Overview of Neuromuscular Junction Toxins

1/1/12 3:09 PMOverview of neuromuscular junction toxins

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Official reprint from UpToDate® www.uptodate.com ©2012 UpToDate®

AuthorsTracy Weimer, MDLaurie Gutmann, MD

Section EditorJeremy M Shefner, MD, PhD

Deputy EditorJohn F Dashe, MD, PhD

Overview of neuromuscular junction toxins

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 processrequired for many of the functions that sustain life. Neuromuscular toxins act in various ways to inhibitthis process. These toxins are naturally occurring [1], and some have been developed as biochemicalweapons.

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 myasthenicsyndrome are discussed separately. (See "Pathogenesis of myasthenia gravis" and "Clinicalmanifestations of myasthenia gravis" and "Neuromuscular junction disorders in newborns andinfants" and "Clinical features and diagnosis of Lambert-Eaton myasthenic syndrome".)

THE NEUROMUSCULAR JUNCTION — The neuromuscular junction consists of a presynaptic axonterminal and a postsynaptic muscle end plate. Within the presynaptic terminal are vesicles containingacetylcholine, adenosine triphosphate (ATP), magnesium, and calcium [2,3]. Most of these vesicles arebound to the actin cytoskeleton by proteins called synapsins. When an action potential induces openingof calcium channels, increased intracellular calcium levels promote phosphorylation of synapsins. Thisphosphorylation results in release of the vesicles from their cytoskeletal sites [4].

After release from the cytoskeleton, vesicles become bound at the presynaptic membrane terminal inareas called active zones [2,5]. This "docking" allows rapid exocytosis of the vesicles. Docking ismediated by proteins termed SNARES (soluble N-ethylmaleimide-sensitive-fusion-attachment proteinreceptors). SNARES attached to the terminal membrane (t-SNARES) form complexes with proteinslocated on the vesicle (v-SNARES) [6-8].

Proteins involved in SNARE complexes include VAMP (vesicle-associated membrane protein), which isfound on the vesicle surface, along with SNAP-25 (synaptosomal-associated protein of 25 kD) andsyntaxin, proteins found at the terminal membrane [6-8]. VAMP, syntaxin, and SNAP-25 are targets ofthe protease activity of botulinum toxin.

Phosphorylation of docking proteins occurs in response to increased calcium levels. This induces SNAREcomplex formation, followed by exocytosis of the vesicle contents [6,8]. The vesicle membrane becomesadded to the terminal membrane. Vesicles are recycled when pits form in the terminal membrane andbecome 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.



The postsynaptic membrane is heavily folded and invaginated. Acetylcholine receptors are found at thecrests of the junctional folds, and voltage-sensitive Na+ channels are concentrated within the folds. Theacetylcholine receptors have an ideal binding constant to allow reversible binding of acetylcholine. Whenbound, ion channels within the receptor are opened with an influx of Na+, and there is a transientdepolarization of the end-plate region. If this end-plate potential is large enough, a muscle fiber actionpotential is generated, which leads to muscle contraction. Acetylcholine remaining in the synapse israpidly 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 theClostridium family. The botulinum neurotoxin is considered the most potent lethal substance known. Inhigh 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, whichhave 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'sgastrointestinal (GI) tract and release toxin produced in vivo

Wound botulism occurs after infection of a wound by Clostridium botulinum with subsequent in vivoproduction of neurotoxin

Adult enteric infectious botulism or adult infectious botulism of unknown source is similar to infantbotulism 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 ofbioterrorism

An average of 110 cases of botulism are reported each year in the United States. Approximately 72percent of these cases are infant botulism, 25 percent are food borne botulism, and the remaining 3percent 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 symmetricdescending weakness to rapid respiratory arrest. Key features of the botulism syndrome include:

Absence of feverSymmetric neurologic deficitsPreserved responsivenessNormal or slow heart rate and normal blood pressureNo 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



wound by non-clostridial species. Food borne botulism produces gastrointestinal (GI) symptoms such asnausea, 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 ofthe bacterial inoculum and host susceptibility. A detailed discussion of infant botulism is presentedseparately. (See "Neuromuscular junction disorders in newborns and infants", section on 'Infantbotulism'.)

