Neuromuscular Transmission Failure in the ED: Recognition, Assessment, and Targe
Neuromuscular Transmission Failure in the ED: Recognition, Assessment, and Targeted Management of a Life-Threatening Disorder
Author: Masood Haque, MD, Attending Physician, Newark Beth Israel Medical Center, Newark, NJ.
Peer Reviewer: Sid M. Shah, MD, FACEP, Assistant Residency Director of Research, Sparrow, Michigan State University Residency Program, Ingham Regional Medical Center, Lansing, MI.
Muscle weakness, double vision, and respiratory failure of acute onset: the classical triad of neuromuscular transmission failure, these symptoms frequently are the only indication of a life-threatening illness that requires aggressive supportive care and pharmacologic intervention. So often, unfortunately, such conditions as myasthenia gravis, paraneoplastic syndromes causing muscle weakness, medication-induced disorders of the neuromuscular junction, and botulism are not recognized by the emergency department physician, which leads to delays in intervention and suboptimal clinical outcomes.
Although disease states associated with neuromuscular malfunction only occasionally initially present in the emergency department (ED), these conditions are potentially fatal ailments, and, therefore, must be considered in all patients who present with isolated or generalized muscle weakness of unknown etiology. Ranging from immune-mediated disorders such as myasthenia gravis to toxin-based poisonings such as botulism, these conditions have the ability to impair neuromuscular transmission at presynaptic or postsynaptic sites. Pharmacologic stimulation tests (Tensilon®), electrophysiologic testing, historical features, and the physical examination usually can pinpoint a specific diagnosis and guide therapy.
With these issues in mind, the purpose of this article is to provide a practical review of disease states characterized by neuromuscular transmission failure and a systematic approach to initial diagnosis and management in the ED.
— The Editor
Overview
The neuromuscular junction is the critical link between the central nervous system and the musculoskeletal system. From an electrochemical perspective, a wave of depolarization along the neuronal sheath induces release of neurotransmitters at the nerve terminal. Upon release, the neurotransmitter, acetylcholine, binds to the muscle fiber and initiates another wave of depolarization, which culminates in muscular contraction. Maintaining integrity of neuromuscular transmission is essential for effective communication between nerve and muscle and is required for maintaining skeletal muscle function, including the mechanism of breathing. Moreover, a failure or deterioration of neuromuscular transmission must be considered in the differential diagnosis of rapidly progressive muscular weakness, especially when bulbar musculature or the respiratory apparatus is involved. (See Figure 1.) Although disorders of neuromuscular transmission are rare, these conditions may be fatal, due to compromise of the respiratory system. Fortunately, the majority of these disorders initially present with more benign symptoms, permitting life-saving intervention early in the course of the illness. In milder forms of transmission failure, subtle bulbar manifestations will predominate, among them double or blurry vision, drooping eyelids, difficulty chewing or swallowing, or changes in speech. In their more fulminant form, disorders of neuromuscular transmission present as a failure to maintain structural integrity of the airway or mechanism of breathing, each of which can result in respiratory failure.
An understanding of normal neuromuscular anatomy and electrophysiology is essential for optimizing clinical management of patients suffering from disorders of neuromuscular transmission.
The Neuromuscular Junction
The neuromuscular junction consists of the presynaptic membrane, the postsynaptic membrane, and the synaptic cleft. The heavily myelinated motor axon of the anterior horn cell branches into many nerve terminals, each of which terminates at a single muscle fiber. The nerve terminal is comprised of a presynaptic membrane, which is separated from the muscular postsynaptic membrane by the synaptic cleft. The portion of the muscle fiber that directly surrounds the nerve terminal is the motor end plate; it is located approximately half way along the length of the muscle fiber. The neuromuscular junction is a nicotinic synapse, which distinguishes it from muscurinic synapses that interface between the CNS and the autonomic system. Transmission failure at the nicotinic synapse produces a predictable type of muscular weakness, whereas impaired transmission at the muscurinic synapse results in systemic anticholinergic symptoms. Generally speaking, disorders limited to the postsynaptic membrane involve limited nicotinic receptors, whereas synaptic and presynaptic derangements may involve both nicotinic and muscurinic receptors. A critical neurochemical feature of the the presynaptic membrane is inclusion of an active zone—voltage gated calcium channels (VGCC)—that facilitates rapid influx of calcium as the depolarization wave reaches the nerve terminal. Increased calcium concentration is required for release of acetylcholine (ACh). Through interactions with the membrane proteins, vesicles containing ACh fuse with the presynaptic nerve terminal and the transmitter is released into the synaptic cleft. Each vesicle contains about 5000-20,000 ACh molecules and represents a quanta of the neurotransmitter. Vesicles containing ACh are segregated into two pools in the nerve terminal, one that is available immediately and another reserve pool that is mobilized during sustained muscular activity.1,2
The acetylcholine receptors (ACh-Rs) located on the postsynaptic membrane, are transmembrane allosteric glycoproteins with a molecular weight of 250 kd. Each receptor is comprised of five subunits arranged around a central channel; each of the two alpha subunits has an ACh-binding site located extracellularly, which is localized in the vicinity of amino acids 192 and 193.3 Sequencing and cloning of genes that script for all receptor subunits in human ACh-Rs have been accomplished over the past several years. Genetic engineering technology has made it possible to produce fusion proteins consisting of large stretches of entire subunits of ACh-Rs. These structurally and functionally intact ACh-Rs have been produced by inserting subunits of messenger RNA into cells such as frog oocytes; clearly, receptors generated using these techniques may have important therapeutic implications in the future.4
