Myasthenia gravis crisis coinciding with asthma exacerbation in a patient with recent heroin use: three causes of acute hypercarbic respiratory failure

Abstract

A 57-year-old woman with a history of asthma, hypertension and substance abuse disorder was admitted to the medical intensive care unit with hypercapnic respiratory failure. After the history was obtained, patient admitted heroin use earlier that day. The initial physical examination revealed right eye ptosis, diplopia, fatigability of neck flexion and extension. She also presented with wheezing and a prolonged expiratory phase. Pupils were 4 mm, with sluggish response to light bilaterally. CT chest with contrast showed a large mediastinal mass. Three different processes coexisted in this patient: simultaneous occurrence of a myasthenia gravis crisis, asthma exacerbation and a component of heroin use. This case highlights a series of overlapping clinical features that could lead to potential confounding and misdiagnosis. Respiratory symptoms improved after initial treatment for asthma exacerbation, but ptosis, diplopia and fatigability of neck muscles persisted.

Background

Myasthenia gravis (MG) is an autoimmune antibody-mediated disorder targeting the acetylcholine receptors (AChRs) on the postsynaptic neuromuscular membrane and reducing neuromuscular transmission. Incidence is approximately 0.3 to 2.8 per 100 000, and it is estimated to affect more than 700 000 people worldwide.¹ Another series indicates a prevalence of 131–145 cases per million.² Initial symptomatology can vary from as mild as ocular fatigability and ptosis to as severe as respiratory failure.

Myasthenia crisis is defined as a life-threatening and rapidly worsening respiratory status from airway compromise that may necessitate non-invasive ventilation or endotracheal intubation.^{3 4} It is important for physicians to not only treat the potential life-threatening symptomatology of MG but also keep a wide differential diagnosis for patients who initially present with muscle weakness, ptosis and respiratory distress. We believe our case has a teaching value given that the history, physical and initial diagnostic work-up provided information to support three different clinical syndromes with overlapping clinical features. A comprehensive history and physical, considering a broad differential diagnosis that includes neuromuscular diseases, would lead to the correct diagnosis and an appropriate treatment in these cases.

Case presentation

A 57-year-old woman with a history of asthma, hypertension and daily heroin use presented to the emergency department (ED) complaining of neck pain, weakness, fatigue, increased work of breathing, diplopia and neck flexion weakness of 1 week duration. During the initial interview, she endorsed neck weakness that made it difficult to keep her head upright. The patient admitted heroin use on the day of presentation. On physical examination, she was awake, alert and answering questions appropriately. Vital signs were blood pressure of 169/112 mm Hg, heart rate of 88 beats/min, respiratory rate of 22 breaths/min, a saturation of 96% on room air and a temperature of 36.7 °C. Neurological examination revealed bilateral ptosis, diplopia, 2/5 strength on neck flexion and extension with fatigability. Pupils were 4 mm, with sluggish response to light bilaterally. No other focal deficits were appreciated. Lung examination was significant for wheezing, accessory muscle use and a prolonged expiratory phase.

The ptosis and diplopia during the neurological examination, in association with patient’s complaint of neck pain, prompted a CT angiography of her chest, head and neck to rule out of carotid dissection. After imaging with contrast, the patient became restless with increasing shortness of breath and worsening wheezing on auscultation. Oxygen saturation decreased to 76% on room air, and she was briefly placed on nasal cannula oxygen supplementation at 3 L/min. Arterial blood gases showed hypercapnic respiratory failure with a pH of 7.27, partial pressure of carbon dioxideof 65 mm Hg, bicarbonate of 30 mmol/L and partial pressure of oxygen of 90 mm Hg, and she was upgraded to bilevel positive pressure ventilation (BiPAP) to treat hypercapnia. CT chest showed a large mediastinal mass and did not reveal an arterial dissection. Patient had been exposed to intravenous (iv) contrast several times in the past; consequently, a contrast-induced allergic reaction was not believed to be the cause of her worsening respiratory status. Critical care team was consulted, and despite having indications for elective endotracheal intubation, patient declined. She was admitted to the medical intensive care unit (MICU) to monitor her respiratory status.

