Etiology

Tetanus is caused by the action of a potent neurotoxin formed in the body during the vegetative growth of Clostridium tetani. C. tetani is a motile, gram-positive, nonencapsulated, anaerobic, spore-forming bacillus. Although strain differences of C. tetani exist throughout the world, an antigenically homogeneous toxin is produced by all strains. Resistant spores of the organism can be found in the environment, especially in the soil, where increased moisture, cultivation, and fertilization favor their survival. Organisms are routinely isolated from the feces of many domestic animals, including the dog and cat.¹⁵ Isolation from human feces occurs with greater frequency in those occupationally exposed to farm animals. Spores can survive adverse weather conditions in the absence of direct sunlight for months or years and can be found readily in dust and debris in indoor environments. Spores are resistant to boiling water, phenol, cresol, and mercury bichloride, and they resist an autoclave temperature of 120° C for 15 to 20 minutes. However, the vegetative phase of C. tetani is no more resistant to chemical and physical inactivation than other microorganisms.

Epidemiology

Tetanus develops when spores are introduced into wounds or penetrating injuries. The spores vegetate in response to anaerobic conditions at the site of injury. The presence of a foreign body, tissue necrosis, other microorganisms, or abscess formation contributes to germination. Two toxins from C. tetani have been identified. Tetanolepsin causes hemolysis of erythrocytes during rapid in vitro growth of the bacteria; however, it is not considered clinically significant. In contrast, tetanospasmin (molecular weight 176,000) enters the body from the wound site and produces marked effects on neurologic function. It is not absorbed from the gastrointestinal (GI) tract because digestive juices usually destroy it. In neonates, absorption may occur, and this syndrome has been observed in humans. Its high molecular weight precludes its entry into the placenta.

The prevalence of the disease in dogs and cats is relatively low compared with that in other domestic animals, which may be related to the natural species resistance of dogs and cats to this toxin. The inherent resistance is related to the inability of the toxin to penetrate and bind to nervous tissue; direct central nervous system (CNS) injections of toxin produce the same signs in different species (Table 41-1). Tetanus also appears to be more severe in younger animals.⁷ This may relate to age-related natural immunity or increased environmental exposure with advancing age.

Pathogenesis

Many experimental studies have been performed with dogs, cats, and other laboratory animals to elucidate the mechanism by which tetanospasmin enters and affects the CNS. The site and route of administration of toxin are important in determining the type of disease that develops. Localized tetanus can be produced by intramuscular or subcutaneous injection of toxin at a specific site. Tetanospasmin is a dimer composed of (1) a heavy chain (100 kDa) that binds to neuronal cells and transport proteins, and (2) a light chain (50 kDa) that blocks the release of neurotransmitters.³⁴ Toxin enters the axons of the nearest motor nerves at the neuromuscular end plate and migrates by retrograde transport within motor axons at a rate of 75 to 250 mm per day to the neuronal cell body within the spinal cord (Fig. 41-1). Within the spinal cord, toxin ascends bilaterally until it reaches the brain (Fig. 41-2).

Systemic intravenous administration of large amounts of toxin usually results in intracranial signs, such as convulsions, facial muscle spasms, or respiratory arrest, before development of generalized limb rigidity. Small amounts of bloodborne toxin are thought to enter the CNS through the intact blood-brain barrier. Alternatively, hematogenously disseminated toxin may localize preferentially in the neuromuscular endings of many motor nerves throughout the body, from which it may ascend by retrograde axonal transport simultaneously into many areas of the nervous system. The initial involvement of facial musculature after hematogenous spread of toxin is explained by the fact that cranial nerve motor axons (e.g., facial nerves) are shorter than those of the limbs. Although all muscles are affected in generalized tetanus, characteristic postures such as outstretched limbs or a closed jaw are observed. The stronger of the opposing muscle groups predominates, such as the extensors rather than the flexors for antigravity support or the muscles used for closing rather than opening the jaw.

The clinical signs of tetanus infection can be explained by the known pathophysiologic effects of tetanus toxin on the nervous system. It inhibits release of glycine and γ-aminobutyric acid (GABA)—neurotransmitters of inhibitory interneurons of the brain and spinal cord. Presynaptic blockade of synapses of Renshaw cells and 1a fibers of alpha motor neurons occurs. The binding of tetanus toxin to presynaptic sites of these inhibitory neurons is irreversible; recovery depends on sprouting of new axon terminals.³⁴ Most experimental evidence has confirmed the effect of toxin at the spinal cord; however, the brain, neuromuscular junctions, and the autonomic nervous system can also be affected. Tetanus toxin has an affinity for gangliosides within the gray matter of the CNS, which may explain the cerebral signs that appear in some animals without obvious spinal cord involvement. The effects of tetanus toxin have also been ascribed to its affinity for binding at the neuromuscular junction, which may induce direct neuromuscular facilitation before the migration of toxin to the CNS. Tetanus toxin may affect sympathetic inhibitory neurons, in the same way it affects motor inhibitory neurons within the spinal cord, causing signs of autonomic dysfunction. Bradycardia associated with tetanus probably results from vagal-parasympathetic hyperactivity. Tetanus toxin also blocks neurotransmitters in the parasympathetic cardiac inhibitory center of the nucleus ambiguus, resulting in increased vagal tone and pronounced bradyarrhythmias. Increased catecholamine release associated with adrenergic stimulation can also cause episodes of hypertension or tachycardia in tetanus.

