Promising therapies for the treatment of myasthenia gravis.

INTRODUCTION: Myasthenia gravis (MG) is an autoimmune condition targeting the neuromuscular junction, which manifests with neuromuscular symptoms of varying severity and significant morbidity. The mainstay of treatment in MG is mitigation of the immune cascade with steroids and non-steroidal immunosuppressive therapies. The therapeutic strategies in MG are transitioning from broad and indiscriminate immunosuppression to novel agents targeting key steps in MG pathogenesis, including T cell activation, B cell proliferation, complement activation, maintenance of pathogenic antibody production, and proinflammatory cytokine production. AREAS COVERED: In this review, an overview of the pathogenesis of MG and traditional MG therapies is presented, followed by a discussion of the novel MG drugs that have been evaluated in phase 3 clinical trials with an emphasis on those which have received regulatory approval. EXPERT OPINION: Novel MG therapeutics belonging to the classes of complement inhibitors, neonatal Fc receptor (FcRn) inhibitors and B cell depletors, as well as the other emerging MG drugs in the pipeline constitute promising treatment strategies with potentially better efficacy and safety compared to the conventional MG treatments. However, further long-term research is needed in order to optimize the implementation of these new treatment options for the appropriate patient populations.

Predicting disability and mortality in CV2/CRMP5-IgG associated paraneoplastic neurologic disorders.

BACKGROUND: We aimed to investigate the prognostic factors associated with clinical outcomes in CV2/Collapsin response-mediator protein 5 (CRMP5)-IgG paraneoplastic neurologic disorders (PND). METHODS: This is a retrospective study of patients with CV2/CRMP5-IgG PND evaluated between 2002-2022. We examined the association of clinical variables (including age, clinical phenotype [autoimmune encephalopathy, myelopathy, polyneuropathy/radiculopathy, MG, cerebellar ataxia, chorea, optic neuropathy], cancer) with three clinical outcomes (wheelchair dependence, modified Rankin Scale [mRS], mortality) using univariate logistic regression and Cox proportional hazards modeling. Kaplan-Meier estimates were used to determine the probability of survival. RESULTS: Twenty-seven patients (56% female) with CV2/CRMP5-IgG PND were identified with a median follow-up of 54 months (IQR = 11-102). An underlying tumor was identified in 15 patients (56%) including small cell lung cancer (SCLC) (8, [53%]), thymoma (4, [27%]), and other histologies (3, [20%]). At last follow-up, 10 patients (37%) needed a wheelchair for mobility and this outcome was associated with myelopathy (HR = 7.57, 95% CI = 1.87-30.64, P = 0.005). Moderate-severe mRS = 3-5 was associated with CNS involvement (encephalopathy, myelopathy, or cerebellar ataxia) (OR = 7.00, 95% CI = 1.18-41.36, P = 0.032). The probability of survival 4 years after symptom onset was 66%. Among cancer subtypes, SCLC (HR = 18.18, 95% CI = 3.55-93.04, P < 0.001) was significantly associated with mortality, while thymoma was not. INTERPRETATION: In this retrospective longitudinal study of CV2/CRMP5-IgG PND, patients with CNS involvement, particularly myelopathy, had higher probability of disability. SCLC was the main determinant of survival in this population.

The role of artificial intelligence in electrodiagnostic and neuromuscular medicine: Current state and future directions.

The rapid advancements in artificial intelligence (AI), including machine learning (ML), and deep learning (DL) have ushered in a new era of technological breakthroughs in healthcare. These technologies are revolutionizing the way we utilize medical data, enabling improved disease classification, more precise diagnoses, better treatment selection, therapeutic monitoring, and highly accurate prognostication. Different ML and DL models have been used to distinguish between electromyography signals in normal individuals and those with amyotrophic lateral sclerosis and myopathy, with accuracy ranging from 67% to 99.5%. DL models have also been successfully applied in neuromuscular ultrasound, with the use of segmentation techniques achieving diagnostic accuracy of at least 90% for nerve entrapment disorders, and 87% for inflammatory myopathies. Other successful AI applications include prediction of treatment response, and prognostication including prediction of intensive care unit admissions for patients with myasthenia gravis. Despite these remarkable strides, significant knowledge, attitude, and practice gaps persist, including within the field of electrodiagnostic and neuromuscular medicine. In this narrative review, we highlight the fundamental principles of AI and draw parallels with the intricacies of human brain networks. Specifically, we explore the immense potential that AI holds for applications in electrodiagnostic studies, neuromuscular ultrasound, and other aspects of neuromuscular medicine. While there are exciting possibilities for the future, it is essential to acknowledge and understand the limitations of AI and take proactive steps to mitigate these challenges. This collective endeavor holds immense potential for the advancement of healthcare through the strategic and responsible integration of AI technologies.

