Tetanus may be either localized or generalized, the latter being more common. The incubation period typically is 2-14 days, but may be as long as several months after the injury. In generalized tetanus, trismus (masseter muscle spasm, or lockjaw) is the presenting symptom in about half the cases. Headache, restlessness and irritability are early symptoms, often followed by stiffness, difficulty chewing, dysphagia and neck muscle spasm. The so-called sardonic smile of tetanus (risus sardonicus) results from the intractable spasm of facial and buccal muscles. When the paralysis extends to abdominal, lumbar, hip and thigh muscles, the patient may assume an arched posture, opisthotonos, in which only the back of the head and the heels touch ground. Opisthotonos is an end-state position that results from the unrelenting total contraction of opposing muscle groups, all of which display the typical 'board-like' rigidity of tetanus (Figure 7.1). Laryngeal and respiratory muscle spasm can lead to airway obstruction and asphyxiation.
Because tetanus toxin does not affect sensory nerves or cortical function, the patient unfortunately remains conscious, in extreme pain and in anxious anticipation of the next tetanic seizure. These seizures are characterized by sudden, severe tonic contractions of the muscles, with fist clenching, flexion and adduction of the arms and hyperextension of the legs. Without treatment, the seizures range from a few seconds to a few minutes with intervening respite periods, but as the illness progresses the spasms become sustained and exhausting. The smallest disturbance by sight, sound or touch may trigger a tetanic spasm. Dysuria and urinary retention result from bladder sphincter spasm; forced defecation may occur. Fever, with temperatures occasionally as high as 40°C, is common because of the substantial metabolic energy consumed by spastic muscles. Notable autonomic effects include tachycardia, arrhythmias, labile hypertension, diaphoresis, and cutaneous vasoconstriction. The tetanic paralysis usually becomes more severe in the first week after onset, stabilizes in the second week, and ameliorates gradually over the ensuing 1-4 weeks.
Neonatal tetanus (tetanus neonatorum), the infantile form of generalized tetanus, typically manifests within 3-12 days of birth as progressive difficulty in feeding (i.e., sucking and swallowing), with associated hunger and crying. Paralysis or diminished movement, stiffness to the touch and spasms, with or without opisthotonos, characterize the disease. The umbilical stump, the usual portal of entry of the spores, may hold remnants of dirt, dung, clotted blood or serum, or it may appear relatively benign.
Localized tetanus results in painful spasms of the muscles adjacent to the wound site and may precede generalized tetanus. Cephalic tetanus is a rare form of localized tetanus involving the bulbar musculature that occurs with wounds or foreign bodies in the head, nostrils or face. It also occurs in association with chronic otitis media. Cephalic tetanus is characterized by retracted eyelids, deviated gaze, trismus, risus sardonicus and spastic paralysis of tongue and pharyngeal musculature.
The image of tetanus is one of the most dramatic in medicine, and the diagnosis is most often made clinically. The typical setting is an unimmunized person who either gave birth, was injured or was born within the preceding 2 weeks and who presents with trismus, other rigid muscles and a clear sensorium. Only intoxication with strychnine produces a clinical picture that may be truly confused with tetanus.
Routine laboratory studies are remarkable for their normality. A peripheral leukocytosis may result from a secondary bacterial infection of the wound or may be stress-induced from the sustained tetanic spasms. Cerebro-spinal fluid (CSF) cellular and chemistry indices are normal, although the intense muscle contractions may raise CSF pressure. Neither the electroencephalogram (EEG) nor the electromyogram (EMG) show a characteristic pattern. C. tetani is not always visible on Gram stain of wound material, and it is isolated in only about one-third of cases.
Management of tetanus requires eradication of C. tetani and the wound environment conducive to its anaerobic multiplication, neutralization of all accessible tetanus toxin, control of seizures and respiration, palliation and provision of meticulous supportive care, and finally, prevention of recurrences.20
Surgical wound excision and debridement is often needed to remove the foreign body or devitalized tissue that created anaerobic growth conditions. Surgery should be performed promptly, but preceded by the administration of human tetanus immune globulin (TIG) and antibiotics. Sedation is needed unless general anesthesia is used. Excision of the umbilical stump in neonatal tetanus is no longer recommended.
