Overview of Neuromuscular Junction Toxins

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Overview of neuromuscular junction toxins

AUTHORS: Laurie Gutmann, MD, Laura Tormoehlen, MD, FACMT, FAAN
SECTION EDITOR: Jeremy M Shefner, MD, PhD
DEPUTY EDITOR: Richard P Goddeau, Jr, DO, FAHA
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Jan 2024.

This topic last updated: Oct 10, 2023.
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
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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'.)
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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'.)
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● 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.
Use of UpToDate is subject to the Terms of Use.
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Topic 5139 Version 26.0
GRAPHICS
Normal neuromuscular junction
Graphic 62694 Version 6.0
Repetitive nerve stimulation showing incremental response
Superimposed median nerve compound muscle action potentials at 50 Hz stimulation, showing

continued incremental response in a patient with a presynaptic neuromuscular junction defect.
Compound muscle action potential postexercise facilitation
Exercise testing in LEMS, 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
(post-exercise facilitation). Pre-exercise and post-exercise testing, looking for an increment, always is
better tolerated by patients than is 50 Hz repetitive nerve stimulation.
CMAP: compound muscle action potential; LEMS: Lambert-Eaton myasthenic syndrome.
Reproduced with permission from: Preston DC, Shapiro BE. Electromyography and Neuromuscular Disorders, 2nd ed,
Butterworth-Heinemann, Boston 1998. Copyright © 1998 Elsevier.
Electromyography in a patient with myokymia
Doublets and triplets with clinical myokymia following rattle snake envenomation.
Comparison of native 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.
Drugs to avoid or use with caution in patients with myasthenia gravis*
Anesthetic agents
Neuromuscular blocking agents (eg, rocuronium, vecuronium, succinylcholine) ¶
Antibiotics
Aminoglycosides Δ (eg, amikacin, gentamicin, neomycin, tobramycin)
Fluoroquinolones Δ (eg, ciprofloxacin, levofloxacin, moxifloxacin, ofloxacin)
Macrolides (eg, azithromycin, clarithromycin, erythromycin)
Cardiovascular drugs
Beta blockers (eg, atenolol, labetalol, metoprolol, propranolol)
Procainamide
Quinidine
Others
Botulinum toxin
Chloroquine
Deferoxamine (desferrioxamine)
Glucocorticoids (eg, dexamethasone, prednisone) ◊
Statins (HMG-CoA reductase inhibitors; eg, atorvastatin, pravastatin, rosuvastatin)
Hydroxychloroquine
Immune checkpoint inhibitors (eg, atezolizumab, ipilimumab, nivolumab, pembrolizumab)
Iodinated contrast §
Magnesium ¥
Penicillamine ‡
Quinine
HMG-CoA: hydroxymethylglutaryl coenzyme A; IVIG: intravenous immune globulin.
* This is not a complete list of all drugs that may, in individual patients, adversely affect
neuromuscular transmission and worsen myasthenia gravis symptoms. If such drugs are used, they
should be administered cautiously with appropriate monitoring. Refer to UpToDate for additional
information.
¶ Response to neuromuscular blocking agents is unpredictable in patients with myasthenia. Use only
when necessary, guided by neuromuscular monitoring.
Δ Reserve use for hospitalized patients when alternative agents are unavailable.
◊ Glucocorticoids at high dose may cause transient worsening of symptoms during first one to two
weeks of treatment. They should be used with caution; when administered for hospitalized patients in
myasthenic crisis, concurrent plasmapheresis or IVIG should be coadministered.
§ Increased weakness in MG has been reported with use of older iodinated contrast agents; modern
iodinated contrast agents appear generally safe.
¥ Intravenous administration (eg, with magnesium sulfate, magnesium chloride) is relatively

contraindicated due to significant inhibitory effect on acetylcholine release.
‡ Strongly associated with worsening myasthenia gravis; avoid use.
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.
Management of nervous system irAEs in patients treated with immune

checkpoint inhibitors*
7.1. Myasthenia gravis
Work-up and evaluation:

