Altered Cardiac Autonomic Regulation in Individuals with Myasthenia Gravis-A Systematic Review and Meta-Analysis.

The aim of this systematic review with meta-analysis was to determine differences in cardiovascular autonomic parameters between patients with myasthenia gravis (MG) and healthy controls (HCs). Two reviewers searched four electronic databases, namely PubMed, Web of Science, EMBASE, and SCOPUS, from database inception to 7 July 2023 for studies investigating cardiovascular autonomic parameters in MG vs. HCs. A random-effects meta-analysis was performed to compute Hedges' g ± 95% confidence intervals (CI). Out of a total of 2200 records, 8 observational studies with a sample size of 301 patients with MG and 454 HCs were included in the systematic review. Meta-analysis revealed lower values of expiration/inspiration ratio (g = -0.45, I2 = 74.7), baroreflex sensitivity (g = -0.56, 95%CI -0.80, -0.33; I2 = 0.3), percentage of adjacent NN intervals differing by more than 50 ms (g = -1.2, I2 = 82.8), square root of the mean of squared differences between successive beat intervals (g = -1.94, I2 = 95.1), mean of the standard deviations of all NN intervals (g = -0.83, 95%CI -1.37, -0.28; I2 = 55.5), and high frequency of HRV during tilt (g = -0.75, 95%CI -0.11, -0.39; I2 = 0). MG patients vs. HCs had higher systolic blood pressure (g = 0.39; I2 = 56.1), sympathovagal balance at rest/during tilt (LF/HF-RRIsupine, g = 0.44; I2 = 0; LF/HF-RRItilt, g = 0.86; I2 = 0; LF/HFtilt, g = 0.40; I2 = 0). As a group, MG patients have altered cardiac autonomic function, including decreased parasympathetic function, lower baroreflex sensitivity, and higher sympathovagal balance at rest and during orthostatic challenges.

Diagnosis and therapy of myasthenia gravis-the patients' perspective: a cross-sectional study.

The survey aimed to explore patients' perspectives with myasthenia gravis (MG) toward the diagnosis made and the therapy used to treat MG. The survey was conducted with a quantitative method, using the CAWI technique. A total of 321 people participated in the survey. More than half of the respondents (56.4%) had suffered from MG for less than 10 years. In three out of 10 cases (30.9%), the diagnosis of MG lasted 3 years or longer. The diagnostic delay was significantly longer in female respondents than in the males (p = 0.029). Cholinergic drugs were used in 92.9% of cases initially, and as maintenance therapy in 84.3% of cases. Corticosteroids were used in initiating therapy (45.8%) and as maintenance therapy (46.4%). One in four respondents (25.5%) reported experiencing very strong and strong side effects after using steroids. The side effects from steroid therapy very strong or strong affected overall physical health in 55.9% of respondents, very strong or strong affected self-acceptance in 52%, to a very large or large extent on mental health in 47.1%, and to a very strong or strong extent influenced the performance of daily activities in 28.2%. More than half of the respondents (57.0%) had had a thymectomy. Seven out of 10 respondents (72.0%) declared that the therapy they were on at the time of the survey allowed them (to varying degrees) to control their course of MG. Low therapy acceptance and less well controlled MG was associated with a preference for non-tablet therapies (p = 0.045). Regular follow-up and cooperation with the specialist health care system should improve MG symptoms, activities of daily living, and quality of life.

A New Score for Sharp Discharges in the EEG Predicts Epilepsy.

PURPOSE: A challenge in EEG interpretation is to correctly classify suspicious focal sharp activity as epileptiform or not. A predictive score was developed from morphologic features of the first focal sharp discharge, which can help in this decision. METHODS: From a clinical standard EEG database, the authors identified 2,063 patients without a previous epilepsy diagnosis who had a focal sharp discharge in their EEG. Morphologic features (amplitude, area of slow wave, etc.) were extracted using an open source one-click algorithm in EEGLAB, masked to clinical classification. A score was developed from these features and validated with the clinical diagnosis of epilepsy over 2 to 6 years of follow-up. Independent external validation was performed in Kural long-term video-EEG monitoring dataset. RESULTS: The score for the first focal sharp discharge had a moderate predictive performance for the clinical designation as the EEG being epileptiform (area under the receiver operating characteristics curve = 0.86). Best specificity was 91% and sensitivity 55%. The score also predicted a future epilepsy diagnosis (area under the receiver operating characteristics curve = 0.70). Best specificity was 86% and sensitivity 38%. Validation on the external dataset had an area under the receiver operating characteristics curve = 0.80. Clinical EEG identification of focal interictal epileptiform discharges had an area under the receiver operating characteristics curve = 0.73 for prediction of epilepsy. The score was based on amplitude, slope, difference from background, slow after-wave area, and age. Interrater reproducibility was high (ICC = 0.91). CONCLUSIONS: The designation of the first focal sharp discharge as epileptiform depends on reproducible morphologic features. Characteristic features were amplitude, slope, slow after-wave area, and difference from background. The score was predictive of future epilepsy. Halford semiquantitative scale had similar diagnostic performance but lower reproducibility.