Finally, ACh-Rs are continually turning over at the neuromuscular junction. Among other factors, motor innervation and stimulation appear to be important regulators of ACh-R synthesis, sub-unit composition, as well as distribution and degradation of postsynaptic receptors. In fact, impaired transmission has been shown to increase transcription of the ACh-R genes, a response that facilitates complete recovery or neuromuscular transmission in patients whose postsynaptic receptors have been destroyed by autoimmune mechanisms.5
Neuromuscular Transmission. In the resting muscle, small fluctuations in membrane potential occur at the end-plate region. These fluctuations, also called miniature end-plate potentials (MEPPs), are produced by spontaneous release of packets or quanta of ACh from the motor nerve terminal. As the nerve action potential arrives, it transiently depolarizes the nerve terminal, which opens up the VGCC. The rapid influx of calcium into the nerve terminal stimulates the fusion of ACh-containing vesicles with the axonal terminal and the subsequent release of hundreds of quanta of ACh into the synaptic cleft.6,7
After diffusing across the synaptic cleft, ACh binds to receptors located on the postsynaptic membrane. The ion channel of the ACh-R is closed during the resting state; binding of ACh to the postsynaptic receptor sites alters the receptor configuration, thereby opening the central ion channel and permitting sodium (Na) influx. This produces a local electrical current within the end-plate region known as the end-plate potential (EPP), which then activates the peri-junctional Na channels and initiates propagation of an action potential that activates the muscle fiber and generates a compound muscle action potential (CMAP). The action potential then propagates across the muscle fiber bidirectionally. The depolarization of muscle fiber results in the release of calcium from the sarcoplasmic reticulum, which, in turn, produces muscle contraction. The ACh molecules that are bound to the receptors are hydrolyzed by the enzyme, acetylcholinesterase, into its component. The choline entity then undergoes re-uptake by the nerve terminal and is recycled.8
A critical EPP amplitude is required to trigger a CMAP. Attaining the threshold EPP depends upon two factors: 1) a sufficient quantity of neurotransmitters; and 2) an adequate number of receptors on the postsynaptic membrane. If either of these features is quantitatively or qualitatively impaired, the electrical current at the EPP will not reach the critical amplitude required to trigger an action potential. Pathophysiologically, the result is suboptimal recruitment of enough muscle fibers to sustain muscular activity. Symptomatically, this failure of transmission clinically manifests as weakness. Fortunately, the EPP generated is almost five times greater than required to trigger an action potential, representing a comfortable "safety margin." In particular, susceptibility of the bulbar musculature to neuromuscular transmission disorders, in part, can be explained by its low safety margin, which makes this group more sensitive to depletion of either transmitter or receptor.
Disorders of Neuromuscular Transmission: A Classification Scheme
As outlined, neuromuscular transmission is a complex process that requires multiple components and biochemical pathways to support normal muscular function. The transmission is sensitive to failure at several levels. Neurotransmission disorders can be broadly divided into two major categories, those characterized by inadequate transmitter release and those in which there is an inadequate number of receptors. Failure may occur at the level of transmitter release or may result from compromised interaction between ACh and the receptor. Although transmission failure may be congenital, it usually is related to autoimmune disorders or toxins. In addition, there are several drugs that can compromise neuromuscular transmission, and their introduction may unmask a vulnerability to neuromuscular transmission failure or exacerbate failure of an existing neuromuscular transmission deficiency state.
For clinical and diagnostic purposes, it is convenient to divide derangements of neurotransmission into three different categories, according to location and nature of dysfunction. (See Tables 1 and 2.)
| Table 1. Etiologies of Neuromuscular Transmission Failure | |
| • Congenital | Congenital myasthenia gravis, acetylcholinesterase deficiency |
| • Infectious | C. botulinum |
| • Autoimmune | Myasthenia gravis, Lambert-Eaton syndrome |
| • Toxins | Snake/Scorpion envenomation, organophosphate poisoning |
| • Drugs | Magnesium, D-penicillamine, aminoglycosides, chloroquine, fluoroquinolones |
| _____________________________________________________________________________ | |
| Table 2. Division of Neurotransmission Derangements by Categories | ||
| Presynaptic | Synaptic | Postsynaptic |
| Lambert-Eaton syndrome
Botulism Hypermagnesemia Scorpion toxin |
Organophosphate poisoning
Acetylcholinesterase deficiency |
Myasthenia gravis
Congenital myasthenia Snake venom |
| ____________________________________________________________________ | ||
Postsynaptic Disorders. This is the most common etiology of clinical disorders characterized by neuromuscular transmission dysfunction. Failure is usually due to loss of ACh-R, either because of autoimmune-mediated destruction (myasthenia gravis) or congenital deficiency of ACh-Rs. Although autoimmune-mediated destruction usually is idiopathic, several medications also have been implicated, most notably D-penicillamine. Moreover, postsynaptic receptors also are vulnerable to such toxins as snake venom, which produces a slowly evolving, non-depolarizing block of neuromuscular transmission. Clinical impairment of neuromuscular function results from occupation and blockade by alpha-bungarotoxin and cobra neurotoxins of ACh-Rs on the post synaptic membrane of the muscle fiber.
Presynaptic disorders. Failure at the presynaptic terminal almost always represents insufficient transmitter (ACh) release. In its congenital form, this is characterized by inadequate synthesis and/or packaging of neurotransmitter vesicles. In its acquired form, this disorder results from an interruption of transmitter release. This malfunction may be a consequence of impaired calcium influx (magnesium intoxication, Eaton-Lambert syndrome) or inhibition of transmitter exocytosis (botulinum toxin). ACh release may also be inhibited by exposure to black widow spider venom (alpha-latroxin) or scorpion toxin, both of which cause depletions of the neurotransmitter from the nerve terminal. Failure at the presynaptic level leads to compromised synaptic transmission in both nicotinic and muscurinic receptors; as a result, muscular weakness may be accompanied by anticholinergic symptoms.
