SEMINARS I N NEUKOL0C;Y-VOI.UME
I I , NO. 3
S E P T E M B E R 1091
Tetanus
Tetanus is characterized by rigidity and spasm of muscles. There are four clinical forms: local, generalized, cephalic, and neonatal. Local tetanus causes rigidity of the group of muscles in close proximity to the site of infection, which is usually a contaminated wound. Generalized tetanus, the most common form o f t h e disease, usually involves bulbar and paraspinous muscles initially. Generalized tetanus is characterized by trismus, risus sardonicus, opisthotonos, difficulty swallowing, marked irritability, and restlessness. Cephalic tetanus, a rare fbr-m, follows injuries of the head o r otitis media. It is characterized by spasm and rigidity of muscles supplied by the cranial nerves. Neonatal tetanus is generalized tetanus; it usually results from contamination of the umbilicus.' T h e clinical features of tetanus are produced by the activity of the neurotoxin tetanospasmin, which is produced in contaminated wounds by Clostridium tetani. Tetanospasmin, a protoplasmic protein, is synthesized within the bacteria and is re. ~h e toxin reaches the leased on their a ~ t o l y s i s T central nervous system (CNS) by retrograde axonal transport in motor neurons. It then passes transsynaptically to bind to the presynaptic membrane on the perikaryon. Tetanus toxin prevents the release of the inhibitory neurotransmitters glycine and gamma-aminobutyric acid (GABA) from the presynaptic terminal. Muscle spasms result from the blockade of inhibitory transmitter release, and thus unopposed excitation, to the motor neurons in the spinal cord and brainstem." There are similarities and differences between tetanus toxin and botulinum toxin. Both neurotoxins are of similar molecular weight and structure and are produced by anaerobic bacteria belonging to the genus Clostridium. Both toxins block transmitter release at presynaptic sites. Botulinum toxin
acts to prevent the release of' acetylcholine from cholinergic nerve endings.' Through this mechanism of action, it prevents neuromuscular transmission, producing progressive weakness of extraocular, bulbar, respiratory, and appendicular musculature. Although both toxins act on the presynaptic terminal, tetanus toxin acts preferentially on inhibitory synapses, resulting in unopposed excitation of muscles, whereas botulinum toxin blocks neuromuscular transmission, producing flaccid paralysis.
HABITAT AND EPIDEMIOLOGY T h e organisms of C. tetani are anaerobic, spore-forming rods that grow and multiply in soil, dung, and dirt, in wet and hot climates. ,retanus bacilli enter the body through lesions of' the skin from wounds, "skin-popping" in heroin addicts, ear-piercing in west African countries, and umbilical wounds in neonates. I n some developing countries, neonates are at particular risk fix tetanus because their umbilical wounds are not sufficiently protected fr-om dirt and because o f the folklore practice of' putting soil o r cow d u n g o n umbilical wounds.' T h e occurrence of tetanus in the United States steadily declined between 1947 and 1976 because of' the routine use of tetanus toxoid; however, the number- of' cases of tetanus reported to the Centers fi)r Disease Control (CDC) has remained relatively constant in the last decade at approximately 90 cases per year.' It is estimated, however, that there are at least as many cases each year that are not reported to the C D C . V n recent years, approximately two thirds of reported cases have been in persons 50 years of age o r older. Of 253 cases of'
Associate Professor of Neurology, Indiana Univcr-sity School ol Medicir~c,Indianapolis, Ir~tiiana Reprint requests: Dr. Roos, Department of Neurology, Irltlia~laUnivrrsity School o f h.letlicinc, 1001 West 10th Street, Incliariapolis, IN 16202 Chpyriglit O 1991 by Thierne Medical Publishers, In c... 381 Pal-k Avenue Sourlr, New E'ork, N\r' 100 16. All rights reserved.
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Karen L. Roos, M D
MICROBIOLOGY
(:. tetarii in an early stage possesses a single cilium at one end. As the bacterium grows, it is surrounded by several cilia, which are gradually lost during aging. After 2 to 1 0 days in culture, the spores of the bacterium become prominent, appearing at one o r both ends as round bodies.' At this stage, the bacteria have the appearance of a drumstick o r a squash racket with one o r two spores at the terminal end of the rod.' While the l~acteriumis gram-positive in young cultures (less than 18 hours old), it is usually gram-negative in older cultures, although it may retain some grarnpositive slairiirig in portions near the spore." .l'etanus toxin is synthesized within the bacterium and is released o n its autolysis.' C. tetarii may not be isolated by culture from an infected wound unless pieces of dead tissue are taken from deep within the wound. T h e identification of C. tetani by cul-
ture and the detection oftetanus toxin are not necessary to make the diagnosis because the clinical manifestations arid course of the disease are so character-istic."
MECHANISM OF ACTION OF TETANUS TOXIN Tetanus toxin produces spasticity by blocking inhibitory neurotransmitter release from presynaptic nerve terminals that synapse on alpha motor neurons in the spinal cord and brainstem, and it causes sympathetic nervous system overactivity by blocking inhibitory synapses in preganglionic neurons in the intern~etiiolateralcell column of the thoracic spinal cor~1.l.~'' 'Tetanus toxin is transported by retrograde axonal transport in motor neurons from its site of formation in a wound infected by C . tetani to its site of action, the motor neuron cell bodies in the ventral gray of the spinal cord and brainstem." There is no evidence that any significant amount of tetanus toxin reaches the CNS directly via the bloodstream, probably because of the blood-brain barrier. I " In local tetanus, toxin travels only in the peripheral nervcs supplying the affected muscles, and rigidity is confined to those muscles. I n generalized tetanus, toxin enters the CNS initially along peripheral nerves supplying the infected muscle but subsequently reaches other motor nerve terminals throughout the body via the bloodstream. Although toxin can enter vessels leading to the CNS, it cannot escape from the vessels because of the blood-brain barrier. Instead, the circulating toxin leaks from the permeable intramuscular vessels and in this way diffuses to reach nerve terminals, where it is subsequently taken u p arid carried by retrograde axonal transport to the alpha motor neuron cell bodies" (Fig. 1). This mechanism of toxin spread results in generalized tetanus, with involvement of' facial muscles followed by trunk and then limb musculature. .l'his sequence of muscle involvement is explained by the length of the neural pathways involved in transport. Assuming a n equal rate of transport in the different nerves, and given that the nerves to the facial muscles are the shortest and those to the limbs are the longest, the toxin will produce rigidity in the facial muscles first and the limbs last."'." 'The result is descending o r generalized tetanus. 'l'he individual steps from the uptake by peripheral nerve terminals to the blockade of inhibitory neurotransmitter release will be reviewed.
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tetanus reported to the C1)C from 1982 through 1984, age was known in 224, of whom 71% were aged 50 o r older, 25% were 20 to 49 years old, and 3% were 1 month to 19 years old.' I n 72%) of cases, tetanus occurred after an acute injury, either- a puncture wound o r a laceration.' 'l'he acute injury was incurred indoors in 415% of cases, contracted in gardening arid other outdoor activities in 39%#,the result of major trauma in 4 % , animal-related in 476, and fr-om other o r unknown circumstances in 12% of cases. Chronic wounds such as skin ulcers, abscesses, o r gangrene were the source of tetanus in 21% of cases, whereas in 2%) tetanus was attributed to parenteral d r u g abuse. In 7%)of patients, the source of' tetanus was unknown..' Neonatal tetanus occurred in infants born in poor hygienic conditions to inadequately immunized mothers. (Women who are immunized against tetanus confer protection to their infants through placental transfer of maternal antibody)." 'The mean incubation period for the 142 patients with a known interval between injury and onset of tetanus was 8 days.4 T h e small number of cases of' tetanus in persons 5 to 19 years of age in the United States is attributed to the childhood vaccination program and the requirement of primary immunization against tetanus for entry into school. T h e high incidence of tetanus in persons aged 50 years arid older is attributed to the decrease in immunity with age. Serologic test surveys since 1977 have demonstrated a lack of' protective levels of tetanus antitoxin antit~odyin 49 to 66%:of persons 60 years of' age and older. '.'-"
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Figure 1. Tetanus toxin diffuses out of intramuscular arteries to reach peripheral nerve terminals where it is carried by retrograde axonal transport to the cell body of the alpha motor neuron.