Investigations

A CT chest with contrast revealed a large heterogeneous, lobulated anterior mediastinal mass measuring 4.5×8.3 cm (figure 1). Medical records obtained from an outside hospital included a CT chest from 2 years prior showing a 3.6×7.4×5.6 cm anterior mediastinal mass and a mediastinal biopsy revealing a thymoma. Pathology from this prior biopsy showed large necrotic foci and scattered epithelial strands in the thymus. The patient was lost to follow-up at that time. Reasons that motivated initial CT chest at outside hospital were unclear. Urine drug screen was positive for opiates. Transthoracic echocardiogram showed a left ventricular outflow tract obstruction with >126 mm Hg consistent with hypertrophic obstructive cardiomyopathy (HOCM).

Figure 1.

CT with contrast of the chest revealing a mediastinal mass. A large heterogeneous, lobulated anterior mediastinal mass measuring 4.5×8.3 cm is seen in the anterior mediastinum.

She was evaluated by cardiology, and HOCM was not considered a contributor of her acute respiratory failure, especially after significant improvement with only steroids and bronchodilators. Antiacetylcholine antibodies were positive. Antimuscle-specific kinase antibody testing was also performed⁵ in anticipation of possible negative testing for anti-AChR antibodies. CT-guided biopsy samples were sent to pathology for immunostaining. This demonstrated an epithelial tumour considered to be a thymic carcinoma with extensive positivity for cytokeratin AE1/3, p63, CK7, CD45 and scattered but strong positivity for CD5.

Differential diagnosis

This 57-year-old woman with a history of hypertension, asthma and recent heroin use presenting with diplopia, ptosis, neck weakness, shortness of breath and hypercarbia raises concern for at least three different diagnoses. We found the differential diagnosis to be of great relevance given that the management of the top three aetiologies significantly differs from each other. The importance of an early diagnosis of MG rises when other comorbidities (ie, infectious, cardiac) require the use of medications that can worsen MG. Antibiotics, such as fluoroquinolones and macrolides, beta blockers, antiretrovirals, magnesium and anaesthetic agents, can unmask MG and, in some cases, trigger MG crisis.

The diagnosis of MG in this case is supported by the neurological findings, history of worsening fatigue with activity, and the mediastinal mass that showed to be a thymic carcinoma. Asthma exacerbation was supported by wheezing and prolonged expiratory phase on examination that rapidly improved with steroids, bronchodilators and BiPAP.

We do not consider the administration of iv contrast as a trigger of asthma in this case given that wheezing and accessory muscle use were noted before iv contrast was administered. Nevertheless, iodinated contrast agents have been shown to unmask MG and that might be a contributing factor for the respiratory failure seen in this patient.

Despite recent heroin use and positive urine drug screen for opiates, we consider heroin overdose an unlikely contributor to the hypercapnic respiratory failure. Patient was not bradypneic (respiratory rate of 22 breaths/min), and pupils were not significantly dilated. Patient was awake and alert in the initial encounter.

Treatment

In the ED, the patient was placed on BiPAP with a fractional inspired oxygen of 60%, inspiratory pressure of 12 and expiratory pressure of 5 cm H₂O. Iv steroids and inhaled short-acting bronchodilators were administered. After consultation with critical care team, she was admitted to the MICU. After 12 hours in the MICU, physical examination revealed resolution of her wheezing and improvement of her respiratory status. Her best negative inspiratory force (NiF) was −28 cm H₂O, and her vital capacity (VC) was 0.6 L. Despite this improvement, bilateral ptosis, diplopia and neck weakness persisted. On further questioning, patient had long-standing (approximately 2 years) history of weakness with activities and fatigability that was worse at the end of the day.

Her respiratory symptoms greatly improved with non-invasive ventilation. Patient received iv solumedrol 40 mg every 6 hours for 4 days and rapidly improved in a matter of hours. IvIg and plasma exchange were therefore not considered.

Outcome and follow-up

By the fourth hospital day, the patient was medically cleared for discharge. Follow-up with oncology, cardiology, neurology and cardiothoracic surgery was arranged. Discharge planning included future thymectomy of her mediastinal mass. Given that the disease was locally invasive, the suggested treatments were radiation versus chemotherapy to reduce the size of the mass with eventual thoracotomy and thymectomy by cardiothoracic surgery.

