Publications by authors named "Angelo Schenone"

133 Publications

Rehabilitation, exercise, and related non-pharmacological interventions for chemotherapy-induced peripheral neurotoxicity: Systematic review and evidence-based recommendations.

Crit Rev Oncol Hematol 2021 Dec 28:103575. Epub 2021 Dec 28.

Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

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.
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http://dx.doi.org/10.1016/j.critrevonc.2021.103575DOI Listing
December 2021

Predicting Outcome in Guillain-Barré Syndrome: International Validation of the Modified Erasmus GBS Outcome Score.

Neurology 2021 Dec 22. Epub 2021 Dec 22.

Department of Medicine, University of Malaya, Lembah Pantai, 50603, Kuala Lumpur, Malaysia.

Background And Objectives: The clinical course and outcome of the Guillain-Barré syndrome (GBS) are diverse and vary among regions. The modified Erasmus GBS Outcome Score (mEGOS) is a clinical model that predicts the risk of walking inability in GBS patients, and was developed with data from Dutch patients. The study objective was to validate the mEGOS in the International GBS Outcome Study (IGOS) cohort and to improve its performance and region-specificity.

Methods: We used prospective data from the first 1500 patients included in IGOS, aged ≥ 6 years and unable to walk independently. We evaluated if the mEGOS at entry and week 1 could predict the inability to walk unaided at 4 and 26 weeks in the full cohort and in regional subgroups, using two measures for model performance: (1) discrimination: area under the receiver operating characteristic curve (AUC), and (2) calibration: observed versus predicted probability of being unable to walk independently. To improve the model predictions we recalibrated the model containing the overall mEGOS score, without changing the individual predictive factors. Finally, we assessed the predictive ability of the individual factors.

Results: For validation of mEGOS at entry 809 patients were eligible (Europe/North America n=677, Asia n=76, other=56), and 671 for validation of mEGOS at week 1 (Europe/North America n=563, Asia n=65, other=43). AUC-values were >0.7 in all regional subgroups. In the Europe/North America subgroup observed outcomes were worse than predicted, while in Asia observed outcomes were better than predicted. Recalibration improved model accuracy and enabled the development of a region-specific version for Europe/North America (mEGOS-Eu/NA). Similar to the original mEGOS, severe limb weakness and higher age were the predominant predictors of poor outcome in the IGOS cohort.

Discussion: The mEGOS is a validated tool to predict the inability to walk unaided at 4 and 26 weeks in GBS patients, also in countries outside The Netherlands. We developed a region-specific version of mEGOS for patients from Europe/North America.

Classification Of Evidence: This study provides Class II evidence that the mEGOS accurately predicts the inability to walk unaided at 4 and 26 weeks in GBS patients.

Clinicaltrialsgov Identifier: NCT01582763.
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http://dx.doi.org/10.1212/WNL.0000000000013139DOI Listing
December 2021

Parsonage-Turner syndrome following coronavirus disease 2019 immunization with ChAdOx1-S vaccine: a case report and review of the literature.

J Med Case Rep 2021 Dec 13;15(1):589. Epub 2021 Dec 13.

Department of Health Sciences, University of Genoa, L.go R. Benzi, 10 (Building 3), 16122, Genoa, Italy.

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.
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http://dx.doi.org/10.1186/s13256-021-03176-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8667016PMC
December 2021

Optimal outcome measures for assessing exercise and rehabilitation approaches in chemotherapy-induced peripheral-neurotoxicity: Systematic review and consensus expert opinion.

Expert Rev Neurother 2022 Jan 11:1-12. Epub 2022 Jan 11.

Department of Neurology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.

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: We 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 gap in the identification of effective rehabilitation and treatment options for CIPN.
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http://dx.doi.org/10.1080/14737175.2022.2018300DOI Listing
January 2022

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

J Peripher Nerv Syst 2021 Nov;26 Suppl 2:S3-S10

Department of Neurosciences, Rehabilitation, Ophthalmology, Genetic and Maternal and Infantile Sciences (DINOGMI), University of Genova, Genova, Italy.

