT patients (137 females) and 56 controls. CMT patient scores for anxiety (mean ± standard deviation, 6.7 ± 4.8), depression (4.5 ± 4.0), and general distress (11.5 ± 8.1) did not differ from controls and the Italian population. However, compared to controls, the percentages of subjects with depression (10% vs 2%) and general distress (14% vs 4%) were significantly higher in CMT patients. We found no association between HADS scores and disease duration or CMT type. Patients with general distress showed more severe disease and higher rate of positive sensory symptoms. Depressed patients also had more severe disease. Nineteen percent of CMT patients took antidepressants/anxiolytics (12% daily) and 70% analgesic/anti-inflammatory drugs. Patients with anxiety, depression, and distress reported higher consumption of anxiolytics/antidepressants. About 50% of patients with depression and/or general distress did not receive any specific pharmacological treatment. Conclusions An appreciable proportion of CMT patients shows general distress and depression. Both correlated with disease severity and consumption of antidepressants/anxiolytics, suggesting that the disease itself is contributing to general distress and depression.

Symptoms referable to central and peripheral nervous system involvement are often evident both during the acute phase of COVID-19 infection and during long-COVID. In this study, we evaluated a population of patients with prior COVID-19 infection who showed signs and symptoms consistent with neurological long-COVID.We prospectively collected demographic and acute phase course data from patients with prior COVID-19 infection who showed symptoms related to neurological involvement in the long-COVID phase. Firstly, we performed a multivariate logistic linear regression analysis to investigate the impact of demographic and clinical data, the severity of the acute COVID-19 infection and hospitalization course, on the post-COVID neurological symptoms at three months follow-up. Secondly, we performed an unsupervised clustering analysis to investigate whether there was evidence of different subtypes of neurological long COVID-19.One hundred and nine patients referred to the neurological post-COVID outpatient clinic. Clustering analysis on the most common neurological symptoms returned two well-separated and well-balanced clusters: long-COVID type 1 contains the subjects with memory disturbances, psychological impairment, headache, anosmia and ageusia, while long-COVID type 2 contains all the subjects with reported symptoms related to PNS involvement. The analysis of potential risk-factors among the demographic, clinical presentation, COVID 19 severity and hospitalization course variables showed that the number of comorbidities at onset, the BMI, the number of COVID-19 symptoms, the number of non-neurological complications and a more severe course of the acute infection were all, on average, higher for the cluster of subjects with reported symptoms related to PNS involvement.We analyzed the characteristics of neurological long-COVID and presented a method to identify well-defined patient groups with distinct symptoms and risk factors. The proposed method could potentially enable treatment deployment by identifying the optimal interventions and services for well-defined patient groups, so alleviating long-COVID and easing recovery.

AIMS: The musician’s hand represents a complex system, which requires important motor skills. Although several studies have already investigated rehabilitation outcomes and techniques in musicians after hand lesions, none have been addressed specifically to objectively quantifiable functional parameters. The purpose of our study was to study hand functionality in violinists in order to provide foundations on which to establish and develop more appropriate rehabilitation protocols. STUDY DESIGN: An observational cross-sectional cohort study consisting of 34 subjects, including 23 students and 11 professional violinists who were either studying or working at a conservatory. Results were compared to a data set of a non-musician control group. METHODS: Nine-hole peg test and hand test system (HTS) were used to perform the study. A hand-held dynamometer was used to measure hand grip and tripod pinch maximal isometric voluntary contraction of both hands. RESULTS: Hand strength did not significantly differ on either side between professional and student violinists. A significant difference was seen when comparing violinists as a whole versus the non-musician control group. HTS highlighted significant differences in dexterity. CONCLUSION: Violinists develop better overall motor performances of the left hand, and their performance is better than normal “non-musician” controls. Dexterity and precision of execution positively correlate to years of practice. We conclude that rehabilitation of a violinist’s hand should be aimed at enhancing motor performance of the left hand and should be focused to maximize dexterity of both hands.

