Neuromuscular Junction Disorders Research Articles

Case Report of Lambert Eaton Myasthenic Syndrome in a Patient with Small Cell Lung Cancer on Immune Checkpoint Inhibitor Therapy

Lambert Eaton myasthenic syndrome (LEMS) is a rare autoimmune neuromuscular junction disorder involving loss of functional pre-synaptic P/Q-type voltage-gated calcium channels. Many cases occur as a paraneoplastic disorder, often in small cell lung cancer (SCLC). Recently, immune checkpoint inhibitors (ICI) have emerged as treatment of choice for various malignancies. While generally well tolerated, certain ICI-treated patients experience neurologic immune-related adverse events (irAEs). Here, we explore therapeutic and diagnostic conundrums from the unclear etiology (paraneoplastic vs. irAE) of a case of LEMS in a patient with SCLC treated with ICI therapy. A 62-year-old female patient with SCLC was referred to EMG laboratory with 7 weeks of progressive weakness, shortness of breath and dysphagia. Due to tumor progression, immunotherapy with pembrolizumab was initiated five months prior to presentation. On examination, she had mild non-fatigable right-sided ptosis and diplopia, normal bulbar strength, and proximal greater than distal weakness of lower greater than upper extremities. Her reflexes were 2-/4 throughout, with left biceps reflex facilitating after 30 seconds of exercise. On nerve conduction studies (NCS), there was an amplitude increase in multiple nerves including the left median nerve (160%) and left ulnar nerve (370%) after 10 seconds of exercise. Paraneoplastic panel came back with elevated LEMS-related anti-P/Q-type voltage gated calcium channel antibodies at 0.19nmol/L (normal: ≤0.02nmol/L). This case illustrates the diagnostic and therapeutic challenges that surround LEMS in SCLC patients on immunotherapy. Diagnosis hinges on clinical presentation, motor NCS, and antibody testing while determination of the etiology (paraneoplastic vs ICI related LEMS) is more complex and may affect selection of the correct treatment. Therapy for ICI-related neuromuscular irAEs depends on symptom severity, but typically should include holding immunotherapy and administration of high dose corticosteroids as first line treatment with possible addition of IVIg and plasmapheresis. This differs from the common first line treatment for paraneoplastic LEMS, highlighting the importance of understanding of the etiology. Further research is needed to better understand optimal management.

The epidemiology of myasthenia gravis.

Neuromuscular junction (NMJ) disorders include several dysfunctions that ultimately lead to muscle weakness. Myasthenia gravis (MG) is the most prevalent NMJ disorder with a highly polymorphic clinical presentation and many different faces. Being an autoimmune disease, MG correlates with the presence of detectable antibodies directed against the acetylcholine receptor, muscle-specific kinase, lipoprotein-related protein 4, agrin, titin, and ryanodine in the postsynaptic membrane at the NMJ. MG has become a prototype serving to understand both autoimmunity and the function of the NMJ better. The aim of this review is to synthesize some of the epidemiological data available. Epidemiological data regarding MG are important for postulating hypotheses regarding its etiology and facilitating the description of MG subtypes. Thus, adequate documentation through broad databases is essential. The incidence and prevalence of MG reported around the globe have been rising steadily and consistently over the past decades. Ethnic aspects, gender-related differences, and environmental risk factors have been described, implying that these might contribute to a specific phenotype, further suggesting that MG may be considered an umbrella term that covers several clinical entities.

Whole-mount Staining of Mouse Diaphragm Neuromuscular Junctions.

The neuromuscular junction (NMJ) is a specialized synapse that connects the terminal end of a motor neuron and a skeletal muscle fiber. Defects in NMJ cause abnormalities of neuromuscular transmission, leading to NMJ disorders. The mammalian diaphragm muscle is essential for respiration and has been widely used to study NMJ formation. Here, we provide a simple and straightforward protocol for preparing diaphragms from embryonic, neonatal, and adult mice and for subsequent NMJ staining.

Knowledge and perceptions of the COVID-19 pandemic among patients with myasthenia gravis.

