OVERVIEW: What every practitioner needs to know

Are you sure your patient has tetanus? What should you expect to find?

  • The initial complaints of patients with generalized tetanus are muscle stiffness and difficulty opening their mouths. As time goes on they develop spasms, which may progress to episodes of opisthotonic posturing that can cause airway compromise and death. Patients with local tetanus have weakness in the vicinity of the site of infection, and thus they may complain of, for example, unilateral facial weakness before the onset of diffuse stiffness and spasms.

  • The hallmarks of the generalized form of the disease are muscle rigidity, which is usually present constantly, spasms, trismus (or lockjaw) when the mouth cannot be opened, and risus sardonicus (grinning expression due to spasms of facial muscles). A wound may or may not be visible at the time the patient presents. Spasms may occur without stimulation but tend to be triggered by any sensory stimulus. After the first week of generalized disease, autonomic dysfunction becomes prominent. Patients with local forms of tetanus have lower motor neuron muscle weakness near the site of toxin production (e.g., a wound, or in the case of facial tetanus, they may have otitis media). Local tetanus frequently goes on to produce generalized manifestations elsewhere, while the local area remains hypotonic.

How did the patient develop tetanus? What was the primary source from which the infection spread?

  • Most patients with tetanus will have a well-defined wound or other portal of entry for the spores of Clostridium tetani.

  • Tetanus is almost completely preventable with adequate immunization and appropriate wound care.

Which individuals are at greater risk of developing tetanus?

  • Those who have never been immunized, especially the newborn children of unimmunized mothers

  • Certain portals of entry are more prone to cause tetanus than others, including puncture wounds, especially with dirty nails, burns, umbilical stumps, surgical procedures, compound fractures, abortions performed outside of medical facilities, and intramuscular injections (particularly of quinine). Injection drug users appear to be at particular risk.

Beware: there are other diseases that can mimic tetanus:

  • The major differential diagnostic considerations for generalized tetanus are strychnine intoxication and the stiff-person syndrome. Strychnine poisoning patients may have relative relaxation of the abdominal musculature between spasms, whereas tetanus patients tend to have diffuse muscular hypertonicity at all times. Patients with stiff-person syndrome almost always have a long history of complaints related to muscle stiffness before they develop spasms.

  • A dystonic reaction to a dopamine antagonist may mimic tetanus, although dystonic reactions almost always involve sustained lateral head movement that is not seen in tetanus. If in doubt, a dose of diphenhydramine or benztropine will relieve a dystonic reaction but will not affect tetanus.

  • Trismus may be a consequence of an alveolar ridge abscess or other oral infections.

What laboratory studies should you order and what should you expect to find?

Results consistent with the diagnosis

  • There is no diagnostic test for tetanus. Strychnine poisoning can be diagnosed by assays of serum or urine. The stiff-person syndrome is most commonly due to antibodies directed against GAD65, one of the enzymes that convert glutamate to gamma-amino-butyric acid (GABA). This antibody should be sought in the CSF to make this diagnosis of stiff-person syndrome. Occasional cases of stiff-person syndrome lack this antibody but have other evidence of autoimmunity.

Results that confirm the diagnosis

  • None. It is reasonable to obtain serum to assay for anti-tetanus antibodies before giving human tetanus immune globulin (HTIG)

What imaging studies will be helpful in making or excluding the diagnosis of tetanus?

  • There are no imaging studies diagnostic for tetanus.

What consult service or services would be helpful for making the diagnosis and assisting with treatment?

If you decide the patient has tetanus, what therapies should you initiate immediately?

The most important aspect of initial therapy for generalized tetanus is to maintain a patent airway. While it may be possible to do this with intravenous benzodiazepines alone, more severely affected patients will require endotracheal intubation. Since laryngoscopy and intubation are very potent spasmogenic procedures, this should be done with neuromuscular junction blockade in addition to sedation. These patients are often remarkably resistant to standard doses of hypnosedative drugs. One should consider an early tracheostomy in order to remove the spasmogenic stimulation of the endotracheal tube. While the initial goal is to have a comfortable, conscious patient who is free of spasms, this is often not possible. If the dose of benzodiazepine needed to stop spasms results in hypotension, then the patient will also need more prolonged neuromuscular junction blockade.

Human tetanus immune globulin, 500 units, should be administered intramuscularly as soon as possible. Larger doses are no more effective. At a separate site, the first dose of the age-appropriate form of vaccine containing tetanus toxoid should also be administered. A complete initial series of toxoid injections should be performed, as the amount of toxin produced during an episode of severe tetanus is not adequate to induce immunity.

1. Anti-infective agents

What anti-infective should I order?

The role of antibiotics in tetanus remains controversial. Although penicillin G has long been used, a single trial showed metronidazole to be superior. However, penicillin is itself a GABAA antagonist, so this result may mean that penicillin administration was deleterious. The absence of a control group leaves open the question of whether metronidazole is useful.

2. Other key therapeutic modalities.

  • Autonomic dysfunction, usually manifested as sympathetic hyperactivity, and should be treated with labetalol to provide both alpha- and beta-adrenergic inhibition. Infusions of morphine and magnesium may also be useful for treating the hypersympathetic state.

