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Objective Juvenile Myoclonic Epilepsy (JME) is a common genetic generalized epilepsy syndrome. Several studies have detailed cognitive and imaging abnormalities pointing to frontal lobe dysfunction, as well as disadvantageous behavioral traits and poor social outcome, challenging the commonly held view of JME being a benign disorder. Social cognition is the ability to elaborate mental representations of social interactions and to use them correctly in social contexts, and includes Theory of Mind (ToM), which pertains to the attribution of cognitive and affective mental states to self and others and seems to rely on complex fronto-temporal interactions. ToM has been recently assessed in focal epilepsy syndromes, but little is available for generalized epilepsies. We performed a cross-sectional study to assess social cognition, with an emphasis on ToM, as well as standard cognitive functions in patients with JME. Method We recruited twenty JME patients and twenty matched controls. Tests used to assess social cognition and ToM included the Emotion Attribution Task, Strange Stories Task (SST), Faux Pas Task (FPT), Reading the Mind in the Eyes Task and Social Situation Task. Subjects were also assessed via an extensive neuropsychological battery. Results Patients exhibited worse performance in the SST and in several scores of the FPT. They also showed widespread cognitive impairment, involving executive functions, psychomotor speed, verbal and visuo-spatial memory. Conclusions In addition to cognitive impairment for fronto-temporal tasks, some features of social cognition are also altered in JME. The latter deficit may underlie the poor social outcome previously described for these patients, and might also relate to imaging findings of frontal lobe dysfunction. [ABSTRACT FROM AUTHOR]

In patients with a first seizure, the identification of early sensitive and specific biomarkers for formulating a diagnosis of epilepsy is fundamental. Sleep deprivation (SD) has long been used as a means of enhancing EEG sensitivity in the diagnostic process. However, huge methodological differences among the studies addressing this topic have led to highly variable results and often confusing assumptions. Here, we provide a detailed description of the correlations between SD and epilepsy, along with their putative mechanistic explanations derived from experimental studies in animals and humans. We also outline the clinical studies evaluating the role of SD EEG and discuss them critically in terms of: (a) study design and SD EEG methodology; (b) EEG sensitivity and specificity; (c) the role of drug-induced sleep EEG and EEG during spontaneously occurring sleep; and (d) the relevance of patient features, syndromes, and subsyndromes, as well as their correlations with neuroimaging details. Finally, we propose specific studies that might increase the role of SD EEG in the diagnosis and prognosis of epilepsy. [ABSTRACT FROM AUTHOR]

Introduction/Aims: The global incidence and prevalence of myasthenia gravis (MG) range between 6–31/million and 10–37/100,000, respectively. Sardinia is a high‐risk region for different immune‐mediated disorders, but the epidemiology of MG remains unclear. We determined the epidemiology of MG with acetylcholine receptor (AChR)‐immunoglobulin G (IgG) and muscle‐specific tyrosine kinase (MuSK)‐IgG in the district of Sassari (North‐Western Sardinia; population, 325,288). Methods: From the laboratory of the University Hospital of Sassari (reference for AChR/MuSK‐IgG testing in Sardinia since 1998) and the main neurology units in Sardinia, we retrospectively identified MG patients with (1) AChR‐IgG and/or MuSK‐IgG positivity by radioimmunoprecipitation assay; and (2) residency in the district of Sassari. Incidence (January 2010–December 2019) and prevalence (December 31, 2019) were calculated. Results: A total of 202 patients were included (incident, 107; prevalent, 180). Antibody specificities were AChR (n = 187 [93%]) and MuSK (n = 15 [7%]). The crude MG incidence (95% confidence interval) was 32.6 (26.8–39.2)/million, while prevalence was 55.3 (47.7–63.9)/100,000. After age‐standardization to the world population, incidence decreased to 18.4 (14.3–22.5)/million, while prevalence decreased to 31.6 (26.1–37.0)/100,000. Among incident cases, age strata (years) at MG onset were: <18 (2%), 18–49 (14%), 50–64 (21%), and ≥65 (63%). Discussion: Sardinia is a high‐risk region for MG, with a prevalence that exceeds the European threshold for rare disease. Identification of the environmental and genetic determinants of this risk may improve our understanding of disease pathophysiology. [ABSTRACT FROM AUTHOR]