Routine lab tests in botulism are generally nonspecific, and specific laboratory confirmation may take upto days. Therefore, the diagnosis is usually clinical. (See "Botulism", section on 'Diagnosis'.)

Neurophysiology — Electrodiagnostic studies (nerve conduction studies and electromyography) arefrequently helpful in diagnosis of botulism. Sensory action potentials and nerve conduction velocities aretypically normal. However, compound motor action potential (CMAP) amplitudes are decreased if thepresynaptic block is severe enough. Repetitive nerve stimulation (RNS) at frequencies of 2 to 5 Hzdepletes readily available stores of acetylcholine from the neuromuscular junction and decreases CMAPamplitudes even further, a finding termed the decremental response [11,12]. A decrement of greaterthan 10 percent is considered abnormal. In more severe cases, the baseline CMAP may be too low to seedecremental response.

In contrast, increased rates of stimulation (20 to 50 Hz) or exercise cause accumulation of calcium in thepresynaptic terminal and increase release of acetylcholine, a finding termed the incremental response, orpostactivation facilitation (figure 1). This can be seen in approximately 60 percent of cases of adultbotulism poisoning [12]. The amount of facilitation seen with botulism (40 to 100 percent) is usually lessthan that seen in Lambert-Eaton myasthenic syndrome (200 percent or more) (figure 2) [11]. Noincrement or only very mild increment will be seen if the block produced by botulism is too severe. Thepost-tetanic facilitation may also be extraordinarily prolonged with botulism, occasionally up to fourminutes. Postactivation exhaustion, a decrease in CMAP amplitude occurring two to four minutes aftermaximal 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 amplitudePostactivation facilitation (between 40 and 200 percent)Absence of postactivation exhaustionPostactivation 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 neuromuscularjunction by blocking influx of sodium ions. This prevents presynaptic terminal axon depolarization andinhibits 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), theAmerican 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), andthe Australian Ixodes holocyclus.



Tick paralysis is briefly reviewed here; a detailed discussion is presented separately. (See "Tickparalysis".)

Clinical features — Symptoms include anorexia, lethargy, muscle weakness, nystagmus, and anascending 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 actionpotentials [14]. No abnormalities are seen with repetitive nerve stimulation studies [14,15]. There maybe 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 approachto diagnosis and management'.)

Treatment — Removal of the tick is the primary treatment of tick paralysis. The tick can be removedwith forceps. However, it should be paralyzed with an insecticide prior to removal to ensure removal ofmouth parts.

Clinical improvement is generally fairly rapid after removal of American ticks. Symptoms may continueand worsen for two to three days after removal of Australian ticks. For severely affected patients, anantivenom derived from dogs is available. (See "Tick paralysis", section on 'Suggested approach todiagnosis 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 ordesert 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. Theycatalyze the hydrolysis of one of the fatty ester linkages in diacyl phosphatides, forminglysophosphatides and releasing both saturated and unsaturated fatty acids [17-19].



The exact mechanism of toxicity is undefined, but initial fusion of synaptic vesicles with the presynapticmembrane is induced, followed by inhibited reformation of the vesicles after exocytosis. Furtherneurotransmitter release is therefore prevented [20,21]. Poisoned nerve terminals show an absence ofvesicles [22], which causes delayed degeneration of the motor nerve terminals. Recovery requires nerveterminal regeneration, a process that may take weeks. The presynaptic neurotoxins also possessmyotoxic 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]. Theybind irreversibly to the acetylcholine receptor site, and prevent the opening of the associated sodiumchannel [23]. As an example, alpha-bungarotoxin from the krait produces a postjunctionalneuromuscular blockade.

Clinical features and diagnosis — Snake venom neurotoxins affect the cranial nerves first, resulting inptosis, ophthalmoplegia, dysarthria, dysphagia, and drooling. This progresses to weakness of limbmuscles [24,25]. Clotting time is also increased [24].

The postsynaptic toxins produce findings on electrodiagnostic studies identical to those seen inmyasthenia gravis, since the mechanism of disease is similar [26]. Repetitive nerve stimulation producesa decremental response. (See "Diagnosis of myasthenia gravis", section on 'Electrophysiologicconfirmation'.)

