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1. Diagnosis and Treatment of Hereditary Transthyretin Amyloidosis (hATTR) Polyneuropathy: Current Perspectives on Improving Patient Care

Author

Luigetti M, Romano A, Di Paolantonio A, Bisogni G, and Sabatelli M

Subjects
amyloid, polyneuropathy, clinical care, therapy, transthyretin., Therapeutics. Pharmacology, RM1-950
Abstract

Marco Luigetti,1,2 Angela Romano,2 Andrea Di Paolantonio,2 Giulia Bisogni,3 Mario Sabatelli2,3 1Neurology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy; 2Università Cattolica del Sacro Cuore, Rome, Italy; 3Centro Clinico NEMO Adulti, Rome, ItalyCorrespondence: Marco LuigettiNeurology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Largo A Gemelli 8, Rome 00168, ItalyTel +39-06-3015 4435Fax +39-06-3550 1909Email mluigetti@gmail.comAbstract: Hereditary transthyretin amyloidosis (hATTR) with polyneuropathy (formerly known as Familial Amyloid Polyneuropathy) is a rare disease due to mutations in the gene encoding transthyretin (TTR) and characterized by multisystem extracellular deposition of amyloid, leading to dysfunction of different organs and tissues. hATTR amyloidosis represents a diagnostic challenge for neurologists considering the great variability in clinical presentation and multiorgan involvement. Generally, patients present with polyneuropathy, but clinicians should consider the frequent cardiac, ocular and renal impairment. Especially a hypertrophic cardiomyopathy, even if usually latent, is identifiable in at least 50% of the patients. Therapeutically, current available options act at different stages of TTR production, including synthesis inhibition (liver transplantation and/or gene-silencing drugs) or tetramer TTR stabilization (TTR stabilizers), increasing survival at different disease stages.Keywords: amyloid, polyneuropathy, clinical care, therapy, transthyretin

Published
2020

2. Impact of 2021 European Academy of Neurology/Peripheral Nerve Society diagnostic criteria on diagnosis and therapy of chronic inflammatory demyelinating polyradiculoneuropathy variants

Author

De&nbsp, Lorenzo, A, Liberatore, G, Doneddu, P, Manganelli, F, Cocito, D, Briani, C, Fazio, R, Mazzeo, A, Schenone, A, Di&nbsp, Stefano, V, Cosentino, G, Marfia, G, Benedetti, L, Carpo, M, Filosto, M, Antonini, G, Clerici, A, Luigetti, M, Matà, S, Rosso, T, Lucchetta, M, Siciliano, G, Lauria&nbsp, Pinter, G, Cavaletti, G, Inghilleri, M, Cantisani, T, Notturno, F, Ricciardi, D, Habetswallner, F, Spina, E, Peci, E, Salvalaggio, A, Falzone, Y, Strano, C, Gentile, L, Vegezzi, E, Mataluni, G, Cotti&nbsp, Piccinelli, S, Leonardi, L, Romano, A, Nobile-Orazio, E, Lorenzo A., Liberatore G., Doneddu P. E., Manganelli F., Cocito D., Briani C., Fazio R., Mazzeo A., Schenone A., Stefano V., Cosentino G., Marfia G. A., Benedetti L., Carpo M., Filosto M., Antonini G., Clerici A. M., Luigetti M., Matà S., Rosso T., Lucchetta M., Siciliano G., Pinter G., Cavaletti G., Inghilleri M., Cantisani T., Notturno F., Ricciardi D., Habetswallner F., Spina E., Peci E., Salvalaggio A., Falzone Y., Strano C., Gentile L., Vegezzi E., Mataluni G., Piccinelli S., Leonardi L., Romano A., Nobile-Orazio E., De&nbsp, Lorenzo, A, Liberatore, G, Doneddu, P, Manganelli, F, Cocito, D, Briani, C, Fazio, R, Mazzeo, A, Schenone, A, Di&nbsp, Stefano, V, Cosentino, G, Marfia, G, Benedetti, L, Carpo, M, Filosto, M, Antonini, G, Clerici, A, Luigetti, M, Matà, S, Rosso, T, Lucchetta, M, Siciliano, G, Lauria&nbsp, Pinter, G, Cavaletti, G, Inghilleri, M, Cantisani, T, Notturno, F, Ricciardi, D, Habetswallner, F, Spina, E, Peci, E, Salvalaggio, A, Falzone, Y, Strano, C, Gentile, L, Vegezzi, E, Mataluni, G, Cotti&nbsp, Piccinelli, S, Leonardi, L, Romano, A, Nobile-Orazio, E, Lorenzo A., Liberatore G., Doneddu P. E., Manganelli F., Cocito D., Briani C., Fazio R., Mazzeo A., Schenone A., Stefano V., Cosentino G., Marfia G. A., Benedetti L., Carpo M., Filosto M., Antonini G., Clerici A. M., Luigetti M., Matà S., Rosso T., Lucchetta M., Siciliano G., Pinter G., Cavaletti G., Inghilleri M., Cantisani T., Notturno F., Ricciardi D., Habetswallner F., Spina E., Peci E., Salvalaggio A., Falzone Y., Strano C., Gentile L., Vegezzi E., Mataluni G., Piccinelli S., Leonardi L., Romano A., and Nobile-Orazio E.

Abstract

Background and purpose: There are different criteria for the diagnosis of different variants of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). The 2021 European Academy of Neurology/Peripheral Nerve Society (EAN/PNS) guidelines provide specific clinical criteria for each CIDP variant even if their therapeutical impact has not been investigated. Methods: We applied the clinical criteria for CIDP variants of the 2021 EAN/PNS guidelines to 369 patients included in the Italian CIDP database who fulfilled the 2021 EAN/PNS electrodiagnostic criteria for CIDP. Results: According to the 2021 EAN/PNS clinical criteria, 245 patients achieved a clinical diagnosis of typical CIDP or CIDP variant (66%). We identified 106 patients with typical CIDP (29%), 62 distal CIDP (17%), 28 multifocal or focal CIDP (7%), four sensory CIDP (1%), 27 sensory-predominant CIDP (7%), 10 motor CIDP (3%), and eight motor-predominant CIDP (2%). Patients with multifocal, distal, and sensory CIDP had milder impairment and symptoms. Patients with multifocal CIDP had less frequently reduced conduction velocity and prolonged F-wave latency and had lower levels of cerebrospinal fluid protein. Patients with distal CIDP more frequently had reduced distal compound muscle action potentials. Patients with motor CIDP did not improve after steroid therapy, whereas those with motor-predominant CIDP did. None of the patients with sensory CIDP responded to steroids, whereas most of those with sensory-predominant CIDP did. Conclusions: The 2021 EAN/PNS criteria for CIDP allow a better characterization of CIDP variants, permitting their distinction from typical CIDP and more appropriate treatment for patients.

Published
2024

3. Early detection of nerve involvement in presymptomatic TTR mutation carriers: exploring potential markers of disease onset

Author

Romano, Angela, Guglielmino, Valeria, Bisogni, Paolo Gaetano, Di Paolantonio, Andrea, Truini, A., Minnella, Angelo Maria, Sciarrone, Maria Ausilia, Vitali, Francesca, Maceroni, Martina, Galosi, E., Sabatelli, Mario, Luigetti, Marco, Romano A., Guglielmino V., Bisogni G., Di Paolantonio A., Minnella A. M. (ORCID:0000-0001-5896-5313), Sciarrone M. A., Vitali F., Maceroni M., Sabatelli M. (ORCID:0000-0001-6635-4985), Luigetti M. (ORCID:0000-0001-7539-505X), Romano, Angela, Guglielmino, Valeria, Bisogni, Paolo Gaetano, Di Paolantonio, Andrea, Truini, A., Minnella, Angelo Maria, Sciarrone, Maria Ausilia, Vitali, Francesca, Maceroni, Martina, Galosi, E., Sabatelli, Mario, Luigetti, Marco, Romano A., Guglielmino V., Bisogni G., Di Paolantonio A., Minnella A. M. (ORCID:0000-0001-5896-5313), Sciarrone M. A., Vitali F., Maceroni M., Sabatelli M. (ORCID:0000-0001-6635-4985), and Luigetti M. (ORCID:0000-0001-7539-505X)

Abstract

Background Hereditary transthyretin (ATTRv) amyloidosis is a heterogeneous, progressive, multisystemic disease with a life-threatening course if left untreated. Given the current availability of effective therapies, close follow-up of presymptomatic TTR mutation carriers is essential to recognize disease onset at the earliest sign. In addition to routine techniques, in recent years several novel tools have been proposed, although a consensus on their use has not been reached yet. In this paper, we aimed to evaluate possible markers of neuropathic disease onset intended to discriminate clinically asymptomatic carriers from early symptomatic patients, thus allowing timely treatment initiation.Methods Thirty-eight presymptomatic carriers were enrolled. Clinical and electrophysiological findings at first evaluation and follow-up were collected. All carriers underwent an extensive clinical and instrumental evaluation according to the standard clinical practice. One or more non-routine investigations, whose use in this field is not yet validated (henceforth "unconventional"), were additionally assessed in a subgroup of individuals.Results Based on the exclusive use of routine investigations, it was possible to define disease onset in 4/38 carriers during the follow-up. Employing additionally one or more "unconventional" tests, abnormal findings, indicative of a possible "conversion" to symptomatic disease, were detected in further 12 cases. More than half of our study cohort showed findings suggestive of small nerve fiber (SF) involvement at either invasive or non-invasive tests.Conclusions A close, multidisciplinary monitoring of presymptomatic TTR mutation carriers is fundamental, and diagnostic workup should include both routine and "unconventional" tests. Assessment of SF involvement is important also in non-endemic countries.

Published
2024

4. Unclassified clinical presentations of chronic inflammatory demyelinating polyradiculoneuropathy

Author

Doneddu, P, Akyil, H, Manganelli, F, Briani, C, Cocito, D, Benedetti, L, Mazzeo, A, Fazio, R, Filosto, M, Cosentino, G, Di Stefano, V, Antonini, G, Marfia, G, Inghilleri, M, Siciliano, G, Clerici, A, Carpo, M, Schenone, A, Luigetti, M, Lauria, G, Mata, S, Rosso, T, Minicuci, G, Lucchetta, M, Cavaletti, G, Liberatore, G, Spina, E, Campagnolo, M, Peci, E, Germano, F, Gentile, L, Strano, C, Cotti Piccinelli, S, Vegezzi, E, Leonardi, L, Mataluni, G, Ceccanti, M, Schirinzi, E, Romozzi, M, Nobile-Orazio, E, Doneddu P. E., Akyil H., Manganelli F., Briani C., Cocito D., Benedetti L., Mazzeo A., Fazio R., Filosto M., Cosentino G., Di Stefano V., Antonini G., Marfia G. A., Inghilleri M., Siciliano G., Clerici A. M., Carpo M., Schenone A., Luigetti M., Lauria G., Mata S., Rosso T., Minicuci G. M., Lucchetta M., Cavaletti G., Liberatore G., Spina E., Campagnolo M., Peci E., Germano F., Gentile L., Strano C., Cotti Piccinelli S., Vegezzi E., Leonardi L., Mataluni G., Ceccanti M., Schirinzi E., Romozzi M., Nobile-Orazio E., Doneddu, P, Akyil, H, Manganelli, F, Briani, C, Cocito, D, Benedetti, L, Mazzeo, A, Fazio, R, Filosto, M, Cosentino, G, Di Stefano, V, Antonini, G, Marfia, G, Inghilleri, M, Siciliano, G, Clerici, A, Carpo, M, Schenone, A, Luigetti, M, Lauria, G, Mata, S, Rosso, T, Minicuci, G, Lucchetta, M, Cavaletti, G, Liberatore, G, Spina, E, Campagnolo, M, Peci, E, Germano, F, Gentile, L, Strano, C, Cotti Piccinelli, S, Vegezzi, E, Leonardi, L, Mataluni, G, Ceccanti, M, Schirinzi, E, Romozzi, M, Nobile-Orazio, E, Doneddu P. E., Akyil H., Manganelli F., Briani C., Cocito D., Benedetti L., Mazzeo A., Fazio R., Filosto M., Cosentino G., Di Stefano V., Antonini G., Marfia G. A., Inghilleri M., Siciliano G., Clerici A. M., Carpo M., Schenone A., Luigetti M., Lauria G., Mata S., Rosso T., Minicuci G. M., Lucchetta M., Cavaletti G., Liberatore G., Spina E., Campagnolo M., Peci E., Germano F., Gentile L., Strano C., Cotti Piccinelli S., Vegezzi E., Leonardi L., Mataluni G., Ceccanti M., Schirinzi E., Romozzi M., and Nobile-Orazio E.

Abstract

Background To 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. Methods The 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'). Results At 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. Conclusions A 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.

Published
2023

5. Recommendations for pre-symptomatic genetic testing for hereditary transthyretin amyloidosis in the era of effective therapy: a multicenter Italian consensus

Author

Grandis, M., Obici, L., Luigetti, M., Briani, C., Benedicenti, F., Bisogni, G., Canepa, M., Cappelli, F., Danesino, C., Fabrizi, G. M., Fenu, S., Ferrandes, G., Gemelli, C., Manganelli, F., Mazzeo, A., Melchiorri, L., Perfetto, F., Pradotto, L. G., Rimessi, P., Tini, G., Tozza, S., Trevisan, L., Pareyson, D., and Mandich, P.

Published
2020
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6. Prolonged distal motor latency of median nerve does not improve diagnostic accuracy for CIDP

Author

Spina, E, Doneddu, P, Liberatore, G, Cocito, D, Fazio, R, Briani, C, Filosto, M, Benedetti, L, Antonini, G, Cosentino, G, Jann, S, Mazzeo, A, Cortese, A, Marfia, G, Clerici, A, Siciliano, G, Carpo, M, Luigetti, M, Lauria, G, Rosso, T, Cavaletti, G, Peci, E, Tronci, S, Ruiz, M, Piccinelli, S, Schenone, A, Leonardi, L, Gentile, L, Piccolo, L, Mataluni, G, Santoro, L, Nobile-Orazio, E, Manganelli, F, Spina E., Doneddu P. E., Liberatore G., Cocito D., Fazio R., Briani C., Filosto M., Benedetti L., Antonini G., Cosentino G., Jann S., Mazzeo A., Cortese A., Marfia G. A., Clerici A. M., Siciliano G., Carpo M., Luigetti M., Lauria G., Rosso T., Cavaletti G., Peci E., Tronci S., Ruiz M., Piccinelli S. C., Schenone A., Leonardi L., Gentile L., Piccolo L., Mataluni G., Santoro L., Nobile-Orazio E., Manganelli F., Spina, E, Doneddu, P, Liberatore, G, Cocito, D, Fazio, R, Briani, C, Filosto, M, Benedetti, L, Antonini, G, Cosentino, G, Jann, S, Mazzeo, A, Cortese, A, Marfia, G, Clerici, A, Siciliano, G, Carpo, M, Luigetti, M, Lauria, G, Rosso, T, Cavaletti, G, Peci, E, Tronci, S, Ruiz, M, Piccinelli, S, Schenone, A, Leonardi, L, Gentile, L, Piccolo, L, Mataluni, G, Santoro, L, Nobile-Orazio, E, Manganelli, F, Spina E., Doneddu P. E., Liberatore G., Cocito D., Fazio R., Briani C., Filosto M., Benedetti L., Antonini G., Cosentino G., Jann S., Mazzeo A., Cortese A., Marfia G. A., Clerici A. M., Siciliano G., Carpo M., Luigetti M., Lauria G., Rosso T., Cavaletti G., Peci E., Tronci S., Ruiz M., Piccinelli S. C., Schenone A., Leonardi L., Gentile L., Piccolo L., Mataluni G., Santoro L., Nobile-Orazio E., and Manganelli F.

Abstract

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.

Published
2022

7. The neurophysiological lesson from the Italian CIDP database

Author

Spina, E, Doneddu, P, Liberatore, G, Cocito, D, Fazio, R, Briani, C, Filosto, M, Benedetti, L, Antonini, G, Cosentino, G, Jann, S, Mazzeo, A, Cortese, A, Marfia, G, Clerici, A, Siciliano, G, Carpo, M, Luigetti, M, Lauria, G, Rosso, T, Cavaletti, G, Peci, E, Tronci, S, Ruiz, M, Piccinelli, S, Schenone, A, Leonardi, L, Gentile, L, Piccolo, L, Mataluni, G, Santoro, L, Nobile-Orazio, E, Manganelli, F, Spina E., Doneddu P. E., Liberatore G., Cocito D., Fazio R., Briani C., Filosto M., Benedetti L., Antonini G., Cosentino G., Jann S., Mazzeo A., Cortese A., Marfia G. A., Clerici A. M., Siciliano G., Carpo M., Luigetti M., Lauria G., Rosso T., Cavaletti G., Peci E., Tronci S., Ruiz M., Piccinelli S. C., Schenone A., Leonardi L., Gentile L., Piccolo L., Mataluni G., Santoro L., Nobile-Orazio E., Manganelli F., Spina, E, Doneddu, P, Liberatore, G, Cocito, D, Fazio, R, Briani, C, Filosto, M, Benedetti, L, Antonini, G, Cosentino, G, Jann, S, Mazzeo, A, Cortese, A, Marfia, G, Clerici, A, Siciliano, G, Carpo, M, Luigetti, M, Lauria, G, Rosso, T, Cavaletti, G, Peci, E, Tronci, S, Ruiz, M, Piccinelli, S, Schenone, A, Leonardi, L, Gentile, L, Piccolo, L, Mataluni, G, Santoro, L, Nobile-Orazio, E, Manganelli, F, Spina E., Doneddu P. E., Liberatore G., Cocito D., Fazio R., Briani C., Filosto M., Benedetti L., Antonini G., Cosentino G., Jann S., Mazzeo A., Cortese A., Marfia G. A., Clerici A. M., Siciliano G., Carpo M., Luigetti M., Lauria G., Rosso T., Cavaletti G., Peci E., Tronci S., Ruiz M., Piccinelli S. C., Schenone A., Leonardi L., Gentile L., Piccolo L., Mataluni G., Santoro L., Nobile-Orazio E., and Manganelli F.