UPTAKE OF TOXIN BY PERIPHERAL NERVE TERMINALS
'Tetanus toxin reaches the alpha motor neuron cell bodies in the spinal cord and brainstem by retrograde axonal transport, which begins in muscles with the uptake of toxin in peripheral nerve terminals. Tetanus toxin appears to bind to neuronal membranes at a receptor, but the exact biochemical nature of the tetanus toxin receptor is not known. Tetanus toxin binds to neuronal membranes but not glial membranes, and gangliosides in neuronal membranes are part of the tetanus toxin receptor. T h e evidence for this is as follows: (1) Neuronal cell lines that lose long-chain gangliosides through serial culturing d o not bind tetanus toxin;",l".14 (2) the addition of exogenous gangliosides to the culture results in binding of tetanus toxin by nerve cells;~~,~:i,~.5 and (3) when toxin is first mixed with
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gangliosides, its uptake into nerve terminals is reduced, presuniably because the receptor-binding site on the toxin molecule is occupied by gangliosides."'.l%embrane ganglioside binding is an initial step in the activity of some hormones and in the mechanism of action of another bacterial toxin, cholera toxin. 'Tetanus and cholera toxin bind to the same receptor in thyroid plasma membranes as does thyroid-stimulating hormone (TSH), suggest-
ing a similarity in these membrane receptors. However, neuronal membranes are better at binding tetanus toxin than TSH, whereas the reverse is true for thyroid membranes, suggesting some tiifferences between these membrane receptors."' A second tetanus toxin receptor, a gangliosideindependent receptor, has also bcen demonstrated. Tetanus toxin may require two receptors, a ganglioside-dependent receptor for initial binding and a ganglioside-independent receptor for the biologic activity of tetanus toxin." ZNTRA-AXONAL ASCENT OF TOXIN
After binding to its receptors, the toxin-receptor complex is internalized by the axon for retrograde transport to the cell body. Tetanus toxin is transported in sensory and adrenergic rieurons as well as motor neurons. Toxin transported in peripheral sensory nerves accu~nulatesin the dorsal root ganglia; that transported by adrenergic nerves accumulates in the lateral gray of the thoracic spinal cord, where the cell bodies of preganglionic sympathetic neurons are located.lO~"T h e rate of transport for toxin in motor, adrenergic, and sensory ricurons has been calculated by Stoeckel et allx to be 7.5 mmlhr, 2.8 mmlhr, and 33 mnilhr, respectively. Toxin may ascend in the epineurium
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SEMINARS I N NEUKOLOGY
TRANSSYNAPTIC TRANSFER OF TOXIN
T h e retrograde transsynaptic transfer of tetanus toxin from the motor neuron to the presynaptic terminals has been demonstrated experimentally. Schwab and Thoenen"' demonstrated radioactivity in nerve terminals synapsing on motor neurons in the ventrolateral spinal cord of rats after intramuscular injection of "'I-tetanus toxin, particularly in animals exhibiting clinical signs of tetanus." Morphologic presynaptic changes include decreased vesicle density and a shift from round to flattened synaptic v e s i c I e ~ . ~ ~ ) ~ l ' Subsequent experiments with injection of radioactively-labeled toxin into the rat anterior eye chamber and the submandibular gland resulted in the localization of 12.8 1.1 % of the label on presynaptic terminals in superior cervical ganglion ,rhese experiments showed that toxin cells.~o.~~,n
*
transfer is mainly restricted to the synaptic region." This transsynaptic transfer appears to show some specificity fbr the tetanus toxin. Similar pat-
terns of uptake of labeled macromolecules such as nerve growth factor, wheat germ agglutinin, and phytohemagglutinin were obtained from superior cervical ganglion cell bodies; however, a retrograde transsynaptic movement to the afferent terminals similar to that of tetanus toxin was not detected. 10.1 1.21.22 TETANUS BLOCKS INHIBITORY NEUROTRANSMITTER RELEASE AT THE PRESYNAPTIC TERMINAL
After crossing the synapse, tetanus toxin acts on the presynaptic terminal, blocking the release of the inhibitory neurotransmitters glycine and GABA in the spinal cord and brainstem.1° With the loss of inhibitory input by glycinergic interneurons, the lower motor neuron activity increases resting muscle tone, producing rigidity. T h e glycinergic system also limits the spread of polysynaptic reflex activity (Fig. 2). Loss of inhibition in the polysynaptic reflex pathways results in the recruitment of more agonist muscles and the excitation, rather than inhibition, of antagonist muscles, producing the reflex spasms of tetanusz3 Patients with tetanus also develop symptoms of sympathetic overactivity, characterized by pe-
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and the perineurium of the nerve supplying the infected muscle, but it is the toxin migrating in the intra-axonal compartment that accumulates in the spinal cord.".'"
inhibitory
lnterneuron
Figure 2. Tetanus toxin blocks the release of glycine that would inhibit flexor muscles during the excitation of extensor muscles. This loss of inhibition results in the simultaneous excitation of both agonist and antagonist muscles and thus the reflex spasms of tetanus.
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SEMINAKS I N NEIJKOIDGY
V O L U M E 1 1 , NUMHk:K 3
SEPTI;:IMBI:'II ! 9 9 1
riods of tachycardia and hypertension. 'letanus toxin accumulates not only in motor rieur-om in the ventral gray matter, but also in the cell bodies of preganglionic sympathetic neurons in the lateral gray of'the thoracic spinal cord. 'I'he result of this loss of' inhibition in the interniediolateral cell column is a markedly elevated secretion of catecholamines by the adrenal glands and signs and symptoms of a hypersympathetic state."." Figure 3. Illustration of a tetanus patient by Sir Charles Bell (1824).
