Myasthenic crisis

DEFINITION — Myasthenic crisis is a life-threatening exacerbation of myasthenia gravis that is defined as worsening of myasthenic weakness requiring intubation or noninvasive ventilation [1]. While the respiratory failure is due to weakness of respiratory muscles, severe bulbar (oropharyngeal) muscle weakness often accompanies the respiratory muscle weakness, or may be the predominant feature in some patients. When this results in upper airway obstruction or severe dysphagia with aspiration, intubation and mechanical ventilation are necessary.

This topic will review the evaluation and treatment of myasthenic crisis and rapidly worsening myasthenia gravis. Other aspects of myasthenia gravis are discussed separately.

●(See "Pathogenesis of myasthenia gravis".)

●(See "Clinical manifestations of myasthenia gravis".)

●(See "Diagnosis of myasthenia gravis".)

●(See "Differential diagnosis of myasthenia gravis".)

●(See "Overview of the treatment of myasthenia gravis".)

EPIDEMIOLOGY — Although data are limited, the proportion of patients with myasthenia gravis who experience at least one myasthenic crisis may be as high as 10 to 20 percent [2,3], and the annual risk of myasthenic crisis among patients with myasthenia gravis is approximately 2 to 3 percent [4]. In 13 to 20 percent of patients who present with myasthenic crisis, it is the first manifestation of myasthenia gravis [4-6]. Most myasthenic crises occur in the first few years after the diagnosis of myasthenia gravis, when the disease is often in its most active phase. (See "Clinical manifestations of myasthenia gravis", section on 'Clinical course'.)

Risk factors for myasthenic crisis include greater disease severity at diagnosis, the presence of thymoma, and the association with muscle-specific receptor tyrosine kinase antibodies [7].

The epidemiology of myasthenia gravis is reviewed in detail separately. (See "Clinical manifestations of myasthenia gravis", section on 'Epidemiology'.)

CLINICAL PRESENTATION — Patients who develop myasthenic crisis typically experience increasing generalized or bulbar weakness as a warning. Occasionally, a patient presents with respiratory insufficiency out of proportion to limb or bulbar weakness. In a report of 44 patients who developed 63 episodes of myasthenic crises, the crisis began with generalized weakness, bulbar symptoms, or weakness of respiratory muscles in 76, 19, and 5 percent, respectively [4].

One particular danger in myasthenic crisis is that the generalized weakness can mask the usual signs of respiratory distress, such as accessory muscle use. In addition, weak respiratory muscles may fatigue suddenly, producing precipitous respiratory collapse. On the other hand, some patients have weakness of the respiratory muscles that is out of proportion to the weakness in other skeletal muscles. In rare cases of myasthenic crisis, ventilatory failure is the only clinically overt manifestation [8,9].

Precipitants — Myasthenic crisis may be precipitated by a variety of factors, most often a concurrent infection [3,4,10]. It can also follow a surgical intervention (eg, thymectomy), pregnancy, childbirth, or tapering of immunotherapeutic medications [11]. In addition, myasthenic crisis can occur spontaneously as part of the natural history of myasthenia gravis itself.

A number of drugs can increase the weakness in myasthenia (table 1) and should be considered as possible precipitants [10]. This is of more concern with certain antibiotics (aminoglycosides, fluoroquinolones [eg, ciprofloxacin and levofloxacin], erythromycin, and azithromycin), cardiac drugs (beta blockers, procainamide, and quinidine), and magnesium. (See "Overview of the treatment of myasthenia gravis", section on 'Avoidance of drugs that may exacerbate myasthenia'.)

Cholinergic crisis — A potential major side effect of excessive anticholinesterase medication is weakness, which can be difficult to distinguish from worsening myasthenia gravis. This paradoxical weakening with anticholinesterase medications is called "cholinergic crisis." However, cholinergic crisis is rarely if ever seen with dose limitation of pyridostigmine to less than 120 mg every three hours. Cholinergic crisis is so rare that it should not be the presumed cause of increasing weakness unless the doses taken are known to significantly exceed this range. Otherwise, even in the presence of cholinergic side effects, it should be assumed that the patient's underlying myasthenia gravis is worsening and appropriate treatment should be initiated.

