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BACKGROUND: Thymomas can benefit of cytoreductive surgery even if a complete resection is not feasible. The pleural cavity is the most common site of progression and the resection of pleural metastases can be performed in selected patients. We evaluated the results of stereotactic body radiation therapy for the treatment of pleural metastases in patients not eligible for surgery. METHODS: We retrospectively selected 22 patients treated with stereotactic body radiation therapy for pleural metastases between 2013 and 2019. According to RECIST criteria 1.1 modified for thymic epithelial tumors, time to local failure and progression free survival were calculated using Kaplan-Meier method. RESULTS: The median age was 40 years (range, 29–73 years). There were 1 A, 3 AB, 3 B1, 3 B2, 3 B2/B3 and 9 B3 thymomas. Pleural metastases and primary tumor were synchronous in 8 patients. Five patients had a single pleural metastatic site and 17 presented multiple localizations. Sixteen patients received stereotactic body radiation therapy on multiple sites of pleural metastases. The median dose of radiation was 30 Gy (range, 24–40 Gy). With a median follow-up of 33.2 months (95% CI: 13.1–53.3 months), ten patients experienced disease progression with a median progression free survival was 20.4 months (95% CI: 10.7–30.0 months). The disease control rate was 79% and 41% after 1 and 2 years, respectively. Local disease control rate was 92% and 78% after 1 and 2 years, respectively. There were not significant differences in progression free survival between patients diagnosed with synchronous and metachronous metastases (P=0.477), across those treated or not with chemotherapy (P=0.189) and between those who received or not a previous surgical resection of the pleural metastases (P=0.871). There were not grade 3–4 toxicities related to the treatment. CONCLUSIONS: Stereotactic body radiation therapy of pleural metastases is feasible and offers a promising local control of diseases. The impact of this treatment on patients’ survival is hardly predictable because of the heterogeneous clinical behavior of thymomas.

Objective Markers of seizure recurrence are needed to personalize antiseizure medication (ASM) therapy. In the clinical practice, EEG features are considered to be related to the risk of seizure recurrence for genetic generalized epilepsies (GGE). However, to our knowledge, there are no studies analyzing systematically specific EEG features as indices of ASM efficacy in GGE. In this study, we aimed at identifying EEG indicators of ASM responsiveness in Juvenile Myoclonic Epilepsy (JME), which, among GGE, is characterized by specific electroclinical features. Methods We compared the features of prolonged ambulatory EEG (paEEG, 22 h of recording) of JME patients experiencing seizure recurrence within a year (“cases”) after EEG recording, with those of patients with sustained seizure freedom for at least 1 year after EEG (“controls”). We included only EEG recordings of patients who had maintained the same ASM regimen (dosage and type) throughout the whole time period from the EEG recording up to the outcome events (which was seizure recurrence for the “cases”, or 1‐year seizure freedom for “controls”). As predictors, we evaluated the total number, frequency, mean and maximum duration of epileptiform discharges (EDs) and spike density (i.e. total EDs duration/artifact‐free EEG duration) recorded during the paEEG. The same indexes were assessed also in standard EEG (stEEG), including activation methods. Results Both the maximum length and the mean duration of EDs recorded during paEEG significantly differed between cases and controls; when combined in a binary logistic regression model, the maximum length of EDs emerged as the only valid predictor. A cut‐off of EDs duration of 2.68 seconds discriminated between cases and controls with a 100% specificity and a 93% sensitivity. The same indexes collected during stEEG lacked both specificity and sensitivity. Significance The occurrence of prolonged EDs in EEG recording might represent an indicator of antiepileptic drug failure in JME patients.

Myasthenia gravis (MG) is a neuromuscular autoimmune disease characterized by prevalence in young women (3:1). Several mechanisms proposed as explanations for gender bias, including skewed X chromosome inactivation (XCI) and dosage or sex hormones, are often involved in the development of autoimmunity. The skewed XCI pattern can lead to an unbalanced expression of some X-linked genes, as observed in several autoimmune disorders characterized by female predominance. No data are yet available regarding XCI and MG. We hypothesize that the preferential XCI pattern may contribute to the female bias observed in the onset of MG, especially among younger women. XCI analysis was performed on blood samples of 284 women between the ages of 20 and 82. XCI was tested using the Human Androgen Receptor Assay (HUMARA). XCI patterns were classified as random (XCI < 75%) and preferential (XCI ≥ 75%). In 121 informative patients, the frequency of skewed XCI patterns was 47%, significantly higher than in healthy controls (17%; p ≤ 0.00001). Interestingly, the phenomenon was observed mainly in younger patients (

Background Thymoma‐associated myasthenia gravis (TAMG) is one of the subtypes of myasthenia gravis with autoantibodies against the acetylcholine receptor (AChR‐Ab). We analyzed the clinical features of our cohort of TAMG patients and the changes in AChR‐Ab titer before and after thymectomy in order to identify factors predicting thymoma relapses. Methods We retrospectively assessed: age of MG onset, MG clinical status according to MGFA (Myasthenia Gravis Foundation of America), epoch of thymectomy, post‐thymectomy status, oncological features and surgical approach. AChR‐Ab dosages were measured both before and after thymectomy. Linear regression models were applied to identify clinical determinants of AChR‐Ab titers and the Cox regression model was fitted to estimate the factors associated with the risk of thymoma recurrence. Results The study sample included 239 MG patients, 27 of whom experienced one or more recurrences (median follow‐up time: 4.8 years). The AChR‐Ab titers decreased after first thymectomy (P, In our paper, we retrospectively analyzed the changes in antiacetylcholine receptor antibody (AChR‐Ab) titer before and after thymectomy and the clinical features of thymoma‐associated myasthenia gravis (TAMG) patients in order to identify clinical and serological predictors of thymoma recurrence. Our study emphasizes the importance of a multidisciplinary approach among Neurologists, Oncologists and Thoracic Surgeons, and identifies subgroups of MG patients with high risk of thymoma recurrence who therefore need a more accurate follow‐up.

BackgroundIgG4 is associated with two emerging groups of rare diseases: 1) IgG4 autoimmune diseases (IgG4-AID) and 2) IgG4-related diseases (IgG4-RLD). Anti-neuronal IgG4-AID include MuSK myasthenia gravis, LGI1- and Caspr2-encephalitis and autoimmune nodo-/paranodopathies (CNTN1 or NF155 antibodies). IgG4-RLD is a multiorgan disease hallmarked by tissue-destructive fibrotic lesions with lymphocyte and IgG4 plasma cell infiltrates and increased serum IgG4 concentrations. It is unclear, whether IgG4-AID and IgG4-RLD share relevant clinical and immunopathological features.MethodsWe collected and analysed serological, clinical, and histopathological data in 50 patients with anti-neuronal IgG4-AID and 16 patients with IgG4-RLD.ResultsA significantly higher proportion of IgG4-RLD patients had serum IgG4 elevation when compared to IgG4-AID patients (50% vs. 16%, p = .015). Moreover, those IgG4-AID patients with elevated IgG4 did not meet the diagnostic criteria of IgG4-RLD, and their autoantibody titres did not correlate with their serum IgG4 concentrations. In addition, patients with IgG4-RLD were negative for anti-neuronal/neuromuscular autoantibodies and among these patients, men showed a significantly higher propensity for IgG4 elevation, when compared to women (p = .041). Last, a kidney biopsy from a patient with autoimmune paranodopathy due to CNTN1/Caspr1-complex IgG4 autoantibodies and concomitant nephrotic syndrome did not show fibrosis or IgG4+ plasma cells, which are diagnostic hallmarks of IgG4-RLD.ConclusionOur observations suggest that anti-neuronal IgG4-AID and IgG4-RLD are most likely distinct disease entities.

