TETANUS

Tetanus is a disease of the nervous system characterized by persistent tonic spasm, with violent brief exacerbations. The spasm almost always commences in the muscles of the neck and jaw, causing closure of the jaws (trismus, lockjaw) and involves the muscles of trunk more than those of the limbs. It is always acute in onset, and a very large proportion of those affected die.

Historic reference

Tetanus was well known to the ancients,descriptions by Egyptian and Greek physicians survive to the present. They recognized the frequent relationship between injuries and the subsequent development of fatal spasms. Cowers provided the quintessential description of tetanus in 1888. Nicolaier isolated a strychnine-like toxin from anaerobic soil bacteria in 1884, 6 years later. Behring and Kitasato described active immunization with tetanus toxoid. This latter discovery should have reduced tetanus to a historical curiosity, but we still fail to fulfill this promise.

Etiology

Clostridium tetani is an obligate anaerobic bacillus that is gram-positive in fresh cultures but that may have variable staining in older cultures or tissue samples. During growth, the bacilli possess abundant flagellae and are sluggishly motile. Two toxins, tetanospasmin (commonly called tetanus toxin) and tetanolysin, are produced during this phase. Tetanospasmin is encoded on a plasmid, which is present in all toxigenic strains. Tetanolysin is of uncertain importance in the pathogenesis of tetanus. Mature organisms lose their flagellae and develop a terminal spore,coming to resemble a squash racquet. The spores are extremely stable in the environment, retaining the ability to germinate and cause disease indefinitely. They withstand exposure to ethanol, phenol, or formalin, but can be rendered noninfectious by iodine, glutaraldehyde hydrogen peroxide, or autoclaving at 121 °Ñ and 103 kPa for 15 minutes. Growth in culture is optimal at 37 °Ñ under strictly anaerobic conditions, but culture results are of no diagnostic value. Antibiotic sensitivity is discussed below.

Epidemiology

The global incidence of tetanus is thought to be about one million cases annually or about 18 per 100,000 population. In developing countries, mortality rates are as high as 28 per 100,000.

Up to one-third of neonatal tetanus cases are in children born to mothers of a previously afflicted child, highlighting failure to immunize as a major cause of tetanus. Immunization programs clearly decrease neonatal tetanus deaths.

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Acute injuries account for about 70 % of cases, evenly divided between punctures and lacerations. Other identifiable conditions are noted in 23 %, leaving about 7 % of cases without an apparent source. Other studies cite rates of cryptogenic tetanus as high as 23 %.

Pathogenesis

Tetanospasmin is synthesized as a single chain. The nature of the receptor to which tetanospasmin binds, previously thought to be a ganglioside, remains debated. ÃÜå toxin enters the nervous system primarily via the presynaptic terminals of ower motor neurons, where it can produce local failure of neuromuscular :ransmission. Tetanospasmin appears to act by selective cleavage of a protein :omponent of synaptic vesicles, synaptobrevfn II. It then exploits the retrograde ixonal transport system, and is carried to the cell bodies of these neurons in the çãà³ï stem and spinal cord, where it expresses its major pathogenic action.

Once the toxin enters the central nervous system, it diffuses to the terminals }f inhibitory cells, including both local glycinergic interneurons and descending leurons from the brain stem. By preventing transmitter release from these cells, :etanospasmin leaves the motor neurons without inhibition. This produces nuscular rigidity by raising the resting firing rate of motor neurons, and also generates spasms by failing to limit reflex responses to afferent stimuli. Excitatory ransmitter release in the spinal cord can also be impaired, but the toxin appears î have greater affinity for the inhibitory systems. The autonomic nervous ystem is affected as well: this is predominantly manifested as a hypersympathetic tate induced by failure to inhibit adrenal release of catecholamines.

Toxin binding appears to be an irreversible event. At the neuromuscular mction recovery depends on sprouting a new axon terminal: this is probably ³å case at other affected synapses as well.