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.
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http://dx.doi.org/10.1111/jns.12468DOI Listing
November 2021

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

Muscle Nerve 2022 Jan 8;65(1):96-104. Epub 2021 Nov 8.

Department of Neurosciences, Rehabilitation, Ophthalmology, Genetic and Maternal and Infantile Sciences, University of Genova, Unit of Neurology, IRCCS Ospedale Policlinico San Martino, Genoa, Italy.

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.
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http://dx.doi.org/10.1002/mus.27448DOI Listing
January 2022

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

Neurol Sci 2021 Oct 6. Epub 2021 Oct 6.

Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics and Maternal/Child Sciences, Genova, Italy.

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.
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http://dx.doi.org/10.1007/s10072-021-05646-9DOI Listing
October 2021

Abnormal sweating and "skin flushing" as possible predictive factor for treatment related fluctuations in Guillain-Barré syndrome: a case series and a review of the literature.

J Neurol Sci 2021 09 25;428:117589. Epub 2021 Jul 25.

IRCCS, Ospedale Policlinico San Martino, Genova, Italy.

Treatment related fluctuations (TRFs) in Guillain-Barré 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.
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http://dx.doi.org/10.1016/j.jns.2021.117589DOI Listing
September 2021

Prolonged distal motor latency of median nerve does not improve diagnostic accuracy for CIDP.

J Neurol 2022 Feb 26;269(2):907-912. Epub 2021 Jun 26.

Dysimmune Neuropathies Unit, Department of Systems Medicine, Tor Vergata University of Rome, Rome, Italy.

Compression of the median nerve at the carpal tunnel can give demyelinating features and result in distal motor latency (DML) prolongation fulfilling the EFNS/PNS demyelinating criteria for chronic inflammatory demyelinating polyneuropathy (CIDP). Accordingly, being carpal tunnel syndrome (CTS) common in the general population, the EFNS/PNS guidelines recommend excluding the DML of the median nerve when DML prolongation may be consistent with median neuropathy at the wrist from CTS. The main aims of this study were to verify whether the inclusion of DML of the median nerve (when consistent with CTS) could improve electrophysiological diagnostic accuracy for CIDP and if the median nerve at the carpal tunnel was more prone to demyelination. We analyzed electrophysiological data from 499 patients included consecutively into the Italian CIDP Database. According to the EFNS/PNS criteria, 352 patients had a definite, 10 a probable, and 57 a possible diagnosis of CIDP, while 80 were not fulfilling the diagnostic criteria. The inclusion of DML prolongation of median nerve did not improve significantly the diagnostic accuracy for CIDP; overall diagnostic class changed in 6 out of 499 patients (1.2%) and electrodiagnostic class of CIDP changed from not fulfilling to possible in only 2 patients (2.5% of not-fulfilling patients). In conclusion, we can infer that excluding DML prolongation of median nerve does not increase the risk of missing a diagnosis of CIDP thus corroborating the current EFNS/PNS criteria.
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http://dx.doi.org/10.1007/s00415-021-10672-wDOI Listing
February 2022

Isolated musculocutaneous nerve involvement in COVID-19 related Neuralgic amyotrophy. Comment on: "Neuralgic amyotrophy and COVID-19 infection: 2 cases of spinal accessory nerve palsy" by Coll et al. Joint Bone Spine 2021;88:105196.

Joint Bone Spine 2021 12 12;88(6):105238. Epub 2021 Jun 12.

Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genova, Genova, Italy; Division of Neurology, Ospedale Policlinico San Martino, IRCCS, Genoa, Italy.

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http://dx.doi.org/10.1016/j.jbspin.2021.105238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8195691PMC
December 2021

Detection of movement related cortical potentials in freehand drawing on digital tablet.

J Neurosci Methods 2021 08 31;360:109231. Epub 2021 May 31.

