Keywords

FormalPara Learning Objectives

  • Diagnosis and differential diagnosis of myasthenia gravis

  • Approach to acute respiratory failure in the myasthenic patient

  • Anesthetic procedure specificities for the patient with myasthenia gravis

  • Treatment of a myasthenic crisis

1 Introduction

Myasthenia gravis (MG) is an autoimmune disorder characterized by fatigable skeletal muscle weakness resulting from an antibody-mediated T cell-dependent immunologic attack directed at acetylcholine receptors in the postsynaptic membrane of the neuromuscular junction. The hallmark of MG is a fluctuating degree and variable combination of weakness in the ocular, bulbar, limb, and respiratory muscles. Clinical presentation may be in two forms: ocular and generalized. The symptoms are often transient in an early phase, and new symptoms often develop weeks or months later. The diagnosis is usually established with clinical history and typical examination findings. Preferably, the diagnosis should be confirmed by immunologic and/or electrophysiologic testing.

A myasthenic crisis is a life-threatening exacerbation of MG, compromising respiratory muscles, and severe enough to necessitate intubation. Common precipitating factors include respiratory infections, aspiration, sepsis, surgical procedures, rapid tapering of immune modulation, beginning treatment with corticosteroids, exposure to drugs that may increase myasthenic weakness, and pregnancy [1]. A myasthenic crisis is an indication for admission to the intensive care unit (ICU) and to rapidly initiate treatment with intravenous application of immunoglobulin or even plasma exchange to avoid fatal complications.

Case Presentation

We present the case of a 69-year-old man with a clinical frailty score of 3, with a past medical history of hypertension, dyslipidaemia, and obesity. No relevant epidemiological context or past family history was found.

The patient was presented to the neurology outpatient clinic to assess a 2-month history of new-onset strabismus that fluctuated during the daytime and became more notorious in the late afternoon, accompanied by diplopia and right-side ptosis. A clinical diagnosis of MG was established. Symptoms evolved rapidly within 2 weeks, followed by severe asthenia, cachexia, chewing difficulties, and dysphagia.

The patient was reassessed at the neurology outpatient clinic and was prescribed 60 mg of pyridostigmine four times daily. A slightly favorable clinical evolution was noticed in the first week of treatment. However, after the second week of treatment, the patient evolved with notable upper limb weakness and difficulty walking. The therapy with 40 mg of prednisolone and immunoglobulin 0.4 mg/kg daily was started. Still, his symptoms continued to exacerbate with worsening asthenia, severe dyspnoea at rest, and inability to complete sentences, which brought him to the emergency department.

Neurological examination at admission revealed preserved superior neurological functions with no field deficits. A right eye in abduction with bilateral eyelid ptosis (more notorious on the right) improved with ice application. The nauseous reflex was preserved. A centred uvula was observed with good palate elevation and tongue protrusion in the midline. Neck flexion deficit and proximal limb deficit aggravated with fatigability.

Although peripheral oxygen saturation was >94%, the patient presented with evident respiratory distress with accessory muscle use. The cardiopulmonary auscultation was normal. No stridor was present.

2 Investigations

The initial arterial blood gas panel revealed an acute hypercapnic respiratory failure with pH 7.43, pCO2 46 mmHg, pO2 64 mmHg, HCO3− 30.5 mmol/L, and SaO2 94%. Initial laboratory tests showed no leukocytosis with a negative C-reactive protein; hemoglobin, platelet count, and renal and hepatic panels were within normal range. Urine and blood cultures were negative.

The chest computed tomography (CT) scan excluded a thymic expansion and revealed two subpleural nodules (approximately 6.8 mm) and radiological signs suggestive of fibrosis and bilateral emphysema.

Autoantibodies against the acetylcholine receptor (AChR-Ab) and a receptor-associated protein, muscle-specific tyrosine kinase (MuSK-Ab), were requested at admission to confirm the presence of MG. AChR-Ab was elevated >9.0 nmol/L (R: >0.50 positive), confirming a seropositive MG. MuSK-Ab were negative 0.01 nmol/L (R: >0.05 positive).

Thyroid function was assessed with peripheral hormones within range. Antithyroglobulin antibodies were negative 36 UI/mL (R: <40 negative), and antithyroid peroxidase was also negative 14 UI/mL (R: <25 negative). Since serum vitamin B12 level was low at 152 pg/mL (N: 191–663), with no apparent malabsorption stigma nor dietary restrictions, anti-parietal cell antibodies were requested. A positive result of 79.39 U/ml (R: <25 negative) was observed, with the absence of anti-intrinsic factor antibodies 0.8 U/mL (R: <10 negative).

Autoimmune rheumatic disorders are more common in patients with MG compared to age- and sex-matched patients without MG. Recommendations are that antinuclear antibody and rheumatoid factor should be performed if there is a clinical suspicion of a rheumatologic disorder. Our patient had referred to some morning rigidity in the past with unspecified joint pain but with no edema. Antinuclear antibodies, antineutrophil cytoplasmic antibodies, rheumatoid factor, and anti-CCP were negative.