O f the four clinic;11 fi)rnis of tetanus, the local and cephalic forms have the potential to become generalized. Neonatal tetanus is usually generalized from the onset."' Fl'he incubation pm-iod is dcf'ined as the time from inoculation with C. tetani spores to the appearance of' the first symptom; it may vary from 2 days to 3 weeks. 'l'he shorter the incubation period, the worse the prognosis. T h e incubation period is fbllowed by the pwiod q f ' o ~ w t of tetanus. 'The period of' onset is defined as the interval from the first symptom to tlie first reflex spasm.':' In severe forms of tetanus, the onset of' symptoms is usually followed by generalized rigidity in less than 3 days. T h e short period of onset arid the severe syniptorns reflect the amount of toxin absorbed. I n mild cases of tetanus, in which a sniall amount oftoxin is absorbecl, the periods of' incubation and onset are long and "spinal co~ivulsions" are I-are."17etanus toxin itself does not permanently damage the CNS; however, hypoxia from tetanigcnic respiratory e~nbar~~assriierit may cause permanent deficits.' Likewise, toxin does not permanently damage muscle. Kesidual rnuscle dysfunction is caused by changes secondary to prolonged muscle contr-action.' GENERALIZED TETANUS
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Muscle stif'f'ness begins in the muscles of the head and neck. Patients i~~itially complain of pain in the ,jaw arid neck. .l'he usual presenting sign is trisrnus, which is a rigidity o f t h e masseter muscles causing an inability to open the mouth to speak o r to chew. Another early sign is risus sardonicus, a sneering grin, which is d u e to stif'f'ness of'the milscles of facial expression."' Stiffness of cervical musculature occurs early. Involvement of' pharyngeal muscles impairs swallowing.' Diffuse muscular r gidity produces opisthotonos because of' its preporitlerance in extensor muscles.' Reflex spasms, o r so-called spinal convulsions, are characteri~etl by "a sudden burst of tonic contraction of' muscle groups causing opisthotonus, flexion, and adduction of the arms, clenching of' the fists on the
thorax, and extc~isionof the lower cxtremities"' (Fig. 3). T h e spasms, which are extremely paitif'ul, are precipitated by external stimuli. Sudden spasms of' the niuscles of' respiration nlay stop respi1-atio11for 10 to 20 seconds; hypoxia may terminatc the spasm. 1,aryngeal o r pharyngeal spasnis may oI)st~-uctthe airway so that the patient feels that he is choking o r may suf'f'ocate.' Respiratory f,lilu~-eis most coninio~ilycaused by upper airway spasm 01-di;~pli~-agniatic tlysf'unction. Prior to the a c l v c ~ ~of't mechanical ventilation, respiratory failure was the niost common cause of death in teta11~1s.~~ Syniptoms of sympathetic overactivity typically begin cluring the second week of' the illness. .l7here are periods of hypertension a ~ tachycar~ d dia, profuse sweating, cardiac al-I-hythmias, and kver-, I-esemt)litig the crisis caused hy a plieochromocytoni:~.2:'Periods of' bradycar-tlia and liypotension may also occur. T h e excessive muscular activity may produc:e t'wer- and rhal~dornyolysis with sulxequent renal fiiilure. Iriaplxopriate secret i o ~ iof' antidiuretic: hol-mone may also occur. Fractures of' thoracic v e r t e h a e result f'r.0111 spasms of the tl-u~icalni~~sculature." Kecovery, which usually begins 1)). the secorid 01-third week, requires 4 weeks o r more. Coniplic;itions from overactivity of' tlie synipatkietic ner\ r o ~systerrl ~s are the most common cause of' death, although pulnionar-y f'i~ilurefrom pneunnonia . ~ n d throliit)oembolis~iimay be life-threa~ening."~As previously stated, tlie toxin itself' does not cause p e r ~ ~ i ; t ~ ineul-ologic ent sequelae, hut the complications of' hypoxia may he severe. NEONATAL TETANUS
Neonatal tetanus, like generalized tetanus, hegins i l l the muscles of the head and neck. 'I'he r~sualpresenting symptom is poor feeding."" 'Fhe inf'i~ntcannot suck, arid when a finger. is put into its mouth, its ,jaw clamps tightly. Stif'kriing of' the upper lip is also an early sign. As the niuscles of' f aclal : . expression become involved, the eyes are
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CLINICAL FORMS O F TETANUS
spasm o r rigidity in the group of muscles in close proxirriity to the wound, with superimposed intermittent, brief, intensely painful spasms. Local tetanus may remain restricted to a limb o r may become generalized. When it remairis restricted, the natural history is one of gradual resolution over a period of weeks to months.'."" CHRONIC TETANUS
closed tightly and there is a deep wrinkling of the forehead, the equivalent of' risus sardonicus. Opisthotonos may be so severe in the neonate that the heels may come close to touching the back of the head. In the less severe fbrm, the legs are hyperextended, the arms tlexed, and the fists tightly closed' (Fig. 4). Kespir-atory arrest caused by pharyngeal and respiratory muscle spasm is a very common complication of ~ieoliataltetanus. Periods of cyanosis arid apriea may occur, with o r without spasms. Electrolyte imbalance, hypothermia, and cardiovasc:i~larshock are frequent complications. CEPHALIC TETANUS
Cephalic tetanus involves the riiuscles supplied by one o r more cranial nerves. It follows an injury to the head o r neck and has a short incubation period of' I o r 2 days. T h e facial nerve is affected most often, with turrowing of'ttie forehead, blephwospasm, and involuntary retraction of'thc corner of' the rnouth. Spasm of' muscles of fjcial expression may be accompanied by paralysis of voluntary movement. 'I'he signs of' hypoglossal arid pharyngeal nerve involvement are dysarthria, dysphagia, and spasnis o f t h e tongue arid throat. Ocular nerve involvement is characterized by diplopia, strabismus, ptosis, miosis, o r mydl-iasis. Tetanus affecting the vagal nerve has been reported, with signs of 1,radycarclia and salivation.'.'" Cephalic tetanus nlay I-apicllyevolve into generalized tctanus. LOCAL TETANUS
1,ocal tetanus is lirnitcd to the extremity in which there is a mntarninated wound." l ' h e patient's initial compliant is stiffness of the rnuscles in that extr-eniity with voluntary movement. This is fbllowed by the development of a continuous
Electrornyography (EMG) is useful in establishing the diagnosis of tetanus anti in distinguishing it from other disorders of muscle stiffness. T h e characteristic EMG changes in local tetanus are: (1) an exaggerated F-response, (2) an absent o r shortened silent period, (3) simultaneous EMG activity in agonist and antagonist muscles during volitional activity, and (4) prolongation of EMG activity of the affected muscles into the period of attempted relaxation." Other EMG findings reported in tetanus include: ( I ) increased insertional activity,"" (2) tienervation changes suggesting an axonal neuropathy o f a "dying-back" type,:" and (3) increased jitter and blocking on single-fiber EMG." Chronic tetanus can be distinguished by EMG from stiff-man syndrome, in which the silent period is normal.'," In extrapyramidal rigidity, the silent period is either normal o r prolonged, there is no abnormality of' insertional activity, and there are no clenervation changes."
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Figure 4. Neonate with tetanus. (From Veronesi R, Fucaccia R. The clinical picture. In: Veronesi R, ed. Tetanus: important new concepts. Amsterdam: Excerpta Medica, 1981:183-206. Reprinted with permission.)
Tetanus that persists for more than 1 to 2 months has been called chronic tetanus. It has historically been confused with the stiff-man syndrome, which is characterized by a stif'f'ness of axial musculature with superimposed muscle spasms.?x.?!l
DIAGNOSIS 'l'he tiif'krential diagnosis of' acute muscular stif'f'ness and spasm (in addition to tetanus) includes: (1) poisoning with a glycine and GABA antagonist such as strychnine, (2) a dystonic reaction secondary to a dopalnine-blockirig agent, (3) peritonitis, (4) hypocalcernia, and (5) rabies (in patients with dysphagia). Strychnine poisoning is characterized by muscle spasms. It is not associated with the generalized rigidity between spasms that is typical of tetanus. 1)ystonic reactions, typified by an oculogyr-iccrisis, are quickly reversed with intravenous anticholinergic agents o r diphenhydramine. T h e presence of strychnine o r dopamine antagonists can be identified by biochemical analysis of serum and urine. Peritonitis is associated with rebound tenderness, abdoniirral distention, nausea, and vomiting. Chvostek's and Trousseau's signs may be elicited in patients with hypocalcemia.'"