Abstract

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.

Published
2022

8. Neurofilament light chain as a disease severity biomarker in ATTRv: data from a single-centre experience

Author

Luigetti, M., Di Paolantonio, A., Guglielmino, V., Romano, A., Rossi, S., Sabino, A., Servidei, S., Sabatelli, M., Primiano, G., Luigetti M. (ORCID:0000-0001-7539-505X), Di Paolantonio A., Guglielmino V., Romano A., Rossi S., Servidei S. (ORCID:0000-0001-8478-2799), Sabatelli M. (ORCID:0000-0001-6635-4985), Primiano G., Luigetti, M., Di Paolantonio, A., Guglielmino, V., Romano, A., Rossi, S., Sabino, A., Servidei, S., Sabatelli, M., Primiano, G., Luigetti M. (ORCID:0000-0001-7539-505X), Di Paolantonio A., Guglielmino V., Romano A., Rossi S., Servidei S. (ORCID:0000-0001-8478-2799), Sabatelli M. (ORCID:0000-0001-6635-4985), and Primiano G.

Abstract

Background: Hereditary transthyretin amyloidosis (ATTRv) is a treatable multisystem disorder with prevalent peripheral nervous system impairment. Besides neurophysiological measures, there are few markers to monitor disease progression. Neurofilament light chain (NfL) has recently been considered a sensitive biomarker for neuroaxonal damage in this setting. Objective: To evaluate NfL levels in a cohort of ATTRv patients and pre-symptomatic carriers and correlate the serum concentrations with other markers of disease severity. Methods: We analysed NfL serum from 17 ATTRv patients or carriers and 26 controls. An exhaustive clinical and instrumental evaluation was performed in all patients. Results: NfL levels were significantly higher in ATTRv cases when compared with controls. A significant correlation was found between NfL values and NIS scale, Sudoscan values from feet, interventricular septum thickness, and Quality of Life-Diabetic Neuropathy (Norfolk QoL-DN) questionnaire. Conclusion: We confirm that NfL is a reliable and promising biomarker to evaluate the ATTRv severity and monitor its progression.

Published
2022

10. Central nervous system involvement in two siblings affected by hereditary transthyretin amyloidosis 30 years after liver transplantation: a model for gene-silencing therapies

Author

Di Paolantonio, Andrea, Romano, A., Guglielmino, Valeria, Vitali, F., Sciarrone, Maria Ausilia, Bisogni, G., Verdolotti, Tommaso, Maceroni, Martina, Minnella, Angelo Maria, Luigetti, Marco, Di Paolantonio A., Guglielmino V., Sciarrone M. A., Verdolotti T., Maceroni M., Minnella A. M. (ORCID:0000-0001-5896-5313), Luigetti M. (ORCID:0000-0001-7539-505X), Di Paolantonio, Andrea, Romano, A., Guglielmino, Valeria, Vitali, F., Sciarrone, Maria Ausilia, Bisogni, G., Verdolotti, Tommaso, Maceroni, Martina, Minnella, Angelo Maria, Luigetti, Marco, Di Paolantonio A., Guglielmino V., Sciarrone M. A., Verdolotti T., Maceroni M., Minnella A. M. (ORCID:0000-0001-5896-5313), and Luigetti M. (ORCID:0000-0001-7539-505X)

Abstract

Hereditary transthyretin amyloidosis (ATTRv) is a genetic, autosomal dominant, severe disease characterized by progressive sensory-motor polyneuropathy, cardiomyopathy, dysautonomia, renal and eyes involvement, provoked by the deposition of the mutated and unstable transthyretin protein. In past decades, liver transplant, avoiding the synthesis of the pathologic protein, has been a good, even if not resolutive, treatment. In this report we describe two siblings affected with ATTRv, who developed first symptoms of disease at a young age and underwent a liver transplant with prompt resolution of clinical manifestations. After several years, central nervous system and eyes symptoms relapsed despite treatment, considering that the synthesis of mutated protein continues in choroid plexus, a locum where current therapies are unable to act. In our opinion, these cases represent a long-term prognostic model for the novel gene-silencers approved for ATTRv, because they share a similar therapeutic effect with liver transplant: the block of mutated protein synthesis limited only in the main transthyretin (TTR) production organ is able to prevent the progression of disease only for some years, but not to avoid long-term clinical worsening due to extra-hepatic production of TTR. Novel future therapeutic strategies are demanded to guarantee a better long-term stabilization of symptomatology.

Published
2023

11. Risk of disease relapse, safety and tolerability of SARS-CoV-2 vaccination in patients with chronic inflammatory neuropathies

Author

Doneddu, P. E., Briani, C., Cocito, D., Manganelli, F., Fabrizi, G. M., Matà, S., Mazzeo, A., Fazio, R., Benedetti, L., Luigetti, M., Inghilleri, M., Ruiu, E., Siciliano, G., Cosentino, G., Marfia, G. A., Carpo, M., Filosto, M., Antonini, G., Notturno, F., Sotgiu, S., Cucurachi, L., Dell'Aquila, C., Bianchi, E., Rosso, T., Giordano, A., Fernandes, M., Campagnolo, M., Peci, E., Spina, E., Tagliapietra, M., Sperti, M., Gentile, L., Strano, C., Germano, F., Romozzi, M., Moret, F., Zarbo, I. R., Viola, D. V., Vegezzi, E., Mataluni, G., Cotti-Piccinelli, S., Leonardi, L., Carta, A., and Nobile-Orazio, E.

Subjects
COVID-19, SARS-CoV-2, chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathy, vaccination, Settore MED/26
Published
2023

12. Ocular involvement in hereditary transthyretin amyloidosis: A case series describing novel potential biomarkers

Author

Minnella, A. M., Rissotto, R., Maceroni, M., Romano, A., Fasciani, R., Luigetti, M., Sabatelli, M., Rizzo, S., Falsini, B., Minnella A. M. (ORCID:0000-0001-5896-5313), Maceroni M., Romano A., Fasciani R., Luigetti M. (ORCID:0000-0001-7539-505X), Sabatelli M. (ORCID:0000-0001-6635-4985), Rizzo S. (ORCID:0000-0001-6302-063X), Falsini B. (ORCID:0000-0002-3569-4968), Minnella, A. M., Rissotto, R., Maceroni, M., Romano, A., Fasciani, R., Luigetti, M., Sabatelli, M., Rizzo, S., Falsini, B., Minnella A. M. (ORCID:0000-0001-5896-5313), Maceroni M., Romano A., Fasciani R., Luigetti M. (ORCID:0000-0001-7539-505X), Sabatelli M. (ORCID:0000-0001-6635-4985), Rizzo S. (ORCID:0000-0001-6302-063X), and Falsini B. (ORCID:0000-0002-3569-4968)

Abstract

Hereditary transthyretin amyloidosis (hATTR) is a rare disease caused by a point mutation in the transthyretin (TTR) gene and inherited in an autosomal dominant fashion. TTR is a plasma protein that functions as a carrier for thyroxine (T4) and retinol (vitamin A). Ophthalmological manifestations are due to both the hepatic and ocular production of mutated TTR. In this case series, we report the ocular manifestations of hATTR in eighteen eyes of nine consecutive patients. Corneal nerve abnormalities as well as morphological and functional changes in the retina were investigated. The study was a single-center, retrospective, observational, clinical case series. In all patients, corneal confocal microscopy (CCM), multimodal imaging of the retina, including fundus photography and Optical Coherence Tomography (OCT), as well as rod and cone electroretinography (ERG) were performed. Eight patients had active disease and one was an unaffected carrier. In all study eyes, corneal nerve plexa examined with CCM were poorly represented or absent. Mixed rod-cone and cone ERG b-wave amplitudes were reduced, and photopic b-wave responses were significantly delayed. Photopic Negative Response (PhNR) amplitude was significantly reduced, while PhNR latency was significantly augmented. In 13/18 eyes, vitreous opacities and abnormalities of vitreo-retinal interface were found. The current results highlight the presence of corneal nerve damage. Functional retinal abnormalities, detected by ERG, can be found even in the presence of minimal or absent structural retinal damage. These findings support the use of CCM and ERGs to detect early biomarkers for primary hATTR.

Published
2021

13. Muscle MRI as a useful biomarker in hereditary transthyretin amyloidosis: A pilot study

Author

Primiano, G., Verdolotti, T., D'Apolito, G., Di Paolantonio, A., Guglielmino, V., Romano, A., Lucioli, G., Luigetti, M., Servidei, S., Primiano G., Verdolotti T., D'Apolito G., Di Paolantonio A., Guglielmino V., Romano A., Lucioli G., Luigetti M. (ORCID:0000-0001-7539-505X), Servidei S. (ORCID:0000-0001-8478-2799), Primiano, G., Verdolotti, T., D'Apolito, G., Di Paolantonio, A., Guglielmino, V., Romano, A., Lucioli, G., Luigetti, M., Servidei, S., Primiano G., Verdolotti T., D'Apolito G., Di Paolantonio A., Guglielmino V., Romano A., Lucioli G., Luigetti M. (ORCID:0000-0001-7539-505X), and Servidei S. (ORCID:0000-0001-8478-2799)

Abstract

Hereditary transthyretin amyloidosis (ATTRv, v for variant) is a severe and heterogeneous multisystem condition with a prevalent peripheral nervous system impairment, due to mutations in the transthyretin gene. Considering the introduction of different disease-modifying therapies in the last few years, a need of reliable biomarkers is emerging. In this study, we evaluated muscle MRI in a cohort of ATTRv patients in order to establish if the severity of muscle involvement correlated with disease severity. Linear regression analysis showed a significant positive correlation between the total fatty infiltration score and NIS, NIS-LL, and Norfolk, and an inverse correlation with Sudoscan registered from feet. In conclusion, we demonstrated the role of muscle MRI in ATTRv as possible disease biomarker, both for diagnostic purposes and for assessing the severity of the disease.

Published
2021

14. Chronic inflammatory demyelinating polyradiculoneuropathy: can a diagnosis be made in patients not fulfilling electrodiagnostic criteria?

Author

Liberatore, G, Manganelli, F, Doneddu, P, Cocito, D, Fazio, R, Briani, C, Filosto, M, Benedetti, L, Mazzeo, A, Antonini, G, Cosentino, G, Jann, S, Cortese, A, Marfia, G, Clerici, A, Siciliano, G, Carpo, M, Luigetti, M, Lauria, G, Rosso, T, Cavaletti, G, Santoro, L, Peci, E, Tronci, S, Ruiz, M, Cotti Piccinelli, S, Schenone, A, Leonardi, L, Toscano, A, Mataluni, G, Spina, E, Gentile, L, Nobile-Orazio, E, Gallia, F, Beronio, A, Piccolo, L, Fierro, B, Verrengia, E, Bianchi, E, Beghi, E, Scrascia, F, Garnero, M, Sabatelli, M, Dacci, P, Schirinzi, E, Balducci, C, Liberatore G., Manganelli F., Doneddu P. E., Cocito D., Fazio R., Briani C., Filosto M., Benedetti L., Mazzeo A., Antonini G., Cosentino G., Jann S., Cortese A., Marfia G. A., Clerici A. M., Siciliano G., Carpo M., Luigetti M., Lauria G., Rosso T., Cavaletti G., Santoro L., Peci E., Tronci S., Ruiz M., Cotti Piccinelli S., Schenone A., Leonardi L., Toscano A., Mataluni G., Spina E., Gentile L., Nobile-Orazio E., Gallia F., Beronio A., Piccolo L., Fierro B., Verrengia E. P., Bianchi E., Beghi E., Scrascia F., Garnero M., Sabatelli M., Dacci P., Schirinzi E., Balducci C., Liberatore, G, Manganelli, F, Doneddu, P, Cocito, D, Fazio, R, Briani, C, Filosto, M, Benedetti, L, Mazzeo, A, Antonini, G, Cosentino, G, Jann, S, Cortese, A, Marfia, G, Clerici, A, Siciliano, G, Carpo, M, Luigetti, M, Lauria, G, Rosso, T, Cavaletti, G, Santoro, L, Peci, E, Tronci, S, Ruiz, M, Cotti Piccinelli, S, Schenone, A, Leonardi, L, Toscano, A, Mataluni, G, Spina, E, Gentile, L, Nobile-Orazio, E, Gallia, F, Beronio, A, Piccolo, L, Fierro, B, Verrengia, E, Bianchi, E, Beghi, E, Scrascia, F, Garnero, M, Sabatelli, M, Dacci, P, Schirinzi, E, Balducci, C, Liberatore G., Manganelli F., Doneddu P. E., Cocito D., Fazio R., Briani C., Filosto M., Benedetti L., Mazzeo A., Antonini G., Cosentino G., Jann S., Cortese A., Marfia G. A., Clerici A. M., Siciliano G., Carpo M., Luigetti M., Lauria G., Rosso T., Cavaletti G., Santoro L., Peci E., Tronci S., Ruiz M., Cotti Piccinelli S., Schenone A., Leonardi L., Toscano A., Mataluni G., Spina E., Gentile L., Nobile-Orazio E., Gallia F., Beronio A., Piccolo L., Fierro B., Verrengia E. P., Bianchi E., Beghi E., Scrascia F., Garnero M., Sabatelli M., Dacci P., Schirinzi E., and Balducci C.

Abstract

Background and purpose: The aim was to identify the clinical and diagnostic investigations that may help to support a diagnosis of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) in patients not fulfilling the European Federation of Neurological Societies and Peripheral Nerve Society (EFNS/PNS) electrodiagnostic criteria. Methods: The data from patients with a clinical diagnosis of CIDP included in a national database were retrospectively reviewed. Results: In all, 535 patients with a diagnosis of CIDP were included. This diagnosis fulfilled the EFNS/PNS criteria in 468 patients (87.2%) (definite in 430, probable in 33, possible in three, while two had chronic immune sensory polyradiculopathy). Sixty-seven patients had a medical history and clinical signs compatible with CIDP but electrodiagnostic studies did not fulfill the EFNS/PNS criteria for CIDP. These patients had similar clinical features and frequency of abnormal supportive criteria for the diagnosis of CIDP compared to patients fulfilling EFNS/PNS criteria. Two or more abnormal supportive criteria were present in 40 (61.2%) patients rising to 54 (80.6%) if a history of a relapsing course as a possible supportive criterion was also included. Increased cerebrospinal fluid proteins and response to immune therapy most frequently helped in supporting the diagnosis of CIDP. Response to therapy was similarly frequent in patients fulfilling or not EFNS/PNS criteria (87.3% vs. 85.9%). Conclusions: Patients with a clinical diagnosis of CIDP had similar clinical findings, frequency of abnormal supportive criteria and response to therapy compared to patients fulfilling EFNS/PNS criteria. The presence of abnormal supportive criteria may help in supporting the diagnosis of CIDP in patients with a medical history and clinical signs compatible with this diagnosis but non-diagnostic nerve conduction studies.

Published
2021

15. Patisiran in hereditary transthyretin-mediated amyloidosis

Author

Luigetti, M., Servidei, S., Luigetti M. (ORCID:0000-0001-7539-505X), Servidei S. (ORCID:0000-0001-8478-2799), Luigetti, M., Servidei, S., Luigetti M. (ORCID:0000-0001-7539-505X), and Servidei S. (ORCID:0000-0001-8478-2799)

Abstract

N/A

Published
2021

16. Monitoring effectiveness and safety of Tafamidis in transthyretin amyloidosis in Italy: a longitudinal multicenter study in a non-endemic area

Author

Cortese, A., Vita, G., Luigetti, M., Russo, M., Bisogni, G., Sabatelli, M., Manganelli, F., Santoro, L., Cavallaro, T., Fabrizi, G. M., Schenone, A., Grandis, M., Gemelli, C., Mauro, A., Pradotto, L. G., Gentile, L., Stancanelli, C., Lozza, A., Perlini, S., Piscosquito, G., Calabrese, D., Mazzeo, A., Obici, L., and Pareyson, D.

Published
2016
Full Text
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17. Chronic inflammatory demyelinating polyradiculoneuropathy: can a diagnosis be made in patients not fulfilling electrodiagnostic criteria?