Zilucoplan: An Investigational Complement C5 Inhibitor for the Treatment of Acetylcholine Receptor Autoantibody-Positive Generalized Myasthenia Gravis.

INTRODUCTION: Generalized myasthenia gravis (gMG) is an autoimmune disorder in which pathogenic autoantibodies damage the neuromuscular junction, causing disabling or life-threatening muscle weakness. Most treatments nonspecifically inhibit aspects of the immune system, do not directly address the causal mechanisms of tissue damage, and often have side-effect profiles that negatively impact patients. Understanding of the central pathogenic role of the complement cascade in gMG is advancing, and a new complement-targeting treatment is under investigation. AREAS COVERED: We provide an overview of gMG etiology, the complement cascade, current treatments, and the investigational gMG therapy zilucoplan. Zilucoplan is a small, subcutaneously administered, macrocyclic peptide that inhibits cleavage of complement component C5 and the subsequent formation of the membrane attack complex. EXPERT OPINION: In a randomized, double-blind, placebo-controlled, phase 2 clinical trial, zilucoplan demonstrated clinically meaningful complement inhibition in patients with acetylcholine receptor-positive gMG. Zilucoplan, a first-of-its-kind cyclic peptide targeting C5, appears to be a therapeutic option for the treatment of gMG based on available pharmacokinetic/pharmacodynamic data and phase 1 and 2 efficacy, safety, and tolerability data with limited long-term follow-up. Zilucoplan use earlier in the treatment paradigm would be suitable in this population should phase 3 efficacy and safety data be equally favorable.

The effect of parity on risk of complications in pregnant women with epilepsy: a population-based cohort study.

INTRODUCTION: Women with epilepsy have increased risk of complications in pregnancy with consequences for the mother and child. There are no studies on the influence of parity on complications in women with epilepsy. MATERIAL AND METHODS: This was a population-based cohort study of all first and second births in the Medical Birth Registry of Norway 1999-2013. Risks were estimated and complication rates were compared in distinct women with epilepsy treatment categories. Outcomes were any hypertensive disorder, bleeding in pregnancy, induction of labor, cesarean section, postpartum hemorrhage and preterm birth. RESULTS: We examined 361 588 women, of whom 211 248 had a second birth and 1074 (0.5%) of these had a diagnosis of epilepsy in both births. Of these, 406 used antiepileptic drugs in both pregnancies with lamotrigine (n = 118), carbamazepine (n = 83), valproate (n = 44) and levetiracetam (n = 27) being the four most common monotherapies. In the second birth, only risk of elective cesarean section (adjusted odds ratio 1.7, 95% confidence interval 1.4-2.0) and induction of labor (adjusted odds ratio 1.5, 95% confidence interval 1.2-1.7) were increased in women with epilepsy compared with women without epilepsy. There was a significant reduction in any hypertensive disorder, mild preeclampsia, emergency cesarean section, postpartum hemorrhage (>500 mL) and preterm birth from first to second birth in women with epilepsy, and also a significant increase in elective cesarean section. CONCLUSIONS: Second births in women with epilepsy do not represent an increased risk of non-iatrogenic complications, independent of antiepileptic drug use. There is a significant reduction in complications from first to second births in women with epilepsy.

International consensus guidance for management of myasthenia gravis: Executive summary.

OBJECTIVE: To develop formal consensus-based guidance for the management of myasthenia gravis (MG). METHODS: In October 2013, the Myasthenia Gravis Foundation of America appointed a Task Force to develop treatment guidance for MG, and a panel of 15 international experts was convened. The RAND/UCLA appropriateness methodology was used to develop consensus guidance statements. Definitions were developed for goals of treatment, minimal manifestations, remission, ocular MG, impending crisis, crisis, and refractory MG. An in-person panel meeting then determined 7 treatment topics to be addressed. Initial guidance statements were developed from literature summaries. Three rounds of anonymous e-mail votes were used to attain consensus on guidance statements modified on the basis of panel input. RESULTS: Guidance statements were developed for symptomatic and immunosuppressive treatments, IV immunoglobulin and plasma exchange, management of impending and manifest myasthenic crisis, thymectomy, juvenile MG, MG associated with antibodies to muscle-specific tyrosine kinase, and MG in pregnancy. CONCLUSION: This is an international formal consensus of MG experts intended to be a guide for clinicians caring for patients with MG worldwide.

Exposure to antiepileptic drugs in utero and child development: a prospective population-based study.

