Efgartigimod in refractory autoimmune myasthenia gravis.

INTRODUCTION/AIMS: Efgartigimod, a neonatal Fc-receptor inhibitor, has recently been approved as treatment for myasthenia gravis (MG). In this retrospective cohort study, we aimed to systematically assess short- and long-term effectiveness of efgartigimod in patients with refractory MG. METHODS: Sixteen patients with refractory autoimmune acetylcholine receptor MG were treated with efgartigimod. Data were collected from January 2021 to March 2023 on Myasthenia Gravis Activities of Daily Living (MG-ADL), Quantitative Myasthenia Gravis score (QMG), Myasthenia Gravis Composite score (MGC) and the 15-item revised version of the Myasthenia Gravis Quality of Life questionnaire (MG-QoL15r). RESULTS: A favorable outcome was seen in 56% of patients at the last measurement. Out of 16 patients, 50% were an MG-ADL responder after the first treatment cycle. After 4 weeks, a clinically meaningful improvement compared to baseline was seen on the MG-ADL, QMG, and MGC. There was a statistically significant improvement on the MGQoL15r from baseline to week 4. The improvement was maintained until the last measurement for the MGC and the MGQoL15r. At the last visit, all patients had discontinued 4-weekly dosages, shifting to administration frequencies of 1, 2, or 3 weeks. Drug doses could be decreased for prednisolone (n = 7), azathioprine (n = 2), and intravenous immunoglobulin (n = 9). Frequency of plasma exchange was decreased in nine patients. DISCUSSION: In patients with refractory MG, efgartigimod was effective for at least half of all patients. Patients required more frequent dosing compared to the ADAPT phase 3 trial. In 80% of the patients concurrent medication could be reduced or discontinued.

Myasthenia gravis-Pathophysiology, diagnosis, and treatment.

Myasthenia gravis (MG) is an autoimmune disease characterized by dysfunction of the neuromuscular junction resulting in skeletal muscle weakness. It is equally prevalent in males and females, but debuts at a younger age in females and at an older age in males. Ptosis, diplopia, facial bulbar weakness, and limb weakness are the most common symptoms. MG can be classified based on the presence of serum autoantibodies. Acetylcholine receptor (AChR) antibodies are found in 80%-85% of patients, muscle-specific kinase (MuSK) antibodies in 5%-8%, and <1% may have low-density lipoprotein receptor-related protein 4 (Lrp4) antibodies. Approximately 10% of patients are seronegative for antibodies binding the known disease-related antigens. In patients with AChR MG, 10%-20% have a thymoma, which is usually detected at the onset of the disease. Important differences between clinical presentation, treatment responsiveness, and disease mechanisms have been observed between these different serologic MG classes. Besides the typical clinical features and serologic testing, the diagnosis can be established with additional tests, including repetitive nerve stimulation, single fiber EMG, and the ice pack test. Treatment options for MG consist of symptomatic treatment (such as pyridostigmine), immunosuppressive treatment, or thymectomy. Despite the treatment with symptomatic drugs, steroid-sparing immunosuppressants, intravenous immunoglobulins, plasmapheresis, and thymectomy, a large proportion of patients remain chronically dependent on corticosteroids (CS). In the past decade, the number of treatment options for MG has considerably increased. Advances in the understanding of the pathophysiology have led to new treatment options targeting B or T cells, the complement cascade, the neonatal Fc receptor or cytokines. In the future, these new treatments are likely to reduce the chronic use of CS, diminish side effects, and decrease the number of patients with refractory disease.

The ClC-1 chloride channel inhibitor NMD670 improves skeletal muscle function in rat models and patients with myasthenia gravis.