Introduction In the last years, many new drugs have been developed targeting different oncology pathways, overall improving both quality of life and survival in several malignancies. However, the increase of those therapies is associated with novel toxicities, mainly immune-related adverse events (irAEs), never observed before. Different irAEs are now well characterized, and, among them, neuromuscular complications, following immune checkpoint inhibitor (ICPi) therapy, are increasingly studied and described. However, there are also neurological complications related to the use of other targeted therapies, less known and probably underestimated. Herein we describe two oncological patients who developed neuromuscular diseases after administration of targeted therapies, different from ICPi. Case reports The first patient was treated with the combination of Vemurafenib and Cobimetinib, BRAF and MEK inhibitors, respectively, for a cutaneous melanoma. One year after the beginning of the combined treatment, she developed a sub-acute motor neuropathy with predominant cranial nerve involvement. She was successfully treated with methylprednisolone. The second patient received therapy with Imatinib, tyrosine kinase inhibitor and precursor of the targeted therapy, for a gastrointestinal stromal tumour. Few days after the first administration, he developed generalized myasthenia gravis with respiratory failure. Clinical remission was obtained with plasma-exchange, intravenous immunoglobulins and steroids. Discussion and Conclusion We strengthen the relevance of neuromuscular complications which may occur long after treatment start or in patients receiving not only the latest ICPi but also “older” and apparently better-known targeted therapies. Also in the latter cases, an immune-mediated “off-target” pathogenic mechanism can be hypothesized, and consequences can be life threatening, if not promptly diagnosed and appropriately managed.

This prospective, multicenter, single‐arm, open‐label phase 3 study aimed to evaluate the efficacy and safety of IqYmune in patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Patients received one induction dose of 2 g/kg and then seven maintenance doses of 1 g/kg at 3‐week intervals. The primary endpoint was the responder rate at the end of study (EOS), defined as an improvement of ≥1 point on the adjusted inflammatory neuropathy cause and treatment (INCAT) disability scale. The responder rate was compared with the responder rate of a historical placebo group (33.3%). Secondary endpoints included changes from baseline to EOS of adjusted INCAT disability score, grip strength, Medical Research Council (MRC) sum score, Rasch‐modified MRC sum score, Rasch‐built overall disability scale score and the clinical global impression. Forty‐two patients, including 23 Ig‐naïve and 19 Ig‐pre‐treated, were included in the efficacy set. The overall response rate at EOS was 76.2% (95% confidence interval [60.5%‐87.9%]). The superiority of IqYmune compared to the historical placebo control was demonstrated (P

Background The immunotherapy strategy for autoimmune encephalitis is based on several types and schedules of both first- and second-line drugs. Failing to respond to the latter prompts the use of non-conventional rescue therapies, with higher risks of severe adverse effects. We report on a protocol that entails the use of intravenous immunoglobulin cycles to bridge the 4-month period that the second-line drug rituximab needs to exert its full therapeutic effects. Methods Three patients with NMDAR encephalitis who were non-responders to first-line treatments entered the study. The protocol consisted of six monthly cycles of intravenous immunoglobulins (IVIG, 0.4 mg/kg/die for 5 days), starting 1 month after the last rituximab infusion (1000 mg at days 0 and 15). Brain MRI and [18F]-FDG-PET were performed at onset and at six and 18 months after onset. Results In the three patients, substantial improvements of disability or complete recovery were achieved, without modifications over the 30-to-50-month follow-up. No adverse events nor laboratory test abnormalities were recorded. Imaging findings paralleled the favorable disease courses. Brain [18F]-FDG-PET was more sensitive than MRI in detecting abnormalities. Discussion Our observations suggest that the herein-described protocol might be used in patients with NMDAR encephalitis at risk for poor prognosis in the mid-term when they need to shift to rituximab. [18F]-FDG-PET confirmed to be a sensitive tool to detect the minimal brain lesions that can underlie isolated cognitive and psychiatric symptoms.

ObjectivesTo compare the sensitivity and specificity of the 2021 European Academy of Neurology/Peripheral Nerve Society (EAN/PNS) diagnostic criteria for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) with those of the 2010 European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS).MethodsSensitivity and specificity of the two sets of criteria were evaluated in 330 patients with CIDP and 166 axonal peripheral neuropathy controls. Comparison of the utility of nerve conduction studies with different number of nerves examined and of the sensitivity and specificity of the two criteria in typical CIDP and its variants were assessed.ResultsEFNS/PNS criteria had a sensitivity of 92% for possible CIDP and 85% for probable/definite CIDP, while the EAN/PNS criteria had a sensitivity of 83% for possible CIDP and 74% for CIDP. Using supportive criteria, the sensitivity of the EAN/PNS criteria for possible CIDP increased to 85% and that of CIDP to 77%, remaining lower than that of the EFNS/PNS criteria. Specificity of the EFNS/PNS criteria was 68% for possible CIDP and 84% for probable/definite CIDP, while the EAN/PNS criteria had a specificity of 88% for possible CIDP and 98% for CIDP. More extended studies increased the sensitivity of both sets of criteria by 4%–7% but reduced their specificity by 2%–3%. The EFNS/PNS criteria were more sensitive for the diagnosis of typical CIDP while the EAN/PNS criteria were more specific for the diagnosis of distal and sensory CIDP.ConclusionsIn our population, the EAN/PNS criteria were more specific but less sensitive than the EFNS/PNS criteria. With the EAN/PNS criteria, more extended nerve conduction studies are recommended to obtain an acceptable sensitivity while maintaining a high specificity.

