Toxins 05 00073 v2

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\li993\sb200\sl-276\slmult0 \up0 \expndtw-3\charscalex100 \ul0\nosupersub\cf1\f2
\fs24 Toxins\ul0\nosupersub\cf2\f3\fs24 \ul0\nosupersub\cf3\f4\fs24 2013\ul0\no
supersub\cf2\f3\fs24 , \ul0\nosupersub\cf1\f2\fs24 5\ul0\nosupersub\cf2\f3\fs24
, 73-83; doi:10.3390/toxins5010073 \par\pard\ql \li9417\sb2\sl-230\slmult0 \up0
\expndtw-3\charscalex100 \ul0\nosupersub\cf9\f10\fs20 OPEN ACCESS \par\pard\ql \
li9111\sb145\sl-648\slmult0 \up0 \expndtw0\charscalex97 \ul0\nosupersub\cf5\f6\f
s72 toxins \par\pard\ql \li9278\sb40\sl-276\slmult0 \up0 \expndtw-3\charscalex10
0 \ul0\nosupersub\cf3\f4\fs24 ISSN 2072-6651 \par\pard\ql \li7965\sb4\sl-276\slm
ult0 \up0 \expndtw-3\charscalex100 \ul0\nosupersub\cf2\f3\fs24 www.mdpi.com/jour
nal/toxins \par\pard\ql \li993\sb64\sl-276\slmult0 \up0 \expndtw-3\charscalex100
\ul0\nosupersub\cf1\f2\fs24 Review \par\pard\qj \li993\ri1418\sb226\sl-420\slmu
lt0 \up0 \expndtw0\charscalex97 \ul0\nosupersub\cf6\f7\fs36 Tetanus: Pathophysio
logy, Treatment, and the Possibility of \up0 \expndtw0\charscalex97 Using Botuli
num Toxin against Tetanus-Induced Rigidity \line \up0 \expndtw0\charscalex98 and
Spasms \par\pard\ql \li993\sb0\sl-264\slmult0 \par\pard\ql\li993\sb45\sl-264\sl
mult0 \up0 \expndtw-5\charscalex100 \ul0\nosupersub\cf3\f4\fs24 Bjrnar Hassel \ul
0\super\cf7\f8\fs23 1,2 \par\pard\ql \li993\sb0\sl-276\slmult0 \par\pard\ql\li99
3\sb31\sl-276\slmult0 \up0 \expndtw-4\charscalex100 \ul0\super\cf8\f9\fs23 1\ul0
\nosupersub\cf2\f3\fs24 Norwegian Defense Research Establishment, N-2027 Kjell
er, Norway; \par\pard\ql \li1281\sb64\sl-276\slmult0 \up0 \expndtw-4\charscalex1
00 E-Mail: bjornar.hassel@ffi.no; Tel.: +47-63-807-846; Fax: +47-63-807-509 \par
\pard\ql \li993\sb64\sl-276\slmult0 \up0 \expndtw-3\charscalex100 \ul0\super\cf8
\f9\fs23 2\ul0\nosupersub\cf2\f3\fs24 Department of Neurology, Oslo University
Hospital-Rikshospitalet, 0027 Oslo, Norway \par\pard\qj \li993\ri1136\sb252\sl-
340\slmult0 \up0 \expndtw-4\charscalex100 \ul0\nosupersub\cf1\f2\fs24 Received:
26 September 2012; in revised form: 25 December 2012 / Accepted: 27 December 201
2 / \up0 \expndtw-5\charscalex100 Published: 8 January 2013 \par\pard\qj \li1555
\sb0\sl-340\slmult0 \par\pard\qj\li1555\ri1355\sb260\sl-340\slmult0 \up0 \expndt
w-1\charscalex100 \ul0\nosupersub\cf3\f4\fs24 Abstract: \ul0\nosupersub\cf2\f3\f
s24 Tetanus toxin, the product of \ul0\nosupersub\cf1\f2\fs24 Clostridium
tetani\ul0\nosupersub\cf2\f3\fs24 , is the cause of tetanus \up0 \expndtw-
4\charscalex100 symptoms. Tetanus toxin is taken up into terminals of lower moto
r neurons and transported \up0 \expndtw-2\charscalex100 axonally to the spinal c
ord and/or brainstem. Here the toxin moves trans-synaptically into \up0 \expndtw
-4\charscalex100 inhibitory nerve terminals, where vesicular release of inhibito
ry neurotransmitters becomes \up0 \expndtw0\charscalex104 blocked, leading to di
sinhibition of lower motor neurons. Muscle rigidity and spasms \up0 \expndtw-4\c
harscalex100 ensue, often manifesting as trismus/lockjaw, dysphagia, opistotonus