  • Intrathecal administration of antitoxin is an attractive option for removing toxin which is in the central nervous system extracellular space, but has not been studied.

What complications could arise as a consequence of tetanus?

What should you tell the family about the patient's prognosis?

  • The complications of tetanus arise from autonomic instability causing respiratory and cardiovascular dysfunction.

  • Aspiration pneumonia as a result of inability to swallow secretions. Spasms of the glottis may cause asphyxiation.

  • Rhabdomyolysis can occur with repeated muscle spasms.

  • The mortality can be as low as 10-20%, depending on the age of the patient, the severity of the disease, and the ability to sustain the patient’s vital functions in an intensive care unit setting until the disease has run its course.

  • The elderly and neonates have the worst prognosis.

What pathogen is responsible for this disease?

Tetanus is caused by toxins produced in vivo by Clostridium tetani

How does this pathogen cause tetanus?

  • Local tetanus has a pathophysiology identical to botulism. In both conditions, the toxin is disseminated to motor neurons via diffusion and then via the bloodstream.

  • Tetanus toxin (tetanospasmin) is zinc-dependent metalloproteinase which is synthesized as a single chain and then nicked to produce a heavy chain and a light chain.

    The heavy chain allows the toxin to bind to its putative receptor on the presynaptic neuron of the neuromuscular junction (or an autonomic synapse for the eye and the gut). The toxin is internalized via receptor-mediated endocytosis, and then released into the cytoplasm.

    The light chain interacts with the synaptic vesicle release mechanism that is responsible for coupling the increase in intracellular free calcium (caused by depolarization of the presynaptic neuron), inhibiting one of the several proteins involved in transmitter release.

    Each toxin type targets an individual component of the release mechanism.

    All of the manifestations of botulism stem from this effect, with the motor manifestations resulting from inhibition of transmitter release at the neuromuscular junction, and the ocular and gastrointestinal effects a consequence of muscarinic synaptic inhibition. The toxin also affects transmission in autonomic ganglia, although the contribution of this effect to its clinical manifestations is uncertain.

  • In tetanus, in addition to its local effect, the toxin is also moved via the neuronal retrograde transport system into the central nervous system, where it appears to have its highest affinity for cells responsible for inhibition.

    At the spinal cord level, glycinergic inhibitory neurons are particularly affected, and in the brainstem, descending GABAergic inhibitory cells are involved.

    The combined loss of these inhibitory systems results in the forceful, widespread, sustained contractions of many muscles whenever a given muscle contracts.

  • Although tetanus toxin will produce seizures if applied directly to the cerebral cortex of experimental animals, seizures do not occur in clinical tetanus; the patients remain awake unless they become hypoxic during a spasm.

How can tetanus be prevented?

  • Tetanus is completely preventable with immunization.

  • Immunization schedule:

    Primary series is 3 doses of tetanus toxoid given with diphtheria toxoid and acellular or whole cell pertussis (DTaP or DPT)

    Booster dose at entry to school

    Booster doses of TDaP every 10 years

  • Neonatal tetanus is prevented if the mother is immune

  • Use of toxoid and human tetanus immunoglobulin (HTIG) after an injury

    Clean minor wounds in patient with documented primary vaccination: HTIG not needed; toxoid not needed unless more than 10 years since last booster vaccination

    Clean minor wounds in patient with no or unknown primary vaccination:Give toxoid and follow with basic immunization series

    All other wounds in patient with documented primary vaccination: No need for HTIG; toxoid if greater than 5 yr since last booster vaccination

    All other wounds in patient with no or unknown primary vaccination: Give HTIG (250 IU) and toxoid followed with basic immunization series

WHAT'S THE EVIDENCE for specific management and treatment recommendations?

Benson, MA, Fu, Z, Kim, JJ, Baldwin, MR. “Unique ganglioside recognition strategies for clostridial neurotoxins”. J Biol Chem. vol. 286. 2011. pp. 34015-22.

Bleck, TP, Cohen, J, Powderly, WG, Opal, S. “Tetanus and botulism”. Infectious Diseases. 2010. pp. 237-242.

Palmateer, NE, Hope, VD, Roy, K, Marongiu, A, White, JM, Grant, KA, Ramsay, CN, Goldberg, DJ, Ncube, F. “Infections with spore-forming bacteria in persons who inject drugs, 2000-2009”. Emerg Infect Dis. vol. 19. 2013. pp. 29-34.

Kati, I, Goktas, U, Cagan, E, Guzel, A, Bartin, S. “The effect of magnesium sulfate on uncontrollable contractions in a tetanus case”. Pediatr Emerg Care. vol. 28. 2012. pp. 366-7.

Reddy, P, Bleck, TP, Tunkel, AR, Roos, K, Aminoff, M, Boller, F, Swaab, D. “Toxin-mediated syndromes”. Bacterial infections of the nervous system. 2010. pp. 257-272.

Reddy, P, Bleck, TP, Mandell, GM, Bennett, JE, Dolin, R. “Clostridium tetani”. Principles and practice of infectious diseases. 2010. pp. 3091-3096.

“Tetanus surveillance — United States, 2001-2008”. MMWR Morb Mortal Wkly Rep . vol. 60. 2011. pp. 365-9.