Background IgG4 is associated with two emerging groups of rare diseases: 1) IgG4 autoimmune diseases (IgG4-AID) and 2) IgG4-related diseases (IgG4-RLD). Anti-neuronal IgG4-AID include MuSK myasthenia gravis, LGI1- and Caspr2-encephalitis and autoimmune nodo-/paranodopathies (CNTN1/Caspr1 or NF155 antibodies). IgG4-RLD is a multiorgan disease hallmarked by tissue-destructive fibrotic lesions with lymphocyte and IgG4 plasma cell infiltrates and increased serum IgG4 concentrations. It is unclear whether IgG4-AID and IgG4-RLD share relevant clinical and immunopathological features. Methods We collected and analyzed clinical, serological, and histopathological data in 50 patients with anti-neuronal IgG4-AID and 19 patients with IgG4-RLD. Results A significantly higher proportion of IgG4-RLD patients had serum IgG4 elevation when compared to IgG4-AID patients (52.63% vs. 16%, p = .004). Moreover, those IgG4-AID patients with elevated IgG4 did not meet the diagnostic criteria of IgG4-RLD, and their autoantibody titers did not correlate with their serum IgG4 concentrations. In addition, patients with IgG4-RLD were negative for anti-neuronal/neuromuscular autoantibodies and among these patients, men showed a significantly higher propensity for IgG4 elevation, when compared to women (p = .005). Last, a kidney biopsy from a patient with autoimmune paranodopathy due to CNTN1/Caspr1-complex IgG4 autoantibodies and concomitant nephrotic syndrome did not show fibrosis or IgG4+ plasma cells, which are diagnostic hallmarks of IgG4-RLD. Conclusion Our observations suggest that anti-neuronal IgG4-AID and IgG4-RLD are most likely distinct disease entities.

In a recent study, we found that during 20.55 ± 1.60 h of artifact-free ambulatory EEG recordings, epileptiform discharges (EDs) longer than 2.68 s occurred exclusively in patients with Juvenile Myoclonic Epilepsy (JME) who experienced seizure recurrence within a year after the EEG. Here we expanded this analysis, exploring whether long EDs (2.68 s), and short ones, were uniformly distributed during the day. Lastly, we evaluated the temporal distribution of seizure relapses. By Friedman test, we demonstrated that hourly frequencies of both short and long EDs were dependent on the hours of day and sleep-wake cycle factors, with an opposite trend. Short EDs were found mostly during the night (with two peaks at 1 AM and 6 AM), and sleep, dropping at the wake onset (p 0.001). Conversely, long EDs surged at the wake onset (0.001), remaining frequent during the whole wake period, when compared to sleep (p = 0.002). Of note, this latter pattern mirrored that of seizures, which occurred exclusively during the wake period, and in 9 out of 13 cases at the wake onset. We therefore suggested that short and long EDs could reflect distinct pathophysiological phenomena. Extended wake EEG recordings, possibly including the awakening, could be extremely useful in clinical practice, as well as in further studies, with the ambitious goal of predicting seizure recurrences.

Consumer "Smartbands" can collect physiological parameters, such as heart rate (HR), continuously across the sleep-wake cycle. Nevertheless, the quality of HR data detected by such devices and their place in the research and clinical field is debatable, as they are rarely rigorously validated. The objective of the present study was to investigate the reliability of pulse photoplethysmographic detection by the Fitbit ChargeHR

Objective The COVID-19 pandemic has strongly affected daily habits and psychological wellbeing, and many studies point to large modifications in several sleep and sleep-related domains. Nevertheless, pre-sleep arousal during the pandemic has been substantially overlooked. Since hyperarousal represents one of the main factors for the development and the perpetuation of chronic insomnia disorder, the assessment of variables associated with high levels of pre-sleep arousal during the pandemic is clinically relevant. The study aimed to assess the prevalence and predictors of perceived sleep quality and pre-sleep arousal in an Italian sample during the COVID-19 lockdown. Methods We used an online survey to collect self-reported sociodemographic, environmental, clinical, sleep, and sleep-related data. Our final sample included 761 participants. Results Beyond a high frequency of poor sleep quality, depressive and stress symptoms, our results show that almost half of the sample suffered from clinically relevant levels of at least one component (ie, cognitive, somatic) of pre-sleep arousal. Subjects with greater pre-sleep arousal exhibited poorer sleep quality. Also, sleep quality was strongly associated with somatic and cognitive pre-sleep arousal. Regarding the predictors of sleep and sleep-related measures, depressive and event-related stress symptoms were the main factors associated with both poor sleep quality and pre-sleep arousal components. Moreover, specific sociodemographic and environmental variables were uniquely related to sleep quality, cognitive or somatic pre-sleep arousal. Conclusions These findings suggest that the assessment of specific sleep-related factors (ie, pre-sleep arousal), together with more global measures of sleep quality, may be crucial to depict the complex impact of the pandemic on sleep, and to help prevent and counteract the spread of insomnia symptoms.

Davide Benedetti,1 Umberto Olcese,2 Simone Bruno,1 Marta Barsotti,3 Michelangelo Maestri Tassoni,3,4 Enrica Bonanni,3,4 Gabriele Siciliano,3,4 Ugo Faraguna1,5 1Department of Translational Research and of New Surgical and Medical Technologies, University of Pisa, Pisa, Italy; 2Cognitive and Systems Neuroscience Group, Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, the Netherlands; 3Neurological Clinics, University Hospital of Pisa, Pisa, Italy; 4Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy; 5Department of Developmental Neuroscience, IRCCS Fondazione Stella Maris, Pisa, ItalyCorrespondence: Ugo Faraguna, Department of Translational Research and of New Surgical and Medical Technologies, University of Pisa, Via San Zeno, 31, Pisa, 56123, Italy, Tel +39 050 2213470, Email ugo.faraguna@unipi.itPurpose: A large portion of the adult population is thought to suffer from obstructive sleep apnoea syndrome (OSAS), a sleep-related breathing disorder associated with increased morbidity and mortality. International guidelines include the polysomnography and the cardiorespiratory monitoring (CRM) as diagnostic tools for OSAS, but they are unfit for a large-scale screening, given their invasiveness, high cost and lengthy process of scoring. Current screening methods are based on self-reported questionnaires that suffer from lack of objectivity. On the contrary, commercial smartbands are wearable devices capable of collecting accelerometric and photoplethysmographic data in a user-friendly and objective way. We questioned whether machine-learning (ML) classifiers trained on data collected through these wearable devices would help predict OSAS severity.Patients and Methods: Each of the patients (n = 78, mean age ± SD: 57.2 ± 12.9 years; 30 females) underwent CRM and concurrently wore a commercial wrist smartband. CRM’s traces were scored, and OSAS severity was reported as apnoea hypopnoea index (AHI). We trained three pairs of classifiers to make the following prediction: AHI < 5 vs AHI ≥ 5, AHI < 15 vs AHI ≥ 15, and AHI < 30 vs AHI ≥ 30.Results: According to the Matthews correlation coefficient (MCC), the proposed algorithms reached an overall good correlation with the ground truth (CRM) for AHI < 5 vs AHI ≥ 5 (MCC: 0.4) and AHI < 30 vs AHI ≥ 30 (MCC: 0.3) classifications. AHI < 5 vs AHI ≥ 5 and AHI < 30 vs AHI ≥ 30 classifiers’ sensitivity, specificity, positive predictive values (PPV), negative predictive values (NPV) and diagnostic odds ratio (DOR) are comparable with the STOP-Bang questionnaire, an established OSAS screening tool.Conclusion: Machine learning algorithms showed an overall good performance. Unlike questionnaires, these are based on objectively collected data. Furthermore, these commercial devices are widely distributed in the general population. The aforementioned advantages of machine-learning algorithms applied to smartbands’ data over questionnaires lead to the conclusion that they could serve a population-scale screening for OSAS.Keywords: obstructive sleep apnoea syndrome, screening, wearable devices, wrist-worn smartbands, artificial intelligence