INTRODUCTION/AIMS: Currently, there are no straightforward guidelines for the clinical and diagnostic management of hyperCKemia, a frequent and nonspecific presentation in muscle diseases. Therefore, we aimed to describe our diagnostic workflow for evaluating patients with this condition. METHODS: We selected 83 asymptomatic or minimally symptomatic patients with persistent hyperCKemia for participation in this Italian multicenter study. Patients with facial involvement and distal or congenital myopathies were excluded, as were patients with suspected inflammatory myopathies or predominant respiratory or cardiac involvement. All patients underwent a neurological examination and nerve conduction and electromyography studies. The first step of the investigation included a screening for Pompe disease. We then evaluated the patients for myotonic dystrophy type II-related CCTG expansion and excluded patients with copy number variations in the DMD gene. Subsequently, the undiagnosed patients were investigated using a target gene panel that included 20 genes associated with isolated hyperCKemia. RESULTS: Using this approach, we established a definitive diagnosis in one third of the patients. The detection rate was higher in patients with severe hyperCKemia and abnormal electromyographic findings. DISCUSSION: We have described our diagnostic workflow for isolated hyperCKemia, which is based on electrodiagnostic data, biochemical screening, and first-line genetic investigations, followed by successive targeted sequencing panels. Both clinical signs and electromyographic abnormalities are associated with increased diagnostic yields. This article is protected by copyright. All rights reserved.

Pharmacological strategies for chemotherapy-induced peripheral neurotoxicity (CIPN) are very limited. We systematically reviewed data on rehabilitation, exercise, physical therapy, and other physical non-pharmacological interventions and offered evidence-based recommendations for the prevention and treatment of CIPN. A literature search using PubMed, Web of Science and CINAHL was conducted from database inception until May 31st, 2021. 2791 records were title-abstract screened, 71 papers were full-text screened, 41 studies were included, 21 on prevention and 20 on treatment of CIPN. Treatment type, cancer type, chemotherapy compounds were heterogeneous, sample size was small (median: N = 34) and intention-to-treat analysis was lacking in 26/41 reports. Because of the methodological issues of included studies, the reviewed evidence should be considered as preliminary. Exercise, endurance, strength, balance, and sensorimotor training have been studied in low-to-moderate quality studies, while the evidence for other treatments is preliminary/inconclusive. We offer recommendation for the design of future trials on CIPN.

Guillain-Barré-Syndrome (GBS) can follow COVID-19 vaccination, with clinical and paraclinical features still to be precisely assessed. We describe a cohort of patients who developed GBS after vaccination with different types of COVID-19 vaccines.Patients with post-COVID-19 vaccination GBS, admitted to the six hospitals that cover the whole Liguria Region, Northwestern Italy, from February 1st to October 30th 2021, were included. Clinical, demographic, and paraclinical data were retrospectively collected.Among the 13 patients with post-COVID-19 vaccination GBS (9 males; mean age, 64 year), 5 were vaccinated with Oxford-AstraZeneca, 7 with Pfizer-BioNTech, and one with Moderna. Mean time between vaccination and GBS onset was 11.5 days. Ten patients developed GBS after the first vaccination dose, 3 after the second dose. Acute inflammatory demyelinating polyradiculoneuropathy (AIDP) was the predominant GBS variant, mainly characterized by sensory involvement. Bilateral seventh cranial nerve involvement followed AstraZeneca vaccination in two cases. Three patients presented treatment-related fluctuations, and 4 mild symptoms that delayed treatments and negatively affected prognosis. Prognosis was poor (GBS-disability score, ≥3) in 5/13 patients, with a disability rate of 3/13.Our findings confirm that most post-COVID-19 vaccination GBS belong to the AIDP subtype, and occur after the first vaccine dose. Treatment-related fluctuations, and diagnosis-delaying, mild symptoms at onset are clinical features that affect prognosis and deserve particular consideration.

