Myasthenic Crisis and Peripheral Neuromuscular Disorders

Christina Ulane

BACKGROUND

The diagnosis and management of peripheral neuromuscular disorders are generally the purview of neurologists in the outpatient setting. However, when these disorders present acutely, they can require the expertise of the emergency physician. This chapter discusses the clinical features, diagnosis, and treatment of the two peripheral neuromuscular disorders most commonly encountered in the emergency department (ED) setting: myasthenia gravis (MG) and Guillain-Barre syndrome (GBS), also known as acute inflammatory demyelinating polyradiculoneuropathy, or AIDP.

The incidence of MG is approximately 20 per 100,000; it is equally prevalent in men and women over age 40, but under the age of 40 is three times more common in women. The incidence of GBS is approximately 0.6 to 1.9 per 100,000; it is equally prevalent in men and women, with people over age 50 at greatest risk. Both MG and GBS are immune-mediated diseases. In MG, autoantibodies against the acetylcholine receptor (AchR) compete with acetylcholine at the neuromuscular junction. This blocks synaptic transmission and causes fluctuating motor weakness, the hallmark clinical feature of MG. MG may also result from antibodies acting against muscle-specific kinase; and finally, MG may be seronegative (lacking an antibody). GBS is an immune-mediated, often postinfectious polyradiculoneuropathy that produces both cellular and humoral responses. The exact pathophysiologic mechanisms of GBS are not completely understood, but it is thought that an antecedent infection or other stimulus activates an immune response, which, through molecular mimicry, cross-reacts with epitopes (the part of an antigen to which the antibody attaches) on the myelin and/or axon of peripheral nerves and nerve roots. Immune reaction to myelin components results in multifocal inflammatory demyelination that starts at the level of the nerve roots. Antibodies against gangliosides (which share antigens with Campylobacter jejuni, a commonly associated preceding infection) and complement deposition along axons are found in patients with acute axonal neuropathy variants.

CLINICAL PRESENTATION AND DIAGNOSTIC EVALUATION

Myasthenia Gravis

Patients with MG may present to the ED for different reasons. They may (1) have stable MG but have an unrelated acute problem, (2) have an MG exacerbation or crisis, (3) present with new symptom onset for yet undiagnosed MG, and (4) present with cholinergic crisis as a result of acetylcholinesterase inhibitor use (this problem has lessened as the use of acetylcholinesterase inhibitor therapy has been replaced by immunosuppressive therapy). The classic clinical features of MG include:

Weakness: proximal, fluctuating, usually worse after activity and at night, and improved after sleep and rest
Ptosis (often asymmetric)
Diplopia (with any combination of extraocular muscle palsies), fatigable upgaze
Bulbar weakness (nasal speech, dysarthria, dysphagia)
Respiratory muscle weakness (dyspnea, hypoxia, hypercapnia)
Absence of any sensory deficits, normal reflexes

The diagnosis of MG is generally accomplished in the outpatient setting with laboratory and electrodiagnostic tests, such as repetitive nerve stimulation (demonstrating decrement in motor response) and single-fiber electromyography (demonstrating increased muscle fiber jitter). Myasthenic crisis—myasthenic weakness sufficient to cause respiratory failure requiring mechanical ventilation—is a true emergency that requires rapid assessment, diagnosis, and treatment. Myasthenic crisis and exacerbations can be triggered by infections, surgery, and medications (see Table 23.1). In the past 60 to 70 years, advances in pulmonary critical care and in the diagnosis of MG have reduced mortality rates for myasthenic crisis from 70% to 80% to approximately 4%.

TABLE 23.1 Medications Exacerbating Myasthenia Gravis

In the ED, for a patient without established MG, making a clinical diagnosis is most practical; two easily administered tests—the ice test and the edrophonium, or Tensilon, test—can help confirm a diagnosis. The ice test is performed at bedside on patients with ptosis: A pack of ice is placed over the ptotic eye for 1 to 2 minutes; resolution or improvement in the ptosis is considered a positive result and is highly specific for MG.¹ In the Tensilon test, the short-acting acetylcholinesterase inhibitor edrophonium is administered in an intravenous (IV) dose of 2 mg, followed by up to 8 mg. Muscles weak from MG will respond within 30 to 45 seconds, with a response lasting up to 5 minutes; an objective improvement in muscle strength is considered a positive result. The sensitivity of the Tensilon test, however, is only 60%, and false positives can occur in motor neuron and other diseases. The Tensilon test carries a low risk of serious cardiac complication, but life-threatening bradyrhythmias and ventricular fibrillation can occur, so the test should be done in a monitored setting with atropine at the bedside. Patients are also at risk for acute decompensation due to edrophonium-induced cholinergic crisis, which may result in excessive secretions and worsening neuromuscular weakness.

Guillain-Barre Syndrome

Guillain-Barre Syndrome and its variants (Miller Fisher syndrome, acute motor axonal neuropathy, acute motor and sensory axonal neuropathy) most often present with a subacute onset of progressive weakness, ascending sensory loss, and areflexia. Many patients will also have dysautonomia (with resultant fluctuations in heart rate and blood pressure), pain (often in the mid-back), and respiratory insufficiency. In the ED, the diagnosis of GBS is primarily made clinically; however, a cerebrospinal fluid analysis showing cytoalbuminologic dissociation (elevated protein in the absence of white blood cells) strongly supports the diagnosis and is recommended in patients with suspected GBS.

Differential Diagnosis

The primary alternative diagnostic considerations for MG and GBS are summarized in Table 23.2. While the differential diagnosis for acute weakness of unclear etiology is broad, alternative peripheral neuromuscular disorders such as amyotrophic lateral sclerosis are rarely encountered in the ED setting. Myopathies, which are slowly progressive, also rarely present to the ED, although fulminant cases with bulbar weakness and respiratory failure do occur.

