Bulbar Myasthenia Gravis Research Articles

From Bad to Worse: The Clinical Spectrum of Immune Checkpoint Inhibitor Myocarditis and Associated 3M Syndrome with Concomitant Myositis and Myasthenia

Immune checkpoint inhibitors (ICIs), though revolutionizing cancer care, are well known to cause a diverse array of autoimmune side effects termed immune-related adverse events (IRAEs). ICI Myocarditis is a rare manifestation of IRAE associated with high mortality. We report two cases of fulminant ICI myocarditis refractory to potent immunosuppressants. Our first patient received pembrolizumab for lymphoma, small cell lung cancer and renal cell carcinoma. After 13 doses of ICIs, he developed fulminant myocarditis with concomitant lower-motor neuron type facial nerve palsy. Despite receiving triple immunosuppressive therapies with pulse steroid, mycophenolate mofetil and basiliximab, his cardiac condition progressively worsened and eventually died of heart failure. Our second patients received dual ICIs with pembrolizumab and ipilimumab for inoperable hepatocellular carcinoma. Shortly after first doses of ICIs, he developed 3M syndrome with the classically described triad of Myocarditis, Myositis and bulbar Myasthenia gravis. Despite receiving pulse steroid, mycophenolate mofetil, tacrolimus, plasmapheresis and intravenous immunoglobulin, he had persistent myocardial inflammation with elevated troponin level, and refractory bulbar myasthenia requiring mechanical ventilation and nasogastric tube feeding. Our case series illustrates challenges with managing ICI myocarditis and its associated clinical syndromes including the 3M syndrome. Given the wide application of ICIs, clinical trials as well as preclinical studies are urgently needed to find out the optimal therapy for ICI myocarditis. As early identification of ICI myocarditis allows prompt cessation of ICIs and initiation of immunosuppressants, which may potentially improve cardiovascular outcome of these patients, it is also crucial to determine to optimal strategies for screening ICI myocarditis.

Spotlight on MuSK positive myasthenia gravis: clinical characteristics, treatment and outcomes

BackgroundTo investigate the clinical characteristics, treatments and outcomes of patients with myasthenia gravis with antibodies to muscle-specific tyrosine kinase (MuSK-MG).MethodsWe retrospectively reviewed the cases of 21 patients with confirmed MuSK-MG between January 2012 and January 2020 in our centre. Detailed clinical data and long-term follow-up information were summarized.ResultsFemales (17/21, 81%) predominated among these MuSK-MG patients, and the mean age of onset in this group was 51.86 ± 16.16 years. MuSK-MG patients were divided into three subgroups according to the symptoms of muscle weakness at onset: ocular myasthenia gravis (OMG, 47.6%), bulbar myasthenia gravis (BMG, 42.9%), and generalized myasthenia gravis (GMG, 9.5%). The mean progression time from symptom onset to other muscle group involvement in OMG patients was 4.38 ± 2.54 months. Pyridostigmine bromide was adopted in 81.0% of patients, and 90.5% of patients received corticosteroids. Compared to usage in hospitals, the median daily dose of corticosteroids decreased significantly at the last follow-up. A total of 85.7% of patients received a long-term follow-up, with an average time of 1202.17 ± 976.73 days. At the end of the follow-up period, 4.8% of patients had achieved complete stable remission, 42.9% of patients had minimal manifestations, 19.0% had improved, the condition of 4.8% of patients remained unchanged, and 9.5% of patients died.ConclusionFemale patients were more prevalent in this study, and MuSK-MG patients rapidly progressed to a generalized state. Although approximately 50% of MuSK-MG patients can achieve a favourable outcome with conventional immunosuppressants, complete stable remission is rare, and approximately 15% respond poorly. More effective medications should be explored in these patients.

Respiratory Assessment of Myasthenia Gravis Patients Using Repetitive Nerve Stimulation of Phrenic and Intercostal Nerves.

