The role of sensory systems in the association between balance and walking in people with multiple sclerosis.

BACKGROUND: In Multiple Sclerosis, it has been demonstrated that balance is related to performances in walking tasks at different levels of complexity. However, it is unknown how the different sensory systems involved in balance control contribute to walking. This observational study investigates the associations between somatosensory, vestibular, and visual systems and measures of self-reported walking and walking capacity at different complexity levels (i.e. low, medium, and high). METHODS: People with MS with EDSS<6 were assessed through the Sensory Organization Test (SOT), 12-Item MS Walking Scale (MSWS-12), Timed 25-Foot Walk (T25FW), Timed Up-and-Go Test (TUG), and Six-Spot-Step-Test (SSST). T25FW, TUG and SSST are measures of low, medium and high walking capacity, respectively. RESULTS: Forty-five PwMS were enrolled (EDSS: 3.4 ± 1.3). Capacity/ability walking measures were moderate-to-highly significantly associated (p < 0.01). Balance measures from SOT showed significant correlation (p < 0.05) between vestibular system and all the walking measures; between visual system and T25FW, SSST and MSWS-12; between the degree to which the patient relies on the visual system to maintain balance with conflicting visual surroundings information (VIS PREF) and T25FW and TUG. In the multivariate analyses, only VIS PREF significantly correlated (p < 0.05) with T25FW (std. Beta=0.42) and TUG (std. Beta=0.38). CONCLUSIONS: Vestibular and visual systems are associated with walking capacity. However, tasks with higher complexity levels require more visual attention towards ground obstacles, as often seen in real-life activities, whereas simpler walking tasks seem to require visual attention towards the surroundings.

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

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

Objective and subjective evaluation of walking ability with and without the use of a passive brace for hip flexor muscles in individuals with multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) affects the cognitive and motor domains. Muscle weakness often leads to abnormal gait. Several solutions are rising, including the use of passive exoskeletons. OBJECTIVE: The purpose of this study is to evaluate the effect of a first-ever use of a passive exoskeleton on walking ability in people with MS. METHODS: We recruited 50 persons with MS. All subjects were assessed using the 2-min walking test, the timed 25-foot walk test, and a two-stage rate of perceived exertion (RPE) without the exoskeleton (T0) and with the exoskeleton (T1). RESULTS: The data showed a significant decrease in walking endurance while the exoskeleton is worn (2-min walking test: T0: 65.19 ± 23.37 m; T1: 59.40 ± 22.99; p < 0.0001) and a not significant difference in walking speed on a shortened distance (T0: 15.71 ± 10.30 s; T1: 15.73 ± 11.86 s; p = 0.25). No significant differences were also found for the effort perception scale (RPE: T0: 13.24 ± 3.01; T1: 13.60 ± 2.9; p = 0.3). Seventy-two percent of subjects reported a positive or neutral global perceived effect. CONCLUSIONS: The exoskeleton does not add any fatiguing or negative effects. Although the walking performance decreases, the overall perception of the subjects is positive. Further studies are needed to evaluate the effect of the exoskeleton on gait quality.

Comparing the Impact of COVID-19 on Vaccinated and Unvaccinated Patients Affected by Myasthenia Gravis.

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.

Virtual Charcot-Marie-Tooth Examination Score: A Validated Virtual Evaluation for People With Charcot-Marie-Tooth Disease.

Background and Objectives: The Charcot-Marie-Tooth Examination Score (CMTES) has been used since 2005 in clinics to measure impairment in patients with CMT and has provided natural history data for patients with CMT1A, CMT1B, CMTX1, CMT2A, and many other subtypes. However, the CMTES requires an in-person visit, and many individuals are unable to travel to CMT centers because of the distance from the clinic or physical disability or more recently because of COVID-19 restrictions. We therefore developed the virtual CMTES (vCMTES) as outlined below. The aim of this study is to create a remote clinical outcome assessment to measure impairment in patients with CMT. Methods: We modified the CMTESv2 replacing the pinprick and vibration items with light touch and position sense, which can be performed remotely by the patient or the patient with an assistant while being observed by the clinic evaluator. Motor evaluations were performed similar to CMTESv2 by the assistant or the patient, while being observed remotely. We developed a standardized protocol to be used with Zoom or a similar format, a training and certification program, and enabled the vCMTES data to be housed in the Inherited Neuropathy Consortium databases. Patients were evaluated in person and remotely for interexaminer and intraexaminer studies. Results: Sixty-four patients with genetically confirmed CMT were evaluated by vCMTES and CMTESv2; 53 patients were evaluated virtually 3 weeks after their initial examination. Ten patients were evaluated with the vCMTES by different examiners 5 days apart. CMTESv2 correlates strongly with the vCMTES in person and virtually (p < 0.0001). There was a strong correlation between the vCMTES made in person and virtually (p < 0.0001). Similar results were obtained comparing symptoms score items, sensory items, and motor items. Interclass correlation coefficients (ICCs) were ≥0.92. Discussion: Statistical analyses demonstrated that the vCMTES was reproducible and reliable as a clinical outcome assessment for CMT. Further studies are needed to test responsiveness to change and progression in different subtypes. The vCMTES also offers the potential to reach diverse populations that do not have access to CMT centers.

