Therapeutic challenges and unmet needs in the management of myasthenia gravis: an Italian expert opinion.

Myasthenia gravis (MG) is a rare, autoimmune, neurological disorder. Most MG patients have autoantibodies against acetylcholine receptors (AChRs). Some have autoantibodies against muscle-specific tyrosine kinase (MuSK) or lipoprotein-receptor-related protein 4 (LRP4), and some are seronegative. Standard of care, which includes anti-cholinesterase drugs, thymectomy, corticosteroids (CS), and off-label use of non-steroidal immunosuppressive drugs (NSISTs), is bounded by potential side effects and limited efficacy in refractory generalized MG (gMG) patients. This highlights the need for new therapeutic approaches for MG. Eculizumab, a monoclonal antibody that inhibits the complement system, has been recently approved in Italy for refractory gMG. A panel of 11 experts met to discuss unmet therapeutic needs in the acute and chronic phases of the disease, as well as the standard of care for refractory patients. Survival was emphasized as an acute phase outcome. In the chronic phase, persistent remission and early recognition of exacerbations to prevent myasthenic crisis and respiratory failure were considered crucial. Refractory patients require treatments with fast onset of action, improved tolerability, and the ability to slow disease progression and increase life expectancy. The Panel agreed that eculizumab would presumably meet the therapeutic needs of many refractory gMG patients. The panel concluded that the unmet needs of current standard of care treatments for gMG are significant. Evaluating new therapeutic options accurately is essential to find the best balance between efficacy and tolerability for each patient. Collecting real-world data on novel molecules in routine clinical practice is necessary to address unmet needs.

Validation of the Italian version of the Myasthenia Gravis Impairment Index (MGII).

OBJECTIVE: To validate the Italian version of the Myasthenia Gravis Impairment Index (MGII). INTRODUCTION: MGII is a recent promising measure developed for MG patient evaluation. It includes a clinical severity evaluation and a patient-reported questionnaire. It has been developed in English and has demonstrated feasibility, reliability, and construct validity. Recently, its Dutch translation has been validated. METHODS: MGII was translated to Italian with a multi-step forward process. We assessed correlations with the following scores: Istituto Nazionale Carlo Besta score for Myasthenia Gravis (INCB-MG), the MG Activities of Daily Living (MG-ADL), the Myasthenia Gravis Composite (MGC), the Quality of Life 15 for Myasthenia Gravis (QOL15-MG), and the Myasthenia Gravis Disability (MGDIS). We also assessed differences in MGII scores by disease severity with the ANOVA Kruskal-Wallis test. RESULTS: One hundred forty-one patients were enrolled. The mean MGII total score was 13.3 ± 11.9 (range 0-49), with a mean ocular subscore of 3.7 ± 4.7 and a mean MGII generalized subscore of 9.6 ± 9.0. As expected, the MGII had a good correlation with the other severity scores. The MGII had a lower floor effect (3.5%) than the other measures. Twenty-five patients were assessed in follow-up; as expected, the MGII change scores had moderate correlations with change in other MG severity measures and lower correlations with quality of life measures. CONCLUSIONS: The MGII score was cross-culturally validated in an Italian cohort of MG patients. We confirmed its lower floor effect and the correlations with other MG measures including INCB-MG that was not evaluated in previous studies.

Age-dependent effect of susceptibility factors on the risk of intracerebral haemorrhage: Multicenter Study on Cerebral Hemorrhage in Italy (MUCH-Italy).