Consumer "Smartbands" can collect physiological parameters, such as heart rate (HR), continuously across the sleep-wake cycle. Nevertheless, the quality of HR data detected by such devices and their place in the research and clinical field is debatable, as they are rarely rigorously validated. The objective of the present study was to investigate the reliability of pulse photoplethysmographic detection by the Fitbit ChargeHR™ (FBCHR, Fitbit Inc.) in a natural setting of continuous recording across vigilance states. To fulfil this aim, concurrent portable polysomnographic (pPSG) and the Fitbit's photoplethysmographic data were collected from a group of 25 healthy young adults, for ≥12 hr. The pPSG-derived HR was automatically computed and visually verified for each 1-min epoch, while the FBCHR HR measurements were downloaded from the application programming interface provided by the manufacturer. The FBCHR was generally accurate in estimating the HR, with a mean (SD) difference of -0.66 (0.04) beats/min (bpm) versus the pPSG-derived HR reference, and an overall Pearson's correlation coefficient (r) of 0.93 (average per participant r = 0.85 ± 0.11), regardless of vigilance state. The correlation coefficients were larger during all sleep phases (rapid eye movement, r = 0.9662; N1, r = 0.9918; N2, r = 0.9793; N3, r = 0.9849) than in wakefulness (r = 0.8432). Moreover, the correlation coefficient was lower for HRs of >100 bpm (r = 0.374) than for HRs of r = 0.84). Consistently, Bland-Altman analysis supports the overall higher accuracy in the detection of HR during sleep. The relatively high accuracy of FBCHR pulse rate detection during sleep makes this device suitable for sleep-related research applications in healthy participants, under free-living conditions.

We demonstrated that the end tidal CO2 oscillation causes oscillations of delta and alpha bands. The analysis of the regional field power showed that different cortical areas respond with different time delays to CO2 challenges. An opposite behavior was found for the end-tidal O2. We can suppose that the different cortical time delay response likely expresses specific ascending pathways to the cortex generated by chemoreceptor nuclei in the brainstem.

Sleep-disordered breathing is highly prevalent in the elderly population. Obstructive sleep apnea (OSA) represents the most common sleep disorder among the adult and elderly population. Recently, OSA diagnosis has been associated with an increased risk of developing cognitive decline and dementia, including vascular dementia and Alzheimer's disease (AD). Subsequently, there have been studies on AD biomarkers investigating cerebrospinal fluid, blood, neuroimaging, and nuclear medicine biomarkers in patients with OSA. Furthermore, studies have attempted to assess the possible effects of continuous positive airway pressure (CPAP) treatment on the cognitive trajectory and AD biomarkers in patients with OSA. This review summarizes the findings of studies on each AD biomarker (cognitive, biofluid, neuroimaging, and nuclear medicine imaging) in patients with OSA, also accounting for the related effects of CPAP treatment. In addition, the hypothetical model connecting OSA to AD in a bi-directional interplay is analyzed. Finally, the sex-based differences in prevalence and clinical symptoms of OSA between men and women have been investigated in relation to AD risk. Further studies investigating AD biomarkers changes in patients with OSA and the effect of CPAP treatment should be auspicated in future for identifying strategies to prevent the development of AD.

STUDY OBJECTIVES: Narcolepsy type 1 (NT1) is a chronic neurological disorder typically arising during adolescence and young adulthood. Recent studies demonstrated that NT1 presents with age-specific features, especially in children. With this study we aimed to describe and to compare the clinical pictures of NT1 in different age groups. METHODS: In this cross-sectional, multicenter study, 106 untreated patients with NT1 enrolled at the time of diagnosis underwent clinical evaluation, a semistructured interview (including the Epworth Sleepiness Scale), nocturnal video-polysomnography, and the Multiple Sleep Latency Test. Patients were enrolled in order to establish 5 age-balanced groups (childhood, adolescence, adulthood, middle age, and senior). RESULTS: The Epworth Sleepiness Scale score showed a significant increase with age, while self-reported diurnal total sleep time was lower in older and young adults, with the latter also complaining of automatic behaviors in more than 90% of patients. Children reported the cataplexy attacks to be more frequent (> 1/d in 95% of patients). “Recalling an emotional event,” “meeting someone unexpectedly,” “stress,” and “anger” were more frequently reported in adult and older adult patients as possible triggers of cataplexy. Neurophysiological data showed a higher number of sleep-onset rapid eye movement periods on the Multiple Sleep Latency Test in adolescent compared to senior patients and an age-progressive decline in sleep efficiency. CONCLUSIONS: Daytime sleepiness, cataplexy features and triggers, and nocturnal sleep structure showed age-related difference in patients with NT1; this variability may contribute to diagnostic delay and misdiagnosis. CITATION: Lividini A, Pizza F, Filardi M, et al. Narcolepsy type 1 features across the life span: age impact on clinical and polysomnographic phenotype. J Clin Sleep Med. 2021;17(7):1363–1370.

The aim was to assess the relationship between continuous positive airway pressure (CPAP) therapy and cognitive function in patients with mild cognitive impairment (MCI) and obstructive sleep apnea (OSA).This was a retrospective chart review of patients with MCI and OSA. CPAP therapy compliance was defined as average use of CPAP therapy for at least 4 hours per night. Kaplan-Meier estimates, log-rank tests, and Cox proportional hazards regression were done to compare the compliance groups in terms of progression to dementia, defined as a Clinical Dementia Rating of 1 or greater. Linear mixed models were used to assess the relationships between CPAP therapy compliance and neurological cognitive function outcomes over time.Ninety-six patients were included with mean age at MCI diagnosis of 70.4 years, mean apnea-hypopnea index of 25.9 events/h, and mean duration of neurology follow-up of 2.8 years. Forty-two were CPAP compliant, 30 were noncompliant, and 24 had no CPAP use. No overall difference between the groups was detected for progression to dementia (P = .928, log-rank test). Patients with amnestic MCI had better CPAP use (P = .016) and shorter progression time to dementia (P = .042), but this difference was not significant after adjusting for age, education, and race (P = .32).CPAP use in patients with MCI and OSA was not associated with delay in progression to dementia or cognitive decline.