AChR and antistriated muscle antibodies in blood. If AChR antibodies are negative, consider
MuSK and LPR4 antibodies in blood – while presence of antibodies is confirmatory, the absence
of antibodies does not rule out the syndrome.
Pulmonary function assessment with NIF and VC.
CPK, aldolase, ESR, and CRP for possible concurrent myositis.
Consider MRI brain and/or spine depending on symptoms to rule out CNS involvement by
disease or alternate diagnosis.
Troponin, ECG, and consider TTE and/or cardiac MRI to evaluate concomitant myocarditis.
Electrodiagnostic studies, under neurologic consultation, including neuromuscular junction
testing with repetitive stimulation and/or jitter studies, NCS to exclude neuropathy, and needle
EMG to evaluate for concomitant myositis.
Inflammatory markers (ESR and CRP).
Consider paraneoplastic work-up.
Review and stop medications with known risk of worsening myasthenia: beta-blockers, IV
magnesium, fluoroquinolones, aminoglycosides, and macrolide antibiotics.
Grading Management
All grades. All grades warrant work-up and intervention given potential
for progressive MG to lead to respiratory compromise.
Inpatient admission may be appropriate at all grades.
No G1. Not applicable.
G2: Some symptoms Hold ICPi and may resume in G2 patients (MGFA 1 and 2) only
interfering with ADLs. MGFA symptoms resolve and steroid taper completed.
severity class I (ocular Neurology consultation.
symptoms and findings only)
Strongly consider inpatient care as patients can deteriorate
and MGFA severity class II
quickly.
(mild generalized weakness).
Pyridostigmine starting at 30 mg orally three times a day and
gradually increase to maximum of 120 mg orally four times a
day as tolerated and based on symptoms and wean based on
improvement. These procedures should be done in close
collaboration with the neurologist.
Administer corticosteroids (prednisone 0.5 mg/kg ¶ orally
daily). Wean based on symptom improvement.
G3-4: Limiting self-care and Follow G2 recommendations as listed, with the following
aids warranted, weakness additions for G3-4:
limiting walking, any Permanently discontinue ICPi.
dysphagia, facial weakness,
Admit patient, may need ICU-level monitoring.
respiratory muscle weakness,
or rapidly progressive Continue steroids, taper should begin 3 to 4 weeks after

symptoms or initiation then wean based on symptom improvement.
MGFA severity class III-V Initiate IVIG 2 g/kg IV over 5 days (0.4 g/kg/day) or
(moderate to severe plasmapheresis for 5 days.
generalized weakness to Consider adding rituximab if refractory to IVIG or
myasthenic crisis). plasmapheresis.
Frequent pulmonary function assessment.
Daily neurologic review.
7.2. Guillain-Barré syndrome

Neurologic consultation.
MRI spine with or without contrast (rule out compressive lesion and evaluate for nerve root
enhancement/thickening).
Lumbar puncture: CSF analysis for cell count and differential, cytology for malignant cells,
protein, glucose, and viral/bacterial cultures. Note that CSF typically has elevated protein and
often elevated WBC as well, although this is not typically seen in classical Guillain-Barre.
Consider paraneoplastic work-up eg ANNA-1 antibody testing.
Serum antiganglioside antibody tests for GBS and its subtypes (eg, anti-GQ1b for Miller Fisher
variant associated with ataxia and ophthalmoplegia).
Flow cytometry in patients with hematologic malignancies.
Electrodiagnostic studies (NCS and EMG) to evaluate polyneuropathy.
Pulmonary function testing (NIF or VC).
Frequent neuro checks.
Grading Management
All grades warrant work-up and intervention given potential for progressive GBS to lead to
respiratory compromise. NOTE: there is no G1 toxicity.
No G1. Not applicable.
G2: Moderate: Some Discontinue ICPi.

interference with ADLs, Neurology consultation.
symptoms concerning to
Admission to inpatient unit with capability of rapid transfer to
patient.
ICU-level monitoring.
G3-4: Severe: Limiting self-care Start IVIG (0.4 g/kg/day for 5 days for a total dose of 2 g/kg) or
and aids warranted, weakness plasmapheresis. NOTE: plasmapheresis immediately after IVIG
limiting walking, any will remove immunoglobulin.
dysphagia, facial weakness,
Corticosteroids are usually not recommended for idiopathic
respiratory muscle weakness,
GBS; however, in ICPi-related forms, a trial is reasonable
or rapidly progressive
(methylprednisolone 2 to 4 mg/kg/day), followed by slow
symptoms.
steroid taper. Pulse steroid dosing (methylprednisolone 1 g
daily for 5 days) may also be considered for G3-4 along with
IVIG or plasmapheresis. After pulse steroids, taper steroids
over 4 to 6 weeks.
Frequent neuro checks and pulmonary function monitoring.
Monitor for concurrent autonomic dysfunction.
Nonopioid management of neuropathic pain, for example,

pregabalin, gabapentin, or duloxetine.
Treatment of constipation/ileus.
Additional considerations:
Extreme caution with rechallenging for severe cases after complete resolution of symptoms
and tapered off immunosuppression.
7.3. Peripheral neuropathy