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SEMINARS I N NEUKOLOGY VOLUME 11. NUMBEK 3 SEP7'b;MHER 1991
TREATMENT 7
7
I here are three goals of treatment in tetanus: stopping production of the toxin by surgical debridement of the wound and antibiotic therapy, neutralization of circulating toxin by the administration of antitoxin, and reversal of the loss of central inhibition caused by toxin that has reached the CNS.' SURGERY
Surgical debridement of the wound will decrease the number of bacilli and the amount o f toxin as well as the anaerobic potential of the wound. C. tetani does not grow in well-oxygenated tissue.' ANTIBIOTIC THERAPY
Antibiotics are minimally effective in the treatment of tetanus, but they have remained part of the standard therapy. They should not be used without the concomitant administration of antitoxin because autolysis of'the bacteria results in release of toxin. Although C. tetani is sensitive to penicillin, metronidazole, cephalosporins, imipenem, tetracycline, and erythromycin, metronidazole, administered intravenously in a dose of 500 mg every 6 hours for 10 days, is the recommended antibiotic for the treatment of tetanus.",'" NEUTRALIZATION OF CIRCULATING TOXIN
This step is the mainstay of therapy. Human tetanus immune globulin (HTIG) will neutralize the circulating toxin that has not yet been taken u p by motor neurons. It is administered intramuscularly. Previously, a dose of 3000 to 5000 IU was recommended. Recently, a dose of 500 IU has been established as being effective. T h e intrathecal administration of 250 U of H T I G has been shown to be superior to a 1000 U intramuscular dose; 2 12
however, the HTIG available in the United States has not been approved for intrathecal use.'" ACTWE IMMUNIZATION
Active immunization with tetanus toxoid must be given in addition to H T I G to prevent recurrent tetanus. This can be started during the acute phase of the illness or during the time of recovery. 1Ptanus-diphtheria toxoid (TD) is recommended for patients 7 years of age or older. For children under 7 years of age, an intramuscular in~ectionof DI'P (diphtheria-tetanus-pertussis) is recommended unless the pertussis vaccine is contraindicated. At least three intramuscular injections of absorbed toxoid (either T D or 1YI'P) must be given, not less than 1 month apart, to ensure immunity from tetanus for at least 5 years.'".'" REVERSAL OF THE LOSS OF CENTRAL INHIBITION PRODUCING SPASMS AND RIGIDITY
T h e benzodiazepines are the best agents to relieve spasms and rigidity. Because thev are GABA agonists, they reverse the effects of the toxin on presynaptic inhibition of spinal reflexes. Lorazepam, given in 2 mg doses, is the preferred agent because of' its long duration of action. A daily dose of 80 mg or more may be required. Large doses of intravenous benzodiazepines can produce metabolic acidosis caused by the propylene glycol vehicle; therefore these agents should be administered through a feeding tube as soon as po~sible.~" Continuous intrathecal baclofen has been successfully used in a small number of patients with generalized tetanus, but there has not been enough experience with this therapy to recommend it at this time."' Neuromuscular blocking agents are required when benzodiazepines cannot control the spasms and when mechanical ventilation is difficult. Vecuronium, in doses of 6 to 8 mglhour, is the recommended agent because it produces minimal autonomic instability. Benzodiazepines should be used with neurornuscular blocking agents to sedate the patient.:':' To treat the hypersympathetic state, combined alpha- and beta-adrenergic blockade with labetalol is recommended. It is given as a constant infusion at 0.25 to 1.0 mg/minute.*",""
TETANUS PROPHYLAXIS When wounds are minor and uncontaminated, a tetanus toxoid booster needs to be given only once every 10 years to persons who have re-
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When tetanus is suspected, a careful irnmunization history should be obtained. Tetanus is unlikely if the patient has received a complete primary series of toxoid injections with booster doses every 10 years and has a detectable serum titer of antitetanus antibody. Levels of antitetanus antibody of 0.01 IUIml are generally considered protective, although there have been occasional reports of patients with higher antibody concentrations who acquired tetanus. A previous history of' tetanus does not exclude the possibility of tetanus because exposure to the toxin in this fashion is insufficient to confer immunity.'"
1. Human tetanus immune globulin (HTIG) Administer HTIG 500 u. intramuscularly 2. Lorazepam Administer in 2 mg doses to control spasms and for sedation. If spasms are not controlled by lorazepam, neuromuscular blockade with vecuronium 6 to 8 mglhour is recommended 3. Airway management Endotracheal intubation followed by tracheostomy, if necessary, to assure adequate ventilation during tetanic spasms 4. Metronidazole Give 500 mg intravenously every 6 hours for 10 days
5. Debridement If a contaminated wound is identified, surgical debridement is recommended 6. Hypersympathetic state Labetalol 0.25 to 1.O mglmin is recommended for treat-
ment 7. Immunization Active immunization with tetanus toxoid should be initiated as outlined in the text
ceived a cornplete primary immunization. For all other wounds, a booster is recommended if the patient has not received tetanus toxoid within the preceding 5 years. Patients with unknown immunization histories should receive a complete series of' tetanus toxoid injections." At least three injections of absorbed toxoid (either 'I'D o r DTP) must be given, not less than 1 month apart, to ensure immunity from tetanus for at least 5 years. Any patient with a wound predisposing to tetanus and an unknown immunization status should receive a n intramuscular injection of' 250 U of H'I'IG.'" Patients who have recovered from tetanus must be actively immunized with tetanus toxoid as outlined previously. T h e immunization status of all adults should be routinely reviewed. T h e C I X reconlmends booster doses of' FrDat mid-decade ages-that is, at 15 years, 25 years, 35 years, and so on."
I he assistarice 01' Linda Hagan arid T h o m a s P. Bleck, M.1). in the preparation of this manuscript is 7
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gratefully a c k n o w l e d g e d .
REFERENCES 1. Weinsteitr I.. 'l'etanus. N Erigl J Med 1973;289:1293-6 2. llabet-rnantr E. 'lktanus. In: Vinkeri P.1, Bruyn GW, cds. Handbook of clinical neurology. An~stcrdam,Elsevicl1078;49 1-547
3. Price DL. Neurons and biological toxins. Presented at the American Academy of Neurology, April 25, 1982 4. 'l'etarius-United States, 1982-84. MMWK 1985;34: 602-1 l 5. Sutter KW, Cochi SI., Brink EW, Sirotkin B1. Assessment of vital statistics and surveillance data for monitoring tetanus mortality, United States, 1979-1984. Am J Epidemiol 1990,131: 132-42 6. Advisory Committee o n Immunization Practices (1985). Diphtheria, tetanus, and pertussis: Guidelines for vaccine prophylaxis and other preventive measures. MMWR 34:405-26 7. Ruhen FL., NagelJ, Fireman P. Antitoxin responses in the elderly to tetanus-diphtheria (.I'D) imn~unization.Arn 1 Epidemiol 1978; 108: 145-9 8. Weiss BP, Strassburg MA, Feeley JC. Tetanus and diphthet-ia inrmunity in an elderly population in Los Angeles County. At11 J I'uhlic Health 1983;73:802-4 9. llathcway (:I.. Bacterial sources of clostridial neurotoxins. In: Sinipson LL., ed. Botulinum neurotoxin and tetanus toxin. San Diego, Academic Press, 1989:3-24. 10. Mcllanby ,I, Green J . Iiow does tetanus toxin act? Neuroscience 198 l;6:28 1-300 I I. B i z ~ i n iB. Axoplasnric trampot-t and transsyriaptic movement of tetanus toxin. In: Sirripson LL, ed. Rotulinum neurotoxin and tetanus toxin. San Diego, Academic Press, 1'.)89:203-29 12. Griffin JW. Biological neurotoxins. Presented at the Atnet-icari Academy of Neurology, April 24, 1983 13. D i m p k l W, Huang KI'C, Habermann E. Gangliosides in nervous tissue cultures and binding of 'ml-labelled tetanus toxin, a neuronal marker. J Neurochern 1977;29:329-34 14. Yavin E, liabig WH. Binding of tetanus toxin to somatic neural hybrid cells with varying ganglioside composition. ,I Neurochem 1984;42: 13 13-20 15. Yavitr El. Gangliosides mediate association of tetanus toxin with neural cells in culture. Arch Biochem Biophys 1984;230: l2IJ-37 16. Stoeckel K , Schwab ME, .l'hoenen H . Kole of gangliosides in the uptake and retrograde axonal transport of cholera and tetanus toxin as compared to nerve growth factor arid wheat gel-nr agglutinin. Brain Res 1977; 132:273-85. 