Synaptic Transmission Disorders. This group of disorders is characterized by persistent acetylcholine in the synapse. The consequence is depolarization block of the neuromuscular junction. Synaptic disorders result from the inability to clear the neurotransmitter from the synaptic cleft. The disorder is caused by toxins that disable acetylcholinesterase or from a congenital lack of acetylcholinesterase.
Neuromuscular Transmission Failure: Clinical Presentation
The hallmark of weakness associated with failure in neuromuscular transmission is fatigability. The patient may present to the ED with complaints of gradual weakness followed by the precipitous onset of muscular exhaustion. Typically, muscle weakness resolves briefly after a short rest and then worsens again. Frequently, the patients can be specific about the muscle weakness, narrowing the involvement to a single muscle group. Typically, symptoms will be directed at the bulbar musculature or respiratory function, although some patients have predominant extremity weakness. The key is to consider neuromuscular transmission in the clinical context of bulbar symptoms (blurry or double vision, difficulty speaking or swallowing, or alteration in taste). There are specific questions the ED physician should ask to determine whether failure of neuromuscular transmission is responsible for the symptoms related to muscle dysfunction. For example, it is helpful to determine if the patient’s vision becomes blurry after prolonged reading, or is it more difficult to swallow at the end of a meal? Does the tonality of speech change with talking? Neuromuscular transmission failure should also be considered in patients who report complaints of more generalized symptoms such as chronic fatigue and shortness of breath, especially when there is no other obvious explanation for the clinical presentation.9
It is essential to inquire about associated autonomic symptoms, such as constipation, erectile dysfunction, dry mucosal surfaces, or loss of sweating. All of the presynaptic neuromuscular disorders are accompanied by autonomic symptomatology, and, therefore, complaints of autonomic dysfunction can help localize the precise area of transmission failure and may even help delineate a specific etiology. Consideration should also be given to medications that might interfere with neuromuscular transmission, most notable among them, D-pencilliamine, fluoroquinolones, magnesium, and aminoglycosides. An inquiry should made into the patient’s dietary habits and any dietary profile should be asked about, as well as any exposure to toxins, including those associated with animal and insect bites. If the patient is unable to provide any history, the clinician should, nevertheless, maintain a high index of suspicion for neuromuscular transmission failure in individuals with etiology of any rapidly progressive weakness. (See Table 3.)
| Table 3. Clinical Features of Neuromuscular Transmission Failure |
• Cranial and proximity muscle weakness___________________________________________________________ |
Physical examination of patients with a suspected neuromuscular transmission disorder should incorporate provocative testing as a diagnostic maneuver to elicit muscle weakness. For example, if a patient complains of weakness in a set of muscles, repeated activity of this group should induce profound muscular fatigue soon after the onset of exertion. In this regard, if a patient complains of droopiness in an eyelid, the ED physician should have the patient stare at the ceiling for few minutes and then re-examine the patient to see if the ptosis worsens. In individuals who present with unexplained shortness of breath (SOB), especially when accompanied by unexplained fatigue of the respiratory musculature, it is important to measure the vital capacity in order to rule out muscular weakness. Clinical features of neuromuscular respiratory failure include confusion and headache, respiratory muscle weakness without evidence of parenchymal disease (i.e., no rales or wheezes can be appreciated), prominent use of accessory muscles of respiration, and paradoxical abdominal movement due to diaphragmatic weakness.10
Diagnostic Evaluation. Routine hematological studies and blood chemistry may help rule out underlying systemic illness or sepsis. Respiratory function assessment is an essential component of the initial ED database, and measurement of vital capacity should be performed in every patient presenting with respiratory symptoms that may be related to neuromuscular failure. Patients who present with vital capacity of 2 L or less should have additional tests and elective intubation should be given strong consideration.11,12
Although usually not performed in the ED setting, electrodiagnostic testing provides vital information that can help establish the diagnosis and, more specifically, localize the disorder to the neuromuscular junction. The electrodiagnostic procedures most often used to evaluate the integrity of neurotransmission are repetitive nerve stimulation and analysis of "Jitter" with single-fiber electromyography (SFEMG).4 (See SFEMG section below.)
Repetitive Nerve Stimulation (RNS). RNS is the most frequently used electrodiagnostic test for assessment of neuromuscular transmission. Abnormal results usually are not diagnostic of a specific clinical disorder, but they can localize the disorder to the neuromuscular junction and help distinguish between pre- and postsynaptic disorders.
In presynaptic disorders of the neuromuscular junction, such as botulism or Lambert-Eaton syndrome (LES), nerve conduction studies are normal except for the finding of a low motor evoked response that can be demonstrated to increase after 10-15 seconds of isometric contraction of the muscle that is stimulated. This post activation facilitation is a hallmark of presynaptic disorders.
In postsynaptic conditions such as myasthenia gravis (MG), initial motor amplitudes are generally normal, but there is a decremental motor response exceeding 10% with nerve stimulation at low rates of 2-3 Hz.13
Single Fiber Electromyography (SFEMG). This test is performed by placing a fine needle electrode between two muscle fibers innervated by a single nerve. The variation in the action potential of the two muscle fibers is recorded and is referred to as a "Jitter." It detects delayed or failed neuromuscular transmission in pairs of muscle fibers supplied by branches of a single nerve fiber. Although a sensitive test, it is not very specific for a failure of neuromuscular transmission.13
Prognosis. Prognosis of patients with neuromuscular transmission depends upon the severity of the underlying condition. If the condition is autoimmune in nature, a number of treatment options are available, including immunosuppression. If a toxin is involved in neuromuscular transmission failure, the treatment will include supportive care and administration of a specific antitoxin. Finally, it is important to consider the role that drugs may play in compromising neuromuscular transmission. Implicated medications should be discontinued in patients in whom the diagnosis of neuromuscular transmission failure has been established.