Fabry disease (FD) is a systemic X-linked lysosomal disorder. A ‘peripheral nerve variant’ of FD has been hypothesized in subjects with neuropathy, without the early manifestations of the classic phenotype. A cohort of undiagnosed neuropathy patients with chronic polyneuropathy of undetermined aetiology and demyelinating neuropathy, unresponsive to immunomodulating treatment, were screened for FD. A total of 103 patients (64% males), were enrolled. No typical pathogenetic mutations for FD were identified. We are aware that the study sample was very small, but only a large, unfeasible theoretical sample size could demonstrate a statistically significant increased prevalence of FD in neuropathy patients, as peripheral neuropathy of undetermined cause is uncommon and there is a low prevalence of FD in the general population. Therefore, we are of the opinion that including tailored FD screening in the neuropathy diagnostic work-up, particularly when there are additional clinical characteristics, should be considered.

Guillain-Barre syndrome (GBS) is often associated with a residual disability. Nonetheless, poor and incomplete studies have been published addressed towards the assessment of importance of physiotherapy (FKT) in the recovery. The aim of the study was to explore the effects of prolonged FKT associated with medical therapy and to evaluate the long-term outcome. A retrospective analysis was carried out on patients with GBS who needed to continue rehabilitation after hospitalization and admitted to the Neurological Department of La Spezia from 2003 to 2017. MRC and GBS-Disability scale (GBS-DS) were performed at the time of greatest clinical disability, after medical therapy, and at the end of the overall FKT. The final outcome evaluation was based on the ability to walk with or without support. ANOVA with Bonferroni post-test were used to compare MRC and GBS-DS. Ninety-six patients were admitted, but only 51 satisfied inclusion criteria. Forty patients performed intensive treatment for an average of 60.95 days, and 31 of them, once discharged, are required to continue FKT as outpatients for a mean period of 96.45 days. The mean value of MRC and GBS-DS post-FKT improved significantly compared with the post-medical therapy. Concerning walking, among the 40 patients who did not walk before therapy, 8 need support after the medical therapy and 4 (11.76%) cannot walk independently at the last follow-up. In conclusion, FKT associated to medical therapy can improve the outcome of the disease, if performed for periods exceeding 6 months.

Objective: In July 2017 a multidisciplinary clinical Center specialized in rare diseases was activated. A rare disease can involve the musculoskeletal system. A multimodality musculoskeletal imaging approach allows for a rapid diagnosis. The purpose of this study was to assess when musculoskeletal radiology, ultrasound in particular, plays a primary role in the diagnostic path of a rare disease. Methods and materials: The Center included a list of 621 main rare diseases. Pathologies in which radiology has a primary diagnostic role were extracted from the list. From September 2017 to January 2018 all conditions involving the musculoskeletal system, including the peripheral nervous system, were systematically evaluated by one radiologist. The second radiologist, an official consultant of the Center, verified the list for consistency. Descriptive analysis was performed. Results: A total of 101/621 (16%) rare diseases can be diagnosed for the first time in the diagnostic path of the patient with medical imaging. A total of 36/101 (36%) rare diseases involve the musculoskeletal system. A total of 14/36 (39%) are pediatric diseases, 10/36 (28%) are adult age diseases, while 12/36 (33%) diseases affect all ages. A total of 23/36 (64%) of the selected rare diseases could be diagnosed with MRI, 19/36 (53%) with CT, 23/36 (64%) with X-ray, 9/36 (25%) with an US, and 1/36 (3%) with PET. Conclusions: Musculoskeletal imaging could be important for a non-invasive diagnosis in up to 36/101 (36%) rare diseases, as well as for outcome prediction, especially in pediatrics. Musculoskeletal imaging plays a crucial role in the diagnosis of rare diseases and could strongly influence the clinical pathway. Ultrasound is crucial in up to 25% of patients with rare diseases affecting the musculoskeletal system.