Myasthenia gravis (MG) is a neuromuscular disease that results in compromised transmission of electrical signals at the neuromuscular junction (NMJ) from motor neurons to skeletal muscle fibers. As a result, patients with MG have reduced skeletal muscle function and present with symptoms of severe muscle weakness and fatigue. ClC-1 is a skeletal muscle specific chloride (Cl-) ion channel that plays important roles in regulating neuromuscular transmission and muscle fiber excitability during intense exercise. Here, we show that partial inhibition of ClC-1 with an orally bioavailable small molecule (NMD670) can restore muscle function in rat models of MG and in patients with MG. In severely affected MG rats, ClC-1 inhibition enhanced neuromuscular transmission, restored muscle function, and improved mobility after both single and prolonged administrations of NMD670. On this basis, NMD670 was progressed through nonclinical safety pharmacology and toxicology studies, leading to approval for testing in clinical studies. After successfully completing phase 1 single ascending dose in healthy volunteers, NMD670 was tested in patients with MG in a randomized, placebo-controlled, single-dose, three-way crossover clinical trial. The clinical trial evaluated safety, pharmacokinetics, and pharmacodynamics of NMD670 in 12 patients with mild MG. NMD670 had a favorable safety profile and led to clinically relevant improvements in the quantitative myasthenia gravis (QMG) total score. This translational study spanning from single muscle fiber recordings to patients provides proof of mechanism for ClC-1 inhibition as a potential therapeutic approach in MG and supports further development of NMD670.

Fully Automatic, Semiautomatic, and Manual Corneal Nerve Fiber Analysis in Patients With Sarcoidosis.

Purpose: No guidelines are available on the preferred method for analyzing corneal confocal microscopy (CCM) data. Manual, semiautomatic, and automatic analyzes are all currently in use. The purpose of the present study was threefold. First, we aimed to investigate the different methods for CCM analysis in patients with and without small fiber neuropathy (SFN). Second, to determine the correlation of different methods for measuring corneal nerve fiber length (CNFL) and nerve fiber area (NFA). Finally, we investigated the added value of automatic NFA analysis. Methods: We included 20 healthy controls and 80 patients with sarcoidosis, 31 with established SFN and 49 without SFN. The CNFL was measured using CCMetrics, ACCMetrics, and NeuronJ. NFA was measured with NFA FIJI and ACCMetrics NFA. Results: CNFL and NFA could not distinguish sarcoidosis with and without SFN or healthy controls. CCMetrics, NeuronJ, and ACCMetrics CNFL highly correlated. Also, NFA FIJI and ACCMetrics NFA highly correlated. Reproducing a nonlinear formula between CNFL and NFA confirmed the quadratic relation between NFA FIJI and ACCMetrics CNFL. CCMetrics and NeuronJ instead showed a square root relationship and seem to be less comparable owing to differences between automatic and manual techniques. Conclusions: ACCMetrics can be used for fully automatic analysis of CCM images to optimize efficiency. However, CNFL and NFA do not seem to have a discriminatory value for SFN in sarcoidosis. Further research is needed to determine the added value and normative values of NFA in CCM analysis. Translational Relevance: Our study improves the knowledge about CCM software and pathophysiology of SFN.

Artificial intelligence-based classification of motor unit action potentials in real-world needle EMG recordings.

OBJECTIVE: To develop an artificial neural network (ANN) for classification of motor unit action potential (MUAP) duration in real-word, unselected and uncleaned needle electromyography (n-EMG) recordings. METHODS: Two nested ANN models were trained, the first discerning muscle rest, contraction and artifacts in n-EMG recordings from 2674 individual muscles from 326 patients obtained as part of daily care. The second ANN model subsequently used segments labeled as contraction for prediction of prolonged, normal and shortened MUAPs. Model performance was assessed in one internal and two external validation datasets of 184, 30 and 50 muscles, respectively. RESULTS: The first model discerned rest, contraction and artifacts with an accuracy of 96%. The second model predicted prolonged, normal and shortened MUAPs with an accuracy of 67%, 83% and 68% in the different validation sets. CONCLUSIONS: We developed a two-step ANN that classifies rest, muscle contraction and artifacts from real-world n-EMG recordings with very high accuracy. MUAP duration classification had moderate accuracy. SIGNIFICANCE: This is the first study to show that an ANN can classify MUAPs in real-world n-EMG recordings highlighting the potential for AI assisted MUAP classification as a clinical tool.

Assessing facial weakness in myasthenia gravis with facial recognition software and deep learning.

