Bulbar Muscles Research Articles

Primary Lateral Sclerosis: An Overview.

Primary lateral sclerosis (PLS) is a rare neurodegenerative disorder which causes the selective deterioration of the upper motor neurons (UMNs), sparing the lower motor neuron (LMN) system. The clinical course is defined by a progressive motor disability due to muscle spasticity which typically involves lower extremities and bulbar muscles. Although classically considered a sporadic disease, some familiar cases and possible causative genes have been reported. Despite it having been recognized as a rare but distinct entity, whether it actually represents an extreme end of the motor neuron diseases continuum is still an open issue. The main knowledge gap is the lack of specific biomarkers to improve the clinical diagnostic accuracy. Indeed, the diagnostic imprecision, together with some uncertainty about overlap with UMN-predominant ALS and Hereditary Spastic Paraplegia (HSP), has become an obstacle to the development of specific therapeutic trials. In this study, we provided a comprehensive analysis of the existing literature, including neuropathological, clinical, neuroimaging, and neurophysiological features of the disease, and highlighting the controversies still unsolved in the differential diagnoses and the current diagnostic criteria. We also discussed the current knowledge gaps still present in both diagnostic and therapeutic fields when approaching this rare condition.

Study on the clinical and electrophysiological characteristics of nerve function in myasthenia gravis patients in Vietnam.

In Vietnam, there is limited research on the role of nerve conduction in myasthenia gravis and its association with clinical features. This study aims to describe the electrophysiological features in patients with myasthenia gravis. This descriptive study was conducted from September 2019 to December 2021. The study included 33 myasthenia gravis patients who sought medical consultation or received inpatient treatment during this period. The Myasthenia Gravis Foundation of America classifies myasthenia gravis into five groups: I, IIa, IIb, IIIa, IIIb, IVa, IVb, and V. Notably, Group I involves pure ocular weakness, whereas Group a primarily impacts limb and axial muscles, and Group b mainly affects bulbar and respiratory muscles. The study revealed that motor and sensory nerve conduction in the upper and lower limbs were within normal limits for the patient group under evaluation. Repetitive nerve stimulation testing at a frequency of 3 Hz showed positive results in 66.7% of myasthenia gravis patients. Myasthenia gravis patients displayed distinct clinical symptoms, with ptosis being the most common (87.9%). Myasthenia Gravis Foundation of America classification indicated the highest proportion in subgroup IIa (24.2%), with myasthenia gravis predominating in limb and axial muscles (Group a) observed in 51.5% of cases. Needle electromyography showed no abnormalities in myasthenia gravis patients. There was an association between acetylcholine receptor antibody titers and the results of the 3 Hz repetitive nerve stimulation test in myasthenia gravis patients, with a significance of p = 0.002. Nerve conduction studies should be performed in patients with suspected neuromuscular disorders to aid in differential diagnosis and definitive diagnosis of myasthenia gravis.

Clinical Features of Myasthenia Gravis as an Immune-related Adverse Event

Neurological and muscular immune-related adverse events (irAEs) associated with cancer treatment using immune checkpoint inhibitors (ICIs) may show a diverse clinical presentation. Myasthenia gravis (MG) represents a serious irAE associated with the aforementioned therapy. Recent studies have discussed the clinical features of MG that occurs as an irAE (irAE-MG). The incidence of irAE-MG is estimated to be 1%. This complication occurs during the early phase of ICI treatment and rapidly worsens, resulting in severe bulbar muscle involvement and myasthenic crisis and significantly elevated serum creatine kinase levels. MG and myositis, which may occur concomitantly as irAEs are often indistinguishable. Myocarditis is occasionally observed in patients with irAE-MG and can cause severe heart failure and lethal arrhythmias, with a fatal outcome. Kv1.4 antibodies serve as biomarkers of severe irAE-MG and myocarditis. Immunotherapy with corticosteroids is effective for management of irAE-MG and should be initiated promptly. Collaboration between consulting neurologists is necessary for safe management of cancer immunotherapy.

Whole-Body Muscle Magnetic Resonance Imaging in 81 Patients with Spinal and Bulbar Muscular Atrophy: A Prospective Study.

