Overview of neuromuscular junction toxins

INTRODUCTION — Signal transduction at the neuromuscular junction is a complex multistep 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 envenomation, latrodectism, 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 "Lambert-Eaton myasthenic syndrome: Clinical features and diagnosis".)

THE NEUROMUSCULAR JUNCTION — The neuromuscular junction consists of a presynaptic axon terminal and a postsynaptic muscle end plate (figure 1). 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 vesicle-associated membrane protein (VAMP), which is found on the vesicle surface, along with synaptosomal-associated protein of 25 kD (SNAP-25) 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.

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 Clostridium bacteria. 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 'Microbiology and pathogenesis'.)

The modern syndrome of botulism occurs in six forms, differentiated by the mode of acquisition:

●Infant botulism occurs after the ingestion of clostridial spores that then colonize the host's gastrointestinal (GI) tract and release toxin produced in vivo.

●Food-borne botulism occurs after ingestion of food contaminated by preformed botulinum toxin.

●Wound botulism occurs after infection of a wound by C. botulinum with subsequent in vivo production of neurotoxin.

●Iatrogenic botulism can occur with incorrect preparation or administration of botulinum 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.

Approximately 200 cases of botulism are reported each year in the United States. In 2019, approximately 70 percent of the cases were infant botulism, 20 percent wound botulism, 10 percent food-borne botulism, and the remaining 1 percent were unknown, iatrogenic, or adult intestinal colonization. The incidence of wound botulism has increased due to the use of intravenous drugs [11]. (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 wound by non-clostridial species. Food-borne botulism produces 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 several 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 muscle 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" [12,13]. 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.

By 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 2). This can be seen in approximately 60 percent of cases of adult botulism poisoning [13]. 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) (waveform 1) [12]. 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.

The electrodiagnostic findings in botulism may change over time. In a small study of 18 patients with food-borne botulism, reduced CMAP amplitudes and postactivation facilitation became less consistent over a period of 4 to 88 days post ingestion [14]. Small voluntary motor unit action potentials were seen in all patients assessed in the acute (4 to 8 days) and early post-acute (32 to 39 days) phases but only 50 percent of patients in the late post-acute phase (66 to 88 days).

Postactivation exhaustion, a decrease in CMAP amplitude occurring two to four minutes after maximal muscle contraction, is not present in cases of botulism poisoning [12,13].

In summary, electromyography diagnosis of botulism should be based on the following findings [12,13,15]:

●Reduced baseline CMAP amplitude

●Postactivation facilitation (between 40 and 200 percent)

●Absence of postactivation exhaustion

●Postactivation facilitation that persists longer than two minutes

●Small motor unit action potentials

The sensitivity of RNS 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 [16,17]. (See "Botulism", section on 'Treatment'.)

TICK PARALYSIS — Tick paralysis is a toxin-mediated illness characterized by acute onset motor weakness. Several tick species produce a toxin that inhibits transduction at the neuromuscular junction including Dermacentor and Ixodes species. Neurotoxins impair motor nerve transmission or neuromuscular junction activity. The neurotoxins of Ixodes species ticks are known as holocyclotoxins or ixovotoxins [18]. These toxins decrease release of acetylcholine from the presynaptic membrane by inhibiting presynaptic voltage-gated calcium channels [19]. This reduces calcium entry into the nerve terminal, thereby decreasing quanta of acetylcholine released [20].

Clinical features and diagnosis — Symptoms include progressive anorexia, lethargy, muscle weakness, nystagmus, and an ascending flaccid paralysis. Symptom onset occurs three to seven days after attachment of the tick. The diagnosis of tick paralysis usually relies on the finding of a tick attached to the patient. Tick paralysis is a rare, but easily remedied, cause of ascending paralysis. Therefore, patients with this presentation should always be thoroughly searched for ticks. Unexposed areas such as the scalp, genitalia, and external meatus should be inspected carefully. (See "Tick paralysis", section on 'Clinical manifestations'.)

Electromyography shows a reduced amplitude of compound muscle action potentials (CMAPs) [21]. No abnormalities are seen with repetitive nerve stimulation (RNS) studies [21,22]. There may be subtle abnormalities of motor nerve conduction velocity and sensory action potentials.