DIAGNOSTIC EVALUATION

Diagnosis — For patients with a known diagnosis of myasthenia gravis, "impending myasthenic crisis" is defined as rapid clinical worsening of myasthenia gravis that, in the opinion of the treating clinician, could lead to crisis in the short term (days to weeks) [12]. "Myasthenic crisis" is defined by increasing respiratory muscle and/or bulbar muscle weakness from the disorder that is severe enough to necessitate intubation and/or mechanical ventilation [12].

In up to 20 percent of cases, myasthenic crisis is the first manifestation of myasthenia gravis, and the cause of neuromuscular respiratory failure may be unknown at presentation [13]. In such instances, the diagnosis of myasthenia gravis should be confirmed, if possible, with immunologic or electrophysiologic testing (table 2). (See "Diagnosis of myasthenia gravis".)

Differential diagnosis — Other than myasthenia gravis, the most common causes of acute neuromuscular respiratory failure are Guillain-Barré syndrome, Lambert-Eaton myasthenic syndrome, and amyotrophic lateral sclerosis [3,14,15]. (See "Guillain-Barré syndrome in adults: Pathogenesis, clinical features, and diagnosis" and "Guillain-Barré syndrome in children: Epidemiology, clinical features, and diagnosis" and "Lambert-Eaton myasthenic syndrome: Clinical features and diagnosis" and "Diagnosis of amyotrophic lateral sclerosis and other forms of motor neuron disease".)

Less common causes of acute neuromuscular respiratory failure include chronic inflammatory demyelinating polyneuropathy, severe rhabdomyolysis, botulism, brainstem stroke, and various types of myopathy [3]. A cause will be undetermined in 5 to 10 percent of patients without known neuromuscular disease at admission [14,15]. (See "Respiratory muscle weakness due to neuromuscular disease: Clinical manifestations and evaluation" and "Chronic inflammatory demyelinating polyneuropathy: Etiology, clinical features, and diagnosis" and "Rhabdomyolysis: Clinical manifestations and diagnosis".)

MANAGEMENT

Overview — There are a number of general concepts common to the treatment of patients with myasthenic crisis or severe exacerbations of myasthenia gravis (table 3) [1,16-18]. These include the following:

●Admit to intensive care unit

●Frequently monitor respiratory muscle strength (see 'Assessment of respiratory function' below)

●Electively intubate if clinical evaluation or tests of respiratory muscle strength suggest impending respiratory failure; may temporarily stop anticholinesterase medications for intubated patients (see 'Elective intubation' below)

●Begin rapid therapy with plasma exchange or intravenous immune globulin (IVIG) (see 'Rapid therapies' below)

●Begin immunomodulating therapy with high-dose glucocorticoids; consider azathioprine or mycophenolate mofetil if glucocorticoids are contraindicated or were previously ineffective (see 'Chronic immunotherapy' below)

●Initiate weaning from mechanical ventilation when respiratory muscle strength is improving after resuming anticholinesterase medications and starting treatment with plasma exchange or IVIG (see 'Weaning from ventilatory support' below)

Intercurrent infections are often a contributing factor and should be sought and treated aggressively, as should any factors or drugs (table 1) that may have precipitated or exacerbated the patient's weakness. (See 'Precipitants' above.)

Assessment of respiratory function — Patients with severe or rapidly increasing generalized weakness from an exacerbation of myasthenia gravis should be admitted to an intensive care unit. This facilitates the frequent monitoring that is required to detect impending respiratory failure and the need for ventilatory support.

