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:
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:
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
VC, vital capacity; NIF, negative inspiratory force; MEP, maximal expiratory pressure; MIP, maximal inspiratory pressure.
Unfortunately, no single clinical or laboratory finding adequately predicts the need for intubation in GBS and MG. The efficacy of bedside PFTs can be limited due to oropharyngeal weakness, and the usual signs of impending respiratory failure—such as distress, hypoxia, and ABG abnormalities—may not be present in patients with neuromuscular weakness. Finally, onset of respiratory muscle fatigue is unpredictable in patients with neuromuscular weakness. Because of this, serial functional and laboratory testing is essential to the management of these patients.
Noninvasive Ventilation
Because mechanical ventilation is, in general, associated with increased morbidity, mortality, and hospital length of stay, several studies have explored the benefits of noninvasive positive pressure ventilation (NIPPV) for patients with MG and GBS. NIPPV delivers continuous positive pressure in adjustable degrees: higher during inspiration (to overcome upper airway resistance and reduce the work of breathing) and lower during expiration (to prevent airway collapse and atelectasis). Two retrospective studies of myasthenic crisis found that more than half of patients placed on NIPPV avoided eventual intubation and that hypercapnia (pCO2 >50 mm Hg) was the only predictor of NIPPV failure.9–12 There are less robust data regarding NIPPV for GBS, but one case report suggests it may not be sufficient to prevent intubation.13
Intubation and Neuromuscular Blockade
Neuromuscular blocking agents should be avoided, if possible, in patients with MG who require intubation and mechanical ventilation. Depolarizing agents such as succinylcholine can be used safely, but because MG patients have reduced functional AchRs, more than twice the normal dose may be required. Nondepolarizing agents such as rocuronium should be avoided; they act as competitive inhibitors of postsynaptic AchR and may cause prolonged neuromuscular blockade because they imitate and thus enhance the effects of existing pathogenic antibodies.
In patients with GBS, because dysautonomia carries the risk of blood pressure and heart rate instability and arrhythmia, succinylcholine should not be used, as it increases the risk of life-threatening hyperkalemia. Succinylcholine should also be avoided in patients with myopathies or with hyperkalemia susceptibility (such as those with periodic paralyses). Only nondepolarizing agents such as rocuronium should be used in GBS, and even these with caution.14
Immunomodulatory Treatment
It is beyond the scope of this chapter to discuss immunomodulatory treatment of peripheral neuromuscular disorders in detail; however, certain general principles relevant to the emergency physician are worth mentioning. The treatment of acute MG exacerbations or crises entails the use of corticosteroids, intravenous immunoglobulin (IVIg), and plasma exchange (PE). If the exacerbation is mild, corticosteroids can be started in the ambulatory setting. It is important to note, however, that corticosteroids are known to cause an acute worsening of myasthenic symptoms within the first 2 weeks of initiating treatment. Thus, they should be administered with caution in the ambulatory setting, especially if the patient exhibits any bulbar weakness or respiratory symptoms. If the patient is in a closely monitored setting or already intubated and receiving mechanical ventilation, high-dose corticosteroids may be initiated, and doses of 60 to 80 mg of oral prednisone are commonly used. After remission is achieved (usually in 1 to 2 months), prednisone is slowly tapered over several months.
Numerous studies demonstrate the efficacy of IVIg and PE for treatment of myasthenic crisis.15,16 These therapies are often given in conjunction with high-dose prednisone to achieve successful remission. As discussed, high-dose prednisone can cause an initial worsening of myasthenic weakness and thus should be initiated only after respiratory status is stabilized. Similarly, while IVIg or PE should begin as soon as possible, stable respiratory status is the first priority, and these definitive treatments can be initiated after admission to the hospital rather than in the ED. Long-term management of MG usually involves maintaining remission with low-dose prednisone and/or steroid-sparing immunosuppressants, such as azathioprine and mycophenolate mofetil.
Treatment of GBS also involves IVIg or PE17 and may require more than one treatment in the acute setting, but long-term therapy is unnecessary as it is a monophasic illness. Similar to MG, IVIg or PE should be initiated after patient stabilization and admission to the hospital. Corticosteroids are not beneficial for GBS and should not be used.18
CONCLUSION
MG and GBS are the peripheral neuromuscular disorders most commonly encountered in the ED setting. Both diseases are associated with rapid respiratory muscle fatigue and respiratory failure. Early identification of these patients and accurate assessment of their need for ventilatory support are essential steps in optimizing patient outcomes.
LITERATURE TABLE
RCT, randomized controlled trial; OR, odds ratio.
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