Treatment — Removal of the tick is the primary treatment of tick paralysis. The tick can be removed with forceps placed as close to the skin as possible. Both the tick and the skin should be inspected carefully to ensure complete removal of the tick's 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 'Management'.)

SNAKE ENVENOMATION

Types of snakes — Five families/subfamilies of snakes produce venom that is toxic to humans, three of which cause clinically significant neuromuscular transmission disorders [23,24]:

●Elapidae (cobras, mambas, coral snakes, sea kraits)

●Hydrophidae (sea snakes)

●Crotalinae (rattlesnakes)

Venom toxins — Snake 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 and are called SPANS (snake presynaptic phospholipase A2 neurotoxins). They catalyze the hydrolysis of phosphatidylcholine, a major component of the plasma membrane, forming lysophosphatides and releasing both saturated and unsaturated fatty acids [25-27].

The exact mechanism of toxicity is undefined, but hydrolysis of these phospholipids leads to massive release of synaptic vesicles. 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 [28,29]. Poisoned nerve terminals show an absence of vesicles [30], 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 [27,31]. They bind irreversibly to the acetylcholine receptor site and prevent the opening of the associated sodium channel [31]. As an example, alpha-bungarotoxin from the krait produces a postjunctional neuromuscular blockade.

Clinical features and diagnosis — Local and systemic symptoms from envenomation vary by species of snake and may be used to help discriminate between species in circumstances when the snake was not identified. (See "Snakebites worldwide: Clinical manifestations and diagnosis".)

In many cases, snake venom neurotoxins affect the cranial nerves first, resulting in ptosis, ophthalmoplegia, dysarthria, dysphagia, and drooling. This progresses to weakness of limb muscles [32,33]. Clotting time may also be increased [32].

The postsynaptic toxins produce findings on electrodiagnostic studies identical to those seen in myasthenia gravis, since the mechanism of disease is similar [34]. Repetitive nerve stimulation (RNS) produces a decremental response. (See "Diagnosis of myasthenia gravis", section on 'Electrodiagnostic confirmation for seronegative and atypical presentations'.)

Envenomation by the timber rattlesnake causes myokymia (waveform 2). Spontaneous bursts of motor unit potentials manifest as doublets and multiplets on electromyography [35].

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 in greater detail separately. (See "Snakebites worldwide: Management" and "Bites by Crotalinae snakes (rattlesnakes, water moccasins [cottonmouths], or copperheads) in the United States: Management" and "Evaluation and management of coral snakebites".)

Frequently, the species of snake producing the bite is unknown (figure 3), 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 [32]. Cutting, biting, sucking, or excising tissue at the site is contraindicated, as these measures do not help remove venom and may introduce infection.

LATRODECTISM — Latrodectus species of spiders, including black widow spiders (Latrodectus mactans), have a multicomponent venom that contains alpha-latrotoxin. Latrotoxin binds to a presynaptic neurexin receptor and calcium-independent receptor for alpha-latrotoxin. This binding stimulates neurotransmitter release, including acetylcholine, resulting in vesicle depletion.

Clinical features and diagnosis — The initial symptom with latrodectism is a sharp, local pain at the bite site. The local reaction is generally mild but can include local erythema with central clearing and swelling of proximal lymph nodes. Neuromuscular symptoms begin with autonomic dysfunction evolving from tachycardia and hypotension to bradycardia and hypertension. Nausea, diaphoresis, diffuse muscle spasms, and rigidity including abdominal musculature follow. Spasms start at the bite site then spread proximally.

Diagnosis is clinical, as laboratory abnormalities are nonspecific (eg, leukocytosis and elevated creatinine kinase). There is no available laboratory assay specific to latrodectism [36-38]. (See "Widow spider bites: Clinical manifestations and diagnosis".)

Treatment — Management begins with supporting respiratory and circulatory status. Symptomatic management with opioids for pain and benzodiazepines for spasms is the mainstay of treatment. Antivenom (if available) is generally reserved for severe or life-threatening cases that are inadequately treated with the supportive and symptomatic care above. Local wound care and tetanus prophylaxis should be given as indicated [37-42]. (See "Widow spider bites: Management".)