Anatomic pathology

Due to spasmatic syndrome bone fractures, especially compressive spinal cord icture, ruptures of muscles and tendines occur. Microscopy of sceletal muscles ows basophylic muscular fibres with signs oS their degeneration and necrosis.

Clinical manifestations

Tetanus is classically divided into four clinical types: generalized, localized, phalic, and neonatal. These are valuable diagnostic and prognostic distinctions, t reflect host factors and the site of inoculation rather than differences in toxin tion. Terms describing the initial stages of tetanus include the incubation riod (time from inoculation to the first symptom) and the period of onset me from the first symptom to the generalized spasm). The shorter these -iods, the worse the prognosis. Various rating scales are available. Certain rtals of entry (compound fractures) are associated with poorer prognoses, tanus may be particularly severe in narcotic addicts, for unknown reasons.

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Generalized tetanus is the most commonly recognized form, and often begins with trismus ("lockjaw", masseter rigidity) and a risus sardonicus (increased tone in the orbicularis oris). Abdominal rigidity may also be present. The generalized spasm resembles decorticate posturing, and consists of opisthotonic posturing with flexion of the arms and extension of the legs. The patient does not lose consciousness, and experiences severe pain during each spasm, which are often triggered by sensory stimuli. During the spasm, the upper airway can be obstructed, or the diaphragm may participate in the general muscular contraction. Either of these compromise respiration, and even the first such spasm may be fatal. In the modern era of intensive care, however, the respiratory problems are easily managed, and autonomic dysfunction, usually occurring after several days of symptoms, has emerged as the leading cause of death.

The illness can progress for about 2 weeks, reflecting the time required to complete the transport of toxin, which is already intra-axonal when antitoxin treatment is given. The severity of illness may be decreased by partial immunity. Recovery takes an additional month, and is complete unless complications supervene. Lower motor neuron dysfunction may not be apparent until spasms remit, and recovery from this deficit in neuromuscular transmission may take additional weeks. Recurrent tetanus may occur if the patient does not receive active immunization, because the amount of toxin produced is inadequate to induce immunity.

Localized tetanus involves rigidity of the muscles associated with the site of spore inoculation. This may be mild and persistent and often resolves spontaneously. Lower motor neuron dysfunction (weakness and diminished muscle tone) is often present in the most involved muscle. This chronic form of the disease probably reflects partial immunity to tetanospasmin. However, localized tetanus is more commonly a prodrome of generalized tetanus, which occurs when enough toxin gains access to the central nervous system.

Cephalic tetanus is a special form of localized disease affecting the cranial nerve musculature. Although earlier reports linked cephalic tetanus to a poor prognosis, more recent studies have revealed many milder cases. A lower motor neuron lesion, frequently producing facial nerve weakness, is often apparent. Extraocular muscle involvement is occasionally noted.

Neonatal tetanus follows infection of the umbilical stump, most commonly due to a failure of aseptic technique where mothers are inadequately immunized. Cultural practices may also contribute. The condition usually presents with generalized weakness and failure to nurse; rigidity and spasms occur later. The mortality rate exceeds 90 %, and developmental delays are common among survivors. Poor prognostic factors include age less than 10 days, symptoms for fewer than 5 days before presentation to hospital, and the presence of risus sardonicus or fever.

Complications

Thre are early and late complications of tetanus. Early complications are pneumonia, muscules ruptures, fractures of bones due to great muscle tension. The most common late complication is muscle contractures.

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Diagnosis

Tetanus is diagnosed by clinical observation, and has a limited differential diagnosis. Laboratory testing cannot confirm or exclude the condition, and is primarily useful for excluding intoxications that may mimic tetanus. Electromyographic studies are occasionally useful in questionable cases. Such testing becomes more important when no portal of entry is apparent. Antitetanus antibodies are undetectable in most tetanus patients, but many reports document the disease in patients with antibody levels above the commonly cited "protective" concentration of 0.01 IU/L. Rare patients apparently develop antibodies that are not protective.

