Continuing Education Activity

Clostridium tetani is an anaerobic, spore-forming bacillus that produces muscle rigidity and hypersympathetic activity leading to tetanus. With around 1 million cases annually, it primarily affects resource-poor regions and unvaccinated populations. Tetanus toxin inhibits neurotransmitter release in the brain stem and spinal cord. Wound contamination is the usual entry mode, but in rare cases, no specific inoculation site is identified. Diagnosis relies on clinical assessment due to the limited confirmatory value of laboratory tests. Treatment involves a comprehensive approach, including airway protection, benzodiazepines, human tetanus immunoglobulin, and tetanus toxoid, addressing sympathetic hyperactivity. Tetanus is preventable through tetanus toxoid immunizations.

Participation in this activity provides clinicians with a thorough understanding of tetanus, from its microbiological basis to practical diagnosis, treatment, and prevention strategies. This knowledge is crucial for enhancing clinical competency and improving patient outcomes in cases of tetanus.

Objectives:

• Differentiate clinical manifestations of tetanus from other neuromuscular disorders, ensuring accurate and prompt diagnoses.

• Apply preventive measures, including tetanus toxoid immunizations, emphasizing their importance in high-risk populations.

• Select appropriate therapeutic interventions, such as airway protection, benzodiazepines, and immunoglobulin administration, based on the clinical presentation of tetanus.

• Collaborate with all multidisciplinary team members, including clinical microbiologists, infectious diseases clinicians, intensivists, and public health officials, to promptly manage patients with tetanus.

Introduction

Clostridium tetani is the causative organism for the disease known as tetanus.[1] This bacillus and its spores are ubiquitous in the environment, and infection by plasmid-containing neurotoxin-producing strains has been a scourge since antiquity. Fortunately, the advent of highly protective vaccines has nearly eliminated tetanus worldwide. However, tetanus remains a significant infectious disease in resource-poor areas where public health outreach may be lacking. Conversely, in resource-rich areas with easily accessible vaccines, tetanus is a rare occurrence for most clinicians. Its rarity in the latter setting can lead to delays in diagnosis and optimal therapy when patients with tetanus seek medical attention.[2] 

Thus, it is important to identify risk factors, recognize typical clinical presentations, and understand the immediate management and treatment of C tetani infection.[3][4][5][6] Tetanus is a life-threatening disorder characterized by painful muscular spasms, hypertonia, and autonomic nervous system dysfunction. Despite widespread vaccination efforts in the US, the disorder still arises.[7]

Tetanus is classified into 4 categories:

• Generalized
• Localized
• Cephalic
• Neonatal 

Mortality rates are highest at the extremes of age, where a combination of diminished immunity and the presence of comorbidities is common. Ideally, individuals with tetanus should receive care from a multispecialty team within a critical care setting. Unfortunately, this optimal care environment is frequently unavailable in regions where it is most urgently needed for treating patients with tetanus. Furthermore, in resource-poor areas, neonatal tetanus is associated with high mortality. 

The management of tetanus relies on experience gained and reported in many case studies. Due to the relatively low incidence of infection and the potentially lethal nature of tetanus, there are no large randomized, placebo-controlled studies for a comprehensive comparison of best practices.[6] Nevertheless, the management approach has been well established through anecdotal reports, case series, and small-scale randomized clinical studies.[8] 

Etiology

C tetani are obligate anaerobic, gram-positive, spore-forming bacilli found ubiquitously in the environment, persisting in soil, domestic animal and human feces, dust, and the gastrointestinal (GI) tract.[1] They appear gram-positive in fresh cultures but may appear gram-variable in mature cultures. Mature bacilli possess a terminal spore resembling tennis and squash racquets.[9] Utilizing the mnemonic association of “tetanus” and “tennis” based on their similar sounds can be helpful when interpreting micrographic images of bacilli.

Spores in the environment germinate into bacteria when inoculated into injured tissue. The spores exhibit remarkable stability and resist eradication from exposure to formalin, ethanol, household disinfectants, boiling, and freezing. Exposure to iodine, hydrogen peroxide, glutaraldehyde, and autoclaving at high temperatures and pressure can render them non-infectious. In clinical practice, culture results lack diagnostic value, as the organism is challenging to culture.[10] Positive culture results may reflect the presence of nontoxigenic strains, and even immunized individuals may show positive cultures of C tetani without disease.

Traumatic wounds are the primary source of infection in most cases, while tetanus can also arise from burn injuries, surgical abscesses, intravenous drug use, circumcision, or gangrene. Occasionally, the source of infection remains unidentified. Incomplete immunization or lack of vaccination is often associated with tetanus cases.

