Overview of Neuromuscular Junction Toxins

Overview of neuromuscular junction toxins
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Official reprint from UpToDate www.uptodate.com 2012 UpToDate

Authors Tracy Weimer, MD Laurie Gutmann, MD Disclosures Last literature review version 19.3: September 2011 | This topic last updated: May 19, 2009 INTRODUCTION Signal transduction at the neuromuscular junction is a multistep, complex process required for many of the functions that sustain life. Neuromuscular toxins act in various ways to inhibit this process. These toxins are naturally occurring [1], and some have been developed as biochemical weapons. This topic will briefly discuss the neuromuscular transmission disorders due to botulism, tick paralysis, snake venom, organophosphates and carbamates, and hypermagnesemia or hypocalcemia. Acquired myasthenia gravis, congenital and neonatal myasthenia gravis, and Lambert-Eaton myasthenic syndrome are discussed separately. (See "Pathogenesis of myasthenia gravis" and "Clinical manifestations of myasthenia gravis" and "Neuromuscular junction disorders in newborns and infants" and "Clinical features and diagnosis of Lambert-Eaton myasthenic syndrome".) THE NEUROMUSCULAR JUNCTION The neuromuscular junction consists of a presynaptic axon terminal and a postsynaptic muscle end plate. Within the presynaptic terminal are vesicles containing acetylcholine, adenosine triphosphate (ATP), magnesium, and calcium [2,3]. Most of these vesicles are bound to the actin cytoskeleton by proteins called synapsins. When an action potential induces opening of calcium channels, increased intracellular calcium levels promote phosphorylation of synapsins. This phosphorylation results in release of the vesicles from their cytoskeletal sites [4]. After release from the cytoskeleton, vesicles become bound at the presynaptic membrane terminal in areas called active zones [2,5]. This "docking" allows rapid exocytosis of the vesicles. Docking is mediated by proteins termed SNARES (soluble N-ethylmaleimide-sensitive-fusion-attachment protein receptors). SNARES attached to the terminal membrane (t-SNARES) form complexes with proteins located on the vesicle (v-SNARES) [6-8]. Proteins involved in SNARE complexes include VAMP (vesicle-associated membrane protein), which is found on the vesicle surface, along with SNAP-25 (synaptosomal-associated protein of 25 kD) and syntaxin, proteins found at the terminal membrane [6-8]. VAMP, syntaxin, and SNAP-25 are targets of the protease activity of botulinum toxin. Phosphorylation of docking proteins occurs in response to increased calcium levels. This induces SNARE complex formation, followed by exocytosis of the vesicle contents [6,8]. The vesicle membrane becomes added to the terminal membrane. Vesicles are recycled when pits form in the terminal membrane and become coated with a protein called clathrin. These clathrin-coated pits then pinch off to form vesicles [9]. Acetylcholine is then synthesized and repackaged into these vesicles.
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Section Editor Jeremy M Shefner, MD, PhD
Deputy Editor John F Dashe, MD, PhD
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The postsynaptic membrane is heavily folded and invaginated. Acetylcholine receptors are found at the crests of the junctional folds, and voltage-sensitive Na+ channels are concentrated within the folds. The acetylcholine receptors have an ideal binding constant to allow reversible binding of acetylcholine. When bound, ion channels within the receptor are opened with an influx of Na+, and there is a transient depolarization of the end-plate region. If this end-plate potential is large enough, a muscle fiber action potential is generated, which leads to muscle contraction. Acetylcholine remaining in the synapse is rapidly degraded by the enzyme acetylcholinesterase, and the muscle is allowed to repolarize [10]. BOTULISM Botulism is an uncommon and life-threatening disease caused by bacteria in the Clostridium family. The botulinum neurotoxin is considered the most potent lethal substance known. In high enough doses, it causes rapid and severe paralysis of skeletal muscles. Botulism is briefly reviewed here and is discussed in detail separately. (See "Botulism".) Epidemiology Organisms of the Clostridium genus are commonly found in soil and include C. botulinum, C baratii, and C butyricum. They are all gram-positive, anaerobic, spore-forming rods, which have evolved to produce a potent neurotoxin. Eight distinct C. botulinum toxin types have been described: A, B, C1, C2, D, E, F, and G. Of these eight, types A, B, E, and rarely F and G cause human disease. (See "Botulism", section on 'Pathogenesis'.) The modern syndrome of botulism occurs in five forms, differentiated by the mode of acquisition: Food borne botulism occurs after ingestion of food contaminated by preformed botulinum toxin Infant botulism occurs after the ingestion of clostridial spores that then colonize the