Discussion

Our patient presented with an interesting combination of symptoms, physical examination findings, laboratory abnormalities and imaging. The coexistence of muscle weakness (characteristic of MG), asthma exacerbation and recent heroin use with hypercapnia makes this case interesting to analyse. It is of paramount importance to identify the cause of respiratory failure in order avoid the inappropriate use of oxygen supplementation in cases of hypercapnic respiratory failure. The role of illicit drug use as a trigger for myasthenia crisis is also an important consideration in our case.

Similar case reports have been published of patients with substance abuse and MG presenting with hypercapnic respiratory failure. Berciano et al⁶ described a case of MG crisis unmasked by cocaine abuse. Wild et al⁷ also described a case of symmetric ptosis initially misinterpreted as an adverse effect of illegal drugs use that resulted to be MG crisis. Similarly, Pujar and Spinello⁸ reported a case of MG crisis in a patient found down at home with a respiratory rate of 10 respirations/min presenting with hypercapnic respiratory failure after heroin use.

While the degree of individual contribution of asthma and MG crisis in our case is difficult to determine, it was clear that MG crisis was playing a preponderant role. In the contrary and based on clinical findings, we think heroin use had very small or any role explaining this patient’s symptoms.

The definition of myasthenia crisis⁴ as a life-threatening condition, characterised by weakness severe enough to necessitate intubation, non-invasive ventilation or to delay extubation following surgery, was certainly met by our patient. Elective intubation should be considered if serial measurements demonstrate that NIF is less negative than −25 to −30 cm H₂O, or VC falls below 15 to 20 mL/kg. Progressive hypercapnic respiratory acidosis despite therapy, inadequate secretion clearance or clear impending respiratory failure are also indications for intubation.^{9 10}

Our patient declined elective intubation but agreed with BiPAP. She also declined electromyography studies to confirm MG. However, anti-AChR was positive, and her symptoms improved with pyridostigmine and steroids. Non-steroidal immunosuppressant (azathioprine, cyclosporine, mycophenolate mofetil, methotrexate and tacrolimus) therapy was considered unnecessary given her adequate response to steroids.¹⁰ After the biopsy revealed a thymic carcinoma, further management usually depends on invasiveness and eligibility for surgery. Even in patients without thymoma, thymectomy is often performed to minimise the dose and duration of immunotherapy or in those intolerant to usual medical treatment.

In general terms, and except for very rare occasions when surgical risks outweigh the benefits, all patients with thymoma should undergo surgical removal. In our case, CT chest with contrast showed a large mass with signs of local invasion to the pericardium, which made the lesion unresectable. This macroscopic characteristic pointed towards a malignant neoplasm rather than a thymoma. A core needle biopsy demonstrated an epithelial tumour compatible with thymic carcinoma that was extensively positive for cytokeratin AE1/3, p63, CK7, CD45 and scattered but strong positivity for CD5. All patients with thymic carcinoma with locally advanced disease should be managed by a multidisciplinary team with experience in the management of this malignancy.

Thymic carcinomas are rare aggressive tumours with a mean 5-year survival rate of 30%–50%. Theses tumours often metastasize to regional and distant lymph nodes.^11–14 Surgical resection is the cornerstone of therapy for thymoma. However, when it coexists with MG, this approach depends on symptom resolution after medical therapy, eligibility for surgery and degree of tumour invasion. For patients like ours with locally invasive disease, chemotherapy prior to re-evaluation for possible tumour resection is necessary. If resectable, patients should undergo surgery with resection of the isolated metastasis and should be considered for subsequent radiation therapy.

For patients whose tumour is still unresectable after first-line chemotherapy, radiotherapy and chemotherapy are recommended.¹⁵ Unfortunately, the recurrence of an invasive thymoma is common. When the thymoma has already invaded into nearby structures, such as the pericardium, pleura and pulmonary vascular structures, radical excision as a definitive treatment with resolution of symptoms is unlikely. In our patient, a team consisting of thoracic surgery, oncology, radiology and neurology was established to collaborate and discuss management to ensure an optimal patient outcome.

Learning points.

• Neuromuscular disease must be considered in every patient presenting with respiratory failure.

• While more common explanations, such as asthma exacerbation and opioid use, are more likely, we must never forget to consider neuromuscular diseases in the differential diagnosis.

• High clinical suspicion of neuromuscular disease and early consultation of critical care in anticipation of worsening respiratory failure are vital.

• Patient in myasthenic crisis must be monitored for impending respiratory compromise, especially those with underlying respiratory disease.