Chapter 238 ◆ Tetanus (Clostridium tetani) 1549

Chapter 238
Tetanus (Clostridium
tetani)
Mark R. Schleiss

ETIOLOGY
Tetanus is an acute, spastic paralytic illness caused by a neurotoxin
produced by Clostridium tetani. Thus, tetanus can be considered more
as a toxin-mediated process than an acute infectious process, since
there are few, if any, symptoms elicited by the presence of replicating
microorganisms or host inflammatory response. Unlike other pathogenic
clostridia species, C. tetani is not a tissue-invasive organism and instead
causes illness through the toxin, tetanospasmin, more commonly referred
to as tetanus toxin. Tetanospasmin is the 2nd most poisonous substance
known, surpassed in potency only by botulinum toxin. The human
lethal dose of tetanus toxin is estimated to be 10−5 mg/kg.
Clostridium tetani is a motile, gram-positive, spore-forming obligate
anaerobe. The organism’s natural habitat worldwide is soil, dust, and
the alimentary tracts of various animals. C. tetani forms spores terminally,
with a classic morphologic appearance resembling a drumstick or tennis
racket microscopically. The formation of spores is a critical aspect of
the organism’s persistence in the environment. Spores can survive boiling
but not autoclaving, whereas the vegetative cells are killed by antibiotics,
heat, and standard disinfectants.

EPIDEMIOLOGY
Tetanus occurs worldwide and is endemic in many developing countries,
although its incidence varies considerably. Public health efforts in recent
years have had an impressive impact on tetanus-associated mortality,
although many challenges remain. Approximately 57,000 deaths were
caused by tetanus globally in 2015. Of these, approximately 20,000 deaths
occurred in neonates and 37,000 in older children and adults. Most
mortality from neonatal (or umbilical) tetanus occurs in South Asia
and Sub-Saharan Africa (Fig. 238.1). Mortality in adults is largely caused
by maternal tetanus, which results from postpartum, postabortal, or
postsurgical wound infection with C. tetani. Reported tetanus cases
in the United States have declined >95% since 1947, and deaths from
tetanus have declined by >99% in that same period. From 2009 through
2015, a total of 197 cases and 16 deaths from tetanus were reported in
the United States. The majority of U.S. childhood cases of tetanus have
occurred in unimmunized children whose parents objected to vaccination.
Most non-neonatal cases of tetanus are associated with a traumatic
injury, often a penetrating wound inflicted by a dirty object such as a
nail, splinter, fragment of glass, or unsterile injection. Tetanus may also
occur in the setting of illicit drug injection. The disease has been associ-
ated with the use of contaminated suture material and after intramuscular
injection of medicines, most notably quinine for chloroquine-resistant
falciparum malaria. The disease may also occur in association with
animal bites, abscesses (including dental abscesses), ear and other body
piercing, chronic skin ulceration, burns, compound fractures, frostbite,
gangrene, intestinal surgery, ritual scarification, infected insect bites,
and female circumcision. Rarely, cases may present to clinical attention
without an antecedent history of trauma.

PATHOGENESIS
Tetanus typically occurs after spores (introduced by traumatic injury)
germinate, multiply, and produce tetanus toxin. A plasmid carries the
toxin gene. Toxin is produced only by the vegetative cell, not the spore.
It is released after the vegetative phase of replication, with replication
occurring under anaerobic conditions. The low oxidation-reduction
potential of an infected injury site therefore provides an ideal environment
for transition from the spore to the vegetative stage of growth. Following
bacterial cell death and lysis, tetanospasmin is produced. The toxin has

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1549.e2 Part XVI ◆ Infectious Diseases

Keywords
Arthus reaction
C. tetani
immunization
lockjaw
maternal tetanus
neonatal tetanus
opisthotonos
rabies
risus sardonicus
tetanus toxin
TIG
trismus
umbilical tetanus