Envenomation by the timber rattlesnake causes myokymia (figure 3). Spontaneous bursts of motor unitpotentials manifest as doublets and multiplets on electromyography [27].

Extensive diagnostic workup is generally unnecessary, since most patients are fully aware of the snakebite.

Treatment — The management of snake bites is briefly reviewed here and discussed separately ingreater detail (algorithm 1). (See "Management of Crotalinae (rattlesnake, water moccasin[cottonmouth], or copperhead) bites in the United States" and "Principles of snake bite managementworldwide".)

Frequently, the species of snake producing the bite is unknown (picture 1), and it is unclear if the bitewas actually venomous. However, with any potentially venomous bite or sting, the patient should beobserved 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 toxinfrom 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 venomand may introduce infection.

DRUGS — In addition to the neuromuscular blocking agents used during anesthesia, a number of otherdrugs can affect transmission at the neuromuscular junction, including the following [28]:

D-penicillamineAminoglycoside antibioticsFluoroquinolone antibiotics [29]Phenytoin and other anticonvulsantsLithiumBeta blockersGlucocorticoidsMagnesium sulfate (see 'Hypermagnesemia/hypocalcemia' below)



D-penicillamine, used to treat rheumatoid arthritis and Wilson's disease, induces production of antibodiesto 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 theneuromuscular junction in cases of overdose, or when used in patients who have underlying disease ofthe neuromuscular junction, such as myasthenia gravis (table 1) or Lambert-Eaton myasthenicsyndrome. (See "Treatment of myasthenia gravis", section on 'Drugs that may exacerbate myasthenia'.)

Aminoglycoside antibiotics inhibit both pre- and postsynaptic transmission [30,31]. Phenytoin causesboth pre- and postsynaptic effects and prevents the depolarization required for neurotransmission. Thereis controversy over the nature of the action of beta blockers on the neuromuscular junction. They mayproduce 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 ofacetylcholine (ACh) from nerve terminals [34].

Clinical features and diagnosis — Generally, the offending drug is simply withdrawn, and thediagnosis is made by the resultant clinical improvement. The diagnosis may also be aided byadministration 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]. Thedecremental response is also larger than occurs in myasthenia.

Since D-penicillamine produces a myasthenia syndrome, the findings on electrodiagnostic studies are thesame 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 alsobe aided by finding elevated serum acetylcholine receptor antibodies. Clinical improvement is usuallycomplete 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 potentinhibitors of acetylcholinesterase, causing excess acetylcholine concentrations in the synapse. Thesecompounds are formed as the esters of phosphoric or phosphorothioic acid or as the esters of carbamicacid, and are commonly used as pesticides. Each year, over 10,000 cases of organophosphate orcarbamate poisoning occur in the United States, and 3,000,000 people are exposed worldwide. Exposureroutes 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 presentedseparately. (See "Organophosphate and carbamate poisoning".)

Pathophysiology — Although the organophosphates and the carbamates have a common mode ofaction (anticholinesterase activity leading to an overabundance of acetylcholine in the synapse), thereare significant differences between their reactions with the enzyme. The bond between anorganophosphorous ester and the active site of the acetylcholinesterase enzyme is extremely stable, andthese compounds are referred to as irreversible inhibitors. The carbamates interact withacetylcholinesterase in a fashion similar to acetylcholine. They bind non-covalently and the free, activeenzyme is regenerated.



The spontaneous hydrolysis of organophosphates from acetylcholinesterase is generally very slow.Oximes, specifically pralidoxime, are typically used to induce more rapid dephosphorylation. If the oximeis not administered soon enough after acetylcholinesterase has been inhibited, an alkoxy group may belost from the phosphorylated enzyme, resulting in a conformational change, known as "aging". Aging canoccur within minutes for some compounds or may take up to days. Once aging has occurred, oximes canno longer induce dephosphorylation.