3 Differential Diagnosis

We did not find an apparent precipitating factor for the myasthenic crisis. There were no signs of infection, acute-phase reactants were negative, there is no recent suspicious epidemiological contact, and the chest X-ray was unremarkable. The patient denied recent use of drugs that could increase myasthenia’s weakness. Therefore, the myasthenic crisis was assumed in the context of a natural evolution of the disease.

This patient presented with a typical course of MG, with a cephalocaudal trend, then evolving into a myasthenic crisis presentation. Other common causes of acute neuromuscular respiratory failure include Guillain-Barré syndrome and amyotrophic lateral sclerosis. Since the patient recently started pyridostigmine, it is essential to recall the possibility of a cholinergic crisis. However, a cholinergic crisis is rarely seen with the dose limitation of pyridostigmine to less than 120 mg every 3 h [2]; therefore, this diagnosis was not presumed as the cause of increasing weakness.

Due to the deficiency of vitamin B12 not associated with anemia, we suspected a type 3 polyglandular syndrome and requested an autoimmune study. Although anti-parietal cell antibodies were positive, with a confirmed MG, autoimmune thyroid disease was not confirmed.

The myasthenic crisis is associated with an in-hospital mortality rate of 5–12% [1, 3]. The most common causes of death are multi-organ failure due to sepsis and respiratory failure despite maximal care.

4 Treatment

Literature was consulted at ICU admission to review drugs to avoid myasthenia exacerbation (e.g., beta-blockers, magnesium, aminoglycosides, and fluoroquinolones).

The prednisolone dose was increased to 1 mg/kg/day, and the patient continued pyridostigmine 60 mg four times a day and completed the intravenous immune globulin (IVIG) scheme with 0.4 g/kg. Due to increased respiratory distress and aggravating respiratory alkalosis (blood gas analysis evolution from pH 7.41, pCO2 46 mmHg, pO2 64 mmHg, HCO3− 30.5 mmol/L, and lactate 0.7 mmol/L to pH 7.49, pCO2 15 mmHg, pO2 126 mmHg, HCO3− 25.7 mmol/L, and lactate 1,9 mmol/L), with poor response to noninvasive ventilation (NIV), we decided to perform awake orotracheal intubation with rapid sequence induction, using propofol and remifentanil. Low-dose rocuronium was necessary for muscle relaxation for intubation, knowing we could have an immediate reversal with sugammadex available if required. The strategy for this patient was to maintain the lowest effective dosage for an “awake ICU” strategy for a Richmond Agitation-Sedation target of 0 to −1.

Given the condition of respiratory difficulty in progression, requiring invasive ventilation, and the expected late response to treatment with immunoglobulin, we decided to start plasma exchange.

Our treatment approach was thoroughly discussed with the neurology and nephrology department. In total, the patient was submitted to seven therapeutic plasma exchanges over 14 days, initially on alternative days, followed by every other day. Fluid albumin replacement was done accordingly.

5 Evolution, Outcome, and Follow-Up

The patient had an excellent response to the plasma exchange. A physical rehabilitation protocol was tailored and initiated on the first day of the ICU stay. Weaning of invasive medical ventilation started early, and the patient was extubated 48 hours later. After extubation, NIV in bi-level positive airway pressure mode was started. The patient tolerated the NIV with no post-extubation respiratory failure, and we decided to intercalate with high-flow nasal cannula for patient comfort.

A nasal pharyngoscopy was performed 24 h after extubation to evaluate the safety of initiating an oral diet. Due to slight edema of the arytenoids, with reduced glottic lumen due to hypomobility of the vocal cords, we maintained the nasogastric tube (initially introduced at admission due to the severe dysphagia) for a few more days until further resolution of the myasthenic crisis.

The rehabilitation specialists also played a crucial part in the patient’s recovery with early respiratory physiotherapy, using a mechanical in-exsufflation device to guarantee bronchial airway hygiene with secretion mobilization. The speech therapist also addressed the patient.

Once the cycles of plasma exchange were completed, with the stabilization of the patient, he was transferred to the neurology department ward, and rituximab therapy was started. An otolaryngologist again evaluated him with the guarantee of a safe airway to initiate an oral diet. The patient was discharged 15 days after hospital admission, with a normal neurological examination, walking on his own feet with no support and no asthenia.

The most common complications associated with the myasthenic crisis are various causes of fever and infection. Our patient had a nosocomial urinary tract infection during the ICU stay with a penicillin-susceptible strain of Enterococcus faecalis isolated in a urine culture. He completed a 7-day course of ampicillin according to the antibiogram.

Follow-up was initially done in the neurology day hospital, with a favorable evolution. He continued to work with rehabilitation specialists for respiratory rehabilitation and general physiotherapy for muscle strengthening.

The patient was referred to a pulmonology consultation for a follow-up of the two subpleural nodules found on the initial CT scan for radiological follow-up.