Author

Liberatore, G., Manganelli, F., Doneddu, P. E., Cocito, D., Fazio, R., Briani, C., Filosto, M., Benedetti, L., Mazzeo, A., Antonini, G., Cosentino, G., Jann, S., Cortese, A., Marfia, G. A., Clerici, A. M., Siciliano, G., Carpo, M., Luigetti, M., Lauria, G., Rosso, T., Cavaletti, G., Santoro, L., Peci, E., Tronci, S., Ruiz, M., Cotti Piccinelli, S., Schenone, A., Leonardi, L., Toscano, A., Mataluni, G., Spina, E., Gentile, L., Nobile-Orazio, E., Gallia, F., Beronio, A., Piccolo, L., Fierro, B., Verrengia, E. P., Bianchi, E., Beghi, E., Scrascia, F., Garnero, M., Sabatelli, M., Dacci, P., Schirinzi, E., Balducci, C., Liberatore, G., Manganelli, F., Doneddu, P. E., Cocito, D., Fazio, R., Briani, C., Filosto, M., Benedetti, L., Mazzeo, A., Antonini, G., Cosentino, G., Jann, S., Cortese, A., Marfia, G. A., Clerici, A. M., Siciliano, G., Carpo, M., Luigetti, M., Lauria, G., Rosso, T., Cavaletti, G., Santoro, L., Peci, E., Tronci, S., Ruiz, M., Cotti-Piccinelli, S., Schenone, A., Leonardi, L., Toscano, A., Mataluni, G., Spina, E., Gentile, L., Nobile-Orazio, E., Gallia, F., Beronio, A., Piccolo, L., Fierro, B., Verrengia, E. P., Bianchi, E., Beghi, E., Scrascia, F., Garnero, M., Sabatelli, M., Dacci, P., Toni, G., Schirinzi, E., Balducci, C., Liberatore, G, Manganelli, F, Doneddu, P, Cocito, D, Fazio, R, Briani, C, Filosto, M, Benedetti, L, Mazzeo, A, Antonini, G, Cosentino, G, Jann, S, Cortese, A, Marfia, G, Clerici, A, Siciliano, G, Carpo, M, Luigetti, M, Lauria, G, Rosso, T, Cavaletti, G, Santoro, L, Peci, E, Tronci, S, Ruiz, M, Cotti Piccinelli, S, Schenone, A, Leonardi, L, Toscano, A, Mataluni, G, Spina, E, Gentile, L, Nobile-Orazio, E, Gallia, F, Beronio, A, Piccolo, L, Fierro, B, Verrengia, E, Bianchi, E, Beghi, E, Scrascia, F, Garnero, M, Sabatelli, M, Dacci, P, Schirinzi, E, and Balducci, C

Subjects
Pediatrics, medicine.medical_specialty, Response to therapy, Databases, Factual, Neural Conduction, Settore MED/26, 03 medical and health sciences, 0302 clinical medicine, Peripheral nerve, Retrospective Studie, Medicine, Humans, Medical history, In patient, 030212 general & internal medicine, Peripheral Nerves, Retrospective Studies, chronic inflammatory demyelinating polyradiculoneuropathy, business.industry, Polyradiculoneuropathy, Polyradiculopathy, medicine.disease, electrophysiology, Settore MED/26 - NEUROLOGIA, Neurology, Polyradiculoneuropathy, Chronic Inflammatory Demyelinating, Clinical diagnosis, Peripheral Nerve, diagnostic criteria, National database, Neurology (clinical), business, 030217 neurology & neurosurgery, Human
Abstract

Background and purpose The aim was to identify the clinical and diagnostic investigations that may help to support a diagnosis of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) in patients not fulfilling the European Federation of Neurological Societies and Peripheral Nerve Society (EFNS/PNS) electrodiagnostic criteria. Methods The data from patients with a clinical diagnosis of CIDP included in a national database were retrospectively reviewed. Results In all, 535 patients with a diagnosis of CIDP were included. This diagnosis fulfilled the EFNS/PNS criteria in 468 patients (87.2%) (definite in 430, probable in 33, possible in three, while two had chronic immune sensory polyradiculopathy). Sixty-seven patients had a medical history and clinical signs compatible with CIDP but electrodiagnostic studies did not fulfill the EFNS/PNS criteria for CIDP. These patients had similar clinical features and frequency of abnormal supportive criteria for the diagnosis of CIDP compared to patients fulfilling EFNS/PNS criteria. Two or more abnormal supportive criteria were present in 40 (61.2%) patients rising to 54 (80.6%) if a history of a relapsing course as a possible supportive criterion was also included. Increased cerebrospinal fluid proteins and response to immune therapy most frequently helped in supporting the diagnosis of CIDP. Response to therapy was similarly frequent in patients fulfilling or not EFNS/PNS criteria (87.3% vs. 85.9%). Conclusions Patients with a clinical diagnosis of CIDP had similar clinical findings, frequency of abnormal supportive criteria and response to therapy compared to patients fulfilling EFNS/PNS criteria. The presence of abnormal supportive criteria may help in supporting the diagnosis of CIDP in patients with a medical history and clinical signs compatible with this diagnosis but non-diagnostic nerve conduction studies.

Published
2021

18. Frequency of diabetes and other comorbidities in chronic inflammatory demyelinating polyradiculoneuropathy and their impact on clinical presentation and response to therapy

Author

Doneddu, P, Cocito, D, Manganelli, F, Fazio, R, Briani, C, Filosto, M, Benedetti, L, Bianchi, E, Jann, S, Mazzeo, A, Antonini, G, Cosentino, G, Marfia, G, Cortese, A, Clerici, A, Carpo, M, Schenone, A, Siciliano, G, Luigetti, M, Lauria, G, Rosso, T, Cavaletti, G, Beghi, E, Liberatore, G, Santoro, L, Spina, E, Peci, E, Tronci, S, Ruiz, M, Cotti Piccinelli, S, Verrengia, E, Gentile, L, Leonardi, L, Mataluni, G, Piccolo, L, Nobile-Orazio, E, Doneddu P. E., Cocito D., Manganelli F., Fazio R., Briani C., Filosto M., Benedetti L., Bianchi E., Jann S., Mazzeo A., Antonini G., Cosentino G., Marfia G. A., Cortese A., Clerici A. M., Carpo M., Schenone A., Siciliano G., Luigetti M., Lauria G., Rosso T., Cavaletti G., Beghi E., Liberatore G., Santoro L., Spina E., Peci E., Tronci S., Ruiz M., Cotti Piccinelli S., Verrengia E. P., Gentile L., Leonardi L., Mataluni G., Piccolo L., Nobile-Orazio E., Doneddu, P, Cocito, D, Manganelli, F, Fazio, R, Briani, C, Filosto, M, Benedetti, L, Bianchi, E, Jann, S, Mazzeo, A, Antonini, G, Cosentino, G, Marfia, G, Cortese, A, Clerici, A, Carpo, M, Schenone, A, Siciliano, G, Luigetti, M, Lauria, G, Rosso, T, Cavaletti, G, Beghi, E, Liberatore, G, Santoro, L, Spina, E, Peci, E, Tronci, S, Ruiz, M, Cotti Piccinelli, S, Verrengia, E, Gentile, L, Leonardi, L, Mataluni, G, Piccolo, L, Nobile-Orazio, E, Doneddu P. E., Cocito D., Manganelli F., Fazio R., Briani C., Filosto M., Benedetti L., Bianchi E., Jann S., Mazzeo A., Antonini G., Cosentino G., Marfia G. A., Cortese A., Clerici A. M., Carpo M., Schenone A., Siciliano G., Luigetti M., Lauria G., Rosso T., Cavaletti G., Beghi E., Liberatore G., Santoro L., Spina E., Peci E., Tronci S., Ruiz M., Cotti Piccinelli S., Verrengia E. P., Gentile L., Leonardi L., Mataluni G., Piccolo L., and Nobile-Orazio E.

Abstract

Objectives To determine the prevalence of different comorbidities in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), and their impact on outcome, treatment choice and response. Methods Using a structured questionnaire, we collected information on comorbidities from 393 patients with CIDP fulfilling the European Federation of Neurological Societies and Peripheral Nerve Society criteria included in the Italian CIDP database. Results One or more comorbidities were reported by 294 patients (75%) and potentially influenced treatment choice in 192 (49%) leading to a less frequent use of corticosteroids. Response to treatment did not differ, however, from that in patients without comorbidities. Diabetes (14%), monoclonal gammopathy of undetermined significance (MGUS) (12%) and other immune disorders (16%) were significantly more frequent in patients with CIDP than expected in the general European population. Patients with diabetes had higher disability scores, worse quality of life and a less frequent treatment response compared with patients without diabetes. Patients with IgG-IgA or IgM MGUS had an older age at CIDP onset while patients with other immune disorders had a younger age at onset and were more frequently females. IgM MGUS was more frequent in patients with motor CIDP than in patients with typical CIDP. Conclusions Comorbidities are frequent in patients with CIDP and in almost 50% of them have an impact on treatment choice. Diabetes, MGUS and other immune diseases are more frequent in patients with CIDP than in the general population. Only diabetes seems, however, to have an impact on disease severity and treatment response possibly reflecting in some patients a coexisting diabetic neuropathy.

Published
2020

19. Impact of environmental factors and physical activity on disability and quality of life in CIDP

Author

Doneddu, P, Bianchi, E, Cocito, D, Manganelli, F, Fazio, R, Filosto, M, Beghi, E, Mazzeo, A, Cosentino, G, Cortese, A, Jann, S, Clerici, A, Antonini, G, Siciliano, G, Marfia, G, Briani, C, Lauria, G, Rosso, T, Cavaletti, G, Carpo, M, Benedetti, L, Schenone, A, Liberatore, G, Peci, E, Spina, E, Tronci, S, Cotti Piccinelli, S, Toscano, A, Gentile, L, Piccolo, L, Leonardi, L, Mataluni, G, Ruiz, M, Sabatelli, M, Santoro, L, Nobile-Orazio, E, Gallia, F, Velardo, D, Topa, A, Cotti-Piccinelli, S, Todeschini, A, Cabona, C, Zuppa, A, Callegari, I, Verrengia, E, Scrascia, F, Garnero, M, Luigetti, M, Dacci, P, Schirinzi, E, Balducci, C, Doneddu P. E., Bianchi E., Cocito D., Manganelli F., Fazio R., Filosto M., Beghi E., Mazzeo A., Cosentino G., Cortese A., Jann S., Clerici A. M., Antonini G., Siciliano G., Marfia G. A., Briani C., Lauria G., Rosso T., Cavaletti G., Carpo M., Benedetti L., Schenone A., Liberatore G., Peci E., Spina E., Tronci S., Cotti Piccinelli S., Toscano A., Gentile L., Piccolo L., Leonardi L., Mataluni G., Ruiz M., Sabatelli M., Santoro L., Nobile-Orazio E., Gallia F., Velardo D., Topa A., Cotti-Piccinelli S., Todeschini A., Cabona C., Zuppa A., Callegari I., Verrengia E. P., Scrascia F., Garnero M., Luigetti M., Dacci P., Schirinzi E., Balducci C., Doneddu, P, Bianchi, E, Cocito, D, Manganelli, F, Fazio, R, Filosto, M, Beghi, E, Mazzeo, A, Cosentino, G, Cortese, A, Jann, S, Clerici, A, Antonini, G, Siciliano, G, Marfia, G, Briani, C, Lauria, G, Rosso, T, Cavaletti, G, Carpo, M, Benedetti, L, Schenone, A, Liberatore, G, Peci, E, Spina, E, Tronci, S, Cotti Piccinelli, S, Toscano, A, Gentile, L, Piccolo, L, Leonardi, L, Mataluni, G, Ruiz, M, Sabatelli, M, Santoro, L, Nobile-Orazio, E, Gallia, F, Velardo, D, Topa, A, Cotti-Piccinelli, S, Todeschini, A, Cabona, C, Zuppa, A, Callegari, I, Verrengia, E, Scrascia, F, Garnero, M, Luigetti, M, Dacci, P, Schirinzi, E, Balducci, C, Doneddu P. E., Bianchi E., Cocito D., Manganelli F., Fazio R., Filosto M., Beghi E., Mazzeo A., Cosentino G., Cortese A., Jann S., Clerici A. M., Antonini G., Siciliano G., Marfia G. A., Briani C., Lauria G., Rosso T., Cavaletti G., Carpo M., Benedetti L., Schenone A., Liberatore G., Peci E., Spina E., Tronci S., Cotti Piccinelli S., Toscano A., Gentile L., Piccolo L., Leonardi L., Mataluni G., Ruiz M., Sabatelli M., Santoro L., Nobile-Orazio E., Gallia F., Velardo D., Topa A., Cotti-Piccinelli S., Todeschini A., Cabona C., Zuppa A., Callegari I., Verrengia E. P., Scrascia F., Garnero M., Luigetti M., Dacci P., Schirinzi E., and Balducci C.

Abstract

A few observational studies and randomized trials suggest that exercise and rehabilitation may improve activity limitation and quality of life (QoL) in patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), but the impact of other modifiable factors on the severity of the disease is not well understood. Using a structured questionnaire, we collected data on lifestyle and dietary habits of the patients included in the Italian CIDP database to investigate the possible influence of modifiable lifestyle factors on disability and QoL. Questionnaire data were available for 323 patients. The effect of lifestyle and dietary exposures on impairment, disability and QoL was evaluated using logistic regression models, adjusting for age, sex, disease duration, physical activity and smoking. Physical activity was associated with lower sensory impairment by the ISS scale, less disability by the INCAT and RODS scale and a better QoL in all the domains of EURO-QoL scale with the exception of anxiety/depression. None of the other parameters had an impact on these scales. This study adds evidence to the possible role of physical activity in improving symptom severity, disability and QoL in patients with CIDP. None of the other environmental factors investigated appeared to have an impact on the severity and health perception of CIDP.

Published
2020

20. Relevance of diagnostic investigations in chronic inflammatory demyelinating poliradiculoneuropathy: Data from the Italian CIDP database

Author

Liberatore, G, Manganelli, F, Cocito, D, Fazio, R, Briani, C, Filosto, M, Benedetti, L, Antonini, G, Cosentino, G, Jann, S, Mazzeo, A, Cortese, A, Marfia, G, Clerici, A, Siciliano, G, Carpo, M, Sabatelli, M, Lauria, G, Rosso, T, Nobile Orazio, E, Doneddu, P, Gallia, F, Nobile-Orazio, E, Peci, E, Tronci, S, Santoro, L, Spina, E, Ruiz, M, Piccinelli, S, Beronio, A, Toscano, A, Gentile, L, Mataluni, G, Piccolo, L, Callegari, I, Fierro, B, Pinuccia, V, Bianchi, E, Beghi, E, Scrascia, F, Garnero, M, Schenone, A, Luigetti, M, Dacci, P, Leonardi, L, Schirinzi, E, Balducci, C, Cavaletti, G, Liberatore G., Manganelli F., Cocito D., Fazio R., Briani C., Filosto M., Benedetti L., Antonini G., Cosentino G., Jann S., Mazzeo A., Cortese A., Marfia G. A., Clerici A. M., Siciliano G., Carpo M., Sabatelli M., Lauria G., Rosso T., Nobile Orazio E., Doneddu P. E., Gallia F., Nobile-Orazio E., Peci E., Tronci S., Santoro L., Spina E., Ruiz M., Piccinelli S. C., Beronio A., Toscano A., Gentile L., Mataluni G., Piccolo L., Callegari I., Fierro B., Pinuccia V. E., Bianchi E., Beghi E., Scrascia F., Garnero M., Schenone A., Luigetti M., Dacci P., Leonardi L., Schirinzi E., Balducci C., Cavaletti G., Liberatore, G, Manganelli, F, Cocito, D, Fazio, R, Briani, C, Filosto, M, Benedetti, L, Antonini, G, Cosentino, G, Jann, S, Mazzeo, A, Cortese, A, Marfia, G, Clerici, A, Siciliano, G, Carpo, M, Sabatelli, M, Lauria, G, Rosso, T, Nobile Orazio, E, Doneddu, P, Gallia, F, Nobile-Orazio, E, Peci, E, Tronci, S, Santoro, L, Spina, E, Ruiz, M, Piccinelli, S, Beronio, A, Toscano, A, Gentile, L, Mataluni, G, Piccolo, L, Callegari, I, Fierro, B, Pinuccia, V, Bianchi, E, Beghi, E, Scrascia, F, Garnero, M, Schenone, A, Luigetti, M, Dacci, P, Leonardi, L, Schirinzi, E, Balducci, C, Cavaletti, G, Liberatore G., Manganelli F., Cocito D., Fazio R., Briani C., Filosto M., Benedetti L., Antonini G., Cosentino G., Jann S., Mazzeo A., Cortese A., Marfia G. A., Clerici A. M., Siciliano G., Carpo M., Sabatelli M., Lauria G., Rosso T., Nobile Orazio E., Doneddu P. E., Gallia F., Nobile-Orazio E., Peci E., Tronci S., Santoro L., Spina E., Ruiz M., Piccinelli S. C., Beronio A., Toscano A., Gentile L., Mataluni G., Piccolo L., Callegari I., Fierro B., Pinuccia V. E., Bianchi E., Beghi E., Scrascia F., Garnero M., Schenone A., Luigetti M., Dacci P., Leonardi L., Schirinzi E., Balducci C., and Cavaletti G.

Abstract

The objective of our work was to report the clinical features and the relevance of diagnostic investigations in patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). We retrospectively reviewed data from patients with a clinical diagnosis of CIDP included in a national database. Among the 500 included patients with a clinical diagnosis of CIDP, 437 patients (87%) fulfilled the European Federation of Neurological Societies and Peripheral Nerve Society criteria for CIDP (definite in 407, probable in 26, possible in four). In 352 patients (86%) motor nerve conduction abnormalities consistent with demyelination were sufficient for the diagnosis of definite CIDP. In 55 patients, this diagnosis required the addition of one or two (from probable or from possible CIDP, respectively) supportive tests, while in 20 cases they improved the diagnosis from possible to probable CIDP, seven patients did not change diagnosis. Considering these 85 patients, cerebrospinal fluid studies were performed in 79 cases (93%) upgrading the certainty of diagnosis in 59% of examined patients. Sensory nerve conduction studies (NCS) were performed in 85% of patients with an improvement of diagnosis in 32% of cases. Nerve biopsy and ultrasound and magnetic resonance imaging (US/MRI) exams resulted positive in about 40% of examined patients, but they were performed in few patients (7 patients and 16 patients, respectively). A response to the therapy was present in 84% of treated patients (n = 77), contributing to support the diagnosis in 40 patients in whom the other supportive criteria were not sufficient. In most patients with CIDP the diagnosis is possible solely with motor NCS while other investigations may help improving the diagnosis in a minority of patients.