Dipartimento di Neuroscienze, Riabilitazione, Oftalmologia, Genetica e Scienze Materno Infantili (DINOGMI), Università degli Studi di Genova, Largo Daneo 3, 16132, Genova, Italy. Electronic address:

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.
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http://dx.doi.org/10.1016/j.jneumeth.2021.109231DOI Listing
August 2021

Prospective Evaluation of Health Care Provider and Patient Assessments in Chemotherapy-Induced Peripheral Neurotoxicity.

Neurology 2021 08 2;97(7):e660-e672. Epub 2021 Jun 2.

From Experimental Neurology Unit (P.A., G.C.) and Bicocca Bioinformatics Biostatistics and Bioimaging Centre-B4 (D.P.B., M.G.V.), School of Medicine and Surgery, University of Milano-Bicocca, Monza; NeuroMI (Milan Center for Neuroscience) (P.A., G.C.), Milan, Italy; Johns Hopkins University School of Medicine (D.R.C.), Baltimore, MD; Department of Neurology (I.S.J.M., C.G.F.), Maastricht University Medical Centre, the Netherlands; Department of Neurology (I.S.J.M.), St Elisabeth Hospital, Willemstad, Curaçao; University of New South Wales (S.B.P.), Sydney, Australia; Unit of Neuro-Oncology, Neurology Department (R.V., J.B.), Hospital Universitari de Bellvitge-ICO l'Hospitalet, IDIBELL, L'Hospitalet de Llobregat, Barcelona; Institute of Neurosciences and Department of Cell Biology, Physiology and Immunology (R.V., J.B.), Universitat Autònoma de Barcelona, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Bellaterra, Spain; Service de Neurologie Mazarin (D.P.), Hôpital de la Pitié-Salpêtrière, Université Paris Sorbonne, Paris, France; Department of Neurology and West German Cancer Center (S.K.), University of Essen, Germany; IRCCS Regina Elena Cancer Institute (A.P.), Neuro-Oncology Unit, Rome, Italy; Department of Pain & Translational Symptom Science (S.G.D.), University of Maryland Baltimore; Neurological Department (A.A.A.), Saint Andrew's General Hospital of Patras; Department of Medicine, Division of Oncology (A.A.A., H.P.K.), Medical School, University of Patras, Greece; Department of Neurosciences (C.B.), University of Padova; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetic and Maternal and Infantile Sciences (DINOGMI) (A.S.), University of Genova; Unit of Neurology and Neuromuscular Diseases (A.M.), Department of Clinical and Experimental Medicine, University of Messina, Italy; and Ludwig Boltzmann Institute for Experimental und Clinical Traumatology (W.G.), Vienna, Austria.

Background And Objective: There is no agreement on the gold standard for detection and grading of chemotherapy-induced peripheral neurotoxicity (CIPN) in clinical trials. The objective is to perform an observational prospective study to assess and compare patient-based and physician-based methods for detection and grading of CIPN.

Methods: Consecutive patients, aged 18 years or older, candidates for neurotoxic chemotherapy, were enrolled in the United States, European Union, or Australia. A trained investigator performed physician-based scales (Total Neuropathy Score-clinical [TNSc], used to calculate Total Neuropathy Score-nurse [TNSn]) and supervised the patient-completed questionnaire (Functional Assessment of Cancer Treatment/Gynecologic Oncology Group-Neurotoxicity [FACT/GOG-NTX]). Evaluations were performed before and at the end of chemotherapy. On participants without neuropathy at baseline, we assessed the association between TNSc, TNSn, and FACT/GOG-NTX. Considering a previously established minimal clinically important difference (MCID) for FACT/GOG-NTX, we identified participants with and without a clinically important deterioration according to this scale. Then, we calculated the MCID for TNSc and TNSn as the difference in the mean change score of these scales between the 2 groups.

Results: Data from 254 participants were available: 180 (71%) had normal neurologic status at baseline. At the end of the study, 88% of participants developed any grade of neuropathy. TNSc, TNSn, and FACT/GOG-NTX showed good responsiveness (standardized mean change from baseline to end of chemotherapy >1 for all scales). On the 153 participants without neuropathy at baseline and treated with a known neurotoxic chemotherapy regimen, we verified a moderate correlation in both TNSc and TNSn scores with FACT/GOG-NTX (Spearman correlation index = 0.6). On the same sample, considering as clinically important a change in the FACT/GOG-NTX score of at least 3.3 points, the MCID was 3.7 for TNSc and 2.8 for the TNSn.