We evaluated decremental response from phrenic and intercostal nerves using slow repetitive nerve stimulation test (RNST) to look for its diagnostic significance in sero-negative predominantly bulbar myasthenia gravis (MG) with normal peripheral or cranial nerve RNST. RNST from phrenic and intercostal nerves was performed along with standard RNST from abductor digiti minimi (ADM), trapezius, nasalis and orbicularis oculi muscles in 10 normal individuals (group I), 10 patients with neurological disorders other than MG (group II) and 10 patients with MG (group III). We evaluated the presence of positive response in first two groups (group I and II) and absence of negative response in group III. Spirometry was also performed in MG patients. Mean baseline decrement in I/C RNST in three groups was -2.06±1.33 %, -2.5±2.18% and -27.1±17.9 % respectively. One minute post exercise decrement in I/C RNST in three groups was -2.9±1.36%,-2.9±1.36% and -32.9±17.9% respectively. RNST of phrenic nerve showed mean baseline decrement of -2.1±2.3%, -3.2±2.6 % and -18.3±30.3% in three groups respectively. One minute post exercise decrement percentage were -2.2±1.18% in group I, -4.8±2.18% in group II and -29.2±19.2% in group III. RNST of peripheral nerves were negative in two patients who were bulbar sero-negative MG, however, significant decrement was seen in intercostal and phrenic nerve RNST. Intercostal and phrenic nerve RNST are a better test for assessing respiratory involvement specially in patients presenting with bulbar symptoms and having negative RNST of peripheral nerves.

STROKE AND MYASTHENIA GRAVIS LEAD TO CRISIS IN THE ELDERLY

SESSION TITLE: Tuesday Medical Student/Resident Case Report Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: 10/22/2019 01:00 PM - 02:00 PM INTRODUCTION: Myasthenia gravis (MG) is frequently underdiagnosed especially in the elderly population with comorbid illness [1]. Late-onset MG is defined as onset after the age of 50 [2]. MG is especially difficult to identify in patients with recent stroke given overlapping signs and symptoms. We present here a case of late-onset MG preceded by an acute stroke that pursued a rapid downhill course leading to myasthenic crisis and acute respiratory failure. CASE PRESENTATION: The patient was a 75 year old male who presented for inpatient rehabilitation after an acute medullary stroke. During rehab, the patient developed new onset diplopia and bilateral ptosis which was initially thought to be due to progression of his stroke. His symptoms continued to worsen, however, and infection, thyroid dysfunction, electrolyte abnormalities, and stroke progression was ruled out by appropriate laboratory and radiographic studies. The patient was subsequently found to have positive AChR antibodies with a positive pyridostigmine test confirming the diagnosis of MG. A CT thorax was negative for thymoma. Despite aggressive treatment with IVIG and systemic steroids, the patient’s disease progressed to the development of a myasthenic crisis. Even with the initiation of plasmapheresis the patient developed acute hypercapneic respiratory failure necessitating endotracheal intubation and mechanical ventilation. The patient failed to respond to therapy and was ultimately withdrawn from life support at the request of the DPOA. DISCUSSION: We present an unusual scenario of late onset MG confounded by the presence of an acute medullary stroke. Acute stroke and MG rarely coincide in the same patient; in fact only a single case is reported that had both conditions concurrently [3]. To our knowledge, this is the first case report of a rare presentation of combined acute stroke and MG progressing to acute myasthenic crisis. With our aging population, prevalence of late-onset MG is on the rise [2]. Although difficult due to physiological changes that occur with aging, prompt diagnosis is crucial especially in the elderly population. Delayed diagnosis can be catastrophic as seen in our patient with abrupt decline. We postulate that the rapid progression of the patient’s respiratory failure and inability to successfully liberate from mechanical ventilation was due to the simultaneous insults to the medullary respiratory center and respiratory musculature from the two neurologic disorders. CONCLUSIONS: MG should remain in the differential diagnosis especially in elderly patients presenting with sudden onset of ocular symptoms even in post stroke patients. Patients can have rapid progression to myasthenia crisis when the respiratory system is already compromised by medullary stroke. Reference #1: Aarli JA. Myasthenia gravis in the elderly: is it different? Ann N Y Acad Sci 2008;1132:238-43. Reference #2: Aarli JA. Late-onset myasthenia gravis: a changing scene. Arch Neurol. 1999;56:25–27. Reference #3: Kim SJ, Park GY, Choi YM, Sohn DG, Kang SR, Im S. Bulbar Myasthenia Gravis Superimposed in a Medullary Infarction Diagnosed by a Fiberoptic Endoscopic Evaluation of Swallowing With Simultaneous Tensilon Application. Ann Rehabil Med. 2017;41(6):1082-1087. DISCLOSURES: No relevant relationships by Nemer Dabage-Forzoli, source=Web Response No relevant relationships by Sana Khan, source=Web Response No relevant relationships by Nick Meyerkord, source=Web Response No relevant relationships by Charles Schroeder, source=Web Response No relevant relationships by Yunna Sinskey, source=Web Response No relevant relationships by Shashank Varakantam, source=Web Response