Once tetanus toxin has begun its axonal ascent to the spinal cord or brainstem, it can no longer be neutralized by TIG. Accordingly, TIG is given as soon as possible to neutralize toxin that diffuses from the wound into the circulation before the toxin can bind to distant neuromuscular sites. An optimal dose of TIG has not been determined, and expert opinion varies. A single intramuscular injection of 500 U of human TIG is sufficient to neutralize systemic tetanus toxin, but doses as high as 3000-6000 have been recommended. Infiltration of TIG into the wound is now considered unnecessary. If TIG is unavailable, use of human intravenous immunoglobulin (IGIV), which contains 4-90 U/ml of TIG, or of equine- or bovine-derived tetanus antitoxin (TAT) may be necessary.21,22 Intrathecal TIG, given to neutralize tetanus toxin in the spinal cord, has not on meta-analysis proved effective.23
Metronidazole has displaced penicillin G as the first-choice antibiotic because of its effective clostridiocidal action, its lack of GABA antagonism and its diffusability - an important consideration because blood flow to injured tissue may be compromised. The dose is 500 mg every 6 h or 1000 mg every 12 h intravenously for 10-14 days.9 If metronidazole is not available, erythromycin and tetracycline (in patients 9 or more years old) are alternatives for penicillin-allergic patients.20
All patients with generalized tetanus need muscle relaxants. Remarkably, botulinum toxin type A was recently and successfully applied for this purpose in a case of cephalic tetanus.24 Because of their more limited durations of action (4-5 weeks versus 3-4 months), botulinum toxin types B and F should especially be considered for this treatment.25 As standard therapy, diazepam provides both relaxation and seizure control; an initial dose of 0.1-0.2 mg/kg is given intravenously and every 3-6 h as needed to control the tetanic spasms, after which the diazepam is sustained for 2-6 weeks before its tapered withdrawal. Magnesium sulfate, other benzodiazepines, chlorpromazine, dantrolene and baclofen have also been used. Intrathecal baclofen produces such complete muscle relaxation that apnea often ensues; like most other agents listed, baclofen should be used only by experienced persons in an intensive care unit setting. The best survival rates in generalized tetanus have been achieved with neuromuscular blocking agents like vecuronium and pancuronium, which produce a general flaccid paralysis then managed by mechanical ventilation. Autonomic instability has been regulated with standard alpha- or beta- (or both) blocking agents; morphine has also proved useful.
Meticulous supportive care of the patient in a quiet, dark secluded setting is highly desirable. Because tetanic spasms may be triggered by minor sensory stimuli, the patient should be sedated and protected from all unnecessary sounds, sights and touch. All therapeutic and other manipulations must be carefully scheduled and coordinated. Endotracheal intubation may not be required, but it should be done to prevent aspiration of secretions before laryngospasm develops. A tracheotomy kit should be at hand for unintubated patients. However, endotracheal intubation and suctioning easily provoke reflex tetanic seizures and spams, and so early tracheostomy deserves consideration for severe cases not managed by pharmacologically induced flaccid paralysis. Cardiorespiratory monitoring, frequent suctioning, and maintenance of the substantial fluid, electrolyte and caloric needs are fundamental. Careful nursing attention to mouth, skin, bladder and bowel function is needed to avoid ulceration, infection and obstipation. Prophylactic subcutaneous heparin use is advised.
The seizures and the severe, sustained rigid paralysis of tetanus predispose the patient to many complications. Aspiration of secretions and pneumonia may have occurred before the first medical attention is received. Maintenance of airway patency often mandates endotracheal intubation and mechanical ventilation with their attendant hazards, including pneumothorax and mediastinal emphysema. The seizures may result in lacerations of the mouth or tongue, in intramuscular hematomas or rhabdomyolysis with myoglobinuria and renal failure, or in long-bone or spinal fractures. Venous thrombosis, pulmonary embolism, gastric ulceration with or without hemorrhage, paralytic ileus, and decubitus ulceration are constant hazards. Excessive use of muscle relaxants, although an integral part of care, may produce iatrogenic apnea. Cardiac arrhythmias, including asystole, unstable blood pressure and labile temperature regulation reflect disordered autonomic nervous system control that may be aggravated by inattention to the maintenance of intravascular volume needs.
Recovery from tetanus occurs through regeneration of synapses within the spinal cord and brainstem and thereby, the restoration of muscle relaxation. However, because illness with tetanus does not induce formation of toxin neutralizing antibodies, initiating active immunization with tetanus toxoid at discharge, with arrangements for completion of the primary series, is mandatory.
The most important factor influencing outcome is the quality of supportive care. Mortality is highest in the very young and the very old. A favorable prognosis is associated with a long incubation period, with the absence of fever and with localized disease. An unfavorable prognosis is associated with an interval of 1 week or less between the injury and the onset of trismus or with 3 days or less between trismus and onset of generalized tetanic spasms. Sequelae of hypoxic brain injury, especially in infants, include cerebral palsy, diminished mental abilities and behavioral difficulties. Most fatalities occur within the first week of illness. Reported case fatality rates for generalized tetanus range between 5% and 35% and for neonatal tetanus extend from less than 10% with intensive care unit management to more than 75% without it. Cephalic tetanus has an especially poor prognosis because of breathing and feeding difficulties.