OBJECTIVE: Myasthenia gravis (MG) is an autoimmune disease leading to fatigable muscle weakness. Extra-ocular and bulbar muscles are most commonly affected. We aimed to investigate whether facial weakness can be quantified automatically and used for diagnosis and disease monitoring. METHODS: In this cross-sectional study, we analyzed video recordings of 70 MG patients and 69 healthy controls (HC) with two different methods. Facial weakness was first quantified with facial expression recognition software. Subsequently, a deep learning (DL) computer model was trained for the classification of diagnosis and disease severity using multiple cross-validations on videos of 50 patients and 50 controls. Results were validated using unseen videos of 20 MG patients and 19 HC. RESULTS: Expression of anger (p = 0.026), fear (p = 0.003), and happiness (p < 0.001) was significantly decreased in MG compared to HC. Specific patterns of decreased facial movement were detectable in each emotion. Results of the DL model for diagnosis were as follows: area under the curve (AUC) of the receiver operator curve 0.75 (95% CI 0.65-0.85), sensitivity 0.76, specificity 0.76, and accuracy 76%. For disease severity: AUC 0.75 (95% CI 0.60-0.90), sensitivity 0.93, specificity 0.63, and accuracy 80%. Results of validation, diagnosis: AUC 0.82 (95% CI: 0.67-0.97), sensitivity 1.0, specificity 0.74, and accuracy 87%. For disease severity: AUC 0.88 (95% CI: 0.67-1.0), sensitivity 1.0, specificity 0.86, and accuracy 94%. INTERPRETATION: Patterns of facial weakness can be detected with facial recognition software. Second, this study delivers a 'proof of concept' for a DL model that can distinguish MG from HC and classifies disease severity.

Eye Muscle MRI in Myasthenia Gravis and Other Neuromuscular Disorders.

INTRODUCTION: MRI of extra-ocular muscles (EOM) in patients with myasthenia gravis (MG) could aid in diagnosis and provide insights in therapy-resistant ophthalmoplegia. We used quantitative MRI to study the EOM in MG, healthy and disease controls, including Graves' ophthalmopathy (GO), oculopharyngeal muscular dystrophy (OPMD) and chronic progressive external ophthalmoplegia (CPEO). METHODS: Twenty recently diagnosed MG (59±19yrs), nineteen chronic MG (51±16yrs), fourteen seronegative MG (57±9yrs) and sixteen healthy controls (54±13yrs) were included. Six CPEO (49±14yrs), OPMD (62±10yrs) and GO patients (44±12yrs) served as disease controls. We quantified muscle fat fraction (FF), T2water and volume. Eye ductions and gaze deviations were assessed by synoptophore and Hess-charting. RESULTS: Chronic, but not recent onset, MG patients showed volume increases (e.g. superior rectus and levator palpebrae [SR+LPS] 985±155 mm3 compared to 884±269 mm3 for healthy controls, p < 0.05). As expected, in CPEO volume was decreased (e.g. SR+LPS 602±193 mm3, p < 0.0001), and in GO volume was increased (e.g. SR+LPS 1419±457 mm3, p < 0.0001). FF was increased in chronic MG (e.g. medial rectus increased 0.017, p < 0.05). In CPEO and OPMD the FF was more severely increased. The severity of ophthalmoplegia did not correlate with EOM volume in MG, but did in CPEO and OPMD. No differences in T2water were found. INTERPRETATION: We observed small increases in EOM volume and FF in chronic MG compared to healthy controls. Surprisingly, we found no atrophy in MG, even in patients with long-term ophthalmoplegia. This implies that even long-term ophthalmoplegia in MG does not lead to secondary structural myopathic changes precluding functional recovery.

Optimal timing of needle electromyography to diagnose lesion severity in traumatic radial nerve injury.

INTRODUCTION/AIMS: In patients with traumatic radial nerve injury (RNI), the chance of spontaneous recovery must be balanced against the benefits of early surgical reconstruction. We aimed to explore the time-specific value of needle electromyography (NEMG) to diagnose nerve lesion severity. METHODS: In this retrospective diagnostic accuracy study at Leiden Nerve Center, patients at least 12 years of age with RNI caused by fractures or fracture treatment were included. The sensitivity and specificity of the patients' first NEMG examination were assessed, stratified by the timing after the nerve injury. The absence of motor unit potentials (MUPs) in muscles distal to the nerve lesion was considered a positive test result. Lesion severity was dichotomized to moderate injury (spontaneous Medical Research Council grade ≥3 recovery) or severe injury (poor spontaneous recovery or surgical confirmation of a mainly neurotmetic lesion). RESULTS: Ninety-five patients were included in our study. The sensitivity of NEMG to detect severe RNI was 75.0% (3 of 4) in the fourth, 66.7% (2 of 3) in the fifth, and 66.7% (2 of 3) in the sixth month after the nerve injury. The specificity in the first to the sixth month was 0.0% (0 of 1), 50.0% (2 of 4), 77.3% (17 of 22), 95.5% (21 of 22), 95.8% (23 of 24), and 100.0% (12 of 12), respectively. DISCUSSION: The specificity of NEMG is higher than 95% and therefore clinically relevant from the fourth month after the nerve injury onward. Absence of MUPs at this time can be considered an indication to plan nerve exploration. Moreover, the presence of MUPs on NEMG does not completely exclude the necessity for surgical reconstruction.