Signs and symptoms — Symptoms and signs that should alert the clinician to respiratory failure include:

●Dyspnea (also reported by patients as "suffocation" or "drowning") that occurs or worsens when the patient lies supine. This symptom is thought to be due to the increased dependence on gravity for diaphragmatic function during a myasthenic crisis.

●Severe dysphagia with weak cough and difficulty clearing secretions.

●Signs of respiratory muscle weakness, such as hypophonia, pausing during speech to take a breath, poor respiratory effort, increased respiratory rate with shallow breaths, use of accessory muscles of respiration, and paradoxical abdominal breathing. However, these signs of respiratory distress may become less apparent as muscle weakness progresses, misleading the clinician into believing that the patient is comfortable and does not need intubation. Therefore, it is critically important to assess measures of respiratory muscle function as discussed below.

●Low baseline vital capacity (VC) that is <30 mL/kg of ideal body weight, even if the patient is breathing without distress.

Measures of respiratory muscle function — Tests of respiratory muscle strength may help monitor respiratory status, identify impending respiratory failure, and facilitate elective rather than emergent intubation. They are objective indicators of muscle weakness, even in patients without overt respiratory distress [16,18-20]. VC and maximal inspiratory pressure (MIP) are quantitative measures commonly used to assess respiratory muscle strength. The maximal expiratory pressure (MEP) may also be used to assess expiratory muscle strength, which is important for cough and secretion clearance.

VC and MIP are useful measures of respiratory muscle involvement in myasthenic crisis:

●The VC reflects the mechanical function of both inspiratory and expiratory muscle strength. It can be performed easily at the bedside. The patient is instructed to take a deep breath in and then to exhale maximally into a spirometer (usually a slow VC maneuver). Some experts recommend assessing both supine and sitting VC, as diaphragmatic weakness is more apparent on the supine measurement. However, the predicted values of VC are based upon measurements in the sitting position. (See "Overview of pulmonary function testing in adults", section on 'Spirometry'.)

●The MIP (also known as negative inspiratory force [NIF]) provides information on inspiratory muscle strength. The patient is instructed to take a few tidal breaths through the spirometer or mask then exhale slowly and completely to residual volume. The patient then breathes in as hard as possible, maintaining the inspiratory effort for at least 1.5 seconds. The largest force/pressure that is generated at the mouth is recorded. Inspiration is a negatively generating force and thus values are recorded as negative numbers; a MIP below one-third of normal (eg, 0 to -30 cmH₂O) predicts severe respiratory muscle weakness and probable hypercarbic respiratory failure, while a MIP of -60 cmH₂O is usually associated with a weak cough only. (See "Tests of respiratory muscle strength".)

VC and MIP should always be interpreted in the context of the clinical symptoms and signs of respiratory failure. Neither measurement has been shown to be superior [21], so the two measures are usually analyzed in combination. Both parameters should be measured frequently, as often as every two hours in some cases, but typically every four hours. In many cases, the trend in numbers over time may be more important than the absolute values. However, caveats exist. As examples, patients with myasthenia gravis may precipitously fatigue with the rapid development of respiratory failure before a downward trend in VC is noted. By contrast, repetitive or end-of-day testing may produce lower values from generalized fatigue. Some patients with facial weakness caused by myasthenia gravis who cannot make a good seal with the mask have a falsely low VC. In these cases, measurements that employ a full face mask might fix this problem. Values that may prompt elective intubation (table 3) are discussed in the section below. (See 'Elective intubation' below.)

Oxygenation should be monitored continuously, although abnormalities of arterial blood gases (eg, hypoxemia and hypercarbia) are insensitive measures of respiratory muscle weakness because they often develop only after the onset of life-threatening respiratory failure [16,18-20]. However, the development of progressive respiratory acidosis despite therapy may provide supportive evidence that prompts early rather than late intubation.