G1:
Consider neurology consultation to guide neuropathy phenotype determination and work-
up.
Serum testing for reversible neuropathy causes: HbA1c, vitamin B12, TSH, vitamin B6,
folate, serum protein electrophoresis, and immunofixation, CPK.
Consider additional testing guided by neuropathy phenotype: ANA, ESR, CRP, ANCA, anti–
smooth muscle, SSA/SSB, RNP, anti-dsDNA, ganglioside ab, anti-MAG, anti-Hu (ANNA-1 ab),
thiamine, Lyme, hepatitis B or C, and HIV.
Consider MRI spine with or without contrast.
G2 – in addition to the above:
MRI spine advised, MRI brain if cranial nerve involvement, and MRI plexus if concern for
plexus involvement.
Consider lumbar puncture: CSF analysis for cell count and differential, cytology for
malignant cells, protein, glucose, and viral or bacterial cultures. Consider EMG or NCS.
G3-4: Refer to section 7.2 on management of grade 3-4 GBS.
Grading Management
G1: Mild: no interference with Low threshold to hold ICPi and monitor symptoms for a week.
function and symptoms not If to continue, monitor very closely for any symptom
concerning to patient. NOTE: progression.
any cranial nerve problem
should be managed as
moderate.
G2: Moderate: some Hold ICPi and resume once return to ≤G1.
interference with ADLs, Initial observation or initiate prednisone 0.5 to 1 mg/kg/day (if
symptoms concerning to progressing from mild).
patient (ie, pain but no
Gabapentin, pregabalin, or duloxetine for pain.
weakness or gait limitation).
G3-4: Severe: limiting self-care Permanently discontinue ICPi.

and aids warranted, weakness Admit patient.
limiting walking or respiratory
Neurology consultation.
problems (ie, leg weakness,
Initiate IV methylprednisolone 2 to 4 mg/kg/day and proceed
foot drop, and rapidly
as per GBS management.
ascending sensory changes).
Severe may be GBS and should
be managed as such.
7.4. Autonomic neuropathy

An evaluation by neurologist or relevant specialist depending on organ system, with testing
that may include:
Screen for other causes of autonomic dysfunction: diabetic screen, adrenal insufficiency,
HIV, paraproteinemia, amyloidosis, and botulism; consider chronic diseases such as
Parkinson's and other autoimmune screen.
Orthostatic vital signs.
Consider electrodiagnostic studies (NCS and EMG) to evaluate for concurrent
polyneuropathy.
Consider paraneoplastic autoimmune dysautonomia antibody testing (eg, antiganglionic
AChR, ANNA-1, and N-type voltage-gated calcium channel antibodies).
Grading Management
G1: Mild: no interference with Low threshold to hold ICPi and monitor symptoms for a week.
function and symptoms not If to continue, monitor very closely for any symptom
concerning to patient. progression.
G2: Moderate: some Hold ICPi and resume once return to ≤G1 and off prednisone i
interference with ADLs, used.
symptoms concerning to Initial observation or initiate prednisone 0.5 to 1 mg/kg/day (if
patient. progressing from mild).
G3-4: Severe: limiting self-care Permanently discontinue ICPi.

and aids warranted. Admit patient.
Initiate methylprednisolone 1 g daily for 3 days followed by
oral steroid taper.
7.5. Aseptic meningitis

MRI brain with or without contrast with pituitary or sellar cuts protocol.
AM cortisol, ACTH to rule out adrenal insufficiency.
Strongly consider lumbar puncture with CSF analysis for opening pressure, cell count and
differential, cytology for malignant cells that could indicate leptomeningeal metastases,
protein, glucose, gram stain, viral or bacterial cultures, PCR for HSV, and other viral PCRs
depending on suspicion.
May see elevated WBC in CSF with normal glucose, normal culture, and gram stain. May see
reactive lymphocytes, neutrophils, or histiocytes on cytology.
Grading Management
G1: Mild: no interference with Hold ICPi and discuss resumption with patient only after taking
function and symptoms not into account the risks and benefits.
concerning to patient. NOTE: Consider neurology consult.
any cranial nerve problem
should be managed as Consider empiric antiviral (IV acyclovir) and antibacterial