Patients with myasthenia gravis (MG) may be particularly vulnerable during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic due to risk of worsening disease during infection, potential adverse impacts of coronavirus disease 2019 (COVID-19) treatments on neuromuscular transmission, and a limited ability to fight off infection related to immunosuppressive treatments. Our goal is to understand how patients are experiencing the COVID-19 pandemic, including where they receive relevant information, how it has affected medical care, and what measures they use to protect themselves. This is a prospective online survey study at large academic practice. All patients with a neuromuscular junction disorder diagnosis code in the Duke Health System were invited to participate. One thousand eight hundred and forty eight patients were approached to participate and 75 completed the survey between 16 April 2020 and 28 May 2020. The most frequently used information sources were non-presidential federal government (75%), state government (57%), local healthcare provider (37%), and television news (36%). Non-presidential federal government (80%), local healthcare providers (55%), state government (33%), and patient support organizations (29%) were considered the most trusted information sources. Thirty-three (44%) of survey responders had attended a telemedicine visit. Patients were taking recommended precautions during the pandemic and remained very concerned (69%) about COVID-19. Generalized Anxiety Disorder-7 scores were moderate-severe in 20% of responders. Healthcare providers, the government, and patient organizations play a critical role in communicating with the MG patient community. Use of targeted messaging strategies by these groups to convey accurate information may increase effectiveness and lead to more informed patients with reduced anxiety.

Modeling the neuromuscular junction in vitro: an approach to study neuromuscular junction disorders.

The neuromuscular junction (NMJ) is a specialized structure that works as an interface to translate the action potential of the presynaptic motor neuron (MN) in the contraction of the postsynaptic myofiber. The design of appropriate experimental models is essential to have efficient and reliable approaches to study NMJ development and function, but also to generate conditions that recapitulate distinct features of diseases. Initial studies relied on the use of tissue slices maintained under the same environment and in which single motor axons were difficult to trace. Later, MNs and muscle cells were obtained from primary cultures or differentiation of progenitors and cocultured as monolayers; however, the tissue architecture was lost. Current approaches include self-assembling 3D structures or the incorporation of biomaterials with cells to generate engineered tissues, although the incorporation of Schwann cells remains a challenge. Thus, numerous investigations have established different NMJ models, some of which are quite complex and challenging. Our review summarizes the in vitro models that have emerged in recent years to coculture MNs and skeletal muscle, trying to mimic the healthy and diseased NMJ. We expect our review may serve as a reference for choosing the appropriate experimental model for the required purposes of investigation.