English

Myasthenia gravis is a neuro-muscular junction disorder characterized by skeletal muscle weakness and fatiguability. It is due to a decrease in the number of available acetylcholine receptors at the neuromuscular junction as a result of antibody mediated autoimmune attack. Weakness of muscles may involve cranial and somatic musculatures. Weakness resembling myasthenia gravis may occur in other conditions as a result of drug, endocrine disease of thyroid, certain malignancies, bacterial toxins and also by non-autoimmune mechanisms involving the neuromuscular junction. The weakness may involve all the skeletal muscles of the body but the distribution of weakness has a characteristic pattern and there is a diurnal variation of symptoms. If the weakness of respiratory muscles becomes so severe as to require respiratory assistance, then it is called myasthenic crisis. The myasthenia may be generalized one involving all the groups of muscles or it may involve the extra ocular muscles and facial muscles. Sometimes the bulbar muscles alone may be involved and the condition is called bulbar myasthenia gravis. In some of the patients, (anti-AchR) Acetyl choline receptor antibodies may be positive and in some it will be negative. In some of the patients, anti-muscle specific tyrosine kinase antibodies will be positive and negative in some of the patients. CONCLUSION : 1. In our study, the commonest age group of presentation of myasthenic crisis is the fourth decade (36%). 2. Male predominance (56%) was noted in our study. 3. The most common predisposing factor is the respiratory infection (28%). 4. In three patients, the presenting symptoms of myasthenia gravis was crisis itself. 5. The mean duration of onset of myasthenia gravis to the onset of crisis was 439.36 days. 6. The duration of myasthenia gravis does not influence the occurrence of myasthenic crisis. 7. Our patients presented with predominant bulbar symptoms with respiratory distress. 8. Ventilator associated pneumonia and other respiratory complications influenced the outcome of treatment of myasthenic crisis. 9. 32% of thymectomised patients had myasthenic crisis. 10. Higher age is a risk factor and younger age is a favourable factor for good outcome. 11. Duration of myasthenia gravis have no role on the outcome of crisis. 12. The better survival rate in ventilated patients outweigh the preventable ventilator related complications.

Bulbar Myasthenia Gravis Superimposed in a Medullary Infarction Diagnosed by a Fiberoptic Endoscopic Evaluation of Swallowing With Simultaneous Tensilon Application.