moderate. therapy until CSF results.
G2: Moderate: some Once bacterial and viral infection negative, may closely
interference with ADLs, monitor off corticosteroids or consider oral prednisone 0.5 to 1
symptoms concerning to mg/kg/day or IV methylprednisolone 1 mg/kg/day if moderate
patient (ie, pain but no or severe symptoms.
weakness or gait limitation). Steroids can be tapered after 2 to 4 weeks, monitoring for
symptom recurrence.
G3-4: Severe: limiting self-care
and aids warranted. Consider hospitalization for G3-4.
7.6. Encephalitis

MRI brain with or without contrast may reveal T2/FLAIR changes typical of what is seen in
autoimmune encephalopathies or limbic encephalitis or may be normal.
Lumbar puncture with CSF analysis for opening pressure, cell count and differential, cytology
for malignant cells that could indicate leptomeningeal metastases, protein, glucose, gram
stain, viral or bacterial cultures, PCR for HSV and other viral PCRs depending on suspicion,
oligoclonal bands, autoimmune encephalopathy, and paraneoplastic panels.
May see elevated WBC with lymphocytic predominance and/or elevated protein.
EEG to evaluate for subclinical seizures.
Serum studies: Chem panel, CBC, ESR, CRP, ANCA (if suspect vasculitic process), thyroid panel
including TPO and thyroglobulin, AM cortisol and ACTH, GQ1b antibodies (Bickerstaff
encephalitis and rhomboencephalitis), celiac antibody panel, and paraneoplastic and
autoimmune encephalitis panels.
Rule out concurrent anemia/thrombocytopenia, which can present with severe headaches and
confusion.
Grading Management
G1: Mild: No interference with Hold ICPi and discuss resumption with patient only after taking
function and symptoms not into account the risks and benefits.
concerning to patient. NOTE: As above for aseptic meningitis suggest concurrent IV acyclovi
any cranial nerve problem until PCR results obtained and negative.
should be managed as
Trial of methylprednisolone 1 to 2 mg/kg/day.
moderate.
G2: Moderate: Some If severe or progressing symptoms or oligoclonal bands
interference with ADLs, present, consider pulse corticosteroids (methylprednisolone 1
symptoms concerning to g IV daily for 3 to 5 days) plus IVIG 2 g/kg over 5 days (0.4
patient (ie, pain but no g/kg/day) or plasmapheresis.
weakness or gait limitation).
Taper steroids following acute management over at least 4 to 6
G3-4: Severe: Limiting self-care weeks.
and aids warranted. If positive for autoimmune encephalopathy or paraneoplastic
antibody or limited or no improvement, consider rituximab in
consultation.
Admit patient for G3-4.
7.7. Demyelinating diseases, including multiple sclerosis, transverse myelitis, ADEM,

ON, and NMO
Ophthalmic or neuro-ophthalmic evaluation if ocular involvement.
MRI with contrast of brain, orbit, cervical, and thoracic spinal cord (tailor to examination
finding).
Lumbar puncture with CSF analysis including autoimmune encephalitis panel and oligoclonal
bands, CNS demyelinating disease antibodies (aquaporin 4 and myelin oligodendrocyte
glycoprotein), and viral PCRs especially JCV PCR to exclude progressive multifocal
leukoencephalopathy.
Serum studies: B12, HIV, RPR, ANA, Ro/La, TSH, aquaporin-4 IgG, paraneoplastic panel or anti-
HU and anti–CRMP5-CV2, thyroid panel including TPO and thyroglobulin, AM cortisol and ACTH
and paraneoplastic and autoimmune encephalitis panels.
Evaluation for urinary retention and constipation.
EEG to evaluate for subclinical seizures.
Although less common, biopsy may provide definitive evidence of CNS demyelination.
Grading Management
G1: Asymptomatic or mild Intervention not indicated.

symptoms; clinical or Continue immunotherapy unless symptoms worsen or do not
diagnostic observations only. improve.
G2: Moderate symptoms; Stop ICPi.

minimal, limiting age- Neurology consultation.
appropriate instrumental ADL.
Start prednisone 1 mg/kg daily and taper over 1 month.
Rule out infection.
G3: Severe or medically Permanently discontinue ICPi.