Neonatal tetanus frequently results from home deliveries with unsanitary cutting of the umbilical cord.[11] Immunity from the tetanus vaccine tends to decline with age in most individuals. Thus, vaccination or booster shots are required for prevention.[1][3][10][12]

Epidemiology

Most instances of tetanus occur in developing countries where immunity is deficient, particularly in areas affected by natural disasters.[12] In resource-rich countries, the unvaccinated and those with waning vaccine immunity are at risk. Among this group, surveillance data highlights individuals who inject drugs and those with insulin-dependent diabetes as particularly vulnerable.[7]

The spores of C tetani are present in the environment irrespective of geographical location, residing in the soil and entering through openings in the skin. Wounds containing devitalized tissue pose the highest risk, making all age groups susceptible to infection. Without high-quality medical care, the case-fatality rate can approach 100%, while with optimal care, the case-fatality ratio ranges from 10% to 20%.[3] Neonates face an increased risk in resource-poor regions when nonhygienic deliveries are performed, nonsterilized materials are used to cut the umbilical cord, or contaminated dressings are applied to the umbilical stump.[11] In 2015, the World Health Organization (WHO) estimated that approximately 34,000 neonates died from neonatal tetanus.[13]

Tetanus is a vaccine-preventable disease, and tetanus toxoid-containing vaccines (TTCV) are included in the routine childhood immunization schedule. The average annual incidence of tetanus in the US from 2001 to 2008 was 0.01 per 100,000 population.[7] From 2009 to 2015, there were 197 reported tetanus cases and 16 associated deaths reported in the US.[14] The age groups at the highest risk are newborns and older individuals. The tetanus toxoid vaccine was first produced in 1924 and used extensively among soldiers during World War II. The pentavalent vaccine, which protects against diphtheria, tetanus, pertussis, Hib, and hepatitis B (DTP-Hib-HepB), is the most commonly used childhood vaccine worldwide.[3] Infection from C tetani does not confer immunity and is not transmitted from person to person.

Pathophysiology

Inoculation of wounds with C tetani spores facilitates germination of bacilli. These bacteria produce 2 toxins: tetanospasmin (tetanus toxin) and tetanolysin. Tetanospasmin circulates through lymphatics and the bloodstream, binding to receptors in the peripheral nervous system at neuromuscular junctions. Subsequently, it is endocytosed and retrogradely transported in the peripheral nerve axons to inhibitory interneurons within the central nervous system (CNS). Within the CNS, tetanospasmin blocks the release of the neurotransmitters gamma amino butyric acid (GABA) and glycine from inhibitory interneurons within the spinal cord and brain stem. In addition, it blocks the release of the inhibitory neurotransmitters within the sympathetic nervous system. The absence of inhibitory signals allows excitatory neurotransmitters to act unchecked, resulting in muscle spasms and hypersympathetic activity. The role of tetanolysin in the pathogenesis of tetanus remains unclear. The unopposed release of excitatory neurotransmitters causes the involuntary muscle spasms of tetanus.[15] 

Hypersympathetic activity results from the uninhibited release of catecholamines by the adrenals.[16] Toxin binding at the neuromuscular junction is irreversible.

History and Physical

A history of a deep penetrating wound resulting in devitalized tissue is often, but not always, evident in tetanus cases. Minor trauma, post-surgical infection, injection drug use, intramuscular injections, compound fractures, decubitus ulcers, and no identifiable inoculation have also been reported.[15][17] In neonates born to unvaccinated women, tetanus can develop from contamination of the umbilical stump.[11] 

The incubation period for tetanus ranges from 1 day to several months after wound inoculation. A shorter incubation period is associated with more severe disease, likely influenced by the inoculum size and a short axonal transport distance. Tetanus typically spans 2 weeks, with full recovery often taking several months, a process probably related to the growth of new axon nerve terminals.

Generalized tetanus is the most prevalent form of the disease, typically beginning with trismus (lockjaw) and orbicularis oris muscle rigidity (risus sardonicus), followed by generalized painful muscle contractions. Hyperextension of back and leg muscles and flexion of arm muscles (opisthotonus) can resemble decorticate posturing. Dysphagia caused by pharyngeal muscle spasms is a common symptom and may be the patient's initial complaint.[18][2] Airway obstruction can arise from neck muscles and diaphragm spasms. The painful spasms can persist for several weeks due to the presence of toxins within axons. The spasms may be provoked by noise, touch, and simple nursing care procedures. Hypersympathetic activity and autonomic dysfunction can manifest with labile blood pressure and cardiac arrhythmias. Notably, the sensorium remains intact in the absence of coexisting brain dysfunction. Morbidity and mortality are significantly influenced by underlying comorbidities and iatrogenic complications that may arise during prolonged hospitalization.

