Double-seronegative myasthenia gravis (dSN-MG, without detectable AChR and MuSK antibodies) presents a serious gap in MG diagnosis and understanding. Recently, autoantibodies against the low-density lipoprotein receptor-related protein 4 (LRP4) have been identified in several dSN-MG sera, but with dramatic frequency variation (∼2-50%). We have developed a cell based assay (CBA) based on human LRP4 expressing HEK293 cells, for the reliable and efficient detection of LRP4 antibodies. We have screened about 800 MG patient sera from 10 countries for LRP4 antibodies. The overall frequency of LRP4-MG in the dSN-MG group (635 patients) was 18.7% but with variations among different populations (range 7-32.7%). Interestingly, we also identified double positive sera: 8/107 anti-AChR positive and 10/67 anti-MuSK positive sera also had detectable LRP4 antibodies, predominantly originating from only two of the participating groups. No LRP4 antibodies were identified in sera from 56 healthy controls tested, while 4/110 from patients with other neuroimmune diseases were positive. The clinical data, when available, for the LRP4-MG patients were then studied. At disease onset symptoms were mild (81% had MGFA grade I or II), with some identified thymic changes (32% hyperplasia, none with thymoma). On the other hand, double positive patients (AChR/LRP4-MG and MuSK/LRP4-MG) had more severe symptoms at onset compared with any single positive MG subgroup. Contrary to MuSK-MG, 27% of ocular dSN-MG patients were LRP4 antibody positive. Similarly, contrary to MuSK antibodies, which are predominantly of the IgG4 subtype, LRP4 antibodies were predominantly of the IgG1 and IgG2 subtypes. The prevalence was higher in women than in men (female/male ratio 2.5/1), with an average disease onset at ages 33.4 for females and 41.9 for males. Overall, the response of LRP4-MG patients to treatment was similar to published responses of AChR-MG rather than to MuSK-MG patients.

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Objectives: To determine if myasthenia gravis (MG) with antibodies to MuSK is a distinct subgroup of seronegative MG. Methods: We assayed antibodies to muscle specific tyrosine kinase (MuSK) in 55 MG patients who had no antibodies to acetylcholine receptors and looked for the specific phenotype, comparing clinical features of anti-MuSK positive and anti-MuSK negative MG patients. Results: MG with anti-MuSK antibodies was characterised by a striking prevalence of female patients (15 women, two men). Age at onset ranged from 22 to 52 years, with 70.6% of patients presenting at ,40 years of age. The majority of patients (82.4%) had prevalent involvement of facial and bulbar muscles. One third of them did not respond well to anticholinesterase drugs. Steroid immunosuppression was effective in eight patients (44.4%). Nine patients underwent thymectomy; six of these had no thymus pathology, while three had a hyperplastic thymus. At the end of the observation period, six (35.3%) patients were in remission, five (29.4%) improved, four (23.6%) did not change, and two (11.7%) had died. Conclusions: MG patients with antibodies to MuSK have characteristic clinical features that are different from features of the remaining seronegative MG patients. This emphasises the predictive value of antiMuSK antibody analysis in seronegative MG patients.

Seronegative myasthenia gravis (MG) presents a serious gap in MG diagnosis and understanding. We applied a cell based assay (CBA) for the detection of muscle specific kinase (MuSK) antibodies undetectable by radioimmunoassay. We tested 633 triple-seronegative MG patients' sera from 13 countries, detecting 13% as positive. MuSK antibodies were found, at significantly lower frequencies, in 1.9% of healthy controls and 5.1% of other neuroimmune disease patients, including multiple sclerosis and neuromyelitis optica. The clinical data of the newly diagnosed MuSK-MG patients are presented. 27% of ocular seronegative patients were MuSK antibody positive. Moreover, 23% had thymic hyperplasia suggesting that thymic abnormalities are more common than believed.

This study provides Class I evidence of efficacy of amifampridine phosphate as a symptomatic treatment for LEMS.

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The aim of this study was to assess factors that might influence the health-related quality of life (HRQoL) in patients with myasthenia gravis (MG). A cross-sectional study was performed including 230 consecutive patients with MG. Severity of the disease was estimated according to the MGFA classification and QMG score. HRQoL was assessed by the SF-36 questionnaire. Depressive and anxiety symptoms were assessed using the Hamilton rating scales for depression and anxiety, respectively. Social support was measured by the Multidimensional Scale of Perceived Social Support (MSPSS), and acceptance of the disease by the Acceptance of Illness Scale. The significant demographic predictors of worse HRQoL in MG patients were older age (p = 0.025) and lower education (p = 0.012). Among clinical features, significant independent contributing factors of worse HRQoL were more severe form of the disease according to MGFA (p = 0.001) and higher QMG score (p = 0.001). Finally, psychosocial predictors of worse quality of life were lower MSPSS score (p = 0.001), poor acceptance of the disease (p = 0.001), as well as higher levels of anxiety and depression (p = 0.001). Our study revealed that the HRQoL in patients with MG is similarly reduced in its psychological and physical aspects. These results may have a practical implication pointing out that different aspects of psychosocial support should be added to the regular therapeutic protocols.

The aim of this study was to investigate autonomic cardiac control in patients with amyotrophic lateral sclerosis (ALS). Fifty-five patients with sporadic ALS (28 female and 27 male; average age 56.00 +/- 10.34 years) were compared to 30 healthy controls (17 female and 13 male; average age 42.87 +/- 11.91 years). Patients with previous history of cardiac disease, diabetes mellitus, and impaired respiratory function were excluded from the study. Cardiovascular autonomic tests according to Ewing, power spectrum analysis of RR variability (low- and high-frequency bands - LF and HF, LF/HF index), real-time beat-to-beat ECG signal monitoring with heart rate variability analysis and baroreflex function analysis were carried out in all patients. Time-domain parameters of heart rate variability (mean RR interval, SDNN, SDANN, SDNN index, rMSSD and pNN50%) were obtained from 24-h ECG monitoring. ALS patients had a significantly higher score of sympathetic (p <0.01) and parasympathetic (p <0.001) dysfunction, as well as of the overall score of autonomic dysfunction (p <0.001). LF/HF index was significantly increased; baroreflex sensitivity and time-domain parameters of heart rate variability were highly significantly decreased in ALS patients (p <0.001). Our results demonstrated impaired cardiac autonomic control in ALS with marked parasympathetic dysfunction and sympathetic predominance.