significant symptoms but not Neurology consultation.
immediately life-threatening;
Nonopioid management of neuropathic pain, for example,
limiting self-care ADL.
pregabalin, gabapentin, or duloxetine.
Admit patient for methylprednisolone pulse dosing 1 g/day
and consider IVIG Δ or plasmapheresis if no improvement or
symptoms worsen after 3 days. ◊
G4: Life-threatening Permanently discontinue ICPi.

consequences. Neurology consultation.
ICU level inpatient care.
Start methylprednisolone pulse dosing 1 g/day and consider
IVIG or plasmapheresis if no improvement or symptoms
worsen after 3 days. ◊
AChR: acetylcholine receptor; MuSK: muscle-specific kinase; LPR4: lipoprotein-related 4; NIF: negative
inspiratory force; VC: vital capacity; CPK: creatine phosphokinase; ESR: erythrocyte sedimentation rate;
CRP: C-reactive protein; MRI: magnetic resonance imaging; CNS: central nervous system; ECG:
electrocardiogram; TTE: transthoracic echocardiogram; CV: cardiovascular; NCS: nerve conduction

study; EMG: electromyography; IV: intravenous; MG: myasthenia gravis; ADL: activity of daily living;
MGFA: Myasthenia Gravis Foundation of America; ICPi: immune checkpoint inhibitor; ICU: intensive
care unit; IVIG: intravenous immune globulin; ANNA-1: antineuronal nuclear antibody type 1; GBS:
Guillain-Barré syndrome; TSH: thyroid-stimulating hormone; ANA: antinuclear antibody; SSA: Sjögren
syndrome A; SSB: Sjögren syndrome B; RNP, ribonucleoprotein; dsDNA: double-stranded DNA; MAG:
myelin-associated glycoprotein; AM: morning; ACTH: adrenocorticotropic hormone; PCR: polymerase
chain reaction; HSV: herpes simplex virus; FLAIR: fluid-attenuated inversion recovery; ANCA:
antineutrophil cytoplasmic antibodies; TPO: thyroid peroxidase; ADEM: acute-disseminated
encephalomyelitis; ON: optic neuritis; NMO: neuromyelitis optica; JCV: John Cunningham virus; RPR:
rapid plasma regain.
* The American Society of Clinical Oncology (ASCO) guidelines are intended to provide initial guidance
in the management of treatment-related side effects. Consultation with appropriate specialists may
be indicated.
¶ The divergence from 1 mg/kg in the setting of MG is because of the potential short-term
exacerbation of MG with high-dose steroid.
Δ IVIG 2 g/kg, administered in divided doses per package insert.
◊ Plasmapheresis immediately after IVIG will remove immunoglobulin.
From: Schneider BJ, et al. Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint
Inhibitor Therapy: ASCO Guideline Update. J Clin Oncol 2021; 39:4073. DOI: 10.1200/JCO.21.01440. Copyright © 2022
American Society of Clinical Oncology. Reproduced with permission from Wolters Kluwer Health. Unauthorized reproduction of
this material is prohibited.
Organophosphate and carbamate poisoning: Rapid overview of emergency

management
To obtain emergency consultation with a medical toxicologist, in the United States, call 1-800-222-1222
for the nearest regional poison control center. Contact information for poison control centers around
the world is available at the WHO website and in the UpToDate topic on regional poison control centers
(society guideline links).
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
Organophosphorus 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 to 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% oxygen via facemask; early intubation often required; avoid succinylcholine
Decontamination if ingestion within 1 hour give single dose activated charcoal, adult 50 g (1 g/kg in
children) unless airway not protected or other contraindication. Aggressive dermal and ocular
irrigation as needed. Bag/discard clothing.
Atropine 2 to 5 mg IV/IM/IO 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
Inhaled ipratropium 0.5 mg with parenteral atropine may be helpful for bronchospasm; may
repeat
Pralidoxime (2-PAM) 2 g (25 mg/kg in children) IV over 30 minutes; may repeat after 30 minutes or
give continuous infusion if severe
Continuous infusion at 8 mg/kg/hour in adults (10 mg/kg/hour in children)
If no IV access, give pralidoxime 600 mg IM (15 mg/kg in children <40 kg). Rapidly repeat as
needed to total of 1800 mg or 45 mg/kg in children.
Pralidoxime is given with atropine
Benzodiazepine therapy
Diazepam 10 mg IV (0.1 to 0.2 mg/kg in children), repeat as necessary if seizures occur. Do not
give phenytoin.