CNM-Au8: an experimental agent for the treatment of amyotrophic lateral sclerosis (ALS).

INTRODUCTION: Two established disease-specific therapies for the treatment of amyotrophic lateral sclerosis (ALS) are riluzole and edaravone. Limitations of these medications include minimal progression slowing or survival benefit, and effectiveness only in selected populations, particularly for edaravone. AMX0035 and tofersen received US FDA approval in September 2022 and April 2023, respectively. However, phase 3 trials, further examining both medications' efficacy, are ongoing. CNM-Au8 is an efficient catalyst of energy metabolism and is therefore a potential disease-modifying treatment for ALS, a neurodegenerative condition in which there is bioenergetics impairment. AREAS COVERED: In this review, we provide an overview of the current ALS treatment market, followed by a description of the pharmacodynamics and pharmacokinetics of CNM-Au8. The main preclinical and available early clinical evidence of CNM-Au8 is then described, as well as its potential as an ALS treatment. EXPERT OPINION: Oral treatment with CNM-Au8 failed to meet primary clinical and electrodiagnostic endpoints in phase 2/3 clinical trials. Despite this failure, a number of exploratory endpoints included in phase 2/3 trials suggest CNM-Au8 has the potential to significantly slow clinical worsening, improve quality of life, and prolong survival in ALS. Further study of CNM-Au8 in a phase 3 clinical trial is currently underway.

Oxymetazoline Hydrochloride Eye-Drops as Treatment for Myasthenia Gravis-Related Ptosis: A Description of Two Cases.

In this article, we described two patients with myasthenia gravis-related ptosis who experienced sustained improvement with the use of oxymetazoline hydrochloride ophthalmic solution 0.1%. Despite the commonly used treatments for ptosis in myasthenia gravis (MG), such as acetylcholinesterase inhibitors and corticosteroids, complete remission of ptosis is not always achieved, and these treatments are often accompanied by systemic side effects. Our case report suggests the long-term efficacy of daily use of oxymetazoline eye drops in improving ptosis, providing a potential alternative or adjunctive treatment option without significant adverse effects. Further research is necessary to confirm these observations across larger cohorts of MG patients and establish the effectiveness of oxymetazoline eye drops in MG-related ptosis.

Myasthenia gravis: Frequently asked questions.

Myasthenia gravis is a disorder of neuromuscular junction transmission, the result of antibodies against the post-synaptic aspect of the neuromuscular junction. Its clinical hallmark is fatigable weakness of skeletal muscles, which tends to vary in location and severity among patients. It is treated with pyridostigmine, immunotherapy, and thymectomy. Treatment is often individualized according to disease severity, antibody status, comorbidities, and other factors. This review uses a question-and-answer format to provide up-to-date, high-yield, clinically relevant information on myasthenia gravis.

Self-reported factors contributing to delay in ALS diagnosis among primary care providers in a large Ohio-based US healthcare network.

OBJECTIVE: This study's primary objective is to identify self-reported factors that contribute to diagnostic delay in ALS among Primary Care Providers (PCPs). METHODS: A de novo email-based survey was deployed to Ohio-based PCPs in the Cleveland Clinic Health System. RESULTS: Of the 77 PCP participants [including 30 Advance Practice Providers (APPs)] only: (a) 18% of physicians, and 3% of APPs were very confident or confident with recognizing signs and symptoms of ALS, (b) 13% of physicians, and 21% of APP s felt very confident or confident with distinguishing between a neurologic cause of dysfunction from other possible causes, and (c) 23% of physicians, and 11% of APPs felt very confident or confident with distinguishing between upper and lower motor neuron signs. If presented with a weak patient without a specific diagnosis, PCPs most frequently ordered electrodiagnostic testing, brain MRI, cervical or thoracic spine MRI, and serum creatine kinase. PCPs identified top reasons for delayed ALS diagnosis as: (a) patient's delay in seeking medical help, (b) diagnostic uncertainty (c) waiting time for neurology/neuromuscular medicine (NM) consultation. The most desired strategies to shorten diagnostic delay involved: (a) educating PCPs and other non-neurologist "gatekeeper" providers, (b) improving access to specialist neurology care, and (c) developing a reliable diagnostic test for ALS. DISCUSSION: Self-reported factors that increase ALS diagnostic delay among PCPs primarily comprise gaps in clinical knowledge and skills required to detect key symptoms and signs, and suboptimal referral access to a neurology/NM provider. These areas represent important opportunities for targeted improvement efforts.