Clinical Findings

Clinical signs of tetanus usually occur within 5 to 10 days after receiving a wound, although ranges of 3 to 18 days have been reported.²⁵ This time varies and is shorter when the wound is closer to the CNS, has numerous organisms, and has a more anaerobic environment, which favors toxin production. Because of the increased resistance of cats and dogs to tetanus, disease onset may be delayed for up to 3 weeks. This delay may account for the absence of a detectable wound at the time of examination. However, because of greater innate resistance of cats as compared to dogs, the wound required to produce disease is so extensive that it is usually obvious. Wounds closer to the head (i.e., brain) are associated with more rapid onset and generalized CNS signs than injuries to distant extremities. In addition to external wounds, tetanus has also been frequently observed as a complication of foreign bodies, broken or deciduous teeth, postoperatively as with ovariohysterectomy, and after pregnancy or parturition, especially when associated with fetal death.^3–5,23,25

Localized tetanus is more common than generalized tetanus in dogs and cats than it is in people and other domestic animals because of the relative resistance of carnivores to the toxin. Localized tetanus is more common in cats⁹ than dogs, presumably because of a greater resistance of cats to toxin. Increased stiffness of a muscle or an entire limb is first noted in close proximity to the wound site (Fig. 41-3). In the thoracic limb, the elbow is usually extended, and the carpus may be held flexed or extended. The stiffness usually spreads, gradually involving the opposite extremity. Although the rigidity may remain localized to both thoracic limbs and associated paraspinal regions,¹¹ it usually spreads over a variable length of time and eventually involves the entire body.²⁸ Localized tetanus in the pelvic limbs has been commonly associated with the female reproductive tracts of dogs and cats. In animals in which a single extremity is affected, the diagnosis may be unclear.

Animals affected with generalized tetanus walk with a stiff gait and generally have an outstretched or a dorsally curved tail. They are not in pain but have difficulty in standing or lying down in comfortable positions because of the extreme muscle rigidity (Figs. 41-4 and 41-5). The rectal temperature is usually increased because of the excessive muscular activity. Postural reaction testing, such as a proprioceptive positioning evaluation, usually reveals normal initiation but stiff performance of the motor response. If the animal is extremely rigid, attempts to correct the knuckled limb may fail. When performing this type of testing, providing weight support is important for obtaining a more accurate evaluation. Myotactic reflexes are generally accentuated and flexor reflexes are depressed, but both may be difficult to elicit because of muscle stiffness.

Intracranial signs develop in the late stages of localized tetanus. They begin earlier in animals with generalized tetanus and usually generalized muscular stiffness. Cranial nerve motor nuclei are affected, resulting in hypertonicity of respective musculature. Protrusion of the third eyelid and enophthalmos result from retraction of the globe, which is caused by extraocular muscle hypertonicity (Fig. 41-6). In addition, miosis is frequently present. The ears are held erect, the lips are drawn back (risus sardonicus), and the forehead is wrinkled as a result of facial muscle spasms. Trismus (“lockjaw”) is caused by excessive contraction of masticatory muscles. Other mechanical causes of trismus¹⁷ can be differentiated from tetanus, because they usually do not involve other body sites and the jaw cannot be opened during anesthesia. Increased salivation, increased heart and respiratory rates, laryngeal spasms, and dysphagia can result from involvement of parasympathetic and somatic cranial nerve nuclei. With laryngeal spasms, signs of labored inspiration may be prominent and phonation altered, although these signs may be compounded by the existing chest-wall muscle spasticity.

Diagnosis

History of a recent wound and clinical signs are the primary means of diagnosing tetanus. Wounds that may be present cause hematologic abnormalities, including leukocytosis with neutrophilia and left shift. Serum biochemistry and cerebrospinal fluid values are unaffected, although moderate to marked elevations of muscle enzyme (creatine kinase, aspartate aminotransferase) activities may be present. Presumably this elevation results from the muscle injury caused by sustained hypertonicity and recumbency.

Results of cardiac testing are frequently abnormal.5,7,7 Tachyarrhythmias and bradyarrhythmias may be noted in individuals with tetanus. Systemic hypertension with dramatic increases in systolic blood pressure are common. Rapid heart rates are usually associated with sinus or supraventricular tachycardia, and less commonly with ventricular tachycardia. Bradycardia (less than 70 beats/min) is characterized by atrioventricular heart block, sinus arrest or atrial standstill, and ventricular escape complexes. Fatality may result with either tachyarrhythmias resulting in ventricular fibrillation, or bradyarrhythmias resulting in cardiac arrest.

In dogs that develop hiatal hernia and megaesophagus, thoracic radiographic changes occur in the caudal region and include increased density and esophageal dilation. Increased alveolar densities will be visible in animals that develop aspiration pneumonia as a result of the increased salivation, recumbency, and pharyngeal and laryngeal dysfunction. Cytologic results of lower airway washings are consistent with aspiration and include suppurative inflammation with intracellular bacteria.

