Question

A 59-year-old man attends the emergency department after sustaining a puncture wound to his palm while working in a farm shed. Over the next few days he develops recurrent, very painful episodes of generalized muscle tightening, but he remains fully awake during the attacks. Examination shows marked jaw stiffness and backward arching of the neck and trunk.

What is the most likely action of the toxin responsible?

A. Persistent activation of adenylate cyclase
B. Blockade of presynaptic acetylcholine vesicle release
C. Antagonism of central dopamine receptors
D. ADP-ribosylation of elongation factor 2
E. Inhibition of gamma-aminobutyric acid (GABA) release

Answer

E. Inhibition of gamma-aminobutyric acid (GABA) release

Detailed explanation

This is classic tetanus, caused by Clostridium tetani.

The clues are:

• Wound contaminated by soil/farm/garden material
• Painful muscle spasms
• Patient remains conscious during spasms
• Trismus, or “lockjaw”
• Opisthotonus, meaning severe extensor spasm causing arching of the back

Clostridium tetani produces tetanospasmin, a potent neurotoxin. It enters peripheral nerves at the wound site and travels retrograde along axons to the spinal cord and brainstem. There, it prevents release of inhibitory neurotransmitters, especially GABA and glycine, from inhibitory interneurons.

Normally, GABA and glycine act as “brakes” on motor neurons. If these inhibitory signals are blocked, alpha motor neurons fire continuously. This causes sustained skeletal muscle contraction, painful spasms, trismus, opisthotonus, and potentially respiratory failure.

So the key mechanism is:

Tetanospasmin → blocks GABA and glycine release → loss of inhibition → uncontrolled motor neuron activity → spastic paralysis

This contrasts strongly with botulinum toxin, which causes flaccid paralysis.

Why the other options are wrong

A. Persistent activation of adenylate cyclase
This is seen with toxins such as cholera toxin, heat-labile E. coli toxin, and oedema factor of Bacillus anthracis. Cholera toxin activates Gs, increasing cAMP and causing profuse watery diarrhoea. Pertussis toxin increases cAMP by inhibiting Gi. These mechanisms do not explain lockjaw, opisthotonus, and painful spasms.

B. Blockade of presynaptic acetylcholine vesicle release
This describes botulinum toxin from Clostridium botulinum. Botulinum toxin blocks acetylcholine release at the neuromuscular junction, causing descending flaccid paralysis, diplopia, ptosis, dysphagia, and respiratory failure. Tetanus causes spastic paralysis due to loss of inhibitory neurotransmission.

C. Antagonism of central dopamine receptors
Dopamine D2 receptor blockade is the mechanism of many antipsychotics and antiemetics. Severe D2 blockade may cause extrapyramidal symptoms or neuroleptic malignant syndrome, with rigidity, fever, autonomic instability, and raised CK. It is not the toxin mechanism in tetanus.

D. ADP-ribosylation of elongation factor 2
This is the mechanism of diphtheria toxin and Pseudomonas exotoxin A. It inhibits protein synthesis by inactivating elongation factor 2. Diphtheria classically causes pharyngitis with a grey pseudomembrane and can cause myocarditis and neuropathy. It does not cause trismus and opisthotonus after a contaminated wound.

E. Inhibition of gamma-aminobutyric acid (GABA) release
Correct. Tetanospasmin prevents release of GABA and glycine from inhibitory interneurons, causing unchecked motor neuron activity and spastic paralysis.

Key exam point

Tetanus toxin blocks inhibitory neurotransmitter release, especially GABA and glycine, causing spastic paralysis.

Botulinum toxin blocks acetylcholine release at the neuromuscular junction, causing flaccid paralysis.

Very important clinical trap

Both tetanus and botulism are caused by Clostridium species and both are neurotoxin-mediated, but their clinical effects are opposite:

Condition	Organism	Toxin action	Clinical result
Tetanus	Clostridium tetani	Blocks GABA and glycine release	Spastic paralysis
Botulism	Clostridium botulinum	Blocks acetylcholine release	Flaccid paralysis

Exam shortcut:

