Overview of Neuromuscular Junction Toxins

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Overview of neuromuscular junction toxins

1/1/12 3:09 PM

Official reprint from UpToDate www.uptodate.com 2012 UpToDate

Overview of neuromuscular junction toxinsAuthors 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.http://www.uptodate.com/contents/overview-of-neuromuscular-junction-toxins?view=print Page 1 of 19

Section Editor Jeremy M Shefner, MD, PhD

Deputy Editor John F Dashe, MD, PhD

Overview of neuromuscular junction toxins

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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 thehttp://www.uptodate.com/contents/overview-of-neuromuscular-junction-toxins?view=print Page 2 of 19

Overview of neuromuscular junction toxins

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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 t