Clinical tetanus is caused by the exotoxin tetanospasmin, a 67-kd protein elaborated by the vegetative form of C. tetani. Tetanospasmin is a potent neurotoxin that is lethal to humans at a dose of less than 150 μg. Because the spores of C. tetani are ubiquitous and resist heat and disinfection, they can contaminate wounds readily. Most tetanus occurs without a history of apparent wound contamination, although puncture wounds and grossly contaminated lacerations commonly are tetanus-prone.

C. tetani is distributed worldwide and has been isolated from diverse sites including soil, feces, house dust, and contaminated heroin. Tetanus ranks high among the infectious diseases as a cause of death throughout the world, and in developing countries it is an important cause of neonatal death. The
incidence of tetanus varies widely throughout the world; in the United States, a sharp decline in the rate of tetanus has occurred, although 50 to 100 cases are reported annually (average incidence, 0.03 cases per 100,000 persons). Neonatal tetanus is rare in the United States. This decline reflects the efficacy of the aggressive immunization program in the United States, especially as compared with developing countries, where mortality rates still are high. Unhygienic childbirth practices in most of the developing world and inadequate immunization of mothers explain most cases of neonatal tetanus. Often, nonmedical abortions and lack of attention to penetrating wounds are responsible for development of tetanus in adults. Climate and soil pH in the tropics probably contribute to the prevalence of C. tetani and its availability to contaminate wounds. In the absence of vigorous hygiene and immunization programs, tetanus remains a major killer.

After introduction into tissues, spores convert to vegetative forms, multiply, and elaborate tetanospasmin. This process occurs only if the oxidation-reduction potential of the inoculated tissue is sufficiently low to allow anaerobic growth to occur. Often, no associated inflammation or local infection is present.

Tetanospasmin enters the peripheral nerve at the site of injury and travels through the nerve to the central nervous system (CNS). The toxin’s effect on the nervous system occurs centrally and peripherally. At the presynaptic nerve ending, the toxin binds to gangliosides in the neuronal membrane, prevents release of neurotransmitters, and affects polarization of postsynaptic membranes in complex polysynaptic reflexes. The resultant lack of inhibitory impulses is manifested in the characteristic spasms, seizures, and sympathetic overactivity of tetanus. The toxin has no apparent effect on mental status, and consciousness is not impaired directly by this disease.

The neuronal transport of the toxin is consistent with the observation that the time that transpires between the occurrence of the injury and the development of disease correlates with the distance between the wound and the CNS. Usually, the incubation period lasts between 3 days and 3 weeks; the most severe cases develop after the shortest incubation periods. In some instances, the toxin remains localized to the neurons associated with the wound, producing a localized form of tetanus. More commonly, the toxin affects the entire nervous system, causing generalized tetanus. In rare cases, the toxin affects only cranial nerves, a condition known as cephalic tetanus.

Tetanospasmin binds irreversibly to neurons and thereafter cannot be neutralized by antitoxin. The course and duration of established disease are determined by the location and “dose” of bound toxin. Usually, the complete course of tetanus lasts from 2 to 4 weeks, but it is influenced greatly by the patient’s age and the development of complications.

The worldwide mortality is 45% to 55%; the mortality rate is approximately 1% in localized tetanus, but mortality rates of more than 60% are reported for tetanus neonatorum. Although survivors generally experience no neurologic sequelae, prolonged convalescence with residual muscle rigidity is observed for several months.

Usually, the clinical presentation of tetanus falls into one of three categories: localized, generalized, or cephalic. Neonatal tetanus, a generalized form of the disease, warrants discussion because of its occurrence worldwide.

Tetanus is an uncommon occurrence in developed nations, where immunization and hygiene practices largely have eliminated the disease. The classic presenting complaint of trismus and of muscle spasms, stiffness, and pain with dysphagia and cranial nerve weakness can be seen in other conditions, although the classic picture is sufficiently characteristic to support the diagnosis of tetanus. Other conditions that can mimic some manifestations of tetanus include parapharyngeal and peritonsillar abscesses, poliomyelitis and other forms of viral encephalomyelitis, Bell palsy, meningoencephalitis (including rabies), hypocalcemic tetany, and dystonic reactions to phenothiazines. These other conditions are differentiated relatively easily from tetanus by specific laboratory or radiographic evaluations or by the clinical course. The absence of altered consciousness in tetanus is an important point in differentiating the disorder from CNS infections. A parapharyngeal inflammatory process can be suspected from clinical examination or radiographs of the airway. Usually, hypocalcemic tetany is confirmed by low serum levels of calcium; idiosyncratic dystonia caused by a phenothiazine resolves promptly after intravenous administration of diphenhydramine.