Myasthenia Gravis
MG is the most common disorder producing clinical symptoms caused by failure at the postsynaptic membrane of the neuromuscular junction. Autoimmune-mediated destruction of ACh-Rs is the key pathophysiologic event producing a fluctuating, fatigable weakness of voluntary muscles. The literal meaning of MG is "grave muscle weakness." Although this condition has been described in medical literature for more than 300 years, it is only over the last three decades that the underlying pathophysiology has been elucidated. Currently, it is the best understood of all the autoimmune diseases and has become a prototype for evaluating other autoimmune derangements.
The incidence of myasthenia is estimated to be about 14 per 100,000 in the general population; total cases of myasthenia in the United States are estimated to be 36,000.14 The incidence is age- and sex-related with two distinct peaks. The first peak is observed in the second and third decades and a later peak is reported in the sixth and seventh decades, when the disease is more likely to afflict men; in contrast, women predominate in the early peak.15 Later onset MG does not differ in its clinical presentation, although the disease may be more severe. There is an increased incidence of associated thymoma and serologic positivity when the disease presents later in life.16
Clinical Pathophysiology. MG is a well established, prototypical autoimmune disease. Antibodies directed against the ACh-R destroy postsynaptic receptors, reducing the number of available binding sites at the neuromuscular junction. Antibody mediated loss of ACh-R is mediated by three mechanism: 1) accelerated endocytosis and degradation of the receptors; 2) complement-mediated damage; and 3) functional blockade of ACh-R (probably only a minor effect).17 Morphologic changes at the postsynaptic membrane of patients with MG demonstrate a simplified membrane with loss of receptor sites, synaptic folds, and an increased gap between the nerve terminal and the postsynaptic membrane. This reduction of postsynaptic ACh-R results in EPPs of diminished amplitude; consequently, there is a failure to trigger action potentials in some muscle fibers, a characteristic feature of MG.
There is a substantial body of evidence confirming the autoimmune nature of MG, including its association with other autoimmune diseases; a chronic, fluctuating course; and demonstration of anti-ACh-R antibodies. Other evidence suggesting an autoimmune process includes the presence of complement at the receptor; the reduction of ACh-R on the postsynaptic membrane; and the favorable, clinical response to immunosuppression (perhaps the most convincing evidence for autoimmunity transferability of MG to mice using IgG from patients with MG).
Although the role of antibody-mediated destruction of the ACh-R is well-established, the triggering factor for this autoimmune attack remains elusive. However, there is compelling evidence that the thymus gland plays a central pathophysiological role. In this regard, thymic hyperplasia has been reported in 70% of MG patients, and a thymoma is identified in up to 15%.18,19 The beneficial effects of thymectomy and the fact that the disease is more aggressive clinically in those with thymic hyperplasia and thymic malignancies substantiate the role of thymic abnormalities.18-21
Clinical Features. MG is a symmetrical descending paralysis with a prominent bulbar component. Almost 75% of patients have bulbar palsy at the time of initial presentation. Intermittent diplopia and ptosis are the most common manifestations and most patients develop these signs within two years of onset of MG. Drooping of the eyelid with a persistent upward gaze and double vision while reading indicate fatigability at the myasthenic, neuromuscular junction.1,2,8,22(See Table 4.) Other prominent, bulbar manifestations include weakness of the tongue and soft palate, which may lead to a change in voice; patients may complain of nasal or slurred speech, especially with continued talking. During a meal, persistent chewing may make the jaw muscles so weak that the patients may have to manually support masticatory functions. Weakness of muscles involved in coughing and swallowing may lead to dysphonia and/or choking on food and secretions, while diminished strength in neck muscles may cause fatigue and require manual assistance for holding up the head. Hearing may be impaired. Weakness of the tensor tympani may cause muffling of low tones, and stapedius weakness may cause hyperacusis.23
| Table 4. Signs and Symptoms of Myasthenia Gravis | |
| • Ptosis, diplopia, blurred vision
• Leg weakness • Generalized fatigue • Dysphagia • Slurred or nasal speech • Difficulty chewing |
53%
10% 10% 5% 5% 5% |
| ______________________________________________ | |
Limb weakness is the initial symptom in fewer than 10% of the patients.11,16,24 Although any limb or truncate muscle may be weak, upper extremity weakness is more prominent than lower extremity weakness, and this weakness tends to be symmetrical and proximal when present. Dyspnea is an uncommon initial presentation, although when present, tends to be exertional.9
On physical examination, findings usually are limited to the motor system; generally, there is no loss of reflexes and no alteration of sensation or coordination. Ptosis tends to be asymmetrical and worsens with upward gaze after 30 seconds; extraocular muscle weakness is symmetrical and fluctuating. Pupillary responses are normal. A combination of ocular palsy with ptosis in the presence of a normal pupillary response strongly suggests a disorder of neuromuscular transmission, including muscular dystrophy. Other maneuvers that may be used to unmask underlying neuromuscular fatigability include having the patient count up to 100 or chew for 30 seconds and observing signs of functional deterioration.
Onset of the aforementioned symptoms usually is insidious and can take place over weeks or months. Occasionally, symptoms are initiated by emotional upset or infection (usually respiratory), or symptoms may appear during pregnancy or in response to drugs used during anesthesia. Once symptoms become manifest, progression inevitably follows.