Social cognition allows us to elaborate mental representations of social relationships and use them appropriately in a social environment. One of its main attributes is the so-called Theory of Mind (ToM), which consists of the ability to attribute beliefs, intentions, emotions, and feelings to self and others. Investigating social cognition may help understand the poor social outcome often experienced by persons with Idiopathic Generalized Epilepsies (IGE), who otherwise present with normal intelligence. In recent years, several studies have addressed social cognition in subjects with focal epilepsies, while literature on social cognition in IGE is scarce, and findings are often conflicting. Some studies on samples of patients with mixed IGE showed difficulties in emotion attribution tasks, which were not replicated in a homogeneous population of patients with Juvenile Myoclonic Epilepsy alone. Impairment of higher order social skills, such as those assessed by Strange Stories Test and Faux Pas Tasks, were consistently found by different studies on mixed IGE, suggesting that this may be a more distinctive IGE-associated trait, irrespective of the specific syndrome subtype. Though an interplay between social cognition and executive functions (EF) was suggested by several authors, and their simultaneous impairment was shown in several epilepsy syndromes including IGE, no formal correlations among the two domains were identified in most studies. People with IGE exhibit subtle brain structural alterations in areas potentially involved in sociocognitive functional networks, including mesial prefrontal and temporoparietal cortices, which may relate to impairment in social cognition. Heterogeneity in patient samples, mostly consisting of groups with mixed IGE, and lack of analyses in specific IGE subsyndromes, represent evident limitations of the current literature. Larger studies, focusing on specific subsyndromes and implementing standardized test batteries, will improve our understanding of sociocognitive processing in IGE. Concomitant high-resolution structural and functional neuroimaging may aid the identification of its neural correlates. This article is part of the Special Issue "Epilepsy and social cognition across the lifespan". • Patients with IGE often present with poor social outcome, despite a normal intelligence. • Social cognition is the ability to elaborate mental representations of social relationships. • In IGE, the Strange Stories and Faux Pas tasks are often affected. • Some abnormalities in social cognition may be related to neuroanatomical features. • Larger studies focused on IGE subtypes are needed to improve knowledge. [ABSTRACT FROM AUTHOR]

Simple Summary: Extended thymectomy is the gold standard in the treatment of patients with thymic neoplasm and affected by myasthenia gravis. For a long time, the traditional approach has been sternotomy, though the application of minimally invasive techniques has spread in recent decades. Several authors have demonstrated the safety and feasibility of minimally invasive thymectomy. This multicenter study aims to compare the outcomes of robotic and open thymectomy in myasthenic patients affected by thymic tumors. Short-term and long-term results were presented, showing how the robotic approach can be considered comparable to open surgery in terms of oncological radicality and the improvement of myasthenic symptomatology, with associated faster recovery. Thymectomy is the gold standard in the treatment of thymic neoplasm and plays a key role in the therapeutic path of myasthenia gravis. For years, sternotomy has been the traditional approach for removing anterior mediastinal lesions, although the robotic thymectomy is now widely performed. The literature is still lacking in papers comparing the two approaches and evaluating long-term oncological and neurological outcomes. This study aims to analyze the postoperative results of open and robotic thymectomy for thymic neoplasms in myasthenic patients. Surgical, oncological and neurological data of myasthenic patients affected by thymic neoplasms and surgically treated with extended thymectomy, both with the open and the robotic approach, in six Italian Thoracic Centers between 2011 and 2021 were evaluated. A total of 213 patients were enrolled in the study: 110 (51.6%) were treated with the open approach, and 103 (48.4%) were treated with robotic surgery. The open surgery, compared with the robotic, presented a shorter operating time (p < 0.001), a higher number of postoperative complications (p = 0.038) and longer postoperative hospitalization (p = 0.006). No other differences were observed in terms of surgical, oncological or neurological outcomes. The robotic approach can be considered safe and feasible, comparable to the open technique, in terms of surgical, oncological and neurological outcomes. [ABSTRACT FROM AUTHOR]