17. Zirnmerman~tJM, I'if'faretti JC. Interaction of tetanus toxin a n d toxoitl with cultured neuroblastoma cells. Naunyn Schtrrietlebergs Arch Pharmacol 1977;296: 271-7 18. Stoerkel K , Schwah M , T h o e n e n H . Comparison between the retrogradc axonal transport of nerve growth factor and tetanus toxin in motor, sensory a n d adrenergic neurons. Brain Kes 1975;W: 1-16 19. Wellhonel- H H , Erdmann G , Wiegand H . Intraaxonal and extt-aaxonal ascent of tetanus toxin. Proceedings of'the IV Intertratiorial Conference on 'l'etanus, Dakar, April 6-12, pp 159-61 20. Schwah ME, 'I'hoerren H . Electron nricroscopic evidence for a transsynaptic rnigl-atiorr of tetanus toxin in spinal cord n r o t o n e ~ r o n s :a11autoradi~gl-aphicand n101-phonrctric study. Brain Kes 1976; 105:2 13-27 21. Schwah ME, Thoenen If. Selective transsynaptic migration of tetanus toxin after retl-ograde axonal transport in peripheral sympathetic nerves: a comparison with nerve growth factor. Brain Kes 1977; 122:459-74 22. Schwab ME, Suda K, l'hoenen FI. Selective retrograde transsyriaptic tratisfc!r of a protein, tetanus toxin, subsequent to its retrograde axotral 11-arrsport.J Cell Riol 1979:82:708-810 23. Bleck TP. Tetanus: dealing with the continuing clinical challenge. J Crit Illness 1987;2:41-52 24. Wellhoner- H H . Clostridial toxins and the central nervous system: studies o n in d u tissues. In: Sinrpson LL, ed. Botulinurri neurotoxin arid tetanus toxin. San Diego, Acaderriic Press, l989;23 1-53
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Table 1. Management of Tetanus
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30. PI-ahhu VC;. Oestcr Y'l'. Electrorr1yogra[>t1ic thangcs in skeletal muscle d u e to tetanus toxin. ,I 1'hartiiac.ol Exp 'l'her 1962; 138:241-8 3 1. Luisto M, Seppalairien A M . F.lcctroneurotnyograph~cscquclac of tetanus, a controlled study of 40 patients. Elecironiyogr Clin Neur-ophysiol 198!1;29:377-81 32. Muller H , H o r n e ~U- , ZicrskiJ, Hcrnpelmann C;. 1ritr.athecal barlofen fi)r treatment of tetanus-induced spasticity. Anesthesiology l987;66:7&9 3 3 . Hleck '1'1'. l'ctanus. In: Scheld W M , Whitley q,Iht-ack LI'I', eds. Infections o l the central ner\.orls system. New York, Kavcri Press, 1991, in press
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25. Bleck I'P. Clinical aspects o f tetanus. In: Simpson LL, cd. Botulinuni neurotoxiri and tetanus toxin. Sari I)iego, Academic Press, 3989;379-98 26. Struppler A, Struppler E, Aciarns KL). I.ocal tetanus in man. Arch Neurol 1963;s: 162-78 27. Woo E, Yu Y-L, Huang C-Y. Local tetanus rcvisiteti: electrodiagnostic study in 2 patients. Electromyogr Clin Neurophysiol 1988;28: 117-22 28. Gordon EE, Januszko DM, Kaufman L. A critical survey of stiff-man syndrome. Am J Med 1967;42:582-99 29. McQuillen MP, Tucker K, Pellegrino EL). Syndrome of subacute generalized muscular stiffness and spasm. Arch Neurol 1967: 16: 165-74
VOI.UME 11, NUMHEK 3
I I , NO. 3
S E P T E M B E R 1091
Tetanus
Tetanus is characterized by rigidity and spasm of muscles. There are four clinical forms: local, generalized, cephalic, and neonatal. Local tetanus causes rigidity of the group of muscles in close proximity to the site of infection, which is usually a contaminated wound. Generalized tetanus, the most common form o f t h e disease, usually involves bulbar and paraspinous muscles initially. Generalized tetanus is characterized by trismus, risus sardonicus, opisthotonos, difficulty swallowing, marked irritability, and restlessness. Cephalic tetanus, a rare fbr-m, follows injuries of the head o r otitis media. It is characterized by spasm and rigidity of muscles supplied by the cranial nerves. Neonatal tetanus is generalized tetanus; it usually results from contamination of the umbilicus.' T h e clinical features of tetanus are produced by the activity of the neurotoxin tetanospasmin, which is produced in contaminated wounds by Clostridium tetani. Tetanospasmin, a protoplasmic protein, is synthesized within the bacteria and is re. ~h e toxin reaches the leased on their a ~ t o l y s i s T central nervous system (CNS) by retrograde axonal transport in motor neurons. It then passes transsynaptically to bind to the presynaptic membrane on the perikaryon. Tetanus toxin prevents the release of the inhibitory neurotransmitters glycine and gamma-aminobutyric acid (GABA) from the presynaptic terminal. Muscle spasms result from the blockade of inhibitory transmitter release, and thus unopposed excitation, to the motor neurons in the spinal cord and brainstem." There are similarities and differences between tetanus toxin and botulinum toxin. Both neurotoxins are of similar molecular weight and structure and are produced by anaerobic bacteria belonging to the genus Clostridium. Both toxins block transmitter release at presynaptic sites. Botulinum toxin
acts to prevent the release of' acetylcholine from cholinergic nerve endings.' Through this mechanism of action, it prevents neuromuscular transmission, producing progressive weakness of extraocular, bulbar, respiratory, and appendicular musculature. Although both toxins act on the presynaptic terminal, tetanus toxin acts preferentially on inhibitory synapses, resulting in unopposed excitation of muscles, whereas botulinum toxin blocks neuromuscular transmission, producing flaccid paralysis.
HABITAT AND EPIDEMIOLOGY T h e organisms of C. tetani are anaerobic, spore-forming rods that grow and multiply in soil, dung, and dirt, in wet and hot climates. ,retanus bacilli enter the body through lesions of' the skin from wounds, "skin-popping" in heroin addicts, ear-piercing in west African countries, and umbilical wounds in neonates. I n some developing countries, neonates are at particular risk fix tetanus because their umbilical wounds are not sufficiently protected fr-om dirt and because o f the folklore practice of' putting soil o r cow d u n g o n umbilical wounds.' T h e occurrence of tetanus in the United States steadily declined between 1947 and 1976 because of' the routine use of tetanus toxoid; however, the number- of' cases of tetanus reported to the Centers fi)r Disease Control (CDC) has remained relatively constant in the last decade at approximately 90 cases per year.' It is estimated, however, that there are at least as many cases each year that are not reported to the C D C . V n recent years, approximately two thirds of reported cases have been in persons 50 years of age o r older. Of 253 cases of'
Associate Professor of Neurology, Indiana Univcr-sity School ol Medicir~c,Indianapolis, Ir~tiiana Reprint requests: Dr. Roos, Department of Neurology, Irltlia~laUnivrrsity School o f h.letlicinc, 1001 West 10th Street, Incliariapolis, IN 16202 Chpyriglit O 1991 by Thierne Medical Publishers, In c... 381 Pal-k Avenue Sourlr, New E'ork, N\r' 100 16. All rights reserved.
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Karen L. Roos, M D
MICROBIOLOGY
(:. tetarii in an early stage possesses a single cilium at one end. As the bacterium grows, it is surrounded by several cilia, which are gradually lost during aging. After 2 to 1 0 days in culture, the spores of the bacterium become prominent, appearing at one o r both ends as round bodies.' At this stage, the bacteria have the appearance of a drumstick o r a squash racket with one o r two spores at the terminal end of the rod.' While the l~acteriumis gram-positive in young cultures (less than 18 hours old), it is usually gram-negative in older cultures, although it may retain some grarnpositive slairiirig in portions near the spore." .l'etanus toxin is synthesized within the bacterium and is released o n its autolysis.' C. tetarii may not be isolated by culture from an infected wound unless pieces of dead tissue are taken from deep within the wound. T h e identification of C. tetani by cul-
ture and the detection oftetanus toxin are not necessary to make the diagnosis because the clinical manifestations arid course of the disease are so character-istic."