Conclusions: MCID for TNSc and TNSn were calculated and the TNSn can be considered a reliable alternative objective clinical assessment if a more extended neurologic examination is not possible. The FACT/GOG-NTX score can be reduced to 7 items and these items correlate well with the TNSc and TNSn.

Classification Of Evidence: This study provides Class III evidence that a patient-completed questionnaire and nurse-assessed scale correlate with a physician-assessed scale.
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http://dx.doi.org/10.1212/WNL.0000000000012300DOI Listing
August 2021

A case series of parainfectious Guillain-Barré syndrome linked to influenza A (H1N1) virus infection.

J Neuroimmunol 2021 08 24;357:577605. Epub 2021 May 24.

IRCCS Ospedale Policlinico San Martino, Genoa, Italy.

Guillain-Barré syndrome (GBS) is an immune-mediated peripheral neuropathy characterized by a typical post-infectious profile. Some post-Zika virus and post-severe acute respiratory syndrome-related coronavirus-2 GBS cases have been reported to occur with very short intervals between the infection and GBS onset. Evaluating 161 GBS patients consecutively admitted to two Italian Regional Hospitals between 2003 and 2019, we found that the only three with an antecedent influenza A (H1N1) virus infection developed GBS within an interval of less than 10 days from the influenza illness. The two of them with a demyelinating subtype promptly recovered without therapy. Overall, the parainfectious cases add heterogeneity to the GBS category, warranting pathogenetic insights.
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http://dx.doi.org/10.1016/j.jneuroim.2021.577605DOI Listing
August 2021

The neurophysiological lesson from the Italian CIDP database.

Neurol Sci 2022 Jan 21;43(1):573-582. Epub 2021 May 21.

Dysimmune Neuropathies Unit, Department of Systems Medicine, Tor Vergata University of Rome, Rome, Italy.

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.
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http://dx.doi.org/10.1007/s10072-021-05321-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8724146PMC
January 2022

RFC1 expansions are a common cause of idiopathic sensory neuropathy.

Brain 2021 06;144(5):1542-1550

Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genoa, Genoa, Italy.

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.
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http://dx.doi.org/10.1093/brain/awab072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8262986PMC
June 2021

Dysregulation of myelin synthesis and actomyosin function underlies aberrant myelin in CMT4B1 neuropathy.

Proc Natl Acad Sci U S A 2021 03;118(10)

Human Inherited Neuropathies Unit, Institute of Experimental Neurology (INSPE) and Division of Neuroscience, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ospedale San Raffaele, 20132 Milan, Italy;

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 () gene. MTMR2 is a ubiquitously expressed catalytically active 3-phosphatase, which in vitro dephosphorylates the 3-phosphoinositides PtdIns3 and PtdIns(3,5) , with a preference for PtdIns(3,5) 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) 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) 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.
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http://dx.doi.org/10.1073/pnas.2009469118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7958260PMC
March 2021

Neuropathic pain and symptoms of potential small-fiber neuropathy in fibromyalgic patients: A national on-line survey.

Joint Bone Spine 2021 Jul 7;88(4):105153. Epub 2021 Feb 7.

Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics and Maternal Infantile Sciences (DINOGMI), University of Genova, Campus of Savona, SV, Italy.

Objective: Recent studies have highlighted that about 50% of fibromyalgic patients has a neuropathy of small- and/or large-fibers which could partially explain the puzzling symptoms of fibromyalgia (FM). Our aim was to investigate the estimated prevalence of self-reported neuropathic pain and small-fiber neuropathic symptoms (SFNS) indicative for the presence of small-fiber pathology in FM patients.