A novel mouse model of CMT1B identifies hyperglycosylation as a new pathogenetic mechanism.

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.

The SPTLC1 p.S331 mutation bridges sensory neuropathy and motor neuron disease and has implications for treatment.

AIMS: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Genetic Workup for Charcot-Marie-Tooth Neuropathy: A Retrospective Single-Site Experience Covering 15 Years.

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.

An integrated approach to the evaluation of patients with asymptomatic or minimally symptomatic hyperCKemia.

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.

Charcot-Marie-Tooth neuropathy score and ambulation index are both predictors of orthotic need for patients with CMT.

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.

Techniques for the standard histological and ultrastructural assessment of nerve biopsies.

It is always a challenge to acquire a clear picture of the pathological processes and changes in any disease. For this purpose, it is advantageous to directly examine the affected organ. Nerve biopsy has been a method of choice for decades to classify peripheral neuropathies and to find clues to uncover their etiology. The histologic examination of the peripheral nerve provides information on axonal or myelin pathology as well as on the surrounding connective tissue and vascularization of the nerve. Minimal requirements of the workup include paraffin histology as well as resin semithin section histology. Cryostat sections, teased fiber preparations and electron microscopy are potentially useful in a subset of cases. Here we describe our standard procedures for the workup of the tissue sample and provide examples of diagnostically relevant findings.

Maintenance treatment with subcutaneous immunoglobulins in the long-term management of anti-HMCGR myopathy.

We describe the clinical response to long-term subcutaneous immunoglobulins (SCIg) in anti-3­hydroxy-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.

Neuromuscular complications following targeted therapy in cancer patients: beyond the immune checkpoint inhibitors. Case reports and review of the literature.

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.

MAM-36 and ABILHAND as outcome measures of multiple sclerosis hand disability: an observational study.

BACKGROUND: Impaired upper limb functionality and dexterity are common in people with multiple sclerosis (PwMS) and lead to increased dependency and reduced quality of life. AIM: The aim of this study was to compare the ability of the Manual Abilites Measure 36 (MAM-36) and the ABILHAND questionnaire to recognize an involvement of the upper limbs in PwMS, and to compare their results with those of other patient reported outcomes (PRO) evaluating disability, functional independence, symptoms of anxiety and depression, fatigue and quality of life. DESIGN: The study design was observational. SETTING: The setting of the study was outpatient. POPULATION: The study population included fifty-one PwMS (mean age of 56.31 years, age range of 33-82 years, 72.5% of patients were females). METHODS: For each patient were collected MAM-36, ABILHAND questionnaire, expanded disability status scale (EDSS), Functional Independence measure (FIM), Hospital Anxiety and Depression Scale (HADS), Modified Fatigue Impact Scale (MFIS) and Life Satisfaction Index (LSI). RESULTS: A strong correlation between MAM-36 and the ABILHAND questionnaire (Spearman r: 0.79; P<0.0001) were found. We obtained a significant correlation between MAM-36 and EDSS (Spearman r: -0.5; P=0.0002), FIM (Spearman r: 0.55; P<0.0001); we did not observe a correlation with MFIS (Spearman r: -0.33; P=0.02); moreover we found a similar trend between ABILHAND and EDSS (Spearman r: -0.47; P=0.0005), FIM (Spearman r: 0.61; P<0.0001), MFIS (Spearman r: -0.41; P=0.002). CONCLUSIONS: In PwMS the assessment of upper limbs is fundamental since it closely related to the level of disability of the person. Both MAM-36 and ABILHAND Questionnaire are equally able to detect upper limb dysfunctions in PwMS. CLINICAL REHABILITATION IMPACT: Both MAM-36 and ABILHAND can be used for upper limbs evaluation, within a multidimensional approach that seems to be the best way to evaluate PwMS.

Validation of a new hand function outcome measure in individuals with Charcot-Marie-Tooth disease.

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.

Comparison of Strength and Dexterity in Professional and Student Violinists: Setting Foundations to Guide Rehabilitation.

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.