Background Cortical activity connected to movements has been investigated long since, and is related, among other factors, to saliency of the gesture. However, experiments performed on movements in actual situations are rare, as most of them have been performed in laboratory simulations. Besides, no research seems to have been carried out on subjects during freehand drawing. New method We propose a method based upon a commercial drawing tablet and wireless pen, that has been synchronized with EEG recording by means of a piezoelectric sensor attached to the pen tip. Complete freedom of movement is allowed, and any kind of drawing style can be performed using currently available graphics software. Results EEG recordings during meaningful drawing were compared with recordings where the pen was tapped and shifted on tablet without specific purpose. With reference to T0 event (pen touching tablet), several components could be observed in pre- and post-T0 epochs. The most important appeared to be a triphasic wave (N-150, P-40 and N + 30), where P-40 showed a striking difference between drawing and tap session, being much larger in the former. Comparison with existing methods Onset of muscle EMG is usually employed for synchronization. In complex and free gestures too many muscles are active to allow reliable identification of such reference. Our method provides a precise trigger event easily detected without movement constraints. Conclusions With this method it will be possible to record EEG activity related to creative aspects of drawing and explore other skilled movements.

Treatment related fluctuations (TRFs) in Guillain-Barre Syndrome (GBS) are described as one or more episodes of deterioration manifesting within two months after disease onset and following an initial improvement or stabilisation after treatment. They may be encountered in 8% to 16% of patients, but currently predictive factors of TRF occurrence and severity are poorly known. To this end, we evaluated the frequency and clinical features of TRFs in a cohort of GBS patients admitted to the Neurological unit of Sant'Andrea Hospital (La Spezia, Italy) from January 1st, 2003 to December 31st, 2017. Among the 98 GBS collected patients, five (5.1%) developed a TRF during disease course. Consistently with the literature, the majority of our GBS patients who developed a TRF did not report a preceding diarrhoea, had a predominant proximal weakness and all of them had sensory disturbances at the clinical onset. Interestingly, 80% of our TRF patients manifested since GBS onset an autonomic dysfunction with abnormal sweating and a peculiar 'skin flushing' in face, neck and chest. Two patients developed respiratory insufficiency at the TRF time, and they both died. We would advise to pay attention to GBS patients with particular 'skin flushing' in face, neck and chest and abnormal sweating, because these findings could be a red flag for TRF.

ObjectiveTo validate sphingomyelin (SM) dosage in the cerebrospinal fluid (CSF) of patients affected by chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and Guillain-Barré syndrome (GBS) as a reliably assessable biomarker.MethodsWe prospectively enrolled 184 patients from six Italian referral centres, in whom CSF SM levels were quantified by a fluorescence-based assay optimised and patented in our laboratory.ResultsWe confirmed increased levels of SM in the CSF of patients affected by typical CIDP (n=35), atypical CIDP (n=18) and acute inflammatory demyelinating polyradiculoneuropathy, AIDP (n=12) compared with patients affected by non-demyelinating neurological diseases, used as controls (n=85) (p=0.0065 and pConclusionsCSF SM is a diagnostic and staging wet biomarker for acquired demyelinating neuropathies and may effectively improve the management of patients affected by GBS and CIDP.

Journal of the peripheral nervous system : JPNS 26(S2), 3-10 (2021). doi:10.1111/jns.12468 special issue: "Special Issue:Images from the Nerve: An Atlas for Neurologists", Published by Wiley-Blackwell, Oxford [u.a.]

The Internet of Things (IoT) framework is moving the research community to provide smart systems and solutions aimed at revolutionizing medical sciences and healthcare. Given the extreme diffusion of Alzheimer’s disease (AD) and Parkinson’s disease (PD), the demand for a solution to early detect neurological symptoms of such diseases strongly arose. According to the medical literature, such early detection can be obtained through the correlation between PD and AD and some external symptoms: the Essential Tremor (ET) and the number of Eye Blinks (EBs). In this paper, which can be considered as an extended version of [1], we present a prototype of wearable smart glasses able to detect the presence of ET of the head and to count the number of EBs at the same time, in a transparent way with respect to the final user. Numerical results demonstrate the reliability of the proposed approach: the proposed algorithms are able to i) correctly recognize the ET with an overall accuracy above 97% and ii) count the number of EBs with an overall error around 9%.

Reduced incidence of stroke during COVID-19 pandemic was sometimes reported. While decrease in stroke incidence and fear of patients to go to the hospitals were sometimes invoked to explain this decrease, reduction in urban pollution was also hypothesized as a possible cause. We investigated statistically the incidence of ischemic and hemorrhagic stroke, and of transient ischemic attacks, at a large Italian tertiary stroke center during the pandemic. We analyzed statistically the number of transient ischemic attacks (TIA), ischemic strokes (IS) and hemorrhagic strokes (HS) between March 8 and May 2, 2020, the peak of the COVID-19 epidemic in Italy, and compared them with the identical period of 2019. We also analyzed the concentration of small particulate matter (PM10) in 2019 and 2020, to see if it could account for modified incidence of strokes or TIA. We found a large, significant drop in TIA (− 51%) during the pandemic compared to the same period of 2019. By contrast, the number of HS was identical, and IS showed a not significant − 24% decrease. PM10 concentration, already low in 2019, did not further decrease in 2020. Patients kept seeking hospital care when experiencing permanent neurological symptoms (stroke), but they tended not go to the hospital when their symptoms were transient (TIA). The fact that we did not observe a significant decrease in strokes may be explained by the fact that in our city the concentration of small particulate matter did not change compared to 2019.