Diagnosing myasthenia gravis using orthoptic measurements: assessing extraocular muscle fatiguability.

INTRODUCTION: Diagnosing ocular myasthenia gravis (MG) can be challenging because serum antibodies are often not detected. We aimed to explore whether determining extraocular muscle (EOM) weakness using orthoptic measures, including an adapted Hess chart examination, can aid in diagnosing MG. METHODS: We conducted a prospective study among patients with acetylcholine receptor antibody positive MG (20 recently diagnosed, 19 chronic) and 14 seronegative MG patients. We compared orthoptic measures to 19 healthy and 18 disease controls with Graves orbitopathy, chronic progressive external ophthalmoplegia or oculopharyngeal muscular dystrophy. Maximal eye duction angles were measured using a synoptophore. Gaze deviations between eyes were measured using standard Hess chart examination with addition of 1 min persistent gaze to assess MG-associated fatiguability. Receiver operating characteristics curve analysis was performed. RESULTS: For duction angles, the area under the curve (AUC) was 0.73 comparing MG to healthy, and 0.69 comparing to patient controls. For the outer field of the Hess chart, the AUC was 0.89 comparing to healthy and 0.54 to patient controls. For drift, the AUC was 0.93 comparing to healthy and 0.93 to patient controls. The sensitivity and specificity of the presence of drift was 81% and 100%. DISCUSSION: Orthoptic measurements can be used to diagnose MG by quantifying EOM weakness and fatiguability. Drift during persistent gaze on a Hess chart is specific for MG and could be used for diagnostic purposes. The Hess chart examination is widely available, inexpensive and fast. Moreover, orthoptic measurements may be a clinically relevant outcome measure for clinical trials.

Warm ears, a red flag for sleepiness?

Core body and skin temperatures are intimately linked to sleep and alertness. The distal-to-proximal skin temperature gradient has been described as a good physiological predictor for sleep onset. Increased ear skin temperature is often caused by increased blood flow reflected in redness, which is commonly noticed in people who are sleepy, especially anecdotally in children. Nonetheless, no prior study investigated the possible relation between sleepiness and ear skin temperature as a separate measurement. We assessed the relation between ear skin temperature and sleepiness in patients undergoing regular electroencephalographic examinations, because of suspicion of epilepsy, both without and after sleep deprivation. Subjective sleepiness was measured using the Stanford Sleepiness Scale, and objective sleepiness by determining sleep onset with electroencephalography. Distal, proximal and ear skin temperature were measured repeatedly using wireless measurement devices (iButtons). Forty-four adult patients were included. Ear skin temperature correlates weakly with distal skin temperature (r = 0.174, p < 0.001) and distal-to-proximal gradient (r = 0.160, p < 0.001), but not with proximal skin temperature (r = -0.001, p = 0.975). Ear skin temperature increased significantly in a subgroup of 13 patients, between 5 and 1 min before sleep onset (p = 0.002; η2  = 0.059), even though this increase was also associated with supine posture. iButtons is a valid method to measure ear skin temperature, which appears to function partly like a distal and partly like a proximal skin temperature measurement. Change in ear skin temperature is associated with sleep onset and supine posture.

Test-Retest Reliability of Repetitive Ocular Vestibular Evoked Myogenic Potentials in Myasthenia Gravis Patients and Healthy Control Subjects.

