Predictors of respiratory failure in Guillain-Barré syndrome: a 22 year cohort study from a single Italian centre.

BACKGROUND AND PURPOSE: The study aimed to identify predictors of respiratory failure leading to mechanical ventilation (MV) and tracheostomy in Guillain-Barré syndrome (GBS). METHODS: Two hundred and thirty adult cases admitted to the Neurology Unit of Modena, Italy, between January 2000 and December 2021 were studied. A cut-off of MV starting within 8 weeks from onset of weakness was used. Univariable, multivariable logistic and Cox regression analyses were used to determine which pre-specified clinical and diagnostic characteristics were capable of predicting MV and tracheostomy, due to weaning failure. The model was internally validated within the full cohort. The Erasmus GBS Respiratory Insufficiency Score was retrospectively applied. RESULTS: One hundred and seventy-six cases (76.5%) were classified as classical sensorimotor GBS and 54 (23.4%) as variants. Thirty-two patients (13.9%) needed MV: 84.3% required respiratory support within 7 days. Independent predictors of respiratory failure and MV were older age, facial, bulbar, neck flexor weakness, dysautonomia, axonal electrophysiological subtype, cardiovascular comorbidities and higher disability score at entry. There was no association with abnormal spinal fluid parameters nor with positive serology for recent infections. Twenty-two patients (68.7%) were ventilated for more than 7 days; 4.7% died within 8 weeks. The patients who required MV were treated more often with plasma exchange. Independent predictors of tracheostomy due to weaning trial failure were facial, bulbar, neck flexor weakness, autonomic dysfunction, associated cardiovascular morbidities and axonal electrophysiological subtype on nerve conduction study. CONCLUSIONS: Our study indicates distinct predictors of MV and tracheostomy in GBS patients.

Myasthenia Gravis crossing Parkinson's disease: a 20 year study from single Italian center.

PURPOSE: The concomitant diagnosis of Parkinson's disease (PD) and Myasthenia Gravis (MG) is rare. The aim of the study was to report our experience of patients with both diagnoses. MATERIAL AND METHODS: We performed a retrospective analysis of patients with MG and PD, seen at Neurology Department, Modena, Italy from 2000 to 2020. We encountered 12 patients with both diagnoses. All had late onset MG (LOMG) and low Myasthenia Gravis Foundation of America (MGFA) severity scores at baseline. In respect of PD assessement, clinical signs were followed and summarized with modified Hoehn and Yahr staging (mHY). Patients were ranked as progressive or non-progressive, according to any change in mHY staging. We compared characteristics and outcome of the patients with age matched myasthenic subjects without PD. RESULTS: The male gender significantly prevailed (p < 0.01) as well as the presence of multiple comorbidities (p < 0.001) in patients with MG associated with PD. In respect of clinical course, MG was benign as most of cases remained stable (66.7%). Six cases showed worsening of mHY scores; only one subject became wheelchair bound by the end of follow up. This uneven progression, at least in our hands, might suggest that MG and PD can evolve independently. CONCLUSION: Clinicians should be alert about the association of PD and MG since early diagnosis and treatment are essential.

Cardiac disorders worsen the final outcome in myasthenic crisis undergoing non-invasive mechanical ventilation: a retrospective 20-year study from a single center.

The study was performed to evaluate the impact of cardiological disorders on the outcome of myasthenic crisis (MC) requiring ventilation. The study includes 90 cases admitted to the Neurology Unit of Modena, Italy (January 2000 - September 2020). All patients were eligible for a non-invasive ventilation (NIV) trial. We analyzed the effect of cardiac comorbidities on the outcomes, which were the need of invasive ventilation, the risk tracheostomy for weaning failure and the duration of intensive care unit (ICU) stay Females were 58.9% and males 41.1%. Median age at diagnosis was 59 and at MC was 65. Patients were classified as early (EOMG) or late (LOMG), 34.4 and 65.6% respectively, according to age above or below 50; 85% of patients were anti- AChR antibody positive. Hypertension and cardiac diseases occurred at the diagnosis in 61 and 44.4%, respectively. Invasive mechanical ventilation (MV) was needed in 34% of cases. Nine subjects (10%) underwent tracheostomy because of weaning failure. Independent predictors of NIV failure were atrial fibrillation (AF), either parossistic or persistent (OR 3.05, p < 0.01), hypertensive cardiopathy (HHD) (OR 2.52, p < 0.01) and ischaemic heart disease (IHD) (OR 3.08, p < 0.01). Hypertension (HT) had no statistical effect on the outcomes. HHD was a predictor of weaning failure (OR 4.01, p = 0.017). Our study shows that HHD, AF and IHD increase the risk of NIV failure in MC receiving ventilation.