Ventilatory support

Elective intubation — Ideally, endotracheal intubation should be performed electively rather than as an emergent response to precipitous respiratory collapse [16,19,20]. This is usually achieved with close monitoring of the patient's respiratory muscle strength using clinical and objective parameters, such as VC and MIP. (See 'Assessment of respiratory function' above.)

The threshold for elective intubation should be low if serial measurements demonstrate one or both of the following:

●VC falls below 15 to 20 mL/kg

●MIP is less negative than -25 to -30 cmH₂0 (ie, between 0 and -30 cmH₂0)

Additional indications for mechanical ventilation include clinical signs of respiratory distress, progressive respiratory acidosis despite therapy, and inadequate secretion clearance (eg, recurrent episodes of acute hypoxemia due to mucus plugging).

In most cases, ventilatory assistance should consist of endotracheal intubation with positive pressure mechanical ventilation. This provides full support and allows for clearance of secretions for patients in whom a prolonged course of crisis is anticipated. The optimal mode of mechanical ventilation is unknown. In general, we use assist control modes of volume-controlled ventilation and low levels of positive end-expiratory pressure (PEEP) with subsequent adjustments to achieve adequate gas exchange. It is important to avoid overventilation, which may impair respiratory drive especially when attempting to wean from ventilatory support. (See "Respiratory muscle weakness due to neuromuscular disease: Clinical manifestations and evaluation" and "Overview of initiating invasive mechanical ventilation in adults in the intensive care unit" and "Respiratory muscle weakness due to neuromuscular disease: Management".)

For intubation, both a sedative and a neuromuscular blocking agent should be coadministered. A nondepolarizing neuromuscular blocking agent (eg, rocuronium) might be preferred to a depolarizing agent (succinylcholine). However, succinylcholine is likely safe in patients with myasthenia gravis and is not associated with the hyperkalemia that may be seen when administered to patients with some myopathies and denervating neuropathies. Due to the relative paucity of acetylcholine receptors in myasthenia gravis, there is a relative resistance to succinylcholine, necessitating higher doses, and a relative sensitivity to nondepolarizing neuromuscular blockers, necessitating lower doses. The techniques and medications for rapid sequence intubation in adults are discussed separately. (See "Rapid sequence intubation in adults for emergency medicine and critical care" and "Neuromuscular blocking agents (NMBAs) for rapid sequence intubation in adults for emergency medicine and critical care", section on 'NMBAs for myasthenia gravis'.)

Role of noninvasive ventilation — Noninvasive ventilation (NIV) may be used on a case-by-case basis in patients with myasthenic crisis who are expected to improve quickly who have adequate cough and can tolerate the mask. It is often used as an early therapy, prior to the development of severe hypercapnia or acidosis, to mitigate atelectasis and to relieve early mild respiratory muscle weakness [22]. We prefer to avoid the prolonged use of NIV (eg, days) and suggest that failure to respond to NIV early in the course of its application might be an indication for invasive mechanical ventilation.

Limited retrospective evidence supports use of NIV in selected patients with myasthenic crisis [2,13,23,24]. In a multicenter series of 250 patients with myasthenic crisis, NIV was attempted in 92 patients and was sufficient to avoid mechanical ventilation in 38 percent of those [13]. Risk factors for failure of NIV included presence of hypercapnia before initiation of NIV, pneumonia, and higher baseline myasthenia gravis disease activity. NIV is not appropriate in patients who are unable to achieve a satisfactory interface or are unable to cooperate, and it can cause complications in those with upper airway obstruction, retention of respiratory secretions, or inadequate cough (table 4). (See "Respiratory muscle weakness due to neuromuscular disease: Management", section on 'Noninvasive ventilation'.)

Supportive respiratory therapies — Meticulous attention to pulmonary toilet is required for patients with myasthenic crisis because of an ineffective cough mechanism. In a retrospective study, "aggressive" respiratory treatment that consisted of the use of suction, intermittent positive pressure breathing or bronchodilator treatments, sighs, and chest physiotherapy appeared to decrease the risk of prolonged respiratory complications compared with historical controls [25]. This observation needs to be validated in a prospective study.

