Tetanus: Pathophysiology, Treatment, and the

Possibility of Using Botulinum Toxin against

Tetanus-Induced Rigidity and Spasms
Bjrnar Hassel 1,2
1

Norwegian Defense Research Establishment, N-2027 Kjeller, Norway; Tel.:

+47-63-807-846; Fax: +47-63-807-509
2

Department of Neurology, Oslo University Hospital-Rikshospitalet, 0027

Oslo, Norway
Received: 26 September 2012; in revised form: 25 December 2012 / Accepted: 27
December 2012 / Published: 8 January 2013

Abstract
: Tetanus toxin, the product of Clostridium tetani, is the cause of tetanus
symptoms. Tetanus toxin is taken up into terminals of lower motor neurons
and transported axonally to the spinal cord and/or brainstem. Here the
toxin moves trans-synaptically into inhibitory nerve terminals, where
vesicular release of inhibitory neurotransmitters becomes blocked, leading
to disinhibition of lower motor neurons. Muscle rigidity and spasms ensue,
often manifesting as trismus/lockjaw, dysphagia, opistotonus, or rigidity
and spasms of respiratory, laryngeal, and abdominal muscles, which may
cause respiratory failure. Botulinum toxin, in contrast, largely remains in
lower motor neuron terminals, inhibiting acetylcholine release and muscle
activity. Therefore, botulinum toxin may reduce tetanus symptoms. Trismus
may be treated with botulinum toxin injections into the masseter and
temporalis muscles. This should probably be done early in the course of
tetanus to reduce the risk of pulmonary aspiration, involuntary tongue
biting, anorexia and dental caries. Other muscle groups are also amenable
to botulinum toxin treatment. Six tetanus patients have been successfully
treated with botulinum toxin A. This review discusses the use of botulinum
toxin for tetanus in the context of the pathophysiology, symptomatology,
and medical treatment of Clostridium tetani infection.
Keywords:
tetanus; tetanospasmin; Clostridium tetani; botulinum toxin; trismus;
lockjaw; dysphagia
1. Introduction
The muscular rigidity and spasms of tetanus are caused by
tetanus toxin (tetanospasmin), which is produced by Clostridium
tetani, an anaerobic bacillus, whose spores survive in soil and
cause infection by contaminating wounds [1]. The global incidence
of tetanus has been estimated at approximately one million cases
annually [1,2]. Mortality rates from tetanus vary greatly across the
world, depending on access to healthcare, and approach 100% in
the absence of medical treatment [3]. This review discusses the
possibility of using botulinum toxin for tetanus-induced rigidity
and spasms in the context of the pathophysiology,
symptomatology, and medical treatment of Clostridium
tetani infection.

2. Pathophysiology of Tetanus Toxin

By a mechanism similar to that of botulinum toxin, tetanus toxin
is taken up into nerve terminals of lower motor neurons, the nerve
cells that activate voluntary muscles [4,5,6]. Tetanus toxin is a
zinc-dependent metalloproteinase that targets a protein
(synaptobrevin/vesicle-associated membrane proteinVAMP) that
is necessary for the release of neurotransmitter from nerve
endings through fusion of synaptic vesicles with the neuronal
plasma membrane [7]. The initial symptom of local tetanus
infection may therefore be flaccid paralysis [8,9], caused by
interference with vesicular release of acetylcholine at the
neuromuscular junction, as occurs with botulinum toxin. However,
unlike botulinum toxin, tetanus toxin undergoes extensive
retrograde transport in the axons of lower motor neurons and thus
reaches the spinal cord or brainstem [3,7]. Here, the toxin is
transported across synapses and taken up by nerve endings of
inhibitory GABAergic and/or glycinergic neurons that control the
activity of the lower motor neurons [10,11]. Once inside inhibitory
nerve terminals, tetanus toxin cleaves VAMP [11], thereby
inhibiting the release of GABA and glycine. The result is a partial,
functional denervation of the lower motor neurons, which leads to
their hyperactivity and to increased muscle activity in the form of
rigidity and spasms. It is not clear to what extent tetanus toxin in
the spinal cord and brainstem is also taken up into excitatory
nerve endings, such as those originating from the upper motor
neurons, or those that convey impulses from the muscle spindles
and constitute the sensory part of the simple, monosynaptic reflex
arc of the tendon reflexes. Experiments in cats have shown
tetanus toxin to augment central polysynaptic, but not
monosynaptic, reflexes [12], suggesting a primary effect on
inhibitory neurons. Studies in vitro and in vivo point to an early
inhibition of inhibitory nerve endings and a later, or dose-
dependent, involvement of excitatory nerve endings [13,14,15]. A
temporary reduction in the number of GABAergic nerve terminals
has been seen after injection of tetanus toxin into eye muscles of
cats [16]; thus, the effect of tetanus toxin may be both
biochemical and structural.