Published
2020

21. Risk factors for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP): antecedent events, lifestyle and dietary habits. Data from the Italian CIDP Database

Author

Doneddu, P, Bianchi, E, Cocito, D, Manganelli, F, Fazio, R, Filosto, M, Mazzeo, A, Cosentino, G, Cortese, A, Jann, S, Clerici, A, Antonini, G, Siciliano, G, Luigetti, M, Marfia, G, Briani, C, Lauria, G, Rosso, T, Cavaletti, G, Carpo, M, Benedetti, L, Beghi, E, Liberatore, G, Santoro, L, Peci, E, Tronci, S, Cotti Piccinelli, S, Toscano, A, Piccolo, L, Verrengia, E, Leonardi, L, Schirinzi, E, Mataluni, G, Ruiz, M, Dacci, P, Nobile-Orazio, E, Doneddu P. E., Bianchi E., Cocito D., Manganelli F., Fazio R., Filosto M., Mazzeo A., Cosentino G., Cortese A., Jann S., Clerici A. M., Antonini G., Siciliano G., Luigetti M., Marfia G. A., Briani C., Lauria G., Rosso T., Cavaletti G., Carpo M., Benedetti L., Beghi E., Liberatore G., Santoro L., Peci E., Tronci S., Cotti Piccinelli S., Toscano A., Piccolo L., Verrengia E. P., Leonardi L., Schirinzi E., Mataluni G., Ruiz M., Dacci P., Nobile-Orazio E., Doneddu, P, Bianchi, E, Cocito, D, Manganelli, F, Fazio, R, Filosto, M, Mazzeo, A, Cosentino, G, Cortese, A, Jann, S, Clerici, A, Antonini, G, Siciliano, G, Luigetti, M, Marfia, G, Briani, C, Lauria, G, Rosso, T, Cavaletti, G, Carpo, M, Benedetti, L, Beghi, E, Liberatore, G, Santoro, L, Peci, E, Tronci, S, Cotti Piccinelli, S, Toscano, A, Piccolo, L, Verrengia, E, Leonardi, L, Schirinzi, E, Mataluni, G, Ruiz, M, Dacci, P, Nobile-Orazio, E, Doneddu P. E., Bianchi E., Cocito D., Manganelli F., Fazio R., Filosto M., Mazzeo A., Cosentino G., Cortese A., Jann S., Clerici A. M., Antonini G., Siciliano G., Luigetti M., Marfia G. A., Briani C., Lauria G., Rosso T., Cavaletti G., Carpo M., Benedetti L., Beghi E., Liberatore G., Santoro L., Peci E., Tronci S., Cotti Piccinelli S., Toscano A., Piccolo L., Verrengia E. P., Leonardi L., Schirinzi E., Mataluni G., Ruiz M., Dacci P., and Nobile-Orazio E.

Abstract

Background and purpose: The role of lifestyle and dietary habits and antecedent events has not been clearly identified in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Methods: Information was collected about modifiable environmental factors and antecedent infections and vaccinations in patients with CIDP included in an Italian CIDP Database. Only patients who reported not having changed their diet or the lifestyle habits investigated in the study after the appearance of CIDP were included. The partners of patients with CIDP were chosen as controls. Gender-matched analysis was performed with randomly selected controls with a 1:1 ratio of patients and controls. Results: Dietary and lifestyle data of 323 patients and 266 controls were available. A total of 195 cases and 195 sex-matched controls were used in the analysis. Patients eating rice at least three times per week or eating fish at least once per week appeared to be at decreased risk of acquiring CIDP. Data on antecedent events were collected in 411 patients. Antecedent events within 1–42 days before CIDP onset were reported by 15.5% of the patients, including infections in 12% and vaccinations in 1.5%. Patients with CIDP and antecedent infections more often had an acute onset of CIDP and cranial nerve involvement than those without these antecedent events. Conclusions: The results of this preliminary study seem to indicate that some dietary habits may influence the risk of CIDP and that antecedent infections may have an impact on the onset and clinical presentation of the disease.

Published
2020

22. Risk factors for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP): antecedent events, lifestyle and dietary habits. Data from the Italian CIDP Database

Author

Doneddu, P. E., Bianchi, E., Cocito, D., Manganelli, F., Fazio, R., Filosto, M., Mazzeo, A., Cosentino, G., Cortese, A., Jann, S., Clerici, A. M., Antonini, G., Siciliano, G., Luigetti, M., Marfia, G. A., Briani, C., Lauria, G., Rosso, T., Cavaletti, G., Carpo, M., Benedetti, L., Beghi, E., Liberatore, G., Santoro, L., Peci, E., Tronci, S., Cotti Piccinelli, S., Toscano, A., Piccolo, L., Verrengia, E. P., Leonardi, L., Schirinzi, E., Mataluni, G., Ruiz, M., Dacci, P., Nobile-Orazio, E., Luigetti M. (ORCID:0000-0001-7539-505X), Doneddu, P. E., Bianchi, E., Cocito, D., Manganelli, F., Fazio, R., Filosto, M., Mazzeo, A., Cosentino, G., Cortese, A., Jann, S., Clerici, A. M., Antonini, G., Siciliano, G., Luigetti, M., Marfia, G. A., Briani, C., Lauria, G., Rosso, T., Cavaletti, G., Carpo, M., Benedetti, L., Beghi, E., Liberatore, G., Santoro, L., Peci, E., Tronci, S., Cotti Piccinelli, S., Toscano, A., Piccolo, L., Verrengia, E. P., Leonardi, L., Schirinzi, E., Mataluni, G., Ruiz, M., Dacci, P., Nobile-Orazio, E., and Luigetti M. (ORCID:0000-0001-7539-505X)

Abstract

Background and purpose: The role of lifestyle and dietary habits and antecedent events has not been clearly identified in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Methods: Information was collected about modifiable environmental factors and antecedent infections and vaccinations in patients with CIDP included in an Italian CIDP Database. Only patients who reported not having changed their diet or the lifestyle habits investigated in the study after the appearance of CIDP were included. The partners of patients with CIDP were chosen as controls. Gender-matched analysis was performed with randomly selected controls with a 1:1 ratio of patients and controls. Results: Dietary and lifestyle data of 323 patients and 266 controls were available. A total of 195 cases and 195 sex-matched controls were used in the analysis. Patients eating rice at least three times per week or eating fish at least once per week appeared to be at decreased risk of acquiring CIDP. Data on antecedent events were collected in 411 patients. Antecedent events within 1–42 days before CIDP onset were reported by 15.5% of the patients, including infections in 12% and vaccinations in 1.5%. Patients with CIDP and antecedent infections more often had an acute onset of CIDP and cranial nerve involvement than those without these antecedent events. Conclusions: The results of this preliminary study seem to indicate that some dietary habits may influence the risk of CIDP and that antecedent infections may have an impact on the onset and clinical presentation of the disease.

Published
2020

23. Sural nerve biopsy in peripheral neuropathies: 30-year experience from a single center

Author

Luigetti, M., Di Paolantonio, A., Bisogni, G., Romano, A., Conte, A., Barbato, F., Del Grande, A., Madia, F., Rossini, P. M., Lauretti, L., Sabatelli, M., Luigetti M. (ORCID:0000-0001-7539-505X), Romano A., Barbato F., Madia F., Rossini P. M. (ORCID:0000-0003-2665-534X), Lauretti L. (ORCID:0000-0002-6463-055X), Sabatelli M. (ORCID:0000-0001-6635-4985), Luigetti, M., Di Paolantonio, A., Bisogni, G., Romano, A., Conte, A., Barbato, F., Del Grande, A., Madia, F., Rossini, P. M., Lauretti, L., Sabatelli, M., Luigetti M. (ORCID:0000-0001-7539-505X), Romano A., Barbato F., Madia F., Rossini P. M. (ORCID:0000-0003-2665-534X), Lauretti L. (ORCID:0000-0002-6463-055X), and Sabatelli M. (ORCID:0000-0001-6635-4985)

Abstract

Introduction: Nerve biopsy has been widely used to investigate patients with peripheral neuropathy, and in many centers, it is still a useful diagnostic tool in this setting. In this study, we reviewed the histopathological spectrum of the nerve biopsies performed in our center in a 30-year period and we analyzed their relevance in the clinical setting. Materials and methods: Retrospective analysis of the retrieved data was done for cases of nerve biopsies performed in our institute between 1988 and 2018. Surgical technique and histopathological analysis were done accordingly to standard protocol. Results: Complete clinical and pathological data were available only for 717 cases. The procedure was generally safe, with only 0.3% superimposed infection. Main pathological results were “unspecific” axonal polyneuropathy (49.8%), vasculitis neuropathy (9.3%), acquired demyelinating neuropathy (8.9%), and Charcot-Marie-Tooth (8.2%). Considering clinical-neurophysiological suspicion of vasculitis, nerve biopsy confirmed the diagnosis in 60.9% of cases. Discussion: In conclusion, for inherited neuropathies, we do not recommend this invasive procedure, but we strongly suggest a genetic test. Conversely, in vasculitic neuropathies or in dysimmune neuropathies not clearly confirmed by neurophysiological examination, nerve biopsy continues to represent a useful and irreplaceable tool.

Published
2020

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

Author

Cortese, A., Lombardi, R., Briani, C., Callegari, I., Benedetti, L., Manganelli, F., Luigetti, M., Ferrari, S., Clerici, A. M., Marfia, G. A., Rigamonti, A., Carpo, M., Fazio, R., Corbo, M., Mazzeo, A., Giannini, F., Cosentino, G., Zardini, E., Curro, R., Gastaldi, M., Vegezzi, E., Alfonsi, E., Berardinelli, A., Kouton, L., Manso, C., Giannotta, C., Doneddu, P., Dacci, P., Piccolo, L., Ruiz, M., Salvalaggio, A., De Michelis, C., Spina, E., Topa, A., Bisogni, G., Romano, A., Mariotto, S., Mataluni, G., Cerri, F., Stancanelli, C., Sabatelli, M., Schenone, A., Marchioni, E., Lauria, G., Nobile-Orazio, E., Devaux, J., Franciotta, D., Luigetti M. (ORCID:0000-0001-7539-505X), Romano A., Sabatelli M. (ORCID:0000-0001-6635-4985), Cortese, A., Lombardi, R., Briani, C., Callegari, I., Benedetti, L., Manganelli, F., Luigetti, M., Ferrari, S., Clerici, A. M., Marfia, G. A., Rigamonti, A., Carpo, M., Fazio, R., Corbo, M., Mazzeo, A., Giannini, F., Cosentino, G., Zardini, E., Curro, R., Gastaldi, M., Vegezzi, E., Alfonsi, E., Berardinelli, A., Kouton, L., Manso, C., Giannotta, C., Doneddu, P., Dacci, P., Piccolo, L., Ruiz, M., Salvalaggio, A., De Michelis, C., Spina, E., Topa, A., Bisogni, G., Romano, A., Mariotto, S., Mataluni, G., Cerri, F., Stancanelli, C., Sabatelli, M., Schenone, A., Marchioni, E., Lauria, G., Nobile-Orazio, E., Devaux, J., Franciotta, D., Luigetti M. (ORCID:0000-0001-7539-505X), Romano A., and Sabatelli M. (ORCID:0000-0001-6635-4985)

Abstract

OBJECTIVE: To assess the prevalence and isotypes of anti-nodal/paranodal antibodies to nodal/paranodal proteins in a large chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) cohort, compare clinical features in seronegative vs seropositive patients, and gather evidence of their isotype-specific pathogenic role. METHODS: Antibodies to neurofascin-155 (Nfasc155), neurofascin-140/186 (Nfasc140/186), contactin-1 (CNTN1), and contactin-associated protein 1 (Caspr1) were detected with ELISA and/or cell-based assay. Antibody pathogenicity was tested by immunohistochemistry on skin biopsy, intraneural injection, and cell aggregation assay. RESULTS: Of 342 patients with CIDP, 19 (5.5%) had antibodies against Nfasc155 (n = 9), Nfasc140/186 and Nfasc155 (n = 1), CNTN1 (n = 3), and Caspr1 (n = 6). Antibodies were absent from healthy and disease controls, including neuropathies of different causes, and were mostly detected in patients with European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) definite CIDP (n = 18). Predominant antibody isotypes were immunoglobulin G (IgG)4 (n = 13), IgG3 (n = 2), IgG1 (n = 2), or undetectable (n = 2). IgG4 antibody-associated phenotypes included onset before 30 years, severe neuropathy, subacute onset, tremor, sensory ataxia, and poor response to intravenous immunoglobulin (IVIG). Immunosuppressive treatments, including rituximab, cyclophosphamide, and methotrexate, proved effective if started early in IVIG-resistant IgG4-seropositive cases. Five patients with an IgG1, IgG3, or undetectable isotype showed clinical features indistinguishable from seronegative patients, including good response to IVIG. IgG4 autoantibodies were associated with morphological changes at paranodes in patients' skin biopsies. We also provided preliminary evidence from a single patient about the pathogenicity of anti-Caspr1 IgG4, showing their ability to penetrate paranodal regions and disrupt the integrity of the Nfasc155/CNTN

Published
2020

25. Relevance of diagnostic investigations in chronic inflammatory demyelinating poliradiculoneuropathy: Data from the Italian CIDP database

Author

Liberatore, G., Manganelli, F., Cocito, D., Fazio, R., Briani, C., Filosto, M., Benedetti, L., Antonini, G., Cosentino, G., Jann, S., Mazzeo, A., Cortese, A., Marfia, G. A., Clerici, A. M., Siciliano, G., Carpo, M., Sabatelli, M., Lauria, G., Rosso, T., Nobile Orazio, E., Doneddu, P. E., Gallia, F., Nobile-Orazio, E., Peci, E., Tronci, S., Santoro, L., Spina, E., Ruiz, M., Piccinelli, S. C., Beronio, A., Toscano, A., Gentile, L., Mataluni, G., Piccolo, L., Callegari, I., Fierro, B., Pinuccia, V. E., Bianchi, E., Beghi, E., Scrascia, F., Garnero, M., Schenone, A., Luigetti, M., Dacci, P., Leonardi, L., Schirinzi, E., Balducci, C., Cavaletti, G., Liberatore, G, Manganelli, F, Cocito, D, Fazio, R, Briani, C, Filosto, M, Benedetti, L, Antonini, G, Cosentino, G, Jann, S, Mazzeo, A, Cortese, A, Marfia, G, Clerici, A, Siciliano, G, Carpo, M, Sabatelli, M, Lauria, G, Rosso, T, Nobile Orazio, E, Doneddu, P, Gallia, F, Nobile-Orazio, E, Peci, E, Tronci, S, Santoro, L, Spina, E, Ruiz, M, Piccinelli, S, Beronio, A, Toscano, A, Gentile, L, Mataluni, G, Piccolo, L, Callegari, I, Fierro, B, Pinuccia, V, Bianchi, E, Beghi, E, Scrascia, F, Garnero, M, Schenone, A, Luigetti, M, Dacci, P, Leonardi, L, Schirinzi, E, Balducci, C, Cavaletti, G, Liberatore, G., Manganelli, F., Cocito, D., Fazio, R., Briani, C., Filosto, M., Benedetti, L., Antonini, G., Cosentino, G., Jann, S., Mazzeo, A., Cortese, A., Marfia, G. A., Clerici, A. M., Siciliano, G., Carpo, M., Sabatelli, M., Lauria, G., Rosso, T., Nobile Orazio, E., Doneddu, P. E., Gallia, F., Nobile-Orazio, E., Peci, E., Tronci, S., Santoro, L., Spina, E., Ruiz, M., Piccinelli, S. C., Beronio, A., Toscano, A., Gentile, L., Mataluni, G., Piccolo, L., Callegari, I., Fierro, B., Pinuccia, V. E., Bianchi, E., Beghi, E., Scrascia, F., Garnero, M., Schenone, A., Luigetti, M., Dacci, P., Leonardi, L., Schirinzi, E., Balducci, C., and Cavaletti, G.

Subjects
medicine.medical_specialty, peripheral neuropathy, Response to therapy, Motor nerve, CIDP, Settore MED/26, chronic inflammatory demyelinating neuropathy, diagnostic criteria, EMG, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, In patient, Nerve biopsy, medicine.diagnostic_test, business.industry, General Neuroscience, Polyradiculoneuropathy, medicine.disease, Chronic inflammatory demyelinating neuropathy, Diagnostic criteria, Peripheral neuropathy, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Clinical diagnosis, Neurology (clinical), business, 030217 neurology & neurosurgery, Sensory nerve
Abstract

The objective of our work was to report the clinical features and the relevance of diagnostic investigations in patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). We retrospectively reviewed data from patients with a clinical diagnosis of CIDP included in a national database. Among the 500 included patients with a clinical diagnosis of CIDP, 437 patients (87%) fulfilled the European Federation of Neurological Societies and Peripheral Nerve Society criteria for CIDP (definite in 407, probable in 26, possible in four). In 352 patients (86%) motor nerve conduction abnormalities consistent with demyelination were sufficient for the diagnosis of definite CIDP. In 55 patients, this diagnosis required the addition of one or two (from probable or from possible CIDP, respectively) supportive tests, while in 20 cases they improved the diagnosis from possible to probable CIDP, seven patients did not change diagnosis. Considering these 85 patients, cerebrospinal fluid studies were performed in 79 cases (93%) upgrading the certainty of diagnosis in 59% of examined patients. Sensory nerve conduction studies (NCS) were performed in 85% of patients with an improvement of diagnosis in 32% of cases. Nerve biopsy and ultrasound and magnetic resonance imaging (US/MRI) exams resulted positive in about 40% of examined patients, but they were performed in few patients (7 patients and 16 patients, respectively). A response to the therapy was present in 84% of treated patients (n = 77), contributing to support the diagnosis in 40 patients in whom the other supportive criteria were not sufficient. In most patients with CIDP the diagnosis is possible solely with motor NCS while other investigations may help improving the diagnosis in a minority of patients.

Published
2020

26. Generation of an induced pluripotent stem cell line (UCSCi002-A) from a patient with a variant in TARDBP gene associated with familial amyotrophic lateral sclerosis and frontotemporal dementia

Author

Martello, Francesco, Lattante, Serena, Doronzio, Paolo Niccolo', Conte, A., Bisogni, G., Orteschi, D., Luigetti, Marco, Marrucci, M. A., Zollino, Marcella, Sabatelli, Mario, Marangi, Giuseppe, Martello F., Lattante S. (ORCID:0000-0003-2891-0340), Doronzio P. N., Luigetti M. (ORCID:0000-0001-7539-505X), Zollino M. (ORCID:0000-0003-4871-9519), Sabatelli M. (ORCID:0000-0001-6635-4985), Marangi G. (ORCID:0000-0002-6898-8882), Martello, Francesco, Lattante, Serena, Doronzio, Paolo Niccolo', Conte, A., Bisogni, G., Orteschi, D., Luigetti, Marco, Marrucci, M. A., Zollino, Marcella, Sabatelli, Mario, Marangi, Giuseppe, Martello F., Lattante S. (ORCID:0000-0003-2891-0340), Doronzio P. N., Luigetti M. (ORCID:0000-0001-7539-505X), Zollino M. (ORCID:0000-0003-4871-9519), Sabatelli M. (ORCID:0000-0001-6635-4985), and Marangi G. (ORCID:0000-0002-6898-8882)

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that selectively affects motor neurons. In 20% of cases, ALS appears in comorbidity with frontotemporal dementia (FTD). We generated patient-derived-induced Pluripotent Stem Cells (iPSCs), from an ALS/FTD patient. The patient had a familial form of the disease and a missense variant in TARDBP gene. We used an established protocol based on Sendai virus to reprogram fibroblasts. We confirmed the stemness and the pluripotency of the iPSC clones, thus generating embryoid bodies. We believe that the iPSC line carrying a TARDBP mutation could be a valuable tool to investigate TDP-43 proteinopathy linked to ALS.