In the elderly, myasthenia gravis (MG) can present with bulbar symptoms, which can be clinically difficult to diagnose from other neurological comorbid conditions. We describe a case of a 75-year-old man who had been previously diagnosed with dysphagia associated with medullary infarction but exhibited aggravation of the dysphagia later on due to a superimposed development of bulbar MG. After recovering from his initial swallowing difficulties, the patient suddenly developed ptosis, drooling, and generalized weakness with aggravated dysphagia. Two follow-up brain magnetic resonance imaging (MRI) scans displayed no new brain lesions. Antibodies to acetylcholine receptor and muscle-specific kinase were negative. Subsequent electrodiagnosis with repetitive nerve stimulation tests revealed unremarkable findings. A diagnosis of bulbar MG could only be established after fiberoptic endoscopic evaluation of swallowing (FEES) with simultaneous Tensilon application. After application of intravenous pyridostigmine, significant improvement in dysphagia and ptosis were observed both clinically and according to the FEES.

Surgical effect of dysphagia in patients with bulbar myasthenia gravis

To retrospectively analyze the clinical data of 42 patients at our department with bulbar myasthenia gravis. They underwent video-assisted thoracoscopic extended thymectomy (VATET) from May 2003 to August 2010. Another 42 patients treated with medications alone were selected as controls. Compared with the control group(4.32±0.23), postoperative dysphagia scores improved significantly in patients undergoing VATET(9.21±0.41). And so did the dysphagia assessment classification (P<0.05). Thus VATET could effectively and definitely relieve dysphagia in patients with bulbar myasthenia gravis. Key words: Myasthenia gravis; Deglutition disorders

Vocal cord dysfunction: A rare cause of stridor in children

Background: Vocal cord dysfunction (VCD) has been defined as adduction of the true vocal cords on inspiration with abduction on expiration. It is most common in females aged between 20 and 45 years. However, cases in children have been reported. Patients with vocal cord dysfunction present with distressing shortness of breath, inspiratory stridor and breathy dysphonia. VCD is most frequently diagnosed as asthma since the attacks in both begin and end suddenly and produce distressing breathing difficulties. Study design: Infants and children presented with respiratory distress secondary to vocal cord dysfunction were included in this study. Diagnosis of VCD depended mainly on direct laryngoscopy either using flexible laryngoscopy with topical anesthesia or direct laryngoscopy under general anesthesia with spontaneous respiration. The typical finding of adduction of the anterior two-third of the vocal cords during inspiration was the key point for diagnosis of VCD. Any further investigation was done according to the etiology of each case. Results: One infant and four children were included in this study. They were three boys and two girls. Their ages were 1, 12, 14, 10 and 2 years. The etiology of VCD was bulbar myasthenia gravis in one case, multiple system atrophy in one case, Laryngopharyngeal reflux in two cases, and post-nasal drip in one case. Diagnosis of VCD was done using pediatric flexible fibreoptic laryngoscopy with topical anesthesia in two cases and by direct laryngoscopy under general anesthesia with spontaneous respiration in three cases (in one of them the vocal cords were visualized during urgent intubation). Three cases were misdiagnosed as bronchial asthma and they were receiving treatment of asthma with no improvement. Conclusion: Vocal cord dysfunction represents a potentially overlooked differential diagnosis of recurrent dyspnea in children. It is always misdiagnosed as bronchial asthma. It should be suspected in every child with atypical or corticosteroid resistant asthma.

Autoimmune Channelopathies and Related Neurological Disorders

Ion channels are crucial elements in neuronal signaling and synaptic transmission, and defects in their function are known to underlie rare genetic disorders, including some forms of epilepsy. A second class of channelopathies, characterized by autoantibodies against ligand- and voltage-gated ion channels, cause a variety of defects in peripheral neuromuscular and ganglionic transmission. There is also emerging evidence for autoantibody-mediated mechanisms in subgroups of patients with central nervous system disorders, particularly those involving defects in cognition or sleep and often associated with epilepsy. In all autoimmune channelopathies, the relationship between autoantibody specificity and clinical phenotype is complex. But with this new information, autoimmune channelopathies are detected and treated with increasing success, and future research promises new insights into the mechanisms of dysfunction at neuronal synapses and the determinants of clinical phenotype.