• Tetanus = too much tone
• Botulinum = blocked ACh = floppy weakness

Cheat sheet for exam

• Clostridium tetani is an anaerobic, Gram-positive, spore-forming bacillus.
• Spores are found in soil, manure, dust, and contaminated wounds.
• Tetanus toxin is tetanospasmin.
• Tetanospasmin travels retrograde along nerves to the CNS.
• It blocks release of GABA and glycine from inhibitory interneurons.
• Loss of inhibition causes continuous motor neuron firing.
• Clinical features: trismus, risus sardonicus, dysphagia, neck stiffness, painful spasms, opisthotonus.
• Patient usually remains conscious during spasms.
• Autonomic instability may occur: hypertension, tachycardia, sweating.
• Death may occur from respiratory muscle spasm or autonomic complications.
• Botulinum toxin blocks acetylcholine release and causes flaccid paralysis.
• Diphtheria toxin and Pseudomonas exotoxin A inhibit EF-2.
• Cholera toxin and heat-labile E. coli toxin increase cAMP.
• Heat-stable E. coli toxin increases cGMP.
• Endotoxin is lipopolysaccharide from Gram-negative bacteria.

Flash cards

Q: What organism causes tetanus?
A: Clostridium tetani, an anaerobic Gram-positive spore-forming bacillus found in soil and manure.

Q: What is the name of the tetanus toxin?
A: Tetanospasmin.

Q: What neurotransmitters are blocked by tetanospasmin?
A: GABA and glycine.

Q: What is the effect of blocking GABA and glycine release?
A: Loss of inhibitory control over motor neurons, causing continuous motor neuron activity and spastic paralysis.

Q: What is the classic jaw finding in tetanus?
A: Trismus, also called lockjaw.

Q: What is opisthotonus?
A: Severe extensor muscle spasm causing backward arching of the neck and spine.

Q: How does botulinum toxin differ from tetanus toxin?
A: Botulinum toxin blocks acetylcholine release at the neuromuscular junction, causing flaccid paralysis.

Q: Which toxins inhibit elongation factor 2?
A: Diphtheria toxin and Pseudomonas exotoxin A.

Q: Which toxin increases cAMP by activating Gs?
A: Cholera toxin.

Q: Which toxin increases cAMP by inhibiting Gi?
A: Pertussis toxin.

MCQs

1. A farmer develops painful generalized spasms and lockjaw after stepping on a rusty nail. Which neurotransmitter pathway is primarily affected?

A. Increased dopamine release
B. Reduced GABA and glycine release
C. Reduced acetylcholine degradation
D. Increased serotonin release
E. Increased glutamate release

Answer: B. Reduced GABA and glycine release

Explanation: Tetanospasmin blocks release of inhibitory neurotransmitters GABA and glycine from spinal inhibitory interneurons. This removes inhibition from motor neurons, causing spastic paralysis.

2. Which of the following best distinguishes tetanus from botulism?

A. Tetanus causes flaccid paralysis; botulism causes spastic paralysis
B. Tetanus blocks acetylcholine release; botulism blocks glycine release
C. Tetanus causes spastic paralysis; botulism causes flaccid paralysis
D. Both cause paralysis through identical neuromuscular junction blockade
E. Botulism primarily causes opisthotonus and lockjaw

Answer: C. Tetanus causes spastic paralysis; botulism causes flaccid paralysis

Explanation: Tetanus blocks inhibitory neurotransmission in the CNS, causing increased motor neuron firing and spasticity. Botulinum toxin blocks acetylcholine release at the neuromuscular junction, causing weakness and flaccid paralysis.

3. Which toxin acts by ADP-ribosylating elongation factor 2?

A. Tetanospasmin
B. Botulinum toxin
C. Cholera toxin
D. Diphtheria toxin
E. Heat-stable E. coli toxin

Answer: D. Diphtheria toxin

Explanation: Diphtheria toxin inhibits protein synthesis by ADP-ribosylating EF-2. Pseudomonas exotoxin A has a similar mechanism.

4. Which of the following is false regarding tetanus?

A. It may occur after contaminated penetrating wounds
B. It is caused by a Gram-positive anaerobic bacillus
C. It causes flaccid descending paralysis
D. It may cause trismus and opisthotonus
E. The toxin blocks inhibitory neurotransmitter release

Answer: C. It causes flaccid descending paralysis

Explanation: This is false. Flaccid descending paralysis is typical of botulism. Tetanus causes spastic paralysis due to loss of GABA and glycine-mediated inhibition.

