Tetanus: A disease that should not be overlooked

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ACHAIKI IATRIKI | 2025; 44(3):144–150

Review

Efstathios Karakasidis

Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece

Received: 09 Oct 2024; Accepted: 21 Jan 2025

Corresponding author: Efstathios Karakasidis, MD, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece, Tel.: +30 6907 377 691, e-mail: stathiskar97@gmail.com

Keywords: Tetanus, spasms, internal medicine

 

Abstract

Tetanus is a bacterial disease caused by Clostridium tetani. It has become preventable and is rare in recent decades due to vaccination and advances in medical care. Tetanus presents with neurological symptoms and lacks a specific cure, apart from treatment according to the presenting symptoms. The purpose of this narrative review is to raise physicians’ awareness about tetanus as early treatment is highly important for survival and to review the epidemiology, pathophysiology, symptoms, and treatment options of tetanus.

Introduction

Tetanus is a non-communicable disease caused by the gram-positive anaerobic bacterium Clostridium tetani which is mainly found in soil [1,2], as well as in the feces of some mammals such as horses, cows, sheep, rats, and pigs [3,4]. It is transmitted to humans via minor wounds. However, in a substantial percentage varying between 20% and 50% no obvious site of entry is recognized [1,2]. The incidence of this disease varies worldwide, and it is more prevalent in developing countries, especially in the farming community [5,6], and reaches mortality rates up to 100% if left untreated [7]. In this narrative review, we aimed to summarize the epidemiology, basic pathophysiological features, and treatment options for tetanus.

Materials and methods

This literature review aims to highlight the main aspects of the diagnostic approach and treatment of tetanus in the everyday clinical practice of clinicians, as in most cases the patients seek help from different specialists. A non-systematic approach was employed, searching the Medline and Scopus databases from July 2024 to August 2024 for relevant articles. The primary keywords used included: “tetanus”, “symptoms”, “clinical presentations”, “epidemiology”, “treatment” and “pathophysiology”, while Boolean operators (“AND”, “OR”) were also used. The existing literature has been reviewed, including original articles, reviews, meta-analyses, and case reports. Only full-text accessible articles published in English were included while articles in other languages were excluded. By screening the references of included articles using the snowball method, additional articles were retrieved. From these, we selected the most representative and high-impact articles for inclusion.

Epidemiology

The spores of C. tetani can remain viable for several months due to their resistance to high temperatures and stability under ambient oxygen tension. Common antiseptics such as ethanol, phenol, and formalin are ineffective in their elimination, whereas iodine or hydrogen peroxide are effective ways to eradicate them [4]. Autoclaving at 120°C for 15 min is another effective method [3]. The incubation period of tetanus varies from one day to several months, with most cases occurring within eight days of exposure. The closer the site of spot entry of spores is to the central nervous system the shorter the incubation period tends to be [6]. Several factors such as urbanization, agricultural activities, especially in summer that enable direct exposure to soil due to light dressing, environmental factors (humidity and temperature), and socioeconomic factors, such as poverty, poor hygiene, and lack of health services, significantly influence tetanus incidence [8,9]. People over 60 years old are at high risk for tetanus, given that vaccine-induced antibody titers decline over time and because they might have been born before vaccination programs. However, cases of both generalized [10-14] and localized [15] tetanus have been reported in patients with adequate anti-tetanus antibodies who have been vaccinated. Although complete vaccination does not seem to guarantee immunity, it is associated with better clinical outcomes [16]. In addition to advanced age, diabetes, immunosuppression, and intravenous drug use are well-known risk factors for tetanus [1,2].

In 2019, 73,662 cases of tetanus and 34,684 related deaths were reported, with most of them occurring in low- and middle-income countries. In contrast, tetanus is rare in high-income countries [17,18,19]. Interestingly, 50% of all tetanus cases reported in 2019 in high-income countries involved people over 70 years old [19]. The majority of cases and deaths during both the neonatal and non-neonatal periods occurred in South Asia and Sub-Saharan Africa [19,20]. A meta-analysis revealed that the fatality rate of tetanus in Africa is 43.2%, indicating that the sociodemographic index is inversely associated with tetanus incidence and mortality [6,19]. Epidemiological studies have shown that neonatal tetanus has contributed significantly to global tetanus cases. In 1990, 370,885 out of 615,728 (60.24%) cases of tetanus occurred in the neonatal period, while in 2019 27,171 out of 73,662 (36.89%) cases were neonatal [19].