Published
2022

27. Clinical features and outcome of patients with autoimmune cerebellar ataxia evaluated with the Scale for the Assessment and Rating of Ataxia

Author

Damato, Valentina, Papi, Claudia, Spagni, Gregorio, Evoli Stampanoni-B, Amelia, Silvestri, Gabriella, Masi, Gianvito, Sabatelli, Eleonora, Campetella, Lucia, Mckeon, A., Andreetta, F., Riso, V., Monte, Gabriele, Luigetti, Marco, Primiano, Guido Alessandro, Calabresi, Paolo, Iorio, Raffaele, Damato V., Papi C., Spagni G., Evoli A. (ORCID:0000-0003-0282-8787), Silvestri G. (ORCID:0000-0002-1950-1468), Masi G., Sabatelli E., Campetella L., Monte G., Luigetti M. (ORCID:0000-0001-7539-505X), Primiano G., Calabresi P. (ORCID:0000-0003-0326-5509), Iorio R. (ORCID:0000-0002-6270-0956), Damato, Valentina, Papi, Claudia, Spagni, Gregorio, Evoli Stampanoni-B, Amelia, Silvestri, Gabriella, Masi, Gianvito, Sabatelli, Eleonora, Campetella, Lucia, Mckeon, A., Andreetta, F., Riso, V., Monte, Gabriele, Luigetti, Marco, Primiano, Guido Alessandro, Calabresi, Paolo, Iorio, Raffaele, Damato V., Papi C., Spagni G., Evoli A. (ORCID:0000-0003-0282-8787), Silvestri G. (ORCID:0000-0002-1950-1468), Masi G., Sabatelli E., Campetella L., Monte G., Luigetti M. (ORCID:0000-0001-7539-505X), Primiano G., Calabresi P. (ORCID:0000-0003-0326-5509), and Iorio R. (ORCID:0000-0002-6270-0956)

Abstract

Background and purpose: This study was undertaken to assess the long-term outcome of patients with paraneoplastic and non paraneoplastic autoimmune cerebellar ataxia (ACA) using the Scale for the Assessment and Rating of Ataxia (SARA). Methods: Patients with subacute cerebellar ataxia admitted to our institution between September 2012 and April 2020 were prospectively recruited. Serum and/or cerebrospinal fluid was tested for neural autoantibodies by indirect immunofluorescence on mouse brain, cell-based assays, and radioimmunoassay. SARA and modified Rankin Scale (mRS) score were employed to assess patients’ outcome. Results: Fifty-five patients were recruited, of whom 23 (42%) met the criteria for cerebellar ataxia of autoimmune etiology. Neural autoantibodies were detected in 22 of 23 patients (Yo–immunoglobulin G [IgG], n = 6; glutamic acid decarboxylase 65–IgG, n = 3; metabotropic glutamate receptor 1–IgG, n = 2; voltage-gated calcium channel P/Q type–IgG, n = 2; Hu-IgG, n = 1; glial fibrillary acidic protein–IgG, n = 1; IgG-binding unclassified antigens, n = 7). Thirteen patients were diagnosed with paraneoplastic cerebellar syndrome (PCS) and 10 with idiopathic ACA. All patients received immunotherapy. Median SARA score was higher in the PCS group at all time points (p = 0.0002), while it decreased significantly within the ACA group (p = 0.049) after immunotherapy. Patients with good outcome (mRS ≤ 2) had less neurological disability (SARA < 15) at disease nadir (p = 0.039) and presented less frequently with paraneoplastic neurological syndrome (p = 0.0028). The univariate linear regression model revealed a good correlation between mRS and SARA score both at disease onset (p < 0.0001) and at last follow-up (p < 0.0001). SARA score < 11 identified patients with good outcome. Conclusions: Patients with idiopathic ACA significantly improved after immunotherapy. SARA score

Published
2022

30. Fahr's Syndrome in a Sporadic Case

Author

Brunetti, V., Ferilli, M., Luigetti, M., Luigetti M. (ORCID:0000-0001-7539-505X), Brunetti, V., Ferilli, M., Luigetti, M., and Luigetti M. (ORCID:0000-0001-7539-505X)

Abstract

NOT AVAILABLE

Published
2019

31. A multicenter retrospective study of charcot-marie-tooth disease type 4B (CMT4B) associated with mutations in myotubularin-related proteins (MTMRs)

Author

Pareyson, D., Stojkovic, T., Reilly, M. M., Leonard-Louis, S., Laura, M., Blake, J., Parman, Y., Battaloglu, E., Tazir, M., Bellatache, M., Bonello-Palot, N., Levy, N., Sacconi, S., Guimaraes-Costa, R., Attarian, S., Latour, P., Sole, G., Megarbane, A., Horvath, R., Ricci, G., Choi, B. -O., Schenone, A., Gemelli, C., Geroldi, A., Sabatelli, M., Luigetti, M., Santoro, L., Manganelli, F., Quattrone, A., Valentino, P., Murakami, T., Scherer, S. S., Dankwa, L., Shy, M. E., Bacon, C. J., Herrmann, D. N., Zambon, A., Tramacere, I., Pisciotta, C., Magri, S., Previtali, S. C., Bolino, A., Sabatelli M. (ORCID:0000-0001-6635-4985), Luigetti M. (ORCID:0000-0001-7539-505X), Santoro L., Pareyson, D., Stojkovic, T., Reilly, M. M., Leonard-Louis, S., Laura, M., Blake, J., Parman, Y., Battaloglu, E., Tazir, M., Bellatache, M., Bonello-Palot, N., Levy, N., Sacconi, S., Guimaraes-Costa, R., Attarian, S., Latour, P., Sole, G., Megarbane, A., Horvath, R., Ricci, G., Choi, B. -O., Schenone, A., Gemelli, C., Geroldi, A., Sabatelli, M., Luigetti, M., Santoro, L., Manganelli, F., Quattrone, A., Valentino, P., Murakami, T., Scherer, S. S., Dankwa, L., Shy, M. E., Bacon, C. J., Herrmann, D. N., Zambon, A., Tramacere, I., Pisciotta, C., Magri, S., Previtali, S. C., Bolino, A., Sabatelli M. (ORCID:0000-0001-6635-4985), Luigetti M. (ORCID:0000-0001-7539-505X), and Santoro L.

Abstract

Objective: Charcot-Marie-Tooth (CMT) disease 4B1 and 4B2 (CMT4B1/B2) are characterized by recessive inheritance, early onset, severe course, slowed nerve conduction, and myelin outfoldings. CMT4B3 shows a more heterogeneous phenotype. All are associated with myotubularin-related protein (MTMR) mutations. We conducted a multicenter, retrospective study to better characterize CMT4B. Methods: We collected clinical and genetic data from CMT4B subjects in 18 centers using a predefined minimal data set including Medical Research Council (MRC) scores of nine muscle pairs and CMT Neuropathy Score. Results: There were 50 patients, 21 of whom never reported before, carrying 44 mutations, of which 21 were novel and six representing novel disease associations of known rare variants. CMT4B1 patients had significantly more-severe disease than CMT4B2, with earlier onset, more-frequent motor milestones delay, wheelchair use, and respiratory involvement as well as worse MRC scores and motor CMT Examination Score components despite younger age at examination. Vocal cord involvement was common in both subtypes, whereas glaucoma occurred in CMT4B2 only. Nerve conduction velocities were similarly slowed in both subtypes. Regression analyses showed that disease severity is significantly associated with age in CMT4B1. Slopes are steeper for CMT4B1, indicating faster disease progression. Almost none of the mutations in the MTMR2 and MTMR13 genes, responsible for CMT4B1 and B2, respectively, influence the correlation between disease severity and age, in agreement with the hypothesis of a complete loss of function of MTMR2/13 proteins for such mutations. Interpretation: This is the largest CMT4B series ever reported, demonstrating that CMT4B1 is significantly more severe than CMT4B2, and allowing an estimate of prognosis. ANN NEUROL 2019.

Published
2019

34. Sex-Related Risk of Cardiac Involvement in Hereditary Transthyretin Amyloidosis: Insights From THAOS

Author

Caponetti, A. G., Rapezzi, C., Gagliardi, C., Milandri, A., Dispenzieri, A., Kristen, A. V., Wixner, J., Maurer, M. S., Garcia-Pavia, P., Tournev, I., Plante-Bordeneuve, V., Chapman, D., Amass, L., van Cleemput, J., Waddington-Cruz, M., Schmidt, H., Dillmann, K. -U., Molgaard, H., Moreno, J. G., Costello, J. G., Beamud, F. M., Davila, L. G., Adams, D., Inamo, J., Lairez, O., Vita, G., Merlini, G., Cirami, C. L., Luigetti, M., Emdin, M., Sekijima, Y., Jeon, E. -S., Oh, J., Gonzalez Duarte Briseno, M. A., Nienhuis, H., Coelho, T., Conceicao, I., Azevedo, O., Badelita, S., Press, R., Parman, Y., Shah, S., Quan, D., Marburger, T., Polydefkis, M., Witteles, R., Gottlieb, S., Sarswat, N., Drachman, B., Steidley, D., Hummel, S., Slosky, D., Jacoby, D., Nativi-Nicolau, J., Tauras, J., Zivkovic, S., Tallaj, J., and Lenihan, D.

Subjects
myocardial involvement, ATTRv amyloidosis, myocardial involvement, registry, sex, sex, registry, NO, ATTRv amyloidosis
Published
2021

35. Ocular Involvement in Hereditary Amyloidosis

Author

Minnella, Angelo Maria, Rissotto, R., Antoniazzi, E., Di Girolamo, M., Luigetti, Marco, Maceroni, Martina, Bacherini, D., Falsini, Benedetto, Rizzo, Stanislao, Obici, L., Minnella A. M. (ORCID:0000-0001-5896-5313), Luigetti M. (ORCID:0000-0001-7539-505X), Maceroni M., Falsini B. (ORCID:0000-0002-3569-4968), Rizzo S. (ORCID:0000-0001-6302-063X), Minnella, Angelo Maria, Rissotto, R., Antoniazzi, E., Di Girolamo, M., Luigetti, Marco, Maceroni, Martina, Bacherini, D., Falsini, Benedetto, Rizzo, Stanislao, Obici, L., Minnella A. M. (ORCID:0000-0001-5896-5313), Luigetti M. (ORCID:0000-0001-7539-505X), Maceroni M., Falsini B. (ORCID:0000-0002-3569-4968), and Rizzo S. (ORCID:0000-0001-6302-063X)

Abstract

The term amyloidosis describes a group of rare diseases caused by protein conformation abnormalities resulting in extracellular deposition and accumulation of insoluble fibrillar aggregates. So far, 36 amyloid precursor proteins have been identified, and each one is responsible for a specific disease entity. Transthyretin amyloidosis (ATTRv) is one of the most common forms of systemic and ocular amyloidosis, due to the deposition of transthyretin (TTR), which is a transport protein mainly synthesized in the liver but also in the retinal pigment epithelial cells. ATTRv amyloidosis may be misdiagnosed with several other conditions, resulting in a significant diagnostic delay. Gelsolin and keratoepithelin are other proteins that, when mutated, are responsible for a systemic amyloid disease with significant ocular manifestations that not infrequently appear before systemic involvement. The main signs of ocular amyloid deposition are in the cornea, irido-corneal angle and vitreous, causing complications related to vasculopathy and neuropathy at the local level. This review aims at describing the main biochemical, histopathological and clinical features of systemic amyloidosis associated with eye involvement, with particular emphasis on the inherited forms. We discuss currently available treatments, focusing on ocular involvement and specific ophthalmologic management and highlighting the importance of a prompt treatment for the potential sight-threatening complications derived from amyloid deposition in ocular tissues.

Published
2021

36. Thr124Met myelin protein zero mutation mimicking motor neuron disease

Author

Bisogni, G., Romano, A., Conte, A., Tasca, Giorgio, Bernardo, D., Luigetti, Marco, Di Paolantonio, Andrea, Fabrizi, G. M., Patanella, A. K., Meleo, Emiliana, Sabatelli, Mario, Tasca G., Luigetti M. (ORCID:0000-0001-7539-505X), Di Paolantonio A., Meleo E., Sabatelli M. (ORCID:0000-0001-6635-4985), Bisogni, G., Romano, A., Conte, A., Tasca, Giorgio, Bernardo, D., Luigetti, Marco, Di Paolantonio, Andrea, Fabrizi, G. M., Patanella, A. K., Meleo, Emiliana, Sabatelli, Mario, Tasca G., Luigetti M. (ORCID:0000-0001-7539-505X), Di Paolantonio A., Meleo E., and Sabatelli M. (ORCID:0000-0001-6635-4985)

Abstract

Mutations in myelin protein zero (MPZ) are associated with heterogeneous manifestations. In this study, we report clinical, electrophysiological, pathological, and muscle MRI findings from two relatives with MPZ Thr124Met variants, disclosing different phenotypes. The proband was a 73-year-old female with a 12-year-story of atrophy, weakness, and fasciculations in her proximal and distal lower limbs. EMG examination showed neurogenic signs with active denervation together with reduced sensory action potentials, without sensory symptoms. The initial diagnosis was of a slowly progressive lower motor neuron disease (MND) with subclinical sensory axonal neuropathy. Two years later, the observation of her 60-year-old nephew, who had a distal sensory-motor neuropathy, prompted the analysis of inherited neuropathies-related genes and revealed a MPZ Thr124Met mutation in both cases. Our findings expand the clinical spectrum of MPZ-related neuropathy and highlight that Thr124Met mutation may cause a syndrome mimicking MND. The challenging issue to detect sensory features in the diagnostic MND work up is discussed.

Published
2021

37. Ixekizumab exposure associated with myelitis: A case report and a literature review

Author

Romozzi, Marina, Bellavia, Simone, Caldarola, Giacomo, De Simone, Clara, Luigetti, Marco, Calabresi, Paolo, Di Filippo, Mario, Masullo, Carlo, Lucchini, Matteo, Romozzi M., Bellavia S., Caldarola G. (ORCID:0000-0002-8837-9232), De Simone C. (ORCID:0000-0002-0898-0045), Luigetti M. (ORCID:0000-0001-7539-505X), Calabresi P. (ORCID:0000-0003-0326-5509), Di Filippo M., Masullo C. (ORCID:0000-0001-7798-3410), Lucchini M. (ORCID:0000-0002-0447-2297), Romozzi, Marina, Bellavia, Simone, Caldarola, Giacomo, De Simone, Clara, Luigetti, Marco, Calabresi, Paolo, Di Filippo, Mario, Masullo, Carlo, Lucchini, Matteo, Romozzi M., Bellavia S., Caldarola G. (ORCID:0000-0002-8837-9232), De Simone C. (ORCID:0000-0002-0898-0045), Luigetti M. (ORCID:0000-0001-7539-505X), Calabresi P. (ORCID:0000-0003-0326-5509), Di Filippo M., Masullo C. (ORCID:0000-0001-7798-3410), and Lucchini M. (ORCID:0000-0002-0447-2297)

Abstract

We describe a case of a 28-year-old man who developed a cervical myelitis while exposed to ixekizumab (IL-17 inhibitor) for psoriatic arthritis. Spinal MRI showed a T2 hyperintense lesion at the C4-C5 level while brain MRI was unspecific. Oligoclonal bands were absent and extensive screening for autoimmunity was negative. Rechallenge with ixekizumab was positive corroborating a relation between drug exposure and the neurological event. To the best of our knowledge, this is the first case of CNS inflammatory adverse event associated with ixekizumab. We also provide a review of case reports of demyelinating disorders associated with the use of biologic drugs for the treatment of psoriasis and psoriatic arthritis.

Published
2021

38. Reassessing IVIg therapy in chronic inflammatory demyelinating polyradiculoneuropathy during COVID-19: a chance to verify the need for chronic maintenance therapy

Author

Romozzi, Marina, Bisogni, G., Sabatelli, Mario, Luigetti, Marco, Romozzi M., Sabatelli M. (ORCID:0000-0001-6635-4985), Luigetti M. (ORCID:0000-0001-7539-505X), Romozzi, Marina, Bisogni, G., Sabatelli, Mario, Luigetti, Marco, Romozzi M., Sabatelli M. (ORCID:0000-0001-6635-4985), and Luigetti M. (ORCID:0000-0001-7539-505X)

Abstract

The outbreak of a severe acute respiratory syndrome caused by a novel coronavirus (COVID-19), has raised health concerns for patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), who are frequently on long-term immunotherapies. Treatment with IVIg does not increase the risk of contracting COVID-19, and the IVIg administration may have a protective role. However, infusions can expose patients to an increased risk of contracting SARS-CoV-2 due to repeated access to Health Facilities. In this report we analyzed the short-term follow-up of CIDP patients who modified their chronic IVIg therapy during pandemic. About half of CIDP patients regularly treated with IVIg tried to stop treatment and about 10% shifted to SCIg. Forty-two percent of the patients who stopped the treatment reported a clinical deterioration after suspension and had to restart IVIg. This study demonstrated that in selected cases it is possible to successfully stop the chronic IVIg treatment, even in patients who have been treated for several years.