After intubation, cholinesterase inhibitor therapy used for myasthenia gravis (eg, pyridostigmine) is usually withdrawn temporarily to avoid the excess secretions that may complicate pulmonary management. These agents should be reintroduced before initiating weaning from mechanical ventilation.

Rapid therapies — The main therapies for myasthenic crisis are plasma exchange and IVIG [12]. These start to work within several days, but the benefits last only a few weeks (table 5). Therefore, initiation of high-dose glucocorticoids is also necessary for most patients. (See 'Chronic immunotherapy' below.)

Plasma exchange — Plasma exchange (plasmapheresis) directly removes acetylcholine receptor antibodies from the circulation, and its clinical efficacy roughly correlates with the reduction in antibody levels. The supportive evidence is discussed separately. (See "Overview of the treatment of myasthenia gravis", section on 'Therapeutic plasma exchange'.)

Plasma exchange is a commonly used treatment for myasthenic crisis [26-28], although it has never been studied in a randomized, controlled trial for this indication. The beneficial clinical effect usually lasts only three to four weeks. In addition, the acetylcholine receptor antibody levels rebound within weeks if concurrent immunotherapy (eg, glucocorticoids) is not used.

A typical course of treatment consists of five exchanges (3 to 5 L of plasma each) over 7 to 14 days. Although performed daily in some circumstances, exchanges done every other day are probably more effective in reducing the antibody levels due to the time it takes for the extravascular immunoglobulin to regain equilibrium after each exchange. (See "Therapeutic apheresis (plasma exchange or cytapheresis): Indications and technology".)

Intravenous immune globulin — IVIG is used in the same setting as plasma exchange to quickly reverse an exacerbation of myasthenia. IVIG is the pooled immunoglobulins from thousands of donors and acts in myasthenia via uncertain mechanisms. (See "Overview of intravenous immune globulin (IVIG) therapy", section on 'Mechanisms of action'.)

The total dose of IVIG is 2 g/kg, usually over two to five days (eg, 400 mg/kg per day over five days). However, there are only limited data directly comparing different IVIG doses for the treatment of myasthenia gravis exacerbations or crisis. One clinical trial, involving 173 patients with acute exacerbation of myasthenia gravis, found no significant difference in the primary outcome measure (the myasthenic muscular score) after IVIG 2 g/kg (given as 1 g/kg on two consecutive days) compared with IVIG 1 g/kg (given as 1 g/kg on day one and placebo on day two) [29]. The investigators concluded that IVIG 1 g/kg administered in a single dose may be the optimal IVIG dose, given the high cost of IVIG infusions.

Spreading the IVIG dose over more days may be preferable in those who have renal disease or heart failure and in older adults.

Like plasma exchange, IVIG has never been compared directly against placebo in a randomized, controlled trial for treatment of myasthenic crisis. Data supporting the use of IVIG in patients with myasthenia gravis outside of the setting of myasthenic crisis are discussed separately. (See "Overview of the treatment of myasthenia gravis", section on 'Intravenous immune globulin (IVIG)'.)

Choosing rapid therapy — There are limited data comparing the two rapid therapies for treatment of myasthenic crisis, and the available evidence has not shown a significant advantage of one over the other.

●The Myasthenia Gravis Clinical Study Group trial randomly assigned 87 patients with severe clinical exacerbation of myasthenia gravis to treatment with IVIG or plasma exchange [27]. Approximately 50 percent of the patients reached the target 20-point improvement on the myasthenia muscle score by day 9 in the plasma exchange group and day 12 in the IVIG group. However, there were no functional or strength differences in the two treatment groups at day 15, and the rate of adverse events was lower in the IVIG group.

●Similarly, a systematic review comparing trials of plasma exchange versus IVIG found no convincing difference in the beneficial effects of these therapies for treating exacerbation or worsening of myasthenia gravis [30].