Over the last three decades, mortality due to tetanus has declined dramatically. In 1990, tetanus was the 41st cause of death and in 2021, it dropped to the 113th [21]. In 1990, there were 275,381 confirmed deaths due to tetanus which declined to 62,866 and 34,684 in 2010 and 2019, respectively [17]. Kyu et al reported a significant decline in both neonatal and non-neonatal tetanus deaths between 1990 and 2015, with neonatal deaths decreasing by 90% and non-neonatal deaths by 81% [20]. An important finding is that neonatal tetanus accounts for a substantial proportion of tetanus-related deaths. In 2010, 57% of the deaths (35,580/62,866) and in 2015, 35% (19,937/56,743) occurred during the neonatal period [17,20]. This high percentage of neonatal tetanus cases and deaths can be attributed to the inability of health systems to provide immunization and sterile conditions during and after birth [20]. The difference in tetanus mortality rates between low- and high-income countries of 54.3% and 35% respectively, as well as the decline in deaths, can be attributed to immigration of populations from rural to urban areas that resulted in decreased exposure to tetanus spores, widespread vaccination of children, adults, pregnant women and women of reproductive age. Better living conditions, differences in medical staff and knowledge and early treatment have also played a significant role. In addition, societal factors such as religious tenets, cultural beliefs and traditional healers may act as barriers to immunization and effective wound care [1,5,6,22]. In 2023, 84% of infants worldwide received three doses of diphtheria-tetanus-pertussis (DTP)- containing vaccine [23]. The differences in medical practice include improvements in wound care, the administration of tetanus immune globulin, ICU facilities, closer monitoring, and pharmacological interventions, and improvements in hygienic delivery practices and umbilical cord care [1,19]. Importantly, the disruption of vaccination programs such as natural disasters or conflicts can affect the incidence of tetanus both in the short term due to hygiene conditions and in the long term as people are more vulnerable to future infections [2].

Pathophysiology

C. tetani spores are introduced into the human body through a wound and, under favorable anaerobic conditions [4], convert to a vegetative form [10]. After autolysis, the bacteria produce [24] two toxins called tetanospasmin and tetanolysin and a protein called collagenase. Tetanospasmin, also known as tetanus toxin, is encoded on a plasmid and consists of a heavy chain that is responsible for binding and entrance to neurons and a light chain that mediates the inhibition of presynaptic neurotransmitter release [10]. This toxin cannot cross the blood-brain barrier [14]. Collagenase affects bacterial growth and toxin production [10,26], while the role of tetanolysin in the pathogenesis of tetanus remains unclear [10].

Tetanospasmin enters the motor neuron axon terminal via endocytosis at the neuromuscular junction. It is then transported retroaxonally to the spinal cord and brainstem, where it binds to nerve terminals, thereby affecting all parts of the body beyond the initial site of infection [7,24,26]. Then, it is transcytosed into inhibitory interneurons [24], and cleaves a protein called vesicle-associated membrane protein 2 (VAMP2) also referred to as synaptobrevin 2 [27], thereby inhibiting the release of Gamma-aminobutyric acid (GABA) and glycine and resulting in sympathetic overactivity and spasticity [7,24,26,28]. The toxin affects both motor and sensory nerves, but it does not impair mental status, as patients remain conscious [26,28].

Clinical presentation

There are four forms of tetanus: 1) generalized 2) neonatal 3) local and 4) cephalic [7]. The symptoms of tetanus differ among generalized, local, and cephalic. Trismus is frequently the initial symptom in all forms of tetanus because cranial nerves have a high affinity for tetanospasmin and toxin is rapidly delivered to the brainstem and spinal cord due to their close anatomical connection [7,26]. Cephalic tetanus, while quite rare, can be associated with head lesions or chronic otitis media and presents with cranial nerve palsy 1 to 2 days after infection [2,29]. Local tetanus is associated with low toxin load and in 2 out of 3 cases evolves into generalized tetanus because tetanus neurotoxin continues being produced and released for days resulting in a general distribution [26]. Generalized tetanus is the classic form of the disease and accounts for more than 80% of cases. It gradually begins approximately 3 to 21 days after the infection, with symptoms typically worsening over a week [29].