Published
2021

39. Patisiran in hereditary transthyretin-mediated amyloidosis

Author

Luigetti, Marco, Servidei, Serenella, Luigetti M. (ORCID:0000-0001-7539-505X), Servidei S. (ORCID:0000-0001-8478-2799), Luigetti, Marco, Servidei, Serenella, Luigetti M. (ORCID:0000-0001-7539-505X), and Servidei S. (ORCID:0000-0001-8478-2799)

Abstract

N/A

Published
2021

40. Meta-analysis of pharmacogenetic interactions in amyotrophic lateral sclerosis clinical trials

Author

van Eijk, Ruben P. A, Jones, Ashley R., Sproviero, William, Shatunov, Aleksey, Shaw, Pamela J., Leigh, P. Nigel, Young, Carolyn A., Shaw, Christopher E., Mora, Gabriele, Mandrioli, Jessica, Borghero, Giuseppe, Volanti, Paolo, Diekstra, Frank P., van Rheenen, Wouter, Verstraete, Esther, Eijkemans, Marinus J. C, Veldink, Jan H., Chio, Adriano, Al-Chalabi, Ammar, van den Berg, Leonard H., van Es, Michael A, For UKMND-LiCALS and LITALS Study Group: Allen C, Counsell C, Farrin A, Al-Chalabi A, Dickie B, Kelly J, Leigh PN, Murphy CL, Payan C, Reynolds G, Shaw P, Steen IN, Thornhill M, Waters J, Zajicek J, Shaw PJ, Young CA, Morrison KE, Dhariwal S, Hornabrook R, Savage L, Burn DJ, Khoo TK, Dougherty A, Wijesekera L, Ellis CM, Ali R, O'Hanlon K, Panicker J, Pate L, Ray P, Wyatt L, Copeland L, Ealing J, Hamdalla H, Leroi I, Murphy C, O'Keeffe F, Oughton E, Partington L, Paterson P, Rog D, Sathish A, Sexton D, Smith J, Vanek H, Dodds S, Williams TL, Clarke J, Eziefula C, Howard R, Orrell R, Sidle K, Sylvester R, Barrett W, Merritt C, Talbot K, Turner MR, Whatley C, Williams C, Williams J, Cosby C, Hanemann CO, Imam I, Phillips C, Timings L, Crawford SE, Hewamadduma C, Hibberd R, Hollinger H, McDermott C, Mills G, Rafiq M, Taylor A, Waines E, Walsh T, Addison-Jones R, Birt J, Hare M, Majid T, Tortelli R, D'Errico E, Bartolomei I, Barbarossa E, Depau B, Costantino E, D'Amico E, Uncini A, Manzoli C, Quatrale R, Sette E, Montanari E, Merello M, Zarcone D, Mascolo M, Vignolo M, Messina S, Morelli C, Marinou K, Papetti L, Lunetta C, Gorni K, De Cicco D, Pipia C, Sola P, Georgoulopoulou E, Sagnelli A, Tedeschi, Gioacchino, Oggioni G, Nasuelli N, D'Ascenzo C, Cima V, Aiello M, Rizzi R, Rinaldi E, Luigetti M, Conte A, Torzini A, Greco G, Mutani R, Fuda G, Tommasi MA, van Eijk, Ruben P. A, Jones, Ashley R., Sproviero, William, Shatunov, Aleksey, Shaw, Pamela J., Leigh, P. Nigel, Young, Carolyn A., Shaw, Christopher E., Mora, Gabriele, Mandrioli, Jessica, Borghero, Giuseppe, Volanti, Paolo, Diekstra, Frank P., van Rheenen, Wouter, Verstraete, Esther, Eijkemans, Marinus J. C, Veldink, Jan H., Chio, Adriano, Al-Chalabi, Ammar, van den Berg, Leonard H., van Es, Michael A, For UKMND-LiCALS and LITALS Study Group: Allen, C, Counsell, C, Farrin, A, Al-Chalabi, A, Dickie, B, Kelly, J, Leigh, Pn, Murphy, Cl, Payan, C, Reynolds, G, Shaw, P, Steen, In, Thornhill, M, Waters, J, Zajicek, J, Shaw, Pj, Young, Ca, Morrison, Ke, Dhariwal, S, Hornabrook, R, Savage, L, Burn, Dj, Khoo, Tk, Dougherty, A, Wijesekera, L, Ellis, Cm, Ali, R, O'Hanlon, K, Panicker, J, Pate, L, Ray, P, Wyatt, L, Copeland, L, Ealing, J, Hamdalla, H, Leroi, I, Murphy, C, O'Keeffe, F, Oughton, E, Partington, L, Paterson, P, Rog, D, Sathish, A, Sexton, D, Smith, J, Vanek, H, Dodds, S, Williams, Tl, Clarke, J, Eziefula, C, Howard, R, Orrell, R, Sidle, K, Sylvester, R, Barrett, W, Merritt, C, Talbot, K, Turner, Mr, Whatley, C, Williams, C, Williams, J, Cosby, C, Hanemann, Co, Imam, I, Phillips, C, Timings, L, Crawford, Se, Hewamadduma, C, Hibberd, R, Hollinger, H, Mcdermott, C, Mills, G, Rafiq, M, Taylor, A, Waines, E, Walsh, T, Addison-Jones, R, Birt, J, Hare, M, Majid, T, Tortelli, R, D'Errico, E, Bartolomei, I, Barbarossa, E, Depau, B, Costantino, E, D'Amico, E, Uncini, A, Manzoli, C, Quatrale, R, Sette, E, Montanari, E, Merello, M, Zarcone, D, Mascolo, M, Vignolo, M, Messina, S, Morelli, C, Marinou, K, Papetti, L, Lunetta, C, Gorni, K, De Cicco, D, Pipia, C, Sola, P, Georgoulopoulou, E, Sagnelli, A, Tedeschi, Gioacchino, Oggioni, G, Nasuelli, N, D'Ascenzo, C, Cima, V, Aiello, M, Rizzi, R, Rinaldi, E, Luigetti, M, Conte, A, Torzini, A, Greco, G, Mutani, R, Fuda, G, and Tommasi, Ma

Subjects
Oncology, R853.C55, medicine.medical_specialty, Genotype, Neuroprotective Agent, Clinical Neurology, Nerve Tissue Proteins, Review, Amyotrophic Lateral Sclerosis, C9orf72 Protein, Lithium Carbonate, Neuroprotective Agents, Proportional Hazards Models, Proteins, Pharmacogenetics, Randomized Controlled Trials as Topic, Neurology (clinical), Article, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Journal Article, 030212 general & internal medicine, Amyotrophic lateral sclerosis, business.industry, Protein, Pharmacogenetic, medicine.disease, Clinical trial, RC0346, Meta-analysis, Nerve Tissue Protein, Proportional Hazards Model, business, 030217 neurology & neurosurgery, Meta-Analysis, Amyotrophic Lateral Sclerosi
Abstract

OBJECTIVE\ud \ud To assess whether genetic subgroups in recent amyotrophic lateral sclerosis (ALS) trials responded to treatment with lithium carbonate, but that the treatment effect was lost in a large cohort of nonresponders.\ud \ud METHODS\ud \ud Individual participant data were obtained from 3 randomized trials investigating the efficacy of lithium carbonate. We matched clinical data with data regarding the UNC13A and C9orf72 genotype. Our primary outcome was survival at 12 months. On an exploratory basis, we assessed whether the effect of lithium depended on the genotype.\ud \ud RESULTS\ud \ud Clinical data were available for 518 of the 606 participants. Overall, treatment with lithium carbonate did not improve 12-month survival (hazard ratio [HR] 1.0, 95% confidence interval [CI] 0.7-1.4; p = 0.96). Both the UNC13A and C9orf72 genotype were independent predictors of survival (HR 2.4, 95% CI 1.3-4.3; p = 0.006 and HR 2.5, 95% CI 1.1-5.2; p = 0.032, respectively). The effect of lithium was different for UNC13A carriers (p = 0.027), but not for C9orf72 carriers (p = 0.22). The 12-month survival probability for UNC13A carriers treated with lithium carbonate improved from 40.1% (95% CI 23.2-69.1) to 69.7% (95% CI 50.4-96.3).\ud \ud CONCLUSIONS\ud \ud This study incorporated genetic data into past ALS trials to determine treatment effects in a genetic post hoc analysis. Our results suggest that we should reorient our strategies toward finding treatments for ALS, start focusing on genotype-targeted treatments, and standardize genotyping in order to optimize randomization and analysis for future clinical trials.

Published
2017

41. Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

Author

Nicolas, A., Kenna, K. P., Renton, A. E., Ticozzi, N., Faghri, F., Chia, R., Dominov, J. A., Kenna, B. J., Nalls, M. A., Keagle, P., Rivera, A. M., van Rheenen, W., Murphy, N. A., van Vugt, J. J. F. A., Geiger, J. T., Van der Spek, R. A., Pliner, H. A., Shankaracharya, Smith, B. N., Marangi, G., Topp, S. D., Abramzon, Y., Gkazi, A. S., Eicher, J. D., Kenna, A., Logullo, F. O., Simone, I. L., Logroscino, G., Salvi, F., Bartolomei, I., Borghero, G., Murru, M. R., Costantino, E., Pani, C., Puddu, R., Caredda, C., Piras, V., Tranquilli, S., Cuccu, S., Corongiu, D., Melis, M., Milia, A., Marrosu, F., Marrosu, M. G., Floris, G., Cannas, A., Capasso, Monica, Caponnetto, C., Mancardi, G., Origone, P., Mandich, P., Conforti, F. L., Cavallaro, S., Mora, G., Marinou, K., Sideri, R., Penco, S., Mosca, L., Lunetta, C., Pinter, G. L., Corbo, M., Riva, N., Carrera, P., Volanti, P., Mandrioli, J., Fini, N., Fasano, A., Tremolizzo, L., Arosio, A., Ferrarese, C., Trojsi, F., Tedeschi, G., Monsurro, M. R., Piccirillo, G., Femiano, C., Ticca, A., Ortu, E., La Bella, V., Spataro, R., Colletti, T., Sabatelli, M., Zollino, M., Conte, A., Luigetti, M., Lattante, S., Santarelli, M., Petrucci, A., Pugliatti, M., Pirisi, A., Parish, L. D., Occhineri, P., Giannini, F., Battistini, S., Ricci, C., Benigni, M., Cau, T. B., Loi, D., Calvo, A., Moglia, C., Brunetti, M., Barberis, M., Restagno, G., Casale, F., Marrali, G., Fuda, G., Ossola, I., Cammarosano, S., Canosa, A., Ilardi, A., Manera, U., Grassano, M., Tanel, R., Pisano, F., Mazzini, L., Messina, S., D'Alfonso, S., Corrado, L., Ferrucci, L., Harms, M. B., Goldstein, D. B., Shneider, N. A., Goutman, S. A., Simmons, Z., Miller, T. M., Chandran, S., Pal, S., Manousakis, G., Appel, S. H., Simpson, E., Wang, L., Baloh, R. H., Gibson, S. B., Bedlack, R., Lacomis, D., Sareen, D., Sherman, A., Bruijn, L., Penny, M., Moreno, C. D. A. M., Kamalakaran, S., Allen, A. S., Boone, B. E., Brown, R. H., Carulli, J. P., Chesi, A., Chung, W. K., Cirulli, E. T., Cooper, G. M., Couthouis, J., Day-Williams, A. G., Dion, P. A., Gitler, A. D., Glass, J. D., Han, Y., Harris, T., Hayes, S. D., Jones, A. L., Keebler, J., Krueger, B. J., Lasseigne, B. N., Levy, S. E., Lu, Y. -F., Maniatis, T., McKenna-Yasek, D., Myers, R. M., Petrovski, S., Pulst, S. M., Raphael, A. R., Ravits, J. M., Ren, Z., Rouleau, G. A., Sapp, P. C., Sims, K. B., Staropoli, J. F., Waite, L. L., Wang, Q., Wimbish, J. R., Xin, W. W., Phatnani, H., Kwan, J., Broach, J., Arcila-Londono, X., Lee, E. B., Van Deerlin, V. M., Fraenkel, E., Ostrow, L. W., Baas, F., Zaitlen, N., Berry, J. D., Malaspina, A., Fratta, P., Cox, G. A., Thompson, L. M., Finkbeiner, S., Dardiotis, E., Hornstein, E., MacGowan, D. J. L., Heiman-Patterson, T., Hammell, M. G., Patsopoulos, N. A., Dubnau, J., Nath, A., Musunuri, R. L., Evani, U. S., Abhyankar, A., Zody, M. C., Kaye, J., Wyman, S. K., LeNail, A., Lima, L., Rothstein, J. D., Svendsen, C. N., Van Eyk, J. E., Maragakis, N. J., Kolb, S. J., Cudkowicz, M., Baxi, E., Benatar, M., Taylor, J. P., Wu, G., Rampersaud, E., Wuu, J., Rademakers, R., Zuchner, S., Schule, R., McCauley, J., Hussain, S., Cooley, A., Wallace, M., Clayman, C., Barohn, R., Statland, J., Swenson, A., Jackson, C., Trivedi, J., Khan, S., Katz, J., Jenkins, L., Burns, T., Gwathmey, K., Caress, J., McMillan, C., Elman, L., Pioro, E. P., Heckmann, J., So, Y., Walk, D., Maiser, S., Zhang, J., Silani, V., Gellera, C., Ratti, A., Taroni, F., Lauria, G., Verde, F., Fogh, I., Tiloca, C., Comi, G. P., Soraru, G., Cereda, C., De Marchi, F., Corti, S., Ceroni, M., Siciliano, G., Filosto, M., Inghilleri, M., Peverelli, S., Colombrita, C., Poletti, B., Maderna, L., Del Bo, R., Gagliardi, S., Querin, G., Bertolin, C., Pensato, V., Castellotti, B., Camu, W., Mouzat, K., Lumbroso, S., Corcia, P., Meininger, V., Besson, G., Lagrange, E., Clavelou, P., Guy, N., Couratier, P., Vourch, P., Danel, V., Bernard, E., Lemasson, G., Laaksovirta, H., Myllykangas, L., Jansson, L., Valori, M., Ealing, J., Hamdalla, H., Rollinson, S., Pickering-Brown, S., Orrell, R. W., Sidle, K. C., Hardy, J., Singleton, A. B., Johnson, J. O., Arepalli, S., Polak, M., Asress, S., Al-Sarraj, S., King, A., Troakes, C., Vance, C., de Belleroche, J., ten Asbroek, A. L. M. A., Munoz-Blanco, J. L., Hernandez, D. G., Ding, J., Gibbs, J. R., Scholz, S. W., Floeter, M. K., Campbell, R. H., Landi, F., Bowser, R., Kirby, J., Pamphlett, R., Gerhard, G., Dunckley, T. L., Brady, C. B., Kowall, N. W., Troncoso, J. C., Le Ber, I., Heiman-Patterson, T. D., Kamel, F., Van Den Bosch, L., Strom, T. M., Meitinger, T., Shatunov, A., Van Eijk, K. R., de Carvalho, M., Kooyman, M., Middelkoop, B., Moisse, M., McLaughlin, R. L., Van Es, M. A., Weber, M., Boylan, K. B., Van Blitterswijk, M., Morrison, K. E., Basak, A. N., Mora, J. S., Drory, V. E., Shaw, P. J., Turner, M. R., Talbot, K., Hardiman, O., Williams, K. L., Fifita, J. A., Nicholson, G. A., Blair, I. P., Esteban-Perez, J., Garcia-Redondo, A., Al-Chalabi, A., Al Kheifat, A., Andersen, P. M., Chio, A., Cooper-Knock, J., Dekker, A., Redondo, A. G., Gotkine, M., Hide, W., Iacoangeli, A., Kiernan, M., Landers, J. E., Mill, J., Neto, M. M., Pardina, J. M., Newhouse, S., Pinto, S., Pulit, S., Robberecht, W., Shaw, C., Sproviero, W., Tazelaar, G., Van Damme, P., van den Berg, L. H., van Vugt, J., Veldink, J. H., Zatz, M., Bauer, D. C., Twine, N. A., Rogaeva, E., Zinman, L., Brice, A., Feldman, E. L., Ludolph, A. C., Weishaupt, J. H., Trojanowski, J. Q., Stone, D. J., Tienari, P., Shaw, C. E., Traynor, B. J., Marangi G. (ORCID:0000-0002-6898-8882), Logroscino G. (ORCID:0000-0003-1301-5343), Mosca L. (ORCID:0000-0003-4641-0841), Fasano A., Sabatelli M. (ORCID:0000-0001-6635-4985), Zollino M. (ORCID:0000-0003-4871-9519), Conte A., Luigetti M. (ORCID:0000-0001-7539-505X), Lattante S. (ORCID:0000-0003-2891-0340), D'Alfonso S., Siciliano G., Valori M., Landi F. (ORCID:0000-0002-3472-1389), Nicolas, A., Kenna, K. P., Renton, A. E., Ticozzi, N., Faghri, F., Chia, R., Dominov, J. A., Kenna, B. J., Nalls, M. A., Keagle, P., Rivera, A. M., van Rheenen, W., Murphy, N. A., van Vugt, J. J. F. A., Geiger, J. T., Van der Spek, R. A., Pliner, H. A., Shankaracharya, Smith, B. N., Marangi, G., Topp, S. D., Abramzon, Y., Gkazi, A. S., Eicher, J. D., Kenna, A., Logullo, F. O., Simone, I. L., Logroscino, G., Salvi, F., Bartolomei, I., Borghero, G., Murru, M. R., Costantino, E., Pani, C., Puddu, R., Caredda, C., Piras, V., Tranquilli, S., Cuccu, S., Corongiu, D., Melis, M., Milia, A., Marrosu, F., Marrosu, M. G., Floris, G., Cannas, A., Capasso, Monica, Caponnetto, C., Mancardi, G., Origone, P., Mandich, P., Conforti, F. L., Cavallaro, S., Mora, G., Marinou, K., Sideri, R., Penco, S., Mosca, L., Lunetta, C., Pinter, G. L., Corbo, M., Riva, N., Carrera, P., Volanti, P., Mandrioli, J., Fini, N., Fasano, A., Tremolizzo, L., Arosio, A., Ferrarese, C., Trojsi, F., Tedeschi, G., Monsurro, M. R., Piccirillo, G., Femiano, C., Ticca, A., Ortu, E., La Bella, V., Spataro, R., Colletti, T., Sabatelli, M., Zollino, M., Conte, A., Luigetti, M., Lattante, S., Santarelli, M., Petrucci, A., Pugliatti, M., Pirisi, A., Parish, L. D., Occhineri, P., Giannini, F., Battistini, S., Ricci, C., Benigni, M., Cau, T. B., Loi, D., Calvo, A., Moglia, C., Brunetti, M., Barberis, M., Restagno, G., Casale, F., Marrali, G., Fuda, G., Ossola, I., Cammarosano, S., Canosa, A., Ilardi, A., Manera, U., Grassano, M., Tanel, R., Pisano, F., Mazzini, L., Messina, S., D'Alfonso, S., Corrado, L., Ferrucci, L., Harms, M. B., Goldstein, D. B., Shneider, N. A., Goutman, S. A., Simmons, Z., Miller, T. M., Chandran, S., Pal, S., Manousakis, G., Appel, S. H., Simpson, E., Wang, L., Baloh, R. H., Gibson, S. B., Bedlack, R., Lacomis, D., Sareen, D., Sherman, A., Bruijn, L., Penny, M., Moreno, C. D. A. M., Kamalakaran, S., Allen, A. S., Boone, B. E., Brown, R. H., Carulli, J. P., Chesi, A., Chung, W. K., Cirulli, E. T., Cooper, G. M., Couthouis, J., Day-Williams, A. G., Dion, P. A., Gitler, A. D., Glass, J. D., Han, Y., Harris, T., Hayes, S. D., Jones, A. L., Keebler, J., Krueger, B. J., Lasseigne, B. N., Levy, S. E., Lu, Y. -F., Maniatis, T., McKenna-Yasek, D., Myers, R. M., Petrovski, S., Pulst, S. M., Raphael, A. R., Ravits, J. M., Ren, Z., Rouleau, G. A., Sapp, P. C., Sims, K. B., Staropoli, J. F., Waite, L. L., Wang, Q., Wimbish, J. R., Xin, W. W., Phatnani, H., Kwan, J., Broach, J., Arcila-Londono, X., Lee, E. B., Van Deerlin, V. M., Fraenkel, E., Ostrow, L. W., Baas, F., Zaitlen, N., Berry, J. D., Malaspina, A., Fratta, P., Cox, G. A., Thompson, L. M., Finkbeiner, S., Dardiotis, E., Hornstein, E., MacGowan, D. J. L., Heiman-Patterson, T., Hammell, M. G., Patsopoulos, N. A., Dubnau, J., Nath, A., Musunuri, R. L., Evani, U. S., Abhyankar, A., Zody, M. C., Kaye, J., Wyman, S. K., LeNail, A., Lima, L., Rothstein, J. D., Svendsen, C. N., Van Eyk, J. E., Maragakis, N. J., Kolb, S. J., Cudkowicz, M., Baxi, E., Benatar, M., Taylor, J. P., Wu, G., Rampersaud, E., Wuu, J., Rademakers, R., Zuchner, S., Schule, R., McCauley, J., Hussain, S., Cooley, A., Wallace, M., Clayman, C., Barohn, R., Statland, J., Swenson, A., Jackson, C., Trivedi, J., Khan, S., Katz, J., Jenkins, L., Burns, T., Gwathmey, K., Caress, J., McMillan, C., Elman, L., Pioro, E. P., Heckmann, J., So, Y., Walk, D., Maiser, S., Zhang, J., Silani, V., Gellera, C., Ratti, A., Taroni, F., Lauria, G., Verde, F., Fogh, I., Tiloca, C., Comi, G. P., Soraru, G., Cereda, C., De Marchi, F., Corti, S., Ceroni, M., Siciliano, G., Filosto, M., Inghilleri, M., Peverelli, S., Colombrita, C., Poletti, B., Maderna, L., Del Bo, R., Gagliardi, S., Querin, G., Bertolin, C., Pensato, V., Castellotti, B., Camu, W., Mouzat, K., Lumbroso, S., Corcia, P., Meininger, V., Besson, G., Lagrange, E., Clavelou, P., Guy, N., Couratier, P., Vourch, P., Danel, V., Bernard, E., Lemasson, G., Laaksovirta, H., Myllykangas, L., Jansson, L., Valori, M., Ealing, J., Hamdalla, H., Rollinson, S., Pickering-Brown, S., Orrell, R. W., Sidle, K. C., Hardy, J., Singleton, A. B., Johnson, J. O., Arepalli, S., Polak, M., Asress, S., Al-Sarraj, S., King, A., Troakes, C., Vance, C., de Belleroche, J., ten Asbroek, A. L. M. A., Munoz-Blanco, J. L., Hernandez, D. G., Ding, J., Gibbs, J. R., Scholz, S. W., Floeter, M. K., Campbell, R. H., Landi, F., Bowser, R., Kirby, J., Pamphlett, R., Gerhard, G., Dunckley, T. L., Brady, C. B., Kowall, N. W., Troncoso, J. C., Le Ber, I., Heiman-Patterson, T. D., Kamel, F., Van Den Bosch, L., Strom, T. M., Meitinger, T., Shatunov, A., Van Eijk, K. R., de Carvalho, M., Kooyman, M., Middelkoop, B., Moisse, M., McLaughlin, R. L., Van Es, M. A., Weber, M., Boylan, K. B., Van Blitterswijk, M., Morrison, K. E., Basak, A. N., Mora, J. S., Drory, V. E., Shaw, P. J., Turner, M. R., Talbot, K., Hardiman, O., Williams, K. L., Fifita, J. A., Nicholson, G. A., Blair, I. P., Esteban-Perez, J., Garcia-Redondo, A., Al-Chalabi, A., Al Kheifat, A., Andersen, P. M., Chio, A., Cooper-Knock, J., Dekker, A., Redondo, A. G., Gotkine, M., Hide, W., Iacoangeli, A., Kiernan, M., Landers, J. E., Mill, J., Neto, M. M., Pardina, J. M., Newhouse, S., Pinto, S., Pulit, S., Robberecht, W., Shaw, C., Sproviero, W., Tazelaar, G., Van Damme, P., van den Berg, L. H., van Vugt, J., Veldink, J. H., Zatz, M., Bauer, D. C., Twine, N. A., Rogaeva, E., Zinman, L., Brice, A., Feldman, E. L., Ludolph, A. C., Weishaupt, J. H., Trojanowski, J. Q., Stone, D. J., Tienari, P., Shaw, C. E., Traynor, B. J., Marangi G. (ORCID:0000-0002-6898-8882), Logroscino G. (ORCID:0000-0003-1301-5343), Mosca L. (ORCID:0000-0003-4641-0841), Fasano A., Sabatelli M. (ORCID:0000-0001-6635-4985), Zollino M. (ORCID:0000-0003-4871-9519), Conte A., Luigetti M. (ORCID:0000-0001-7539-505X), Lattante S. (ORCID:0000-0003-2891-0340), D'Alfonso S., Siciliano G., Valori M., and Landi F. (ORCID:0000-0002-3472-1389)

