Differential Diagnosis in Neurology

11.4. Drugs/Toxins that Alter Neuromuscular Transmission

• General Features:
  • All decrease the safety factor of neuromuscular transmission
  • Neurotoxins may affect both the pre and post synapse components of the NMJ
  • Most common neurotoxin is envenomation (worldwide)
  • Extraocular muscles, neck flexors and extensors and girdle muscles are particularly sensitive; involvement of respiratory and pharyngeal muscles is common; cognition is spared (unless there is secondary hypercarbia) as is sensation. Reflexes are intact until late in the course of the illness.
• Analgesics:
  • Morphine and its deritatives do not depress neuromuscular transmission
    • Depress respiration (centrally)
    • Are potentiated by anticholinesterases
• General anesthetics:
  • Potentiation of neuromuscular blocking agents in MG patients (weakness and respiratory depression)
  • Ethrone and nitrous oxide do not cause neuromuscular blockade
• Local Anesthetics:
  • Lidocaine, procaine, mexiletine potentiate neuromuscular blockade when administered intravenously.
  • Impairment of nerve action potential propagation (not the case with lidocaine) and possible reduction of Ach release; possible decreased sensitivity of the post synaptic membrane to Ach.
• Antibiotics:
  • Aminoglycosides:
    • Weakness related to dose and serum level
    • Blocking effects occur by any route administration
    • Inhibition of Ach release
  • Tobramycin:
    • Inhibition of Ach release
  • Neuromuscular toxicity demonstrated for:
    • Kanamycin
    • Gentamicin
    • Neomycin (most toxic)
    • Streptomycin
  • Macrolide antibiotics known to demonstrate neuromuscular toxicity:
    • Erythromycin
    • Azithromycin
  • Polypeptide and monobasic amino acid antibiotics known to demonstrate neuromuscular toxicity:
    • Penicillin
    • Sulfonamides
    • Tetracycline
    • Fluoroquinolone
      • Potentiate neuromuscular blocking agents
      • Cause weakness in MG patients alone
    • Lincomycin and clindamycin:
      • Monobasic amino acids
      • Difficult to reverse effects with cholinesterase inhibitors
      • Mechanisms of action:
        • Decreased motor end plate potential frequency
        • Decrease evoked transmitter release
        • Decrease postjunctional Ach sensitivity
      • Lincomycin:
        • Effects reversed with calcium or aminopyridine
        • Cholinesterase inhibitors worsen their effect
      • Clindamycin:
        • Blocks muscle contractibility
        • Has local anesthetic action
      • Polymyxin B; colistimethate and colistin:
        • Renal disease patients are susceptible
        • Potentiates effects of other antibiotics and neuromuscular blocking agents
        • Decreased Ach release and postjunctional block of AchR
      • Tetracycline, oxytetracycline and rolitetracycline exacerbate MG
    • Bretylium (potentiates blocking drugs)
    • Calcium channel blockers (presynaptic inhibitions of Ach release)
    • Procainamide (impaired formation or release of Ach)
    • Quinidine and quinine (prevents formation or release of Ach or a curare-like effect); potentiate depolarizing and non-depolarizing blocking drugs
    • Trimethaphan; potentiates depolarizing and non-depolarizing drugs
    • Progesterone: reported to aggravate MG after 3–5 days
    • Interferon alpha:
      • May aggravate MG weeks to months after the initiation of therapy
      • Has induced MG crisis
    • Iodinated contrast agents: possibly decrease ionized calcium that induces failure of Ach release
    • Magnesium:
      • Decreases release of Ach; blocks calcium entry at the terminal motor terminal
      • Induces post synaptic membrane excitability
      • Effects seen parenteral > oral administration
      • Potentiates neuromuscular blocking drugs
      • 10 mEq/liter may cause respiratory depression
    • Neuromuscular blocking drugs:
      • MG patients more sensitive to competitive non depolarizing agents
      • Succinylcholine:
        • Potentiated by cholinesterase inhibitors
        • Prolonged weakness may occur with plasma exchange or in the setting of congenital absence of cholinesterase inhibitors
        • Corticosteroids may potentiate the effects of muscle relaxants

Ophthalmic Drugs

• Beta-adrenergic agents
• Echothiophate (long acting cholinesterase inhibitor)