host's gastrointestinal (GI) tract and release toxin produced in vivo Wound botulism occurs after infection of a wound by Clostridium botulinum with subsequent in vivo production of neurotoxin Adult enteric infectious botulism or adult infectious botulism of unknown source is similar to infant botulism in that toxin is produced in vivo in the GI tract of an infected adult host Inhalational botulism is the form that would occur if aerosolized toxin was released in an act of bioterrorism An average of 110 cases of botulism are reported each year in the United States. Approximately 72 percent of these cases are infant botulism, 25 percent are food borne botulism, and the remaining 3 percent are wound botulism. The incidence of wound botulism has increased due to the use of heroin. Adult infectious botulism is only occasionally reported. (See "Botulism", section on 'Epidemiology'.) Clinical features Symptoms range from minor cranial nerve palsies associated with symmetric descending weakness to rapid respiratory arrest. Key features of the botulism syndrome include: Absence of fever Symmetric neurologic deficits Preserved responsiveness Normal or slow heart rate and normal blood pressure No sensory deficits with the exception of blurred vision Fever may be seen with wound botulism, but it probably results from concurrent bacterial infection of the
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wound by non-clostridial species. Food borne botulism produces gastrointestinal (GI) symptoms such as nausea, vomiting, or diarrhea. These may precede neurologic symptoms. (See "Botulism", section on 'Clinical manifestations'.) Disease presentation and severity are quite variable in infant botulism, most likely as a result of size of the bacterial inoculum and host susceptibility. A detailed discussion of infant botulism is presented separately. (See "Neuromuscular junction disorders in newborns and infants", section on 'Infant botulism'.) Routine lab tests in botulism are generally nonspecific, and specific laboratory confirmation may take up to days. Therefore, the diagnosis is usually clinical. (See "Botulism", section on 'Diagnosis'.) Neurophysiology Electrodiagnostic studies (nerve conduction studies and electromyography) are frequently helpful in diagnosis of botulism. Sensory action potentials and nerve conduction velocities are typically normal. However, compound motor action potential (CMAP) amplitudes are decreased if the presynaptic block is severe enough. Repetitive nerve stimulation (RNS) at frequencies of 2 to 5 Hz depletes readily available stores of acetylcholine from the neuromuscular junction and decreases CMAP amplitudes even further, a finding termed the decremental response [11,12]. A decrement of greater than 10 percent is considered abnormal. In more severe cases, the baseline CMAP may be too low to see decremental response. In contrast, increased rates of stimulation (20 to 50 Hz) or exercise cause accumulation of calcium in the presynaptic terminal and increase release of acetylcholine, a finding termed the incremental response, or postactivation facilitation (figure 1). This can be seen in approximately 60 percent of cases of adult botulism poisoning [12]. The amount of facilitation seen with botulism (40 to 100 percent) is usually less than that seen in Lambert-Eaton myasthenic syndrome (200 percent or more) (figure 2) [11]. No increment or only very mild increment will be seen if the block produced by botulism is too severe. The post-tetanic facilitation may also be extraordinarily prolonged with botulism, occasionally up to four minutes. Postactivation exhaustion, a decrease in CMAP amplitude occurring two to four minutes after maximal muscle contraction, is not present in cases of botulism poisoning [11,12]. In summary, EMG diagnosis of botulism should be based on the following findings [11-13]: Reduced baseline CMAP amplitude Postactivation facilitation (between 40 and 200 percent) Absence of postactivation exhaustion Postactivation facilitation which persists longer than two minutes The sensitivity of repetitive nerve stimulation is much greater in cases of infantile botulism. (See "Neuromuscular junction disorders in newborns and infants", section on 'Infant botulism'.) Treatment Botulinum antitoxin should be given as soon as botulism is suspected. (See "Botulism", section on 'Treatment'.) TICK PARALYSIS Several tick species produce a toxin that inhibits transduction at the neuromuscular junction by blocking influx of sodium ions. This prevents presynaptic terminal axon depolarization and inhibits release of acetylcholine at the nerve terminal. The toxin has not been fully identified. The ticks primarily responsible include the Rocky Mountain wood tick (Dermacentor andersoni), the American dog tick (D. variabilis), the Lone Star tick (Amblyomma americanum), the black-legged tick (Ixodes scapularis), the western black-legged tick (I. pacificus), the Gulf coast tick (A. maculatum), and the Australian Ixodes holocyclus.