Open in new tab Download slide OBJECTIVES Total thymectomy in addition to medical treatment is an accepted standard therapy for myasthenia gravis (MG). Patients with severe generalized MG present life-threatening events, poor prognosis and higher risk of postoperative myasthenic crisis. The aim of our study is to investigate neurological and surgical results in patients with Myasthenia Gravis Foundation of America (MGFA) class IV and V MG following thymectomy. METHODS Data on 76 MG patients with preoperative MGFA classes IV and V who underwent thymectomy were retrospectively collected. Primary end points included short-term surgical outcomes and long-term neurological results including the achievement of complete stable remission and any improvement as defined by MGFA Post-Intervention Status criteria. RESULTS There were 27 (35.5%) males and 49 (64.5%) females; 53 (69.7%) were classified as MGFA class IV and 23 (30.3%) as class V. Thymectomy was performed through sternotomy in 25 (32.9%) patients, Video-assisted thoracic surgery (VATS) in 5 (6.6%) and Robot-assisted thoracic surgery (RATS) in 46 (60.5%). The median operative time was 120 (interquartile range: 95; 148) min. In-hospital mortality was observed in 1 (1.3%) patient and postoperative complications in 14 (18.4%) patients. The median postoperative hospital stay was 4 (interquartile range: 3; 6) days. Pathological examination revealed 31 (40.8%) thymic hyperplasia/other benign and 45 (59.2%) thymomas. Cumulative complete stable remission and improvement probabilities were 20.6% and 83.7% at 5 years and 66.9% and 97.6% at 10 years, respectively. A significant improvement rate was found in patients with age at the time of thymectomy of ≤50 years (P  = 0.0236), MGFA class V (P  = 0.0154) and acetylcholine receptor antibodies positivity (P  = 0.0152). CONCLUSIONS Thymectomy in patients with severe MG yields good perioperative outcomes and satisfactory long-term neurological improvement, especially for patients younger than 50 years, with MGFA class V and anti-AChR+ MG. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 (<45 years; p ≤ 0.00001). Furthermore, considering the XCI pattern and the other clinical characteristics of patients, no significant differences were found. In conclusion, we observed preferential XCI in MG female patients, suggesting its potential role in the aetiology of MG, as observed in other autoimmune diseases in women. [ABSTRACT FROM AUTHOR]

Myasthenia gravis is a chronic autoimmune disease characterized by autoantibody-mediated interference of signal transmission across the neuromuscular junction. We performed a genome-wide association study (GWAS) involving 1,873 patients diagnosed with acetylcholine receptor antibody-positive myasthenia gravis and 36,370 healthy individuals to identify disease-associated genetic risk loci. Replication of the discovered loci was attempted in an independent cohort from the UK Biobank. We also performed a transcriptome-wide association study (TWAS) using expression data from skeletal muscle, whole blood, and tibial nerve to test the effects of disease-associated polymorphisms on gene expression. We discovered two signals in the genes encoding acetylcholine receptor subunits that are the most common antigenic target of the autoantibodies: a GWAS signal within the cholinergic receptor nicotinic alpha 1 subunit (CHRNA1) gene and a TWAS association with the cholinergic receptor nicotinic beta 1 subunit (CHRNB1) gene in normal skeletal muscle. Two other loci were discovered on 10p14 and 11q21, and the previous association signals at PTPN22, HLA-DQA1/HLA-B, and TNFRSF11A were confirmed. Subgroup analyses demonstrate that early- and late-onset cases have different genetic risk factors. Genetic correlation analysis confirmed a genetic link between myasthenia gravis and other autoimmune diseases, such as hypothyroidism, rheumatoid arthritis, multiple sclerosis, and type 1 diabetes. Finally, we applied Priority Index analysis to identify potentially druggable genes/proteins and pathways. This study provides insight into the genetic architecture underlying myasthenia gravis and demonstrates that genetic factors within the loci encoding acetylcholine receptor subunits contribute to its pathogenesis. [ABSTRACT FROM AUTHOR]

EEG after sleep deprivation (SD-EEG) iswidely used in many epilepsy centers as an important tool in the epilepsy diagnosis process. However, aftermore than 40 years of use, there are a number of issueswhich still need to be clarified concerning its features and role. In particular, the many scientific papers addressing its role in epilepsy diagnosis often differ remarkably from each other in terms of the type of patients assessed, their description and study design. Furthermore, also the length and the type of EEG performed after SD, as well as the length of SD itself, vary dramatically from one study to another. In this paper we shortly underscore the abovementioned differences among the different reports, as well as some interpretations of the findings obtained in the different studies. This analysis emphasizes, if needed, how SD-EEG still represents a crucial step in epilepsy diagnosis, and how additional, controlled studies might further shape its precise diagnostic/prognostic role. [ABSTRACT FROM AUTHOR]