The first symptom of tetanus is flaccid paralysis with the craniofacial muscles first affected followed by the trunk and finally, the limbs, which are less severely affected [3,7,10]. Spasms can be triggered by a stimulus (auditory, tactile, or visual) and can affect all muscle groups. The typical symptoms of tetanus apart from trismus are opisthotonus and risus sardonicus. Tetanus toxin can affect both the pharyngeal and laryngeal muscles causing dysphagia, aspiration, and respiratory failure as well as abdominal rigidity [2,7]. Tetanospasmin inhibits the release of neurotransmitters in the spinal cord, brainstem, and thoracic sympathetic ganglia thereby affecting the inhibition of adrenal release of catecholamines resulting in excitability of the sympathetic nervous system due to increased levels of noradrenaline and adrenaline in the blood circulation [2,26,30]. As a result, the patient suffers from autonomic dysfunction in the second week after the onset of symptoms. The symptoms include hypertension, tachycardia, and sweating that follow symptoms of the motor system. Notably, rapid fluctuations in blood pressure as well as bradycardia can occur thereby complicating the management of the patient [2,7,30]. Although in the past the majority of deaths were attributed to respiratory insufficiency due to the act of tetanus toxin, currently because of advancements in intensive care most patients with tetanus pass away due to autonomic dysfunction [2,7]. Apart from the motor nerves, tetanus toxin also affects the sensory nerves causing altered sensations, such as pain and allodynia [7]. Other unusual symptoms are diplopia, nystagmus, and vertigo that result from neuronal inactivation [7]. Because of the severe muscle spasms, the patients can suffer from fractures of the spinal or long bones, tendon avulsion, hyperpyrexia, pneumonia, pulmonary emboli, and rhabdomyolysis that can cause acute kidney injury [3-5]. All these complications contribute to the high fatality observed in severe tetanus cases.

Predictors that negatively affect the outcome of the patients are an incubation period of less than seven days, an interval between the first symptom and the first muscle spasm of less than 48 hours, age over 60 years, physical status, the presence of sepsis and severe autonomic dysfunction [2,3,6,26]. Other factors that significantly affect survival are lower wound debridement, the presence of abdominal rigidity and aspiration pneumonia, the need for high sedation, severe tetanus requiring neuromuscular blockade, and mechanical ventilation [3, 6].

Diagnosis – Differential diagnosis

Tetanus should be suspected in a patient with a history of antecedent tetanus-prone injury, especially if medical help was not sought and a history of inadequate immunization for tetanus is present. However, other diseases should be excluded (Table 1).

There is no specific laboratory test for the diagnosis of tetanus which is based on clinical suspicion and manifestations. Anti-tetanus antibody levels cannot be used for tetanus diagnosis but they can be used to consider the likelihood of diagnosis with a level up to 0,1 IU by standard ELISA can be protective and therefore the likelihood of tetanus can be considered unlike, but the diagnosis cannot be excluded [1,2].

Treatment

The severity of the disease is assessed by the Ablett score (Table 2). The Ablett score ranges from 1 to 4, with grades 1 and 2 indicating that mechanical ventilation may not be needed while grades 3 and 4 require mechanical ventilation [31,32].

The first step of treatment in a patient with suspected tetanus infection is to place them in a room without light or noise that may provoke spasms. Additionally, proper cleaning and debridement of necrotic tissue must be performed to reduce the bacterial load and prevent bacterial growth [4,29]. Benzodiazepines such as diazepam, midazolam, and lorazepam should be administered to control muscle spasms and induce sedation and anxiolysis [5,10,29]. The most popular option of these drugs is diazepam, which is inexpensive and available in many resource-limited settings where tetanus is a significant public health problem [5]. The dosing of this drug should be adjusted according to the patient’s clinical response due to its potential toxicity. There is a risk of inducing metabolic acidosis due to preservative propylene glycol [5], withdrawal symptoms (aggressive behavior and noncooperation), and venous thrombosis that can complicate the treatment of the patient [25]. Tolerance to benzodiazepines is frequently observed, and propofol can be used as an alternative drug to induce sedation [5,10,33]. This drug is a GABA-A agonist with sedative, anxiolytic, anti-inflammatory, and anticonvulsant properties [34–36] that has a rapid onset of action and short half-life (30-60 min after infusion) [34]. Administration should be performed with caution, as propofol can induce the severe propofol infusion syndrome. This syndrome is characterized by high anion gap metabolic acidosis, rhabdomyolysis, hyperkalemia, acute kidney injury, hypotension, and bradycardia. Other adverse effects of propofol include pancreatitis and hypertriglyceridemia [34-37].