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1550 Part XVI ◆ Infectious Diseases
Elimination status
MNT eliminated since 2000
MNT not eliminated
Eliminated prior to 2000
Fig. 238.1 Global elimination status of maternal and neonatal tetanus (MNT). (From World Health Organization: Maternal and neonatal tetanus
(MNT) elimination. http://www.who.int/immunization/diseases/MNTE_initiative/en.)
no known function for clostridia in the soil environment where they
normally reside. Tetanus toxin is a 150 kDa simple protein consisting
of a heavy (100 kDa) and a light (50 kDa) chain joined by a single
disulfide bond. Tetanus toxin binds at the neuromuscular junction and
enters the motor nerve by endocytosis, after which it undergoes retrograde
axonal transport, facilitated by dyneins, to the cytoplasm of the
α-motoneuron. In the sciatic nerve, the transport rate was found to be
3.4 mm/hr. The toxin exits the motoneuron in the spinal cord and next
enters adjacent spinal inhibitory interneurons, where it prevents release
of the neurotransmitters glycine and γ-aminobutyric acid (GABA).
Tetanus toxin thus blocks the normal inhibition of antagonistic muscles
on which voluntary coordinated movement depends; as a consequence,
affected muscles sustain maximal contraction and cannot relax. This
aspect of pathogenesis led to the term lockjaw, classically applied to
the clinical manifestations of tetanus in the affected individual. The
autonomic nervous system is also rendered unstable in tetanus.
The phenomenal potency of tetanus toxin is enzymatic. The 50 kDa
light chain (A-chain) of tetanus toxin is a zinc-containing endoprotease
whose substrate is synaptobrevin, a constituent protein of the docking
complex that enables the synaptic vesicle to fuse with the terminal
neuronal cell membrane. The cleavage of synaptobrevin is the final
target of tetanus toxin, and even in low doses the neurotoxin will inhibit
neurotransmitter exocytosis in the inhibitory interneurons. The blockage
of GABA and glycine causes the physiologic effects of tetanus toxin.
The 100 kDa heavy chain (B-chain) of the toxin contains its binding
and internalization domains. It binds to disialogangliosides (GD2 and
GD1b) on the neuronal membrane. The translocation domain aids the
movement of the protein across that membrane and into the neuron.
Because C. tetani is not an invasive organism, its toxin-producing
vegetative cells remain where introduced into the wound, which may
display local inflammatory changes and a mixed bacterial flora.
CLINICAL MANIFESTATIONS
Tetanus is most often generalized but may also be localized. The incuba-
tion period typically is 2-14 days but may be as long as months after
the injury. In generalized tetanus the presenting symptom in about
half of cases is trismus (masseter muscle spasm, or lockjaw). 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 intractable
spasms of facial and buccal muscles. When the paralysis extends to
abdominal, lumbar, hip, and thigh muscles, the patient may assume an
arched posture of extreme hyperextension of the body, or opisthotonos,
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with the head and the heels bent backward and the body bowed forward.
In severe cases, only the back of the head and the heels of the patient
are noted to be touching the supporting surface. Opisthotonos is an
equilibrium position that results from unrelenting total contraction of
opposing muscles, all of which display the typical boardlike rigidity of
tetanus. 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 fearful anticipation of the next tetanic
seizure. The seizures are characterized by sudden, severe tonic contrac-
tions of the muscles, with fist clenching, flexion, and adduction of the
arms and hyperextension of the legs. Without treatment, the duration
of these seizures may range from a few seconds to a few minutes in
length with intervening respite periods. 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, occasionally as high as 40°C (104°F), is common and is
caused by the substantial metabolic energy consumed by spastic muscles.
Notable autonomic effects include tachycardia, dysrhythmias, labile
hypertension, diaphoresis, and cutaneous vasoconstriction. The tetanic
paralysis usually becomes more severe in the 1st wk after onset, stabilizes
in the 2nd wk, and ameliorates gradually over the ensuing 1-4 wk.
Neonatal tetanus, the infantile form of generalized tetanus, typically
manifests within 3-12 days of birth. It presents as progressive difficulty
in feeding (sucking and swallowing), associated hunger, and crying.
Paralysis or diminished movement, stiffness and rigidity to the touch,
and spasms, with or without opisthotonos, are characteristic. The
umbilical stump, which is typically the portal of entry for the microorgan-
ism, may retain 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 the tongue and pharyngeal