Methods: A nationwide sample of patients was recruited to participate in an on-line survey. Two groups of patients were considered in post-hoc analysis: those positive (FM+) to the Fibromyalgia Research Criteria (FRC) and those complaining typical symptoms of fibromyalgia without fulfilling the FRC (FM-).

Results: We collected data from 854 patients (749 FM+ and 105 FM-). Patients that scored=50/100 at the Neuropathic Pain Symptoms Inventory (NPSI), indicating severe neuropathic pain, were 57.3% (62.4% in FM+ and 21.0% in FM-). Around 46% of patients presented three or more SFNS that could be suggestive of small fiber pathology, the most frequent being dry eyes/mouth, allodynia, and dyshidrosis. The NPSI score showed significant moderate/strong associations with disability (Spearman's rho=0.61), pain (rho=0.66), stiffness level (rho=0.46), number of painful sites (rho=0.40), and SFNS (rho=0.44). Despite the high prevalence of neuropathic pain and other symptoms attributable to potential small and/or large fibers pathology, neurophysiologic investigations were performed in 43.6% of cases and skin punch biopsy only in 1.9% of patients enrolled, as well as the assumption of anti-neuropathic pain drugs (13.2%).

Conclusions: Our findings underscore the high estimated prevalence of neuropathic pain and SFNS in FM patients.
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http://dx.doi.org/10.1016/j.jbspin.2021.105153DOI Listing
July 2021

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

Neuromuscul Disord 2021 02 28;31(2):134-138. Epub 2020 Dec 28.

Department of Neurosciences, Rehabilitation, Ophthalmology, Genetic and Maternal and Infantile Sciences (DINOGMI), University of Genova, Largo P. Daneo3, 16132 Genova, Italy; IRCCS Ospedale Policlinico San Martino, Genova, Italy. Electronic address:

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.
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http://dx.doi.org/10.1016/j.nmd.2020.12.012DOI Listing
February 2021

Predictors of self-perceived health worsening over COVID-19 emergency in ALS.

Neurol Sci 2021 Apr 14;42(4):1231-1236. Epub 2021 Jan 14.

Department of Neurology, Ospedale Policlinico San Martino, IRCCS, Genoa, Italy.

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.
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http://dx.doi.org/10.1007/s10072-020-04997-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7807220PMC
April 2021

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

J Peripher Nerv Syst 2020 12 5;25(4):413-422. Epub 2020 Nov 5.

University of Iowa, Iowa City, Iowa, USA.

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.
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http://dx.doi.org/10.1111/jns.12421DOI Listing
December 2020

hATTR Pathology: Nerve Biopsy Results from Italian Referral Centers.

Brain Sci 2020 Oct 26;10(11). Epub 2020 Oct 26.

Dipartimento di Neuroscienze, Università Cattolica del Sacro Cuore, 00168 Roma, Italy.

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. 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 () mutations. Sural nerve biopsy was performed according to standard protocols. 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. 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.
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http://dx.doi.org/10.3390/brainsci10110780DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692609PMC
October 2020

CSF sphingomyelin: a new biomarker of demyelination in the diagnosis and management of CIDP and GBS.

J Neurol Neurosurg Psychiatry 2021 03 22;92(3):303-310. Epub 2020 Oct 22.

DINOGMI, University of Genoa, Genoa, Italy

Objective: To 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.

Methods: We 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.

Results: We 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<0.0001, p0.0065 and p<0.0001, respectively). In patients with CIDP classified for disease stage, SM was higher in active CIDP compared with both controls and stable CIDP (p<0.0001), applying for a selective tool to treatment tailoring or withdrawal. SM was also increased in AIDP compared with axonal GBS, discerning the demyelinating from axonal variant of the disease. SM did not correlate with CSF protein levels, stratifying patients independently from commonly used CSF indexes, and displaying high specificity to avoid potential misdiagnosis. Finally, SM correlated with the main clinical scores and some neurophysiological parameters in patients with CIDP and AIDP.

Conclusions: CSF 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.
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http://dx.doi.org/10.1136/jnnp-2020-324445DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892388PMC
March 2021

People with Charcot-Marie-Tooth disease and COVID-19: Impaired physical conditions due to the lockdown. An International cross-sectional survey.