For the treatment of tetanus, antibiotics are also used to prevent the generation of tetanospasmin through the killing of bacilli. The antibiotics used are metronidazole 500 mg intravenously every 6-8 h for 7-10 days or alternatively penicillin G 2–4 million units intravenously every 4–6 h [10,29]. Metronidazole is preferred over penicillin because penicillin produces a non-competitive voltage-dependent inhibition of GABA-A receptors obtunding postsynaptic inhibitory potentials that can potentiate the action of tetanospasmin and can induce seizures [25,38]. Another drug that is commonly used for the treatment of tetanus is magnesium sulfate which is administered intravenously. It is a calcium antagonist causing vasodilation, presynaptic neuromuscular blockade, and prevention of catecholamine release helping in controlling the spasms and autonomic dysfunction [2,9,29]. Its administration is not associated with a lower need for mechanical ventilation [39] or changes in mortality in patients with tetanus [40], but it does reduce the need for other drugs to control muscle spasms and cardiovascular instability [39]. However, the administration of magnesium can have some adverse effects such as loss of the patellar reflex, hypocalcemia, excessive sedation, hypotension, and muscle weakness resulting even in respiratory failure [9,40]. To deal with the spasms also neuromuscular blockers such as pipecuronium, vecuronium, and pancuronium can be used [5]. In case spasms cannot be controlled with the administration of the aforementioned drugs, intrathecal baclofen can be administered [5,41]. Baclofen is a GABA-B receptor agonist that cannot cross the blood-brain barrier, so it is administered intrathecally [41,42]. Its adverse effects include drowsiness, weakness, dizziness, nausea, confusion, and hypotension. Its dosage should be decreased gradually as its sudden cessation might induce severe withdrawal symptoms such as excessive spasticity, fever, and malignant syndrome. On the other hand, overdose may result in coma which is reversible with flumazelin administration [41,42].

For the treatment of autonomic dysfunction β blockers, clonidine, and morphine are used because of their sedative effects. Morphine sulfate maintains cardiac stability, decreasing blood pressure and heart rate without deleterious effects on cardiac performance. It replaces endogenous opioids and reduces reflex sympathetic activity and histamine release [43]. In the past, propranolol was used but nowadays it is not recommended because it can cause hypotension and sudden death [29,43]. It is replaced by labetalol that has a dual effect on α- and β- receptors, and esmolol, which has a short time of duration and whose effects in blood pressure and heart rate are reversible [43].

Furthermore, human tetanus immune globulin (TIG) should be administered intramuscularly into either the deltoid muscle or the lateral thigh muscle. TIG acts by binding unbound tetanus toxin, thereby preventing disease progression [29,44]. Studies have shown that there is no benefit from the intrathecal administration of tetanus immunoglobulin. When human tetanus immunoglobulin is unavailable, equine antitoxin can be used at doses of 1500–3000 IU intramuscularly or intravenously [10]. Potential advantages of human TIG include its longer half-life and fewer hypersensitivity reactions than equine antitoxin in which hypersensitivity reactions are observed in 20% of cases in which it is administered [33,44]. Recovery from tetanus does not confer immunity and as a result, all patients should be given three doses of tetanus and diphtheria toxoid at least two weeks apart, immediately upon diagnosis [10]. Contraindications for the administration of tetanus toxoid vaccination are fever or acute infection at the time of vaccination request, a history of an allergic reaction to a previously given tetanus vaccine/booster, and hypersensitivity to any element of the vaccine, including the thimerosal component [44]. The pharmacological choices for the treatment of tetanus are summarized in Table 3.

Due to muscle spasms, autonomic dysfunction, pyrexia, and critical illness, patients have high nutritional needs. Early nutritional support and adequate fluid resuscitation are therefore essential [4,25]. The preferred route of administration is enteral feeding, necessitating the placement of a nasogastric tube [4,25]. Central venous nutrition is necessary if severe abdominal spasms or ileus are present [4].

Notably, in most cases, patients with tetanus should be admitted to the intensive care unit as it is easier to manage complications of both the disease mainly that of the airways and the drugs administered [10]. Nakajima et al examined the treatment course of 499 patients with tetanus in Japan. They reported that half of the patients required mechanical ventilation, with the majority of them (80.6%) needing it in the first three days after admission and 77.5 % undergoing tracheostomy. They pointed out that despite the low mortality rate the patients required either a long hospital stay or nursing care in facilities other than their homes [8]. Deep sedation and paralysis with artificial ventilation in an ICU have its drawbacks. The patient may require prolonged periods of intubation and ventilation, increasing vulnerability to ventilator-associated pneumonia, tracheal stenosis, difficulty in weaning and adult respiratory distress syndrome, paralytic ileus, weight loss, atelectasis, deep vein thrombosis, and pressure sores [5,25].

Conclusions

Tetanus is caused by the bacterium Clostridium tetani and mainly presents with neurological symptoms. Despite being a more common disease in developing countries, tetanus cases still occur in developed countries. Therefore, clinicians should remain vigilant, as prevention and early diagnosis are critical to improving disease course and outcomes.

Conflict of interest disclosure

None to declare.

Declaration of funding sources

None to declare.

Author contributions

EK was responsible for the conception, research, writing and the final draft of this review.

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