OBJECTIVE: To investigate the age-dependent impact of traditional stroke risk factors on the occurrence of intracerebral haemorrhage (ICH). METHODS: We performed a case-control analysis, comparing consecutive patients with ICH with age-matched and sex-matched stroke-free controls, enrolled in the setting of the Multicenter Study on Cerebral Hemorrhage in Italy (MUCH-Italy) between 2002 and 2014 by multivariable logistic regression model within subgroups stratified by age quartiles (Q1-Q4). RESULTS: We analysed 3492 patients and 3492 controls. The impact of untreated hypertension on the risk of ICH was higher in the lower than in the upper age quartile (OR 11.64, 95% CI 7.68 to 17.63 in Q1 vs OR 6.05, 95% CI 3.09 to 11.85 in Q4 with intermediate ORs in Q2 and Q3), while the opposite trend was observed for untreated hypercholesterolaemia (OR 0.63, 95% CI 0.45 to 0.97 in Q1 vs OR 0.36, 95% CI 0.26 to 0.56 in Q4 with intermediate ORs in Q2 and Q3). The effect of untreated diabetes and excessive alcohol intake was detected only in the older age group (OR 3.63, 95% CI 1.22 to 10.73, and OR 1.69, 95% CI 1.13 to 2.51, respectively). CONCLUSIONS: Our findings provide evidence of age-dependent differences in the effects of susceptibility factors on the risk of ICH.

Virtual visits for chronic neurologic disorders during COVID-19 pandemic.

BACKGROUND: COVID-19 pandemic has boosted telemedicine in medical clinical practice. Experiences in the management of chronic neurological disorders are limited and scattered. The aim of the study was to evaluate feasibility and efficacy of virtual visit for chronic neurological disorders during COVID-19 pandemic. METHODS: All patients scheduled for a visit during the lockdown period were contacted. The patients fell into four categories: (1) long-term follow-up, the patient was re-scheduled; (2) visit was necessary, teleconsultation was accepted; (3) problem was solved by phone call; and (4) visit was necessary and teleconsultation was not feasible, then visit was maintained. Google Meet was used. During the virtual visit, neurological examination was performed, and demographic and clinical characteristics were recorded. RESULTS: At the end of May 2020, 184 virtual visits for 178 patients were performed for the following diseases: myasthenia gravis (47 patients), multiple sclerosis (79), epilepsy (12), headache (6), and parkinsonism (34). The patients were 70 males and 108 females with a mean age of 53.5 years (range 13-90). During virtual visit, we were able to obtain a satisfactory neurological examination. CONCLUSIONS: We demonstrated feasibility and effectiveness of virtual visit in the management of a large group of patients with common chronic neurological disorders.

Different Clinical Phenotypes of Embolic Stroke of Undetermined Source: A Subgroup Analysis of 86 Patients.

INTRODUCTION AND STUDY AIM: Embolic strokes of undetermined source (ESUS) represent a rather recent diagnostic entity under clinical research for relapse prevention in cryptogenic stroke patients. Despite strict diagnostic criteria, ESUS definition ignores major clinical and radiological aspects, so including heterogeneous cases and probably influencing trial results. This study researches clinically relevant phenotypes among ESUS patients. PATIENTS AND METHODS: We evaluated ESUS patients admitted at Trento Stroke Unit over a 4-year period. Vascular risk factors (RFs), neurological deficit severity, presence of potential embolic sources, and ASCOD phenotype were recorded. Ischemic lesions were categorized considering their extension in 4 groups. Subgroup comparisons by predefined differences in age, amount of RFs, history of previous stroke, deficit severity, and stroke lesion extension were done. RESULTS: ESUS cases were 86. Patients younger than 50 years old (n = 17) had a lower prevalence of RFs, left atrial enlargement, left ventricle diastolic dysfunction, a higher proportion of ASCOD score A0 (P < .05). Patients without RFs (n = 18) differed from those with greater than or equal to 3 RFs (n = 23) for a younger age and a lower prevalence of potential causes of embolism (P < .05). Patients without a previous stroke (n = 70) were younger, had a lower prevalence of RFs, left ventricle diastolic dysfunction, a higher prevalence of ASCOD score A0 (P < .05). No differences were observed comparing minor and major clinical and radiological strokes. DISCUSSION AND CONCLUSIONS: ESUS patients can be distinguished in 2 opposite phenotypes defined by a lower and a higher load of atherosclerotic pathology. They may suggest possible underlying pathogenic mechanisms and support interpretation of ongoing trials results.