Psychotropic Drugs

• Chlorpromazine and promazine:
  • Post synaptic block
  • Antagonize Ach
  • Prolong the effects of succinylcholine
• Lithium:
  • Possible decrease of quantal release or synthesis of Ach
  • Possibly induces increased rate of receptor degradation

Rheumatologic Drugs

• Chloroquine:
  • Decreased Ach release
  • Competitive postjunctional blockade
  • Depresses excitability of the sarcolemmal membrane

D-Penicillamine

• MG may be precipitated in 7% of patients treated
  • May be restricted to extraocular muscles
  • Mild generalized weakness

Bone Marrow Transplant

• Autoimmune etiology
• Possibly more common in those with aplastic anemia

D, L-Carnitine

• NMJ block occurs during dialysis
• Presynaptic block similar to that produced by hemicholinium
• Postsynaptic block due to possibly by the accumulation of acylcarnitine esters

Diuretics

• MG weakness aggravated by hypokalemia

Reports of Drugs that Exacerbated MG Weakness

• Emetine
• Riluzole
• IV sodium lactate
• Tetanus antitoxin
• Trasylol
• Trihexyphenidyl
• Diphenhydramine

Drugs that Alter Neuromuscular Transmission in Specific Clinical Situations

• Safety factor for neuromuscular transmission is reduced due to the underlying disease
• Superimposition of drug on pre-existing disorder such as MG or ALS
• Patients with renal, hepatic or electrolyte disorders (may have depressed NMJ or membrane excitability)
• After general anesthesias with concomitant neuromuscular blocking drugs (succinylcholine; pancuronium) which are still active
• Component of drug induced generalized immunologic disease (penicillamine)
• Presynaptic induced dysfunction:
  • Calcium-magnesium
  • Calcium channel blocking agents; some antibiotics; some beta blocking drugs
• Postsynaptic induced dysfunction:
  • Penicillamine
  • Carnitine
  • Cholinesterase inhibitors
• Pre and Post synaptic dysfunction
  • Aminoglycosides
  • Enhances or induces autoimmune reaction against the NMJ
  • MG more commonly induced during treatment of rheumatoid arthritis rather than Wilson's disease (penicillamine)
  • 70% of patients remit within one year after discontinuance of the drug (penicillamine)

Envenomation from Snake Bites

• General features:
  • Usually affect the cholinergic system:
    • Increase the release of Ach
    • Block AchR
  • Major species:
    • Viperidae (pit vipers)
    • Crotalidae (rattle snakes and pit vipers)
    • Elapidae (coral snakes, mamba, Kraits and cobras)
    • Hydrophiidae (sea snakes)
  • Neuromuscular blockade occurs with:
    • Elapidae
    • Hydrophiidae
    • Crotalidae (South American rattle snake)
  • Presynaptic toxins:
    • β-bungarotoxins
    • Tai pexin
    • Decrease the release of Ach:
      • Initial augmented release
      • Late depletion of the neurotransmitter
    • More potent than post synaptic toxins
  • Post synaptic toxins:
    • α-neurotoxins
    • Non depolarizing neuromuscular block
  • Most toxins are mixtures of pre and postsynaptic compounds
  • Sea snakes inject less toxin, but it is more potent
  • α-neurotoxins:
    • Bind the nicotinic Ach receptor of muscle
    • More potent than curare
    • Slower onset of action and longer duration than presynaptic toxins
  • β-Neurotoxins:
    • Contain phospholipases
    • All suppress release of presynaptic Ach
    • Tai pexin has additional Myotoxin (rapid muscle necrosis)
• Clinical presentation:
  • Pit viper or cobra
    • Local pain
    • No pain with other Elapidae and Hydrophiidae
  • Swelling and necrosis within one hour of bite from Viperidae, Crotalidae
    • No swelling from mamba, Krait or Coral snakes
  • Pre paralytic stage (Viperidae and Crotalidae)
    • Headache, nausea and vomiting
    • Loss of consciousness
    • Paraesthesias
    • Hematuria and hemoptysis
    • Above manifestations rarely seen with cobra or mamba envenomation
  • Neuromuscular Toxicity:
    • Usual time from envenomation to paralysis:
      • 1/2 hour to 19 hours
      • Mamba envenomation as short as 10 minutes
      • Location of the bite and direct venous access are determining features as is variant of injected toxin
    • Sequence of clinical signs:
      • Ptosis and ophthalmoparesis
      • Facial and bulbar weakness
      • Extremity, diaphragms and intercostal weakness
      • a) May progress over 2–3 day period
      • No sensory abnormality accept at the site of envenomation
      • Cardiovascular collapse, seizures and coma are terminal events
    • Hematoxic effects:
      • Cerebral hemorrhage
      • SAH
      • ICH
      • Leading cause of Viperidae deaths
    • Crotalidae:
      • Persistent fasciculations long after clinical recovery of the affected muscles