Spinal and bulbar muscular atrophy (SBMA) is characterized by slow, progressive bulbar and limb muscle weakness; however, the pattern of progression of muscle fat infiltration remains unclear. We assessed the progression of muscle involvement in 81 patients with SBMA using whole-body muscle magnetic resonance imaging (MRI), alongside clinical and laboratory findings. This prospective study included patients with genetically confirmed SBMA who underwent whole-body muscle MRI. We analyzed muscle fat infiltration and the pattern of involved muscles using cluster analysis, visualizing the sequential progression of fat infiltration. Muscle clusters demonstrated correlation with clinical scales and laboratory findings. Additionally, linear regression analysis was performed to identify the MRI section most strongly associated with 6-minute walk test (6MWT). We included 81 patients with SBMA (age = 54.3 years). After categorizing the patients into 6 clusters based on the pattern of muscle fat infiltration, we observed that muscle involvement began in the posterior calf and progressed to the posterior thigh, pelvis, trunk, anterior thigh, medial thigh, anterior calf, and upper extremity muscles. These muscle clusters correlated significantly with disease duration (τ = 0.47, p < 0.001), 6MWT (τ = -0.49, p < 0.001), and serum creatinine level (τ = -0.46, p < 0.001). The whole-body MRI indicated the thigh as the section most significantly correlated with 6MWT. We used whole-body muscle MRI to determine the sequential progression of the fat infiltration in SBMA. Our findings may enable the identification of objective and reliable imaging outcome measures in the study of the natural history or future clinical trials of SBMA. ANN NEUROL 2024;95:596-606.

Myasthenia Gravis: A Systematic Review.

Myasthenia gravis (MG), a rare disease, is the most common neuromuscular junction problem. It's the quintessential autoimmune disease with ocular, bulbar, respiratory, axial, and limb muscles exhibiting a typical fatigable weakening due to the development of antibodies against the acetylcholine receptor (AChR). Infections, stress, surgeries, thymus gland anomalies, and pharmaceutical side effects can also cause it. Ocular symptoms are initially experienced by most of the sufferers. The majority of the sufferers will go through at least one episode of symptom exacerbation during their illness. The immune system in MG interferes with nerve-muscle communication, causing muscles to become weak and tired quickly. The actual cause is not yet known, but a problem in the thymus gland may be the cause. In a person suffering from this disease, the size of the thymus becomes larger than normal, which is also called thymic hyperplasia. It is more common for women to have early-onset MG (EOMG) than for males to have late-onset MG (LOMG). Merely clinical evidence, encompassing the patients' medical history and physical indications of fluctuating muscle weakness in a specific region, is utilized to diagnose MG. Complementary diagnostic procedures and lab techniques aid in confirming the synaptic dysfunction and characterizing its kind and degree. Early diagnosis and the availability of effective treatments have reduced the burden of severe impairment and high mortality previously associated with MG. Current immunomodulation-based therapies come with side effects brought on by persistent immune suppression. Improved knowledge of this relatively uncommon but curable condition is required among primary carers. The objective of this review is to provide information about MG and to help people recognize its symptoms and start treatment without panic so that the progression of this disease can be stopped and complications can be avoided.

Spinal bulbar muscular atrophy-Kennedy's disease.

A middle age man complained of progressive bilateral hand tremor and occasional muscle cramps. Examination showed tongue muscle atrophy and limb muscle fasciculation with resting and postural tremor in the upper extremities. Deep tendon reflexes were decreased. He had bilateral breast enlargement. Nerve conduction study and Electromyography revealed chronic sensory-motor neuropathy. DNA analysis identified an expanded number of CAG trinucleotide repeats in the androgen receptor gene consistent with a diagnosis of Kennedy's disease (KD). KD, also known as Spinal Bulbar Muscular Atrophy (SBMA), is a rare X-linked recessive lower motor neuron disorder characterized by proximal and bulbar muscle wasting due to degeneration of motor neurons in the brain stem and spinal cord. KD can present with non-specific symptoms initially and may be misdiagnosed as Amyotrophic Lateral Sclerosis or other neurological conditions. Molecular genetic testing enables the diagnosis by identifying the CAG trinucleotide repeat expansion.