Attempts to culture C. tetani from wounds are not useful in diagnosis, because (7) even carefully performed anaerobic cultures are frequently negative; (2) a positive culture does not indicate whether the organism contains the toxin-producing plasmid; and (3) a positive culture may be present without disease in patients with adequate immunity.

Differential diagnosis

Strychnine poisoning, in which glycine is antagonized, is the only condition that truly mimics tetanus; toxicologic studies of serum and urine should be performed when tetanus is suspected, and tetanus should be considered even if strychnine poisoning appears likely. Because the initial treatment of tetanus and strychnine intoxication are similar, therapy is instituted before the assay results are available. Dystonic reactions to neuroleptic drugs or other central dopamine antagonists may be confused with the neck stiffness of tetanus, but the posture of patients with dystonic reactions almost always involves lateral head turning, which is rare in tetanus. Treatment with anticholinergic agents (benztropine or diphenhydramine) is rapidly effective against dystonic reactions. Dental infections may produce trismus, and should be sought, but do not cause the other manifestations of tetanus.

Treatment

The patient with tetanus requires simultaneous attention to several concerns. Attention to the airway and to ventilation is paramount at the time of presentation, but the other aspects of care, especially passive immunization, must be pursued as soon as the respiratory system is secure.

Tetanic spasms sometimes demand that the airway be secured before other lines of therapy are possible. An orotracheal tube can be passed under sedation and neuromuscular junction blockade; a feeding tube should be placed at the same time. Because the endotracheal tube may stimulate spasms, an early tracheostomy may be beneficial.

Benzodiazepines have emerged as the mainstay of symptomatic therapy for tetanus. These drugs are GABA agonists, and thereby indirectly antagonize the

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effect of the toxin. They do not restore glycinergic inhibition. The patient should be kept free of spasms, and may benefit from the amnestic effects of the drugs as well. Diazepam has been studied most intensively, but lorazepam or midazolam appear equally effective. Tetanus patients have unusually high tolerance for the sedating effect of these agents, and commonly remain alert at doses normally expected to produce anesthesia.

The intravenous formulations of both diazepam and lorazepam contain propylene glycol; at the doses required to control generalized tetanus,this vehicle may produce lactic acidosis. Nasogastric delivery of these agents is often possible, but some tetanus patients develop gastrointestinal motility disorders and do not absorb drugs well. Intravenous midazolam (5-15 mg/h or more) is effective and does not contain propylene glycol, but must be given as a continuous infusion because of its brief half-life. Propofol infusion is also effective, but is currently very expensive, and the amount necessary to control symptoms may exceed the patient's tolerance of the lipid vehicle. When the symptoms of tetanus subside, these agents must be tapered over at least 2 weeks to prevent withdrawal. Intrathecal baclofen is also effective in controlling tetanus, but has no clear advantage over benzodiazepines. Neuroleptic agents and barbiturates, previously used for tetanus, are inferior for this indication and should not be used.

Rare patients cannot be adequately controlled with benzodiazepines alone; neuromuscular junction blockade is then indicated, with the caveat that sedation is still required for psychological reasons. All of the available drugs have side effects, including the potential for prolonged effect after the drug is discontinued. Vecuronium (by continuous infusion) or pancuronium (by intermittent injection) are adequate choices. These agents should be stopped at least once daily to assess the patient's progress, and to observe for possible complications.

Most tetanus patients will still have the portal of entry apparent when they present. If the wound itself requires surgical attention. This may be performed after spasms are controlled. However, the course of tetanus is not affected by wound debridement.

Passive immunization with human tetanus immunoglobulin (HTIG) shortens the course of tetanus and may lessen its severity. A dose of 500 units appears as effective as larger doses. There is no apparent advantage to intrathecal HTIG administration. Intrathecal HTIG has also been shown ineffective in neonatal tetanus. Pooled intravenous immunoglobulin has been proposed as an alternative to HTIG. Active immunization must also be initiated.