ACUTE RESPIRATORY FAILURE SECONDARY NIVOLUMAB MYOSITIS

SESSION TITLE: Medical Student/Resident Critical Care Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: Nivolumab is a monoclonal antibody that binds to PD-1 receptors blocking the actions of PDL-1 pathway, which translate to an enhancement of immune respond against tumor. Checkpoint inhibitor immunotherapy has been associated with autoimmune reactions such as pneumonitis, endocrinopathies, vasculitis and more rarely myositis.1 We present a case of nivolumab-related myositis causing severe acute respiratory failure. CASE PRESENTATION: A 53-year old female with history of RCC metastatic to lung complicated by bronchial obstruction requiring stenting presented with dyspnea and new evidence of right upper lobe collapse. Bronchoscopy revealed mucus plug in the bronchial stent, which was removed. Despite airway patency, patient failed extubation requiring tracheostomy placement. Due to refractory nature, differential was broad and neurological exam showed symmetric ptosis, sustained upward gaze, neck weakness, poor respiratory effort and clonus in lower extremities. Brain MRI was unremarkable. Blood work showed CK 1357 U/L, aldolase 8.5 U/L, CRP 197 mg/dl, sed rate >120 mm/Hr. Anti-Musk antibody, VGCC antibody, ANA, and AChR Antibody were negative. Myositis panel including anti-JO1, EJ, PL-7, PL-12, Mi-2, SRP, TIF-1y and NXP-2 was negative. Electromyography was inconsistent with neuromuscular junction disorder (myasthenia or Lambert Eaton syndrome) but instead showed finding suggesting inflammatory myopathy. Biceps biopsy showed diffuse MHC class I antigen expression in the muscle and necrosis confirming diagnosis. Patient was started on solumedrol 100 mg IV with subsequent prednisone taper over 4 weeks. Patient recovered normal muscular strength and was able to be decannulated after 4 months. Nivolumab was discontinued. DISCUSSION: Nivolumab has been used as second line for renal cell carcinoma (RCC) in addition to its usual therapeutic role in stage IV non-small cell lung cancer and metastatic melanoma. Nivolumab has known autoimmune adverse effects such as pneumonitis (2.9%), vasculitis (0.7%), myocarditis (0.13%) and myasthenia gravis (0.12%). Nevertheless, the incidence of nivolumab-induced myositis has not been able to be determined.1 Disruption of the PDL-1/PD-1 pathway in the regulatory B-cell might lead to autoimmune response caused by checkpoint inhibitors. Nivolumab myositis is usually seronegative and affects primary axial and respiratory muscles. Histology usually reveals necrosis and T-cell infiltrates.3 In our case, symptom improvement after steroids and Nivolumab discontinuation strongly suggests an adverse effect to the medication rather than a paraneoplastic myositis. Early discontinuation of Nivolumab and treatment with steroids, IgG and plamaspheresis has shown complete remission of symptoms in up to 50% of cases. 2,3 CONCLUSIONS: As the use of checkpoint inhibitors spreads, pulmonologist and intensives should become familiar with pulmonary and systemic manifestations. Reference #1: Moreira A, Loquai C, Pfohler C et al. Myositis and neuromuscular side-effects induced by immune checkpoint inhibitors. Eur J Cancer. 2019 Jan;106:12-23. Reference #2: 2.Bourgeois-Vionnet, J, Joubert B, Bernard E et al. Nivolumab-induced myositis: A case report and a literature review. J of Neurol Sci. 2018. April;387:51-53. Reference #3: 3.Touat M, Maisobe T, Knaus S et al. Immune checkpoint inhibitor-related myositis and myocarditis in patients with cancer. Neurology. 2018 Sep 4;91(10):e985-e994. DISCLOSURES: No relevant relationships by Daniel Alape, source=Web Response No relevant relationships by Jared Mickelson, source=Web Response No relevant relationships by Rahul Sood, source=Web Response

Neuromuscular presentations in patients with COVID-19.

COVID-19 is caused by the coronavirus SARS-CoV-2 that has an affinity for neural tissue. There are reports of encephalitis, encephalopathy, cranial neuropathy, Guillain-Barrè syndrome, and myositis/rhabdomyolysis in patients with COVID-19. In this review, we focused on the neuromuscular manifestations of SARS-CoV-2 infection. We analyzed all published reports on SARS-CoV-2-related peripheral nerve, neuromuscular junction, muscle, and cranial nerve disorders. Olfactory and gustatory dysfunction is now accepted as an early manifestation of COVID-19 infection. Inflammation, edema, and axonal damage of olfactory bulb have been shown in autopsy of patients who died of COVID-19. Olfactory pathway is suggested as a portal of entry of SARS-CoV-2 in the brain. Similar to involvement of olfactory bulb, isolated oculomotor, trochlear and facial nerve has been described. Increasing reports Guillain-Barrè syndrome secondary to COVID-19 are being published. Unlike typical GBS, most of COVID-19-related GBS were elderly, had concomitant pneumonia or ARDS, more prevalent demyelinating neuropathy, and relatively poor outcome. Myalgia is described among the common symptoms of COVID-19 after fever, cough, and sore throat. Duration of myalgia may be related to the severity of COVID-19 disease. Few patients had muscle weakness and elevated creatine kinase along with elevated levels of acute-phase reactants. All these patients with myositis/rhabdomyolysis had severe respiratory complications related to COVID-19. A handful of patients with myasthenia gravis showed exacerbation of their disease after acquiring COVID-19 disease. Most of these patients recovered with either intravenous immunoglobulins or steroids.