Abstract

To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS. Using a large-scale genome-wide association study and exome sequencing, we identified KIF5A as a novel gene associated with ALS. Our data broaden the phenotype resulting from mutations in KIF5A and highlight the importance of cytoskeletal defects in the pathogenesis of ALS.

Published
2018

42. Does albuterol have an effect on neuromuscular junction dysfunction in spinal muscular atrophy?

Author

Pera, Mc, Luigetti, M, Sivo, S, Lapenta, Leonardo, Granata, G, Antonaci, Laura, Coratti, G, Forcina, N, Pane, M, Mercuri, E., Pera MC (ORCID:0000-0001-6777-1721), Luigetti M (ORCID:0000-0001-7539-505X), Sivo S, Granata G, Coratti G (ORCID:0000-0001-6666-5628), Pane M (ORCID:0000-0002-4851-6124), Mercuri E. (ORCID:0000-0002-9851-5365), Pera, Mc, Luigetti, M, Sivo, S, Lapenta, Leonardo, Granata, G, Antonaci, Laura, Coratti, G, Forcina, N, Pane, M, Mercuri, E., Pera MC (ORCID:0000-0001-6777-1721), Luigetti M (ORCID:0000-0001-7539-505X), Sivo S, Granata G, Coratti G (ORCID:0000-0001-6666-5628), Pane M (ORCID:0000-0002-4851-6124), and Mercuri E. (ORCID:0000-0002-9851-5365)

Abstract

No abstract.

Published
2018

43. Assessment of neurological manifestations in hospitalized patients with COVID-19

Author

Luigetti, M., Iorio, R., Bentivoglio, A. R., Tricoli, L., Riso, V., Marotta, J., Piano, C., Primiano, G., Zileri Del Verme, L., Lo Monaco, M. R., Calabresi, P., Abbate, Valeria, Acampora, Nicola, Addolorato, Giovanni, Agostini, Fabiana, Ainora, Maria Elena, Akacha, Karim, Amato, Elena, Andreani, Francesca, Andriollo, Gloria, Annetta, Maria Giuseppina, Annicchiarico, Brigida Eleonora, Antonelli, Mariangela, Antonucci, Gabriele, Anzellotti, Gian Marco, Armuzzi, Alessandro, Baldi, Fabiana, Barattucci, Ilaria, Barillaro, Christian, Barone, Fabiana, Bellantone, Rocco Domenico Alfonso, Bellieni, Andrea, Bello, Giuseppe, Benicchi, Andrea, Benvenuto, Francesca, Berardini, Ludovica, Berloco, Filippo, Bernabei, Roberto, Bianchi, Antonio, Biasucci, Daniele Guerino, Biasucci, Luigi Marzio, Bibbò, Stefano, Bini, Alessandra, Bisanti, Alessandra, Biscetti, Federico, Bocci, Maria Grazia, Bonadia, Nicola, Bongiovanni, Filippo, Borghetti, Alberto, Bosco, Giulia, Bosello, Silvia, Bove, Vincenzo, Bramato, Giulia, Brandi, Vincenzo, Bruni, Teresa, Bruno, Carmine, Bruno, Dario, Bungaro, Maria Chiara, Buonomo, Alessandro, Burzo, Livia, Calabrese, Angelo, Calvello, Maria Rosaria, Cambieri, Andrea, Cambise, Chiara, Cammà, Giulia, Candelli, Marcello, Canistro, Gennaro, Cantanale, Antonello, Capalbo, Gennaro, Capaldi, Lorenzo, Capone, Emanuele, Capristo, Esmeralda, Carbone, Luigi, Cardone, Silvia, Carelli, Simone, Carfì, Angelo, Carnicelli, Annamaria, Caruso, Cristiano, Casciaro, Francesco Antonio, Catalano, Lucio, Cauda, Roberto, Cecchini, Andrea Leonardo, Cerrito, Lucia, Cesarano, Melania, Chiarito, Annalisa, Cianci, Rossella, Cicchinelli, Sara, Ciccullo, Arturo, Cicetti, Marta, Ciciarello, Francesca, Cingolani, Antonella, Cipriani, Maria Camilla, Consalvo, Maria Ludovica, Coppola, Gaetano, Corbo, Giuseppe Maria, Corsello, Andrea, Costante, Federico, Costanzi, Matteo, Covino, Marcello, Crupi, Davide, Cutuli, Salvatore Lucio, DAddio, Stefano, DAlessandro, Alessia, DAlfonso, Maria Elena, DAngelo, Emanuela, DAversa, Francesca, Damiano, Fernando, De Berardinis, Gian Maria, De Cunzo, Tommaso, De Gaetano, Donati Katleen, De Luca, Giulio, De Matteis, Giuseppe, De Pascale, Gennaro, De Santis, Paolo, De Siena, Martina, De Vito, Francesco, Del Gatto, Valeria, Del Giacomo, Paola, Del Zompo, Fabio, DellAnna, Antonio Maria, Della, Polla Davide, Di Gialleonardo, Luca, Di Giambenedetto, Simona, Di Luca, Roberta, Di Maurizio, Luca, Di Muro, Mariangela, Dusina, Alex, Eleuteri, Davide, Esperide, Alessandra, Fachechi, Daniele, Faliero, Domenico, Falsiroli, Cinzia, Fantoni, Massimo, Fedele, Annalaura, Feliciani, Daniela, Ferrante, Cristina, Ferrone, Giuliano, Festa, Rossano, Fiore, Maria Chiara, Flex, Andrea, Forte, Evelina, Franceschi, Francesco, Francesconi, Alessandra, Franza, Laura, Funaro, Barbara, Fuorlo, Mariella, Fusco, Domenico, Gabrielli, Maurizio, Gaetani, Eleonora, Galletta, Claudia, Gallo, Antonella, Gambassi, Giovanni, Garcovich, Matteo, Gasbarrini, Antonio, Gasparrini, Irene, Gelli, Silvia, Giampietro, Antonella, Gigante, Laura, Giuliano, Gabriele, Giuliano, Giorgia, Giupponi, Bianca, Gremese, Elisa, Grieco, Domenico Luca, Guerrera, Manuel, Guglielmi, Valeria, Guidone, Caterina, Gullì, Antonio, Iaconelli, Amerigo, Iafrati, Aurora, Ianiro, Gianluca, Iaquinta, Angela, Impagnatiello, Michele, Inchingolo, Riccardo, Intini, Enrica, Iorio, Raffaele, Izzi, Immacolata Maria, Jovanovic, Tamara, Kadhim, Cristina, La Macchia, Rosa, La Milia, Daniele Ignazio, Landi, Francesco, Landi, Giovanni, Landi, Rosario, Landolfi, Raffaele, Leo, Massimo, Leone, Paolo Maria, Levantesi, Laura, Liguori, Antonio, Liperoti, Rosa, Lizzio, Marco Maria, Lo Monaco Maria, Rita, Locantore, Pietro, Lombardi, Francesco, Lombardi, Gianmarco, Lopetuso, Loris, Loria, Valentina, Losito, Angela Raffaella, Lucia, Mothanje Barbara Patricia, Macagno, Francesco, Macerola, Noemi, Maggi, Giampaolo, Maiuro, Giuseppe, Mancarella, Francesco, Mangiola, Francesca, Manno, Alberto, Marchesini, Debora, Maresca, Gian Marco, Marrone, Giuseppe, Martis, Ilaria, Martone, Anna Maria, Marzetti, Emanuele, Mattana, Chiara, Matteo, Maria Valeria, Maviglia, Riccardo, Mazzarella, Ada, Memoli, Carmen, Miele, Luca, Migneco, Alessio, Mignini, Irene, Milani, Alessandro, Milardi, Domenico, Montalto, Massimo, Montemurro, Giuliano, Monti, Flavia, Montini, Luca, Morena, Tony Christian, Morra, Vincenzina, Morretta, Chiara, Moschese, Davide, Murace, Celeste Ambra, Murdolo, Martina, Murri, Rita, Napoli, Marco, Nardella, Elisabetta, Natalello, Gerlando, Natalini, Daniele, Navarra, Simone Maria, Nesci, Antonio, Nicoletti, Alberto, Nicoletti, Rocco, Nicoletti, Tommaso Filippo, Nicolò, Rebecca, Nicolotti, Nicola, Nista, Enrico Celestino, Nuzzo, Eugenia, Oggiano, Marco, Ojetti, Veronica, Pagano, Francesco Cosimo, Paiano, Gianfranco, Pais, Cristina, Pallavicini, Federico, Palombo, Andrea, Paolillo, Federico, Papa, Alfredo, Papanice, Domenico, Papparella, Luigi Giovanni, Paratore, Mattia, Parrinello, Giuseppe, Pasciuto, Giuliana, Pasculli, Pierpaolo, Pecorini, Giovanni, Perniola, Simone, Pero, Erika, Petricca, Luca, Petrucci, Martina, Picarelli, Chiara, Piccioni, Andrea, Piccolo, Annalisa, Piervincenzi, Edoardo, Pignataro, Giulia, Pignataro, Raffaele, Pintaudi, Gabriele, Pisapia, Luca, Pizzoferrato, Marco, Pizzolante, Fabrizio, Pola, Roberto, Policola, Caterina, Pompili, Maurizio, Pontecorvi, Flavia, Pontecorvi, Valerio, Ponziani, Francesca, Popolla, Valentina, Porceddu, Enrica, Porfidia, Angelo, Porro, Lucia Maria, Potenza, Annalisa, Pozzana, Francesca, Privitera, Giuseppe, Pugliese, Daniela, Pulcini, Gabriele, Racco, Simona, Raffaelli, Francesca, Ramunno, Vittoria, Rapaccini, Gian Ludovico, Richeldi, Luca, Rinninella, Emanuele, Rocchi, Sara, Romanò, Bruno, Romano, Stefano, Rosa, Federico, Rossi, Laura, Rossi, Raimondo, Rossini, Enrica, Rota, Elisabetta, Rovedi, Fabiana, Rubino, Carlotta, Rumi, Gabriele, Russo, Andrea, Sabia, Luca, Salerno, Andrea, Salini, Sara, Salvatore, Lucia, Samori, Dehara, Sandroni, Claudio, Sanguinetti, Maurizio, Santarelli, Luca, Santini, Paolo, Santolamazza, Danilo, Santoliquido, Angelo, Santopaolo, Francesco, Santoro, Michele Cosimo, Sardeo, Francesco, Sarnari, Caterina, Saviano, Angela, Saviano, Luisa, Scaldaferri, Franco, Scarascia, Roberta, Schepis, Tommaso, Schiavello, Francesca, Scoppettuolo, Giancarlo, Sedda, Davide, Sessa, Flaminio, Sestito, Luisa, Settanni, Carlo, Siciliano, Matteo, Siciliano, Valentina, Sicuranza, Rossella, Simeoni, Benedetta, Simonetti, Jacopo, Smargiassi, Andrea, Soave, Paolo Maurizio, Sonnino, Chiara, Staiti, Domenico, Stella, Claudia, Stella, Leonardo, Stival, Eleonora, Taddei, Eleonora, Talerico, Rossella, Tamburello, Elio, Tamburrini, Enrica, Tanzarella, Eloisa Sofia, Tarascio, Elena, Tarli, Claudia, Tersali, Alessandra, Tilli, Pietro, Timpano, Jacopo, Torelli, Enrico, Torrini, Flavia, Tosato, Matteo, Tosoni, Alberto, Tricoli, Luca, Tritto, Marcello, Tumbarello, Mario, Tummolo, Anita Maria, Vallecoccia, Maria Sole, Valletta, Federico, Varone, Francesco, Vassalli, Francesco, Ventura, Giulio, Verardi, Lucrezia, Vetrone, Lorenzo, Vetrugno, Giuseppe, Visconti, Elena, Visconti, Felicia, Viviani, Andrea, Zaccaria, Raffaella, Zaccone, Carmelina, Zelano, Lorenzo, Zileri Dal Verme, Lorenzo, and Zuccalà, Giuseppe

