Respiratory failure as first presentation of myasthenia gravis: a case report

Abstract

Myasthenia gravis (MG) is often complicated by respiratory failure, an exacerbation known as myasthenic crisis. However, most patients with MG develop respiratory symptoms during the late course of the disease. Respiratory failure as an exclusive initial and primary complaint in patients with MG is rare and seldom reported. We herein describe a woman in her late 50s who presented with respiratory failure and was diagnosed with obesity hypoventilation syndrome at a local hospital. Her condition gradually worsened during the next 4 months and became accompanied by dysphagia. After 1 year of medical investigation, she was diagnosed in our hospital. A high level of anti-muscle-specific receptor tyrosine kinase antibody was found in her serum, and stimulation and electromyography results suggested MG. The patient’s symptoms were improved by intravenous immunoglobulin and hormone therapy. This case reminds physicians to consider MG when encountering a patient who initially presents with respiratory failure.

Introduction

Myasthenia gravis (MG) is a postsynaptic neuromuscular junction disease caused by the production of antibodies against components of the postsynaptic membrane. The most common form of MG involves antibodies against postsynaptic extracellular portions of the nicotinic acetylcholine receptor (AChR). Approximately 10% to 15% of patients with MG are seronegative for AChR antibody. Among these patients, approximately 40% are positive for anti-muscle-specific receptor tyrosine kinase (MuSK) antibodies, representing 5% to 8% of the total MG population. ¹ MuSK-MG is usually characterized by acute onset, and it mainly affects the facial and bulbar muscles. Respiratory failure as the first or only symptom is rare and readily leads to misdiagnosis. We herein present a case involving a patient with anti-MuSK antibody-positive MG who developed respiratory failure at onset.

Case report

A timeline of the main events in this case is shown in Figure 1. A woman in her late 50s visited our neurological outpatient clinic because of a >1-year history of dyspnea and a 9-month history of dysphagia. The patient had developed dyspnea, wheezing, impaired consciousness, and failure to exhale >1 year previously with no apparent trigger. She was diagnosed with type 2 respiratory failure and respiratory acidosis and received an unknown treatment regimen. She was then released from the hospital and required noninvasive ventilator-assisted breathing at night. One month later, her respiratory condition deteriorated and she returned to the hospital. Her arterial blood gas analysis with the ventilator showed the following results: pH, 7.3; partial pressure of oxygen, 84.38 mmHg; partial pressure of carbon dioxide, 85.70 mmHg; and lactic acid, <1.0 mmol/L. Chest computed tomography (CT) suggested right-sided diaphragmatic elevation and compressed opacification of the middle and lower lobes of the right lung (Figure 2(a)). Lung function tests showed the following: forced expiratory volume in 1 second/forced vital capacity (FVC) (post-inhaled bronchodilator), 84.3%; FVC, 43.3% of predicted; forced expiratory flow at 25% of FVC (FEF25), 41.8% of predicted; FEF50, 22.0% of predicted; FEF75, 20.8% of predicted; severe restrictive ventilatory dysfunction; and small airway dysfunction. These results combined with her body mass index of 32.46 kg/m² led to a diagnosis of obesity hypoventilation syndrome (also termed Pickwickian syndrome), and the patient was discharged from the hospital after being given phlegm-reducing therapy, airway dilatation, and anti-infective treatment. She also still required noninvasive ventilator-assisted breathing at night. However, she required no respiratory assistance in the sitting and standing positions. Four months later, the patient developed dysphagia after exercise and had difficulty eating solid food. Six months later, her dysphagia worsened and she could only eat liquid foods. After 1 year, the patient’s symptoms further worsened; she struggled to breathe despite ventilator assistance, and she could not eat any food. Therefore, she visited our hospital and underwent gastric tube placement. The patient also had a >2-year history of nephrotic syndrome.

Figure 1.

Timeline of main events described in the text.

Figure 2.

Patient’s test results. (a) Chest computed tomography suggested right-sided diaphragmatic elevation (red arrow) and compressed opacification of the middle and lower lobes of the right lung (blue arrow) in August 2022. (b) Chest computed tomography suggested that the diaphragm (red arrow) and lobes (blue arrow) were normal in July 2023 and (c) Decreasing amplitude of low-frequency electrical stimulation in right trapezius muscle.