6 Discussion

We describe a clinical case of a patient with a myasthenic crisis with respiratory failure—a clear indication for admission to an ICU. In a myasthenic crisis, the initial use of NIV to avoid intubation must be individualized [3]. However, it should not delay invasive mechanical ventilation, with a low threshold for elective intubation. In the post-extubation period, poor cough strength is associated with significant in-hospital morbidity in these patients. Respiratory physiotherapy is essential, and there may be benefits to using NIV in this period to prevent extubation failure [3].

Plasma exchange and IVIG are the recommended rescue therapy for myasthenic crisis as they have a rapid onset, usually over days, and can be used as bridge therapy [4]. We decided on plasma exchange, as the expert consensus suggests that plasma exchange is more effective and works more quickly [4]. IVIG was continued as he had begun treatment with IVIG recently. We decided to begin glucocorticoid to provide a more extended benefit period, and rituximab was started before the patient’s discharge as immunomodulatory therapy for refractory generalized MG.

The anesthesia management in patients with MG is complex. Generally, ultrashort- or short-acting anesthetic agents are preferred, and neuromuscular blocking agents (NMBA) should be avoided. In anesthesia induction, propofol is most used due to its short duration and rapid onset. It can be used in combination, preferably with remifentanil, since it is an ultrashort-acting opioid. If necessary, nondepolarizing NMBA can be used, such as rocuronium or vecuronium, as patients with MG are resistant to depolarizing NMBAs. Patients with MG are highly sensitive to low doses of nondepolarizing NMBAs, and their use is not advised if sugammadex is unavailable.

A myasthenic crisis can be precipitated by concurrent infection, surgery, pregnancy, childbirth, certain medications, tapering of immunotherapeutic drugs, or spontaneously as part of the natural history of the disease. After excluding the several triggers, the myasthenic crisis in our patient was assumed in the context of a natural evolution of the disease.

AChR-Ab has a high sensitivity for generalized MG of 80–90% [5]. Our patient had positive AChR-Ab, providing the laboratory confirmation of MG. In our case, MuSK-Ab were unnecessarily requested and usually only requested if AChR-Ab are negative, with high clinical suspicion. MG can also be considered a paraneoplastic effect of thymoma but rarely of extrathymic tumors. With the confirmation of MG, a chest CT scan was done to exclude thymic abnormalities. Nonetheless, MG has been associated with small cell lung cancer and Hodgkin lymphoma. Therefore, it was essential to follow up on the subpleural nodules found on the initial CT scan.

Take-Home Messages

  • Myasthenia gravis is a rare autoimmune condition characterized by fluctuating weakness involving the ocular, bulbar, limb, and/or respiratory muscles. The severity of symptoms ranges from ocular muscle palsy to generalized muscular weakness with neuromuscular respiratory fatigue.

  • Myasthenic crisis is a life-threatening exacerbation of myasthenia gravis that is defined as worsening of myasthenic weakness requiring intubation or NIV frequently accompanied by severe bulbar muscle weakness. NIV should not postpone orotracheal intubation.

  • Careful use of anesthetic drugs is recommended during induction. Ultrashort- or short-acting anesthetic agents are preferred, and NMBAs should be avoided.

  • Treatment for MG may be symptomatic with pyridostigmine or immunosuppressant. When a myasthenic crisis installs, rapid onset treatment must be initiated, with plasmapheresis having the quickest time to onset of 1–7 days.

Summary

MG is an autoimmune disorder characterized by fatigable skeletal muscle weakness resulting from an antibody-mediated reaction against acetylcholine receptors in the postsynaptic membrane of the neuromuscular junction. A myasthenic crisis is an MG exacerbation that may require ventilatory support.

We present the case of a 69-year-old man recently observed in the outpatient clinic due to ocular manifestations of MG. He was started on pyridostigmine but evolved with out-of-proportion muscle weakness when chewing and later difficulty walking due to extreme weakness. He presented to the emergency room with respiratory failure and was admitted to the intensive care unit to rapidly initiate plasma exchange, high-dose glucocorticoid, and intravenous immune globulin. Initially, we attempted noninvasive ventilation, but orotracheal intubation was necessary. Induction of anesthesia was done with a caution of choice of drugs, preferably with ultrashort- and short-acting agents, and avoiding using neuromuscular blocking agents.

The patient responded well to plasma exchange and was extubated in 48 hours. After extubation, noninvasive ventilation was initiated. The rehabilitation team was crucial for the patient’s recovery. Rituximab was started, and the patient was discharged 15 days after hospital admission, with a normal neurological examination, walking on his own feet with no support and no asthenia.

No precipitation factor was identified; therefore, the myasthenic crisis was assumed to be part of the natural history of MG. In our diagnostic workup, the patient also presented with pernicious anemia that raised suspicion of type 3 autoimmune polyglandular syndrome. However, thyroid function was normal, and no thyroid antibodies were found.

The case report highlights the importance of initiating treatment early, with a lower threshold for orotracheal intubation in patients with respiratory failure. Precautions must be considered when treating a patient with MG, especially when considering which drugs to administer.