Tetanus
Robert J. MacKay
Tetanus is characterized by muscular rigidity and spasms. Death is common and results from respiratory compromise or tetanic convulsions. Clinical signs are caused by tetanospasmin, an exotoxin produced by the anaerobic, spore-forming, Grampositive bacterium Clostridium tetani.
Horses are exceptionally sensitive to tetanospasmin; cattle are relatively resistant, and small ruminants have intermediate sensitivity to the toxin. Spores are long-lived and resistant to most disinfectants and environmental extremes. They are not completely destroyed by boiling but can be eliminated by autoclaving at 115° C (239° F) for 20 minutes.1 C. tetani is a ubiquitous soil inhabitant and can be isolated from feces of herbivorous domestic animals, with highest frequency in horses.2,3 Tetanus is usually a disease of individual animals, but herd outbreaks of tetanus in livestock have been described.4-8■ Pathogenesis The most common route of infection is inoculation of wounds with C. tetani spores. Deep puncture wounds contaminated by manure, soil, or rusty metal are especially likely to cause tetanus. In horses, such wounds are typically in the lower limb, although contaminated surgical sites, the postpartum uterus, injection abscesses, and infected umbilical structures are also potential sites for C. tetani infection.9-11 Causative wounds are not found or reported in up to 50% of equine cases. Dairy cattle are infected most frequently after bacterial contamination of the uterus postpartum. Reestablishment of anaerobic conditions in the involuting uterus favors germination and proliferation of C. tetani spores. Other sites for growth of C. tetani in livestock include lesions caused by elastrator bands, sharp castration or tail docking, dehorning or disbudding, insertion of bull rings or ear tags, shearing, fly strike, intramuscular injection of anthelmintics or vaccines, and umbilical infections.4,5,7,8 Outbreaks of “idiopathic tetanus” occur occasionally in young cattle, usually in association with the grazing on rough, fibrous feed, and it is likely that this is analogous to the pathogenesis of toxicoinfec- tious and forage poisoning forms of botulism wherein toxin is produced in wounds in the mouth or GI tract or is ingested preformed in contaminated feed.12,13
The crucial event in development of tetanus is germination of C.
tetani spores, followed by vegetative growth and elaboration of exotoxins. Factors that enhance the germination and growth of C. tetani include necrotic tissue, pus, concomitant bacterial infection, and foreign bodies. Spores inoculated into the tissues are highly resistant to normal host defenses and may remain dormant for months or years before germinating. C. tetani produces at least two exotoxins: tetanospasmin and tetanolysin.1 Tetanolysin damages viable tissue, thereby lowering the redox potential and creating favorable conditions for expansion of the anaerobic infection.3 The neurotoxin tetanospasmin is a 150-kD polypeptide that is immediately cleaved by tissue proteases into active heavy and light chains connected by a single disulfide bond. It diffuses from the site of production into the vascular system and is distributed hematogenously to somatic neuromuscular junctions and autonomic ganglia, where it binds to nerve terminals. Once bound, the toxin is internalized and transported in a retrograde manner 75 to 250 mm/day in axons of both somatic and autonomic motor neurons.15 After 1 to 14 days, the toxin enters the CNS, reaches the neuronal cell body, traverses the synaptic cleft, and binds irreversibly to presynaptic inhibitory interneurons. Intact toxin is internalized, and then toxin light chain is released into the cytosol, where it acts to inhibit membrane fusion and recycling, events crucial in the release of the inhibitory neurotransmitters glycine and GABA.14 The resulting disinhibition of motor neurons is the proximate cause of muscle rigidity and spasms.3Preganglionic autonomic motor neurons in the lateral column of the gray matter and parasympathetic centers in the brainstem are affected by a similar mechanism but with delayed kinetic action in comparison with somatic motor neurons.16 Both a basal increase in sympathetic activity and episodes of intense hyperactivity (“autonomic storms”) occur, involving α-adrenergic and β-adrenergic receptors.
During autonomic storms, the concentration of circulating epinephrine increases up to 10-fold. The resulting sympathetic overactivity causes hemodynamic instability and is an important cause of death in ventilated human patients with tetanus.17 Its significance in large animal patients is unclear, although horses with either bradycardia or extreme tachycardia were reported as part of a large recent European case series.18Neuronal binding of toxin is thought to be irreversible.19 Recovery requires sprouting and growth of new nerve terminals, a process that is completed in weeks to months.