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Tick paralysis is briefly reviewed here; a detailed discussion is presented separately. (See "Tick paralysis".) Clinical features Symptoms include anorexia, lethargy, muscle weakness, nystagmus, and an ascending flaccid paralysis. Symptom onset occurs three to seven days after attachment of the tick. (See "Tick paralysis", section on 'Clinical features'.) Neurophysiology Electromyography shows a reduced amplitude of compound muscle action potentials [14]. No abnormalities are seen with repetitive nerve stimulation studies [14,15]. There may be subtle abnormalities of motor nerve conduction velocity and sensory action potentials. Diagnosis The diagnosis of tick paralysis usually relies on the finding of a tick attached to the patient. Unexposed areas such as the scalp, genitalia, and external meatus should be inspected carefully. (See "Tick paralysis", section on 'Differential diagnosis' and "Tick paralysis", section on 'Suggested approach to diagnosis and management'.) Treatment Removal of the tick is the primary treatment of tick paralysis. The tick can be removed with forceps. However, it should be paralyzed with an insecticide prior to removal to ensure removal of mouth parts. Clinical improvement is generally fairly rapid after removal of American ticks. Symptoms may continue and worsen for two to three days after removal of Australian ticks. For severely affected patients, an antivenom derived from dogs is available. (See "Tick paralysis", section on 'Suggested approach to diagnosis and management'.) SNAKE VENOM Four families of snakes produce venom causing neuromuscular transmission disorders [16]: Atractaspididae (African mole viper) Colubridae (boomslang, twig snake) Elapidae, with three major subfamilies: Elapinae (cobras, mambas, coral snakes) Hydrophiinae (sea snakes) Laticaudinae (sea kraits) Viperidae, with two major subfamilies: Crotalinae, the pit vipers (copperheads, cottonmouth, moccasins, and rattlesnakes) Viperinae, the classic "Old World" vipers (carpet viper, common adder, puff adder, horned or desert vipers, Russell's viper) The toxins produced affect either the presynaptic or postsynaptic junction. Toxins affecting the presynaptic junction include beta-bungarotoxin (krait), notexin (tiger snake), taipoxin (Taipan), and crotoxin (Brazilian rattlesnake). These toxins have phospholipase A2 activity. They catalyze the hydrolysis of one of the fatty ester linkages in diacyl phosphatides, forming lysophosphatides and releasing both saturated and unsaturated fatty acids [17-19].
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The exact mechanism of toxicity is undefined, but initial fusion of synaptic vesicles with the presynaptic membrane is induced, followed by inhibited reformation of the vesicles after exocytosis. Further neurotransmitter release is therefore prevented [20,21]. Poisoned nerve terminals show an absence of vesicles [22], which causes delayed degeneration of the motor nerve terminals. Recovery requires nerve terminal regeneration, a process that may take weeks. The presynaptic neurotoxins also possess myotoxic activity, which may lead to degeneration of skeletal muscle and death from acute renal failure. The postsynaptic-acting toxins are present in venom of snakes from the Elapidae family [19,23]. They bind irreversibly to the acetylcholine receptor site, and prevent the opening of the associated sodium channel [23]. As an example, alpha-bungarotoxin from the krait produces a postjunctional neuromuscular blockade. Clinical features and diagnosis Snake venom neurotoxins affect the cranial nerves first, resulting in ptosis, ophthalmoplegia, dysarthria, dysphagia, and drooling. This progresses to weakness of limb muscles [24,25]. Clotting time is also increased [24]. The postsynaptic toxins produce findings on electrodiagnostic studies identical to those seen in myasthenia gravis, since the mechanism of disease is similar [26]. Repetitive nerve stimulation produces a decremental response. (See "Diagnosis of myasthenia gravis", section on 'Electrophysiologic confirmation'.) Envenomation by the timber rattlesnake causes myokymia (figure 3). Spontaneous bursts of motor unit potentials manifest as doublets and multiplets on electromyography [27]. Extensive diagnostic workup is generally unnecessary, since most patients are fully aware of the snake bite. Treatment The management of snake bites is briefly reviewed here and discussed separately in greater detail (algorithm 1). (See "Management of Crotalinae (rattlesnake, water moccasin [cottonmouth], or copperhead) bites in the United States" and "Principles of snake bite management worldwide".) Frequently, the species of snake producing the bite is