Enhancing diagnostic accuracy using a side-to-side cross-sectional area ratio for the diagnosis of unilateral ulnar mononeuropathy at the elbow.

INTRODUCTION: Neuromuscular ultrasonography (NMUS) is a valuable adjunct to electrodiagnostic testing for the diagnosis of entrapment neuropathy. The aim of this study was to determine whether diagnostic accuracy of NMUS could be enhanced in patients with unilateral ulnar mononeuropathy at the elbow (UNE) by utilizing side-to-side ulnar nerve cross-sectional area (CSA) ratios. METHODS: Retrospective case-control analysis of unilateral UNE cases identified cutoff values for elbow segment ulnar nerve maximum CSA (MCSA) of the symptomatic/asymptomatic limb (M ratio), as well as side-to-side ratios comparing MCSA with ipsilateral CSA at the Guyon canal (E/G), middle forearm (E/F), and middle humerus (E/H). Diagnostic accuracy values were calculated. RESULTS: The optimal M-ratio cut-off was 1.22 (sensitivity, 92.9%; specificity, 97.8%; accuracy, 95.4%). Optimal cutoffs for inter-E/G, -E/F, and -E/H ratios were 1.07 (sensitivity, 98%; specificity, 78%; accuracy, 87.7%), 1.11 (sensitivity, 95%; specificity, 80%; accuracy, 87.2%), and 1.18 (sensitivity, 95%; specificity, 93%; accuracy, 94%), respectively. DISCUSSION: The M ratio and inter-E/H ratio exhibited high diagnostic accuracy for unilateral UNE. Prospective studies are needed to compare the accuracy of the new measures with a single MCSA measurement.

Using and interpreting electrodiagnostic tests.

Electrodiagnostic testing, consisting of nerve conduction studies and needle electrode examination, serves as an extension of a neurologic examination for evaluating a variety of focal and generalized neuromuscular conditions. By providing important clues on location, chronicity, severity, and pathophysiology, it can help to establish a diagnosis, evaluate the need for surgery, and assess patients who do not improve as expected after surgery.

Time to diagnosis and factors affecting diagnostic delay in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a progressive, degenerative neuromuscular disease with limited treatment options. The diagnosis of ALS can be challenging for numerous reasons, resulting in delays that may compromise optimal management and enrollment into clinical trials. Several studies have examined the process and challenges regarding the clinical diagnosis of ALS. Twenty-one studies that were almost exclusively from the English literature published between 1990 and 2020 were identified via PubMed using relevant search terms and included patient populations from the United States, Canada, Japan, Egypt, and several countries in South America and Europe. Probable or definitive ALS patients were identified using El Escorial or revised El Escorial/Airlie House Criteria. Time to diagnosis or diagnostic delay was defined as mean or median time from patient-reported first symptom onset to formal diagnosis by a physician, as recorded in medical records. The typical time to diagnosis was 10-16 months from symptom onset. Several points of delay in the diagnosis course were identified, including specialist referrals and misdiagnoses, often resulting in unnecessary procedures and surgeries. Bulbar onset was noted to significantly reduce time to ALS diagnosis. Future interventions and potential research opportunities were reviewed.

Maintenance immunosuppression in myasthenia gravis, an update.