Localized tetanus is rare and tends to be limited to an extremity where the initial injury occurred. This form can progress into the generalized form of the disease. Moreover, localized tetanus resulting from injury to the face or scalp can evolve into cephalic tetanus involving the cranial nerve musculature.

Cephalic tetanus presents with cranial nerve dysfunction potentially resembling stroke symptoms.[5] This form of tetanus can evolve into generalized tetanus.

Neonatal tetanus can arise from the contamination of the umbilical stump in offspring born to unvaccinated mothers.[11] The incubation period is around 7 days. Affected infants develop symptoms such as failure to suckle followed by generalized rigidity, often leading to opisthotonus. Mortality is high as infants frequently succumb to complications such as apnea and sepsis.

Evaluation

The diagnosis of tetanus is primarily clinical, and reliance on radiology, hematology, clinical chemistry, and microbiology is generally insufficient for confirmation.[1][4][12][15] Obtaining a patient's immunization status and history of a recent traumatic wound should be sought, although obtaining reliable information may be challenging.[19] In neonatal cases, information regarding the mother's immunization status is key, as well as considering the possibility of unsanitary practices during delivery.

Treatment / Management

The approach to treatment requires a collaborative effort between infectious disease clinicians and critical care intensivists. Acute tetanus management should focus on toxin mitigation and aggressive symptom management.[6][20] Immediate cleansing and debridement of tetanus-prone wounds are essential for eradicating spores and preventing the further spread of toxins from tissue to the bloodstream. Patients exhibiting signs and symptoms of tetanus should be closely monitored, preferably in an intensive care unit (ICU).[21] Efforts to minimize noise, bright light, and tactile stimuli should be attempted in ICU and non-ICU settings. Close observation for signs of impending airway compromise is imperative, and intubation should be anticipated.

It is important to note that many aspects of treatment are based on small case series, case reports, and relatively few randomized trials. Furthermore, literature reports are often confounded by differences in disease severity. 

Tetanospasmin binds irreversibly at the neuromuscular junction, so neutralization focuses on unbound toxins circulating in the bloodstream. Passive immunization involving the intramuscular administration of human tetanus immune globulin (HTIG) is recommended as soon as tetanus is suspected and has been shown to shorten the course and reduce the severity of the disease.

In resource-poor countries where HTIG may not be available, intravenous administration of equine antitetanus serum is an alternative, with the caveat that anaphylactic reactions may develop. Skin testing should be performed before administering equine antitetanus serum. Currently, conflicting data exist regarding the benefits of intrathecal administration of antisera, and no definitive recommendation can be made.[8][20] If human and equine antitetanus antisera are unavailable, administering pooled human immunoglobulin is recommended.

Sedation and control of spasms and hypersympatheic activity are crucial in managing tetanus. Benzodiazepines, offering sedative, muscle relaxant, and anxiolytic effects, play an important role. The critical care team should anticipate that the doses required can produce oversedation, respiratory suppression, and coma. Neuromuscular blocking agents such as vecuronium have been reported to be effective in patients with severe tetanus who are not responding to benzodiazepines.[21]

There is limited data concerning the use of intravenous magnesium sulfate in tetanus management.[6][20] It has been used alone and in combination with benzodiazepines to manage spasms and catecholamine release. The limited number of studies suggest a therapeutic benefit, particularly in less severe cases of tetanus. However, the optimal dose and duration of magnesium sulfate infusion remain to be determined.

Intrathecal baclofen has been utilized to control tetanic spasms, showing benefit in the few reports in the literature. However, the optimal dose and duration of infusion have not been established, and the potential for intrathecal baclofen to cause respiratory depression and cardiac instability necessitates administration in an ICU setting.[20]

Antimicrobial therapy with either metronidazole or penicillin for the wound is typically administered for 7 to 10 days, although no randomized controlled trials have established a specific therapy duration. The aim of using these antibiotics is to eradicate C tetani from the wound, but they have no value in managing muscle spasms and autonomic nervous system dysfunction. In addition to metronidazole, broader spectrum agents may be used to treat infected wounds containing mixed flora. There is a theoretical concern regarding high-dose intravenous penicillin, as it may compete with inhibitory post-synaptic neurotransmitters.[20] 

Comparative studies between metronidazole and penicillin in the management of tetanus-associated wounds are limited, and their results are inconclusive regarding the benefit of one antibiotic over the other in this setting. 