COVID-19 and Myasthenia Gravis Exacerbation in an Elderly Patient: a Case Report

Treatment of COVID-19 in elderly patients with myasthenia gravis (MG), an autoimmune disease characterized by increased dynamic muscle weakness, is associated with a number of challenges, such as chronic immunosuppression, exacerbation of MG, and polymorbidity.We present the case of an elderly patient with generalized seropositive MG who contracted COVID-19. Aggravating factors are the patient’s age, the duration of myasthenia gravis, COVID-19, and comorbidity (chronic coronary heart disease, diffuse cardiosclerosis, atrial fibrillation, NYHA class I heart failure, hyper­tension). The patient had a favorable outcome despite the exacerbation. The patient required intravenous injections of immunoglobulin (1 mg/kg) for 2 days, non-invasive ventilatory support, and treatment of respira­tory and urogenital nosocomial infections (Pseudomonas aeruginosa and Klebsiella oxytoca).COVID-19 led to exacerbation of MG, progression of muscle weakness, development of respiratory failure, and hypoxia in an elderly patient. Intravenous immunoglobulin is a possible effective medication in the treatment of this comorbid pathology.During the COVID-19 pandemic patients with MG may be at greater risk of worse outcomes than healthy individuals due to an immunodeficient state associated with immunotherapy and possible respiratory and bulbar muscle weakness. The examination of patients with MG and a COVID-19 may reveal new pathogenetic patterns and change the therapeutic strategy.Knowledge of the essence of the disease, the main links of its pathogenesis, the spectrum of modern therapeutic agents, and algorithms for their use allow us to improve the quality of medical care for patients with MG. The implementation of a comprehensive multidisciplinary approach in the treatment of these patients allows us to significantly reduce the mortality rate, prolong the life of patients, and improve its quality.

Role of circulating biomarkers in spinal muscular atrophy: insights from a new treatment era.

Spinal muscular atrophy (SMA) is a lower motor neuron disease due to biallelic mutations in the SMN1 gene on chromosome 5. It is characterized by progressive muscle weakness of limbs, bulbar and respiratory muscles. The disease is usually classified in four different phenotypes (1-4) according to age at symptoms onset and maximal motor milestones achieved. Recently, three disease modifying treatments have received approval from the Food and Drug Administration (FDA) and the European Medicines Agency (EMA), while several other innovative drugs are under study. New therapies have been game changing, improving survival and life quality for SMA patients. However, they have also intensified the need for accurate biomarkers to monitor disease progression and treatment efficacy. While clinical and neurophysiological biomarkers are well established and helpful in describing disease progression, there is a great need to develop more robust and sensitive circulating biomarkers, such as proteins, nucleic acids, and other small molecules. Used alone or in combination with clinical biomarkers, they will play a critical role in enhancing patients' stratification for clinical trials and access to approved treatments, as well as in tracking response to therapy, paving the way to the development of individualized therapeutic approaches. In this comprehensive review, we describe the foremost circulating biomarkers of current significance, analyzing existing literature on non-treated and treated patients with a special focus on neurofilaments and circulating miRNA, aiming to identify and examine their role in the follow-up of patients treated with innovative treatments, including gene therapy.

Critical Care Management of Myasthenic Crisis: A Case Report

Background: The annual incidence of myasthenia gravis is 1-2 cases in 100,000 population. 30% of all cases will develop bulbar or respiratory muscle weakness. About 15-20% of myasthenia gravis patients will develop myasthenia crisis.&#x0D; Case presentation: An 18-year-old female patient complained of difficulty swallowing two days ago difficulty swallowing solid and liquid food, and this complaint caused the patient to cough and choke. Complaints were accompanied by difficulty opening the eyelids, especially in the afternoon. Complaints were also accompanied by double vision, especially when looking to the right. There was a nasal sound, and the patient had difficulty pronouncing vocal letters. The patient was admitted to ICU, In the ICU patient was intubated and given plasma exchange therapy.&#x0D; Conclusion: Myasthenic crisis is a neurological emergency that requires prompt diagnosis and treatment. Adequate intensive care, judicious weaning, and extubation decisions, along with specifically targeted therapy, will improve the outcome of myasthenia gravis.