Ann Phys Rehabil Med 2020 Nov 13;63(6):557-559. Epub 2020 Oct 13.

Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics and Maternal and Infantile Sciences (DINOGMI), University of Genova, L.go P. Daneo 3, Genova, Italy; IRCCS Ospedale Policlinico San Martino, Genova, Italy.

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http://dx.doi.org/10.1016/j.rehab.2020.10.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7553142PMC
November 2020

Request of hospital care dropped for TIA but remained stable for stroke during COVID-19 pandemic at a large Italian university hospital.

Intern Emerg Med 2021 04 15;16(3):735-739. Epub 2020 Oct 15.

Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics and Mother and Child Sciences (DINOGMI), University of Genoa, Genoa, Italy.

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 (PM) 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. PM 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.
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http://dx.doi.org/10.1007/s11739-020-02522-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7561243PMC
April 2021

Exploiting Sphingo- and Glycerophospholipid Impairment to Select Effective Drugs and Biomarkers for CMT1A.

Front Neurol 2020 25;11:903. Epub 2020 Aug 25.

DINOGMI, University of Genoa, Genoa, Italy.

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.
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http://dx.doi.org/10.3389/fneur.2020.00903DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7477391PMC
August 2020

COVID-19-related and not related Guillain-Barré syndromes share the same management pitfalls during lock down: The experience of Liguria region in Italy.

J Neurol Sci 2020 11 2;418:117114. Epub 2020 Sep 2.

Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genova, Genova, Italy; IRCCS, Ospedale Policlinico San Martino, Genova, Italy.

Recently, during the pandemic infection of the novel SARS-CoV-2, some cases of Guillan-Barré Syndrome (GBS) have been reported. The aim of this work is to report the natural history of patients with GBS, both COVID and not-COVID related, hospitalized in Liguria region, during lock down period, in order to assess clinical features of both groups and possible managements pitfalls due to pandemic emergency. Fifteen GBS patients were admitted to the Hospitals of Liguria, from February 15th to May 3rd 2020, six with SARS-CoV-2 infection and nine without infection. In COVID-19 related GBS five patients presented with classical GBS and one with variant. Two patients presented neurologic symptoms during or shortly after the viral syndrome, suggesting the pattern of a para-infectious profile. Multi-organ involvement, delay in the diagnosis, incomplete work up and start of therapy, were registered in 50% of cases with a GBS-Disability scale ≥4 at follow-up evaluation. In not-COVID-19 related GBS, main problem was diagnostic delay. In three patients the first neurological observation took place after a mean of 33,6 days. Moreover, five patients went to emergency room after an average of 30 days since the onset of neurological symptoms because of fear of contagion. In conclusion, not only SARS-CoV-2 infection can cause GBS, but it can also, due to effects of pandemic on the health organization, affect the outcome of patients with not COVID-19 related GBS.
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http://dx.doi.org/10.1016/j.jns.2020.117114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7462770PMC
November 2020

Pregnancy in Charcot-Marie-Tooth disease: Data from the Italian CMT national registry.

Neurology 2020 12 14;95(24):e3180-e3189. Epub 2020 Sep 14.

From the Fondazione IRCCS Istituto Neurologico Carlo Besta (C. Pisciotta, D.C., I.T., P.S., D.P.), Milan; Department of Neurosciences, Reproductive Sciences and Odontostomatology (L.S., F.M., S.T.), Federico II University of Naples; Department of Neuroscience, Biomedicine and Movement Sciences (G.M.F., T.C.), University of Verona; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics and Maternal Infantile Sciences (A.S., M.G.), University of Genoa; IRCCS Ospedale Policlinico San Martino (A.S., M.G.), Genoa; Division of Neuroscience and INSPE (S.C.P.), IRCCS Ospedale San Raffaele, Milan; A.O. di Parma (I.A., M.C.T.), U.O. Neurologia; Università Cattolica del Sacro Cuore (L.P.); Fondazione Policlinico Universitario A. Gemelli IRCCS (L.P., C. Pazzaglia), Rome; Neuroscience Centre (A.Q.), Magna Graecia University and Neuroimaging Research Unit, IBFM-CNR, Germaneto, Catanzaro; Department of Medical Sciences (P.V.), Magna Graecia University, Catanzaro; Unit of Neurology and Neuromuscular Diseases (L.G., M.R., A.M., G.V.), Department of Clinical and Experimental Medicine, University of Messina; and Department of Woman, Newborn and Child (F.P.), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, and University of Milan, Italy.