The excess synaptic acetylcholine produced by organophosphates and carbamates binds muscarinicreceptors in the central nervous system (CNS) and the parasympathetic portion of the autonomicnervous 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 oforganophosphate and carbamate poisoning include typical muscarinic signs (lacrimation, bradycardia,bronchospasm) and nicotinic signs (mydriasis, tachycardia, weakness, hypertension). These result fromthe accumulation of acetylcholine in sympathetic ganglia and at the adrenal medulla (table 2). Increaseddepolarization 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 "Organophosphateand 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 afterorganophosphorous agent poisoning, referred to as the "intermediate syndrome." Characteristicneurologic 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 delayedneuropathy (OPIDN), may occur one to three weeks after exposure to specific organophosphorousagents, including chlorpyrifos.

Neurophysiology — Electrodiagnostic studies in organophosphate poisoning demonstrate repetitivecompound muscle action potentials in response to a single stimulus to the nerve [36]. This is caused byexcess accumulation of acetylcholine in the synapse and subsequent depolarization of the postsynapticmuscle membrane. The presynaptic receptors are also activated. This combined effect results inrepetitive discharges in response to a single stimulus. Repetitive nerve stimulation results in decrementof the compound motor action potential (CMAP) [36]. In early stages of organophosphate poisoning, adecrement-increment response may be seen with higher rates of stimulation. This response may recurlater, as clinical improvement is seen [36,37].

Diagnosis — The diagnosis of organophosphate or carbamate poisoning is made on clinical grounds; theclinical 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 requiresendotracheal intubation and volume resuscitation (table 2). All cases require aggressive decontaminationwith complete removal of the patient's clothes and vigorous irrigation of the affected areas. (See



"Organophosphate and carbamate poisoning", section on 'Management'.)

Atropine is used for symptomatic relief of muscarinic symptoms. It does not reverse the paralysiscaused by neuromuscular blockade that results from nicotinic receptor stimulation. Atropine dosingshould be titrated to the therapeutic end point of the clearing of respiratory secretions and thecessation 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 worseningsymptoms due to transient oxime-induced acetylcholinesterase inhibition. Oxime therapy should begiven to all patients with evidence of cholinergic toxicity, neuromuscular dysfunction, or exposureto organophosphorous agents known to cause delayed neurotoxicity. Dosing regimens arediscussed separately. (See "Organophosphate and carbamate poisoning", section on 'Pralidoxime'.)

HYPERMAGNESEMIA/HYPOCALCEMIA — A surplus of magnesium or a deficiency of calcium maycause inhibition of acetylcholine release. The administration of magnesium sulfate to mothers witheclampsia has resulted in hypermagnesemia in infants with the development of weakness and respiratorydepression. Hypermagnesemia is an uncommon problem in the absence of magnesium administration orrenal failure. Concentrated sources of magnesium include antacids, enemas, and total parenteralnutrition. (See "Causes and treatment of hypermagnesemia".)

Magnesium has a calcium channel blocking effect that decreases entry of calcium into cells. It alsodecreases 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. Ocularmuscles are generally spared. (See "Symptoms of hypermagnesemia", section on 'Neuromusculareffects'.)

Fast synaptic transmission is steeply dependent on external calcium concentrations. Hypocalcemia resultsin an uncoupling of synaptic release of neurotransmitters (glutamate, acetylcholine, GABA) in responseto an action potential at the nerve terminal. This is because the proteins involved in synaptic vesicledocking and fusion interact in a calcium-dependent manner [6]. (See "Clinical manifestations ofhypocalcemia".)

Electrodiagnostic studies show low-amplitude compound muscle action potentials, decremental responseto low-frequency stimulation, and post-tetanic facilitation.

Diagnosis — The diagnosis of hypermagnesemia or hypocalcemia is generally made by demonstratingelevated serum magnesium levels or decreased calcium levels and observing clinical improvement aslevels normalize.

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GRAPHICS

RNS incremental response

Superimposed median nerve compound muscle actionpotentials at 50 Hz stimulation, showing continued incrementalresponse in a patient with presynaptic neuromuscular junctiondefect.