■ Diagnosis Routine blood work is unhelpful, and abnormalities found are nonspecific. Gram stain of wound exudates reveal the characteristic drumstick-shaped Gram-positive bacilli in approximately 30% of human patients with tetanus,20 but Gram stain and culture are seldom attempted in large animals with tetanus.18 With the development of a real-time PCR assay for the tetanospasmin gene,21 timely confirmation of C. tetani wound infection is now theoretically possible, and this assay may have application to veterinary cases.
Necropsy findings of animals with tetanus are nonspecific; secondary signs of musculoskeletal trauma and pulmonary congestion, atelectasis, and edema are most common.9,10 The diagnosis can theoretically be confirmed by detection of tetanospasmin antigen in spinal cord ventral or intermediate horn cells with immunohistochemical staining in which antibody ia directed against tetanus toxin.22
■ Clinical Signs Signs occur 1 to 60 days after wound inoculation by C. tetani spores; most affected animals show signs between 7 and 21 days.9,10,18,23 1 he incubation period varies, depending on the size of the wound, redox potential of the contaminated tissue, number of spores inoculated, and host's antitoxin titer. Probably because cranial somatic nerves are shorter than nerves to the limbs, the first signs of tetanus are associated with rigidity of muscles around the head and neck.
These signs are commonly missed in livestock that are not closely watched but are usually recognized in horses. Increased tonus of the masticatory muscles (trismus), rigidity of facial expression (risus sardonicus), and neck stiffness are typical early signs.9,24 Prolapse of the membrana nictitans begins during this phase and may be a prominent sign in the horse but is inconsistent in cattle and usually not observed in sheep.12 The head and neck are held in an extended position, and the face has a fixed, anxious expression. The ears and commissures of the lips are retracted caudally, and the upper eyelids are elevated. Often the mouth is clamped shut and the jaws cannot be pried apart manually (lockjaw). Hyperthermia (usually and blood pressure may be increased or dramatically fluctuant with profuse sweating in horses.9,11,18 It is not clear whether these signs represent tetanospasmin-induced sympathetic overactivity or are physiologic responses to the pain of muscle rigidity and spasms and the anxiety they cause. Signs of sympathetic overactivity are usually overlooked until after muscle spasms have been controlled. It is reported in humans that hypersalivation, increased respiratory secretion, and late-onset hypotension occur because of parasympathetic overactivity.25Severely affected animals are at high risk of falling to the ground, especially during spasms. Once recumbent, they lie in lateral recumbency with the head and legs in full extension and the ears held almost parallel to the back. Frothy saliva accumulates at the commissures of the lips because the animals are unable to swallow. Spontaneous deaths are usually due to respiratory failure because of laryngeal spasm and asphyxia; contractions of the chest wall, diaphragm, and abdomen; accumulation of excessive respiratory secretions; and aspiration pneumonia. Autonomic overactivity may cause fatal cardiac dysrhythmia or heart failure and death secondary to hypertension.
In advanced tetanus of cattle, ventrolateral strabismus may occur, and pupils may become dilated and fixed. Many animals die during a tetanic convulsion.■ Treatment The general principles that guide tetanus treatment of large animals are as follows: provide muscle relaxation, ensure good footing, eliminate the infection, neutralize the unbound toxin, maintain hydration and nutritional status, and establish active antitoxic immunity.26
PROVIDE MUSCLE RELAXATION. All possible external stimuli, including light and noise, should be minimized. Packing the animal's ears with cotton to minimize auditory stimulation can also help reduce muscle spasms. Sedatives and muscle relaxers are administered for control of muscle spasms and rigidity.27 The cornerstone of this approach is the combination of a phenothiazine-based ataractic sedative such as acepromazine with a GABA-ergic agent such as pentobarbital or diazepam.19 An IV catheter should be placed to minimize treatment- associated stimulation.