Coincidental Onset of Ocular Myasthenia Gravis Following ChAdOx1 n-CoV-19 Vaccine against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2).

BACKGROUND: The Oxford-AstraZeneca vaccine ChAdOx1 (AZD1222, Vaxzevria) is playing a crucial role in counteracting the coronavirus disease-2019 (COVID-19) pandemic [1]. Since March 2021, reports of unexpected thrombotic events associated with thrombocytopenia and vaccination have been published [2]. To the best of our knowledge there is only one report about vaccination-associated myasthenia gravis (MG) occurring after a second dose of BNT162b2 (Pfizer-BioNTech).

Predictors of outcome in patients with myasthenic crisis undergoing non-invasive mechanical ventilation: A retrospective 20 year longitudinal cohort study from a single Italian center.

About 20% of patients with myasthenia gravis (MG) may develop myasthenic crisis (MC) requiring ventilation, either invasive (MV) or non-invasive (NIV) and intensive unit care (ICU). NIV failure in patients with MC can occur up to 60% of cases admitted to ICU. Moreover it is not known the outcome of MC receiving NIV. Purpose of this study was to identify predictors of outcome in MC who underwent non-invasive ventilator support outside ICU setting. We enrolled 90 patients, 53 females and 37 males admitted to University Hospital of Modena (Italy) between January 2000 and September 2020. Median age at MC was 65 years. Thirty-four patients (37.8%) required MV. Thymectomy was performed in 45 cases, associated with thymoma in 55%, with hyperplastic thymus in 33%. First-line treatment was plasmaexchange (38.8%) or intravenous immunoglobulins (45.6%). Males exhibited higher risk of MV than females .Patients in MV were treated with plasmaexchange as first-line therapy . Our in-hospital mortality rate was low. Nine patients underwent tracheostomy which was significantly related to male gender. Comorbidities had significant effect on length of ICU .Our study confirms as predictors of prognosis in our patients male gender, older age at onset, infections as trigger, pneumonia.

Next-generation sequencing application to investigate skeletal muscle channelopathies in a large cohort of Italian patients.

Non-dystrophic myotonias and periodic paralyses are a heterogeneous group of disabling diseases classified as skeletal muscle channelopathies. Their genetic characterization is essential for prognostic and therapeutic purposes; however, several genes are involved. Sanger-based sequencing of a single gene is time-consuming, often expensive; thus, we designed a next-generation sequencing panel of 56 putative candidate genes for skeletal muscle channelopathies, codifying for proteins involved in excitability, excitation-contraction coupling, and metabolism of muscle fibres. We analyzed a large cohort of 109 Italian patients with a suspect of NDM or PP by next-generation sequencing. We identified 24 patients mutated in CLCN1 gene, 15 in SCN4A, 3 in both CLCN1 and SCN4A, 1 in ATP2A1, 1 in KCNA1 and 1 in CASQ1. Eight were novel mutations: p.G395Cfs*32, p.L843P, p.V829M, p.E258E and c.1471+4delTCAAGAC in CLCN1, p.K1302R in SCN4A, p.L208P in ATP2A1 and c.280-1G>C in CASQ1 genes. This study demonstrated the utility of targeted next generation sequencing approach in molecular diagnosis of skeletal muscle channelopathies and the importance of the collaboration between clinicians and molecular geneticists and additional methods for unclear variants to make a conclusive diagnosis.

Predictors of respiratory decline in myotonic dystrophy type 1 (DM1): a longitudinal cohort study.