A feature of thymomas is their frequent association with myasthenia gravis (MG), an autoimmune disease characterized by the production of autoantibodies directed to different targets at the neuromuscular junction. Indeed, almost 30–40% of thymomas are found in patients with a type of MG termed thymoma-associated MG (TAMG). Recent studies suggest that TAMG-associated thymomas could represent a molecularly distinct subtype of thymic epithelial tumors (TETs), but few data are still available concerning the epigenetic modifications occurring in TAMG tissues. The promoter methylation levels of DNA repair (MLH1 and MGMT) and tumor suppressor genes (CDKN2A and RASSF1A) have been frequently investigated in TETs, but methylation data in TAMG tissues are scarce and controversial. To further address this issue, we investigated MLH1, MGMT, CDKN2A, and RASSF1A methylation levels in blood samples and surgically resected thymomas from 69 patients with TAMG and in the adjacent normal thymus available from 44 of them. Promoter methylation levels of MLH1, MGMT, CDKN2A, and RASSF1A genes were not increased in cancer with respect to healthy tissues and did not correlate with the histological or pathological features of the tumor or with the MG symptoms. The present study suggests that hypermethylation of these genes is not frequent in TAMG tissues.

Background Hypermethylation of the growth hormone secretagogue receptor gene (GHSR) is increasingly observed in human cancers, suggesting that it could represent a pan-cancer biomarker of clinical interest. However, little is still known concerning GHSR methylation levels in thymic epithelial tumors, and particularly in thymomas from patients with Myasthenia Gravis (TAMG). Material and Methods In the present study we collected DNA samples from circulating lymphocytes and surgically resected tumor tissues of 65 TAMG patients, and from the adjacent healthy thymic tissue available from 43 of them. We then investigated GHSR methylation levels in the collected tissues searching for correlation with the clinical characteristics of the samples. Results GHSR hypermethylation was observed in 18 thymoma samples (28%) compared to the healthy thymic tissues (P Conclusions GHSR hypermethylation is not a pan-cancer marker or an early event in TAMG, but occurs in almost 1/4 of them and mainly from stage II onward. Subsequent studies are required to clarify the molecular pathways leading to GHSR hypermethylation in TAMG tissues and their relevance to disease progression.

Excessive daytime sleepiness (EDS) and fatigue are some of the most frequent symptoms in neurological diseases and could impact on quality of life by increasing the risk of accidents and generally affecting daily life activities. In this review, we will examine the variety of causes responsible for EDS in neurological diseases, including nocturnal sleep alterations, CNS pathological abnormalities with alterations in arousal and/or REM regulation systems, circadian rhythms disorders, drugs, and comorbid psychiatric or primary sleep disorders. Among neurological diseases, epilepsy, dementia, Parkinson disease, multiple sclerosis, and myotonic dystrophies represented a model for these interactions between EDS and neurological diseases. A complete diagnostic workup in neurological patients with EDS should be undertaken since EDS can worsen many different aspects such as psychiatric symptoms, cognitive deficit, and in some cases, the severity of the neurological disease per se. Moreover, quality of life and risk of accidents are dependent on EDS. An individualized approach to this symptom in neurological patients should be considered with a focus on modifiable causes such as SDB, psychiatric comorbidities, and drugs. When considering EDS and fatigue in neurological diseases, close attention to lifestyle and sleep hygiene is advisable. A critical review of ongoing pharmacological therapy should not be overlooked. Possible diagnosis and treatment of SDB should be always considered.

Background: Circadian and sleep disturbances are associated with increased risk of mild cognitive impairment (MCI) and Alzheimer’s disease (AD). Wearable activity trackers could provide a new approach in diagnosis and prevention. Objective: To evaluate sleep and circadian rhythm parameters, through wearable activity trackers, in MCI and AD patients as compared to controls, focusing on sex dissimilarities. Methods: Based on minute level data from consumer wearable devices, we analyzed actigraphic sleep parameters by applying an electromedical type I registered algorithm, and the corresponding circadian variables in 158 subjects: 86 females and 72 males (42 AD, 28 MCI, and 88 controls). Moreover, we used a confusion-matrix chart method to assess accuracy, precision, sensitivity, and specificity of two decision-tree models based on actigraphic data in predicting disease or health status. Results: Wake after sleep onset (WASO) was higher (p

STUDY OBJECTIVES: The influence of obstructive sleep apnea (OSA) on thoracic aortic size is debated. We aimed to identify possible relations between sleep parameters and the sizes of the ascending aorta (AA), the descending thoracic aorta (DTA), and the main pulmonary artery (MPA) in patients with untreated OSA and in a subgroup of participants without comorbidities capable of affecting the size of great thoracic vessels. METHODS: We retrospectively measured AA, DTA, and MPA sizes on the chest computed tomography scans of 60 patients with OSA who underwent sleep studies within 1 year before or after the computed tomography. Univariate and multivariate analyses were performed on all patient findings, while an additional univariate analysis was conducted on the data for 22 participants without comorbidities. The latter had been divided into subgroups depending on the sleep parameters, and comparisons were made between them. RESULTS: The logarithm of the time of oxygen saturation below 90% (CT90) significantly predicted AA and MPA sizes in all patients with OSA (P < .05). Oxygen desaturation index and minimum oxygen saturation were moderately correlated with AA and DTA sizes in patients without comorbidities (P < .01). In this group, subjects with oxygen desaturation index > 30 or minimum oxygen saturation < 81% had greater AA and DTA dimensions (P < .05). CONCLUSIONS: In patients with OSA, time of oxygen saturation < 90% influenced AA and MPA sizes. In those patients without comorbidities, oxygen desaturation index and minimum oxygen saturation were moderately correlated with both AA and DTA sizes. Participants without comorbidities with oxygen desaturation index > 30 or minimum oxygen saturation < 81% had greater AA and DTA dimensions. CITATION: Castellana R, Aringhieri G, Gargani L, et al. Effects of obstructive sleep apnea on the thoracic aorta and the main pulmonary artery: assessment by CT. J Clin Sleep Med. 2021;17(1):3–11.

ObjectiveTo determine whether an SRC homology 2 domain-containing phosphotyrosine phosphatase 2 (SHP2) inhibitor would increase muscle-specific kinase (MuSK) phosphorylation and override the inhibitory effect of MuSK-antibodies (Abs).MethodsThe effect of the SHP2 inhibitor NSC-87877 on MuSK phosphorylation and AChR clustering was tested in C2C12 myotubes with 31 MuSK-myasthenia gravis (MG) sera and purified MuSK-MG IgG4 preparations.ResultsIn the absence of MuSK-MG Abs, NSC-87877 increased MuSK phosphorylation and the number of AChR clusters in C2C12 myotubes in vitro and in DOK7-overexpressing C2C12 myotubes that form spontaneous AChR clusters. In the presence of MuSK-MG sera, the AChR clusters were reduced, as expected, but NSC-87877 was able to protect or restore the clusters. Two purified MuSK-MG IgG4 preparations inhibited both MuSK phosphorylation and AChR cluster formation, and in both, clusters were restored with NSC-87877.ConclusionsStimulating the agrin-LRP4-MuSK-DOK7 AChR clustering pathway with NSC-87877, or other drugs, could represent a novel therapeutic approach for MuSK-MG and could potentially improve other NMJ disorders with reduced AChR numbers or disrupted NMJs.