EL4-1 Diagnosis for neuromuscular junction disorders

EL4-1 Diagnosis for neuromuscular junction disorders

Myasthenia Gravis and its Association With Thyroid Diseases.

Myasthenia gravis (MG) is a rare autoimmune neuromuscular junction disorder, and thyroid disorder is a disorder involving the thyroid receptor, of which Graves' disease (GD) is the most common autoimmune thyroid disorder, in which antibodies develop against thyroid receptors. Both may have similar clinical features. In myasthenia gravis, autoimmune antibodies develop against postsynaptic neuromuscular junction disrupting the neuromuscular transmission, resulting in fluctuating muscle weakness and fatigue. It is a disease of young women and older men. The two pathologies may coexist in a patient or can precede one another. Graves' disease (GD) among thyroid diseases is most often associated with MG. Similarities in clinical features lead to difficulty in distinguishing MG and GD. Despite the standard treatment of myasthenia gravis, including steroids, acetylcholinesterases, rituximab, immunosuppressants, and thymectomy, there is still an increased number of relapses and myasthenia crisis. Eculizumab and plasmapheresis are the two new treatment options for MG, with supporting evidence of marked improvement in recent studies. Myasthenia gravis and Graves' disease have a see-saw relationship. Treating one pathology may worsen the other, so physicians should always consider MG as a differential in patients of hyperthyroidism presenting with new symptoms of fatigue or respiratory failure or neuromuscular weakness.In this comprehensive review article, we tried to establish an association between myasthenia gravis and Graves' disease (GD) by exploring currently available literature from PubMed. However, more studies need to be done to establish an association between pathologies.

Neuromuscular Complications of Statin Therapy.

This review provides an overview of neuromuscular side effects associated with statin use, their diagnosis, and treatment. The discovery of anti-HMGCR antibodies led to a better understanding of clinical aspects of statin-associated anti-HMGCR myopathy and its treatment. Statins are widely prescribed medications with well-established benefits in the treatment of cardiovascular diseases and stroke. Adherence to statins is influenced by development of side effects, especially muscle related. There is wide range of neuromuscular side effects associated with statin therapy. Documented neuromuscular side effects include asymptomatic elevation of muscle enzymes, mild-moderate myalgias and cramps, toxic and immune-mediated severe necrotizing myopathy, and rare cases of rhabdomyolysis. In addition, statins can lead to unmasking or triggering of underlying muscle and neuromuscular junction disorders. This article identifies the risk factors and provides a review of neuromuscular side effects associated with statin use, their diagnosis and treatment.

End-Plate Disorders in Intensive Care Unit.

Even if nerves and muscles are the principal targets of intensive care unit-acquired weakness, the neuromuscular junction may be as well involved. In intensive care units, neuromuscular blocking agents are classically used, and side effects are possible. Sepsis, immobilization, and denervation which are common in intensive care units may be the cause of neuromuscular junction disorders and participate to the pathophysiology of weakness. We propose here a review of end-plate disorders in intensive care units to highlight their mechanisms and propose diagnosis tools.

Carotid-Cavernous Fistula Presenting With Bilateral Abducens Palsy.

Carotid-Cavernous Fistula Presenting With Bilateral Abducens Palsy.

Miller Fisher syndrome with bilateral vocal cord paralysis: a case report

BackgroundMiller Fisher syndrome is a variant of acute inflammatory demyelinating polyneuropathy classically characterized by ataxia, ophthalmoplegia, and areflexia. Miller Fisher syndrome can present with uncommon symptoms such as bulbar, facial, and somatic muscle palsies and micturition disturbance.Case presentationWe describe the case of a 76-year-old white man with new-onset ataxia, stridor, areflexia, and upper and lower extremity weakness who required intubation at presentation. An initial work-up including imaging studies and serum tests was inconclusive. Eventually, neurophysiological testing and cerebrospinal fluid analysis suggested a diagnosis of Miller Fisher syndrome. Our patient responded to treatment with intravenous immunoglobulin and supportive therapy.ConclusionThe occurrence of acute or subacute descending paralysis with involvement of bulbar muscles and respiratory failure can often divert clinicians to a diagnosis of neuromuscular junction disorders (such as botulism or myasthenia gravis), vascular causes like stroke, or electrolyte and metabolic abnormalities. Early identification of Miller Fisher syndrome with appropriate testing is essential to prompt treatment and prevention of further, potentially fatal, deterioration.