Objective: To collect information on frequency of pregnancy and delivery complications in Charcot-Marie-Tooth (CMT) disease and on CMT course during pregnancy.

Methods: Through an ad hoc online questionnaire, we investigated pregnancy and neuropathy course in women with CMT adhering to the Italian CMT Registry. Data were compared to those of controls (recruited among friends and unaffected relatives) and the Italian (or other reference) population.

Results: We collected data on 193 pregnancies from 86 women with CMT (age 20-73 years) with 157 deliveries (81.4%) after a mean of 38.6 gestational weeks. In women with CMT, there were no differences compared to controls (59 pregnancies and 46 deliveries from 24 controls) and the reference population for miscarriages (11.4%) and planned (21.0%) and emergency (14.0%) cesarean sections. We found a significantly higher frequency of placenta previa (1.6% vs 0.4%), abnormal fetal presentations (8.4% vs 4.5%), and preterm deliveries (20.3% vs 6.9%; most in week 34-36 of gestation) compared to reference populations. Excluding twins, newborn weight did not differ from the reference population. Postpartum bleeding rate in patients with CMT (2.1%) was similar to that of the general population (2.4%). CMT status worsened during 18 of 193 pregnancies (9.3%) with no recovery in 16 of them and with similar figures in the CMT1A and non-CMT1A subtypes.

Conclusions: We observed higher rates of placenta previa, abnormal presentations, and preterm deliveries in CMT, but pregnancy outcome and newborn weight and health were similar to those of the reference populations. Worsening of CMT is not infrequent and occurs not only in CMT1A. Pregnant women with CMT should be monitored with particular care.
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http://dx.doi.org/10.1212/WNL.0000000000010860DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836663PMC
December 2020

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

J Neurol Neurosurg Psychiatry 2020 11 11;91(11):1166-1174. Epub 2020 Sep 11.

Department of Neurology/Stroke Unit, Bolzano Hospital, Bolzano, Trentino-Alto Adige, Italy.

Objective: To retrospectively investigate safety and efficacy of nusinersen in a large cohort of adult Italian patients with spinal muscular atrophy (SMA).

Methods: Inclusion criteria were: (1) clinical and molecular diagnosis of SMA2 or SMA3; (2) nusinersen treatment started in adult age (>18 years); (3) clinical data available at least at baseline (T0-beginning of treatment) and 6 months (T6).

Results: We included 116 patients (13 SMA2 and 103 SMA3) with median age at first administration of 34 years (range 18-72). The Hammersmith Functional Rating Scale Expanded (HFMSE) in patients with SMA3 increased significantly from baseline to T6 (median change +1 point, p<0.0001), T10 (+2, p<0.0001) and T14 (+3, p<0.0001). HFMSE changes were independently significant in SMA3 sitter and walker subgroups. The Revised Upper Limb Module (RULM) in SMA3 significantly improved between T0 and T14 (median +0.5, p=0.012), with most of the benefit observed in sitters (+2, p=0.018). Conversely, patients with SMA2 had no significant changes of median HFMSE and RULM between T0 and the following time points, although a trend for improvement of RULM was observed in those with some residual baseline function. The rate of patients showing clinically meaningful improvements (as defined during clinical trials) increased from 53% to 69% from T6 to T14.

Conclusions: Our data provide further evidence of nusinersen safety and efficacy in adult SMA2 and SMA3, with the latter appearing to be cumulative over time. In patients with extremely advanced disease, effects on residual motor function are less clear.
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http://dx.doi.org/10.1136/jnnp-2020-323822DOI Listing
November 2020

Estimating the impact of COVID-19 pandemic on services provided by Italian Neuromuscular Centers: an Italian Association of Myology survey of the acute phase.