●A retrospective series of 54 patients in myasthenic crisis found plasma exchange to be superior to IVIG [28]. The study reported a more prominent clinical improvement (scored by a uniform scheme) one week after initiation of treatment with plasma exchange than with IVIG, even though patients in the plasma exchange group had only received three or four treatments, while the IVIG group had completed the five treatments.

●An observational report identified 1606 patients admitted for the treatment of myasthenia gravis from an administrative database [31]. Among the 698 patients with myasthenic crisis, those treated with plasma exchange (n = 529) had significantly higher mortality and complication rates than those treated with IVIG (n = 169). However, the strength of this finding is limited by the observational nature of this study, which does not exclude possible selection bias (eg, sicker patients were more likely to be treated with plasma exchange). Among the whole group of myasthenics, the adjusted mortality and complication rates were not significantly different between the two treatment groups.

Although the trials do not show a clear difference between IVIG and plasma exchange in the treatment of myasthenia exacerbations or crisis, some evidence and personal clinical experience suggests that plasma exchange works more quickly than IVIG and might shorten ICU length of stay [32]. Most neuromuscular experts still prefer plasma exchange as a first-line therapy for myasthenic crisis, in part because the onset of action appears to be more rapid [12,13,17,33,34]. However, others prefer IVIG because it is easier to administer and has a lower incidence of serious side effects, but similar efficacy, compared with plasma exchange [35,36]. A 2016 international consensus statement by the Myasthenia Gravis Foundation of America concluded that although clinical trials suggest equivalence, expert consensus suggests that plasma exchange is more effective and works more quickly in the treatment of impending or manifest myasthenic crisis [12].

Chronic immunotherapy — We recommend concurrent initiation of chronic immunomodulating therapy with rapid therapy to sustain the benefit beyond the few weeks provided by the more rapid but short-lived therapies (plasma exchange and IVIG). For most patients with myasthenic crisis, we start oral or nasogastric glucocorticoids at moderate to high doses (eg, prednisone 60 to 80 mg daily). We also start glucocorticoid-sparing immunotherapy for longer-term benefit as well as for patients with a contraindication to glucocorticoids.

●Glucocorticoids – The onset of benefit with glucocorticoids for myasthenia gravis generally begins within two to three weeks and peaks after a mean of 5.5 months. (See "Chronic immunotherapy for myasthenia gravis", section on 'Glucocorticoids'.)

The initiation of high-dose glucocorticoids is associated with a transient worsening of weakness that may be serious in up to 50 percent, and additionally with respiratory failure requiring mechanical ventilation in up to 10 percent. The transient worsening usually occurs within 5 to 10 days after the initiation of glucocorticoids and lasts approximately five or six days. However, concern regarding initial worsening of myasthenia gravis with high-dose glucocorticoids is ameliorated when the patient is receiving concurrent treatment with plasma exchange or IVIG. The quick onset of action of these rapid therapies helps to prevent the transient worsening that would otherwise occur due to the glucocorticoids. (See "Chronic immunotherapy for myasthenia gravis", section on 'Glucocorticoids'.)

●Other immunotherapies – Other chronic immunomodulatory treatments used for myasthenia gravis may also be started during myasthenic crisis for long-term benefit or when glucocorticoids are contraindicated. These include azathioprine, mycophenolate mofetil, efgartigimod alfa, ravulizumab, rozanolixizumab, cyclosporine, tacrolimus, and rituximab. These agents are typically used for longer term glucocorticoid-sparing immunotherapy. However, these agents may not provide immediate benefit during a myasthenic crisis since many take weeks to months to take effect (table 6). For patients with a contraindication to glucocorticoids, options such as maintenance IVIG, efgartigimod, or ravulizumab may provide a faster benefit than other chronic immunomodulatory treatments used for myasthenia gravis. These immunotherapies are discussed in detail separately. (See "Chronic immunotherapy for myasthenia gravis".)