On admission, her temperature was 36.5°C, heart rate was 71 beats per minute, respiratory rate was 16 breaths per minute, and blood pressure was 140/90 mmHg. She was breathing with a noninvasive ventilator, her speech was unclear, and she had inflexibility in both eyes looking upward, left, and right. Physical examination also revealed weakened bilateral eyelid closure, grade 3 muscle strength in her arms, grade 5 muscle strength in her legs, an unstable bilateral finger-nose test result, negative Babinski sign, and bilateral Chaddock reflex. Laboratory tests (routine blood testing, coagulation series, thyroid function, tumor markers, liver and kidney function, and electrolytes) revealed no significant abnormalities. Antinuclear antibody was positive at 1:100. Arterial blood gas analysis with the ventilator showed a lactic acid concentration of <2.59 mmol/L. Neuromyography revealed neurogenic injury and abnormal repetitive nerve stimulation of the right trapezius muscle, suggesting a postsynaptic membrane lesion of the neuromuscular junction (Figure 2(c)). Ancillary examinations (chest CT, cranial plain magnetic resonance imaging, and susceptibility-weighted imaging) revealed no findings of clinical significance (Figure 2(b)). Serum tests showed the following results: anti-MuSK antibody, 1.175 (reference range, <0.05); anti-AChR antibody, negative; paraneoplastic 14 antibody test, negative. The patient was hospitalized for treatment with pyridostigmine bromide (60 mg three times daily, ongoing). She developed adverse effects including diarrhea, flushing, and sweating during treatment with this medication, and her symptoms did not improve. Five days after admission, she was treated with intravenous immunoglobulin (IVIg) therapy (25 g once daily for 5 days). Six days after admission, she was given intravenous methylprednisolone sodium succinate (80 mg once daily for 5 days), which was then switched to oral methylprednisolone tablets (60 mg once daily, ongoing). On day 13 after the IVIg therapy and day 12 of hormone therapy, the patient’s dyspnea improved. She was able to breathe without the ventilator for >4 hours in the sitting and standing positions, and sputum expectoration was significantly more effective. However, she still had trouble swallowing. The patient was discharged from the hospital. After discharge, she continued to regularly take pyridostigmine bromide at 60 mg three times daily and methylprednisolone at 60 mg once daily. On day 23 after administration of IVIg and day 22 of hormone therapy, the dyspnea significantly improved and the patient was able to remove the ventilator for 10 to 12 hours during the day. On day 27 after administration of IVIg and day 26 of hormone therapy, the gastric tube was removed and the patient was able to eat soft food. Serum tests at this time showed an anti-MuSK antibody level of 1.004 nmol/L (reference range, <0.05). The need for plasmapheresis was explained to the patient; however, she declined this therapy. A timeline of the patient’s medical treatment is shown in Figure 3.

Figure 3.

Timeline of medical treatments. IVIg, intravenous immunoglobulin.

The reporting of this study conforms to the CARE guidelines. ²

Discussion

MG is an autoimmune disease caused by the presence of specific antibodies targeting different postsynaptic components of the neuromuscular junction, and it is most prevalent in patients aged 30 to 50 years. ³ Approximately 5% of patients with MG have autoantibodies against MuSK. These autoantibodies are predominantly of the IgG4 subclass. ⁴ In vitro studies have shown that MuSK IgG4 autoantibodies block the interaction between MuSK and low-density lipoprotein receptor-related protein 4, ⁵ thereby preventing AChR clustering; this explains the impaired neuromuscular transmission in patients with MG. ⁶ MuSK-MG differs from AChR-MG in that the former is characterized by more focal muscle involvement, including neck, shoulder, facial, and bulbar-innervated muscles, as well as wasting of the involved muscles. Apart from this, Ricciardi et al. ⁷ reported a case of a patient with MuSK antibody-positive MG who presented with a 2-year history of diplopia, and orbital nuclear magnetic imaging showed bilateral extraocular muscle atrophy. Santilli and Stitt ⁸ reported a case of MuSK antibody-positive MG with dysphonia and exertional dyspnea as the main manifestations. Cases of MG in which the first manifestation is acute respiratory failure have rarely been reported, and most such cases have occurred in MuSK antibody-positive patients. ⁹ Previously published cases of MG with a respiratory problem as the first symptom are listed in Table 1.

Table 1.

Previously published cases of MG with respiratory problem as the first symptom.

Reference	Country	Sex/age (years)	First symptom	Lung examination findings	Misdiagnosis	MG-related Abs
Vaidya (2006) 10	USA	Female/21	Acute respiratory failure	Normal	Pulmonary embolism	–
Wang and Zhao (2023) 11	China	Female/48	Dyspnea	Bibasilar inflammation	Bronchial asthma	Anti-MUSK Abs(+)
Tsai et al. (2021) 12	USA	Female/40	Progressive dyspnea	–	Respiratory failure	Anti-MUSK Abs(+)
Li and Pu (2017) 13	China	Female/71	Dyspnea	Striated dense shadows in bibasilar region	Pneumonia respiratory failure	–
Ali et al. (2021) 14	USA	Female/49	Progressive dyspnea	Normal	–	Anti-MUSK Abs(+)
Scopelliti et al. (2020) 15	Italy	Female/46	Progressive dyspnea	Mild interstitial pneumoniaModest bibasilar infiltrates	COVID-19	Anti-AChR Abs(−)Anti-MUSK Abs(−)
Kim et al. (2010) 16	Korea	Female/68	Dyspnea	Bibasilar atelectasis	–	Anti-AChR Abs(+)
Dushay et al. (1990) 17	USA	Male/64	Dyspnea on exertion	–	Obesity hypoventilation syndrome	–
Lee et al. (2015) 18	Korea	Male/77	Respiratory failure	Thymoma	–	–
Payus et al. (2021) 19	Malaysia	Male/43	Respiratory failure	Consolidation over the right lower zone	Severe community-acquired pneumoniaRespiratory failure	Anti-AChR Abs(+)
Sharma et al. (2012) 20	India	Female/22	Dyspnea	Reduced lung volume	–	Anti-AChR Abs(+)