We describe the clinical response to long-term subcutaneous immunoglobulins (SCIg) in anti-3‑hydroxy-3-methyl-glutaryl-coenzyme-A-reductase (anti-HMCGR) myopathy previously treated with intravenous immunoglobulins (IVIg). We collected data from patients affected by anti-HMGCR myopathy, switched from IVIg to SCIg therapy, after achieving clinical stabilization. The Medical Research Council sum score, creatine kinase (CK) levels, and anti-HMGCR antibodies were used to assess the response. We identified three patients with anti-HMGCR myopathy treated with SCIg with a favourable clinical course, allowing the maintenance of clinical stability, the reduction or suspension of steroids therapy and in two of them a complete CK normalization. Finally, anti-HMGCR antibodies tested in all patients after 12 months from SCIg starting, showed a global decrease. SCIg represent an useful alternative to long-term IVIg as already well known in several autoimmune neuromuscular disorders and inflammatory myopathies with advantages of lower side effects and home self-administration.

Introduction Factors influencing self-perceived health status over Corona Virus Disease 2019 (COVID-19) emergency in vulnerable populations, such as patients with chronic neurological diseases, are still unknown. In this work, we aimed at testing whether clinical care changes imposed by the quarantine, together with certain demographic and disease-specific features, might have determined a self-perceived worsening of health status in patients with amyotrophic lateral sclerosis (ALS). Methods A brief web-based questionnaire investigating self-perceived anxiety, depression, and motor worsening, as well as clinical care changes over COVID-19 emergency, was administered to ALS patients currently followed at San Martino Hospital. Ordinal and logistic regression analyses were applied to identify significant predictors of health status. Results Fifty-seven ALS patients completed the questionnaire. A total of 35.08% of cases reported anxiety symptoms, 36.84% depressive symptoms, and 35.08% reported worsening of motor symptoms. Significant predictors of anxiety symptoms severity included female gender, greater motor impairment, more aggressive disease course, and rehabilitation therapy suspension. The only significant predictor of depressive symptoms severity was a more aggressive disease course. Significant predictors of motor worsening were shorter disease duration and exams/visits cancelation. Discussion COVID-19 emergency and its management exerted a significant impact on self-perceived health status in patients with ALS, particularly in those cases in the earliest disease phases and with a more aggressive disease course. These findings have potential to improve personalized medicine strategies in the next phase.

Background Parsonage–Turner syndrome is an acute peripheral neuropathy that affects the upper brachial plexus region. Previously published reports demonstrate that the condition can be triggered by surgery, infection, autoimmune diseases, strenuous exercise, trauma, radiation, and vaccination. Parsonage–Turner syndrome has already been reported in three other patients who were vaccinated against coronavirus disease 2019. Case presentation We report the case of a 51-year-old Caucasian man without comorbidities who received the first dose of the ChAdOx1-S recombinant vaccine (Vaxzevria, AstraZeneca, Oxford, UK) against coronavirus disease 2019 and was diagnosed with Parsonage–Turner syndrome. A few days after getting vaccinated, the patient reported a progressive increase in pain in the region of vaccine administration. One month later, the shoulder pain was followed by symptoms of hypoesthesia and muscle weakness on abduction and elevation of the left upper limb. Neurological examination revealed an atrophy of the proximal muscles of the left upper limb, accompanied by paresis of the left deltoid, biceps brachii, triceps brachii, and infraspinatus muscles. Electroneuromyography carried out 3 months after the onset of symptoms showed signs consistent with brachial plexus neuritis. The adverse reaction has been properly reported to the Italian Pharmacovigilance System (Italian Medicines Agency—Agenzia Italiana del Farmaco. Conclusion The increased awareness of such association is essential for early identification and diagnosis and, thus, better clinical outcomes.