Confirming a specific diagnosis of tetanus by routine laboratory tests is difficult. Routine blood counts are normal or elevated slightly; cerebrospinal fluid (CSF) evaluations are normal; and electroencephalograms and electromyograms are normal and nonspecifically abnormal, respectively. Gram stains and anaerobic cultures of wounds reveal the characteristic gram-positive bacilli with terminal spores in as many as one-third of patients with tetanus. Although positive cultures from wounds may support the diagnosis in patients with clinical disease suggestive of tetanus, a positive culture from a contaminated wound in the absence of symptoms does not indicate that tetanus intoxication will develop.

Without specific confirmatory laboratory tests, appropriate treatment based on the clinical diagnosis is warranted. The goals of therapy are to eradicate C. tetani, to neutralize its toxin, and to provide appropriate supportive care (Box 153.1).

Specific therapy includes intramuscular administration of tetanus immune globulin (TIG) to neutralize circulating toxin before it binds to neuronal cell membranes. The American Academy of Pediatrics Committee on Infectious Diseases (AAP CID) recommends a dose of 3,000 to 6,000 units for children and adults. The recommended dose for neonatal tetanus is 500 units. The efficacy of additional intrathecal administration of TIG has not been proven. Equine tetanus antitoxin given early in the disease may prevent spread of the toxin within the CNS; however, this antitoxin is associated with serum sickness in 10% to 20% of patients, and it no longer is produced in the United States.

Additional specific therapy should include antimicrobial therapy for C. tetani. The AAP CID recommends oral or intravenous metronidazole, 30 mg/kg/day given every 6 hours for 10 to 14 days. Alternatively, parenteral penicillin G, 100,000 U/kg/day given every 4 to 6 hours, may be administered. Oral tetracycline and intravenous vancomycin are effective against C. tetani, but the cephalosporins are not reliably active.

Local wound care, including surgical débridement, is essential. Foreign bodies must be removed, and wounds must be irrigated well and left open. Local antibiotic or TIG instillation is not of proven benefit. Excision of necrotic tissue may be required, but excision of the umbilical stump no longer is recommended in cases of neonatal tetanus.

Supportive care of patients with tetanus always involves meticulous nursing care, ventilatory support, and intense pharmacologic intervention to stabilize vital signs (Box 153.2). If possible, patients should be managed in an intensive care setting of a tertiary-care center. Transfer to such a setting should be accomplished early in the course of the disease, before the severity of spasms precludes moving affected patients; the clinical condition deteriorates during the first week of the disease.

Equipment and facilities that should be available include a quiet darkened room, suction equipment and oxygen, cardiac and respiratory monitors, a ventilator, and tracheostomy equipment. In the initial days of the illness, minimizing external
stimuli and maintaining intravenous hydration may be sufficient supportive care. Sedation and muscle relaxation should be instituted, usually with diazepam. Diazepam in a dose of 0.1 to 0.2 mg/kg given intravenously every 4 to 6 hours provides smooth, safe muscle relaxation and may be adequate for relatively mild cases. Additional sedation with phenothiazines may be used, although these drugs alone are less effective than is diazepam. If spasms are not controlled adequately, therapeutic paralysis must be induced. These patients must be treated by experienced caregivers highly skilled in ventilatory support and maintenance of cardiovascular stability.