unknown (picture 1), and it is unclear if the bite was actually venomous. However, with any potentially venomous bite or sting, the patient should be observed for several hours before it is decided that the event is benign. Antivenom is available and effective for postsynaptic neurotoxins. It accelerates dissociation of the toxin from the postsynaptic receptor. Presynaptic toxins have no response to antivenom [24]. Cutting, biting, sucking, or excising tissue at the site is contraindicated, as these measures do not help remove venom and may introduce infection. DRUGS In addition to the neuromuscular blocking agents used during anesthesia, a number of other drugs can affect transmission at the neuromuscular junction, including the following [28]: D-penicillamine Aminoglycoside antibiotics Fluoroquinolone antibiotics [29] Phenytoin and other anticonvulsants Lithium Beta blockers Glucocorticoids Magnesium sulfate (see 'Hypermagnesemia/hypocalcemia' below)
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D-penicillamine, used to treat rheumatoid arthritis and Wilson's disease, induces production of antibodies to acetylcholine receptors. This results in a syndrome clinically similar to myasthenia gravis. (See "Differential diagnosis of myasthenia gravis", section on 'Penicillamine-induced myasthenia'.) The other drugs listed above are generally safe, but may cause reduced transmission at the neuromuscular junction in cases of overdose, or when used in patients who have underlying disease of the neuromuscular junction, such as myasthenia gravis (table 1) or Lambert-Eaton myasthenic syndrome. (See "Treatment of myasthenia gravis", section on 'Drugs that may exacerbate myasthenia'.) Aminoglycoside antibiotics inhibit both pre- and postsynaptic transmission [30,31]. Phenytoin causes both pre- and postsynaptic effects and prevents the depolarization required for neurotransmission. There is controversy over the nature of the action of beta blockers on the neuromuscular junction. They may produce a depolarizing or non-depolarizing blockade or have a local anesthetic action [32,33]. Lithium, with chronic use, may compete with calcium in the presynaptic region and reduce the release of acetylcholine (ACh) from nerve terminals [34]. Clinical features and diagnosis Generally, the offending drug is simply withdrawn, and the diagnosis is made by the resultant clinical improvement. The diagnosis may also be aided by administration of cholinesterase inhibitors. In aminoglycoside poisoning, low rates of repetitive nerve stimulation produce a decremental response, with post-tetanic facilitation [30]. The facilitation exceeds that seen in myasthenia gravis [30]. The decremental response is also larger than occurs in myasthenia. Since D-penicillamine produces a myasthenia syndrome, the findings on electrodiagnostic studies are the same as those in patients with myasthenia (figure 4). (See "Diagnosis of myasthenia gravis", section on 'Electrophysiologic confirmation'.) The clinical features are usually mild and affect primarily the extraocular muscles. The diagnosis can also be aided by finding elevated serum acetylcholine receptor antibodies. Clinical improvement is usually complete within one year of drug discontinuation. (See "Differential diagnosis of myasthenia gravis", section on 'Penicillamine-induced myasthenia'.) ORGANOPHOSPHATE AND CARBAMATE TOXICITY Organophosphates and carbamates are potent inhibitors of acetylcholinesterase, causing excess acetylcholine concentrations in the synapse. These compounds are formed as the esters of phosphoric or phosphorothioic acid or as the esters of carbamic acid, and are commonly used as pesticides. Each year, over 10,000 cases of organophosphate or carbamate poisoning occur in the United States, and 3,000,000 people are exposed worldwide. Exposure routes include oral ingestion, inhalation, or dermal contact. Organophosphorous "nerve gases" (eg, tabun [GA], sarin [GB], soman [GD]) have also been developed. Organophosphate and carbamate toxicity is briefly reviewed here; a detailed discussion is presented separately. (See "Organophosphate and carbamate poisoning".) Pathophysiology Although the organophosphates and the carbamates have a common mode of action (anticholinesterase activity leading to an overabundance of acetylcholine in the synapse), there are significant differences between their reactions with the enzyme. The bond between an organophosphorous ester and the active site of the acetylcholinesterase enzyme is extremely stable, and these compounds are referred to as irreversible inhibitors. The carbamates interact with acetylcholinesterase in a fashion similar to acetylcholine. They bind non-covalently and the free, active enzyme is regenerated.