The National Israeli Registry for Oculo-Pharyngeal Muscular Dystrophy (IsrO-PMD): rationale and design

BackgroundOculo-pharyngeal muscular dystrophy (OPMD) is a rare disease, caused by trinucleotide repeat expansion in the PABPN1 gene, inherited in an autosomal dominant (AD) manner. Its main features are eyelid ptosis and dysphagia, which manifest at the end of the fifth decade of life. Other symptoms include proximal muscle weakness and bulbar muscle weakness. Although OPMD is prevalent worldwide, a higher prevalence has been reported in the Jewish population from Bukhara. Currently, no specific drugs are available for OPMD.ObjectiveOur National Israeli Registry for Oculo-Pharyngeal Muscular Dystrophy (IsrO-PMD) study aims to provide a framework for the assessment and documentation of the natural history of the diseases as we as a multi-disciplinary management of patients with OPMD. The IsrO-PMD may be the cornerstone of future clinical trials for novel therapies for OPMD.MethodsThe IsrO-PMD is a national prospective registry that involves non-interventional data collection based on the Global Rare Diseases Patient Registry (GRDPR) and data repository standard. Inclusion criteria are clinical diagnosis of OPMD and positive genetic testing. Patients who meet inclusion criteria will be examined using a series of multi-disciplinary investigations and questionnaires including periodic follow-up examinations. Specific attention is given to comprehensive neurological, swallowing, and ophthalmological evaluations.DiscussionThe establishment of this national registry will enhance our understanding of the natural history of OPMD, establish quality care benchmarks, and develop treatment strategies in addressing the multi-system pathophysiology of the disease and associated comorbidities. Our registry provides a foundation for the use of new cutting-edge treatments as they become available.

Anti-Kv1.4 Antibody-positive Nivolumab-induced Myasthenia Gravis and Myositis Presenting with Bilateral Ptosis and Demonstrating Different Pathophysiologies.

Nivolumab blocks inhibitors of T-cell activation and restores antitumor immunity but promotes T-cell activity in host tissues by blocking inhibition of the T-cell function, resulting in immune-related adverse effects. We herein report an 80-year-old man presenting with nivolumab-related myasthenia gravis with anti-muscular voltage-gated potassium channel-complex (Kv1.4) antibodies. On day 29 after nivolumab administration, he simultaneously developed rapidly progressing right ptosis and left facial paralysis. Nivolumab administration was discontinued. He subsequently presented with bulbar paralysis, dyspnea, and muscle weakness and received intravenous immunoglobulin, methylprednisolone, and plasma exchange. The severity of nivolumab-related myasthenia gravis with anti-Kv1.4 antibodies presented with diverse clinical findings.

Airway Clearance Strategies and Secretion Management in Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is a rare, neurodegenerative motor neuron disease that affects voluntary muscle movement. Often, difficulty in coughing, breathing, and swallowing are sequela associated with the condition, and the presence of bulbar muscle predominant weakness results in deleterious effects on airway clearance and secretion management. This narrative review will provide practical guidance for clinicians treating this population. Cough insufficiency in this population typically manifests as a prolonged, slow, weak cough effort that impedes the clearability of secretions and airway protection. Dystussia and dysphagia frequently occur simultaneously in bulbar dysfunction, subsequently impacting respiratory health. Measures of respiratory strength should be obtained and monitored every 3-6 months, preferably in a multidisciplinary clinic setting. Cough augmentation, whether manual or mechanical techniques, should be sought as early in the disease progression as possible to adequately control secretions in the proximal airways. This airway clearance strategy can aid in the prevention and treatment of respiratory tract infections (RTIs), which can pose a significant clinical hurdle to those with ALS. The use of mechanical insufflation-exsufflation may be complicated by severe bulbar dysfunction rendering this technique ineffective. Though peripheral airway clearance strategies, such as high-frequency chest-wall compression, have the advantage of being less impacted by bulbar dysfunction, it is only recommended this modality be used in conjunction with, versus in lieu of, proximal strategies. Salivary secretion management includes the use of anticholinergics, botulinum toxin, and radiation therapy depending on severity and desire for relief.

Role of complement in myasthenia gravis.

Myasthenia gravis is a prototypic neuroimmune disorder with autoantibodies targeting the acetylcholine receptor complex at the neuromuscular junction. Patients present with mainly ocular muscle weakness and tend to have a generalized muscle weakness later in the clinical course. The weakness can be severe and fatal when bulbar muscles are heavily involved. Acetylcholine receptor antibodies are present in the majority of patients and are of IgG1 and IgG3 subtypes which can activate the complement system. The complement involvement plays a major role in the neuromuscular junction damage and the supporting evidence in the literature is described in this article. Complement therapies were initially studied and approved for paroxysmal nocturnal hemoglobinuria and in the past decade, those have also been studied in myasthenia gravis. The currently available randomized control trial and real-world data on the efficacy and safety of the approved and investigational complement therapies are summarized in this review.