Neuromuscular Junction Disorders and Floppy Infant Syndrome: A Comprehensive Review.

Floppy infant syndrome, also sometimes referred to as rag-doll syndrome, is characterized by hypotonia that could present as either peripheral hypotonia or central. Depending on the origin of hypotonia, the infant will present with different symptoms that ultimately have the characteristic feature of hypotonia. The clinical examination is crucial in diagnosing floppy infant syndrome in the neonate period, but the most critical factor is investigating and diagnosing the underlying cause of hypotonia. Regardless of whether the underlying cause of hypotonia is peripheral or central in origin, the presentation of floppy infant syndrome focuses on observing for the presence or absence of specific signs such as ‘frog-leg’ posture, significant head lag on traction or pull-to-sit maneuver, or the feeling of ‘slipping through the hands’ when the infant is held under the arms. Infantile botulism, transient neonatal myasthenia gravis, congenital myasthenia gravis, hypermagnesemia, and aminoglycoside toxicity are all neuromuscular junction disorders that are considered to be a differential diagnosis of floppy infant syndrome. These neuromuscular junction disorders ultimately impact the presence of acetylcholine within the neuromuscular junction. While some of these disorders may impact the acetylcholine receptors, others may cause a depletion within the end-plate anticholinesterase enzyme. A deficiency within the anticholinesterase deficiency may cause desensitization to acetylcholine, which could also cause present with floppy infant syndrome as well. Depending on the underlying causative disorder leading to the presence of floppy infant syndrome, the treatment will vary considerably. Treatment of the underlying causative syndrome resulting in the presentation of floppy infant syndrome deals with the symptoms of hypotonia, and as a result, the decreased muscle tone, diminished tendon reflexes, any feeding or respiratory difficulties diminish.

Transient neonatal myasthenia gravis following maternal myasthenia gravis presenting in pregnancy after treatment with Alemtuzumab

Abstract Ojectives Transient neonatal Myasthenia gravis is a postsynaptic neuromuscular junction disorder seen in 10–21% of infants born to mothers with myasthenia gravis. Alemtuzumab is an anti-CD52 monoclonal antibody used in the treatment of multiple sclerosis. The possibility of developing Myasthenia gravis in a pregnant mother treated with Alemtuzumab is rare. Case presentation We report a case of transient neonatal myasthenia gravis following treatment with Alemtuzumab for multiple sclerosis in the mother. Conclusions Therapy with Alemtuzumab increases the risk of secondary autoimmune diseases including Myasthenia gravis.

Reference Jitter Values for Concentric Needle Electrode of Orbicularis Oculi and Frontalis Muscles Using Voluntary Activation Method in Sudanese Population

Single fibre electromyography is the most sensitive neurophysiological test for the diagnosis of neuromuscular junction disorders, particularly myasthenia gravis. The study aimed at establishing concentric needle (CN) normal jitter values for voluntarily activated orbicularis-oculi (V-OOc) & Frontalis (V-FRO) muscles in Sudanese population. 57 healthy volunteers (20 males & 37 females) were included in the study (mean Age 43.6 ± 14.2 years, range 18–70 years). V-OOc and V-FRO were tested in the same individual using CN. Jitter values were expressed as the mean consecutive difference (MCD) of 30 potential pairs in microseconds. The mean jitter, mean individual fibre pairs jitter & mean outliers jitter values with (upper 95% Confidence Limit-CL) for [OOc] were [26.9 ± 3.3 (31.97), 26.1 ± 8.9 (41.8) & 38.5 ± 5.7 (49.0) µs] & for [FRO] were [27.1 ± 3.0 (31.32), 26.4 ± 9.4 (42.9) & 39.9 ± 5 (49.2) µs] respectively. The suggested practical upper limits for mean jitter & for outliers were (32, 49 µs) for OOc & (31, 49 µs) for FRO. Our CN-jitter values were within the range of the few published studies. The study was unique in that it established and compared between CN reference jitter values of two voluntarily activated facial muscles (V-OOc & V-FRO) in the same individual in large number of healthy subjects.