Neuromuscular blockade can be accomplished with the curariform drugs. The agents used most often are pancuronium and vecuronium. Vecuronium is an intermediate-acting neuromuscular blocking agent; in an initial dose of 0.08 to 0.10 mg/kg intravenously, with maintenance doses of 0.01 to 0.15 mg/kg every 30 to 60 minutes as needed, it appears to have fewer adverse effects on blood pressure and heart rate, a significant benefit in patients for whom hypertension and tachycardia are major complicating factors. Doxacurium, a long-acting agent of the same class with a similar safety profile for the cardiovascular system, may offer smoother patient management and more prolonged effect with each dose. The recommended initial dose is 0.03 to 0.05 mg/kg intravenously, followed by 0.01 mg/kg in 60 to 90 minutes, as needed. Subsequent intervals between maintenance doses may be lengthened or shortened by the administration of smaller or larger doses. Patients who undergo therapeutic paralysis must be sedated to avoid the anxiety that occurs in a conscious patient.

Therapy may be required also to manage the hypertension that results from sympathetic overactivity. Beta-blocking agents appear to be the agents of choice, with propranolol used most commonly (usual dose, 0.01 to 0.10 mg/kg every 6 to 8 hours). Propranolol may be useful for the management of tachyarrhythmias. For either indication, the dosage must be titrated to achieve optimal effect. The duration of these pharmacologic manipulations is dictated by the duration of effect of tetanospasmin but ranges from 2 to 3 weeks. Careful monitoring of all vital signs and activities and their correlation with drug effect will indicate when the toxin’s effects have resolved.

Maintenance of adequate nutrition and hydration is mandatory. Because of the likely duration of the disease and the undesirability of oral or nasogastric feedings, usually parenteral nutrition is required for children with tetanus. Optimal nutritional support can minimize the severe weight loss that traditionally has been considered an expected outcome, and maintenance of adequate electrolyte balance can improve management of arrhythmias. Careful attention must be paid to skin care, especially in the paralyzed patient, and excretory functions must be monitored closely for urinary retention or serious constipation.

In the absence of optimal tertiary-care facilities and personnel for modern management, minimal stimulation, muscle relaxation, sedation short of respiratory depression, and adequate hydration may be the best that can be achieved. Tracheostomy may be needed (preferably on an elective rather than on an emergency basis) to avoid fatal laryngospasm, which greatly increases the mortality rate of the disease.

An important aspect of treatment is initiation of active immunization with tetanus toxoid. Patients must be immunized to prevent further disease because the amount of toxin required to produce disease is far less than that needed to stimulate immunity.

Although tetanus still is a very serious disease, the prognosis with modern techniques of intensive care is markedly better than that predicted by earlier statistics. With appropriate intensive care, the ultimate mortality rate of tetanus in the United States has been reduced greatly. The overall case-fatality rate in the United States has declined from 91% in 1947, to 24% during 1989 to 1991, to 11% during 1995 to 1997. Age plays an important part in outcome, with only 5% mortality rate for patients younger than 50 years of age, as compared with 42% for those older than 50. No mortality was observed in the United States between 1995 and 1997 in individuals younger than 25 years of age. Survivors are left largely without sequelae of tetanus, although the sequelae of modern intensive care may occur in time.

The primary predictors of prognosis remain the rapidity of symptom onset and the rate of progression from trismus to severe spasms. Poor outcome is predicted by an interval between injury and trismus shorter than 7 days or by progression from trismus to spasms in less than 3 days.

Tetanus is an entirely preventable disease, and the fact that fewer than 5% of cases in the United States between 1995 and 1997 occurred in children younger than age 20 years attests to the efficacy of vigorous primary immunization. (A comprehensive immunization schedule is presented in Chapter 15.) The primary series of tetanus toxoid, administered as diphtheria and tetanus toxoids and pertussis vaccine to children at 2, 4, and 6 months and a booster between 12 and 18 months later, ensures protection in childhood. Boosters of tetanus toxoid should be administered each decade throughout life, with further tetanus prophylaxis given after acute wounds occur, as advocated by the AAP CID (Table 153.1).

Patients who have documentation of full primary immunization and appropriate boosters need no tetanus prophylaxis beyond appropriate local wound care for clean minor wounds, but they should receive a toxoid booster after sustaining a dirty, tetanus-prone injury if the most recent dose was received more than 5 years previously. Patients who are not known to have completed the primary series require a tetanus toxoid booster after incurring any penetrating wound and TIG after sustaining a tetanus-prone injury. The prophylactic dose of TIG is 250 to 500 units, given intramuscularly. A human gamma-globulin
product, TIG does not carry the risk of serum sickness seen with equine antitoxin, and performing skin testing for hypersensitivity is unnecessary. U.S. statistics reveal that only 13% of patients who subsequently developed tetanus received appropriate tetanus toxoid boosters at the time of injury and that TIG was not given to any of the patients who should have received it. A continuing effort to educate the public about the need for tetanus immunoprophylaxis after childhood is necessary to prevent this disease. Prevention is much less costly than is treatment.