Therapies for myasthenia gravis (MG) include symptomatic and immunosuppressive/immunomodulatory treatment. Options for immunosuppression include corticosteroids, azathioprine, mycophenolate mofetil, cyclosporine, tacrolimus, methotrexate, rituximab, cyclophosphamide, eculizumab, intravenous immunoglobulin, subcutaneous immunoglobulin, plasmapheresis, and thymectomy. The practical aspects of long-term immunosuppressive therapy in MG are critically reviewed in this article. Application of one or more of these specific therapies is guided based on known efficacy, adverse effect profile, particular disease subtype and severity, and patient co-morbidities.

Utility of electrodiagnostic studies in patients referred with a diagnosis of polyneuropathy.

BACKGROUND: Peripheral polyneuropathies (PN) are common neuromuscular conditions. The role of electrodiagnostic study (EDX) in diagnosis of PN is not well-defined. METHODS: We performed a retrospective chart review of patients referred for EDX evaluation of PN. RESULTS: Of 162 patients analyzed, 23 had pure peripheral neuropathy (pPN; 14.2%), 29 had peripheral neuropathy and another diagnosis (PN+; 17.9%), 51 had an alternative diagnosis (nonPN; 31.5%), and 59 had normal studies (36.4%). In univariable analysis, age (P < .001) and gender (P = .004) were weakly associated with final diagnosis. In multinomial logistic regression analysis, significant predictors included age (odds ratio [OR] for nonPN/PN+:1.07 per year; 95% confidence interval [CI], 1.03-1.11), gender (OR for PN+:0.2, 95% CI, 0.07-0.61), and diabetes/prediabetes (OR for pPN:3.29; 95% CI, 1.17-9.27). CONCLUSIONS: These data suggest that EDX commonly yields additional or nonPNs in patients referred with a diagnosis of PN, and although some variables predict electrodiagnosis, none have a large enough effect to suggest poor utility in any subpopulation.

Ultrasound in the diagnosis and management of fibular mononeuropathy.

INTRODUCTION: Ultrasound (US) evaluation of peripheral nerves is a noninvasive, cost-effective approach to diagnosing focal mononeuropathies and guiding surgical management. We used the intranerve ratio to evaluate for possible cut-off values in diagnosis of fibular mononeuropathies (FNs). METHODS: A retrospective analysis of FN confirmed by electrodiagnosis (EDx) was performed to identify intranerve ratio values between affected and unaffected limbs at the fibular head and popliteal fossa. RESULTS: The optimal fibular head/popliteal fossa intranerve ratio to discriminate between limbs with and without disease was 1.25 (sensitivity, 51%; specificity, 71%). There was no statistically significant difference between affected vs unaffected limbs (ratio, 1.13; P = .15) nor in subgroup analyses. However, 25% of patients had structural lesions amenable to surgery. DISCUSSION: The utility of US in diagnosis of FN is limited using intranerve ratio data, but US has a distinct advantage over EDx for identifying treatable structural lesions.

Myasthenia gravis with muscle-specific tyrosine kinase antibodies: A narrative review.

Growing evidence provides new insights about myasthenia gravis (MG) with antibodies against muscle-specific tyrosine kinase (MuSK-MG), including its pathogenesis, clinical and electrophysiological manifestations, and treatment. Data now support the presence of both presynaptic and postsynaptic dysfunction in MuSK-MG. This is 1 of many key differences between MuSK-MG and acetylcholine receptor antibody-MG (AChR-MG), especially as it pertains to potential therapeutic implications. In comparison to AChR-MG, MuSK-MG is generally more refractory to treatment. However, because MuSK-MG is better understood and more readily recognized today, there are more reports of a relatively benign course. The most effective immunotherapies for MuSK-MG are corticosteroids, plasmapheresis, and rituximab. With appropriate therapy, most patients with MuSK-MG achieve minimal manifestation status or better on the postintervention status outlined by the Myasthenia Gravis Foundation of America. A minority of patients remain refractory to treatment, and optimal management for this group remains a considerable challenge. Muscle Nerve 58: 344-358, 2018.

Diagnostic Accuracy of Single Fiber Electromyography for Myasthenia Gravis in Patients Followed Longitudinally.