MG, myasthenia gravis; Abs, antibodies; MuSK, muscle-specific receptor tyrosine kinase; AChR, acetylcholine receptor.

The first-line medication for MG is IVIg therapy, which is highly effective at 3 to 10 days following commencement. However, studies have shown that the effect of IVIg in MuSK-MG treatment varies widely, with only 11% to 61% of patients having a favorable outcome, ²¹ and that it is less effective than plasma exchange. IVIg is not the first choice in patients with severe MG or MuSK-MG. ²² In the present case, however, we treated the patient with IVIg therapy because the patient could not afford the high cost of plasma exchange. Unexpectedly, the IVIg therapy was very effective. Many nonsteroidal immunosuppressive therapies, such as azathioprine, cyclosporine, methotrexate, thimerosal, and tacrolimus, have also been extensively studied in the treatment of AChR-MG and have been shown to be poorly effective, with low rates of disease remission and high rates of therapy dependence. ²³ Plasmapheresis is an effective treatment in which the patient’s plasma is removed and replaced with healthy plasma. Five treatments are usually given over a period of 1 to 2 weeks. Plasmapheresis is used primarily as salvage therapy in MG. In addition, rituximab has shown promising therapeutic results in patients with MuSK antibody-positive MG, with a significant reduction in antibody titers after treatment. ²⁴ Rituximab increases the probability of a favorable outcome. ²⁵ Overall, the treatment of MuSK-positive MG is currently less effective than classical treatments (e.g., IVIg therapy), and the need for prolonged and high-dose steroids make it difficult to gradually reduce antibody titers and control symptoms. However, plasma exchange and rituximab have more significant clinical effects. ²⁶

Our patient initially developed type 2 respiratory failure, and her lung function indices suggested restrictive ventilation disorder. Chest CT did not indicate pulmonary fibrosis, pneumonia, or lung space occupation. These findings combined with her body mass index of 32.46 kg/m² and carbon dioxide storage in the waking state led to the diagnosis of obesity hypoventilation syndrome, which persisted for 1 year without improvement. This case was misdiagnosed because of failure to check for neuromuscular junction disease, which led to a worsening of the patient’s symptoms during her weight loss exercises. According to the International Consensus Guidance for Management of Myasthenia Gravis 2020, ²⁷ immunoglobulin typically takes 5 to 10 days to take effect; however, our patient’s symptoms improved slightly on day 13 after administration of immunoglobulin and on day 12 of hormone therapy and then improved significantly on day 23 after administration of immunoglobulin and on day 22 of hormone therapy. Her antibody titers remained high approximately 1 month after treatment, reflecting the unsatisfactory effect of immunoglobulin and hormone therapy.

Neurologic diseases such as amyotrophic lateral sclerosis (ALS) and Guillain–Barré syndrome (GBS) should also be considered when respiratory failure occurs. Chapagain et al. ²⁸ reported a case involving a 58-year-old man who presented with limping in the left leg and left foot weakness; this was followed by right upper limb weakness, shortness of breath, and wide fluctuations in blood pressure. He required intensive care unit admission and was diagnosed with ALS with dysautonomia and respiratory failure. Cases of ALS with respiratory failure as the first symptom are rarely reported. Kishore et al. ²⁹ reported a case of GBS in a 5-month-old girl. The child presented with cough, loose stools, breathing difficulty, and listlessness, and she was treated for pneumonia with respiratory failure. A nerve conduction velocity study and cerebrospinal fluid study suggested GBS. Additionally, various neuromuscular disorders such as metabolic myopathies, linear myopathies, inflammatory myopathies, and myotonic dystrophies can lead to respiratory muscle weakness and respiratory failure, ³⁰ necessitating differential diagnosis.

In conclusion, respiratory failure is not only seen in the end-stage crisis period of MG but may be the first and only symptom of MG. Physicians should always consider neurological diseases when dyspnea cannot be explained by cardiac or respiratory causes. It is important to perform neostigmine tests and electromyography as soon as possible to exclude or diagnose MG and avoid misdiagnosis.

Data availability statement

All data included in this study are available upon request from the corresponding author.

Research ethics and patient consent

Our institution does not require ethics approval for case reports. Written informed consent for treatment and publication of this case report were obtained from the patient; a scanned copy of the patient’s informed consent agreement is available on request.