Tetanus is an entirely preventable disease; a serum antibody level of 3=0.01 U/ ml, as determined by a suitable in vivo neutralization assay, is considered protective.26 Active immunization should begin in early infancy with combined diphtheria toxoid-tetanus toxoid-pertussis (DTP) vaccine at 2, 4 and 6 months of age, with a booster at 4-6 years of age and at 10-year intervals thereafter throughout adult life with tetanus-diphtheria (Td) toxoids. Immunization of women of childbearing age with tetanus toxoid will prevent neonatal tetanus; a single dose of toxoid that contains 250 Lf (limits of flocculation) units may be safely given in the third trimester of pregnancy and is capable of providing enough transplacental antibody to protect the child for at least 4 months.27 For unimmunized persons 7 or more years of age, the primary immunization series consists of three doses of Td toxoid given intramuscularly, the second 4-6 weeks after the first and the third 6-12 months after the second.
Tetanus prevention measures following trauma consist of inducing active immunity to tetanus toxin and of passively providing neutralizing antitoxin antibody. Tetanus prophylaxis is an essential part of all wound management, but the specific measures taken depend on the nature of the injury and the immunization status of the patient. Tetanus toxoid should be given after a dog or other animal bite, even though C. tetani is infrequently found in canine mouth flora, if five or more years have elapsed since the last booster. Human TIG is not given for clean and minor wounds, regardless of prior immunization status; it is also not given to patients with 'dirty' or other traumatic injuries who have received a full primary immunization series and a tetanus toxoid booster within the last five years. In other circumstances (e.g., patients with an unknown or incomplete immunization history, with crush, puncture or projectile wounds or wounds contaminated with saliva, soil or feces, avulsion injuries, compound fractures, frostbite, etc.), 250 U of TIG should be given intramuscularly, and increased to 500 U for highly tetanus prone wounds (i.e., undebridable, with substantial bacterial contamination, or more than 24 h old). If TIG is unavailable, then use of human IGIV may be considered.22
The wound itself should have immediate, thorough surgical cleansing and debridement to remove foreign bodies and any necrotic tissue in which anaerobic conditions might develop. Tetanus toxoid should be given to stimulate active immunity and may be administered concurrently with TIG (or TAT) if given in separate syringes at separate sites. A tetanus toxoid booster (preferably Td) is given to all persons with any wound if their tetanus immunization status is unknown or incomplete. Also, a booster is given to injured persons who have completed their primary immunization series if (1) the wound is clean and minor but 10 years or more have passed since the last booster, or (2) the wound is more than clean and minor, and 5 years or more have passed since the last booster. With delayed wound care, active immunization should be started at once. Although fluid tetanus toxoid produces a more rapid immune response than the adsorbed or precipitated toxoids, the adsorbed toxoid results in a more durable titer. The constant threat of tetanus, both in developed and in less developed countries, is highlighted by the recent finding that one-fifth of children aged 10-16 years in the United States did not possess a protective level of tetanus antibody.15
A. The disease, the organism, the toxins
Botulism is the acute, flaccid paralysis caused by the neurotoxins of Clostridium botulinum, or rarely, by an equivalent neurotoxin produced by unique strains of Clostridium butyricum or Clostridium baratii. Three forms of human botulism are known: infant botulism (the most common in the United States), foodborne (classical) botulism, and wound botulism. Each form of human botulism has a different pathogenesis and epidemiology.
As already mentioned, botulinum toxin is the most poisonous substance known. Its potency derives from its ability to block neuromuscular transmission and cause death through paralysis of airway and respiratory musculature. Seven antigenic toxin types, arbitrarily assigned the letters A-G, can be distinguished by the inability of protective (neutralizing) antibody raised against one toxin type to protect against poisoning by a different toxin type. The seven toxin types are often used as convenient clinical and epidemiological markers. Neurotoxi-genic C. butyricum strains produce a type E-like toxin, while neurotoxigenic C. baratii strains produce a type F-like toxin. Toxin types A, B, E, and F are well-established causes of human botulism, while types C and D cause illness in other animals. Type G was discovered in an Argentinean cornfield in 1970 and has not been established as a cause of either human or animal disease.28
The phenomenal potency of botulinum toxin was finally explained by the recent discovery that its seven light chains are Zn2+-containing endopeptidases, whose substrates are one of three protein components of the docking complex by which synaptic vesicles fuse with the terminal cell membrane and release acetylcholine into the synaptic cleft. Of these three substrates, synaptobrevin is cleaved by tetanus toxin and by botulinum toxin types B, D, F, G; SNAP-25 is cleaved by botulinum toxins types A, C and E, and syntaxin is cleaved by botulinum toxin type C (see Chapter 18).29
Clostridium botulinum is a Gram-positive, spore-forming obligate anaerobe whose natural habitat worldwide is soil, dust and marine sediments, and consequently, it is frequently found in a wide variety of fresh and cooked agricultural products. Spores of some C. botulinum strains can survive boiling for several hours, which enables the organism occasionally to outlast human efforts at food preservation. In contrast, botulinum toxin is heat-labile and is easily destroyed by heating at 80°C or above for 5-10 min. Little is known about the ecology of neurotoxigenic strains of C. butyricum and C. baratii.
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