Clinical Utility of Videofluorography with Concomitant Tensilon Administration in the Diagnosis of Bulbar Myasthenia Gravis

Myasthenia gravis (MG) classically presents with ocular, bulbar, and predominantly proximal muscle weakness. Isolated bulbar symptoms occur in less than 25% of cases and can mimic stroke (1-3). If left untreated, MG can lead to significant morbidity and mortality, including myasthenic crisis and recurrent aspiration pneumonia. We describe a case of a 68-year-old man who presented with isolated bulbar symptoms. We used a novel approach to diagnosis which included a videofluorographic swallow study with concomitant Tensilon (edrophonium) injection.

SEVERE GASTROINTESTINAL DYSMOTILITY SECONDARY TO PARANEOPLASTIC ANTIBODIES IN A PATIENT WITH A REMOTE HISTORY OF MALIGNANT THYMOMA

CASE: 65-year-old male with history of successfully treated malignant thymoma 8 years ago, presented with increasing dysphagia, vomiting, constipation and a 40 lb weight loss over a 3 year period. Other symptoms included disabling dysarthria, facial weakness, orthostatic dizziness, dry mouth, anhydrosis and erectile dysfunction. EGD showed retained solid food in the stomach. Esophagogram showed abnormal motility in the distal esophagus with absent primary peristaltic wave and tertiary contractions. Manometry showed abnormal esophageal body peristalsis. These findings were consistent with achalasia. Radionuclide study showed delayed gastric emptying and small bowel transit, with only 5% of the activity having left the small bowel at 6 hours. The patient had an impacted colon with no evidence of obstruction. EMG was consistent with bulbar myasthenia gravis. Paraneoplastic studies were positive for muscle Ach R binding, blocking, and modulating antibodies and high titers of striated muscle antibodies. CRMP-5 was also detected by western blot. We did not detect ganglionic Ach R antibodies or calcium channel antibodies. The panel was highly suggestive of recurrent thymoma, however, despite thorough investigation, a neoplasia was not identified. The patient was treated with pyridostigmine, IVIG And plasmapheresis with significant improvement of his symptoms. DISCUSSION: Gastrointestinal dysmotility is a manifestation of paraneoplastic dysautonomia. Various neoplasms have been implicated including thymoma and small cell lung carcinoma, and in fact this remains the main differential diagnosis. The association of myasthenia gravis and dysautonomia has been suggested previously in the literature. In a published case series of 7 patients with both these disorders 4/7 patients had thymoma. This case is of particular interest because a thymoma has not yet been identified despite the high likelihood of its presence due to the previous history. This could suggest that gastrointestinal dysautonomia could potentially be a very early presentation of thymoma. The extensive involvement of the esophagus with the presentation of severe dysphagia and achalasia is another unusual manifestation. As previously reported, paraneoplastic dysautonomia with GI dysmotility has been successfully managed with steroids, plasmapheresis and IVIG.

Repetitive nerve stimulation in myasthenia gravis—relative sensitivity of different muscles

Objective: To correlate repetitive nerve stimulation (RNS) decrement in different muscles with the predominant clinical presentation in myasthenia gravis (MG), and to study single fibre EMG (SFEMG) sensitivity in ocular MG. Methods: Sixty-nine, untreated, consecutive patients suspected for MG were observed prospectively for a minimum of 6 months. Those who improved on medical treatment were diagnosed as MG. The others, in whom the neurophysiological studies were normal and that did not improve on medical treatment served as a control group, from which normative data for RNS and SFEMG was obtained. The MG patients were further classified in 3 subgroups according to the predominant clinical presentation: group I (ocular); group b (bulbar); and group a (axial). We performed RNS in nasalis, trapezius, anconeus, and abductor digiti minimi. All patients with ocular MG underwent jitter determination of the orbicularis oculi muscle. Results: Thirty-seven patients were diagnosed as MG (group I, 15; group b, 13; group a, 9). In group I, RNS was abnormal in 33% of the patients. RNS studies disclosed at least one abnormal muscle response in every patient in groups a and b. Trapezius was significantly more sensitive in group a, and anconeus and nasalis in group b ( P<0.01). Jitter was abnormal in all patients in group I, and the most sensitive parameter was an increased number of unstable pairs, 100%. Conclusions: Based on these observations, we recommend that a shoulder muscle, as the trapezius, should be studied first in the limb-axial presentation of MG, and the anconeus–nasalis muscles in predominant bulbar MG. In ocular MG, RNS is not sensitive and jitter should be performed in facial muscles. Significance: This paper shows the unequal sensitivity of several muscles to RNS in different forms of MG.