Compound muscle action potential postexercisefacilitation

A) Exercise testing in Lambert-Eaton myasthenic syndrome,with the median nerve stimulated supramaximally at the wristand the abductor pollicis brevis muscle recorded. Top:Baseline. Bottom: Immediately after 10 seconds of maximalvoluntary exercise. Note marked increase in compound muscleaction potential amplitude (postexercise facilitation).Preexercise and postexercise testing, looking for an increment,always is better tolerated by patients than is 50-Hz repetitivenerve stimulation. B) Slow (3 Hz) repetitive nerve stimulationin 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) issignificantly larger compared with the CMAP before exercise.In this case, the CMAP increment after brief exercise was 2000percent. CMAP: compound muscle action potential. Reproduced withpermission from: Preston, DC, Shapiro, BE. Electromyography andNeuromuscular Disorders, 2nd ed, Butterworth-Heinemann, Boston



1998. Copyright © 1998 Elsevier.



EMG in patient with myokymia

Doublets and triplets with clinical myokymia following rattlesnake envenomation.



Algorithm for the management of snake bites



Comparison of venomous snakes (pit vipers) and nonvenomoussnakes in the United States

Reproduced with permission from: Hodge III D. Bites and Stings. In: Textbook of PediatricEmergency Medicine, 6th edition, Fleisher GR, Ludwig S (Eds), Lippincott Williams & Wilkins,Philadelphia, 2010. Copyright © 2010 Lippincott Williams & Wilkins.



Drugs that may unmask or exacerbate myasthenia gravis*

Anesthetic agentsChloroprocaine

Diazepam

Ether

Halothane

Ketamine

Lidocaine

Neuromuscular blocking agents

Propanidid

Procaine

AntibioticsAminoglycosides

Amikacin

Gentamicin

Kanamycin

Neomycin

Netilmicin

Paromomycin

Spectinomycin

Streptomycin

Tobramycin

Fluoroquinolones

Ciprofloxacin

Gemifloxacin

Levofloxacin

Moxifloxacin

Norfloxacin

Ofloxacin

Others

Ampicillin

Clarithromycin

Clindamycin

Colistin

Erythromycin

Lincomycin

Antirheumatic drugsChloroquine

Penicillamine

Cardiovascular drugsBeta blockers

Bretylium

Procainamide

Propafenone

Quinidine

Verapamil and calcium channel blockers

GlucocorticoidsCorticotropin

Methylprednisolone

Prednisone

Neuromuscular blockers and muscle relaxantsBotulinum toxin

Magnesium sulfate and magnesium salts

Methocarbamol

Ophthalmologic drugsBetaxolol

Echothiophate

Timolol

Tropicamide

Proparacaine

Other drugsAnticholinergics

Carnitine

Cholinesterase inhibitors

Deferoxamine

Diuretics



Quinine

Telithromycin

Tetracyclines

AnticonvulsantsGabapentin

Phenytoin

Trimethadione

AntipsychoticsChlorpromazine

Lithium

Phenothiazines

Emetine (Ipecac syrup)

Interferon alpha

Iodinated contrast agents

Narcotics

Oral contraceptives

Oxytocin

Ritonavir and antiretroviral protease inhibitors

Statins

Thyroxine

* Drugs listed here should be used with caution in patients with myasthenia gravis. Aminoglycosidesshould be used only if absolutely necessary with close monitoring. Please refer to the text for furtherinformation.



Repetitive nerve stimulation (RNS) study inmyasthenia gravis

Successive compound motor action potentials (CMAPs) fromthe abductor pollicis brevis muscle are displayed after sixstimuli at 3 Hertz. A decremental response (ie, a decline in theresponse amplitude) is seen. It is maximal at 38 percent bythe fourth response in this example. Sensitivity: 5 mV/div;Sweep speed: 5 msec/div.



Rapid overview of organophosphate and carbamate poisoning

To obtain emergent consultation with a medical toxicologist, call the United States Poison ControlNetwork at 1-800-222-1222, or access the World Health Organization's list of international poisoncenters (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, increasedsecretions, 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 toxicityAtropine 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) stronglysuggests poisoning with organophosphate or carbamate

Draw blood sample for measurement of RBC acetylcholinesterase activity to confirm diagnosis

Treatment of acute toxicityDeliver 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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