Charcot-Marie-Tooth type 4B1 (CMT4B1) is a severe autosomal recessive demyelinating neuropathy with childhood onset, caused by loss-of-function mutations in the myotubularin-related 2 (MTMR2) gene. MTMR2 is a ubiquitously expressed catalytically active 3-phosphatase, which in vitro dephosphorylates the 3-phosphoinositides PtdIns3P and PtdIns(3,5)P(2), with a preference for PtdIns(3,5)P(2). A hallmark of CMT4B1 neuropathy are redundant loops of myelin in the nerve termed myelin outfoldings, which can be considered the consequence of altered growth of myelinated fibers during postnatal development. How MTMR2 loss and the resulting imbalance of 3′-phosphoinositides cause CMT4B1 is unknown. Here we show that MTMR2 by regulating PtdIns(3,5)P(2) levels coordinates mTORC1-dependent myelin synthesis and RhoA/myosin II-dependent cytoskeletal dynamics to promote myelin membrane expansion and longitudinal myelin growth. Consistent with this, pharmacological inhibition of PtdIns(3,5)P(2) synthesis or mTORC1/RhoA signaling ameliorates CMT4B1 phenotypes. Our data reveal a crucial role for MTMR2-regulated lipid turnover to titrate mTORC1 and RhoA signaling thereby controlling myelin growth.

Neuromuscular diseases may manifest with focal or generalized distribution of reduced strength. Sometimes the diagnosis is delayed because this feature may be due also to a disorder of the central nervous system (see Chap. 10).

Charcot–Marie–Tooth (CMT) disease is the most commonly inherited neurological disorder. This study includes patients affected by CMT during regular follow-ups at the CMT clinic in Genova, a neuromuscular university center in the northwest of Italy, with the aim of describing the genetic distribution of CMT subtypes in our cohort and reporting a peculiar phenotype. Since 2004, 585 patients (447 index cases) have been evaluated at our center, 64.9% of whom have a demyelinating neuropathy and 35.1% of whom have an axonal neuropathy. A genetic diagnosis was achieved in 66% of all patients, with the following distribution: CMT1A (48%), HNPP (14%), CMT1X (13%), CMT2A (5%), and P0-related neuropathies (7%), accounting all together for 87% of all the molecularly defined neuropathies. Interestingly, we observe a peculiar phenotype with initial exclusive lower limb involvement as well as lower limb involvement that is maintained over time, which we have defined as a “strictly length-dependent” phenotype. Most patients with this clinical presentation shared variants in either HSPB1 or MPZ genes. The identification of distinctive phenotypes such as this one may help to address genetic diagnosis. In conclusion, we describe our diagnostic experiences as a multidisciplinary outpatient clinic, combining a gene-by-gene approach or targeted gene panels based on clinical presentation.

Pathological evidence of amyloid on nerve biopsy has been the gold standard for diagnosis in hereditary transthyretin amyloidosis polyneuropathy (hATTR-PN) for a long time. In this article, we reviewed the pathological findings of a large series of sural nerve biopsies from a cohort of hATTR-PN patients, collected by different Italian referral centers. Patients and Methods: We reviewed clinical and pathological data from hATTR-PN patients, diagnosed and followed in five Italian referral centers for peripheral neuropathies. Diagnosis was formulated after a positive genetic test for transthyretin (TTR) mutations. Sural nerve biopsy was performed according to standard protocols. Results: Sixty-nine sural nerve biopsies from hATTR-PN patients were examined. Congo red positive deposits were found in 73% of cases. Only the Phe64Leu mutation failed to show amyloid deposits in a high percentage of biopsies (54%), as already described. Unusual pathological findings, such as myelin abnormalities or inflammatory infiltrates, were detected in occasional cases. Conclusions: Even if no longer indicated to confirm hATTR-PN clinical suspicion, nerve biopsy remains, in expert hands, a rapid and inexpensive tool to detect amyloid deposition. In Italy, clinicians should be aware that a negative biopsy does not exclude hATTR-PN, particularly for Phe64Leu, one of the most frequent mutations in this country.

Given the extreme diffusion of Alzheimer’s disease (AD) and Parkinson’s disease (PD), the necessity for a solution to early detect neurological symptoms of such diseases strongly arose. According to the medical literature, such early detection can be achieved by exploiting the correlation between PD and AD and some external symptoms: the Essential Tremor (ET) and the number of Eye Blinks (EBs). In this paper we present NeuroGlasses, a prototype of sensored glasses able to detect the presence of ET of the head and to count the number of EBs at the same time. To the best of authors’ knowledge this is the first attempt to monitor such external symptoms with a transparent and wearable device without any a-priori training. Numerical results prove the reliability of the proposed approach: NeuroGlasses are able to i) correctly recognize the ET with an overall accuracy above 97% and ii) count the number of EBs with a Root Mean Square Error (RMSE) around 0.4.