Masticatory performance in patients with myasthenia gravis

Masticatory muscle electromyograms (EMGs) were recorded while patients with bulbar myasthenia gravis chewed artificial food and compared with those of patients with ocular myasthenia gravis, patients in clinical remission who had previously suffered from bulbar myasthenia gravis and healthy individuals. Masticatory performance and EMGs were significantly smaller in the bulbar group. There were no indications of subclinical masticatory muscle weakness in patients with bulbar myasthenia gravis in remission and in patients with ocular myasthenia gravis. Patients with bulbar myasthenia gravis barely compensated for muscular weakness by chewing at a higher percentage of their maximal EMG. These quantitative findings, when combined with subjective reports of masticatory muscle weakness, show that a need to support the jaw is characteristic of patients with bulbar myasthenia gravis who produce low EMG activity.

PS-50-3 Improved decremental responses in hemiplegic limbs of two patients with myasthenia gravis and cerebral infarction

Objective: To correlate repetitive nerve stimulation (RNS) decrement in different muscles with the predominant clinical presentation in myasthenia gravis (MG), and to study single fibre EMG (SFEMG) sensitivity in ocular MG.Methods: Sixty-nine, untreated, consecutive patients suspected for MG were observed prospectively for a minimum of 6 months. Those who improved on medical treatment were diagnosed as MG. The others, in whom the neurophysiological studies were normal and that did not improve on medical treatment served as a control group, from which normative data for RNS and SFEMG was obtained. The MG patients were further classified in 3 subgroups according to the predominant clinical presentation: group I (ocular); group b (bulbar); and group a (axial). We performed RNS in nasalis, trapezius, anconeus, and abductor digiti minimi. All patients with ocular MG underwent jitter determination of the orbicularis oculi muscle.Results: Thirty-seven patients were diagnosed as MG (group I, 15; group b, 13; group a, 9). In group I, RNS was abnormal in 33% of the patients. RNS studies disclosed at least one abnormal muscle response in every patient in groups a and b. Trapezius was significantly more sensitive in group a, and anconeus and nasalis in group b (P<0.01). Jitter was abnormal in all patients in group I, and the most sensitive parameter was an increased number of unstable pairs, 100%.Conclusions: Based on these observations, we recommend that a shoulder muscle, as the trapezius, should be studied first in the limb-axial presentation of MG, and the anconeus–nasalis muscles in predominant bulbar MG. In ocular MG, RNS is not sensitive and jitter should be performed in facial muscles.Significance: This paper shows the unequal sensitivity of several muscles to RNS in different forms of MG.

Immune activation in myasthenia gravis: Soluble interleukin-2 receptor, interferon-γ and tumor necrosis factor-α levels in patients' serum

Soluble interleukin-2 receptor (sIL-2R), interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) levels were evaluated in serum from patients affected by myasthenia gravis (MG). sIL-2R titers were significantly increased in generalized and bulbar MG patients while ocular cases were not different from controls. Patients showing a recent clinical worsening had significantly higher sIL-2R titers when compared to the whole MG population. sIL-2R levels did not correlate with the corresponding anti-acetylcholine receptor antibody titer (Anti-AChR Ab). IFN-γ was not detected in serum of both MG patients and healthy subjects while TNF-α levels were not statistically different from controls. The finding of increased sIL-2R levels supports the hypothesis of circulating activated autoreactive T cells in myasthenic patients.