Botulism represents acute neurologic disease caused by another potent clostridial toxin, elaborated by C. botulinum. Botulinal toxin is the most potent poison known, causing death in mice that receive as little as 10 pg. Disease is caused in humans by less than 100 ng. Seven antigenically distinct botulinal toxins are distinguished (i.e., types A through G) and are produced by four groups of C. botulinum, each distinguished by its characteristic biochemical activities. The production of each toxin appears to depend on the presence of a plasmid that encodes the toxin gene. Elimination of the plasmid renders the bacteria nontoxigenic. The molecular weights of the toxins, which now are thought to be cellular proteins released during lysis, vary within the range of 130 to 150 kd. The active moiety of the protein may be as small as 10 kd. The toxin is destroyed by heat and pressure (e.g., 100°C for 10 minutes or 80°C for 30 minutes), but it is resistant to chemical deactivation. The bacterial spores highly resist heat, but they may be killed by autoclaving at 120°C for 20 minutes.

Botulinal toxin acts at the neuromuscular junction, where it inhibits the release of acetylcholine, producing a flaccid paralysis. It has no effect on the CNS or on mentation, although the earliest effect is seen on the cranial nerves. Progression of paralysis occurs in a characteristic descending fashion, ultimately affecting the entire peripheral nervous system. Respiratory failure is the major cause of death as the paralytic effect of the toxin reaches the muscles of respiration.

Botulinum spores are common in soil, dust, lakes, and other environmental matter and can contaminate fruits, vegetables, meats, and fish. Honey has become recognized as a potential source of C. botulinum spores in one form of botulism.

In view of the widespread occurrence of C. botulinum spores and their remarkable resistance to destruction, the epidemiology of the disease correlates most closely with circumstances in which contaminated foods are heated inadequately and the preformed toxin is ingested. Often, the contaminated food correlates with geographic location and the type of botulinal toxin involved. Most cases of botulism in humans are caused by types A, B, and E; more than one-half of foodborne cases in the United States are type A, and 25% are type B. Type A causes two-thirds of cases in the western half of the United States, and type B exhibits similar prevalence east of the Mississippi. Usually, cases of type E botulism involve fish from the Pacific Northwest and Alaska; worldwide, most type E disease occurs in Japan, Scandinavia, and the former Soviet Union, presumably because of dietary habits.

Most outbreaks of botulism in the United States are associated with food products (e.g., home-canned vegetables) that are not heated adequately before consumption and in which spores generate and form toxins. Other food products that have been incriminated include smoked meats, raw and fermented fish products, and potato salad and commercial frozen pot pies prepared improperly at home.

Ingestion of C. botulinum spores may lead to generation of toxin in the intestine of susceptible hosts and to botulism. This mechanism is operative in infantile botulism, which has been linked to the addition of honey (a natural, unpasteurized product) to infant formula. This form of botulism, which represents two-thirds of reported cases in the United States, first was recognized and still predominates in the western United States among families favoring “natural” food products, although now it is recognized throughout the country. A similar mechanism of acquisition of botulinal toxin has been implicated in rare cases in older children and adults. Prolonged or recurrent paralysis in some patients with typical foodborne botulism may be caused by intestinal infection with C. botulinum and resultant continued elaboration and absorption of toxin. Rarely, contamination of wounds with C. botulinum results in parenteral absorption of botulinal toxin and in “wound botulism.”

Botulism is caused by the binding of botulinal toxin to the neuromuscular junction. Whether from absorption of toxin from the gastrointestinal tract or from locally infected wounds, the toxin enters the lymphatics and bloodstream and circulates and gains access to neuromuscular junctions. The toxin does not cross the blood brain barrier, but it is bound to the cytoplasmic membrane of peripheral cholinergic nerve endings, where it inhibits the exocytosis of acetylcholine, resulting in flaccid paralysis. The toxin is bound irreversibly, like tetanus toxin, and recovery occurs only with regeneration of nerve endings. Unbound toxin may be neutralized with antitoxin early in the course of the disease, indicating the importance of early establishment of the diagnosis and institution of therapy.