INTRODUCTION: The literature lacks data on accuracy of single fiber electromyography (SFEMG) for myasthenia gravis (MG) patients followed longitudinally. METHODS: We included patients with a clinical suspicion of MG who received SFEMG and follow-up at our institution between 2003 and 2013. Data collected included demographics, symptom details, clinical deficits, other diagnostic testing results, MG medication regimen, duration on treatment, response to therapy, and ultimate diagnosis after follow-up. When available, information was also extracted from the MG-specific Activities of Daily Living, MG Quality of Life, and European Quality of Life assessments before and after SFEMG. RESULTS: Three hundred forty eight SFEMG patients met inclusion criteria. Myasthenia gravis was ultimately diagnosed in 31% (19% ocular, 12% generalized). A sensitivity of 78% was seen for MG regardless of subtype, 73% for ocular MG, and 85% for generalized MG. A specificity of 91% was obtained for MG of either ocular or generalized subtype. CONCLUSIONS: The diagnostic accuracy of SFEMG using this methodology minimizing incorporation bias is more reliable than that usually described in previous studies. There is utility in increasing diagnostic yield when SFEMG results are combined with clinical data and those from other diagnostic tests, particularly serology.

Stroke literacy, behavior, and proficiency in a South Florida population.

BACKGROUND: Our goal was to assess stroke literacy, behavior, and proficiency in our South Florida service population. METHODS: Data were obtained from the 2006 to 2010 Cleveland Clinic Florida annual "stroke prevention screening" questionnaires. "Stroke risk factor awareness" was attributed to participants correctly identifying at least 5 out of the 7 stroke risk factors presented. "Stroke symptom awareness" was assigned if one correctly selected all 5 listed stroke symptoms and not any of the 3 inappropriate responses. Participants had "stroke literacy" if they: (1) demonstrated stroke risk factor awareness; (2) demonstrated stroke symptom awareness; and (3) they correctly identified the brain as where a stroke occurs. To assess appropriate "stroke behavior," respondents had to choose "call 911 immediately" if one were to experience stroke symptoms. "Stroke proficiency" was attributed to individuals showing both stroke literacy and appropriate stroke behavior. RESULTS: There were a total of 298 participants. Sixty-seven percent of participants correctly identified the brain as the organ where stroke occurs. Almost three-fourths (74.2%) demonstrated stroke risk factor awareness, 28.2% had stroke symptom awareness, 17.8% had stroke literacy, 87.9% declared appropriate stroke behavior, and 16.1% had stroke proficiency. CONCLUSIONS: Stroke behavior and stroke proficiency are useful novel concepts in stroke epidemiology. Although our South Florida community is relatively well-educated and affluent, there are tangible gaps in knowledge, attitudes, and behavior as it pertains to stroke, similar to that seen in less advantaged populations. We recommend intensified usage of the media with information provided by qualified health professionals in a variety of formats and languages appropriate to the ethnic and cultural diversities that define this population.

Prevalence and control of stroke risk factors in a South Florida population.

OBJECTIVE: To assess the prevalence and control of stroke risk factors in our South Florida service population. METHODS: We obtained data from the 2006-2010 Cleveland Clinic Florida annual "stroke prevention screening" questionnaires. Participants responded to questions regarding demographic information and stroke risk factors including pertinent comorbidity, alcohol consumption, and smoking. Onsite weight, height, blood pressure, and cholesterol levels were obtained. Our hospital's Director of Research did not identify any issues requiring formal institutional review board evaluation. Those with three or more modifiable risk factors breaching recommended targets met criteria for "poorly controlled." RESULTS: There were 298 participants, average age: 62.5 years, 65% were females. 36.9% had hypercholesterolemia, 32.9% hypertension, 14.4% diabetes mellitus, 8% transient ischemic attack/stroke, 7% coronary artery disease, 5.7% atrial fibrillation, and 2.7% carotid artery disease. 81.8% had a BMI of 25 or more and 37.8% had inadequate exercise. 38.3% had elevated cholesterol levels, 26.4% had blood pressures of 140/90mmHg or more, 6% were smokers, and 2.1% had excessive alcohol intake. 29.1% of the composite sample met the criteria outlined for "poorly controlled" stroke risk factors. CONCLUSION: Control of stroke risk factors especially obesity was worse compared to United States national data. Additionally, there is a higher prevalence of hypercholesterolemia and physical inactivity compared to statewide data. There is a definite need for local healthcare professionals to disseminate more stroke risk factor information. However, health promotion at the public policy or patient level should advocate personal responsibility especially pertaining to lifestyle and behavioral changes necessary for stroke prevention.