In Charcot-Marie-Tooth type 1A (CMT1A), Schwann cells exhibit a preponderant transcriptional deficiency of genes involved in lipid biosynthesis. This perturbed lipid metabolism affects the peripheral nerve physiology and the structure of peripheral myelin. Nevertheless, the identification and functional characterization of the lipid species mainly responsible for CMT1A myelin impairment currently lack. This is critical in the pathogenesis of the neuropathy since lipids are many and complex molecules which play essential roles in the cell, including the structural components of cellular membranes, cell signaling, and membrane trafficking. Moreover, lipids themselves are able to modify gene transcription, thereby affecting the genotype-phenotype correlation of well-defined inherited diseases, including CMT1A. Here we report for the first time a comprehensive lipid profiling in experimental and human CMT1A, demonstrating a previously unknown specific alteration of sphingolipid (SP) and glycerophospholipid (GP) metabolism. Notably, SP, and GP changes even emerge in biological fluids of CMT1A rat and human patients, implying a systemic metabolic dysfunction for these specific lipid classes. Actually, SP and GP are not merely reduced; their expression is instead aberrant, contributing to the ultrastructural abnormalities that we detailed by X-ray diffraction in rat and human internode myelin. The modulation of SP and GP pathways in myelinating dorsal root ganglia cultures clearly sustains this issue. In fact, just selected molecules interacting with these pathways are able to modify the altered geometric parameters of CMT1A myelinated fibers. Overall, we propose to exploit the present SP and GP metabolism impairment to select effective drugs and validate a set of reliable biomarkers, which remain a challenge in CMT1A neuropathy.

The symptomatology of Charcot-Marie-Tooth (CMT) disease mainly involves the feet and the hands. To date, there is no consensus on how to evaluate hand function in CMT. The aim of this study is to correlate the data of the engineered glove Hand Test System (HTS) with specific tests and the CMT examination score (CMTES). We analyzed 45 patients with the diagnosis of CMT using HTS, which measures the hand dexterity by specific sequences performed at maximum velocity. We completed the evaluation with the CMTES, tripod pinch and hand grip strength tested by a dynamometer, thumb opposition test (TOT), and Sollerman Hand function test (SHFT), and we conducted a test-retest with 20 normal subjects. Finger tapping (FT) and index-medium-ring-little (IMRL) sequence showed a significant correlation with CMTES (FT: dominant hand (DH): P = .036; non-dominant hand (NDH): P = .033; IMRL: DH: P = .009; NDH: P = .046). TOT correlated with CMTES significantly in both hands (P < .0001). tripod pinch showed a statistically significant correlation with CMTES (DH: P = .002; NDH: P = .005). Correlation between the hand grip and CMTES was significant only in DH (DH: P = .002). SHFT had a significant correlation with the CMTES (DH: P = .002). Test-retest showed a good reliability. HTS parameters correlate with CMTES confirming that this tool is sensitive to the hand deficits. In conclusion, we can state that HTS is a good, simple to use, and objective instrument to evaluate the hand function of CMT patients, but more studies on responsiveness and sensitivity are needed.

Peripheral myelin protein 2 (PMP2) is a small protein located on the cytoplasmic side of compact myelin, involved in the lipids transport and in the myelination process. In the last years few families affected with demyelinating Charcot-Marie-Tooth neuropathy (CMT1), caused by PMP2 mutations, have been identified. In this study we describe the first case of a PMP2 in-frame deletion. PMP2 was analyzed by direct sequencing after exclusion of the most frequent CMT-associated genes by using a next generation sequencing (NGS) genes panel. Sanger sequencing was used for family's segregation analysis. Molecular modeling analysis was used to evaluate the mutation impact on the protein structure. A novel PMP2: p.I50del has been identified in a child with early onset CMT1 and in three affected family members. All family members show an early onset demyelinating neuropathy without other distinguish features. Molecular modeling analysis and in silico evaluations do not suggest a strong impact on the overall protein structure, but a most likely altered protein function. This study suggests the importance to add PMP2 in CMT NGS genes panels or, at most, to test it after major CMT1 genes exclusion, due to the lack of diagnostic-addressing additional features.