In mildly to moderately affected animals, acepromazine (or chlorpromazine) produces obvious muscle relaxation within minutes that lasts for hours. Acepromazine also has α-adrenergic antagonist and anticholinergic actions that may help suppress autonomic overactivity.28 Pentobarbital sodium provides additional muscle relaxation in cattle, but in horses it must be titrated carefully in order to prevent recumbency.9,29 Phenobarbital, at a dose of 10 mg/kg IV and then by nasogastric tube q8h, provided effective muscle relaxation for a neonatal foal with tetanus whose spasms to that point had not been controlled by high and frequent doses of diazepam.30 Large doses of diazepam or midazolam by repeated injection or constant-rate infusion are effective for control of muscle rigidity, but these drugs are expensive and impractical in many settings. The direct muscle relaxant dantrolene is used in horses for prevention of myopathy and might be useful in the treatment of tetanus.
This drug has been used successfully in human tetanus.31 Methocarbamol, glycerol guaiacolate, mephenesin, and d-tubocurarine have all been used for muscle relaxation in horses with tetanus but have been used widely.Magnesium infusion has multiple potentially useful actions against spasms and autonomic dysfunction and is inexpensive. It blocks neuromuscular transmission, interferes with catecholamine release from nerves and the adrenal medulla, reduces receptor responsiveness to released catecholamines, antagonizes the actions of calcium, and is an anticonvulsant and vasodila- tor.32,33 Magnesium has been shown to reduce the requirements for other drugs used to control muscle spasms and cardiovascular instability in human patients with tetanus.32 Of interest is that electromyographic studies show that magnesium tends to spare the respiratory muscles, which is a marked advantage. Effective serum/plasma magnesium concentrations are 5 to 10 mg/dL. An electrocardiogram should be monitored continuously and infusion discontinued if the width of the QRS complex increases by more than 25%.
ENSURE GOOD FOOTING. The affected animal should be moved carefully to a large well-bedded stall. Feed and water should be hung so that the animal does not need to lower its head. Horses and, theoretically, cattle in danger of falling may be maintained in a body sling, tackle and girdle, stocks, or walking frame. Appropriate caution must be exercised to ensure that such procedures do not cause the patient to become frantic.
ELIMINATE THE INFECTION. Because C. tetani grows in nonvascularized sites, the infection is best eliminated by surgical debridement of the affected area. If a recent wound or other infection can be identified, it must be opened, cleaned, debrided, and flushed. Penicillin (procaine penicillin G, 22,0θO IU/kg IM bid) traditionally has been given to kill remaining C. tetani organisms and remains the drug of choice for food animals; however, penicillin might have anti-GABA and proconvulsant activities.34 Metronidazole is now the preferred antimicrobial28 and has outperformed penicillin in two clinical trials in human patients. It can be given at 25 mg/kg PO every 12 hours (q12h)
for 3 to 5 days. If the horse's condition precludes oral medication, 50 mg/kg can be given rectally, or 10 to 20 mg/kg can be given IV, q6-8h (neonates). Use of metronidazole in foodproducing animals, however, is illegal in the United States and Canada.
NEUTRALIZE THE UNBOUND TOXIN. Tetanus antitoxin can be infiltrated into the tissues around the lesion, although this procedure is not recommended in protocols for treatment of human tetanus.3 Despite the lack of evidence for efficacy of large doses of tetanus antitoxin, it is prudent to ensure neutralization of any residual unbound toxin by administration of at least 20 IU/kg IV, IM, or SC, repeated daily for up to 5 days. The results of intrathecal therapy as reported in small case series in horses have been inconclusive but generally not positive.9,10,18,35 Although the data from human studies before 1991 were not supportive, meta-analysis of 12 more recent studies of both neonatal and adult cases detected a statistical survival advantage for intrathecal tetanus antitoxin over intramuscular administration.36 A suggested protocol is 400 to 1000 IU/kg by slow installation via the lumbosacral space, including frequent cycles of aspiration of CSF into the loaded installation syringe in order to dilute the biological before delivery. Alternatively, tetanus antitoxin can be infused into the atlantooccipital cistern, but this route requires general anesthesia.