Acta Myol 2020 Jun 1;39(2):57-66. Epub 2020 Jun 1.

Child and Adolescent Unit, IRCCS Mondino Foundation, Pavia, Italy.

Introduction: Since February 2020, the outbreak of COVID-19 in Italy has forced the health care system to undergo profound rearrangements in its services and facilities, especially in the worst-hit areas in Northern Italy. In this setting, inpatient and outpatient services had to rethink and reorganize their activities to meet the needs of patients during the "lockdown". The Italian Association of Myology developed a survey to estimate the impact of these changes on patients affected by neuromuscular disorders and on specialized neuromuscular centers during the acute phase of COVID-19 pandemic.

Methods: We developed an electronic survey that was sent to neuromuscular centers affiliated with the Italian Association of Myology, assessing changes in pharmacological therapies provision, outpatient clinical and instrumental services, support services (physiotherapy, nursing care, psychological support) and clinical trials.

Results: 40% of surveyed neuromuscular centers reported a reduction in outpatient visit and examinations (44.5% of centers in Northern regions; 25% of centers in Central regions; 50% of centers in Southern regions). Twenty-two% of centers postponed in-hospital administration of therapies for neuromuscular diseases (23.4% in Northern regions; 13.0% in Central regions; 20% in Southern regions). Diagnostic and support services (physiotherapy, nursing care, psychological support) were suspended in 57% of centers (66/43/44% in Northern, Central and Southern centers respectively) Overall, the most affected services were rehabilitative services and on-site outpatient visits, which were suspended in 93% of centers. Strategies adopted by neuromuscular centers to overcome these changes included maintaining urgent on-site visits, addressing patients to available services and promoting remote contact and telemedicine.

Conclusions: Overall, COVID-19 pandemic resulted in a significant disruption of clinical and support services for patients with neuromuscular diseases. Despite the efforts to provide telemedicine consults to patients, this option could be promoted and improved further. A close collaboration between the different neuromuscular centers and service providers as well as further implementation of telehealth platforms are necessary to ensure quality care to NMD patients in the near future and in case of recurrent pandemic waves.
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http://dx.doi.org/10.36185/2532-1900-008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7460733PMC
June 2020

Neurological Manifestations of Severe SARS-CoV-2 Infection: Potential Mechanisms and Implications of Individualized Mechanical Ventilation Settings.

Front Neurol 2020 12;11:845. Epub 2020 Aug 12.

Department of Anesthesia and Intensive Care, San Martino Policlinico Hospital, IRCCS for Oncology and Neuroscience, Genoa, Italy.

In December 2019, an outbreak of illness caused by a novel coronavirus (2019-nCoV, subsequently renamed SARS-CoV-2) was reported in Wuhan, China. Coronavirus disease 2019 (COVID-19) quickly spread worldwide to become a pandemic. Typical manifestations of COVID-19 include fever, dry cough, fatigue, and respiratory distress. In addition, both the central and peripheral nervous system can be affected by SARS-CoV-2 infection. These neurological changes may be caused by viral neurotropism, by a hyperinflammatory and hypercoagulative state, or even by mechanical ventilation-associated impairment. Hypoxia, endothelial cell damage, and the different impacts of different ventilatory strategies may all lead to increased stress and strain, potentially exacerbating the inflammatory response and leading to a complex interaction between the lungs and the brain. To date, no studies have taken into consideration the possible secondary effect of mechanical ventilation on brain recovery and outcomes. The aim of our review is to provide an updated overview of the potential pathogenic mechanisms of neurological manifestations in COVID-19, discuss the physiological issues related to brain-lung interactions, and propose strategies for optimization of respiratory support in critically ill patients with SARS-CoV-2 pneumonia.
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http://dx.doi.org/10.3389/fneur.2020.00845DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7434832PMC
August 2020
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