PURPOSE: Repetitive ocular vestibular evoked myogenic potentials (ROVEMP) are a novel diagnostic test to quantify neuromuscular transmission deficits in extraocular muscles in myasthenia gravis. We aimed to investigate the test-retest reliability of the ROVEMP and the effect of amplitude and age. METHODS: We performed the ROVEMP test twice in 19 patients with myasthenia gravis (52.7 ± 19.8 years) and in 15 healthy control subjects (46.5 ± 16 years). The Bland-Altman level of agreement was determined. The relationship between test-retest reliability and signal quality, participant age and signal amplitude was studied. RESULTS: Limits of agreement were from -179.9 to 139.3 in myasthenia gravis patients and from -56.9 to 89.5 in healthy control subjects. Difference between measurements correlated with signal amplitude (r = -0.50, P < 0.001). Combining the primary cohort with previously published data from 114 subjects, we found a significant negative correlation between age and reference amplitude (r = -0.163, P = 0.045). CONCLUSIONS: This study shows that in our hands, the test-retest reliability of the ROVEMP is not optimal. Measurements with higher reference amplitude had a better quality, higher reproducibility, and increased diagnostic yield. We caution against the use of ROVEMP measurements of lower amplitude in clinical practice. In addition, given the correlation between age and amplitude, age matching of healthy control subjects and patients is essential in future studies.

Enrichment of serum IgG4 in MuSK myasthenia gravis patients.

Muscle-specific kinase (MuSK) myasthenia gravis (MG) is a neuromuscular autoimmune disease belonging to a growing group of IgG4 autoimmune diseases (IgG4-AIDs), in which the majority of pathogenic autoantibodies are of the IgG4 subclass. The more prevalent form of MG with acetylcholine receptor (AChR) antibodies is caused by IgG1-3 autoantibodies. A dominant role for IgG4 in autoimmune disease is intriguing due to its anti-inflammatory characteristics. It is unclear why MuSK autoantibodies are predominantly IgG4. We hypothesized that MuSK MG patients have a general predisposition to generate IgG4 responses, therefore resulting in high levels of circulating IgG4. To investigate this, we quantified serum Ig isotypes and IgG subclasses using nephelometric and turbidimetric assays in MuSK MG and AChR MG patients not under influence of immunosuppressive treatment. Absolute serum IgG1 was increased in both MuSK and AChR MG patients compared to healthy donors. In addition, only MuSK MG patients on average had significantly increased and enriched serum IgG4. Although more MuSK MG patients had elevated serum IgG4, for most the IgG4 serum levels fell within the normal range. Correlation analyses suggest MuSK-specific antibodies do not solely explain the variation in IgG4 levels. In conclusion, although serum IgG4 levels are slightly increased, the levels do not support ubiquitous IgG4 responses in MuSK MG patients as the underlying cause of dominant IgG4 MuSK antibodies.

The effectiveness and side effects of pyridostigmine in the treatment of myasthenia gravis: a cross-sectional study.

Pyridostigmine is the most commonly used drug in the symptomatic treatment of myasthenia gravis (MG); however, research into its effectiveness and side effects is scarce. The aim of this study was to assess the effectiveness, prevalence of side effects and net benefit of pyridostigmine. All MG patients participating in the Dutch-Belgian myasthenia patient registry were included. A dynamic online questionnaire was developed to assess the effectiveness, side effects and net benefit of pyridostigmine. Out of 642 invited patients, 410 patients (64%) fully completed the questionnaire; 61% reported that they currently used pyridostigmine, 36% had discontinued pyridostigmine and 2% reported to never have used pyridostigmine. Patients reported a median effectiveness of 60, IQR 28-78 and net benefit of 65, IQR 45-84. Of all patients currently using pyridostigmine, 91% reported side effects (vs. 55% in the control group). Most frequently reported side effects were flatulence, urinary urgency, muscle cramps, blurred vision and hyperhidrosis. In the group of patients who discontinued pyridostigmine, side effects were the reason for discontinuation in 26%. Diarrhea, abdominal cramps and muscle twitching were the most frequently cited reasons to discontinue pyridostigmine. These results can be used to guide shared decision making prior to starting symptomatic treatment for MG.

Muscle velocity recovery cycles as pharmacodynamic biomarker: Effects of mexiletine in a randomized double-blind placebo-controlled cross-over study.