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The spontaneous hydrolysis of organophosphates from acetylcholinesterase is generally very slow. Oximes, specifically pralidoxime, are typically used to induce more rapid dephosphorylation. If the oxime is not administered soon enough after acetylcholinesterase has been inhibited, an alkoxy group may be lost from the phosphorylated enzyme, resulting in a conformational change, known as "aging". Aging can occur within minutes for some compounds or may take up to days. Once aging has occurred, oximes can no longer induce dephosphorylation. The excess synaptic acetylcholine produced by organophosphates and carbamates binds muscarinic receptors in the central nervous system (CNS) and the parasympathetic portion of the autonomic nervous system. It also binds nicotinic receptors in the CNS, sympathetic and parasympathetic ganglia, and the neuromuscular junction. (See "Organophosphate and carbamate poisoning", section on 'Mechanism of action'.) Clinical features Since both sympathetic and parasympathetic systems are involved, symptoms of organophosphate and carbamate poisoning include typical muscarinic signs (lacrimation, bradycardia, bronchospasm) and nicotinic signs (mydriasis, tachycardia, weakness, hypertension). These result from the accumulation of acetylcholine in sympathetic ganglia and at the adrenal medulla (table 2). Increased depolarization at nicotinic neuromuscular synapses results in muscle weakness and flaccid paralysis. The dominant clinical features of acute cholinergic toxicity include bradycardia, miosis, lacrimation, salivation, bronchorrhea, bronchospasm, urination, emesis, and diarrhea [35]. (See "Organophosphate and carbamate poisoning", section on 'Clinical features'.) CNS symptoms may be present, with suppression of central medullary centers resulting in anxiety, confusion, seizures, and coma. Ten to 40 percent of patients develop a distinct neurologic disorder 24 to 96 hours after organophosphorous agent poisoning, referred to as the "intermediate syndrome." Characteristic neurologic findings include cranial nerve abnormalities, neck flexion and proximal muscle weakness, respiratory insufficiency, and decreased deep tendon reflexes. A delayed symmetrical motor polyneuropathy, termed organophosphorous agent-induced delayed neuropathy (OPIDN), may occur one to three weeks after exposure to specific organophosphorous agents, including chlorpyrifos. Neurophysiology Electrodiagnostic studies in organophosphate poisoning demonstrate repetitive compound muscle action potentials in response to a single stimulus to the nerve [36]. This is caused by excess accumulation of acetylcholine in the synapse and subsequent depolarization of the postsynaptic muscle membrane. The presynaptic receptors are also activated. This combined effect results in repetitive discharges in response to a single stimulus. Repetitive nerve stimulation results in decrement of the compound motor action potential (CMAP) [36]. In early stages of organophosphate poisoning, a decrement-increment response may be seen with higher rates of stimulation. This response may recur later, as clinical improvement is seen [36,37]. Diagnosis The diagnosis of organophosphate or carbamate poisoning is made on clinical grounds; the clinical features of cholinergic excess should indicate the possibility of organophosphate poisoning. (See "Organophosphate and carbamate poisoning", section on 'Diagnosis'.) Treatment Emergency management of organophosphate or carbamate poisoning often requires endotracheal intubation and volume resuscitation (table 2). All cases require aggressive decontamination with complete removal of the patient's clothes and vigorous irrigation of the affected areas. (See