Weaning from ventilatory support — The decision to initiate weaning from mechanical ventilation should be individualized for each patient. The median duration of mechanical ventilation after myasthenic crisis is approximately two weeks [13,37]. The principles of weaning in patients with a myasthenic crisis should be the same as for the general population. However, particular attention should be paid to measuring indices of respiratory muscle strength and secretion clearance.

There is no agreed-upon best approach to weaning in this population. However, similar to the general population, the performance of daily spontaneous breathing trials (SBTs) is our preferred method of weaning. An SBT refers to a patient spontaneously breathing through the endotracheal tube (ETT) for a set period of time (usually 30 minutes to two hours) either with or without a small amount of ventilator support. (See "Initial weaning strategy in mechanically ventilated adults", section on 'Choosing a weaning method'.)

Generally, for patients with a myasthenic crisis, SBTs should only begin after the patient has resumed anticholinesterase medications and started treatment with plasma exchange or IVIG and the patient shows evidence of improving respiratory muscle strength, ie, with a VC >15 to 20 mL/kg and a MIP more negative than -25 to -30 cmH₂O (eg, -30 to -60 cmH₂O). When a patient successfully passes an SBT and no contraindication to extubation is present (eg, patient has adequate cough and excessive secretions requiring frequent suctioning are absent), the ETT is typically removed; if a patient fails or a contraindication is present then the patient cannot be liberated from mechanical ventilation. (See "Initial weaning strategy in mechanically ventilated adults".)

All patients should be closely monitored following extubation for early failure using VC and MIP measurements to detect those who may need reintubation. In many patients, early aggressive management with oxygenation and airway clearance can prevent reintubation. The value of NIV in this setting is unknown. (See "Extubation management in the adult intensive care unit".)

Regardless of the approach used, weaning should proceed in a manner that prevents respiratory muscle fatigue and allows for adequate rest between weaning trials. In one series of patients with myasthenic crisis, both extubation failure (44 percent) and reintubation (26 percent) were not uncommon [38]. Lower VC at the time of extubation, atelectasis, and need for bilevel positive airway pressure (BPAP) ventilation after extubation predicted the need for reintubation.

Early tracheostomy is an option if prolonged intubation is anticipated. The indications for tracheostomy and management of patients requiring prolonged mechanical ventilation are discussed separately. (See "Management and prognosis of patients requiring prolonged mechanical ventilation" and "Tracheostomy: Rationale, indications, and contraindications", section on 'Predicted need for prolonged mechanical ventilation'.)

Complications — The most common complications associated with myasthenic crisis are various causes of fever and infection, including pneumonia, bronchitis, urinary tract infection, colitis caused by Clostridioides difficile, bacteremia, and sepsis [2,37]. Patients with myasthenic crisis are at increased risk for vascular complications including deep vein thrombosis, heart failure, acute myocardial infarction, cardiac arrhythmias, and cardiac arrest [2]. There are also several case reports of stress-induced cardiomyopathy (Takotsubo cardiomyopathy) associated with myasthenic crisis [39].

PROGNOSIS

Mortality — Myasthenic crisis is associated with an in-hospital mortality rate of 5 to 12 percent with modern therapies and specialized neurologic intensive care [13,16,31,40].

The most common causes of death are multiorgan failure due to sepsis and respiratory failure despite maximal care [13]. In a multicenter series of 250 patients with myasthenic crisis, approximately 50 percent of patients required inpatient rehabilitation upon discharge, including 20 percent who were not yet weaned from mechanical ventilation at the time of discharge [13]. The median duration of mechanical ventilation was 12 days. Risk factors for prolonged ventilation (>15 days) included older age, higher baseline disease severity, and pneumonia.