3. Symptomatology of Tetanus
Tetanus toxin causes hyperactivity of voluntary muscles in the
form of rigidity and spasms. Rigidity is the tonic, involuntary
contraction of muscles, while spasms are shorter lasting muscle
contractions that can be elicited by stretching of the muscles or by
sensory stimulation; they are termed reflex spasms. For instance,
rigidity of the temporal and masseter muscles leads to trismus
(lockjaw), a highly reduced ability to open the mouth. Attempts at
opening the mouth, e.g., during physical examination, may induce
spasms that cause the complete clenching of the jaws.
Tetanus is categorized into generalized, neonatal (which is a
generalized form in children less than one month), local, and
cephalic (which is tetanus is localized to the head region).
Generalized and neonatal tetanus affect muscles of the whole
body and lead to opistotonus (the backward arching of the
columna due to rigidity of the extensor muscles of the neck and
back) and may cause respiratory failure and death due to rigidity
and spasms of the laryngeal and respiratory muscles [1]. Local
and cephalic tetanus account for only a minority of cases;
however, they can develop into the generalized form.
Depending on whether it is local/cephalic or
generalized/neonatal, tetanus typically manifests as
trismus/lockjaw, risus sardonicus, dysphagia, neck stiffness,
abdominal rigidity, and opistotonus, i.e., hyperactivity of muscles
of the head, neck, and trunk. The limbs tend to be less severely
affected, but with full opistotonus there is also flexion of the arms
and extension of the legs, as in a decorticate posture. Trismus is
frequently the initial symptom in both local/cephalic and
generalized tetanus [17,18], but the disease may present in any of
the above-mentioned ways. In addition, general muscle ache, focal
flaccid paralysis, and an array of unusual symptoms reflecting
unusual patterns of neuronal inactivation, including diplopia [19],
nystagmus [20], and vertigo [21], may occur.
The action of tetanus toxin is not confined to the motor system.
Autonomic dysfunction with episodes of tachycardia, hypertension,
and sweating, sometimes rapidly alternating with bradycardia and
hypotension are common, especially in generalized tetanus
[18,22,23]. Such symptoms are paralleled by dramatic increases in
circulating adrenaline and noradrenaline [22,24], which may cause
myocardial necrosis [25]. Autonomic symptoms tend to occur a
week after the occurrence of motor symptoms. They have been
interpreted to reflect an effect of tetanus toxin on the brainstem
[24], although entry of tetanus toxin into preganglionic nerve
terminals of the sympathetic nervous system has been
demonstrated in experimental animals [26]; an effect of tetanus
toxin on these neurons would be expected to cause autonomic
dysregulation. With the advent of modern intensive care, which
has made tetanus-mediated respiratory insufficiency a treatable
condition, autonomic dysfunction has become a major cause of
death in tetanus victims [2].
Sensory nerves may also become invaded by tetanus toxin
[4,26], causing altered sensation, such as pain and allodynia
[9,27]. It is unclear where this effect takes place, since
experimental evidence suggests that the toxin is unable to pass
spinal sensory ganglia [3]. Therefore, a sensory effect of the toxin
should be peripheral. However, the vesicular release of
neurotransmitters from sensory neurons occurs centrally, in the
spinal cord or brainstem [28]. This apparent paradox may reflect
the fact that altered sensation in tetanus is predominantly seen in
the region of the head [9,27], i.e., in the area of the (cranial)
trigeminal nerve, the ganglion of which may differ from those of
spinal sensory nerves with respect to axonal transport of tetanus
toxin.
It is not known whether tetanus toxin that arrives in the
brainstem spreads to structures involved in higher functions, such
as cognition and mood regulation. Such symptoms are rarely
reported. In a recent survey of 68 patients from Ethiopia, altered
mentation was noted at an early stage in three patients, but it was
not stated whether such symptoms could be attributed to the
tetanus itself [18]. Sequelae of tetanus in the newborn include
intellectual disability [29], which may suggest an effect of tetanus
toxin on higher cerebral functions. Animal studies show clear
effects of tetanus toxin on neuronal activity after focal application
to the cerebral cortex [30], implying that if the toxin reaches the
brain in tetanus victims, higher cerebral functions may become
affected.