PURPOSE: Antiepileptic drugs may cause congenital malformations. Less is known about the effect on development in infancy and childhood. The aim of this study was to examine whether exposure to antiepileptic drugs during pregnancy has an effect on early child development. METHODS: From mid-1999 through December 2008, children of mothers recruited at 13-17 weeks of pregnancy were studied in the ongoing prospective Norwegian Mother and Child Cohort Study. Information on birth outcomes were obtained from the Medical Birth Registry (108,264 children), and mothers reported on their child's motor development, language, social skills, and autistic traits using items from standardized screening tools at 18 months (61,351 children) and 36 months (44,147 children) of age. The relative risk of adverse outcomes in children according to maternal or paternal epilepsy with and without prenatal exposure to antiepileptic drugs was estimated as odds ratios (ORs), using logistic regression with adjustment for maternal age, parity, education, smoking, depression/anxiety, folate supplementation, and child congenital malformation or low birth weight. KEY FINDINGS: A total of 333 children were exposed to antiepileptic drugs in utero. At 18 months, the exposed children had increased risk of abnormal scores for gross motor skills (7.1% vs. 2.9%; OR 2.0, 95% confidence interval [CI] 1.1-3.7) and autistic traits (3.5% vs. 0.9%; OR 2.7, CI 1.1-6.7) compared to children of parents without epilepsy. At 36 months, the exposed children had increased risk of abnormal score for gross motor skills (7.5% vs. 3.3%; OR 2.2, CI 1.1-4.2), sentence skills (11.2% vs. 4.8%; OR 2.1, CI 1.2-3.6), and autistic traits (6.0% vs. 1.5%; OR 3.4, CI 1.6-7.0). The drug-exposed children also had increased risk of congenital malformations (6.1% vs. 2.9%; OR 2.1, CI 1.4-3.4), but exclusion of congenital malformations did not affect the risk of adverse development. Children born to women with epilepsy who did not use antiepileptic drugs had no increased risks. Children of fathers with epilepsy generally scored within the normal range. SIGNIFICANCE: Exposure to antiepileptic drugs during pregnancy is associated with adverse development at 18 and 36 months of age, measured as low scores within key developmental domains rated by mothers. Exposures to valproate, lamotrigine, carbamazepine, or multiple antiepileptic drugs were associated with adverse outcome within different developmental domains.

Myasthenia and the neuromuscular junction.

PURPOSE OF REVIEW: Myasthenic syndromes are distinct disorders at the neuromuscular junction, most often with well characterized autoimmune or genetic pathology. New aspects of the dysfunctions give insight into the normal neuromuscular function in addition to giving therapeutic clues and tailoring the therapy to the pathophysiology in individual patients. RECENT FINDINGS: Patients with myasthenia gravis and congenital myasthenic syndromes should be further classified into distinct subgroups. Myasthenia gravis with low-affinity acetylcholine receptor (AChR) antibodies and myasthenia gravis with antibodies to the postsynaptic low-density lipoprotein receptor-related protein 4 represent new groups, whereas a myasthenia gravis subgroup without any detectable antibodies still persists. Myasthenia gravis with antibodies against muscle-specific kinase (MuSK) is, due to new reports, now as established as AChR-myasthenia gravis regarding disease mechanisms and recommended therapy. SUMMARY: Myasthenic syndromes and myasthenia gravis are well characterized disorders. The prognosis is generally good, apart from paraneoplastic Lambert-Eaton myasthenic syndrome. However, patients need long-term symptomatic and immunoactive treatment, this treatment to be balanced against present and potential side effects. New and more selective treatment is needed, especially for severe generalized disease. Well controlled long-term studies of sufficient power are much wanted, but new therapy has often to be tried in patients before high-class evidence of effect on myasthenia gravis has been published.

Are MRI high-signal changes of alar and transverse ligaments in acute whiplash injury related to outcome?