In one landmark study evaluating clinical course of MG with 1487 patients, investigators characterized the pattern of weakness, outcomes, and severity of symptoms during the first three years after onset of illness. In 15% of patients, weakness remained localized to the extraocular muscles, whereas in 85%, the disease became generalized, usually within the first year. Maximum severity of the illness was observed in about 50% of patients within the first year and in 85% within the first five years. Moreover, the course of the illness is extremely variable. Rapid spread from one muscle group to another occurs in some individuals, but in others the disease remains unchanged for months before progression ensues. Remissions may take place without explanation, but this happens in less than 50% of cases. If the disease remits for a year or longer and then recurs, it tends to be progressive.18
The risk of death from MG is greatest in the first year after the onset of the disease. A second phase characterized by life-threatening progression occurs 4-7 years after onset. After this time, the disease tends to stabilize and risk of severe relapse diminishes.18
Diagnostic Evaluation. In addition to the distinct clinical features of MG, there are several other modalities that aid in establishing the diagnosis of MG.
Tensilon Test. (See Figure 2.) Intravenous edrophonium (Tensilon) is an anticholinesterase inhibitor with rapid a onset of action (i.e., about 30 seconds) and a short duration of action (i.e., about 5 minutes). Administration produces rapid improvement of ocular symptoms in patients with MG. Theoretically, although any muscle group can be tested, this provocative test is most useful and is most sensitive when improvement of ptosis and double vision are used as diagnostic end points.25 Despite its advantages, edrophonium should be used with caution, especially in cardiac patients, because of its potential for causing bradycardia. Accordingly, the patient should be placed on a monitor when this test is performed and atropine should be available at the bedside. A "test dose" of 0.1 or 0.2 mg of edrophonium should always be given, due to extreme sensitivity in certain patients. Interpretation of this test may be difficult due to a possible placebo effect or the subjective nature of improvement in muscular strength. The key is to identify precisely which muscle or muscles are being tested. Objective improvement in strength is more important than the patient’s perception of improvement, which may be due to the placebo effect.
Immunologic Testing. Measurement of ACh-R antibodies is a highly specific test for MG. Ach-R antibodies are present in 90-95% of patients with MG, but the percentage is lower (70%) in patients with the purely ocular form of the disease. In the right clinical context, the test is specific enough to obviate the need for further diagnostic testing. Generally, there is no correlation between the level of antibody titers and disease activity. Overall, up to 19% of the patients with MG do not have ACh-R antibody detectable by radioimmunoassay. Nevertheless, the clinical presentation and natural history of the disease in these patients are similar to those patients who are seropositive. It is interesting to note that almost all patients with thymoma have elevated ACh-R antibody levels.
Electrophysiologic Studies. Repetitive nerve stimulation shows a decremental response in MG; a 15% decrease in successive action potential is considered a positive response. SFEMG shows increased "Jitter" in up to 95% of the patients with MG.
Management. Currently, there are five, major therapeutic options in managing patients with MG. These modalities have significantly improved the prognosis and quality of life of patients with this condition.
Anticholinesterase Agents. Anticholinesterases are considered first-line agents for treatment of MG. Their primary action is to increase the concentration of ACh at the synapse; pyridostigmine is the most frequently used agent in this class. The exact dosage and dosing schedule of this medication can be tailored to the needs and clinical response of the patient. The starting dose is 15-60 mg q4h. Despite an initial improvement in symptoms, however, many patients find that muscle weakness does resolve and that anticholinesterase agents lose their efficacy over time. Consequently, additional treatment modalities are almost always required.
Immunosuppression. Immunosuppressive therapy has been used to treat patients with MG since the 1950s. It usually is added to the medication regimen of patients whose symptoms are inadequately controlled by anticholinesterase drugs. Among immunosuppressive agents, corticosteroids represent initial agents of choice; however, other agents such as azathioprine, cyclosporine, or cyclophosphamide also can be introduced, if steroids are contraindicated or ineffective.
Corticosteroids reduce the levels of ACh-R antibodies. Initiation of steroid therapy may require hospitalization because of risk of inducing transient exacerbation of MG. This risk is the greatest during the first few weeks following initiation of therapy and may be seen in up to one-half of patients started on corticosteroids. Gradually increasing the steroid dose, with close clinical follow-up, tends to diminish these risks. Recently, a double-blind study using single IV methylprednisolone pulse therapy has shown promise and may be useful in selected patients.26
Thymectomy. Thymectomy is indicated in selected patients younger than 60 years of age who have the generalized form of MG, as well as in those individuals who have thymoma. The improvement may be dramatic after the thymectomy, but the course remains unpredictable. If weakness persists one year after the surgical procedure, the disease is unlikely to remit. Overall, about 59% of patients with MG have sustained improvement after thymectomy.18-20
Short-term Treatment. Plasmapheresis and IV immunoglobulin are two short-term therapeutic options that are particularly useful when rapid clearance of antibody is required either to improve symptoms in myasthenic crisis or in patients in whom immunosuppressive treatment has been initiated. It is also useful in patients who are being prepared for surgery.
Plasmapheresis removes circulating anti-ACh-R antibodies from the plasma. This therapeutic option is indicated when a rapid, significant reduction of circulating antibodies is required. Despite several open, uncontrolled clinical trials suggesting plasmapheresis induces short-term improvement in patients with MG, as well as numerous anecdotal reports, a controlled trial has never been performed.27,28 A newer modality, which uses protein A immunoadsorption, can remove IgG, with high efficacy, from plasma, without significant modification of other plasma proteins.27 A majority of patients with MG show temporary improvement after plasma exchange; maximum improvement may be achieved as early as the first exchange or it may be delayed for several weeks. Clinical improvement can be maintained for weeks to months following plasmapheresis.29,30
Intravenous Immune Globulin (IVIG). Several studies have shown a favorable response to IVIG. Although several attractive hypotheses have been proposed for its benefits, including down regulation of antibody production, the mechanism of IVIG in MG remains unknown. The usual dose is 400 mg/kg/d for five days, and the improvement begins within 4-5 days following administration.27,30
Myasthenic Crisis. Involving respiratory muscles (including those maintaining the upper airway, intercostal muscles, or the diaphragm), myasthenic crisis is a true emergency and usually requires respiratory support. Up to 20% of myasthenic patients will experience at least one episode of myasthenic crisis.31 Patients who survive one episode of myasthenic crisis are at risk for a recurrent attack; as many as one-third of these patients will experience another episode. About 75% of myasthenic crises occur within the first two years after the onset of disease, with a median of eight months following onset of initial symptoms. Patients with an associated thymoma are at a much higher risk of experiencing myasthenic crisis.31
In the majority of patients with myasthenic crisis, an underlying precipitating event can be identified. Infection is the most common risk factor, followed by aspiration pneumonitis and changes in medication (especially initiation or withdrawal of corticosteroid). In up to one-third of the patients with myasthenic crisis, no precipitating factor can be identified.