musculature.
DIAGNOSIS
The picture of tetanus is one of the most dramatic in medicine, and
the diagnosis may be established clinically. The typical setting is an
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unimmunized patient (and/or mother) who was injured or born within
the preceding 2 wk, who presents with trismus, dysphagia, generalized
muscle rigidity and spasm, and a clear sensorium.
Results of routine laboratory studies are usually normal. A peripheral
leukocytosis may result from a secondary bacterial infection of the
wound or may be stress-induced from the sustained tetanic spasms.
The cerebrospinal fluid analysis is normal, although the intense muscle
contractions may raise intracranial pressure. Serum muscle enzymes
(creatine kinase, aldolase) may be elevated. Neither the electroencepha-
logram nor the electromyogram shows a characteristic pattern, although
EMG may show continuous discharge of motor subunits and shortening,
or absence of the silent interval normally observed after an action
potential. An assay for antitoxin levels is not readily available, although
a serum antitoxin level of ≥0.01 IU/mL is generally considered protective
and makes the diagnosis of tetanus less likely. C. tetani is not always
visible on Gram stain of wound material and is isolated by culture in
only approximately 30% of cases. The spatula test is a simple diagnostic
bedside test that involves touching the oropharynx with a spatula or
tongue blade. Normally this maneuver will elicit a gag reflex, as the
patient tries to expel the spatula (negative test). If tetanus is present,
patients develop a reflex spasm of the masseter muscles and bite the
spatula (positive test). This bedside diagnostic maneuver is said to have
a high sensitivity and specificity.
Differential Diagnosis
Florid and generalized tetanus is typically not mistaken for any other
disease. However, trismus may result from parapharyngeal, retropha-
ryngeal, or dental abscesses or rarely from acute encephalitis involving
the brainstem. Either rabies or tetanus may follow an animal bite, and
rabies may manifest as trismus with seizures. Rabies may be distinguished
from tetanus by hydrophobia, marked dysphagia, predominantly clonic
seizures, and pleocytosis (see Chapter 300). Although strychnine
poisoning may result in tonic muscle spasms and generalized seizure
activity, it seldom produces trismus, and unlike in tetanus, general
relaxation usually occurs between spasms. Hypocalcemia may produce
tetany that is characterized by laryngeal and carpopedal spasms, but
trismus is absent. Occasionally, epileptic seizures, narcotic withdrawal,
or other drug reactions may suggest tetanus.
TREATMENT
Management of tetanus requires eradication of C. tetani, correction of
wound environment conditions conducive to its anaerobic replication,
neutralization of all accessible tetanus toxin, control of seizures and
respiration, palliation, provision of meticulous supportive care, and
prevention of recurrences.
Surgical wound excision and debridement are often needed to remove
the foreign body or devitalized tissue that created the anaerobic growth
conditions necessary for vegetative replication. Surgery should be
performed promptly after administration of human tetanus immuno-
globulin (TIG) and antibiotics. Excision of the umbilical stump in the
neonate with tetanus is no longer recommended.
Tetanus toxin cannot be neutralized by TIG after it has begun its
axonal ascent to the spinal cord. However, TIG should be given as soon
as possible, toward the goal of neutralizing toxin that diffuses from the
wound into the circulation before the toxin can bind at distant muscle
groups. The optimal dose of TIG has not been determined. Some experts
recommend a single intramuscular injection of 500 units of TIG to
neutralize systemic tetanus toxin, but total doses as high as 3,000-6,000 U
are also recommended. Infiltration of part of the dose of TIG into the
wound is recommended by the Red Book Committee of the American
Academy of Pediatrics, although the efficacy of this approach has not
been proved. If TIG is unavailable, use of human intravenous immu-
noglobulin may be necessary. IVIG contains 4-90 U/mL of TIG; the
optimal dosage of IVIG for treating tetanus is not known, and its use
is not approved for this indication. In parts of the world where it is
available, another alternative may be equine-derived tetanus antitoxin
(TAT). This product is no longer available in the United States. A dose
of 1,500-3,000 U is recommended and should be administered after
appropriate testing for sensitivity and desensitization, since up to 15%
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Chapter 238 ◆ Tetanus (Clostridium tetani) 1551
of patients given the usual dose of TAT will experience serum sickness.
The human-derived immunoglobulins are much preferred because of