We studied 33 patients affected by juvenile and adult myotonic dystrophy type 1 (DM1). The aim of the study was to assess clinical and laboratory parameters that could predict the requirement of noninvasive ventilation (NIV) in DM1. Secondary outcome was to assess the interplay between genetic profile, muscle impairment severity and presence of cardiac comorbidities.Patients with genetic diagnosis of DM1 were recruited. An abnormal trinucleotide repeat (CTG) expansion of dystrophy protein kinase gene (DMPK) on chromosome 19q13.3 was the prerequisite for inclusion. The number of triplet repeats was measured in genomic DNA to classify subjects. A multidisciplinary team evaluated the patients every 6-8 months up to 18 years with serial cardiological and respiratory function assessments. Neurological progression was monitored using a validated DM1-specific rating scale (MIRS). Independent variables considered for the study outcomes were gender, genetic status, age of presentation, MIRS scores, and results of pulmonary function tests (PFTs).Patients were 17 males (51.5%) and 16 females (48.5%). 16 cases were younger than mean age of 31.4 years, the remaining 17 were up to 65. 12 subjects (36.4%) underwent NIV during follow up. Cardiac comorbidities were detected in 63.6% of cases and in 91% of patients in NIV. Among PFTs, forced vital capacity (FVC) was a reliable indicator of respiratory decline. FVC values were significantly associated with clinical muscle severity assessed by MIRS.Severity of muscular impairment, CTG expansion size, age and presence of cardiac comorbidities predict respiratory impairment in DM1.

Predictors of prognosis in type 1 myotonic dystrophy (DM1): longitudinal 18-years experience from a single center.

The aim of the study was to identify possible predictors of neurological worsening and need of non-invasive ventilation (NIV) in individuals affected by myotonic dystrophy type 1 (DM1), the most common form of adult-onset muscular dystrophy. METHODS: A retrospective observational cohort study was undertaken. Thirty-three patients with genetic diagnosis of DM1 were followed at our Neuromuscular unit in Modena. Abnormal trinucleotide repeat (CTG) expansion of dystrophy protein kinase gene (MDPK) on chromosome 19q 13.3 was the prerequisite for inclusion. The number of CTG repeats was determined. All the participants were older than 14 at the time of enrolment, therefore they could be included into the juvenile or adult form of the disease. Participants were neurologically evaluated every 6-8 months up to 18 years. Neurological impairment was assessed by Muscular Impairment Rating (MIRS), Medical Research Council (MRC), and modified Rankin (mRS) scales. The independent variables considered for prognosis were age at first evaluation, duration of the disease, CTG repeat number, gender, and presence of cardiac and vascular morbidities.Male patients were 51.5% and female patients 48.5%. Sixteen patients were younger than the mean age of 30.1 years, while the remaining 17 were up to 65. Twelve subjects (36.4%) underwent NIV before the end of follow-up. Muscle force and disability scores showed statistically significant deterioration (p < 0.001) during follow-up. The worsening was significantly higher among patients carrying higher number of CTG repeats and of younger age. The presence of cardio-vascular involvement has significant impact on neurological and respiratory progression.Neurological worsening is predicted by CTG expansion size, young age and presence of cardio-vascular morbidities.

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

INTRODUCTION: Since February 2020, the outbreak of COVID-19 in Italy has forced the health care system to undergo profound rearrangements in its services and facilities, especially in the worst-hit areas in Northern Italy. In this setting, inpatient and outpatient services had to rethink and reorganize their activities to meet the needs of patients during the "lockdown". The Italian Association of Myology developed a survey to estimate the impact of these changes on patients affected by neuromuscular disorders and on specialized neuromuscular centers during the acute phase of COVID-19 pandemic. METHODS: We developed an electronic survey that was sent to neuromuscular centers affiliated with the Italian Association of Myology, assessing changes in pharmacological therapies provision, outpatient clinical and instrumental services, support services (physiotherapy, nursing care, psychological support) and clinical trials. RESULTS: 40% of surveyed neuromuscular centers reported a reduction in outpatient visit and examinations (44.5% of centers in Northern regions; 25% of centers in Central regions; 50% of centers in Southern regions). Twenty-two% of centers postponed in-hospital administration of therapies for neuromuscular diseases (23.4% in Northern regions; 13.0% in Central regions; 20% in Southern regions). Diagnostic and support services (physiotherapy, nursing care, psychological support) were suspended in 57% of centers (66/43/44% in Northern, Central and Southern centers respectively) Overall, the most affected services were rehabilitative services and on-site outpatient visits, which were suspended in 93% of centers. Strategies adopted by neuromuscular centers to overcome these changes included maintaining urgent on-site visits, addressing patients to available services and promoting remote contact and telemedicine. CONCLUSIONS: Overall, COVID-19 pandemic resulted in a significant disruption of clinical and support services for patients with neuromuscular diseases. Despite the efforts to provide telemedicine consults to patients, this option could be promoted and improved further. A close collaboration between the different neuromuscular centers and service providers as well as further implementation of telehealth platforms are necessary to ensure quality care to NMD patients in the near future and in case of recurrent pandemic waves.