MECHANISM OF ACTION OF TETANUS TOXIN Tetanus toxin produces spasticity by blocking inhibitory neurotransmitter release from presynaptic nerve terminals that synapse on alpha motor neurons in the spinal cord and brainstem, and it causes sympathetic nervous system overactivity by blocking inhibitory synapses in preganglionic neurons in the intern~etiiolateralcell column of the thoracic spinal cor~1.l.~'' 'Tetanus toxin is transported by retrograde axonal transport in motor neurons from its site of formation in a wound infected by C . tetani to its site of action, the motor neuron cell bodies in the ventral gray of the spinal cord and brainstem." There is no evidence that any significant amount of tetanus toxin reaches the CNS directly via the bloodstream, probably because of the blood-brain barrier. I " In local tetanus, toxin travels only in the peripheral nervcs supplying the affected muscles, and rigidity is confined to those muscles. I n generalized tetanus, toxin enters the CNS initially along peripheral nerves supplying the infected muscle but subsequently reaches other motor nerve terminals throughout the body via the bloodstream. Although toxin can enter vessels leading to the CNS, it cannot escape from the vessels because of the blood-brain barrier. Instead, the circulating toxin leaks from the permeable intramuscular vessels and in this way diffuses to reach nerve terminals, where it is subsequently taken u p arid carried by retrograde axonal transport to the alpha motor neuron cell bodies" (Fig. 1). This mechanism of toxin spread results in generalized tetanus, with involvement of' facial muscles followed by trunk and then limb musculature. .l'his sequence of muscle involvement is explained by the length of the neural pathways involved in transport. Assuming a n equal rate of transport in the different nerves, and given that the nerves to the facial muscles are the shortest and those to the limbs are the longest, the toxin will produce rigidity in the facial muscles first and the limbs last."'." 'The result is descending o r generalized tetanus. 'l'he individual steps from the uptake by peripheral nerve terminals to the blockade of inhibitory neurotransmitter release will be reviewed.
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tetanus reported to the C1)C from 1982 through 1984, age was known in 224, of whom 71% were aged 50 o r older, 25% were 20 to 49 years old, and 3% were 1 month to 19 years old.' I n 72%) of cases, tetanus occurred after an acute injury, either- a puncture wound o r a laceration.' 'l'he acute injury was incurred indoors in 415% of cases, contracted in gardening arid other outdoor activities in 39%#,the result of major trauma in 4 % , animal-related in 476, and fr-om other o r unknown circumstances in 12% of cases. Chronic wounds such as skin ulcers, abscesses, o r gangrene were the source of tetanus in 21% of cases, whereas in 2%) tetanus was attributed to parenteral d r u g abuse. In 7%)of patients, the source of' tetanus was unknown..' Neonatal tetanus occurred in infants born in poor hygienic conditions to inadequately immunized mothers. (Women who are immunized against tetanus confer protection to their infants through placental transfer of maternal antibody)." 'The mean incubation period for the 142 patients with a known interval between injury and onset of tetanus was 8 days.4 T h e small number of cases of' tetanus in persons 5 to 19 years of age in the United States is attributed to the childhood vaccination program and the requirement of primary immunization against tetanus for entry into school. T h e high incidence of tetanus in persons aged 50 years arid older is attributed to the decrease in immunity with age. Serologic test surveys since 1977 have demonstrated a lack of' protective levels of tetanus antitoxin antit~odyin 49 to 66%:of persons 60 years of' age and older. '.'-"
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Figure 1. Tetanus toxin diffuses out of intramuscular arteries to reach peripheral nerve terminals where it is carried by retrograde axonal transport to the cell body of the alpha motor neuron.
UPTAKE OF TOXIN BY PERIPHERAL NERVE TERMINALS
'Tetanus toxin reaches the alpha motor neuron cell bodies in the spinal cord and brainstem by retrograde axonal transport, which begins in muscles with the uptake of toxin in peripheral nerve terminals. Tetanus toxin appears to bind to neuronal membranes at a receptor, but the exact biochemical nature of the tetanus toxin receptor is not known. Tetanus toxin binds to neuronal membranes but not glial membranes, and gangliosides in neuronal membranes are part of the tetanus toxin receptor. T h e evidence for this is as follows: (1) Neuronal cell lines that lose long-chain gangliosides through serial culturing d o not bind tetanus toxin;",l".14 (2) the addition of exogenous gangliosides to the culture results in binding of tetanus toxin by nerve cells;~~,~:i,~.5 and (3) when toxin is first mixed with
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gangliosides, its uptake into nerve terminals is reduced, presuniably because the receptor-binding site on the toxin molecule is occupied by gangliosides."'.l%embrane ganglioside binding is an initial step in the activity of some hormones and in the mechanism of action of another bacterial toxin, cholera toxin. 'Tetanus and cholera toxin bind to the same receptor in thyroid plasma membranes as does thyroid-stimulating hormone (TSH), suggest-
ing a similarity in these membrane receptors. However, neuronal membranes are better at binding tetanus toxin than TSH, whereas the reverse is true for thyroid membranes, suggesting some tiifferences between these membrane receptors."' A second tetanus toxin receptor, a gangliosideindependent receptor, has also bcen demonstrated. Tetanus toxin may require two receptors, a ganglioside-dependent receptor for initial binding and a ganglioside-independent receptor for the biologic activity of tetanus toxin." ZNTRA-AXONAL ASCENT OF TOXIN
After binding to its receptors, the toxin-receptor complex is internalized by the axon for retrograde transport to the cell body. Tetanus toxin is transported in sensory and adrenergic rieurons as well as motor neurons. Toxin transported in peripheral sensory nerves accu~nulatesin the dorsal root ganglia; that transported by adrenergic nerves accumulates in the lateral gray of the thoracic spinal cord, where the cell bodies of preganglionic sympathetic neurons are located.lO~"T h e rate of transport for toxin in motor, adrenergic, and sensory ricurons has been calculated by Stoeckel et allx to be 7.5 mmlhr, 2.8 mmlhr, and 33 mnilhr, respectively. Toxin may ascend in the epineurium
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SEMINARS I N NEUKOLOGY
TRANSSYNAPTIC TRANSFER OF TOXIN
T h e retrograde transsynaptic transfer of tetanus toxin from the motor neuron to the presynaptic terminals has been demonstrated experimentally. Schwab and Thoenen"' demonstrated radioactivity in nerve terminals synapsing on motor neurons in the ventrolateral spinal cord of rats after intramuscular injection of "'I-tetanus toxin, particularly in animals exhibiting clinical signs of tetanus." Morphologic presynaptic changes include decreased vesicle density and a shift from round to flattened synaptic v e s i c I e ~ . ~ ~ ) ~ l ' Subsequent experiments with injection of radioactively-labeled toxin into the rat anterior eye chamber and the submandibular gland resulted in the localization of 12.8 1.1 % of the label on presynaptic terminals in superior cervical ganglion ,rhese experiments showed that toxin cells.~o.~~,n
*
transfer is mainly restricted to the synaptic region." This transsynaptic transfer appears to show some specificity fbr the tetanus toxin. Similar pat-
terns of uptake of labeled macromolecules such as nerve growth factor, wheat germ agglutinin, and phytohemagglutinin were obtained from superior cervical ganglion cell bodies; however, a retrograde transsynaptic movement to the afferent terminals similar to that of tetanus toxin was not detected. 10.1 1.21.22 TETANUS BLOCKS INHIBITORY NEUROTRANSMITTER RELEASE AT THE PRESYNAPTIC TERMINAL
After crossing the synapse, tetanus toxin acts on the presynaptic terminal, blocking the release of the inhibitory neurotransmitters glycine and GABA in the spinal cord and brainstem.1° With the loss of inhibitory input by glycinergic interneurons, the lower motor neuron activity increases resting muscle tone, producing rigidity. T h e glycinergic system also limits the spread of polysynaptic reflex activity (Fig. 2). Loss of inhibition in the polysynaptic reflex pathways results in the recruitment of more agonist muscles and the excitation, rather than inhibition, of antagonist muscles, producing the reflex spasms of tetanusz3 Patients with tetanus also develop symptoms of sympathetic overactivity, characterized by pe-
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and the perineurium of the nerve supplying the infected muscle, but it is the toxin migrating in the intra-axonal compartment that accumulates in the spinal cord.".'"
inhibitory
lnterneuron
Figure 2. Tetanus toxin blocks the release of glycine that would inhibit flexor muscles during the excitation of extensor muscles. This loss of inhibition results in the simultaneous excitation of both agonist and antagonist muscles and thus the reflex spasms of tetanus.