DRUGS

Common agents — In addition to the neuromuscular blocking agents used during anesthesia, several other drugs [43,44] can affect transmission at the neuromuscular junction, including the following [45]:

●Neuromuscular blocking anesthetic agents

●D-penicillamine

●Immune checkpoint inhibitors (ICI)

●Aminoglycoside antibiotics

●Fluoroquinolone antibiotics [46]

●Macrolide antibiotics

●Beta blockers

●Glucocorticoids

●Magnesium sulfate (see 'Hypermagnesemia/hypocalcemia' below)

●Botulinum toxin

D-penicillamine, used to treat Wilson disease and rheumatoid arthritis, can induce production of antibodies to acetylcholine receptors. This results in a clinical presentation of myasthenia gravis (MG) with the antibodies affecting post-synaptic transmission. (See "Differential diagnosis of myasthenia gravis", section on 'Other conditions'.)

Therapy with ICI, immunomodulatory antibodies to treat several forms of cancer, can cause neuromuscular disorders such as MG and other neurologic complications such as Guillain-Barré syndrome, aseptic meningitis, encephalitis, or transverse myelitis [47-52]. ICI therapy may produce acetylcholine receptor (AChR) antibodies and cause exacerbation of underlying MG or new-onset clinical presentation of MG [47,53]. (See "Toxicities associated with immune checkpoint inhibitors", section on 'Neurologic'.)

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 "Overview of the treatment of myasthenia gravis", section on 'Avoidance of drugs that may exacerbate myasthenia'.)

Aminoglycoside antibiotics inhibit both pre- and postsynaptic transmission [54,55]. 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 nondepolarizing blockade or have a local anesthetic action [56,57]. Lithium, with chronic use, may compete with calcium in the presynaptic region and reduce the release of acetylcholine from nerve terminals [58].

Clinical features and management — 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 (RNS) produce a decremental response, with post-tetanic facilitation [54]. The facilitation exceeds that seen in myasthenia gravis [54]. 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 (waveform 3). (See "Diagnosis of myasthenia gravis", section on 'Electrodiagnostic confirmation for seronegative and atypical presentations'.)

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 'Other conditions'.)

●In ICI-induced neuropathies or MG, onset of symptoms may begin within four weeks after ICI therapy initiation. There is a higher incidence of severe bulbar and respiratory compromise in the presentation of MG, requiring early recognition and treatment to potentially avoid intubation. Treatment depends on symptom severity but typically includes withdrawal of ICI therapy, supportive care, and immunosuppressive treatment with glucocorticoids or other therapies (table 2). (See "Paraneoplastic syndromes affecting spinal cord, peripheral nerve, and muscle", section on 'Checkpoint inhibitor-associated neuropathies'.)

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 3000 cases of organophosphate or carbamate poisoning occur in the United States, and 3,000,000 people are exposed worldwide [59]. Exposure routes include oral ingestion, inhalation, or dermal contact. Organophosphorus "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 organophosphorus 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 noncovalently and the free, active enzyme is released.

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 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 3). 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 [60]. (See "Organophosphate and carbamate poisoning", section on 'Clinical features'.)

CNS symptoms may also be present including anxiety, confusion, seizures, and coma.

Ten to 40 percent of patients develop a distinct neurologic disorder 24 to 96 hours after organophosphorus 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 axonal polyneuropathy, termed "organophosphorus agent-induced delayed neuropathy" (OPIDN), may occur one to three weeks after exposure to specific organophosphorus agents, including chlorpyrifos.

Neurophysiology — Electrodiagnostic studies in organophosphate poisoning demonstrate repetitive compound muscle action potentials (CMAPs) in response to a single stimulus to the nerve [61]. 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 (RNS) results in decrement of the CMAP [61]. 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 [61,62].

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 3). All cases require aggressive decontamination with 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 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 is reserved for patients with evidence of severe cholinergic toxicity inadequately treated with atropine, neuromuscular dysfunction, or exposure to organophosphorus 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. 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 [63].

Hypocalcemia results in an uncoupling of synaptic release of neurotransmitters (glutamate, acetylcholine, gamma-aminobutyric acid [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".)