Patients in whom the diagnosis of MG has been established and who are taking anticholinesterase agents present a management dilemma, especially in the setting of suspected crisis. Often, these patients will increase their medication dosage as the weakness progresses. This can lead to progressive weakness as a result of depolarizing blockade of the postsynaptic membrane (cholinergic crisis). This makes it difficult to distinguish between a true deterioration associated with underlying MG and an iatrogenic complication of therapy. As a rule, in cholinergic crisis, worsening muscle weakness should be accompanied by symptoms of cholinergic excess, including salivation, lacrimation, urination, diarrhea, gastric distress (cramps), emesis, miosis, and bradycardia. Edrophonium can be a useful tool; this agent should make myasthenic weakness better and should exacerbate the cholinergic crisis. Unfortunately, edrophonium has limited use in an acutely decompensating, apprehensive patient. Therefore, it is recommended that all anticholinesterase medications be stopped in myasthenic crisis.11,31
Management of the patient with myasthenic crisis requires general supportive measures and rapid reduction in anti-ACh-R antibody load. Patients suffering from myasthenic crisis will require admission to the ICU, where vigilant monitoring of respiratory status is mandatory. The decision to intubate the patient will depend on the patient’s clinical status and respiratory parameters. These values suggest respiratory failure requiring intubation. Plasmapheresis is beneficial in myasthenic crisis, and improvement in the patient’s clinical status can be seen within a few days. Intravenous immunoglobulin (IG) should also be considered. In a critically ill patient with a secured airway, high-dose steroid therapy should be initiated immediately. All medications that may impair neuromuscular transmission should be discontinued.
Despite a significant reduction in mortality in myasthenic crisis, this emergency continues to carry a mortality rate as high as 10%. This high mortality is the result of associated complications, including sepsis and cardiac or respiratory arrest.31
The ED physician’s approach to patients with MG depends upon the severity of the patient’s symptoms. Bella and Chad’s classification of myasthenia severity is particularly helpful in the ED setting.11 They classify MG as mild, moderate, and/or severe based upon neurologic function and respiratory compromise. Early neurologic consultation is important. If the patient has limited, mild bulbar symptoms and a disorder of neuromuscular transmission is suspected, close follow-up with the neurologist is mandatory.
Presynaptic Disorders of Neuromuscular Transmission
Lambert-Eaton Syndrome (LES). LES is a rare, autoimmune condition affecting the presynaptic membrane. It exists in a primary form but may be a manifestation of a paraneoplastic disorder. The incidence of the primary form of LES is not known, but the prevalence of LES in patients with small-cell carcinoma of the lung is estimated to be 3%. It also has been described with other neoplasms. The majority of patients with LES are older than 60 years of age, but it has been described in all age groups. The paraneoplastic form of LES is a disease of the middle to late years; there is a distinct male predominance.32 In the paraneoplastic form, LES may precede the diagnosis of lung carcinoma by up to three years.
Several clinical features can help distinguish LES from MG. For example, the weakness reported in LES is severe at the onset, but improves somewhat soon after initiation of activity, and then deteriorates. Moreover, there is a propensity for developing extremity weakness, in the absence of bulbar symptoms and autonomic dysfunction.
Clinical Pathophysiology. Failure of neuromuscular transmission in LES is due to the insufficient release of a neurotransmitter at the presynaptic terminal. Antibody-mediated blockade of the VGCC compromises rapid influx of calcium which, in turn, results in deficient neurotransmitter release. Electron microscope studies of the presynaptic membranes of patients with LES show depletion of the active zone, which represents the VGCC; depletion of the active zone is secondary to autoimmune destruction.33 The evidence for an autoimmune etiology comes from several observations: LES is associated with other organ-specific autoimmune diseases,34 the disease responds to immunosuppressive therapy,32 and it can be passively transferred to mice with purified IgG from LES patients.33 Also, immunocolonization of the motor end plate provides direct evidence for the autoimmune nature of this disorder.33 More recently, calcium channel autoantibodies have been detected in up to 60% of the patients with LES.35 In paraneoplastic cases, the antigenic stimulus for antibody production is believed to be present in the membranes of small-cell carcinoma cells.36
Clinical Features. Primary and paraneoplastic forms of LES generally present with similar clinical manifestations.36 Due to the vague nature of initial symptoms and the insidious onset of this condition, the diagnosis of LES is often delayed. However, the classic triad of muscle weakness, hyporeflexia, and autonomic dysfunction in an elderly patient should lead to the consideration of LES
Muscle weakness in LES tends to be symmetrical and is most pronounced in the lower extremities. Altered gait after prolonged walking usually is the initial symptom. This may progress to inability to rise from a chair or walk up stairs. Ocular and bulbar symptoms are not common and are mild in nature when present. Autonomic symptoms are common and occur in more than half of the patients. Prominent among anticholinergic symptoms are dry mouth and erectile dysfunction.34 On physical examination, proximal muscle weakness is the most prominent clinical finding. The peculiar weakness in LES patients may be demonstrated during hand grip. The initial grip may be weak but gets stronger only to weaken again. Autonomic findings, especially pupillary abnormalities and dryness of the oral mucosa may also be appreciated. Hyporeflexia is usually most prominent in the weakest muscles. The diagnosis can be confirmed by the presence of VGCC antibodies and electrophysiologic studies.