Background and aims: Acquired Neuromyotonia (NMT) is an autoimmune condition frequently associated with anti-contactin-associated-protein-like-2 (Caspr2) antibodies. NMT can occur as a paraneoplastic disorder in patients with thymoma, alone or in combination with Myasthenia Gravis (MG). Recently, antibodies against netrin-1-receptors (DCC and UNC5A) have been reported as predictors of thymoma in 6/9 patients with concomitant NMT and MG. We aimed to clinically characterize a large cohort of patients with thymoma-associated MG, and to explore serological correlation of NMT symptoms. Methods: 268 consecutive patients with thymoma-associated MG were retrospectively collected. NMT was defined as muscle twitching/cramps in at least 2 skeletal districts. Patients with NMT(23) were screened for anti-neuronal antibodies by immunohistochemistry on rat brain and cell based assay. Results: 23/268 patients developed NMT symptoms (muscle twitching, 3; cramps, 3, or both, 17). Overall, 33/268 patients with thymoma had a tumor recurrence, which was more frequent in those with (8/23) vs those without NMT (25/245, p=0.003). NMT onset preceded the tumor recurrence in 5/6 patients. In univariate analysis predictors of thymoma recurrence were younger age at thymectomy (odds ratio-OR:0.95, confidence interval-CI:0.93-0.97), Masaoka staging (OR:10.73, CI:2.38-48.36) and NMT (OR:4.69, CI:1.76-12.46). 6 patients with NMT had anti-neuronal antibodies (patient#1: Caspr2; patient#2: AMPAR; patient#3: DCC; patient#4: LGI1; patient#5: Caspr2+LGI1+DCC+UNC5A; patient#6: Caspr2+LGI1+DCC). Thymoma recurrence was found less frequently in negative (3/17) vs positive patients with NMT (4/6, #1, #2, #5 and #6; p=0.045). Conclusion: The occurrence of NMT symptoms in patients with thymoma-associated MG can predict tumor recurrence, and warrants a closer oncologic follow-up. Anti-neuronal surface autoantibodies may be useful to further stratify the recurrence risk. Disclosure: This work was funded by the ‘Ricerca finalizzata ministeriale 2015-2017’ provided by the Italian ministry of health

Background Complement is likely to have a role in refractory generalised myasthenia gravis, but no approved therapies specifically target this system. Results from a phase 2 study suggested that eculizumab, a terminal complement inhibitor, produced clinically meaningful improvements in patients with anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis. We further assessed the efficacy and safety of eculizumab in this patient population in a phase 3 trial. Methods We did a phase 3, randomised, double-blind, placebo-controlled, multicentre study (REGAIN) in 76 hospitals and specialised clinics in 17 countries across North America, Latin America, Europe, and Asia. Eligible patients were aged at least 18 years, with a Myasthenia Gravis-Activities of Daily Living (MG-ADL) score of 6 or more, Myasthenia Gravis Foundation of America (MGFA) class II-IV disease, vaccination against Neisseria meningitides, and previous treatment with at least two immunosuppressive therapies or one immunosuppressive therapy and chronic intravenous immunoglobulin or plasma exchange for 12 months without symptom control. Patients with a history of thymoma or thymic neoplasms, thymectomy within 12 months before screening, or use of intravenous immunoglobulin or plasma exchange within 4 weeks before randomisation, or rituximab within 6 months before screening, were excluded. We randomly assigned participants (1:1) to either intravenous eculizumab or intravenous matched placebo for 26 weeks. Dosing for eculizumab was 900 mg on day 1 and at weeks 1, 2, and 3; 1200 mg at week 4; and 1200 mg given every second week thereafter as maintenance dosing. Randomisation was done centrally with an interactive voice or web-response system with patients stratified to one of four groups based on MGFA disease classification. Where possible, patients were maintained on existing myasthenia gravis therapies and rescue medication was allowed at the study physician's discretion. Patients, investigators, staff, and outcome assessors were masked to treatment assignment. The primary efficacy endpoint was the change from baseline to week 26 in MG-ADL total score measured by worst-rank ANCOVA. The efficacy population set was defined as all patients randomly assigned to treatment groups who received at least one dose of study drug, had a valid baseline MG-ADL assessment, and at least one post-baseline MG-ADL assessment. The safety analyses included all randomly assigned patients who received eculizumab or placebo. This trial is registered with ClinicalTrials.gov, number NCT01997229. Findings Between April 30, 2014, and Feb 19, 2016, we randomly assigned and treated 125 patients, 62 with eculizumab and 63 with placebo. The primary analysis showed no significant difference between eculizumab and placebo (least-squares mean rank 56·6 [SEM 4·5] vs 68·3 [4·5]; rank-based treatment difference -11·7, 95% CI -24·3 to 0·96; p=0·0698). No deaths or cases of meningococcal infection occurred during the study. The most common adverse events in both groups were headache and upper respiratory tract infection (ten [16%] for both events in the eculizumab group and 12 [19%] for both in the placebo group). Myasthenia gravis exacerbations were reported by six (10%) patients in the eculizumab group and 15 (24%) in the placebo group. Six (10%) patients in the eculizumab group and 12 (19%) in the placebo group required rescue therapy. Interpretation The change in the MG-ADL score was not statistically significant between eculizumab and placebo, as measured by the worst-rank analysis. Eculizumab was well tolerated. The use of a worst-rank analytical approach proved to be an important limitation of this study since the secondary and sensitivity analyses results were inconsistent with the primary endpoint result; further research into the role of complement is needed. Funding Alexion Pharmaceuticals.

Purpose Sleep deprivation (SD) increases the occurrence of interictal epileptiform discharges (IED) compared to basal EEG in temporal lobe epilepsy (TLE). In adults, EEG after SD is usually performed in the morning after SD. We aimed to evaluate whether morning sleep after SD bears additional IED-inducing effects compared with nocturnal physiological sleep, and whether changes in sleep stability (described by the cyclic alternating pattern-CAP) play a significant role. Methods Adult patients with TLE underwent in-lab night polysomnography (n-PSG) and, within 7 days from n-PSG, they underwent also a morning EEG after night SD (SD-EEG). We included only TLE patients in which both recordings showed IED. SD-EEG consisted of waking up patients at 2:00 AM and performing video EEG at 8:00 AM. For both recordings, we obtained the following markers for the first sleep cycle: IED/h (Spike Index, SI), sleep macrostructure, microstructure (NREM CAP rate; A1, A2 and A3 Indices), and SI association with CAP variables. Results The macrostructure of the first sleep cycle was similar in n-PSG and morning SD-EEG, whereas CAP rate and SI were significantly higher in SD-EEG. SI increase was selectively associated with CAP phases. Conclusions SD increases the instability of morning recovery sleep compared with n-PSG, and particularly enhances CAP A1 phases, which are associated with the majority of IED. Thus, higher instability of morning recovery sleep may account at least in part for the increased IED yield in SD-EEG in TLE patients.