Antibody profile may predict outcome in ocular myasthenia gravis.

An unsolved issue remains whether there are clinical and immunological features to predict in a single patient the risk of conversion from ocular Myasthenia Gravis (OMG) to generalized disease (GMG) as 50-60% of patients may progress within 1-2 years since onset. Anti-acetylcholine receptor antibodies (AChR Abs) are found in up to 50% of OMG patients; muscle-specific tyrosine kinase antibodies (MuSK-Abs) are present in about 70% of the whole seronegative (SN), who usually develop a severe disease with bulbar involvement. We surveyed a cohort of 175 OMG patients with purely ocular symptoms and we compare the outcome of patients with antibodies to AChR or to MuSK with those seronegative for both Abs (DSN). All patients had purely ocular signs for at least 24 months. Gender, age at onset, time to generalization or to worsening in quantitative ocular QMG scores, electrophysiological results were analyzed. Males were 58.9%, females 41.1%. Patients with late onset of symptoms after 50 years (LOMG) were 78.3%. We assayed anti-MuSK-Abs in 4.7%, anti-AChR Abs in 38.5%; 57.3% were defined DSN. Thirty-seven patients (21.1%) progressed to GMG during the observational time: 23 were females, 62% of the whole group of the generalized subjects, 75% of MuSK-positive OMG converted to GMG versus the 26.2% of AChR positive and 13.7% of DSN. Statistical analysis showed that gender and presence of antibodies either to AChR or to MuSK were independent predictors of worse outcome; the DSN subjects had lower risk of conversion to GMG.

Identification and characterization of the novel m.8305C>T MTTK and m.4440G>A MTTM gene mutations causing mitochondrial myopathies.

We report on two novel mtDNA mutations in patients affected with mitochondrial myopathy. The first patient, a 44-year-old woman, had bilateral eyelid ptosis and the m.8305C>T mutation in the MTTK gene. The second patient, a 56-year-old man, had four-limb muscle weakness and the MTTM gene m.4440G>A mutation. Muscle biopsies in both patients showed ragged red fibers and numerous COX-negative fibers as well as a combined defect of complex I, III and IV activities. The two mutations were heteroplasmic and detected only in muscle tissue, with a higher mutation load in COX-negative fibers. Additionally, both mutations occurred in highly conserved mt-tRNA sites, and were not found by an in silico search in 30,589 human mtDNA sequences. Our report further expands the mutational and phenotypic spectrum of diseases associated with mutations in mitochondrial tRNA genes and reinforces the notion that mutations in mitochondrial tRNAs represent hot spots for mitochondrial myopathies in adults.

Factors affecting outcome in ocular myasthenia gravis.

AIM OF THE STUDY: 50%-60% of patients with ocular myasthenia gravis (OMG) progress to generalized myasthenia gravis (GMG) within two years. The aim of our study was to explore factors affecting prognosis of OMG and to test the predictive role of several independent clinical variables. MATERIALS AND METHODS: We reviewed a cohort of 168 Caucasian patients followed from September 2000 to January 2016. Several independent variables were considered as prognostic factors: gender, age of onset, results on electrophysiological tests, presence and level of antibodies against acetylcholine receptors (AChR Abs), treatments, thymic abnormalities. The primary outcome was the progression to GMG and/or the presence of bulbar symptoms. Secondary outcomes were either achievement of sustained minimal manifestation status or worsening in ocular quantitative MG subscore (O-QMGS) or worsening in total QMG score (T-QMGS), assessed by Myasthenia Gravis Foundation of America (MGFA) quantitative scores. Changes in mental and physical subscores of health-related quality of life (HRQoL) were assessed with SF-36 questionnaire. Variance analysis was used to interpret the differences between AChR Ab titers at different times of follow up among the generalized and non-generalized patients. RESULTS: Conversion to GMG occurred in 18.4% of patients; it was significantly associated with sex, later onset of disease and anti-AChR Ab positivity. Antibody titer above the mean value of 25.8 pmol/mL showed no significant effect on generalization. Sex and late onset of disease significantly affected T-QMGS worsening. None of the other independent variables significantly affected O-QMGS and HRQoL. CONCLUSIONS: Sex, later onset and anti-AChR Ab positivity were significantly associated with clinical worsening.