The role of antimicrobial therapy in tetanus remains debated. The in vitro susceptibilities of C. tetani include metronidazole, penicillins, cephalosporins, imipenem,macrolides,and tetracycline. A study comparing oral metronidazole to intramuscular penicillin showed better survival, shorter hospitalization, and less progression of disease in the metronidazole group. This may reflect a true advantage of metronidazole over penicillin, but it more likely corresponds to a

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negative effect of penicillin, a known GABA antagonist. Topical antibiotic application to the umbilical stump appears to reduce the risk of neonatal tetanus.

Autonomic dysfunction generally reflects excessive catechol-amine release, and may respond to combined a- and p-adrenergic blockade with intravenous Iabetalol. Beta blockade alone is rarely employed, because the resulting unopposed alpha effect may produce severe hypertension. If beta blockade is chosen, the short-acting agent esmolol should be employed. Other approaches to hypertension include morphine infusion, magnesium sulfate infusion, and epidural blockade of the renal nerves. Hypotension is less common, but if present may require norepinephrine infusion. Myocardial dysfunction is also common, and may represent a further reflection of catecholamine excess.

Nutritional support should be started as soon as the patient is stable. The volume of enteral feeding needed to meet the exceptionally high caloric and protein requirements of these patients may exceed the capacity of the gastrointestinal system.

The mortality rate in mild and moderate tetanus is presently about 6 %; for severe tetanus, it may reach as high as 60 %, even in expert centers. Among adults, age has very little effect on mortality, with octogenarians and nonagenarians faring as well as middle-aged patients. Tetanus survivors often have serious psychological problems related to the disease and its treatment that persist after recovery,and that may require psychotherapy.

Prophylaxis

Tetanus is preventable in almost all patients, leading to its description as the "inexcusable disease". A series of 3 monthly intramuscular injections of alum-adsorbed tetanus toxoid provides almost complete immunity for at least 5 years. Patients less than 7 years of age should receive combined diphtheria-tetanus-pertussis vaccine and other patients combined diphtheria-tetanus vaccine. Routine booster injections are indicated every 10 years; more frequent administration may increase the risk of a reaction. Some patients with humoral immune deficiencies may not respond adequately to toxoid injection: such patients should receive passive immunization for tetanus-prone injuries regardless of the period since the last booster. Most young patients with human immunodeficiency virus (HIV) infection appear to retain antitetanus antibody production if their primary immunization series was completed prior to acquiring HIV. Vitamin A deficiency interferes with the response to tetanus toxoid. A recent report documented tetanus in babies of women immunized with toxoid later shown to be devoid of potency; this disconcerting report underscores the need for quality control in toxoid production.

Although any wound may be inoculated with tetanus spores. Some types of injury are more frequently associated with tetanus and are therefore deemed tetanus-prone. These include wounds that are contaminated with dirt, saliva or

Infectious diseases

feces; puncture wounds, including unsterile injections, missile injuries, burns, frostbite, avulsions and crush injuries. Patients with these wounds who have not received adequate active immunization in the past 5 years,or in whom immunodeficiency is suspected should receive passive immunization with HTIG (250-500 IU intramuscularly) in addition to active immunization.

Mild reactions to tetanus toxoid (local tenderness, edema, low-grade fever) are common. More severe reactions are rare, some are actually due to hypersensitivity to the preservative thiomersal.

Control questions:

1. Etiology, epidemiology and incidence of tetanus.

2. Pathogenesis of tetanus.

3. Anatomic pathology of disease.

4. Main clinical symptoms and signs of tetanus.

5. Laboratory diagnosis of tetanus.

6. Criteria of tetanus diagnosis.

7. Differential diagnosis of tetanus.

8. Treatment of tetanus.

9. Preventive measures against tetanus.

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Date: 2014-12-21; view: 1028