The muscle spasms that develop in animals with tetanus are usually reduced but not always abolished by general anesthesia. Deep anesthesia in mildly affected animals may resolve all evidence of muscle hypertonicity. Even when clinically evident relaxation occurs, characteristic electromyographic changes can usually be detected. Insertion of the needle or tapping of the muscles or tendons is followed by persistent electrical motor unit discharges rather than the expected period of electrical silence. Continuous spontaneous motor unit discharge with simultaneous activity in both agonist and antagonist muscles is a characteristic finding.10,39 Muscle biopsy results are usually unremarkable in acute cases of tetanus, and any observed abnormalities may be attributed to muscle trauma caused by constant hypertonicity or prolonged recumbency.

Measurement of serum antibody titers to tetanus toxin has been used to substantiate the diagnosis of tetanus. Values must be compared with those from control animals. Such measurements might be helpful in a clinical setting to confirm the cause of undiagnosed muscle stiffness.

Isolation of C. tetani from wounds can be a difficult procedure and is unrewarding in a majority of cases. The organisms are usually present in very low concentrations, and although gram-stained smears may demonstrate gram-positive rods and dark-staining spherical endospores, the morphology of C. tetani is not unlike that of many other anaerobic bacteria. If culture is attempted, it should be performed under strict anaerobic conditions at 37° C for 12 days. Biochemical reactions or bioassays can be evaluated in an attempt to classify the organism. Mouse inoculation with isolates is not a readily available procedure.

Therapy

Mildly affected animals often respond well to treatment and have minimal hospitalization time. Therapy for tetanus in severely affected animals is costly and time consuming, and owners must be advised of the possibility of complications and a lengthy hospitalization. Time of hospitalization of severely affected animals can range from 7 to 40 days with a mean of approximately 20 days. Fortunately, the disease is often localized or mild in dogs and cats because of their innate resistance. However, untreated cases can prove fatal. In contrast, with successful recovery, there are no residual neurologic deficits. Because of their natural resistance, dogs and cats are not vaccinated with toxoid as a means of prophylaxis or treatment. Recommended dosages for the drugs used in the following treatment are summarized in Table 41-2.

TABLE 41-2

Recommended Drug Dosages for Tetanus

Druga	Species	Doseb	Route	Interval (hours)	Duration (days)
ANTIMICROBIALS
Penicillin G potassiumc	B	20,000–40,000 U/kg	IV, IM	6–8	10
Penicillin G procaine	B	20,000–40,000 U/kg	IM, SC	12–24	10
Amoxicillin-clavulanate	B	12 mg/kg	PO	12	10
Metronidazole	D	10–12 mg/kg	PO, IV	8	10
	B	15 mg/kg	PO, IV	12	10
	C	10–25 mg/kg	PO	24	10
Tetracycline	B	20–22 mg/kg	PO	8	10
Clindamycin	D	11–33 mg/kg	PO	12	10
	C	11–33 mg/kg	PO	24	10
	B	10 mg/kg	IV, SC, IM	12	10
IMMUNOTHERAPEUTIC AGENTS
Equine antitoxind		100–1000 U/kg	IV, IM, SC		Once
		500-1000 U per site	Intralesional		Once
		1–10 U/kg	Intrathecal		Once
Human tetanus immune globulin	B	500-2000 U near wound if found	IM		Once
SEDATIVES AND ANALGESICS
Acetylpromazine	B	0.01–0.07 mg/kge	IV	2–6	prn
	B	0.1–0.25 mg/kge	IM	4	prn
	B	1.0 mg/kg	PO	6–8	prn
Chlorpromazine	D	0.5 mg/kg	IM, SC	6–8	prn
	C	0.2–0.4 mg/kg	IM, SC	6–8	prn
Midazolam	B	0.1–0.2 mg/kg	IM, IV	2–4	prnf
Diazepam	D	5.0–10 mg total	IV, PO, IM	2–4	prn
	B	0.2–0.5 mg/kg	IV	4–6	prng
Pentobarbital	B	3–10 mg/kg	IV, IM	2–6	prnh
Phenobarbital	B	1–6 mg/kg	PO, IM	6–12	prni
Propofol	D	1–2 mg/kg	IV	Prn	prnj
Butorphanol	D	0.2–0.4 mg/kg	IV	4–6	prn
MUSCLE RELAXANTS
Methocarbamol	B	22–44 mg/kg, up to 130 mg/kg	PO, IV	8	prnk
Dantrolene	D	1–5 mg/kg	POl	8	prn
Magnesium	D	100 mg/kg	IV	24	prnm
AUTONOMIC AGENTS
Atropinen	B	0.05 mg/kg	SC	Prn	prn
Glycopyrrolaten	B	0.005–0.01 mg/kg	SC, IV	Prn	prn
		1 mg total	PO	8	prn
Metoclopramide	B	0.28 mg/kg	POn	8	prn
SUPPLEMENT
Pyridoxine	B	100 mg total	PO	24	prn

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