4. Treatment of Tetanus
Acute treatment of tetanus is based on wound cleaning and
antibiotic eradication of Clostridium tetani, e.g., with intravenous
metronidazole, 500 mg three times daily, or penicillin, 100,000
200,000 IU/kg/day [31,32]. Treatment is continued for seven to ten
days. The notion that one should avoid penicillin because of a
possible inhibition of the GABAA receptor, which could increase
muscle rigidity, does not seem to be supported by studies [31].
Tetanus antitoxin is given once intramuscularly; doses of 500 IU,
3000 IU, or higher have been used, but it is debatable whether the
higher doses are more effective [33]. The antitoxin is given to
inactivate any free tetanus toxin. The toxin that has been taken up
into nerve terminals is probably not available to the antitoxin.
Therefore, muscle symptoms may develop further, although the
clostridia have been eradicated and antitoxin has been given,
because tetanus toxin continues to be transported axonally and
trans-synaptically and to cleave VAMP. Intrathecal administration
of antitoxin, e.g. via lumbar puncture, could inactivate tetanus
toxin during its trans-synaptic transport; a meta-analysis indicated
that intrathecal administration was superior to the intramuscular
route with respect to survival [34]. Because immunity may not
develop after an episode of tetanus, vaccination is included in the
treatment.
Treatment of the muscular rigidity and spasms in tetanus is of
vital importance, since this feature of the disease often interferes
with respiration and is a likely cause of death [1,18]. Rigidity and
spasms also cause severe pain, which stimulates muscle activity.
Muscle relaxation is customarily achieved with benzodiazepines
[35], which augment the effect of GABA on the GABAA receptors of
lower motor neurons. Baclofen, which acts on GABAB receptors,
may also be effective; when given intrathecally its sedative effect
is avoided [36]. In the setting of an intensive care unit, propofol,
another GABAA receptor modulator, may be used [37], as may
non-depolarizing muscle relaxants (pancuronium, pipecuronium)
[38], which act directly on the muscle motor end plates by
competing for the acetylcholine binding site. Magnesium, a
calcium antagonist that acts both by reducing acetylcholine
release and by reducing the muscle response to acetylcholine
[39,40,41], may be effective in relieving rigidity and spasms [42].
Magnesium also seems to reduce autonomic dysfunction [42,43],
which is of importance, because anti-adrenergic drugs, especially
beta-blockers, may produce untoward effects, including cardiac
arrest [24]. Dantrolene, which binds to the ryanodine receptor in
muscle and reduces calcium mobilization and thereby muscle
contraction, is also in use [44,45].
Tetanus patients should be in a calm environment to avoid the
triggering of spasms by noise or other sensory stimulation. This
objective must be balanced against the need to avoid sensory
deprivation, which predisposes to delirium, a condition that
tetanus patients are prone to, given their often lengthy stays in
intensive care units with mechanical ventilation and treatment
with neuroactive drugs such as benzodiazepines and propofol [46].
Prophylaxis against tetanus consists of immunization with
formaldehyde-inactivated tetanus toxin (toxoid) and measures to
achieve good hygiene. For instance contamination of the umbilical
stump of the newborn is a primary cause of neonatal tetanus.
These issues are interrelated: a good immunization status in
pregnant women leads to reduction in the prevalence of neonatal
tetanus [47], because maternal anti-tetanus toxin antibodies are
transferred across the placenta to the child in utero [48].

Table 1. Summary of case reports on the use of botulinum toxin against

tetanus-induced muscle rigidity and spasms.

5. The Use of Botulinum Toxin against Tetanus-Induced Rigidity and

Spasms
Botulinum toxins enter nerve terminals of lower motor neurons
[6,7]. The toxins are zinc metalloproteinases that attack synaptic
vesicle proteins, but they do so differentially: botulinum toxin A
cleaves synaptosomal-associated protein (SNAP-25), botulinum
toxins B, D, F, and G cleave synaptobrevin (which is also attacked
by tetanus toxin); botulinum toxin C cleaves SNAP-25 and syntaxin
[7]. Compared to tetanus toxin, the botulinum toxins undergo less
axonal and trans-synaptic transport, although some transport does
seem to occur [53,54]. Therefore, the effects of botulinum toxins
remain fairly confined to the nerve terminals of lower motor
neurons, inhibiting release of acetylcholine and activation of
voluntary muscles. For this reason they may have a role in
reducing the muscular hyperactivity in tetanus patients.
In six reported cases of tetanus, all with symptom severity that
amounted to grade 3 in the Ablett symptom severity grading
system, botulinum toxin A was used successfully to control muscle
rigidity and spasms [9,45,49,50,51]. In three cases the tetanus
was cephalic or fairly local; in three it was generalized (Table 1). In
all cases beneficial effects of treatment were seen. However, only
in one patient was the treatment given within the first week after
admission to the hospital; in the remainder, botulinum toxin was
given two to eight weeks after admission, although symptom
severity was greatest in the earlier phase of the disease.
Therefore, one cannot rule out the possibility that the
improvement seen after treatment with botulinum toxin to some
extent reflected the natural history of tetanus, including
spontaneous resolution of muscle rigidity. In some cases
[45,50,51] botulinum toxin was used to treat residual muscle
rigidity that proved especially resistant to other muscle-relaxing
therapies.
In the four reports that give details on onset of action,
improvement of rigidity was noted within one to four days.
Maximal effect was reached after one to three weeks, except in
one case, in which maximal effect was seen one day after injection
of botulinum toxin (Table 1). The activity of botulinum toxin is
reported to be increased by neuronal activity [55,56].
Theoretically, the action of botulinum toxin could be more rapid in
tetanus, in which the activity of the lower motor neurons is much
increased.
Dosage varied somewhat (Table 1), but resembled those
commonly used to treat dystonia [57]. It should be noted that the
two preparations of botulinum toxin A that were used, Botox and
Dysport , are not equipotent and somewhat difficult to compare
[52].
Only in one patient was treatment repeated (two months after
the initial injection) [51]. In the remaining cases, the effect of
botulinum toxin apparently outlasted the symptoms of tetanus.
Only in one case was a side effect noted: a certain atrophy of the
masseter muscles after botulinum toxin injection for trismus [49].