Serum cholesterol levels, HMG-CoA reductase inhibitors and the risk of intracerebral haemorrhage. The Multicenter Study on Cerebral Haemorrhage in Italy (MUCH-Italy).

OBJECTIVE: Although a concern exists that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) might increase the risk of intracerebral haemorrhage (ICH), the contribution of these agents to the relationship between serum cholesterol and disease occurrence has been poorly investigated. METHODS: We compared consecutive patients having ICH with age and sex-matched stroke-free control subjects in a case-control analysis, as part of the Multicenter Study on Cerebral Haemorrhage in Italy (MUCH-Italy), and tested the presence of interaction effects between total serum cholesterol levels and statins on the risk of ICH. RESULTS: A total of 3492 cases (mean age, 73.0±12.7 years; males, 56.6%) and 3492 control subjects were enrolled. Increasing total serum cholesterol levels were confirmed to be inversely associated with ICH. We observed a statistical interaction between total serum cholesterol levels and statin use for the risk of haemorrhage (Interaction OR (IOR), 1.09; 95% CI 1.05 to 1.12). Increasing levels of total serum cholesterol were associated with a decreased risk of ICH within statin strata (average OR, 0.87; 95% CI 0.86 to 0.88 for every increase of 0.26 mmol/l of total serum cholesterol concentrations), while statin use was associated with an increased risk (OR, 1.54; 95% CI 1.31 to 1.81 of the average level of total serum cholesterol). The protective effect of serum cholesterol against ICH was reduced by statins in strictly lobar brain regions more than in non-lobar ones. CONCLUSIONS: Statin therapy and total serum cholesterol levels exhibit interaction effects towards the risk of ICH. The magnitude of such effects appears higher in lobar brain regions.

Predictors of long-term recurrent vascular events after ischemic stroke at young age: the Italian Project on Stroke in Young Adults.

BACKGROUND: Data on long-term risk and predictors of recurrent thrombotic events after ischemic stroke at a young age are limited. METHODS AND RESULTS: We followed 1867 patients with first-ever ischemic stroke who were 18 to 45 years of age (mean age, 36.8±7.1 years; women, 49.0%), as part of the Italian Project on Stroke in Young Adults (IPSYS). Median follow-up was 40 months (25th to 75th percentile, 53). The primary end point was a composite of ischemic stroke, transient ischemic attack, myocardial infarction, or other arterial events. One hundred sixty-three patients had recurrent thrombotic events (average rate, 2.26 per 100 person-years at risk). At 10 years, cumulative risk was 14.7% (95% confidence interval, 12.2%-17.9%) for primary end point, 14.0% (95% confidence interval, 11.4%-17.1%) for brain ischemia, and 0.7% (95% confidence interval, 0.4%-1.3%) for myocardial infarction or other arterial events. Familial history of stroke, migraine with aura, circulating antiphospholipid antibodies, discontinuation of antiplatelet and antihypertensive medications, and any increase of 1 traditional vascular risk factor were independent predictors of the composite end point in multivariable Cox proportional hazards analysis. A point-scoring system for each variable was generated by their ß-coefficients, and a predictive score (IPSYS score) was calculated as the sum of the weighted scores. The area under the receiver operating characteristic curve of the 0- to 5-year score was 0.66 (95% confidence interval, 0.61-0.71; mean, 10-fold internally cross-validated area under the receiver operating characteristic curve, 0.65). CONCLUSIONS: Among patients with ischemic stroke aged 18 to 45 years, the long-term risk of recurrent thrombotic events is associated with modifiable, age-specific risk factors. The IPSYS score may serve as a simple tool for risk estimation.

Innate immunity and neuroinflammation.

