Studies have elucidated the pathophysiological process of tetanus infections, which starts with the production of metalloprotease tetanus toxin, otherwise known as tetanospasmin [1, 3]. Tetanus toxin is produced by C. tetani, after spores of C. tetani have inoculated infected human tissue. The tetanus toxin is subsequently transported to the peripheral nervous system through blood and lymphatic vessels. Retrograde axonal transport then allows the tetanus toxin to reach the central nervous system, where it enters inhibitory interneurons. Inhibitory interneurons affected by tetanus toxins lose their ability to inhibit anterior horn cells and autonomic neurons, resulting in hypertonia, muscle spasms and autonomic dysregulation [3]. This process has been illustrated in Fig. 2.

Illustration of the mechanism of action of tetanus toxin [45]. schematic illustration of pathophysiology in tetanus induced spastic paralysis: in an anaerobic environment (e.g. during active inflammation from the contaminated tissue) C. tetani spores germinate and produce the tetanospasmin toxin. Tetanospasmin binds to the presynaptic neuron, eventually allowing the light chain part of the protein to reach the spinal cord. The toxin specifically enters the central inhibitory neurons, prohibiting the release of GABA- and glycine containing vesicles from the cell membrane. This results in a loss of inhibition and subsequently continuous excitatory stimulation in motor neurons and the autonomic nervous system, causing uncontrolled motoric contractions [46]

Treating tetanus starts with adequate antibiotic therapy, wound cleaning and neutralization of circulating antibodies using tetanus immune globulins [1, 3, 10]. The importance of adequate wound cleaning has been illustrated in two cases where C. tetani was still found in wound cultures despite 16 days of intravenous penicillin [11]. Equine tetanus immune globulins were first developed in 1910, with humane tetanus immune globulins (HTIG) becoming available in the 1960s [12]. From that moment on the use of HTIG has become standard practice in the treatment of tetanus in resource-rich countries, since equine immune globulins may induce allergic reactions [1, 10, 13]. However, HTIG are still costly and may be difficult to acquire in resource-limited countries. In such countries, equine tetanus immune globulins are more commonly used, despite its risk of concomitant anaphylaxis [13]. The ideal use of HTIG is still a subject of research, with current studies mainly focusing on the potential benefits of intrathecal administration of HTIG in comparison to intravenous or intramuscular administration. So far, several studies have compared the effects of different routes of administration and have shown potential benefits of intrathecal HTIG [14,15,16]. Such benefits include a significant reduction in mortality, hospital stay, and an improvement in controlling muscle spasms [14,15,16]. However, subsequent meta-analyses have provided conflicting results, leaving the optimal route of administration a subject to discussion [17, 18].

Though the clinical advantages of antibiotic therapy in patients with tetanus have not yet been established, antibiotic therapy should always be considered due to possible coinfection by other bacteria. Evidence supporting the role of antibiotic treatment in tetanus is, however, scarce. One of the earliest studies was conducted in 1985, and favored metronidazole over penicillin [19]. These results were contradicted when a study compared benzathine penicillin, benzyl penicillin and oral metronidazole, and found no significant difference in hospital stay, use of neuromuscular blockade or the need for mechanical ventilation [20]. Currently, metronidazole and penicillin G are the preferred drugs of choice regarding tetanus infections [1, 10, 21].

During both treatment and the recovery period, managing symptoms still poses a challenge. Key aspects of alleviation of symptoms include the reduction of muscle rigidity, muscle spasms and autonomic dysregulation [3, 10]. Current literature is scarce, however increased survival rates have been achieved with the use of sedation and muscle relaxants, combined with mechanical ventilation if necessary [10]. A suitable option to achieve muscle relaxation is the use of benzodiazepines, such as diazepam and midazolam (enhancement of the binding of gamma-aminobutyric acid (GABA) to its receptor) [10, 21, 22]. However, high quality evidence on the use of benzodiazepines and their optimal utilization is lacking, in part due to ethical limitations to studies required to provide such evidence.

An alternative treatment consists of the use of intravenous magnesium sulfate. Its value in controlling muscle spasms secondary to tetanus infections was first established in the 1980s [23]. Since then, more evidence has supported the beneficial effects of magnesium sulfate. However, only a small number of randomized clinical studies have been performed comparing magnesium to placebo. The studies that have compared magnesium to placebo have not provided conclusive evidence that magnesium decreases the need for mechanical ventilation [24]. A meta-analysis of three studies concerning treatment using magnesium showed that magnesium did not reduce overall mortality in tetanus, though these studies have shown beneficial effects in controlling muscle spasms and autonomic dysregulation [25].