Measuring muscle velocity recovery cycles (MVRCs) is a method to obtain information on muscle cell excitability, independent of neuromuscular transmission. The goal was to validate MVRC as a pharmacodynamic (PD) biomarker for drugs targeting muscle excitability. As proof-of-concept, sensitivity of MVRC to detect effects of mexiletine, a voltage-gated sodium channel (Nav ) blocker, was assessed. In a randomized, double-blind, two-way crossover study, effects of a single pharmacologically active oral dose of 333 mg mexiletine was compared to placebo in 15 healthy male subjects. MVRC was performed predose, and 3- and 5-h postdose using QTrac. Effects of mexiletine versus placebo were calculated using a mixed effects model with baseline as covariate. Mexiletine had significant effects on MVRC when compared to placebo. Early supernormality after five conditioning stimuli was decreased by mexiletine (estimated difference -2.78% [95% confidence interval: -4.16, -1.40]; p value = 0.0003). Moreover, mexiletine decreased the difference in late supernormality after five versus one conditioning stimuli (5XLSN; ED -1.46% [-2.26, -0.65]; p = 0.001). These results indicate that mexiletine decreases the percentage increase in velocity of the muscle fiber action potential after five conditioning stimuli, at long and short interstimulus intervals, which corresponds to a decrease in muscle membrane excitability. This is in line with the pharmacological activity of mexiletine, which leads to use-dependent NaV 1.4 blockade affecting muscle membrane potentials. This study shows that effects of mexiletine can be detected using MVRC in healthy subjects, thereby indicating that MVRC can be used as a tool to demonstrate PD effects of drugs targeting muscle excitability in early phase drug development.

Clinical and imaging clues to the diagnosis and follow-up of ptosis and ophthalmoparesis.

Ophthalmoparesis and ptosis can be caused by a wide range of rare or more prevalent diseases, several of which can be successfully treated. In this review, we provide clues to aid in the diagnosis of these diseases, based on the clinical symptoms, the involvement pattern and imaging features of extra-ocular muscles (EOM). Dysfunction of EOM including the levator palpebrae can be due to muscle weakness, anatomical restrictions or pathology affecting the innervation. A comprehensive literature review was performed to find clinical and imaging clues for the diagnosis and follow-up of ptosis and ophthalmoparesis. We used five patterns as a framework for differential diagnostic reasoning and for pattern recognition in symptomatology, EOM involvement and imaging results of individual patients. The five patterns were characterized by the presence of combination of ptosis, ophthalmoparesis, diplopia, pain, proptosis, nystagmus, extra-orbital symptoms, symmetry or fluctuations in symptoms. Each pattern was linked to anatomical locations and either hereditary or acquired diseases. Hereditary muscle diseases often lead to ophthalmoparesis without diplopia as a predominant feature, while in acquired eye muscle diseases ophthalmoparesis is often asymmetrical and can be accompanied by proptosis and pain. Fluctuation is a hallmark of an acquired synaptic disease like myasthenia gravis. Nystagmus is indicative of a central nervous system lesion. Second, specific EOM involvement patterns can also provide valuable diagnostic clues. In hereditary muscle diseases like chronic progressive external ophthalmoplegia (CPEO) and oculo-pharyngeal muscular dystrophy (OPMD) the superior rectus is often involved. In neuropathic disease, the pattern of involvement of the EOM can be linked to specific cranial nerves. In myasthenia gravis this pattern is variable within patients over time. Lastly, orbital imaging can aid in the diagnosis. Fat replacement of the EOM is commonly observed in hereditary myopathic diseases, such as CPEO. In contrast, inflammation and volume increases are often observed in acquired muscle diseases such as Graves' orbitopathy. In diseases with ophthalmoparesis and ptosis specific patterns of clinical symptoms, the EOM involvement pattern and orbital imaging provide valuable information for diagnosis and could prove valuable in the follow-up of disease progression and the understanding of disease pathophysiology.

Advances and ongoing research in the treatment of autoimmune neuromuscular junction disorders.

Myasthenia gravis and Lambert-Eaton myasthenic syndrome are antibody-mediated autoimmune diseases of the neuromuscular junction that usually present with weakness in ocular muscles and in proximal muscles of the limb and trunk. Prognosis regarding muscle strength, functional abilities, quality of life, and survival is generally good. However, some patients do not respond to treatment. Symptomatic drugs, corticosteroids, and steroid-sparing immunosuppressive drugs remain the cornerstone of treatment. In the past few years, new biological agents against complement, the FcRn receptor, or B-cell antigens have been tested in clinical trials. These new therapies extend the possibilities for targeted immunotherapies and promise exciting new options with a relatively rapid mode of action. Challenges in their use might occur, with barriers due to an increase in cost of care and additional considerations in the choice of drugs, and potential consequences of infection and vaccination due to the COVID-19 pandemic.

Accuracy of patient-reported data for an online patient registry of autoimmune myasthenia gravis and Lambert-Eaton myasthenic syndrome.