5. A patient develops diplopia, dysphagia, dry mouth, and descending weakness after eating home-preserved food. Which toxin mechanism is most likely?

A. Inhibition of acetylcholine release
B. Inhibition of GABA release
C. Activation of guanylate cyclase
D. Inhibition of EF-2
E. Superantigen-mediated cytokine release

Answer: A. Inhibition of acetylcholine release

Explanation: This is botulism. Botulinum toxin prevents acetylcholine release at the neuromuscular junction, producing flaccid paralysis.

6. Cholera toxin causes diarrhoea by which mechanism?

A. Inhibition of protein synthesis via EF-2
B. Activation of guanylate cyclase
C. Inhibition of acetylcholine release
D. Activation of adenylate cyclase via Gs
E. Blockade of GABA release

Answer: D. Activation of adenylate cyclase via Gs

Explanation: Cholera toxin activates Gs, causing increased adenylate cyclase activity, raised cAMP, chloride secretion, reduced sodium absorption, and watery diarrhoea.

7. Which of the following toxins is a superantigen?

A. Tetanospasmin
B. Toxic shock syndrome toxin-1
C. Botulinum toxin
D. Shiga toxin
E. Pseudomonas exotoxin A

Answer: B. Toxic shock syndrome toxin-1

Explanation: TSST-1 from Staphylococcus aureus is a superantigen. It bridges MHC class II and T-cell receptors, causing massive cytokine release, fever, rash, and shock.

8. Which of the following is false?

A. Pertussis toxin increases intracellular cAMP
B. Botulinum toxin causes flaccid paralysis
C. Tetanus toxin blocks GABA and glycine release
D. Shiga toxin activates adenylate cyclase
E. Diphtheria toxin inhibits EF-2

Answer: D. Shiga toxin activates adenylate cyclase

Explanation: Shiga toxin inactivates the 60S ribosomal subunit, impairing protein synthesis. Cholera toxin and heat-labile E. coli toxin increase cAMP.

9. Heat-stable E. coli toxin causes watery diarrhoea mainly by increasing which second messenger?

A. cAMP
B. cGMP
C. IP3
D. DAG
E. Calcium-calmodulin kinase

Answer: B. cGMP

Explanation: Heat-stable E. coli toxin activates guanylate cyclase, increasing cGMP and causing secretory watery diarrhoea.

10. Which clinical picture most strongly suggests tetanus rather than neuroleptic malignant syndrome?

A. Fever and rigidity after haloperidol use
B. Autonomic instability with high CK after antipsychotics
C. Lockjaw and painful spasms after a contaminated wound while conscious
D. Lead-pipe rigidity after dopamine blockade
E. Hyperthermia after starting metoclopramide

Answer: C. Lockjaw and painful spasms after a contaminated wound while conscious

Explanation: Tetanus classically follows wound contamination and causes trismus, painful spasms, opisthotonus, and preserved consciousness. Neuroleptic malignant syndrome is linked to dopamine antagonist exposure.

Summary for quick exam revision

Tetanus is caused by Clostridium tetani, an anaerobic Gram-positive spore-forming bacillus found in soil, dust, and manure. Infection usually follows a contaminated wound, especially a puncture wound or injury involving soil. The toxin responsible is tetanospasmin. Tetanospasmin enters peripheral nerves and travels retrograde to the spinal cord and brainstem. It blocks release of the inhibitory neurotransmitters GABA and glycine from inhibitory interneurons. This removes the normal brake on alpha motor neurons. The result is continuous motor neuron activity and painful spastic paralysis. Classic features include trismus, lockjaw, risus sardonicus, dysphagia, neck stiffness, opisthotonus, and generalized muscle spasms. Patients often remain conscious during the spasms, which is an important clinical clue. Severe cases may cause respiratory failure and autonomic instability. The key exam contrast is botulism, caused by Clostridium botulinum, which blocks acetylcholine release at the neuromuscular junction and causes flaccid paralysis. Tetanus causes too much tone, whereas botulism causes floppy weakness. Diphtheria toxin and Pseudomonas exotoxin A inhibit EF-2. Cholera toxin increases cAMP through Gs activation, while pertussis toxin increases cAMP by inhibiting Gi. Heat-stable E. coli toxin increases cGMP. For exams, the single most important phrase is: tetanospasmin blocks GABA and glycine release, causing spastic paralysis.