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"Organophosphate and carbamate poisoning", section on 'Management'.) Atropine is used for symptomatic relief of muscarinic symptoms. It does not reverse the paralysis caused by neuromuscular blockade that results from nicotinic receptor stimulation. Atropine dosing should be titrated to the therapeutic end point of the clearing of respiratory secretions and the cessation of bronchoconstriction. Specific dosing regimens are discussed separately. (See "Organophosphate and carbamate poisoning", section on 'Atropine'.) Pralidoxime and other oximes are effective in treating both muscarinic and nicotinic symptoms. Pralidoxime should not be administered without concurrent atropine, which prevents worsening symptoms due to transient oxime-induced acetylcholinesterase inhibition. Oxime therapy should be given to all patients with evidence of cholinergic toxicity, neuromuscular dysfunction, or exposure to organophosphorous agents known to cause delayed neurotoxicity. Dosing regimens are discussed separately. (See "Organophosphate and carbamate poisoning", section on 'Pralidoxime'.) HYPERMAGNESEMIA/HYPOCALCEMIA A surplus of magnesium or a deficiency of calcium may cause inhibition of acetylcholine release. The administration of magnesium sulfate to mothers with eclampsia has resulted in hypermagnesemia in infants with the development of weakness and respiratory depression. Hypermagnesemia is an uncommon problem in the absence of magnesium administration or renal failure. Concentrated sources of magnesium include antacids, enemas, and total parenteral nutrition. (See "Causes and treatment of hypermagnesemia".) Magnesium has a calcium channel blocking effect that decreases entry of calcium into cells. It also decreases the amount of acetylcholine released and depresses the excitability of the muscle membrane [38]. This produces proximal muscle weakness, which may progress to respiratory insufficiency. Ocular muscles are generally spared. (See "Symptoms of hypermagnesemia", section on 'Neuromuscular effects'.) Fast synaptic transmission is steeply dependent on external calcium concentrations. Hypocalcemia results in an uncoupling of synaptic release of neurotransmitters (glutamate, acetylcholine, GABA) in response to an action potential at the nerve terminal. This is because the proteins involved in synaptic vesicle docking and fusion interact in a calcium-dependent manner [6]. (See "Clinical manifestations of hypocalcemia".) Electrodiagnostic studies show low-amplitude compound muscle action potentials, decremental response to low-frequency stimulation, and post-tetanic facilitation. Diagnosis The diagnosis of hypermagnesemia or hypocalcemia is generally made by demonstrating elevated serum magnesium levels or decreased calcium levels and observing clinical improvement as levels normalize. Use of UpToDate is subject to the Subscription and License Agreement.
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GRAPHICS
RNS incremental response
Superimposed median nerve compound muscle action potentials at 50 Hz stimulation, showing continued incremental response in a patient with presynaptic neuromuscular junction defect.
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Compound muscle action potential postexercise facilitation
A) Exercise testing in Lambert-Eaton myasthenic syndrome, with the median nerve stimulated supramaximally at the wrist and the abductor pollicis brevis muscle recorded. Top: Baseline. Bottom: Immediately after 10 seconds of maximal voluntary exercise. Note marked increase in compound muscle action potential amplitude (postexercise facilitation). Preexercise and postexercise testing, looking for an increment, always is better tolerated by patients than is 50-Hz repetitive nerve stimulation. B) Slow (3 Hz) repetitive nerve stimulation in LEMS, before and after brief exercise. In both situations, there is a prominent decrement. However, after brief exercise, the baseline compound muscle action potential (CMAP) is significantly larger compared with the CMAP before exercise. In this case, the CMAP increment after brief exercise was 2000 percent. CMAP: compound muscle action potential. Reproduced with
permission from: Preston, DC, Shapiro, BE. Electromyography and Neuromuscular Disorders, 2nd ed, Butterworth-Heinemann, Boston
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1998. Copyright 1998 Elsevier.
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EMG in patient with myokymia
Doublets and triplets with clinical myokymia following rattle snake envenomation.
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Algorithm for the management of snake bites
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Comparison of venomous snakes (pit vipers) and nonvenomous snakes in the United States
Reproduced with permission from: Hodge III D. Bites and Stings. In: Textbook of Pediatric Emergency Medicine, 6th edition, Fleisher GR, Ludwig S (Eds), Lippincott Williams & Wilkins, Philadelphia, 2010. Copyright 2010 Lippincott Williams & Wilkins.