Disorders of the neuromuscular junction (NMJ) comprise a spectrum of rare diseases causing muscle fatigability and weakness, leading to life-long effects on quality of life. We established the Dutch-Belgian registry for NMJ disorders, based on a unique combination of patient- and physician-reported information. Information on natural course, disease burden, prevalence of complications and comorbidity is collected through patient-reported standardized questionnaires and verified using medical documentation. Currently, the registry contains information of 565 Myasthenia Gravis (MG) patients and 38 Lambert-Eaton myasthenic syndrome (LEMS) patients, constituting approximately 25% (MG) and 80% (LEMS) of patients in the Netherlands. This is a very large registry, with the highest participation rate per capita. In addition to confirming many disease characteristics previously described in the literature, this registry provides several novel insights. The reported rate of potentially corticosteroid-related comorbidity, including hypertension, heart disease, osteoporosis and type 2 diabetes was high, emphasizing the need to commence corticosteroid-sparing immune suppressive treatment as soon as possible. The reported rate of other auto-immune diseases is far higher than previously expected: 27% of MG and 38% of LEMS patients, and a surprisingly high number of MG patients (47%) is unaware of their antibody status. In conclusion, this registry provides a valuable collection of information regarding MG and LEMS disease course. Continuous collection of annual follow-up data will provide further longitudinal insights in disease burden, course and treatment effect.

Preoperative Electroencephalography-Based Machine Learning Predicts Cognitive Deterioration After Subthalamic Deep Brain Stimulation.

BACKGROUND: Subthalamic deep brain stimulation (STN DBS) may relieve refractory motor complications in Parkinson's disease (PD) patients. Despite careful screening, it remains difficult to determine severity of alpha-synucleinopathy involvement which influences the risk of postoperative complications including cognitive deterioration. Quantitative electroencephalography (qEEG) reflects cognitive dysfunction in PD and may provide biomarkers of postoperative cognitive decline. OBJECTIVE: To develop an automated machine learning model based on preoperative EEG data to predict cognitive deterioration 1 year after STN DBS. METHODS: Sixty DBS candidates were included; 42 patients had available preoperative EEGs to compute a fully automated machine learning model. Movement Disorder Society criteria classified patients as cognitively stable or deteriorated at 1-year follow-up. A total of 16,674 EEG-features were extracted per patient; a Boruta algorithm selected EEG-features to reflect representative neurophysiological signatures for each class. A random forest classifier with 10-fold cross-validation with Bayesian optimization provided class-differentiation. RESULTS: Tweny-five patients were classified as cognitively stable and 17 patients demonstrated cognitive decline. The model differentiated classes with a mean (SD) accuracy of 0.88 (0.05), with a positive predictive value of 91.4% (95% CI 82.9, 95.9) and negative predictive value of 85.0% (95% CI 81.9, 91.4). Predicted probabilities between classes were highly differential (hazard ratio 11.14 [95% CI 7.25, 17.12]); the risk of cognitive decline in patients with high probabilities of being prognosticated as cognitively stable (>0.5) was very limited. CONCLUSIONS: Preoperative EEGs can predict cognitive deterioration after STN DBS with high accuracy. Cortical neurophysiological alterations may indicate future cognitive decline and can be used as biomarkers during the DBS screening. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Prevalence and associated factors of fatigue in autoimmune myasthenia gravis.

Fatigue is usually defined as a subjective perception of lacking energy, mentally or physically, with a difficulty sustaining voluntary activities. It is a common symptom of many diseases and most likely has a multifactorial cause. In myasthenia gravis (MG), fatigue has a high prevalence and is correlated with female sex and disease severity. However, no large scale studies have been performed. Therefore, we aimed to evaluate fatigue in the Dutch participants (n = 420) of the Dutch-Belgian Myasthenia Patient Registry using an online survey. Additional information was obtained on mood, sleep, coping, quality of life, disease severity, physical activities and medication. Severe fatigue was present in 62% with a mean score of 37.1 ±â€¯13.2 points. Fatigue severity and prevalence increased significantly with disease severity. A positive correlation was found for female gender, BMI, disease severity and depressive symptoms. A negative correlation was found for strenuous physical activities and older age. The strong association with disease severity suggests that fatigue should be recognized as an element of the symptomatology of MG. The observed association between strenuous activity and fatigue and differences in coping style between fatigued and non-fatigued patients warrant future clinical trials on exercise and cognitive behavioral therapy.