Arthropod Envenomation

• General features:
  • Mechanism of NMJ effects
    • Increased release of Ach followed by depletion
  • Facilitated release without depletion of transmitter
  • Decreased Ach release
• Clinical presentation:
  • Black widow spider (Latrodectus) release followed by depletion
    • CNS and PNS stimulation; facilitation of Ach release
    • Neuromuscular effects noted within 15 to 60 minutes of envenomation
    • Severe painful abdominal cramps and rigidity; followed by truncal and appendicular cramps; later affects are muscle weakness (depolarizing block)
  • Funnel-Web spider; red back
    • Male toxins have potency greater than female
    • Nausea, vomiting, dizziness are first symptoms
    • Fasciculations and paralysis of striated muscle and the diaphragm
    • Death by cardiac arrest (asphyxia)
  • Scorpion
    • Toxins effect sodium and potassium channel function; some enhance release of Ach
    • Increased secretion of saliva
    • Severe sweating, nausea, vomiting, disorientation and dizziness
    • Less motor weakness

Tick Paralysis

• General Features:
  • Dermacentor (acronine, variabilis, occidentalis, amblyomma americanum and maculatum) species are toxic
  • In North America most often seen in states West of the Rocky Mountains
  • Possible temperature dependent block of Ach release
• Clinical Presentation:
  • Symptoms require 5–6 days of attachment
    • Headache, malaise, nausea and vomiting
    • On 6–8 days there is symmetric ascending paralysis; may affect respiration and bulbar muscles
    • Normal sensation
    • Depressed reflexes
    • Improvement begins within hours of removing the engorged tick
    • Tick attaches mot often in the scalp, perineum, and neck
    • Some patients ataxia is more severe than weakness

Marine Toxins

• General features:
  • Marine toxins affecting the NMJ
    • Poisonous fish
    • Mollusks
    • Dinoflagellates
  • Due to ingestion
  • Shellfish poisoning:
    • Caused by dinoflagellates (single-celled, bi flagellated, algae-like)
    • Toxin absorbed through GI tract:
      • Within 30 minutes there is burning and paresthesias of the face and mouth that spreads to neck and limbs
      • Sensory symptoms abate and are followed by numbness, ataxia and generalized weakness; respiratory failure can ensue
    • Neurotoxins from dinoflagellates and diatoms (not flagellated and are encased in a shell):
      • Sodium channel blockers
      • Include: saxitoxin and tetrodotoxin
    • Brevetoxins:
      • Derived from shellfish
      • Depolarizes cholinergic systems by opening sodium channels

Gonotoxins

• General Features:
  • Derived from predatory cone snails (mollusks); dart like proboscis that injects toxin
  • α-Gonotoxin:
    • Blocks binding of Ach
  • W-Gonotoxins:
    • Block voltage gated calcium channel of the presynaptic terminal
• Clinical Presentation:
  • Severe local pain
  • Within 30 minutes generalized weakness
  • Respiratory failure occurs within 1–2 hours
  • 60% of stings may be fatal

Venomous Fish

• General features:
  • Most venomous is the stone fish
  • Pacific oceans, Red Sea and Japan
  • Toxin:
    • Toxin is injected from dorsal spines
    • Ach release with later depletion of stores
• Clinical presentation:
  • Excruciating local pain that lasts for two days
  • Edema and necrosis: hyaluronidase injected that promotes spread of toxin
  • GI, autonomic, cognitive dysfunction
  • Generalized muscle weakness

Plant Toxins

• General features:
  • Hemlock (conium maculatum)
  • Piperidine alkaloid
  • Coniine is the toxin
• Clinical presentation:
  • Rapidly ascending paralysis
  • Severe sensory symptoms