The incubation period, duration, and severity of botulism are related directly to the quantity of toxin absorbed and bound to nerve endings. Speed of recovery depends entirely on the extent of involvement of nerve endings, which must be regenerated to replace those inactivated by botulinal toxin.

The clinical manifestations of botulism are related in some measure to age, with considerably less specific symptoms in infants than in older patients. At 18 to 48 hours after ingestion of tainted food, patients with botulism typically present with cranial nerve dysfunction manifested by diplopia, dysphagia, and difficulty speaking. Patients remain lucid, although anxiety and agitation may develop. Generally, fever is absent unless superinfection occurs. Additional signs may include pupillary dilation, vertigo, tinnitus, and dry mouth and mucous membranes. The descending progression of paralysis in botulism occurs at various rates, spreading and involving muscles of respiration and most voluntary musculature. The major manifestation is respiratory embarrassment, which may appear gradually or suddenly. If progression is slow, repeated measurements of tidal volume and other pulmonary function tests may be useful to predict the need for ventilatory support.

Involvement of the gastrointestinal tract varies and is related somewhat to the toxin serotype. Types A and B, the most common causes of botulism in the United States, cause abdominal complaints (e.g., abdominal pain, bloating, cramps, diarrhea) in approximately one-third of patients. These complaints are replaced quickly by constipation or obstipation. Type E produces more significant gastrointestinal complaints than do the other types. Gastrointestinal complaints do not accompany wound botulism. The incubation period spans 4 to 14 days,
and the progression of paralysis otherwise is similar to that in foodborne disease.

Botulism in infants may present suddenly with respiratory failure, and infant botulism has been implicated in some cases of apparent sudden infant death syndrome. More commonly, weakness and flaccidity are insidious, with slow progression from poor feeding and constipation to weakness, hypotonia, and respiratory insufficiency. Most parents describe a weak cry and diminished movement. Ptosis, loss of the gag reflex, and poor head control are common findings.

The duration of flaccidity and respiratory embarrassment in all forms of botulism may be fairly prolonged. The typical duration of symptoms exceeds 1 month, and full recovery from weakness and fatigability may require as long as 1 year. Usually, recovery is complete. Although no additional specific complications of botulism intoxication are listed, the potential complications of prolonged paralysis, assisted ventilation, and nutritional support are significant. Patients who progress to significant respiratory compromise should be treated in tertiary-care centers where experienced ventilatory support teams are available. The susceptibility to hospital-acquired infections of skin, respiratory tree, urinary tract, and indwelling intravascular devices defines the additional clinical signs and symptoms that may be present in these patients.

The clinical constellation of acute onset of symmetric descending flaccid paralysis, initially involving cranial nerves but sparing mentation and unassociated with fever, should be considered botulism, regardless of whether a history of consuming tainted food can be obtained. The entities confused most frequently with botulism are Guillain-Barré syndrome, myasthenia gravis, cerebrovascular accidents, other paralytic food poisonings, and some drug toxicities. Infectious encephalomyelitis may be confused with botulism in older children. Infant botulism is mistaken easily for septicemia, hypoglycemia, encephalitis, Werdnig-Hoffmann disease, or congenital myopathies.

Infectious conditions of the CNS can be differentiated from botulism by inflammatory changes in the CSF. Neither CSF pleocytosis nor chemical changes are characteristic of botulism. Similarly, Guillain-Barré syndrome is differentiated by its characteristic elevated CSF protein (i.e., albuminocytologic dissociation). The diagnosis of myasthenia gravis rests on a positive response to edrophonium (i.e., Tensilon test), and radiographic or nuclear imaging of the CNS usually demonstrates cerebrovascular accidents. Differentiating other forms of paralytic food poisonings (e.g., ciguatera) may be difficult without a positive ingestion history, but such forms probably are extraordinarily rare in the United States. Toxicity caused by aminoglycosides, phenothiazines, or atropine can be determined by affected patients’ histories.