Finally, baclofen (a derivative of gamma-aminobutyric acid) can be considered for the treatment of severe muscle spasms. Oral baclofen is, however, deemed ineffective due to its poor penetration across the blood-brain-barrier. Therefore, baclofen should be administered intrathecally, which is expensive and limited to specialized clinics. Its potential benefits have only been described in case reports and high-quality evidence comparing intrathecal baclofen to other modes of treatment is lacking [26,27,28,29,30,31,32,33,34,35,36]. Moreover, these case reports have reported adverse effects such as hemodynamic instability and the need of ventilatory support secondary to respiratory depression. Consequently, use of intrathecal baclofen is currently not recommended according to the current literature and little is known about its ideal application in the alleviation of muscle spasms [10].

While treatment of muscle spasms is necessary in almost all cases of tetanus, some cases require additional treatment of autonomic dysregulation. Several treatment modalities have been reported to be effective, though their evidence consists of only a small number of case reports [10]. One of the first drugs that was used to treat autonomic dysregulation in tetanus patients, specifically tachycardia and hypertension, was labetalol (a non-selective ß-adrenergic receptor antagonist) [37]. Labetalol has been shown to be useful in cases of adrenergic crises and can reduce subsequent tachycardia and hypertension [3, 22, 38, 39]. However, labetalol does not reduce variability in heart rate and blood pressure, and in some cases co-administration of clonidine (α2-adrenergic receptor agonist) is necessary to achieve adequate response. Treatment with intravenous clonidine alone has also been studied and has been reported to be effective in reducing blood pressure fluctuations and mortality [40]. In cases where adrenergic blockers are unavailable or otherwise unfavorable, intravenous morphine can be used. Intravenous morphine, partially due to its analgesic effects, has been shown to successfully control autonomic dysregulation [41].

In addition to treatment of muscle spasms and autonomic dysregulation, all tetanus patients should receive supportive care as needed [3, 21, 22]. Due to high metabolism and energy demand, suppletion of fluids and parental feeding should be considered in patients whose oral intake is diminished due to trismus [3].

In resource-limited areas, the aforementioned therapies may not always be readily available. In order to reduce the incidence of maternal and neonatal tetanus, adequate preventative measures are advised by the WHO. Such measures include, but are not limited to, the vaccination of women of childbearing age, use of sterile instruments during deliveries, disinfection of surfaces and protection of the umbilical stump to prevent infection. Since tetanus is a disease with high morbidity and significant mortality regardless of gender or age, intensification of tetanus vaccination programmes for general populations is necessary to further reduce and ultimately minimalize the incidence in resource-limited countries. If infection does occur, use of equine tetanus immune globulin may be considered in order to prevent worsening of symptoms. Symptoms may be managed by high dosed diazepam, or continuous midazolam infusions, since magnesium sulphate and intrathecal baclofen are likely unavailable [5, 13, 21].

Prevention of tetanus infections by increasing vaccination rates and adequate post-exposure prophylaxis remains key in decreasing the incidence of tetanus infections worldwide. Post-exposure prophylaxis using TTCV and HTIG depends on wound characteristics and whether patients have previously been vaccinated using TTCV or not. Current literature recommends catch-up vaccination using TTCV in patients with clean, minor wounds and an unknown TTCV-vaccination status or patients who have received less than three previous doses of TTCV in their lifetime. Use of HTIG is not indicated in patients with clean, minor wounds. Additionally, if patients have three or more previous TTCV-vaccinations but the last dose was given more than ten years ago, a catch-up vaccination using TTCV is advised. Patients who suffer from larger or unclean wounds should receive TTCV if they have not been previously vaccinated using TTCV, or if they have previously received less than three doses of TTCV. Catch-up vaccination using TTCV is advised if the last dose was given more than five years ago. Use of HTIG is only recommended in patients with larger, contaminated wounds who have received less than three TTCV-vaccinations or if their vaccination status is not known [42].

Dutch national guidelines regarding post-exposure prophylaxis recommend similar uses of TTCV-vaccines and HTIG. These guidelines do not discriminate between size and or contamination of wounds, but recommend post-exposure prophylaxis in patients presenting with (possibly) contaminated open wounds, wounds resulting from animal bites and second- or third-degree burns. Patients with a full TTCV vaccination history who have received their last dosage of TTCV-vaccines less than ten years ago do not require additional vaccination. For male patients born after 1936 and female patients born after 1950 with a presumed full vaccination history, it is recommended to administer TTCV-catch up vaccination. This is based on conscription of male patients in military service, requiring vaccination against tetanus due to increased risk of exposure. Male patients born before 1936 or female patients born before 1950 are recommended to receive a TTCV-catch up vaccination and HTIG. Patients who have not (fully) been vaccinated with TTCV should receive both HTIG and a full TTCV vaccination regimen at 0, 1 and 7 months after exposure [43]. In retrospect, the patient presented in this case report should have received a TTCV-catch up vaccination, HTIG, and the full TTCV-vaccination regimen after her first visit to the general physician, since she was born in 1943.