Comparing Safety and Efficacy of Rituximab and Eculizumab in Treating Refractory Myasthenia Gravis: A Systematic Review

Myasthenia gravis is a common autoimmune disease in which patients experience weakness primarily in the ocular, respiratory, bulbar, and limb muscles. Although the symptoms of most patients with myasthenia gravis are well controlled with conventional immunotherapies, about 15% of them experience a refractory disease. This systematic review will focus on the safety and efficacy of monoclonal antibodies, specifically rituximab and eculizumab, in treating myasthenia gravis

Complement inhibition in Myasthenia – from basics to RCT data

Myasthenia gravis (MG) is the prototypic autoimmune neurological disorder causing fatiguable muscle weakness either limited to the ocular muscles or becoming generalised involving the limb and bulbar muscles. Nine out of 10 generalised MG patients have IgG1 or IgG3 antibodies against the acetylcholine receptor (AChR). AChR antibodies cause neuromuscular weakness by internalisation of AChR, receptor blockade and by activating the complement pathway. Complement activation causes formation of the membrane attack complex (MAC) leading to degradation of the neuromuscular junction (NMJ). Several animal models have confirmed the role of complement in the pathogenesis of MG, with the experimental models (EAMG) often needing complement inhibitory therapies to prevent or reverse the disease. Various molecules that target the complement system have now been developed to treat myasthenia gravis. The vast majority of the currently studied molecules target the C5 protein, thereby preventing the formation of MAC and subsequent NMJ destruction. The currently studied anti-complement therapies for MG include Eculizumab, Zilucoplan, Ravulizumab, Pozelimab, Cemdisiran, Gefurilimab, Danicopan and few others in the pipeline. Eculizumab has been shown in clinical trials to be effective in the treatment of refractory MG, but further sub-group analysis and real-life experience have shown that this can be beneficial in various patients including those receiving regular IVIG, plasma exchange or Rituximab. It was approved for use by FDA in Oct 2017. Ravulizumab is a long-acting monoclonal antibody which has similar mechanism of action to Eculizumab and was approved for use in MG by FDA in April 2022. Zilucoplan is a macrocyclic peptide which binds to C5 and C5b thus preventing terminal complement activation, which can be given subcutaneously (FDA new drug application accepted in Nov 2022). Many of these have also been shown to have long term benefit in different sub-groups of patients with MG. Patients would need to be vaccinated against Neisseria meningitidis because of the risk of Gram-negative septicaemia, although no major safety signatures have been noted in the studies so far. Future studies may be able to identify specific biomarkers which might aid in selecting the most appropriate patients who might respond to these therapies.

Immunotherapies in MuSK-positive Myasthenia Gravis; an IgG4 antibody-mediated disease.

Muscle-specific kinase (MuSK) Myasthenia Gravis (MG) represents a prototypical antibody-mediated disease characterized by predominantly focal muscle weakness (neck, facial, and bulbar muscles) and fatigability. The pathogenic antibodies mostly belong to the immunoglobulin subclass (Ig)G4, a feature which attributes them their specific properties and pathogenic profile. On the other hand, acetylcholine receptor (AChR) MG, the most prevalent form of MG, is characterized by immunoglobulin (Ig)G1 and IgG3 antibodies to the AChR. IgG4 class autoantibodies are impotent to fix complement and only weakly bind Fc-receptors expressed on immune cells and exert their pathogenicity via interfering with the interaction between their targets and binding partners (e.g. between MuSK and LRP4). Cardinal differences between AChR and MuSK-MG are the thymus involvement (not prominent in MuSK-MG), the distinct HLA alleles, and core immunopathological patterns of pathology in neuromuscular junction, structure, and function. In MuSK-MG, classical treatment options are usually less effective (e.g. IVIG) with the need for prolonged and high doses of steroids difficult to be tapered to control symptoms. Exceptional clinical response to plasmapheresis and rituximab has been particularly observed in these patients. Reduction of antibody titers follows the clinical efficacy of anti-CD20 therapies, a feature implying the role of short-lived plasma cells (SLPB) in autoantibody production. Novel therapeutic monoclonal against B cells at different stages of their maturation (like plasmablasts), or against molecules involved in B cell activation, represent promising therapeutic targets. A revolution in autoantibody-mediated diseases is pharmacological interference with the neonatal Fc receptor, leading to a rapid reduction of circulating IgGs (including autoantibodies), an approach already suitable for AChR-MG and promising for MuSK-MG. New precision medicine approaches involve Chimeric autoantibody receptor T (CAAR-T) cells that are engineered to target antigen-specific B cells in MuSK-MG and represent a milestone in the development of targeted immunotherapies. This review aims to provide a detailed update on the pathomechanisms involved in MuSK-MG (cellular and humoral aberrations), fostering the understanding of the latest indications regarding the efficacy of different treatment strategies.