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Drugs that may unmask or exacerbate myasthenia gravis*

Anesthetic agents
Chloroprocaine Diazepam Ether Halothane Ketamine Lidocaine Neuromuscular blocking agents Propanidid Procaine
Antirheumatic drugs
Chloroquine Penicillamine
Cardiovascular drugs
Beta blockers Bretylium Procainamide Propafenone Quinidine Verapamil and calcium channel blockers
Antibiotics
Aminoglycosides
Amikacin Gentamicin Kanamycin Neomycin Netilmicin Paromomycin Spectinomycin Streptomycin Tobramycin
Glucocorticoids
Corticotropin Methylprednisolone Prednisone
Neuromuscular blockers and muscle relaxants

Botulinum toxin Magnesium sulfate and magnesium salts Methocarbamol
Fluoroquinolones
Ciprofloxacin Gemifloxacin Levofloxacin Moxifloxacin Norfloxacin Ofloxacin
Ophthalmologic drugs
Betaxolol Echothiophate Timolol Tropicamide Proparacaine
Others
Ampicillin Clarithromycin Clindamycin Colistin Erythromycin Lincomycin
Other drugs
Anticholinergics Carnitine Cholinesterase inhibitors Deferoxamine Diuretics
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Quinine Telithromycin Tetracyclines
Emetine (Ipecac syrup) Interferon alpha Iodinated contrast agents Narcotics Oral contraceptives Oxytocin Ritonavir and antiretroviral protease inhibitors Statins Thyroxine
Anticonvulsants
Gabapentin Phenytoin Trimethadione
Antipsychotics
Chlorpromazine Lithium Phenothiazines
* Drugs listed here should be used with caution in patients with myasthenia gravis. Aminoglycosides should be used only if absolutely necessary with close monitoring. Please refer to the text for further information.
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Repetitive nerve stimulation (RNS) study in myasthenia gravis
Successive compound motor action potentials (CMAPs) from the abductor pollicis brevis muscle are displayed after six stimuli at 3 Hertz. A decremental response (ie, a decline in the response amplitude) is seen. It is maximal at 38 percent by the fourth response in this example. Sensitivity: 5 mV/div; Sweep speed: 5 msec/div.
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Rapid overview of organophosphate and carbamate poisoning

To obtain emergent consultation with a medical toxicologist, call the United States Poison Control Network at 1-800-222-1222, or access the World Health Organization's list of international poison centers (www.who.int/ipcs/poisons/centre/directory/en).
Clinical syndromes
Acute toxicity Generally manifests in minutes to hours Evidence of cholinergic excess
SLUDGE = Salivation, Lacrimation, Urination, Defecation, Gastric Emptying BBB = Bradycardia, Bronchorrhea, Bronchospasm
Respiratory insufficiency can result from muscle weakness, decreased central drive, increased secretions, and bronchospasm Intermediate syndrome Occurs 24-96 hours after exposure Bulbar, respiratory, and proximal muscle weakness are prominent features Generally resolves in 1-3 weeks Organophosphorous Agent-Induced Delayed Peripheral Neuropathy (OPIDN) Usually occurs several weeks after exposure Primarily motor involvement May resolve spontaneously, but can result in permanent neurologic dysfunction
Diagnostic evaluation of acute toxicity

Atropine challenge if diagnosis is in doubt (1 mg IV in adults, 0.01-0.02 mg/kg in children)
Absence of anticholinergic signs (tachycardia, mydriasis, decreased bowel sounds, dry skin) strongly suggests poisoning with organophosphate or carbamate
Draw blood sample for measurement of RBC acetylcholinesterase activity to confirm diagnosis
Treatment of acute toxicity

Deliver 100 percent oxygen via facemask; early intubation often required; avoid succinylcholine Atropine 2-5 mg IV bolus (0.05 mg/kg IV in children)
Escalate (double) dose every 3-5 minutes until bronchial secretions and wheezing stop TACHYCARDIA AND MYDRIASIS ARE NOT CONTRAINDICATIONS TO ATROPINE USE; Hundreds of milligrams may be needed over several days in severe poisonings
Pralidoxime (2-PAM) 2 g (25-50 mg/kg in children ) IV over 30 minutes

Continuous infusion at 8 mg/kg/hour in adults (10-20 mg/kg/hour in children)
Benzodiazepine therapy
Diazepam 0.1-0.2 mg/kg IV, repeat as necessary if seizures occur
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Overview of Neuromuscular Junction Toxins

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Overview of neuromuscular junction toxins

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