Differential Diagnosis

Teanus has a limited differential diagnosis, as noted below. However, due to the rarity of cases, most clinicians may encounter difficulty in promptly identifying or may even miss the diagnosis, which can have lethal consequences.[2][4][5][17][18] The differential diagnosis includes:

• Oropharyngeal abscess: Depending on the location and extent of the abscess, dysphagia and trismus may be observed.  

• Stroke: Ischemic or hemorrhagic strokes can lead to cranial nerve palsies. 

• Meningitis: Inflammation of the meninges may present with muscle rigidity but without the characteristic spasms of tetanus. An early symptom is neck stiffness. 

• Strychnine poisoning: Similar spasms but generally lack the autonomic dysfunction seen in tetanus. Poisoning can occur due to intentional and unintentional poisoning; the latter has occurred due to adulterated cocaine and heroin.[22][23]

• Botulism: A severe neurological condition caused by a toxin produced by Clostridium botulinum manifests with distinct clinical features, including dysphagia and cranial nerve palsies followed by flaccid paralysis. Unlike tetanus, botulism does not involve muscle spasms or hypertonia.

• Hypocalcemia: Low calcium levels may cause muscle spasms, but the autonomic features of tetanus are usually absent. 

• Neuroleptic malignant syndrome: Drug-induced condition with hyperthermia, altered mental status, and muscle rigidity. This condition is distinguished from tetanus based on clinical history.

Prognosis

The prognosis following tetanus depends on the time to symptom onset or the incubation period. Generally, a shorter incubation period often signifies a more severe disease. Adverse prognostic factors include an incubation period of fewer than 48 hours, addiction to narcotics, the presence of generalized tetanus, a high fever exceeding 104 °F, acquiring tetanus from surgical procedures, burns, intravenous drug use, or a septic abortion. Unfavorable outcomes are particularly associated with cephalic and neonatal tetanus.

Individuals with localized tetanus experience low mortality and morbidity rates. While recovery is generally slow, it may extend over months or years for a full recovery. Surviving individuals should undergo active immunization since recovery from tetanus does not confer any immunity.  

Complications

Respiratory compromise resulting from airway obstruction, aspiration, and medication-associated respiratory suppression are the primary contributors to tetanus-associated morbidity and mortality. Cardiac arrhythmias, labile blood pressure, and profuse sweating due to hypersympathetic activity are common complications. Physical exhaustion due to diffuse muscle spasms further complicates management. Iatrogenic complications associated with prolonged hospitalization frequently complicate the management of tetanus.

Deterrence and Patient Education

The key to eliminating tetanus globally is ensuring widespread acceptance and availability of the tetanus toxoid vaccine.[13][24] Achieving this goal requires resourceful and strategic public health outreach.[25] Additionally, educating people about the significance of adhering to tetanus toxoid vaccine booster schedules and seeking medical attention after sustaining a tetanus-prone wound is most important.

Importantly, there is no consensus on recommendations for routine tetanus booster vaccinations in previously immunized adults.[26] While the World Health Organization (WHO) does not advocate routine tetanus boosters in adults who have completed their childhood vaccination series, tetanus boosters are recommended every 10 years in adults residing in the US.

Enhancing Healthcare Team Outcomes

Tetanus elimination begins with public health outreach that encompasses educating the public about the value of immunizations. Overcoming cultural barriers to vaccine administration may be necessary. Neonatal tetanus is the leading cause of tetanus worldwide, and ongoing efforts to eradicate tetanus through maternal and neonatal vaccination programs have not yet achieved the target goal.[27] 

Equally important and challenging is the task of educating people about proper wound care and the necessity of seeking medical attention in the event of sustaining a tetanus-prone wound. Primary care and emergency medicine clinicians must remain aware of tetanus immunization schedules. Due to its rare occurrence in modern times, clinicians may not be familiar with the signs and symptoms of tetanus. Patients presenting with early tetanus symptoms might approach dentists, otolaryngologists, primary care clinicians, or neurologists who have never encountered a previous case. Although tetanus has characteristic features and a limited differential diagnosis, its scarcity may delay diagnosis. Moreover, the reliance on radiologic and laboratory results is limited in establishing the diagnosis.

Managing a patient with tetanus requires a multidisciplinary team, ideally including infectious diseases and critical care clinicians. Due to the scarcity of cases, there is a lack of large randomized clinical trials establishing definitive best practices for managing its manifestations. Recommendations for management have emerged from various small randomized control studies, case series, and expert opinions.[6][8][10][13]