their longer half-life (30 days) and the virtual absence of allergic and
serum sickness adverse effects. Results of studies examining the potential
benefit of intrathecal administration of TIG are conflicting. The TIG
preparation available for use in the United States is neither licensed
nor formulated for intrathecal or intravenous use.
Oral (or intravenous) metronidazole (30 mg/kg/day, given at 6 hr
intervals; maximum dose, 4 g/day) decreases the number of vegetative
forms of C. tetani and is currently considered the antibiotic of choice.
Parenteral penicillin G (100,000 U/kg/day, administered at 4-6 hr inter-
vals, with a daily maximum 12 million U) is an alternative treatment.
Antimicrobial therapy for a total duration of 7-10 days is recommended.
Supportive care and pharmacologic interventions targeted at control
of tetanic spasms are of critical importance in the management of tetanus.
Toward this goal, all patients with generalized tetanus should receive
muscle relaxants. Diazepam provides both relaxation and seizure control.
The initial dose of 0.1-0.2 mg/kg every 3-6 hr intravenously is subse-
quently titrated to control the tetanic spasms, after which the effective
dose is sustained for 2-6 wk before a tapered withdrawal. Magnesium
sulfate, other benzodiazepines (midazolam), chlorpromazine, dantrolene,
and baclofen are also used. Intrathecal baclofen produces such complete
muscle relaxation that apnea often ensues; as with most other agents
listed, baclofen should be used only in an intensive care unit setting.
Favorable survival rates in generalized tetanus have been described
with the use of neuromuscular blocking agents such as vecuronium
and pancuronium, which produce a general flaccid paralysis that is
then managed by mechanical ventilation. Autonomic instability is
regulated with standard α- or β-adrenergic (or both) blocking agents;
morphine has also proved useful.
SUPPORTIVE CARE
Meticulous supportive care in a quiet, dark, secluded setting is most
desirable. Because tetanic spasms may be triggered by minor stimuli,
the patient should be sedated and protected from all unnecessary sounds,
sights, and touch, and 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 tracheostomy kit should be immediately
at hand for unintubated patients. Endotracheal intubation and suctioning
easily provoke reflex tetanic seizures and spasms, so early tracheostomy
should be considered in severe cases not managed by pharmacologically
induced flaccid paralysis. Therapeutic botulinum toxin has been used
to overcome trismus.
Cardiorespiratory monitoring, frequent suctioning, and maintenance
of the patient’s 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 may be of value, but it must be
balanced with the risk of hemorrhage. Enoxaparin would be an alternative
for the patient for whom deep vein thrombosis prophylaxis is warranted.
COMPLICATIONS
The seizures and the severe, sustained rigid paralysis of tetanus predispose
the patient to many complications. Aspiration of secretions with attendant
pneumonia is an important complication to consider and may be present
at initial diagnosis. Maintaining airway patency often mandates endo-
tracheal 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 described as complications. Excessive
use of muscle relaxants, which are 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
maintenance of intravascular volume needs.
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 Table 238.1 Tetanus Vaccination and Immune Globulin Use in Wound Management
CLEAN, MINOR WOUNDS ALL OTHER WOUNDS*
HISTORY OF ABSORBED
† ‡
TETANUS TOXOID DTaP, Tdap, or Td TIG DTaP, Tdap, or TD† TIG‡
Uncertain or <3 doses Yes No Yes Yes
≥3 doses No if <10 yr since last dose of tetanus-containing No No if <5 yr since last tetanus-containing No
vaccine vaccine§
Yes if ≥10 yr since last dose of tetanus-containing No Yes if ≥5 yr since last tetanus-containing No
vaccine vaccine dose
*Such as, but not limited to, wounds contaminated with dirt, feces, and saliva; puncture wounds; avulsions; and wounds resulting from missiles, crushing, burns, and
frostbite.
†
DTaP is used for children <7 yr old. Tdap is preferred over Td for underimmunized children ≥7 yr old who have not received Tdap previously.
‡
Intravenous immune globulin should be used when TIG is unavailable.
§
More frequent boosters are not needed and can accentuate adverse events.
DT, Diphtheria and tetanus toxoid vaccine; DTaP, combined diphtheria toxoid–tetanus toxoid–acellular pertussis vaccine; Td, tetanus toxoid and reduced
diphtheria toxoid vaccine; Tdap, tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine; TIG, tetanus immune globulin.
Data from Tetanus (lockjaw). In Kimberlin DW, Brady MT, Jackson MA, Long SS, editors: Red book: 2015 report of the Committee on Infectious Diseases, ed 30, Elk
Grove Village, IL, 2015, American Academy of Pediatrics.