Prognostic factors — Factors associated with poor outcome include lower baseline and admission vital capacity, the presence of medical comorbidities, duration of ventilatory support, and the onset of crisis triggered by systemic infection [3,7,41].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Myasthenia gravis".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Myasthenia gravis (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Definition and precipitants – Myasthenic crisis is a life-threatening exacerbation of myasthenia gravis characterized by neuromuscular respiratory failure. Myasthenic crisis may be precipitated by a variety of factors including infection, surgery, or tapering of immunotherapy. Several medications that can increase weakness in myasthenia (table 1) can precipitate myasthenic crisis. The crisis may also occur as a spontaneous event. (See 'Precipitants' above.)

●Diagnosis – Myasthenic crisis is defined by increasing respiratory muscle and/or bulbar muscle weakness in a patient with myasthenia gravis that is severe enough to necessitate intubation and/or mechanical ventilation. In a minority of cases, myasthenic crisis is the first manifestation of myasthenia gravis, and the cause of neuromuscular respiratory failure may be unknown at presentation. (See 'Diagnostic evaluation' above.)

●Management

•Monitor in an intensive care setting – Patients with moderate to severe exacerbations of myasthenia who are deteriorating should be admitted to an intensive care setting so they can be closely monitored (table 3). Vital capacity (VC) and/or maximal inspiratory pressure (MIP) should be measured frequently, as often as every two hours in some cases. (See 'Management' above.)

•Early use of ventilatory support – Consider early use of noninvasive mechanical ventilation or elective intubation based upon overall clinical status, particularly when the VC falls below 15 to 20 mL/kg body weight, the MIP is less negative than -30 cmH₂O, or clinical signs of respiratory distress are present. (See 'Elective intubation' above.)

•Discontinue anticholinesterase medications – For patients with myasthenic crisis who are intubated, we suggest withdrawal of anticholinesterase medications used for myasthenia gravis (eg, pyridostigmine) to reduce airway secretions (Grade 2C). These medications can be restarted after the patient has improved with rapid immunotherapeutic treatment. (See 'Elective intubation' above.)

•Treat with rapid immunotherapy – We recommend rapid therapy with plasma exchange or intravenous immunoglobulin (IVIG) to treat patients with rapidly worsening myasthenia gravis or myasthenic crisis (Grade 1B). We suggest the use of plasma exchange over IVIG for most patients with severe myasthenia gravis or myasthenic crisis because it has a slightly more rapid onset of action (table 5) (Grade 2C). (See 'Rapid therapies' above.)

•Start chronic immunotherapy – We recommend concurrent initiation of chronic immunomodulating therapy with rapid therapy (Grade 1B), anticipating that the chronic immunotherapy will provide benefit for myasthenia gravis after the transient benefit of the rapid therapy has dissipated (table 6). The choice of specific agent (ie, prednisone, azathioprine, mycophenolate mofetil, efgartigimod alfa, ravulizumab, rozanolixizumab, cyclosporine, or tacrolimus) depends on many factors. This issue is discussed separately. (See "Chronic immunotherapy for myasthenia gravis".)

•Criteria for weaning from mechanical ventilation – Weaning from mechanical ventilation with spontaneous breathing trials (SBTs) should be considered after the patient has resumed anticholinesterase medications and started treatment with plasma exchange or IVIG and shows evidence of improving respiratory muscle strength (ie, VC >15 to 20 mL/kg and MIP more negative than -25 to -30 cmH₂O), has an adequate cough, and has manageable respiratory secretions. Early tracheostomy is an option if prolonged intubation is anticipated. (See 'Weaning from ventilatory support' above and "Weaning from mechanical ventilation: Readiness testing" and "Initial weaning strategy in mechanically ventilated adults" and "Tracheostomy: Rationale, indications, and contraindications", section on 'Predicted need for prolonged mechanical ventilation'.)

●Prognosis – Myasthenic crisis is associated with substantial morbidity, including prolonged mechanical ventilation, and a mortality rate of approximately 5 percent. (See 'Prognosis' above.)