On-chip 3D neuromuscular model for drug screening and precision medicine in neuromuscular disease

This protocol describes the design, fabrication and use of a 3D physiological and pathophysiological motor unit model consisting of motor neurons coupled to skeletal muscles interacting via the neuromuscular junction (NMJ) within a microfluidic device. This model facilitates imaging and quantitative functional assessment. The 'NMJ chip' enables real-time, live imaging of axonal outgrowth, NMJ formation and muscle maturation, as well as synchronization of motor neuron activity and muscle contraction under optogenetic control for the study of normal physiological events. The proposed protocol takes ~2-3 months to be implemented. Pathological behaviors associated with various neuromuscular diseases, such as regression of motor neuron axons, motor neuron death, and muscle degradation and atrophy can also be recapitulated in this system. Disease models can be created by the use of patient-derived induced pluripotent stem cells to generate both the motor neurons and skeletal muscle cells used. This is demonstrated by the use of cells from a patient with sporadic amyotrophic lateral sclerosis but can be applied more generally to models of neuromuscular disease, such as spinal muscular atrophy, NMJ disorder and muscular dystrophy. Models such as this hold considerable potential for applications in precision medicine, drug screening and disease risk assessment.

Neuromuscular Disease Affecting the Larynx.

Neuromuscular diseases (NMDs) are diseases involving the motor nuclei of the cranial nerves and anterior horn cells of the spinal cord, the peripheral nerves, the neuromuscular junction, and/or muscle itself. The following groups of disorders from the WHO International Classification of Diseases are usually included in the classification of NMDs: (1) Motor neuron diseases or related disorders; (2) Disorders of nerve root, plexus or peripheral nerves; (3) Diseases of neuromuscular junction or muscle. These diseases include myasthenia gravis or certain specified neuromuscular junction disorders, primary disorders of muscle, and secondary myopathies. The following discussion selects NMDs from each group, which may have unique laryngeal features and more commonly involve the laryngologist and highlights different diagnostic and treatment considerations related to the larynx.

Digestive involvement in a patient with Lambert-Eaton syndrome

We present the case of a 50-year-old male diagnosed with myasthenia gravis, secondary to thymoma or Lambert-Eaton syndrome during the study of repeated vomiting. Gastrointestinal symptoms persisted despite the treatment of the thymoma. He suffered from sigma volvulus that required sigmoidectomy 9 years after diagnosis. Neuromuscular junction disorders are not characterized by gastrointestinal involvement, as in our case. They have previously sporadically been related to intestinal motility dysfunction.

Chapter 12 - Neuromuscular disorders in pregnancy

Many neuromuscular disorders preexist or occur during pregnancy. In some cases, pregnancy unmasks a latent hereditary disorder. Most available information is based on case reports or series or retrospective clinical experience or patient surveys. Of special interest are pregnancy-induced changes in disease course or severity and likelihood for baseline recovery of function postpartum. Labor and delivery present special challenges in many conditions that affect skeletal but not smooth (uterine) muscle; so labor complications must be anticipated. Anesthesia for cesarean section surgery requires special precautions in many disorders. The types of conditions reviewed are broad and include examples of autoimmune, hereditary, and compressive/mechanical processes. Disorders include carpal tunnel syndrome and other focal neuropathies, Bell palsy, myasthenia gravis, and other neuromuscular junction disorders, acute and chronic inflammatory neuropathy, hereditary and acquired muscle diseases, spinal muscular atrophy, amyotrophic lateral sclerosis, channelopathies, autonomic neuropathy, and dysautonomia. Many commonly used therapies have fetal animal but no proven human toxicity concerns, complicating treatment and risk decisions. Weaning off effective therapeutic agents or preemptive aggressive treatment or surgery prior to planned pregnancy is an option in some conditions.