Open in new tab Download slide Open in new tab Download slide OBJECTIVES The goal of this study was to analyse the outcomes in 53 patients with thymoma, 34 of whom had myasthenia gravis (MG), who were treated with robotic surgery. The oncological outcomes of the whole series of patients were analysed. Furthermore, because consistent data are not yet available in the literature, the main focus was the analysis of the neurological results of the patients affected by MG and thymoma. METHODS The clinical outcomes of 53 patients with a diagnosis of thymoma who underwent robotic thymectomy between January 2014 and December 2019 in our institution were collected and evaluated; 34 of these patients had a concomitant diagnosis of MG. The neurological status of the patients was determined from a clinical evaluation according to the Osserman classification and on pre- and post-surgery Myasthenia Gravis Composite scores, whereas neurological clinical outcomes were assessed using the Myasthenia Gravis Foundation of America Post-Intervention Score. Reduction of steroid therapy was also considered. The recurrence rate, adjuvant radiotherapy and overall survival of the patients with a thymoma were evaluated. RESULTS Neurological outcomes: improvement of the clinical conditions was obtained in 26 patients (76.5%) following the operation: complete stable remission was observed in 5 patients (14.7%), pharmacological remission in 10 (29.4%) and minimal manifestation in 11 (32.3%). Four patients (11.8%) exhibited no substantial change from the pretreatment clinical manifestations or reduction in MG medication and 4 (11.8%) patients experienced worsening of clinical conditions. In 21 patients (61.7%) a reduction of the dosage of steroid therapy was obtained. Oncological outcomes: at an average follow-up of 36 months, the overall survival was 96%, 4 patients (7.5%) had pleural relapses and 12 patients (22.6%) underwent postoperative radiotherapy, according to their stage. In accordance with Masaoka staging, 34% were in stage I, 56.6% in stage II and 9.4% in stage III CONCLUSIONS Our results suggest that robotic surgical treatment of patients with thymoma and concomitant MG is effective in improving the neurological outcomes. Moreover, the oncological results obtained in this series confirm the efficacy of robotic surgery for the treatment of thymic malignancies, with results in line with those of open surgery. However, due to the indolent growth of thymomas, further observations with longer follow-up are necessary. [ABSTRACT FROM AUTHOR]

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 < 0.001); the decrease was more pronounced in female patients (P = 0.05), in patients diagnosed with MG at an older age (P = 0.003), and in those who had lower MG stage before surgery (P = 0.02) or higher Masaoka‐Koga stage (P = 0.005). The risk of relapse was closely linked with the age of the patient, the Masaoka‐Koga stage and the surgical approach. Conclusions: Presurgery levels of AChR‐Ab or their change after surgery were not associated with thymoma recurrence. The reduction of AChR‐Ab titers after thymectomy confirms an immunological role of thymoma in the pathogenesis of MG. Key points: Significant findings of the study: Young MG patients with an advanced Masaoka staging score of the primary tumor who underwent thymectomy with approaches different from sternotomy and VATS should be monitored for high risk of recurrence.What this study adds: No other study has ever investigated the changes in AChR‐Ab titers before and after thymectomy in a large cohort of TAMG patients. The reduction of AChR‐Ab titers after thymectomy suggests an immunological role of thymoma in the pathogenesis of MG. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: General paresis (GP) is a late form of parenchymal neurosyphilis causing dementia and neuropsychiatric disorders. The diagnosis is often difficult since the clinical signs are protean. So far, neuroimaging has played a minor role as radiological findings are not specific.Methods: We studied three immunocompetent patients, admitted to hospital for cognitive impairment. The diagnosis of neurosyphilis was formulated on the basis of serological texts and cerebrospinal fluid analysis. The patients underwent a 3 T MR examination including susceptibility-weighted imaging (SWI) sequence before and after the initiation of penicillin therapy.Results: In all patients, SWI revealed cortical hypointensity, mostly distributed in frontal and temporal lobes. In drug-naive patients, the hypointensity extended over the whole cortical thickness, from the cortical/subcortical junction to the pial surface. After starting the penicillin therapy, the cortical hypointensity partially reversed, involving only the deep cortical layers.Conclusions: The MRI pattern at SWI observed in patients with GP was not reported in other infectious or inflammatory disease of the central nervous system, thus we suggest it could be a peculiar radiological finding of the disease. On the basis of previous pathological data, we hypothesise that cortical SWI hypointensity could be expression of iron deposits within activated microglia. [ABSTRACT FROM AUTHOR]