Clinical features — Hypermagnesemia produces proximal muscle weakness, which may progress to respiratory insufficiency. Ocular muscles are generally spared. The administration of magnesium sulfate to mothers with eclampsia has resulted in hypermagnesemia in infants with the development of weakness and respiratory depression. (See "Hypermagnesemia: Causes, symptoms, and treatment", section on 'Neuromuscular effects'.)

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 "Hypermagnesemia: Causes, symptoms, and treatment".)

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.

Electrodiagnostic studies show low-amplitude compound muscle action potentials (CMAPs), decremental response to low-frequency stimulation, and post-tetanic facilitation.

SUMMARY AND RECOMMENDATIONS

●Anatomy – The neuromuscular junction consists of a presynaptic axon terminal and a postsynaptic muscle end plate (figure 1). (See 'The neuromuscular junction' above.)

●Botulism – Botulism is an uncommon and life-threatening disease caused by Clostridium bacteria. The botulinum neurotoxin is considered the most potent lethal substance known. Symptoms range from minor cranial nerve palsies associated with symmetric descending weakness to rapid respiratory arrest. In high doses, it causes rapid and severe paralysis of skeletal muscles. Botulinum antitoxin should be given as soon as botulism is suspected. (See 'Botulism' above and "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. Symptoms include anorexia, lethargy, muscle weakness, nystagmus, and an ascending flaccid paralysis. Removal of the tick is the primary treatment. (See 'Tick paralysis' above and "Tick paralysis", section on 'Diagnosis'.)

●Snake envenomation – Three families of snakes produce venom causing neuromuscular transmission disorders. Snake venom neurotoxins affect the cranial nerves first, resulting in ptosis, ophthalmoplegia, dysarthria, dysphagia, and drooling. Symptoms progress to weakness of limb muscles. Antivenom is available and effective for postsynaptic neurotoxins. (See 'Snake envenomation' above and "Snakebites worldwide: Management" and "Bites by Crotalinae snakes (rattlesnakes, water moccasins [cottonmouths], or copperheads) in the United States: Management" and "Evaluation and management of coral snakebites".)

●Latrodectism – Latrodectism from a black widow spider bite causes diffuse muscle spasms and rigidity with hypertension, nausea, diaphoresis. Treatment includes benzodiazepines for muscle spasms, opioids for pain management, and respiratory support. Antivenom (equine derived) is reserved for severe cases but does carry risk of anaphylaxis and serum sickness. (See 'Latrodectism' above.)

●Drugs – In addition to the neuromuscular blocking agents used during anesthesia, a number of other drugs can affect transmission at the neuromuscular junction, including neuromuscular blocking anesthetic agents, D-penicillamine, immune checkpoint inhibitors (ICI), aminoglycoside, fluoroquinolone, and macrolide antibiotics, beta blockers, glucocorticoids, magnesium sulfate, and botulinum toxin. Typically, the offending drug is withdrawn, and the diagnosis is made by the resultant clinical improvement. Management of symptoms due to ICI may also include administration of glucocorticoids. (See 'Drugs' above.)

●Organophosphates and carbamates – Organophosphates and carbamates are potent inhibitors of acetylcholinesterase and are commonly used as pesticides. Symptoms of organophosphate and carbamate poisoning include typical muscarinic signs (lacrimation, bradycardia, bronchospasm) and nicotinic signs (mydriasis, tachycardia, weakness, hypertension). The diagnosis of organophosphate or carbamate poisoning is made on clinical grounds. Emergency management includes respiratory support. Atropine is used for muscarinic symptoms; pralidoxime is added for severe symptoms, including weakness (table 3). (See 'Organophosphate and carbamate toxicity' above and "Organophosphate and carbamate poisoning", section on 'Management'.)

●Electrolyte abnormalities – A surplus of magnesium or a deficiency of calcium may cause inhibition of acetylcholine release. The administration of magnesium sulfate may cause weakness and respiratory depression. Hypermagnesemia is an uncommon problem in the absence of magnesium administration or renal failure. (See 'Hypermagnesemia/hypocalcemia' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Tracy Weimer, MD (deceased), who contributed to an earlier version of this topic review.