TABLE 23.2 Differential Diagnosis for Peripheral Neuromuscular Weakness

Neuromuscular Respiratory Failure

In the ED, MG and GBS are the most common causes for neuromuscular respiratory failure. Twenty-five to fifty percent of GBS patients and 15% to 27% of MG patients will ultimately require intubation¹⁹^–²² though not necessarily upon arrival in the ED. Neuromuscular respiratory failure in both conditions is due to the following:

Facial, laryngeal, and oropharyngeal muscle weakness (resulting in mechanical obstruction, especially when patient is supine, and increasing aspiration risk)
Inspiratory muscle weakness (resulting in insufficient lung expansion and hypoxemia)
Expiratory muscle weakness (resulting in hypoventilation, inadequate cough, and impaired secretion clearance)

MANAGEMENT GUIDELINES

Assessment and Monitoring of Pulmonary Function

Because neuromuscular weakness can result in respiratory muscle fatigue and rapid progression to respiratory failure, early identification of MG or GBS patients who will require intubation is important. Complicating this, however, are two factors: First, overt signs of respiratory distress may be absent; second, patients with known MG who are experiencing an exacerbation or crisis may be taking higher doses of acetylcholinesterase inhibitors as symptomatic treatment for increasing weakness, the cholinergic side effects of which can lead to increased oral secretions. Clinical assessment should focus on identifying clear indications for intubation, such as an inability to protect the airway, failure of ventilation or oxygenation, expected rapid deterioration, and paradoxical breathing, whereby the abdomen contracts and moves inward (rather than outward) with respiration, due to diaphragmatic weakness. Hypoxia, measured by pulse oximetry, is a late finding.

Tests of respiratory muscle strength (pulmonary function tests, or PFTs) and gas exchange (arterial blood gas, or ABG) are predictive of outcome in patients with neuromuscular weakness and are necessary to complement the clinical assessment and monitoring of respiratory function. Note that while the ABG is often abnormal in patients with MG, it can be normal even when respiratory fatigue and failure are imminent. Bedside PFTs include negative inspiratory force (NIF) or the similar measure maximal inspiratory pressure (MIP), vital capacity (VC), maximal expiratory pressure (MEP), and maximal single-breath count (normal ~50, impaired <30, very impaired <15). MIP and NIF reflect diaphragmatic and other inspiratory muscle strength, while MEP reflects the strength of expiratory muscles (intercostal and abdominal muscles) and indirectly the ability to cough and clear secretions. A normal MIP is > −100 cm H₂O in men and > −70 cm H₂O in women, with a critical cutoff value for all patients of −25 cm H₂O. A normal MEP is >200 cm H₂O in men and >140 cm H₂O in women, with a critical value of 40 cm H₂O. Depending on the particular manometer utilized, MIP, NIF, and MEP values are reported as either negative or positive pressures, but it is the absolute value in cm H₂O that is most significant. Normal VC is 40 to 70 mL/kg, with a critical cutoff value of 15 to 20 mL/kg. In a normal person, the VC decreases by <10% in the supine position; decreases >10% suggest diaphragmatic weakness (a 25% decrease is 79% sensitive and 90% specific for diaphragmatic weakness).² MIP and VC demonstrate a linear relationship in both acute and chronic neuromuscular respiratory failure.³ In ED patients with suspected MG or GBS, a respiratory technician should be called to document respiratory function including PFTs. If a technician is not available, maximal single-breath count is an effective semiquantitative bedside test for VC and expiratory flow rate, with normal values in the range of 30 to 50.

A retrospective review of mechanically ventilated patients with neuromuscular diseases (of all types) found that (a) pre–mechanical ventilation ABGs with lower pH and pO₂ and higher pCO₂ were associated with poor functional outcome, (b) mechanical ventilation was required for more than 7 days if MIP was > −28 cm H₂O and/or MEP was ≤30 cm H₂O, and (c) death during hospitalization was predicted by pH < 7.30, serum bicarbonate >30 mg/dL, and pCO₂ >50 mm Hg.⁴

Predicting the Need for Intubation

Several studies have attempted to identify predictors of the need for intubation and mechanical ventilation in patients with MG or GBS. A retrospective review of 55 patients admitted to the intensive care unit (ICU) for MG identified three respiratory function parameters in patients unlikely to require mechanical ventilation: VC >20 mL/kg, MEP >40 cm H₂O, or MIP <−40 cm H₂O. Patients with a >30% decline in MIP and hypercapnia (pCO₂ >50 mm Hg) were more likely to require mechanical ventilation.⁵

A number of retrospective and prospective studies have evaluated the factors predicting the need for mechanical ventilation in patients with GBS and report similar findings. The most reliable bedside PFT predictors of the need for intubation are VC <20 mL/kg and an MIP >−30 cm H₂O. Other suggestive predictors include VC <60% of predicted and reduction of PFT values by >30% from baseline, inability to lift the head from the bed (a surrogate marker for neck flexor and extensor weakness), rapid disease progression (defined as reaching clinical nadir or worst neurologic status before clinical stabilization, within 7 days), bulbar dysfunction (identified by impaired gag reflex, dysarthria, and/or dysphagia), and dysautonomia (identified by unexplained dysrhythmias, blood pressure fluctuations, and/or bowel and bladder dysfunction). Elevated liver enzymes and inability to stand or cough are also predictive, but are considered less regularly in practice.⁶^–⁸ Indicators of impending respiratory failure in neuromuscular respiratory weakness are summarized in Table 23.3.

TABLE 23.3 Signs of Impending Neuromuscular Respiratory Failure