Autoimmunity mediated by IgG4 subclass autoantibodies is an expanding field of research. Due to their structural characteristics a key feature of IgG4 antibodies is the ability to exchange Fab-arms with other, unrelated, IgG4 molecules, making the IgG4 molecule potentially monovalent for the specific antigen. However, whether those disease-associated antigen-specific IgG4 are mono- or divalent for their antigens is unknown. Myasthenia gravis (MG) with antibodies to muscle specific kinase (MuSK-MG) is a well-recognized disease in which the predominant pathogenic IgG4 antibody binds to extracellular epitopes on MuSK at the neuromuscular junction; this inhibits a pathway that clusters the acetylcholine (neurotransmitter) receptors and leads to failure of neuromuscular transmission. In vitro Fab-arm exchange-inducing conditions were applied to MuSK antibodies in sera, purified IgG4 and IgG1-3 sub-fractions. Solid-phase cross-linking assays were established to determine the extent of pre-existing and inducible Fab-arm exchange. Functional effects of the resulting populations of IgG4 antibodies were determined by measuring inhibition of agrin-induced AChR clustering in C2C12 cells. To confirm the results, κ/κ, λ/λ and hybrid κ/λ IgG4s were isolated and tested for MuSK antibodies. At least fifty percent of patients had IgG4, but not IgG1-3, MuSK antibodies that could undergo Fab-arm exchange in vitro under reducing conditions. Also MuSK antibodies were found in vivo that were divalent (monospecific for MuSK). Fab-arm exchange with normal human IgG4 did not prevent the inhibitory effect of serum derived MuSK antibodies on AChR clustering in C2C12 mouse myotubes. The results suggest that a considerable proportion of MuSK IgG4 could already be Fab-arm exchanged in vivo. This was confirmed by isolating endogenous IgG4 MuSK antibodies containing both κ and λ light chains, i.e. hybrid IgG4 molecules. These new findings demonstrate that Fab-arm exchanged antibodies are pathogenic. publisher: Elsevier articletitle: IgG4 autoantibodies against muscle-specific kinase undergo Fab-arm exchange in myasthenia gravis patients journaltitle: Journal of Autoimmunity articlelink: http://dx.doi.org/10.1016/j.jaut.2016.11.005 content_type: article copyright: © 2016 The Authors. Published by Elsevier Ltd. ispartof: Journal of Autoimmunity vol:77 pages:104-115 ispartof: location:England status: published

In the field of sleep disorders, the quality of couple relationship is arousing increasing attention, given its implications for quality of life and treatment adherence. The aim of the present study was to evaluate relationship quality in a sample of treated or untreated patients with Obstructive Sleep Apnoea Syndrome. Eighty-seven patients were recruited in a hospital-based Centre for Sleep Medicine. Subjects were administered the Dyadic Adjustment Scale (DAS) to evaluate relationship quality, and the Epworth Sleepiness Scale (ESS). Apnoea-hypopnoea indexes (AHI) were collected through nocturnal polysomnography or home testing with a portable monitoring device. Although the DAS average scores were similar to local normative values, relationship quality was significantly lower in the untreated patients when compared with the ones treated. The ESS scores showed a negative correlation with many DAS scores, whereas no significant correlation emerged for AHI. Such data suggest a significant impact of perceived sleep apnoea symptoms on marital satisfaction, even though in the absence of striking differences between the whole sample and the general population.

To update the current knowledge concerning sleep complaints and breathing disorders in myotonic dystrophy type 2 (DM2) and to better understand if sleep and breathing symptoms may add a further clinical definition of DM2. Although DM2 has been poorly evaluated, the most relevant sleep disorders are sleep-disordered breathing (SDB) (37.5–66.7%) and restless legs syndrome (RLS) (50–60%). Excessive daytime somnolence (EDS) is not consistent with SDB, and a large percentage of patients with sleep complaints (58–69%) report pain. In addition, respiratory dysfunctions are reported in 6 to 15% of DM2 patients, albeit few data are available regarding pulmonary restriction, hypoventilation, and non-invasive ventilation (NIV). SDB, RLS, and pain may contribute to sleep fragmentation and EDS in DM2. In addition, few studies report hypoventilation and pulmonary restriction, although there are no studies at all on NIV, except for limited clinical experiences. These findings suggest performing a careful pulmonary examination and NIV when required. Furthermore, sleep studies and respiratory evaluation should be recommended if OSA or respiratory muscle dysfunctions are suspected. A large polysomnographic study should be performed to clarify the link between sleep disorders, pain, and sleep disruption in DM2.

Insomnia, vasomotor symptoms (VMS) and depression often co-occur after the menopause, with consequent health problems and reductions in quality of life. The aim of this position statement is to provide evidence-based advice on the management of postmenopausal sleep disorders derived from a systematic review of the literature. The latter yielded results on VMS, insomnia, circadian rhythm disorders, obstructive sleep apnea (OSA) and restless leg syndrome (RLS). Overall, the studies show that menopausal hormone therapy (MHT) improves VMS, insomnia, and mood. Several antidepressants can improve insomnia, either on their own or in association with MHT; these include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), and mirtazapine. Long-term benefits for postmenopausal insomnia may also be achieved with non-drug strategies such as cognitive behavioral therapy (CBT) and aerobic exercise. Continuous positive airway pressure (CPAP) and mandibular advancement devices (MADs) both reduce blood pressure and cortisol levels in postmenopausal women suffering from OSA. However, the data regarding MHT on postmenopausal restless legs syndrome are conflicting.

The increased prevalence of sleep disorders associated with menopause has been emphasized by multiple international studies. Many factors are associated with insomnia during menopause, among them: hot flashes (HF), anxiety and depression, other medical conditions, behavioral and psychosocial factors and primitive sleep patterns. The domino hypothesis connects various factors and suggests that HF disturb sleep, thereby causing insomnia, which in turn increases vulnerability to depression. Nevertheless, sleep disorders predict mood disturbances more robustly than vasomotor symptoms (VMS), indicating that sleep also influences mood via other mechanisms. The medical conditions that may compromise sleep in this age group are common; they include obesity, gastroesophageal reflux, cancer, urinary incontinence and nocturia, thyroid dysfunction, chronic pain, fibromyalgia (often starting or worsening in menopause), and hypertension. Common causes of sleep disorders in middle-aged women include poor sleep hygiene, volitional factors, environmental disturbances, alcohol intake, marital dissatisfaction, requests for care from children, grandchildren and/or elderly parents, and financial worries. Evidence from other populations suggests that if insomnia is not treated, it may negatively affect the outcome of comorbid conditions. Taken together, these observations suggest that insomnia should be considered a disorder requiring specific attention and treatment. Moreover, recent cross-sectional data link sleep with subclinical markers of cardiovascular risk. It should also be noted that insomnia is common in patients with mild to moderate obstructive sleep apnea syndrome (OSAS).