BACKGROUND: Upper neck ligament high-signal changes on magnetic resonance imaging (MRI) have been found in patients with whiplash-associated disorders (WAD) but also in non-injured controls. The clinical relevance of such changes is controversial. Their prognostic role has never been evaluated. The purpose of this study was to examine if alar and transverse ligament high-signal changes on MRI immediately following the car accident are related to outcome after 12 months for patients with acute WAD grades 1-2. METHODS: Within 13 days after a car accident, 114 consecutive acute WAD1-2 patients without prior neck injury or prior neck problems underwent upper neck high-resolution proton-weighted MRI. High-signal changes of the alar and transverse ligaments were graded 0-3. A questionnaire including the impact of event scale for measuring posttraumatic stress response and questions on patients' expectations of recovery provided clinical data at injury. At 12 months follow-up, 111 (97.4%) patients completed the Neck Disability Index (NDI) and an 11-point numeric rating scale (NRS-11) on last week neck pain intensity. Factors potentially related to these outcomes were assessed using multiple logistic regression analyses. RESULTS: Among the 111 responders (median age 29.8 years; 63 women), 38 (34.2%) had grades 2-3 alar ligament changes and 25 (22.5%) had grades 2-3 transverse ligament changes at injury. At 12 months follow-up, 49 (44.1%) reported disability (NDI > 8) and 23 (20.7%) neck pain (NRS-11 > 4). Grades 2-3 ligament changes in the acute phase were not related to disability or neck pain at 12 months. More severe posttraumatic stress response increased the odds for disability (odds ratio 1.46 per 10 points on the impact of event scale, p = 0.007) and so did low expectations of recovery (odds ratio 4.66, p = 0.005). CONCLUSIONS: High-signal changes of the alar and transverse ligaments close after injury did not affect outcome for acute WAD1-2 patients without previous neck problems. High-resolution upper neck MRI has limited value for the initial examination and follow-up of such patients.

Pregnancy, delivery, and outcome for the child in maternal epilepsy.

PURPOSE: To investigate pregnancy, delivery, and child outcome in an unselected population of women with both treated and untreated epilepsy. METHODS: In the compulsory Medical Birth Registry of Norway, all 2,861 deliveries by women with epilepsy recorded from 1999-2005 were compared to all 369,267 nonepilepsy deliveries in the same period. RESULTS: The majority (66%, n = 1900) in the epilepsy group did not use antiepileptic drugs (AEDs) during pregnancy. A total of 961 epilepsy-pregnancies were exposed to AEDs. Compared to nonepilepsy controls, AED-exposed infants were more often preterm (p = 0.01), and more often had birth weight <2,500 g (p < 0.001), head circumference <2.5 percentile (p < 0.001), and low Apgar score (p = 0.03). Small-for-gestational-age (SGA) infants (<10 percentile) occurred more frequently in both AED-exposed (p = 0.05) and unexposed (p = 0.02) epilepsy-pregnancies. Frequency of major congenital malformations (MCMs) was 2.8% (n = 81) in the epilepsy group versus 2.5% in controls (p = 0.3). Increased risk for MCMs could be demonstrated only for exposure to valproate (5.6%, p = 0.005) and AED polytherapy (6.1%, p = 0.02). Neonatal spina bifida was not significantly increased, but was a major indication for elective pregnancy termination among women with epilepsy. Cesarean section was performed more often in maternal epilepsy, regardless of AED-exposure (p < 0.001). DISCUSSION: Adverse pregnancy and birth outcome in women with epilepsy is mainly confined to AED-exposed pregnancies, although some risks are associated also with untreated epilepsy. The risk for congenital malformations was lower than previously reported. This could be due to a shift in AED selection, folic acid supplement, or possibly reflect the true risks in an unselected epilepsy population.

Polygenic disease associations in thymomatous myasthenia gravis.

BACKGROUND: Relevant genetic markers for myasthenia gravis (MG) include tumor necrosis factors alpha and beta, Fcgamma receptor IIa, and interleukin 10. The corresponding gene products are thought to be involved in MG pathogenesis. OBJECTIVES: To investigate whether MG susceptibility correlates with specific combinations of genetic markers and to compare the contribution of each marker. PARTICIPANTS: Forty-seven patients with MG and 92 healthy blood donors. MAIN OUTCOME MEASURES: Presence of tumor necrosis factors alpha and beta, Fcgamma receptor IIa, and interleukin 10 genotypes and autoantibodies against nicotinic acetylcholine receptor, titin, and ryanodine receptor. RESULTS: Susceptibility to MG increases with an increasing number of genetic markers in both thymomatous MG and MG with titin antibodies but not in early-onset MG. In thymomatous MG, Fcgamma receptor IIa allelic variants seem to be the most important determinant of disease. CONCLUSION: Specific combinations of allelic variants individually associated with MG synergize in predisposing to thymomatous MG and MG with titin antibodies.

Thymectomy and antimuscle antibodies in nonthymomatous myasthenia gravis.

The clinical effect of thymectomy in early- and late-onset myasthenia gravis (MG) and the correlation to MG severity, pharmacological treatment, and antimuscle antibodies were examined in two series of consecutive acetylcholine receptor (AChR) antibody-positive nonthymoma MG patients. The results indicate a benefit of thymectomy in early-onset MG, but no obvious clinical benefit in late-onset MG. The presence of muscle autoantibodies did not influence the outcome of thymectomy in early-onset MG. In late-onset MG, improvement is least likely in patients with titin and/or RyR antibodies. Thymectomy should always be considered shortly after MG onset in early-onset MG patients and might only be considered in late-onset patients who have early-onset-like immunological characteristics.