Calcium channel antibodies are found in both the primary and the paraneoplastic forms of LES. They are detected in 50-60% of patients with LES.35 Electrophysiologic studies, although not specific for LES, will localize the problem to the presynaptic terminal. In muscles with weakness due to presynaptic disorders, the resting compound muscle action potential is low and a decrement is noted with slow, repetitive stimulation. With rapid stimulation or after brief exercise, the compound muscle action potential facilitates to at least twice its baseline amplitude. This post-tetanic facilitation is the hallmark of presynaptic disorders.
Management. Management of patients with LES includes a search for and treatment of an underlying tumor, potentiation of neuromuscular transmission through anticholinesterase medication, and immunosuppression.
Malignancy is a more common cause of rapidly evolving symptomatology in patients with LES. Successful treatment of the underlying malignancy often results in remission of neuromuscular symptoms.8 Occasionally, tumor recurrence may be heralded by recurrent LES.
Like MG, enhancement of neuromuscular transmission is the primary objective of therapy. Anticholinesterase agents, such as pyridostigmine, provide some relief, but in many cases may not to be effective. Other neurotransmitter enhancers, such as aminopyridines, have shown more promise in LES. Aminopyridines are potassium channel blockers that enhance the release of neurotransmitters. Blocking of the potassium channels prolongs the action potential that keeps the calcium channels open for a longer period of time. The resulting increase in calcium influx facilitates neurotransmitter release. Two common agents in this class, 4-aminopyridine (4-AP) and 3,4-diaminopyridine (3,4-DAP), are currently in favor.28,37 Immunosuppressive regimens are also used but tend not to be as effective as they are in MG and have a slower onset of action.32 The prognosis of the paraneoplastic form of LES depends on the status of the underlying malignancy.
Botulism
Clostridium botulinum is a spore-forming, anaerobic, gram-positive bacillus that is the source of one of the most lethal neurotoxins known to man. The toxin’s actions are linked to its effect on neuromuscular transmission, which can lead to respiratory failure. C. botulinum toxin irreversibly binds to the presynaptic membrane and prevents release of ACh. A rapidly progressive descending paralysis follows and is accompanied by prominent, autonomic symptoms and respiratory involvement.
Botulinum Neurotoxins. Seven strains of C. botulinum (designated type A through G) have been identified. Only some of these have been implicated in human disease, and they have a geographical distribution. Type A causes disease primarily west of Mississippi and type B east Mississippi. Type E is found in the Pacific Northwest; it usually is restricted to fish and seafood and is capable of growing and producing toxin in near-freezing temperatures. Neurotoxins from A, B, E, and F are well-established causes of human botulism, while C and D primarily cause illness in other animals.38
C. Botulinum spores proliferate in an anaerobic environment and can survive under the most adverse conditions. They can withstand boiling (100°C) for hours and produce a neurotoxin that is lethal at a concentration of 0.05-0.1 mcg. C. Botulinum can cause human disease when either the spores or the toxin are ingested (classical, food-borne), when spores colonize the GI tract (infant botulism and its closely related, poorly defined adult form), or when the spores germinate and produce the toxin in a traumatic wound (wound botulism). In the United States, infant botulism is the most common form and wound botulism is the rarest form of botulism, although wound botulism has been reported in intravenous drug abusers.
The seven strains of C. Botulinum produce related, heat labile neurotoxins. The human neuromuscular junction seems to be sensitive primarily to strains A, B, and E, although toxin C has shown toxicity in vitro.39 The neurotoxin consists of a light (50 kd) and a heavy chain (100 kd) linked together by a disulfide bond. Due to the high molecular weight of these neurotoxins, they are rapidly inactivated by heat, but not by the acid or proteolytic activity of the stomach. In its natural form, it exists in complex with several other proteins from which it disassociates in the alkaline environment of the intestines.40,41 The neurotoxin exerts its inhibitory effects against the excretory apparatus that facilitates neurotransmitter release. The neurotoxin binds to the presynaptic membrane (the exact binding site varies with toxin type but is confined to the presynaptic membrane), and after endocytosis it interacts with three crucial SNARE proteins that are responsible for synaptic vesicle fusion; SNARE proteins include synaptobrevin, syntaxin, and SNAP-25. Zinc-dependent catalytic action prevents the synaptic vesicle from fusing with the membrane, thereby inhibiting neurotransmitter release. The exact molecular target for various toxin types may be different, but all produce the same end result.42,43
Clinical Presentation. Cranial nerve findings in the presence of GI symptoms should alert the ED physician to the diagnosis of botulism. The history should confirm the initial impression. Although the neurologic signs of botulism may be delayed for weeks, more typically the onset is within 12-36 hours after ingestion of the toxin. The most prominent symptoms relate to the bulbar musculature. Patients most commonly will complain of blurry or double vision, dysarthria, and dysphagia. Skeletal muscle paralysis follows, with a symmetrical, descending, and progressive weakness that may abruptly culminate in respiratory failure. Progression from onset of symptoms to respiratory failure can occur in as little as 24 hours, making this the most fulminant of all the neuromuscular transmission disorders. The presence of anticholinergic symptoms aids in the diagnosis.44-46
On physical examination, the patient remains alert, oriented, and without fever. Postural hypotension may be noted, along with dry mucous membranes. Eyelid ptosis and pupillary abnormalities are important early bulbar signs; pupils tend to be dilated and, at times, fixed. Patients may have a compromised gag reflex. The extent of extremity weakness varies depending upon the degree of progression. Deep tendon reflexes range from normal to absent and correlate with the extent of muscular weakness.