Overview of Neuromuscular Junction Toxins

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21/2/24, 19:53 Overview of neuromuscular junction toxins - UpToDate

Official reprint from UpToDate®

Overview of neuromuscular junction toxins

Literature review current through: Jan 2024.

Signal transduction at the neuromuscular junction is a complex multistep process required

THE NEUROMUSCULAR JUNCTION

The neuromuscular junction consists of a presynaptic axon terminal and a postsynaptic

promote phosphorylation of synapsins. This phosphorylation results in release of the vesicles

Proteins involved in SNARE complexes include vesicle-associated membrane protein (VAMP),

Phosphorylation of docking proteins occurs in response to increased calcium levels. This

Botulism is an uncommon and life-threatening disease caused by Clostridium bacteria. The

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

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

● Iatrogenic botulism can occur with incorrect preparation or administration of

● Adult enteric infectious botulism or adult infectious botulism of unknown source is

Neurophysiology — Electrodiagnostic studies (nerve conduction studies and

By contrast, increased rates of stimulation (20 to 50 Hz) or exercise cause accumulation of

Postactivation exhaustion, a decrease in CMAP amplitude occurring two to four minutes

In summary, electromyography diagnosis of botulism should be based on the following

● Reduced baseline CMAP amplitude

Treatment — Botulinum antitoxin should be given as soon as botulism is suspected [16,17].

Tick paralysis is a toxin-mediated illness characterized by acute onset motor weakness.

Clinical features and diagnosis — Symptoms include progressive anorexia, lethargy,

Electromyography shows a reduced amplitude of compound muscle action potentials

Types of snakes — Five families/subfamilies of snakes produce venom that is toxic to

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

● Hydrophidae (sea snakes)

Envenomation by the timber rattlesnake causes myokymia ( waveform 2). Spontaneous

Antivenom is available and effective for postsynaptic neurotoxins. It accelerates dissociation

Diagnosis is clinical, as laboratory abnormalities are nonspecific (eg, leukocytosis and

Treatment — Management begins with supporting respiratory and circulatory status.

Common agents — In addition to the neuromuscular blocking agents used during

● Neuromuscular blocking anesthetic agents

Aminoglycoside antibiotics inhibit both pre- and postsynaptic transmission [54,55].

● In aminoglycoside poisoning, low rates of repetitive nerve stimulation (RNS) produce a

● Since D-penicillamine produces a myasthenia syndrome, the findings on

compromise in the presentation of MG, requiring early recognition and treatment to

ORGANOPHOSPHATE AND CARBAMATE TOXICITY

Organophosphates and carbamates are potent inhibitors of acetylcholinesterase, causing

Organophosphate and carbamate toxicity is briefly reviewed here; a detailed discussion is

Pathophysiology — Although the organophosphates and the carbamates have a common

The spontaneous hydrolysis of organophosphates from acetylcholinesterase is generally very

The excess synaptic acetylcholine produced by organophosphates and carbamates binds

Ten to 40 percent of patients develop a distinct neurologic disorder 24 to 96 hours after

A delayed symmetrical motor axonal polyneuropathy, termed "organophosphorus agent-

Neurophysiology — Electrodiagnostic studies in organophosphate poisoning demonstrate

Diagnosis — The diagnosis of organophosphate or carbamate poisoning is made on clinical

Treatment — Emergency management of organophosphate or carbamate poisoning often

A surplus of magnesium or a deficiency of calcium may cause inhibition of acetylcholine

Hypocalcemia results in an uncoupling of synaptic release of neurotransmitters (glutamate,

Clinical features — Hypermagnesemia produces proximal muscle weakness, which may

Hypermagnesemia is an uncommon problem in the absence of magnesium administration

Diagnosis — The diagnosis of hypermagnesemia or hypocalcemia is generally made by

clinical improvement as levels normalize.

Electrodiagnostic studies show low-amplitude compound muscle action potentials (CMAPs),

SUMMARY AND RECOMMENDATIONS

● Anatomy – The neuromuscular junction consists of a presynaptic axon terminal and a

● Botulism – Botulism is an uncommon and life-threatening disease caused by

● Snake envenomation – Three families of snakes produce venom causing

● Drugs – In addition to the neuromuscular blocking agents used during anesthesia, a

checkpoint inhibitors (ICI), aminoglycoside, fluoroquinolone, and macrolide antibiotics,

● Organophosphates and carbamates – Organophosphates and carbamates are potent