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SEPTI;:IMBI:'II ! 9 9 1
riods of tachycardia and hypertension. 'letanus toxin accumulates not only in motor rieur-om in the ventral gray matter, but also in the cell bodies of preganglionic sympathetic neurons in the lateral gray of'the thoracic spinal cord. 'I'he result of this loss of' inhibition in the interniediolateral cell column is a markedly elevated secretion of catecholamines by the adrenal glands and signs and symptoms of a hypersympathetic state."." Figure 3. Illustration of a tetanus patient by Sir Charles Bell (1824).
O f the four clinic;11 fi)rnis of tetanus, the local and cephalic forms have the potential to become generalized. Neonatal tetanus is usually generalized from the onset."' Fl'he incubation pm-iod is dcf'ined as the time from inoculation with C. tetani spores to the appearance of' the first symptom; it may vary from 2 days to 3 weeks. 'l'he shorter the incubation period, the worse the prognosis. T h e incubation period is fbllowed by the pwiod q f ' o ~ w t of tetanus. 'The period of' onset is defined as the interval from the first symptom to tlie first reflex spasm.':' In severe forms of tetanus, the onset of' symptoms is usually followed by generalized rigidity in less than 3 days. T h e short period of onset arid the severe syniptorns reflect the amount of toxin absorbed. I n mild cases of tetanus, in which a sniall amount oftoxin is absorbecl, the periods of' incubation and onset are long and "spinal co~ivulsions" are I-are."17etanus toxin itself does not permanently damage the CNS; however, hypoxia from tetanigcnic respiratory e~nbar~~assriierit may cause permanent deficits.' Likewise, toxin does not permanently damage muscle. Kesidual rnuscle dysfunction is caused by changes secondary to prolonged muscle contr-action.' GENERALIZED TETANUS
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Muscle stif'f'ness begins in the muscles of the head and neck. Patients i~~itially complain of pain in the ,jaw arid neck. .l'he usual presenting sign is trisrnus, which is a rigidity o f t h e masseter muscles causing an inability to open the mouth to speak o r to chew. Another early sign is risus sardonicus, a sneering grin, which is d u e to stif'f'ness of'the milscles of facial expression."' Stiffness of cervical musculature occurs early. Involvement of' pharyngeal muscles impairs swallowing.' Diffuse muscular r gidity produces opisthotonos because of' its preporitlerance in extensor muscles.' Reflex spasms, o r so-called spinal convulsions, are characteri~etl by "a sudden burst of tonic contraction of' muscle groups causing opisthotonus, flexion, and adduction of the arms, clenching of' the fists on the
thorax, and extc~isionof the lower cxtremities"' (Fig. 3). T h e spasms, which are extremely paitif'ul, are precipitated by external stimuli. Sudden spasms of' the niuscles of' respiration nlay stop respi1-atio11for 10 to 20 seconds; hypoxia may terminatc the spasm. 1,aryngeal o r pharyngeal spasnis may oI)st~-uctthe airway so that the patient feels that he is choking o r may suf'f'ocate.' Respiratory f,lilu~-eis most coninio~ilycaused by upper airway spasm 01-di;~pli~-agniatic tlysf'unction. Prior to the a c l v c ~ ~of't mechanical ventilation, respiratory failure was the niost common cause of death in teta11~1s.~~ Syniptoms of sympathetic overactivity typically begin cluring the second week of' the illness. .l7here are periods of hypertension a ~ tachycar~ d dia, profuse sweating, cardiac al-I-hythmias, and kver-, I-esemt)litig the crisis caused hy a plieochromocytoni:~.2:'Periods of' bradycar-tlia and liypotension may also occur. T h e excessive muscular activity may produc:e t'wer- and rhal~dornyolysis with sulxequent renal fiiilure. Iriaplxopriate secret i o ~ iof' antidiuretic: hol-mone may also occur. Fractures of' thoracic v e r t e h a e result f'r.0111 spasms of the tl-u~icalni~~sculature." Kecovery, which usually begins 1)). the secorid 01-third week, requires 4 weeks o r more. Coniplic;itions from overactivity of' tlie synipatkietic ner\ r o ~systerrl ~s are the most common cause of' death, although pulnionar-y f'i~ilurefrom pneunnonia . ~ n d throliit)oembolis~iimay be life-threa~ening."~As previously stated, tlie toxin itself' does not cause p e r ~ ~ i ; t ~ ineul-ologic ent sequelae, hut the complications of' hypoxia may he severe. NEONATAL TETANUS
Neonatal tetanus, like generalized tetanus, hegins i l l the muscles of the head and neck. 'I'he r~sualpresenting symptom is poor feeding."" 'Fhe inf'i~ntcannot suck, arid when a finger. is put into its mouth, its ,jaw clamps tightly. Stif'kriing of' the upper lip is also an early sign. As the niuscles of' f aclal : . expression become involved, the eyes are
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CLINICAL FORMS O F TETANUS
spasm o r rigidity in the group of muscles in close proxirriity to the wound, with superimposed intermittent, brief, intensely painful spasms. Local tetanus may remain restricted to a limb o r may become generalized. When it remairis restricted, the natural history is one of gradual resolution over a period of weeks to months.'."" CHRONIC TETANUS
closed tightly and there is a deep wrinkling of the forehead, the equivalent of' risus sardonicus. Opisthotonos may be so severe in the neonate that the heels may come close to touching the back of the head. In the less severe fbrm, the legs are hyperextended, the arms tlexed, and the fists tightly closed' (Fig. 4). Kespir-atory arrest caused by pharyngeal and respiratory muscle spasm is a very common complication of ~ieoliataltetanus. Periods of cyanosis arid apriea may occur, with o r without spasms. Electrolyte imbalance, hypothermia, and cardiovasc:i~larshock are frequent complications. CEPHALIC TETANUS
Cephalic tetanus involves the riiuscles supplied by one o r more cranial nerves. It follows an injury to the head o r neck and has a short incubation period of' I o r 2 days. T h e facial nerve is affected most often, with turrowing of'ttie forehead, blephwospasm, and involuntary retraction of'thc corner of' the rnouth. Spasm of' muscles of fjcial expression may be accompanied by paralysis of voluntary movement. 'I'he signs of' hypoglossal arid pharyngeal nerve involvement are dysarthria, dysphagia, and spasnis o f t h e tongue arid throat. Ocular nerve involvement is characterized by diplopia, strabismus, ptosis, miosis, o r mydl-iasis. Tetanus affecting the vagal nerve has been reported, with signs of 1,radycarclia and salivation.'.'" Cephalic tetanus nlay I-apicllyevolve into generalized tctanus. LOCAL TETANUS
1,ocal tetanus is lirnitcd to the extremity in which there is a mntarninated wound." l ' h e patient's initial compliant is stiffness of the rnuscles in that extr-eniity with voluntary movement. This is fbllowed by the development of a continuous
Electrornyography (EMG) is useful in establishing the diagnosis of tetanus anti in distinguishing it from other disorders of muscle stiffness. T h e characteristic EMG changes in local tetanus are: (1) an exaggerated F-response, (2) an absent o r shortened silent period, (3) simultaneous EMG activity in agonist and antagonist muscles during volitional activity, and (4) prolongation of EMG activity of the affected muscles into the period of attempted relaxation." Other EMG findings reported in tetanus include: ( I ) increased insertional activity,"" (2) tienervation changes suggesting an axonal neuropathy o f a "dying-back" type,:" and (3) increased jitter and blocking on single-fiber EMG." Chronic tetanus can be distinguished by EMG from stiff-man syndrome, in which the silent period is normal.'," In extrapyramidal rigidity, the silent period is either normal o r prolonged, there is no abnormality of' insertional activity, and there are no clenervation changes."