The presentation of wound botulism is similar, with prominent bulbar findings associated with a history of a traumatic wound. It should be appreciated that the current target population for wound botulism appears to be IV drug abusers. In any active IV drug abuser presenting with bulbar findings, botulism should be the initial diagnostic consideration. Symptoms present within 3-4 days, although a lag of up to three weeks has been described. The median age for all the cases is 19 years with a range of 6 to 44 years. Symptoms and signs are identical to those in other forms of botulism.47-49
Infant botulism should be considered in a listless baby with a weak cry, poor suck, and constipation. This may evolve into generalized weakness in an acute or subacute manner. The pattern remains symmetrical and evolves into a descending paralysis. On physical exam, the child is hypotonic and, therefore, frequently described as "floppy." Cranial nerve findings include sluggish pupillary response to light, ptosis, ophthalmoplegia, and diminished gag reflex. Bowel sounds are hypoactive and there is poor anal sphincter tone. Severity can range from mild infection to a fulminant, fatal course including respiratory failure with respiratory arrest.50
Diagnosis requires isolation of C. botulinum toxin from a suspected food source, stool, or wound. Isolation of C. botulinum from the stool is helpful, but not always present in those with clinical botulism. Up to 40% of the patients may not have C. botulinum in their stool and only 36% may be positive after three days. If there is a delay in securing serum sample, two days after a toxin ingestion the chances of obtaining a positive test is less than 30%. Electrophysiologic studies aid when lab data is pending or non-confirmatory. Electrophysiologic studies show classic pattern of presynaptic neuromuscular defect with decreased amplitude of muscle action potential, an incremental response of the muscle action potential (MAP) to slow rates of nerve stimulation, and post-tetanic facilitation.
Management. Treatment of all forms of botulism consists of meticulous supportive care with special attention to respiratory status. Infant botulism does not require antitoxin administration and antibiotic treatment is not required (antibiotics can lead to bacterial cell death and toxin release).50 Antitoxin administration in other forms of botulism also is controversial because of lack of efficacy in many cases and the risk of allergic reactions. Beneficial effects are more likely with type A and E botulism. To be of benefit, antitoxin must be given early while the toxin is still in the blood and before it is internalized and bound to the nerve terminal. Serious side effects related to antitoxin therapy occur in as many as 20% of the patients. In a series of 268 patients, there was a 3% rate of anaphylaxis.51 Most commercially available botulinum antitoxins are of equine origin, and allergic reactions are attributed to antibody products of non-human origin. Currently, administration of antitoxin is recommended by most experts regardless of delay in diagnosis.52
Guanidine and 4-aminopyridine have been studied and seem to be helpful in patients with bulbar symptoms, although these agents have no effect on respiratory paralysis. Both of these drugs have serious side effects that limit their use.
The prognosis of patients with botulism has improved significantly with advances in critical care. Respiratory management and good supportive care are key to improved survival. Despite a protracted course, complete recovery follows, which requires regeneration of terminal motor neurons and formation of new motor nerve end plates.
Medications that Interfere with Neuromuscular Transmission
The neuromuscular junction is vulnerable to the effects of several medications. Drugs can act presynaptically, postsynaptically, or in combination to produce neuromuscular transmission disturbances. Administration of these drugs can unmask venerability of the neuromuscular junction to transmission failure. It is important to avoid such medications in those with an established diagnosis of neuromuscular transmission failure and recognize that these medications can produce worsening of symptoms in patients with underlying neuromuscular transmission failure.
The best studied medication producing neuromuscular transmission failure of is D-penicillamine, a medication used in Wilson’s disease and in several other rheumatologic disorders. D-penicillamine is known to be an iatrogenic cause of MG, with MG occurring in up to 7% of patients on this medication. Serologically and electrophysiologically, drug-induced inhibition of neuromuscular transmission is indistinguishable from idiopathic forms of MG, although its clinical course tends to be milder.53
Among drugs causing presynaptic inhibition, magnesium is of particular interest. Despite its increasing popularity, it should be stressed that hypermagnesemia can lead to impaired neuromuscular transmission and respiratory paralysis. At the presynaptic membrane, magnesium regulates calcium influx through VGCC; specifically, hypermagnesemia interferes with neuromuscular transmission by competitively blocking calcium influx at the motor nerve terminal, thereby preventing calcium-mediated exocytosis of the neurotransmitter.54-56 This presynaptic action produces autonomic cholinergic blockade. Use of magnesium potentiates the action of neuromuscular blocking agents and is responsible for prolonged respiratory muscle weakness. This has been effectively demonstrated in women who had C-section after treatment with magnesium for eclampsia.55
Several antibiotics also are known to compromise neuromuscular transmission and exacerbate symptoms in patients with MG. Chief among them are aminoglycosides, chloroquine, and fluoroquinolones.37,51 All of these agents have pre- and postsynaptic effects.57,58
Summary
Disorders of neuromuscular transmission represent a category of life-threatening conditions of which the ED physician should be aware. These potentially fatal disorders should be considered in patients with muscle weakness of unknown etiology. Supportive management, including intubation and pharmacologic intervention should be initiated in a systemic approach to patient care.
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Recommended Reading
• Engel AG, Tsujihata M, Lindstrom JM, et al. The motor end plate in myasthenia gravis and in experimental autoimmune myasthenia gravis: A quantitative ultrastructural study. Ann N Y Acad Sci 1976;274:60-79.
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• Sanders DB. Clinical neurophysiology of disorders of neuromuscular junction. J Clin Neurophysiol 1993;10:167-180.
• Huang D, et al. No evidence for interleukin-4 gene conferring susceptibility to myasthenia gravis. J Neuroimmunol 1998;92: 208-211.
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