The main condition at increased risk of dementia is considered to be mild cognitive impairment. Mild cognitive impairment has been defined as a transitional state between normal aging and dementia, of which it may represent a prodrome. The aim of our study was to evaluate whether sleep variables (both conventional and microstructural ones) in subjects with mild cognitive impairment correlate with conversion to dementia. Nineteen subjects with amnestic mild cognitive impairment (mean age 68.5 ± 7.0 years) and 11 cognitively intact healthy elderly individuals (mean age 69.2 ± 12.6 years) underwent ambulatory polysomnography for the evaluation of nocturnal sleep architecture and cyclic alternating pattern parameters. Amnestic mild cognitive impairment subjects were clinically and cognitively re-evaluated after 2 years, during routine follow-up, and further classified as amnestic mild cognitive impairment converters (that is, patients developing Alzheimer's disease, N = 11) and amnestic mild cognitive impairment non-converters. Compared with healthy elderly individuals, amnestic mild cognitive impairment showed disrupted sleep with decreased rapid eye movement sleep, cyclic alternating pattern rate and cyclic alternating pattern slow-wave-related phases (A1 index). Standard sleep architecture analysis did not show significant differences between the two subgroups of amnestic mild cognitive impairment, whereas cyclic alternating pattern analysis showed that cyclic alternating pattern rate, A1 index and A3 index are significantly reduced in converters compared with non-converters. Our data confirm that in amnestic mild cognitive impairment subjects there is a sleep impairment, particularly when considering more refined sleep parameters and that sleep variables at baseline are different among converters versus non-converters at the 2-year follow-up. Specific sleep alterations might represent potential further biomarkers for the diagnosis and prognosis of early-phase cognitive impairment.

Background Myasthenia Gravis (MG) is caused, in approximately 80% of the patients, by autoantibodies against the nicotinic acetylcholine receptor (AChR). The disease is often associated with pathological changes of the thymus: thymic epithelial tumours are present in about 10–20% of the patients, while up to 80% of the patients with early disease onset have thymic hyperplasia. Folate metabolism is required for the production of DNA precursors and for proper DNA methylation reactions, and impaired folate metabolism has been often associated with cellular growth and cancer. Methods We investigated if major polymorphisms of folate-related genes, namely MTHFR c.677C > T, MTR c.2756A > G, MTRR c.66A > G and TYMS TSER (a 28-bp tandem repeat in the 5′ promoter enhancer region of TYMS) increase the risk of pathological changes of the thymus in AChR + MG patients. A total of 526 AChR + MG patients, including 132 patients with normal (involuted) thymus, 146 patients with thymic hyperplasia, and 248 patients with a thymoma were included in the study. Allele and genotype comparisons were performed among the three study groups, after correcting for multiple testing. Results The frequency of the TYMS TSER 3R allele was significantly higher in MG patients with thymic hyperplasia (P = 0.004), and the TYMS TSER 3R3R genotype was significantly associated with increased risk of thymic hyperplasia [OR 2.71 (95% CI: 1.34–5.47)]. Conclusions The 3R allele in the thymidylate synthase promoter enhancer region results in increased protein production, required for the synthesis of DNA precursors. The present study suggests that the TYMS TSER 3R allele increases the risk of thymic lymphoid hyperplasia in AChR + MG patients.

Sleep disruption and excessive daytime sleepiness are well recognised symptoms in myotonic dystrophy type 1 (DM1), where a central dysfunction of sleep-wake regulation may play a pivotal role. Few studies evaluated sleep macrostructure in DM1, but none investigated more refined sleep variables. Eight DM1 patients (6 male, aged 20-50 years) and 10 healthy controls (7 male, aged 22-67 years) underwent nocturnal polysomnography and multiple sleep latency test. Sleep stages and events were scored according to standard criteria; sleep microstructure was analyzed through cyclic alternating pattern. Relative and absolute delta powers were computed for whole non REM and each non REM period. DM1 patients showed increased REM sleep and decreased N2. N3, although not significantly, was increased. Three patients, but no controls, had sleep-onset REM period in nocturnal sleep. DM1 patients showed slower delta power dissipation across the night, and increased sleep instability (CAP rate). Multiple sleep latency tests showed shorter sleep latencies, five patients presenting at least one sleep-onset REM period and, when including also night sleep, two sleep-onset REM periods. Our data confirm a narcoleptic-like phenotype in DM1 with a prominent REM sleep dysregulation, that may account for daytime sleepiness, together with increased sleep instability and impaired delta power dissipation that seem peculiar of the disease.

Sleep-related rhythmic movements (SRRMs) are typical in infancy and childhood, where they usually occur at the wake-to-sleep transition. However, they have rarely been observed in adults, where they can be idiopathic or associated with other sleep disorders including sleep apnea. We report a case series of 5 adults with sleep-related rhythmic movement disorder, 4 of whom had a previous history of SRRMs in childhood. SRRMs mostly occurred in consolidated sleep, in association with pathological respiratory events, predominantly longer ones, especially during stage R sleep, and recovered in 1 patient with continuous positive airway pressure therapy. We hypothesize that sleep apneas may act as a trigger of rhythmic motor events through a respiratory-related arousal mechanism in genetically predisposed subjects.

Age-related cognitive impairment and dementia are an increasing societal burden. Epidemiological studies indicate that lifestyle factors, e.g. physical, cognitive and social activities, correlate with reduced dementia risk; moreover, positive effects on cognition of physical/cognitive training have been found in cognitively unimpaired elders. Less is known about effectiveness and action mechanisms of physical/cognitive training in elders already suffering from Mild Cognitive Impairment (MCI), a population at high risk for dementia. We assessed in 113 MCI subjects aged 65–89 years, the efficacy of combined physical-cognitive training on cognitive decline, Gray Matter (GM) volume loss and Cerebral Blood Flow (CBF) in hippocampus and parahippocampal areas, and on brain-blood-oxygenation-level-dependent (BOLD) activity elicited by a cognitive task, measured by ADAS-Cog scale, Magnetic Resonance Imaging (MRI), Arterial Spin Labeling (ASL) and fMRI, respectively, before and after 7 months of training vs. usual life. Cognitive status significantly decreased in MCI-no training and significantly increased in MCI-training subjects; training increased parahippocampal CBF, but no effect on GM volume loss was evident; BOLD activity increase, indicative of neural efficiency decline, was found only in MCI-no training subjects. These results show that a non pharmacological, multicomponent intervention improves cognitive status and indicators of brain health in MCI subjects.