Because of severe reactions to intrathecal equine serum in ruminants, intrathecal administration of equine-origin tetanus antitoxin is contraindicated.26 Administration of tetanus antitoxin has been associated with acute hepatic necrosis in horses.37,38 The first clinical sign of this potentially fatal adverse reaction may appear 4 to 10 weeks after administration of tetanus antitoxin and has been reported in horses that received this treatment for treatment of clinical tetanus (see Acute Hepatitis in Horses section, Chapter 33).
MAINTAIN HYDRATION AND NUTRITIONAL STATUS. The patient's hydration and food intake should be monitored daily. As mentioned, food should be placed off the ground, in an elevated feed bunk or hay net, to allow easier access. Intravenous fluids should be administered as needed to correct dehydration and electrolyte abnormalities. Alimentation via a nasogastric tube may be attempted in horses with tetanus, but because of adverse reactions, supplementation via an indwelling esoph- agotomy tube or IV may be necessary. A 5- to 10-cm-diameter rumenostomy should be created in affected cattle in which tetanus is worse than mild.39 This has the dual advantage of relieving bloat and providing a portal for water and feed (usually alfalfa pellets).
ESTABLISH ACTIVE ANTI-TOXIC IMMUNITY. Clinical tetanus does not elicit a protective immune response. Affected animals should begin a primary toxoid series (see Prevention section).
■ Prognosis The fatality rate for adult dairy cattle is up to 50% and, for horses, was between 65 and 75% in several published reports.9,10,18,23,26 Outbreaks of tetanus associated with contaminated procedure wounds in small ruminants usually produce high mortality rates (>80%). Most affected animals that die are recumbent by 24 to 48 hours after admission to a clinic. In survivors, signs usually stabilize by 2 to 7 days, with gradual recovery over the next several weeks. However, one horse reportedly remained stiff at 6 months but was normal at 9 months after onset of signs.
On the basis of various prognostic scoring systems used for tetanus in humans28 and the few large animal series published, negative prognostic indicators are an incubation period of less than 7 days, period of onset (time from first sign to first spasm) of less than 2 days, umbilical or uterine entry site, no vaccination within the previous year, and presence of comorbid disease. Severe signs at presentation, recumbency, or initial rapid progression of clinical signs are all predictive of poor outcome.
■ Prevention Because cattle are more resistant to tetanus than horses and small ruminants, they are not routinely immunized against the disease unless outbreaks have occurred previously.26 Adult horses not previously vaccinated should be given an initial series of tetanus toxoid in two doses administered 3 to 6 weeks apart. Protective responses are usually attained within 2 weeks after the second dose. Current recommendations are to give booster doses annually thereafter or in addition at the time of injury or surgical procedure.40 Broodmares should be revaccinated 4 to 6 weeks before foaling to provide for colostral transfer of immunity to their foals. Passively transferred antibody suppresses the IgG response of foals to toxoid vaccination at 3 months but not 6 months of age41; therefore it is recommended that foals from vaccinated mares be given a three-dose initial series beginning at 4 to 6 months of age, with a second dose 4 to 6 weeks later and the third dose at 11 to 12 months. Foals from nonvaccinated mares are vaccinated three times at 4-week intervals beginning at 1 to 4 months of age. Pregnant ewes and does should receive boosters with trivalent vaccine (C. perfringens types C and D and tetanus toxoid) approximately 4 weeks before parturition to cover lambs and kids during the early high-risk period around common husbandry procedures.42 Young replacement animals can be given a primary series of inoculations at 1 and 2 months of age and annual boosters thereafter.
Tetanus antitoxin is produced by hyperimmunization of donor horses with tetanus toxoid. Administration of one vial of antitoxin (1500 IU) to a nonvaccinated horse should provide immediate protection that lasts for 2 to 3 weeks. Antitoxin is indicated in foals from nonvaccinated mares and in any wounded horse that has not been vaccinated within the previous year. In these cases, antitoxin and toxoid should be administered concurrently, with separate syringes at separate sites. Because the use of antitoxin is associated with hepatic necrosis (serum hepatitis) in a small number of horses, antitoxin should not be given in horses that are adequately covered by toxoid vaccination. Also, occasional failures are reported for both passive and active immunization protocols. Two of 16 foals and 10 of 74 adults developed tetanus after they were given tetanus antitoxin at birth or after injury, respectively.18 In this same series, there were four cases in adults that had been vaccinated appropriately.