6. Advantages and Disadvantages of Botulinum Toxin Treatment in

Tetanus
Trismus and dysphagia are early and common symptoms of
tetanus, both generalized and cephalic. They constitute major
hazards for the patient, irrespective of the threats of respiratory
failure and autonomic dysfunction described above. Normal
salivation predisposes to aspiration in a patient who cannot
swallow normally or evacuate the mouth, wherefore aspiration and
pneumonia commonly occur in tetanus [58,59]. Trismus further
interferes with eating and with oral hygiene, which is an important
issue, because the condition may last for many weeks,
endangering dental health. Lastly, trismus is associated with
involuntary tongue biting, which may be very painful [9].
The use of botulinum toxin to ameliorate tetanus-induced
trismus must be considered a safe procedure, given that the
masseter and temporalis muscles are at some distance from the
larynx; injection into the cricopharyngeal muscles to alleviate
dysphagia, in contrast, requires electromyographic guidance [45].
Treatment of trismus and dysphagia with botulinum toxin should
probably be considered at an early stage in tetanus, because it
may contribute to a more favorable course of the disease,
reducing the risk of aspiration and pneumonia, allowing dental
care, and, possibly, food intake.
Injections into the trapezius, splenius capitis, levator scapulae
and sternocleidomastoid muscles may alleviate painful neck
rigidity; care must be taken to avoid neighboring vital structures,
such as the carotid artery, and spread of botulinum toxin to the
larynx.
No information exists on the use of botulinum toxin on large
truncal muscles in tetanus, such as the abdominal and erector
spinae muscles, which are affected in generalized tetanus.
Successful use of botulinum toxin to treat hyperactivity of
abdominal muscles has been reported in Parkinsons disease [60]
and dystonia [61]. Botulinum toxin has been used for back pain
syndromes with injection of the toxin into several levels of the
erector spinae muscles in the L1L5 area [62]. The total dose of
botulinum toxin A (Botox ) in these cases was 240500 IU. From
such reports it seems feasible to use botulinum toxin in large
truncal muscles affected by tetanus, although it must be
emphasized that no clinical experience with such treatment has
been published.
Additional advantages of botulinum toxin in the treatment of
tetanus include the reduced need for muscle relaxants that affect
consciousness [63] and the long lasting effect of botulinum toxins
(>3 months) [64], which in most cases outlasts that of tetanus
toxin.
Disadvantages of the botulinum toxin approach to tetanus
include the difficulty of treating all affected muscle groups in
generalized tetanus. Even so, botulinum toxin should be
considered in generalized tetanus, in which the rigidity of certain
muscle groups may pose a special therapeutic challenge. The slow
onset of action and gradual increase in effect over one to three
weeks necessitates simultaneous treatment with other muscle-
relaxing drugs. The possibility of overdosing, the evidence of
which may become manifest days after injection of botulinum
toxin, makes it important to monitor patients closely. The
protracted effect of botulinum toxin [64] implies that such side
effects may be of some duration. A main obstacle to the use of
botulinum toxin for tetanus may prove to be the cost of treatment,
especially in generalized tetanus, in which large doses may be
needed to reduce rigidity and spasms of large muscles.

7. Conclusions
There is limited experience with the use of botulinum toxin for
the treatment of muscle rigidity and spasms in tetanus. However,
from a few published case reports it would seem that such
treatment is useful. This may be especially true for trismus, which
constitutes a major problem in itself, predisposing to pulmonary
aspiration, painful, involuntary tongue biting, anorexia, and dental
caries. The treatment of trismus with botulinum toxin is probably a
fairly safe procedure, since injection into the masseter and
temporalis muscles can be achieved without endangering
neighboring vital structures. However, the possibility of
complications caused by distant spread of the toxin must be kept
in mind. There is a general lack of randomized clinical trials with
respect to both antibiotic [31,32] and muscle-relaxing therapies
[35] in tetanus. It is to be hoped that the potential usefulness of
botulinum toxin in the treatment of tetanus will lead to its
evaluation in clinical trials.