Introduction Myasthenia gravis (MG) with autoantibodies to muscle-specific tyrosine kinase (MuSK) represents a distinct type of disease, as compared MG with antibodies against acetylcholine receptor (AchR-Abs). MuSK-MG patients have peculiar clinical features characterized by predominant oculo-bulbar symptoms and a lack of response to conventional MG treatments. Since the role of electrophysiological tests in MuSK patients is still argued, our aim was to investigate their electrophysiological profile in order to arise a light over this darkness. Methods We retrospectively evaluated repetitive nerve stimulation (RNS) and single-fibre electromyography (SF-EMG) reports of 63 MuSK patients, at the time of MG diagnosis, and we compared them with 35 non-timomatous AChR-Abs positive patients matched with MuSK group according to gender, age at onset of MG, age at MG diagnosis and severity of the disease. Disease severity was graded according to Myasthenia Gravis Foundation of America (MGFA) classification. Seronegative patients and thymoma-associated MG patients were excluded from the study. Results Sixty-three MuSK patients (11 males; 52 females; mean age at MG onset: 37 ± 2.0; mean age at diagnosis: 38.7 ± 2.0) and 35 AChR-Abs positive patients (9 males; 26 females; mean age at MG onset: 31.2 ± 2.7: mean age at diagnosis: 33.1 ± 2.5) were enrolled in the study. Fifty-nine MuSK patients (93.6%) and 31 AChR-Abs positive patients (88.5%) underwent RNS, whereas SF-EMG was tested in 17 MuSK patients and in 7 AChR-Abs patients. RNS showed a significant decrement in a higher percentage of AChR-Abs positive patients than the MuSK group (p Conclusion While SR-EMG positivity was significantly higher in AChR-Abs group, there was no difference regarding SF-EMG. In MusK group, the decrement of RNS was more evident in proximal muscles while RNS in distal muscles can be negative. Although neurophysiological evaluation is still important for MG diagnosis, it plays a secondary role after anti-MuSK titration.

Introduction Although Myasthenia gravis (MG) is the most common autoimmune disease associated with thymoma, a small proportion of thymomatous patients can suffer from limbic autoimmune encephalitis (LE). LE is usually characterized by rapid progressive short-term memory deficits, psychiatric symptoms, and seizures. Patients can present antibodies against cell surface antigens, including contactin-associated protein-like 2 (CASPR2) and a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR). Our aim was to analyze the EEG findings of these patients to find possible EEG homologies among their patterns. Methods Clinical information was obtained from a retrospective review of medical records and EEG recordings of three patients with thymoma and LE: two with seropositivity for AMPAR antibodies and one for CASPR2 antibodies. Results The first case was a 37 years-old man with a subacute onset of memory loss, confusion, anxiety and behavioral disorders in the setting of an invasive thymoma (type B2-B3). Brain MRI and dosage of acetylcholine receptor antibodies (AChR-Abs) were normal. EEG showed bilateral fronto-temporal spikes together with slow theta and delta activity. Clinical suspicion of a paraneoplastic neurological syndrome associated with thymoma was confirmed by the serological presence of AMPAR-Abs. The second case was a 47 years-old female patient with Myasthenia Gravis (MG) and seropositivity for AChR-Abs, treated for recurrent thymoma (type B2). She presented three episodes of generalized seizures, together with mental disorientation, impairment of recent memory and insomnia. Brain MRI was normal. EEG showed a peculiar pattern, comprising lateralized right fronto-temporal spikes and generalized sharp waves. Serological tests detected the presence of antibodies to CASPR2. The third case was a 52 years-old female patient with thymoma (type B2-B3) who developed confusion, short-term memory loss and psychomotor agitation after thymectomy. Cerebrospinal fluid (CSF) examination showed a mild blood-CSF barrier damage and brain MRI revealed increased T2 signal involving mesio-temporal cortical areas. EEG showed electrical abnormalities in the fronto-temporal regions. Antibodies to the glutamate receptor 1 (GluR1) and GluR3 subunits of AMPAR were detected both in serum and CSF. Conclusion Limbic autoimmune encephalitis should be suspected in patients with invasive thymoma and subacute onset of confusion, memory loss and seizures. In all these three cases EEG showed epileptiform activity, especially in the fronto-temporal regions, together with slow theta and delta activity, without a pathognomonic pattern. Our results strongly emphasize the importance of testing biological samples when a possible autoimmune CNS involvement is suspected. Even if antibody testing remains the cornerstone in the diagnostic pathway, EEG is paramount in the differential diagnosis with similar disorders, in orienting toward limbic encephalopathy, especially when MRI is inconclusive.

8565 Background: Thymomas but not thymic carcinomas can benefit of cytoreductive surgery even if a complete resection is not achievable. Surgical resection of pleural metastases, the most common site of progression, can be performed in selected patients. We evaluated the outcome of stereotactic body radiation therapy (SBRT) for treatment of pleural metastases in patients’ not eligible for surgery. Methods: We retrospectively identified 22 patients treated with SBRT for pleural metastases between 2004 and 2019. According to RECIST criteria, time to local failure and progression free survival (PFS) were calculated using Kaplan-Meier estimation. Results: Twelve of the 22 patients were male. The median age was 40 years (range 29-73). There were 1 A, 3 AB, 3 B1, 3 B2, 3 B2/B3 and 9 B3 thymomas. The Masaoka stage at diagnosis was IIA in 2, IIB in 7, III in 5, IVA in 7 and IVB in 1 patient. Pleural metastases and primary tumor were synchronous in 8 patients. Thymectomy was performed in 21 patients. Seven patients received pre-operative chemotherapy and 12 post-operative radiotherapy. One patient received chemotherapy and radiotherapy after a macroscopically incomplete thymectomy. Five patients had a single pleural metastatic site and 17 presented multiple localizations. Sixteen patients received SBRT on multiple sites of pleural metastases. At the time of the analysis a patient received SBRT exclusively on one of 3 pleural metastases. The median dose of radiation was 30Gy (range 25-40) given in 3 fractions. Ten patients experienced a progression of treated lesions with a median time to local failure of 25.5 months (95%CI 20.9-30.1). The median PFS was 20.4 months (95%CI 10.7-30). There were not significant differences in PFS between patients diagnosed with synchronous and metachronous metastases (p=0.477), across those treated with chemotherapy or naive (p=0.189) and between those who received or not a previous surgical resection of the pleural metastases (p=0.871). Conclusions: SBRT of pleural metastases is feasible and offer an interesting local control of diseases. The impact of this treatment on patients’ survival is hardly predictable because of the heterogenous clinical behavior of thymomas.

The aims of our study were to evaluate excessive daytime sleepiness in a group of de novo untreated people with epilepsy using a comprehensive and standardized approach, including subjective evaluation and neurophysiological and performance tests, and to compare these results with those obtained in a control group. Forty-seven patients with epilepsy (17 affected by primary generalized epilepsy and 30 by partial epilepsy), with a new epilepsy diagnosis and never treated, and 44 controls underwent Multiple Sleep Latency Test (preceded by nocturnal polysomnography), simple/complex visual reaction times, and Epworth Sleepiness Scale evaluation. Newly diagnosed and drug-free patients with epilepsy did not differ from controls in any of the tests performed to evaluate daytime sleepiness. In clinical practice, daytime sleepiness is a well-known and frequent complaint of patients with epilepsy, but different mechanisms and causes, such as associated psychiatric or sleep disorders, nocturnal seizures, sleep fragmentation, and antiepileptic drugs, must be taken into account. Excessive daytime sleepiness should not be considered an unavoidable consequence of epilepsy. Thus, a complete diagnostic work-up in patients with epilepsy and sleepiness should be undertaken whenever possible.