Occurrence and severity of myasthenic crisis in an unselected Turkish cohort of patients with myasthenia gravis.

Myasthenia gravis (MG) is a disorder of the neuromuscular junction that can deteriorate into myasthenic crisis, involving weakness of bulbar and respiratory muscles. In this study, we describe the clinical manifestations of myasthenic crisis, identify risk factors, and examine treatments and outcomes. All 95 patients with generalized MG treated at our center during the last 10 years were included in this retrospective study. We collected data from the patients' records, including clinical follow-ups, muscle antibodies, thymic status, and treatments. The characteristics of patients who did and did not experience myasthenic crisis were compared. Features of all myasthenic crises were also assessed. Twelve patients (13%) developed myasthenic crisis during the observation period. Men were more often affected at older ages. Seven patients experienced multiple myasthenic crises. Thymoma increased the risk of a crisis, whereas thymic hyperplasia decreased the risk. Myasthenic crises were more common in the summer months. No patients died during a myasthenic crisis. Risk factors for myasthenic crisis were thymoma, older age, MuSK antibodies, and previous crises. Individualized and active immunosuppressive treatment and optimal intensive care during crises provide a good outcome for patients with generalized MG.

Development of an International SMA Bulbar Assessment for Inter-professional Administration.

Progressive weakness can affect bulbar muscles in individuals with moderate to severe forms of spinal muscular atrophy (SMA). The paucity of standardized, valid bulbar assessments capturing clinically significant deficits in SMA impedes the ability to monitor function, facilitate intervention, or detect treatment response. To fill this void, an international multidisciplinary team gathered to develop an agreed upon consensus-derived assessment of bulbar function in SMA for inter-professional administration to enhance our ability to monitor disease progression, support clinical management, and evaluate treatment effects. Fifty-six international clinicians experienced in SMA were invited and engaged using the Delphi method over multiple rounds of web-based surveys to establish consensus. Serial virtual meetings occurred with 42 clinicians (21 speech and language therapists, 11 physical therapists, 5 neurologists, 4 occupational therapists, and 1 dentist). Seventy-two validated assessments of bulbar function were identified for potential relevance to individuals with SMA (32 accessible objective, 11 inaccessible objective, 29 patient-reported outcomes). Delphi survey rounds (n = 11, 15, 15) achieved consensus on individual items with relevance and wording discussed. Key aspects of bulbar function identified included: oral intake status, oral facial structure and motor strength, swallowing physiology, voice & speech, and fatigability. Multidisciplinary clinicians with expertise in bulbar function and SMA used Delphi methodology to reach consensus on assessments/items considered relevant for SMA across all age groups. Future steps include piloting the new scale moving towards validation/reliability. This work supports the advancement of assessing bulbar function in children and adults with SMA by a variety of professionals.

Infant Botulism.

Infant Botulism.

Probable Kennedy Disease Mimicking Hirayama Disease: A Case Report

Spinal and bulbar muscular atrophy (Kennedy disease) is an X-linked, adult-onset motor neuron disease characterized by slow, progressive weakness of the bulbar and extremity muscles with CAG triplet repeat expansion in the androgen receptor gene. Hirayama disease (HD) is characterized by the juvenile onset of asymmetric weakness and amyotrophy of the hand and is most common in males in Asia. We report a patient with atypical Kennedy disease presenting with asymmetric hand weakness and atrophy typical of HD.