PROGNOSIS
Recovery in tetanus occurs through regeneration of synapses within
the spinal cord that results in restoration of muscle relaxation. Interest-
ingly, an episode of tetanus does not result in the production of toxin-
neutralizing antibodies, presumably because the infinitesimally small
amounts of toxin required to cause disease are not sufficient to elicit
an immune response. Therefore, active immunization with tetanus toxoid
during convalescence and/or at discharge, with provision for completion
of the primary vaccine series, is mandatory.
The most important factor that influences outcome is the quality
of supportive care. Mortality is highest in very young and very old
patients. A favorable prognosis is associated with a long incubation
period, absence of fever, and localized disease. An unfavorable prognosis
is associated with onset of trismus <7 days after injury and onset of
generalized tetanic spasms <3 days after onset of trismus. Sequelae
of hypoxic brain injury, especially in infants, include cerebral palsy,
diminished mental abilities, and behavioral difficulties. Most fatalities
occur within the 1st wk of illness. Reported case fatality rates for
generalized tetanus are 5–35%, and for neonatal tetanus they extend
from <10% with intensive care treatment to >75% without it. Cephalic
tetanus has an especially poor prognosis because of breathing and
feeding difficulties.
PREVENTION
Tetanus is an entirely and easily preventable disease. A serum antibody
titer of ≥0.01 U/mL is considered protective. Active immunization should
begin in early infancy with combined diphtheria toxoid–tetanus
toxoid–acellular pertussis (DTaP) vaccine at 2, 4, 6, and 15-18 mo of
age, with boosters at 4-6 yr (DTaP) and 11-12 yr (Tdap) of age, and at
10 yr intervals thereafter throughout adult life with tetanus and reduced
diphtheria toxoid (Td). Immunization of women with tetanus toxoid
prevents neonatal tetanus, and pregnant women should receive 1 dose
of reduced diphtheria and pertussis toxoids (Tdap) during each pregnancy,
preferably at 27-36 wk of gestation. Recommended immunization
schedules are regularly updated (http://www.cdc.gov/vaccines/schedules).
Arthus reactions (type III hypersensitivity reactions), a localized
vasculitis associated with deposition of immune complexes and activation
of complement, are reported rarely after tetanus vaccination. Mass
immunization campaigns in developing countries have occasionally
provoked a widespread hysterical reaction.
Tetanus toxoid should always be given after a dog or other animal
bite, even though C. tetani is infrequently found in canine mouth flora.
Non-minor wounds require human TIG except those in a fully immunized
patient (i.e., ≥3 doses of adsorbed tetanus toxoid). In any other circum-
stances (e.g., patients with an unknown or incomplete immunization
history; crush, puncture, or projectile wounds; wounds contaminated
with saliva, soil, or feces; avulsion injuries; compound fractures; or
frostbite), TIG 250 units should be administered intramuscularly,
regardless of the patient’s age or weight. If TIG is unavailable, use of
human IVIG may be considered. If neither of these products is available,
3,000-5,000 units of equine-derived TAT (in regions of the world where
it is available) may be given intramuscularly after testing for hypersensitiv-
ity. Serum sickness may occur with this agent.
The wound should undergo 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 widely separated
sites. A tetanus toxoid booster (preferably Tdap) is administered to all
persons with any wound if the tetanus immunization status is unknown
or incomplete. A booster is administered to injured persons who have
completed the primary immunization series if (1) the wound is clean
and minor but ≥10 yr have passed since the last booster or (2) the
wound is more serious and ≥5 yr have passed since the last booster
(Table 238.1). Persons who experienced an Arthus reaction after a dose
of tetanus toxoid–containing vaccine should not receive Td more fre-
quently than every 10 yr, even for tetanus prophylaxis as part of wound
management. In a situation of delayed wound care, active immunization
should be started at once.
Bibliography is available at Expert Consult.

Wound Management
Tetanus prevention measures after trauma consist of inducing active
immunity to tetanus toxin and of passively providing antitoxic antibody
(Table 238.1). Tetanus prophylaxis is an essential part of all wound
management, but specific measures depend on the nature of the injury
and the immunization status of the patient. Prevention of tetanus must
be included in planning for the consequences of bombings, natural
disasters, and other possible civilian mass-casualty events.

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