Inflammation of central nervous system (CNS) is usually associated with trauma and infection. Neuroinflammation occurs in close relation to trauma, infection, and neurodegenerative diseases. Low-level neuroinflammation is considered to have beneficial effects whereas chronic neuroinflammation can be harmful. Innate immune system consisting of pattern-recognition receptors, macrophages, and complement system plays a key role in CNS homeostasis following injury and infection. Here, we discuss how innate immune components can also contribute to neuroinflammation and neurodegeneration.

Patient satisfaction with televisit in chronic neurologic disorders during Covid-19 pandemic.

BACKGROUND: Covid-19 pandemic has boosted telemedicine in medical clinical practice. Experience in the management of chronic neurological disorders is limited as well as patient opinion. During Covid-19 pandemic, we evaluated patients' satisfaction and opinion about televisits in a large group of patients with chronic neurological disorders. METHODS: All patients with chronic neurological disorders who had a virtual visit during the first phase of pandemic were invited to fill an online anonymous questionnaire about their global satisfaction and satisfaction regarding continuity of care, possibility to stay at home, doctor-patient relationship, the future of teleconsultation after pandemic and the possibility of understanding medical information and instructions. RESULTS: We received 123 questionnaires among 232 e-mail (response rate 53%). Almost all (120 out of 121 patients, 99%) were satisfied with the overall experience with video-consultation. Comprehension of medical information was the same for 113 out of 122 patients (93%) and also the doctor-patient relationship was the same for 107 out of 122 respondents (88%) or better for 10 (8%). Ninety-three percent of patients (112 out of 120) were keen to integrate televisits with the traditional modality and only 11 out of 121 patients (9%) judged televisits as an option to discard. As a whole, 114 out of 122 respondents (93%) would suggest this modality to other patients. CONCLUSIONS: Our large cohort of patients with chronic neurologic disorders rated experience with televisits satisfactory. Comprehension of medical information and doctor-patient interaction was considered good. Eventually, patients are keen to integrate this modality with traditional follow-up visits.

Exploratory Study on Chemosensory Event-Related Potentials in Long COVID-19 and Mild Cognitive Impairment: A Common Pathway?

People affected by the Long COVID-19 (LC) syndrome often show clinical manifestations that are similar to those observed in patients with mild cognitive impairments (MCI), such as olfactory dysfunction (OD), brain fog, and cognitive and attentional diseases. This study aimed to investigate the chemosensory-evoked related potentials (CSERP) in LC and MCI to understand if there is a common pathway for the similarity of symptoms associated with these disorders. Eighteen LC patients (mean age 53; s.d. = 7), 12 patients diagnosed with MCI (mean age 67; s.d. = 6), and 10 healthy control subjects (mean age 66; s.d. = 5, 7) were recruited for this exploratory study. All of them performed a chemosensory event-related potentials (CSERP) task with the administration of trigeminal stimulations (e.g., the odorants cinnamaldehyde and eucalyptus). Study results highlighted that MCI and LC showed reduced N1 amplitude, particularly in the left frontoparietal network, involved in working memory and attentional deficits, and a reduction of P3 latency in LC. This study lays the foundations for evaluating aspects of LC as a process that could trigger long-term functional alterations, and CSERPs could be considered valid biomarkers for assessing the progress of OD and an indicator of other impairments (e.g., attentional and cognitive impairments), as they occur in MCI.

Your actions in my cerebellum: subclinical deficits in action observation in patients with unilateral chronic cerebellar stroke.