Subjects
Male, Hospitalized patients, muscle, Settore M-PSI/02 - PSICOBIOLOGIA E PSICOLOGIA FISIOLOGICA, neurological disorders, 0302 clinical medicine, Hyposmia, 030212 general & internal medicine, Respiratory system, education.field_of_study, Brain Diseases, Headache, virus diseases, Neuromuscular Diseases, Middle Aged, Hospitalization, medicine.anatomical_structure, Neurology, Female, medicine.symptom, Adult, medicine.medical_specialty, SARS‐CoV2, Coronavirus disease 2019 (COVID-19), Patients, Short Communication, Anosmia, precision medicine, Population, Encephalopathy, Short Communications, Clinical Neurology, Settore MED/26, 03 medical and health sciences, COVID‐19, Internal medicine, Throat, Influenza, Human, medicine, Humans, education, Aged, Retrospective Studies, business.industry, SARS-CoV-2, COVID-19, Hypoxia (medical), medicine.disease, respiratory tract diseases, body regions, Neurology (clinical), Nervous System Diseases, business, 030217 neurology & neurosurgery
Abstract

Background and purpose The objective of this study was to assess the neurological manifestations in a series of consecutive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-positive patients, comparing their frequency with a population hospitalized in the same period for flu/respiratory symptoms, finally not related to SARS-CoV-2. Methods Patients with flu/respiratory symptoms admitted to Fondazione Policlinico Gemelli hospital from 14 March 2020 to 20 April 2020 were retrospectively enrolled. The frequency of neurological manifestations of patients with SARS-CoV-2 infection was compared with a control group. Results In all, 213 patients were found to be positive for SARS-CoV-2, after reverse transcriptase polymerase chain reaction on nasal or throat swabs, whilst 218 patients were found to be negative and were used as a control group. Regarding central nervous system manifestations, in SARS-CoV-2-positive patients a higher frequency of headache, hyposmia and encephalopathy always related to systemic conditions (fever or hypoxia) was observed. Furthermore, muscular involvement was more frequent in SARS-CoV-2 infection. Conclusions Patients with COVID-19 commonly have neurological manifestations but only hyposmia and muscle involvement seem more frequent compared with other flu diseases.

Published
2020

44. Chronic inflammatory demyelinating polyradiculoneuropathy: can we make a diagnosis in patients not fulfilling electrodiagnostic criteria?

Author

Liberatore, G, Manganelli, F, Doneddu, Pe, Cocito, D, Fazio, R, Briani, C, Filosto, M, Benedetti, L, Mazzeo, A, Antonini, G, Cosentino, G, Jann, S, Cortese, A, Marfia, Ga, Clerici, Am, Siciliano, G, Carpo, M, Luigetti, M, Lauria, G, Rosso, T, Cavaletti, G, Santoro, L, Peci, E, Tronci, S, Ruiz, M, Piccinelli, Sc, Schenone, A, Leonardi, L, Toscano, A, Mataluni, G, Spina, E, Gentile, L, and Nobile-Orazio, E

Subjects
therapy, CIDP, EFNS/PNS
Published
2020

45. Epigenetic profiling of Italian patients identified methylation sites associated with hereditary transthyretin amyloidosis

Author

De Lillo, A., Pathak, G. A., De Angelis, F., Di Girolamo, M., Luigetti, Marco, Sabatelli, Mario, Perfetto, F., Frusconi, S., Manfellotto, D., Fuciarelli, M., Polimanti, R., Luigetti M. (ORCID:0000-0001-7539-505X), Sabatelli M. (ORCID:0000-0001-6635-4985), De Lillo, A., Pathak, G. A., De Angelis, F., Di Girolamo, M., Luigetti, Marco, Sabatelli, Mario, Perfetto, F., Frusconi, S., Manfellotto, D., Fuciarelli, M., Polimanti, R., Luigetti M. (ORCID:0000-0001-7539-505X), and Sabatelli M. (ORCID:0000-0001-6635-4985)

Abstract

Hereditary transthyretin (TTR) amyloidosis (hATTR) is a rare life-threatening disorder caused by amyloidogenic coding mutations located in TTR gene. To understand the high phenotypic variability observed among carriers of TTR disease-causing mutations, we conducted an epigenome-wide association study (EWAS) assessing more than 700,000 methylation sites and testing epigenetic difference of TTR coding mutation carriers vs. non-carriers. We observed a significant methylation change at cg09097335 site located in Beta-secretase 2 (BACE2) gene (standardized regression coefficient = −0.60, p = 6.26 × 10–8). This gene is involved in a protein interaction network enriched for biological processes and molecular pathways related to amyloid-beta metabolism (Gene Ontology: 0050435, q = 0.007), amyloid fiber formation (Reactome HSA-977225, q = 0.008), and Alzheimer’s disease (KEGG hsa05010, q = 2.2 × 10–4). Additionally, TTR and BACE2 share APP (amyloid-beta precursor protein) as a validated protein interactor. Within TTR gene region, we observed that Val30Met disrupts a methylation site, cg13139646, causing a drastic hypomethylation in carriers of this amyloidogenic mutation (standardized regression coefficient = −2.18, p = 3.34 × 10–11). Cg13139646 showed co-methylation with cg19203115 (Pearson’s r2 = 0.32), which showed significant epigenetic differences between symptomatic and asymptomatic carriers of amyloidogenic mutations (standardized regression coefficient = −0.56, p = 8.6 × 10–4). In conclusion, we provide novel insights related to the molecular mechanisms involved in the complex heterogeneity of hATTR, highlighting the role of epigenetic regulation in this rare disorder.

Published
2020

46. hATTR pathology: Nerve biopsy results from Italian referral centers

Author

Luigetti, Marco, Romozzi, Marina, Bisogni, G., Cardellini, D., Cavallaro, T., Di Paolantonio, Andrea, Fabrizi, G. M., Fenu, S., Gentile, L., Grandis, M., Marucci, G., Massucco, S., Mazzeo, A., Pareyson, D., Romano, Angela, Russo, M., Schenone, A., Tagliapietra, M., Tozza, S., Vita, G., Sabatelli, Mario, Luigetti M. (ORCID:0000-0001-7539-505X), Romozzi M., Di Paolantonio A., Romano A., Sabatelli M. (ORCID:0000-0001-6635-4985), Luigetti, Marco, Romozzi, Marina, Bisogni, G., Cardellini, D., Cavallaro, T., Di Paolantonio, Andrea, Fabrizi, G. M., Fenu, S., Gentile, L., Grandis, M., Marucci, G., Massucco, S., Mazzeo, A., Pareyson, D., Romano, Angela, Russo, M., Schenone, A., Tagliapietra, M., Tozza, S., Vita, G., Sabatelli, Mario, Luigetti M. (ORCID:0000-0001-7539-505X), Romozzi M., Di Paolantonio A., Romano A., and Sabatelli M. (ORCID:0000-0001-6635-4985)

Abstract

ObjectivePathological 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.

Published
2020

47. Hereditary transthyretin amyloidosis overview

Author

Manganelli, F., Fabrizi, G. M., Luigetti, Marco, Mandich, P., Mazzeo, A., Pareyson, D., Luigetti M. (ORCID:0000-0001-7539-505X), Manganelli, F., Fabrizi, G. M., Luigetti, Marco, Mandich, P., Mazzeo, A., Pareyson, D., and Luigetti M. (ORCID:0000-0001-7539-505X)

Abstract

Hereditary amyloidogenic transthyretin (ATTRv) amyloidosis is a rare autosomal dominantly inherited disorder caused by mutations in the transthyretin (TTR) gene. The pathogenetic model of ATTRv amyloidosis indicates that amyloidogenic, usually missense, mutations destabilize the native TTR favouring the dissociation of the tetramer into partially unfolded species that self-assemble into amyloid fibrils. Amyloid deposits and monomer-oligomer toxicity are the basis of multisystemic ATTRv clinical involvement. Peripheral nervous system (autonomic and somatic) and heart are the most affected sites. In the last decades, a better knowledge of pathomechanisms underlying the disease led to develop novel and promising drugs that are rapidly changing the natural history of ATTRv amyloidosis. Thus, clinicians face the challenge of timely diagnosis for addressing patients to appropriate treatment. As well, the progressive nature of ATTRv raises the issue of presymptomatic testing and risk management of carriers. The main aim of this review was to focus on what we know about ATTRv so far, from pathogenesis to clinical manifestations, diagnosis and hence patient’s monitoring and treatment, and from presymptomatic testing to management of carriers.

Published
2020

48. Sporadic hereditary neuropathies misdiagnosed as chronic inflammatory demyelinating polyradiculoneuropathy: Pitfalls and red flags

Author

Campagnolo, M., Taioli, F., Cacciavillani, M., Ruiz, M., Luigetti, Marco, Salvalaggio, A., Castellani, F., Testi, S., Ferrarini, M., Cavallaro, T., Gasparotti, R., Fabrizi, G. M., Briani, C., Luigetti M. (ORCID:0000-0001-7539-505X), Campagnolo, M., Taioli, F., Cacciavillani, M., Ruiz, M., Luigetti, Marco, Salvalaggio, A., Castellani, F., Testi, S., Ferrarini, M., Cavallaro, T., Gasparotti, R., Fabrizi, G. M., Briani, C., and Luigetti M. (ORCID:0000-0001-7539-505X)

Abstract

Hereditary neuropathies may be misdiagnosed with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). A correct diagnosis is crucial for avoiding unnecessary therapies and access genetic counseling. We report on nine patients (seven men, mean age 49.2 ± 16.1) diagnosed with and treated as CIDP, in whom mutations or variants of unknown significance (VUS) in genes associated with hereditary neuropathies were reported. All underwent neurological and neurophysiological examination, eight also cerebrospinal fluid (CSF) analysis. In 4/9, nerve ultrasound and/or MR-neurography were performed. All the patients complained of progressive upper or lower limbs sensory-motor symptoms, with heterogeneous disease duration (1-34 years, mean 8.6 ± 10.8). Neurophysiology showed demyelinating signs in seven patients, mixed findings with predominant axonal damage in two patients. Neuroimaging disclosed diffuse abnormalities at proximal and distal segments. Molecular screening showed PMP22 duplication in two patients, mutations in the MPZ, EGR2, and GJB1 genes were reported in each of the remaining patients. The two patients with mixed neurophysiological findings had p.Val30Met mutation in the transthyretin gene. Two patients had VUS in the MARS and HSPB1 genes. Four patients had partial response to immunomodulant therapies, and CSF and neurophysiological features suggesting an inflammatory condition concomitant with the hereditary neuropathy. Hereditary neuropathy may be misdiagnosed with CIDP. The most common pitfalls are CSF (high protein levels and oligoclonal bands), incorrect interpretation of neurophysiology, and transient benefit from therapies. Neuroimaging may be helpful in cases with atypical presentations or when severe axonal damage complicate the neurophysiological interpretation.

Published
2020

49. Frequency of diabetes and other comorbidities in chronic inflammatory demyelinating polyradiculoneuropathy and their impact on clinical presentation and response to therapy

Author

Doneddu, P. E., Cocito, D., Manganelli, F., Fazio, R., Briani, C., Filosto, M., Benedetti, L., Bianchi, E., Jann, S., Mazzeo, A., Antonini, Gabriele, Cosentino, G., Marfia, G. A., Cortese, A., Clerici, Anna Marina, Carpo, M., Schenone, A., Siciliano, Giovanni, Luigetti, Marco, Lauria, G., Rosso, T., Cavaletti, G., Beghi, E., Liberatore, G., Santoro, Luca, Spina, E., Peci, E., Tronci, S., Ruiz, M., Cotti Piccinelli, S., Verrengia, E. P., Gentile, L., Leonardi, L., Mataluni, G., Piccolo, L., Nobile-Orazio, E., Antonini G., Clerici A. M., Siciliano G., Luigetti M. (ORCID:0000-0001-7539-505X), Santoro L., Doneddu, P. E., Cocito, D., Manganelli, F., Fazio, R., Briani, C., Filosto, M., Benedetti, L., Bianchi, E., Jann, S., Mazzeo, A., Antonini, Gabriele, Cosentino, G., Marfia, G. A., Cortese, A., Clerici, Anna Marina, Carpo, M., Schenone, A., Siciliano, Giovanni, Luigetti, Marco, Lauria, G., Rosso, T., Cavaletti, G., Beghi, E., Liberatore, G., Santoro, Luca, Spina, E., Peci, E., Tronci, S., Ruiz, M., Cotti Piccinelli, S., Verrengia, E. P., Gentile, L., Leonardi, L., Mataluni, G., Piccolo, L., Nobile-Orazio, E., Antonini G., Clerici A. M., Siciliano G., Luigetti M. (ORCID:0000-0001-7539-505X), and Santoro L.

Abstract

Objectives To determine the prevalence of different comorbidities in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), and their impact on outcome, treatment choice and response. Methods Using a structured questionnaire, we collected information on comorbidities from 393 patients with CIDP fulfilling the European Federation of Neurological Societies and Peripheral Nerve Society criteria included in the Italian CIDP database. Results One or more comorbidities were reported by 294 patients (75%) and potentially influenced treatment choice in 192 (49%) leading to a less frequent use of corticosteroids. Response to treatment did not differ, however, from that in patients without comorbidities. Diabetes (14%), monoclonal gammopathy of undetermined significance (MGUS) (12%) and other immune disorders (16%) were significantly more frequent in patients with CIDP than expected in the general European population. Patients with diabetes had higher disability scores, worse quality of life and a less frequent treatment response compared with patients without diabetes. Patients with IgG-IgA or IgM MGUS had an older age at CIDP onset while patients with other immune disorders had a younger age at onset and were more frequently females. IgM MGUS was more frequent in patients with motor CIDP than in patients with typical CIDP. Conclusions Comorbidities are frequent in patients with CIDP and in almost 50% of them have an impact on treatment choice. Diabetes, MGUS and other immune diseases are more frequent in patients with CIDP than in the general population. Only diabetes seems, however, to have an impact on disease severity and treatment response possibly reflecting in some patients a coexisting diabetic neuropathy.

Published
2020

50. Nerve ultrasound in hereditary transthyretin amyloidosis: red flags and possible progression biomarkers

Author

Salvalaggio, A., Coraci, Daniele, Cacciavillani, M., Obici, L., Mazzeo, A., Luigetti, Marco, Pastorelli, F., Grandis, M., Cavallaro, T., Bisogni, G., Lozza, A., Gemelli, C., Gentile, L., Ermani, M., Fabrizi, G. M., Plasmati, R., Campagnolo, M., Castellani, F., Gasparotti, Roberto, Martinoli, C., Padua, Luca, Briani, C., Coraci D., Luigetti M. (ORCID:0000-0001-7539-505X), Gasparotti R., Padua L. (ORCID:0000-0003-2570-9326), Salvalaggio, A., Coraci, Daniele, Cacciavillani, M., Obici, L., Mazzeo, A., Luigetti, Marco, Pastorelli, F., Grandis, M., Cavallaro, T., Bisogni, G., Lozza, A., Gemelli, C., Gentile, L., Ermani, M., Fabrizi, G. M., Plasmati, R., Campagnolo, M., Castellani, F., Gasparotti, Roberto, Martinoli, C., Padua, Luca, Briani, C., Coraci D., Luigetti M. (ORCID:0000-0001-7539-505X), Gasparotti R., and Padua L. (ORCID:0000-0003-2570-9326)

Abstract

Background: Diagnostic delay of hereditary transthyretin amyloidosis (ATTRv, v for variant) prevents timely treatment and, therefore, concurs to the mortality of the disease. The aim of the present study was to explore with nerve ultrasound (US) possible red flags for early diagnosis in ATTRv patients with carpal tunnel syndrome (CTS) and/or polyneuropathy and in pre-symptomatic carriers. Methods: Patients and pre-symptomatic carriers with a TTR gene mutation were enrolled from seven Italian centers. Severity of CTS was assessed with neurophysiology and clinical evaluation. Median nerve cross-section area (CSA) was measured with US in ATTRv carriers with CTS (TTR-CTS). One thousand one hundred ninety-six idiopathic CTS were used as controls. Nerve US was also performed in several nerve trunks (median, ulnar, radial, brachial plexi, tibial, peroneal, sciatic, sural) in ATTRv patients with polyneuropathy and in pre-symptomatic carriers. Results: Sixty-two subjects (34 men, 28 women, mean age 59.8 years ± 12) with TTR gene mutation were recruited. With regard to CTS, while in idiopathic CTS there was a direct correlation between CTS severity and median nerve CSA (r = 0.55, p < 0.01), in the subgroup of TTR-CTS subjects (16 subjects, 5 with bilateral CTS) CSA did not significantly correlate with CTS severity (r = − 0.473). ATTRv patients with polyneuropathy showed larger CSA than pre-symptomatic carriers in several nerve sites, more pronounced at brachial plexi (p < 0.001). Conclusions: The present study identifies nerve morphological US patterns that may help in the early diagnosis (morpho-functional dissociation of median nerve in CTS) and monitoring of pre-symptomatic TTR carriers (larger nerve CSA at proximal nerve sites, especially at brachial plexi).

Published
2020

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