Highlights: [•] We assessed retrospectively the role of a simple method of EEG after sleep deprivation (SD-EEG) on a large population of de novo patients evaluated for suspected seizures, bearing a normal basal EEG. [•] In these patients SD-EEG often reveals interictal abnormalities and bears a high specificity in epilepsy diagnosis. [•] Interictal abnormalities are different in generalized versus focal epilepsies, and in the latter the interictal abnormalities yield in SD-EEG is higher than in a repeated routine EEG. [Copyright &y& Elsevier]

Our aim was to evaluate the EEG and clinical modifications induced by the new antiepileptic drug lacosamide (LCM) in patients with epilepsy.We evaluated 10 patients affected by focal pharmacoresistant epilepsy in which LCM (mean 250mg/day) was added to the preexisting antiepileptic therapy, which was left unmodified. Morning waking EEG recording was performed before (t0) and at 6 months (t1) after starting LCM. At t0 and t1, patients were also administered questionnaires evaluating mood, anxiety, sleep, sleepiness, and fatigue (Beck Depression Inventory; State-Trait Anxiety Inventory Y1 and Y2; Pittsburgh Sleep Quality Index; Epworth Sleepiness Scale; Fatigue Severity Scale). We performed a quantitative analysis of EEG interictal abnormalities and background EEG power spectrum analysis. LCMas an add-on did not significantly affect anxiety, depression, sleepiness, sleep quality, and fatigue scales. Similarly, adding LCM to preexisting therapy did not modify significantly patient EEGs in terms of absolute power, relative power, mean frequency, and interictal abnormalities occurrence. In conclusion, in this small cohort of patients, we confirmed that LCM as an add-on does not affect subjective parameters which play a role, among others, in therapy tolerability, and our clinical impression was further supported by evaluation of EEG spectral analysis. [ABSTRACT FROM AUTHOR]

• We investigated GHSR methylation levels in thymomas from patients with Myasthenia Gravis. • GHSR hypermethylation was observed in 18 thymomas,28% of the total. • Samples showing GHSR hypermethylation were enriched in advanced disease stages than stage I. • GHSR hypermethylation is not a pan-cancer marker and is infrequent in encapsulated tumors. 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). 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. GHSR hypermethylation was observed in 18 thymoma samples (28%) compared to the healthy thymic tissues (P < 1 × 10−4), and those samples were particularly enriched in advanced disease stages than stage I (94% were in stage II or higher). GHSR was demethylated in the remaining 47 thymomas, as well as in all the investigated healthy thymic samples and in circulating lymphocytes. 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. [ABSTRACT FROM AUTHOR]

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 < 0.0008) whereas no significant difference was found in the two groups regarding SF-EMG (p = 0.5). RNS was positive in 30 MuSK patients (50.8%), negative in 25 MuSK patients (42.4%) and in 4 patients only facial muscles examined showed a significant decrement whereas the examination of extremity muscles was negative. On the other hand, RNS was positive in 27 AChR-Abs positive patients (87%), it was negative in three patients (9.7%) and in one patient only one examined muscle showed a significant decrement. In MuSK positive group, proximal muscles showed a significant decrement, more than distal ones (p < 0.02) whereas no significant differences were found in controls. In MuSK patients, the presence of pathological RNS was not in correlation neither with MG severity (p = 0.9) nor with the length of drug-free-period (p = 0.4). Increased jitter was present in 14 (82.3%) MuSK and 5 (71.4%) AChR-Abs patients; it was absent in 2 MuSK patients (11.7%) and in 2 AChR-Abs positive patients (28.5%). In one MuSK patient SF-EMG was borderline. 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]