Empirical evidence indicates that cognitive consequences of cerebellar lesions tend to be mild and less important than the symptoms due to lesions to cerebral areas. By contrast, imaging studies consistently report strong cerebellar activity during tasks of action observation and action understanding. This has been interpreted as part of the automatic motor simulation process that takes place in the context of action observation. The function of the cerebellum as a sequencer during executed movements makes it a good candidate, within the framework of embodied cognition, for a pivotal role in understanding the timing of action sequences. Here, we investigated a cohort of eight patients with chronic, first-ever, isolated, ischemic lesions of the cerebellum. The experimental task consisted in identifying a plausible sequence of pictures from a randomly ordered group of still frames extracted from (a) a complex action performed by a human actor ("biological action" test) or (b) a complex physical event occurring to an inanimate object ("folk physics" test). A group of 16 healthy participants was used as control. The main result showed that cerebellar patients performed significantly worse than controls in both sequencing tasks, but performed much worse in the "biological action" test than in the "folk physics" test. The dissociation described here suggests that observed sequences of simple motor acts seem to be represented differentially from other sequences in the cerebellum.

Vaccines and myasthenia gravis: a comprehensive review and retrospective study of SARS-CoV-2 vaccination in a large cohort of myasthenic patients.

INTRODUCTION: Myasthenia gravis (MG) is an autoimmune disease, for which the risk of exacerbation after vaccines is debated. The aim of this study is to review the available literature concerning safety and efficacy of vaccines in MG. In addition, we also conducted a retrospective research of MG exacerbations and new onset MG after anti-SARS-CoV-2 vaccination in a large cohort of patients. METHODS: A study of the available literature regarding vaccines and MG was carried out through research in the online database "Pubmed". We also retrospectively collected data from 80 MG patients, who were followed at the Treviso Hospital and completed an anti-SARS-CoV-2 vaccination cycle. For each patient, we recorded MG exacerbations between first and second doses and within a window period of 1 day - 6 weeks after the second dose. RESULTS: We found 26 relevant articles about influenza, SARS-CoV-2 and other vaccines. No clear associations between most vaccines and MG exacerbations were found. Moreover, cases of new onset post-vaccine MG are mostly anecdotal, except for Japanese encephalitis virus vaccine. Concerning our cohort, 4/80 (5%) MG patients experienced an exacerbation within the post-vaccine window period. In addition, we report a case of new onset post-vaccine MG. DISCUSSION: Inactivated and subunit vaccines are safe and effective in MG. Although some of them, such as anti-SARS-CoV-2 vaccine, might uncommonly cause MG exacerbations, data from our review suggest that benefits still outweigh by far the potential risks, thus they should be recommended to these patients. Nevertheless, large prospective studies are needed for further investigations.

Patient with Corticobasal Syndrome Showing Disease-Associated Biomarkers of Dementia with Lewy Bodies: A Treviso Dementia (TREDEM) Registry Case Report.

Background: An 82-year-old right-handed man, a retired teacher, reported the occurrence, three years earlier, of difficulties in moving his left arm and foot, tremor in his left hand, and gestures of the left upper limb that appeared to be independent of the patient's will. Objective: We describe an unusual case of corticobasal syndrome (CBS) showing disease-associated biomarkers of dementia with Lewy bodies (DLB). Methods: Clinical, neuropsychological, imaging, and biomarker evaluations were conducted, including tau and amyloid-ß levels in the cerebrospinal fluid (CSF) and a RT-QuIC assay for α-synuclein both in the CSF and olfactory mucosa (OM), as well as a QEEG assessment. Results: The patient presented resting tremor, mild extrapyramidal hypertonus, mild bradykinesia on the left side, and severe apraxia on the left upper limb. Brain MRI showed a diffuse right hemisphere atrophy which was prominent in the posterior parietal and temporal cortices, and moderate in the frontal cortex and the precuneus area. 18F-FDG PET imaging showed reduced glucose metabolism in the right lateral parietal, temporal, and frontal cortices with involvement of the right precuneus. The putamen did not appear to be pathological at DaTQUANT. Neuropsychological tests showed memory and visual-perceptual deficits. CSF tau and amyloid measurements did not show clear pathological values. RT-QuIC for α-synuclein in CSF and OM samples were positive. The QEEG analysis showed a pre-alpha dominant frequency in posterior derivations, typical of early stages of DLB. Conclusion: Although in the present patient the clinical diagnosis was of probable CBS, unexpectedly positive biomarkers for DLB suggested the co-presence of multiple pathologies.