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Figure 4. Neonate with tetanus. (From Veronesi R, Fucaccia R. The clinical picture. In: Veronesi R, ed. Tetanus: important new concepts. Amsterdam: Excerpta Medica, 1981:183-206. Reprinted with permission.)
Tetanus that persists for more than 1 to 2 months has been called chronic tetanus. It has historically been confused with the stiff-man syndrome, which is characterized by a stif'f'ness of axial musculature with superimposed muscle spasms.?x.?!l
DIAGNOSIS 'l'he tiif'krential diagnosis of' acute muscular stif'f'ness and spasm (in addition to tetanus) includes: (1) poisoning with a glycine and GABA antagonist such as strychnine, (2) a dystonic reaction secondary to a dopalnine-blockirig agent, (3) peritonitis, (4) hypocalcernia, and (5) rabies (in patients with dysphagia). Strychnine poisoning is characterized by muscle spasms. It is not associated with the generalized rigidity between spasms that is typical of tetanus. 1)ystonic reactions, typified by an oculogyr-iccrisis, are quickly reversed with intravenous anticholinergic agents o r diphenhydramine. T h e presence of strychnine o r dopamine antagonists can be identified by biochemical analysis of serum and urine. Peritonitis is associated with rebound tenderness, abdoniirral distention, nausea, and vomiting. Chvostek's and Trousseau's signs may be elicited in patients with hypocalcemia.'"
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TREATMENT 7
7
I here are three goals of treatment in tetanus: stopping production of the toxin by surgical debridement of the wound and antibiotic therapy, neutralization of circulating toxin by the administration of antitoxin, and reversal of the loss of central inhibition caused by toxin that has reached the CNS.' SURGERY
Surgical debridement of the wound will decrease the number of bacilli and the amount o f toxin as well as the anaerobic potential of the wound. C. tetani does not grow in well-oxygenated tissue.' ANTIBIOTIC THERAPY
Antibiotics are minimally effective in the treatment of tetanus, but they have remained part of the standard therapy. They should not be used without the concomitant administration of antitoxin because autolysis of'the bacteria results in release of toxin. Although C. tetani is sensitive to penicillin, metronidazole, cephalosporins, imipenem, tetracycline, and erythromycin, metronidazole, administered intravenously in a dose of 500 mg every 6 hours for 10 days, is the recommended antibiotic for the treatment of tetanus.",'" NEUTRALIZATION OF CIRCULATING TOXIN
This step is the mainstay of therapy. Human tetanus immune globulin (HTIG) will neutralize the circulating toxin that has not yet been taken u p by motor neurons. It is administered intramuscularly. Previously, a dose of 3000 to 5000 IU was recommended. Recently, a dose of 500 IU has been established as being effective. T h e intrathecal administration of 250 U of H T I G has been shown to be superior to a 1000 U intramuscular dose; 2 12
however, the HTIG available in the United States has not been approved for intrathecal use.'" ACTWE IMMUNIZATION
Active immunization with tetanus toxoid must be given in addition to H T I G to prevent recurrent tetanus. This can be started during the acute phase of the illness or during the time of recovery. 1Ptanus-diphtheria toxoid (TD) is recommended for patients 7 years of age or older. For children under 7 years of age, an intramuscular in~ectionof DI'P (diphtheria-tetanus-pertussis) is recommended unless the pertussis vaccine is contraindicated. At least three intramuscular injections of absorbed toxoid (either T D or 1YI'P) must be given, not less than 1 month apart, to ensure immunity from tetanus for at least 5 years.'".'" REVERSAL OF THE LOSS OF CENTRAL INHIBITION PRODUCING SPASMS AND RIGIDITY
T h e benzodiazepines are the best agents to relieve spasms and rigidity. Because thev are GABA agonists, they reverse the effects of the toxin on presynaptic inhibition of spinal reflexes. Lorazepam, given in 2 mg doses, is the preferred agent because of' its long duration of action. A daily dose of 80 mg or more may be required. Large doses of intravenous benzodiazepines can produce metabolic acidosis caused by the propylene glycol vehicle; therefore these agents should be administered through a feeding tube as soon as po~sible.~" Continuous intrathecal baclofen has been successfully used in a small number of patients with generalized tetanus, but there has not been enough experience with this therapy to recommend it at this time."' Neuromuscular blocking agents are required when benzodiazepines cannot control the spasms and when mechanical ventilation is difficult. Vecuronium, in doses of 6 to 8 mglhour, is the recommended agent because it produces minimal autonomic instability. Benzodiazepines should be used with neurornuscular blocking agents to sedate the patient.:':' To treat the hypersympathetic state, combined alpha- and beta-adrenergic blockade with labetalol is recommended. It is given as a constant infusion at 0.25 to 1.0 mg/minute.*",""
TETANUS PROPHYLAXIS When wounds are minor and uncontaminated, a tetanus toxoid booster needs to be given only once every 10 years to persons who have re-
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When tetanus is suspected, a careful irnmunization history should be obtained. Tetanus is unlikely if the patient has received a complete primary series of toxoid injections with booster doses every 10 years and has a detectable serum titer of antitetanus antibody. Levels of antitetanus antibody of 0.01 IUIml are generally considered protective, although there have been occasional reports of patients with higher antibody concentrations who acquired tetanus. A previous history of' tetanus does not exclude the possibility of tetanus because exposure to the toxin in this fashion is insufficient to confer immunity.'"
1. Human tetanus immune globulin (HTIG) Administer HTIG 500 u. intramuscularly 2. Lorazepam Administer in 2 mg doses to control spasms and for sedation. If spasms are not controlled by lorazepam, neuromuscular blockade with vecuronium 6 to 8 mglhour is recommended 3. Airway management Endotracheal intubation followed by tracheostomy, if necessary, to assure adequate ventilation during tetanic spasms 4. Metronidazole Give 500 mg intravenously every 6 hours for 10 days
5. Debridement If a contaminated wound is identified, surgical debridement is recommended 6. Hypersympathetic state Labetalol 0.25 to 1.O mglmin is recommended for treat-
ment 7. Immunization Active immunization with tetanus toxoid should be initiated as outlined in the text
ceived a cornplete primary immunization. For all other wounds, a booster is recommended if the patient has not received tetanus toxoid within the preceding 5 years. Patients with unknown immunization histories should receive a complete series of' tetanus toxoid injections." At least three injections of absorbed toxoid (either 'I'D o r DTP) must be given, not less than 1 month apart, to ensure immunity from tetanus for at least 5 years. Any patient with a wound predisposing to tetanus and an unknown immunization status should receive a n intramuscular injection of' 250 U of H'I'IG.'" Patients who have recovered from tetanus must be actively immunized with tetanus toxoid as outlined previously. T h e immunization status of all adults should be routinely reviewed. T h e C I X reconlmends booster doses of' FrDat mid-decade ages-that is, at 15 years, 25 years, 35 years, and so on."
I he assistarice 01' Linda Hagan arid T h o m a s P. Bleck, M.1). in the preparation of this manuscript is 7
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gratefully a c k n o w l e d g e d .
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Table 1. Management of Tetanus
SEMINAKS I N NEUKOLOGY
SEI'7b:MREK 1991
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VOI.UME 11, NUMHEK 3