Opinion, knowledge, and clinical experience with functional neurological disorders among Italian neurologists: results from an online survey.

BACKGROUND: Functional neurological disorders (FND) are disabling medical conditions commonly seen in neurological practice. Neurologists play an essential role in managing FND, from establishing a diagnosis to coordination of multidisciplinary team-based treatment for patients. With this study, we investigated the knowledge and the clinical experience of Italian neurologists in managing patients with FND. METHODS: Members of the Italian Society of Neurology were invited via e-mail to participate in this ad hoc online survey; 492 questionnaires were returned completed. RESULTS: The term "Functional neurological disorders" in reference to FND was used more frequently than other psychological (e.g., psychogenic or conversion), or descriptive terms (e.g., non-organic or stress-related). When speaking with patients, the respondents stated that they preferred explaining symptoms based on abnormal functioning of the nervous system than discussing mental illness and that they would refer their patient to a psychologist rather than to a psychiatrist. Few considered that physiotherapy and psychiatric interventions are useful approaches to treating FND. Some believed that patients simulate their symptoms. CONCLUSIONS: Overall, the responses suggest that knowledge about scientific advances in FND is somewhat sparse. A psychiatric-centered view of FND opens the way to an approach in which neurobiological and psychological aspects constitute essential factors of the condition. In this context, professional education could improve understanding of FND and optimize patient management.

Change in myasthenia gravis epidemiology in Trento, Italy, after twenty years.

BACKGROUND: The recent literature suggests that the incidence and prevalence of myasthenia gravis (MG) are changing. We performed a population-based study of MG in the province of Trentino (524,826 inhabitants) and compared the results with those collected 20 years ago. METHODS: Multiple sources of information (discharge diagnosis, antibody tests and anticholinesterase drugs) were analyzed. Incidence was calculated from 2005 to 2009. Prevalence was calculated on December 31, 2009. Comparison was made with descriptive statistics for 1981-1990 for the identical region. RESULTS: Incidence and prevalence greatly increased in comparison with 1981-1990 data. The prevalence rate increased from 82.9 (95% confidence interval, CI, 58.4-114.3) in 1990 to 129.6 (95% CI 100.6-164.3) per million population, whereas the average annual incidence increased from 7.4 (95% CI 5-10.4) per million person-years in 1981-1990 to 14.8 (95% CI 10.5-20.3) in 2005-2009. This increase was mainly due to male patients with late-onset MG. CONCLUSIONS: The study confirms the increase in incidence and prevalence of late-onset MG in the same region 20 years apart. So we should consider MG also as a disease of the elderly.

Role of complement in neurodegeneration and neuroinflammation.

The complement system provides an innate defence mechanism against pathogenic microorganisms. Although viewed for many years as an immune-privileged organ, the central nervous system contains many components of the immune system, including components of the complement system that are synthesized by astrocytes, microglia, and neurons. During the past two decades, a wide range of inflammatory markers, typically absent in the normal elderly population, have been reported in Alzheimer's disease brains. It is becoming evident that sustained brain inflammation might be an essential cofactor in Alzheimer disease and other neurodegenerative disorders such as Parkinson disease, dementia with Lewy bodies, Huntington's and prion diseases. The complement system may be useful in eliminating aggregated and toxic proteins associated with these neurological disorders and thus have a protective effect. However, an exaggerated or insufficient activation of the complement system can have deleterious effect through the activation of microglia, secretion of many proinflammatory cytokines, and generation of oxidative products. The role of complement-mediated inflammation in Alzheimer disease has drawn greater attention recently in view of new therapeutic advances made in the management of the disease. This review is meant to update the role of complement in Alzheimer's disease and other neurodegenerative disorders in view of recent vaccination and immunotherapeutic approaches.