, or rigidity and spasms \up0 \expndtw0\charscalex102 of respiratory, laryngeal,
and abdominal muscles, which may cause respiratory failure. \up0 \expndtw-1\cha
rscalex100 Botulinum toxin, in contrast, largely remains in lower motor neuron t
erminals, inhibiting \up0 \expndtw-1\charscalex100 acetylcholine release and mus
cle activity. Therefore, botulinum toxin may reduce tetanus \up0 \expndtw-1\char
scalex100 symptoms. Trismus may be treated with botulinum toxin injections into
the masseter and \up0 \expndtw-2\charscalex100 temporalis muscles. This should p
robably be done early in the course of tetanus to reduce \up0 \expndtw0\charscal
ex102 the risk of pulmonary aspiration, involuntary tongue biting, anorexia and
dental caries. \up0 \expndtw-1\charscalex100 Other muscle groups are also amenab
le to botulinum toxin treatment. Six tetanus patients \up0 \expndtw0\charscalex1
00 have been successfully treated with botulinum toxin A. This review discusses
the use of \up0 \expndtw0\charscalex100 botulinum toxin for tetanus in the conte
xt of the pathophysiology, symptomatology, and \up0 \expndtw-5\charscalex100 med
ical treatment of \ul0\nosupersub\cf1\f2\fs24 Clostridium tetani\ul0\nosupersub\
cf2\f3\fs24 infection. \par\pard\qj \li1555\ri1358\sb240\sl-340\slmult0 \up0 \e
xpndtw0\charscalex103 \ul0\nosupersub\cf3\f4\fs24 Keywords:\ul0\nosupersub\cf2\f
3\fs24 tetanus; tetanospasmin; \ul0\nosupersub\cf1\f2\fs24 Clostridium teta
ni\ul0\nosupersub\cf2\f3\fs24 ; botulinum toxin; trismus; \up0 \expndtw-5\cha
rscalex100 lockjaw; dysphagia
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mult0\par\pard\li993\sb70\sl-276\slmult0\fi0\tx10671 \up0 \expndtw-3\charscalex1
00 \ul0\nosupersub\cf1\f2\fs24 Toxins \ul0\nosupersub\cf3\f4\fs24 2013\ul0\nosup
ersub\cf2\f3\fs24 , \ul0\nosupersub\cf1\f2\fs24 5\tab \up0 \expndtw-3\charscalex
100 \ul0\nosupersub\cf3\f4\fs24 74\par\pard\ql \li993\sb0\sl-276\slmult0 \par\pa
rd\ql\li993\sb58\sl-276\slmult0 \up0 \expndtw-3\charscalex100 1. Introduction \p
ar\pard\qj \li993\ri635\sb252\sl-340\slmult0\fi288 \up0 \expndtw-2\charscalex100
\ul0\nosupersub\cf2\f3\fs24 The muscular rigidity and spasms of tetanus are cau
sed by tetanus toxin (tetanospasmin), which is \line \up0 \expndtw-4\charscalex1
00 produced by \ul0\nosupersub\cf1\f2\fs24 Clostridium tetani\ul0\nosupersub\cf2
\f3\fs24 , an anaerobic bacillus, whose spores survive in soil and cause infecti
on \line \up0 \expndtw-4\charscalex100 by contaminating wounds [1]. The global i
ncidence of tetanus has been estimated at approximately one \line \up0 \expndtw-
2\charscalex100 million cases annually [1,2]. Mortality rates from tetanus vary
greatly across the world, depending on \line \up0 \expndtw0\charscalex105 access
to healthcare, and approach 100% in the absence of medical treatment [3]. Thi
s review \line \up0 \expndtw0\charscalex104 discusses the possibility of using b
otulinum toxin for tetanus-induced rigidity and spasms in the \line \up0 \expndt
w-5\charscalex100 context of the pathophysiology, symptomatology, and medical tr
eatment of \ul0\nosupersub\cf1\f2\fs24 Clostridium tetani\ul0\nosupersub\cf2\f3\
fs24 infection. \par\pard\ql \li993\sb0\sl-276\slmult0 \par\pard\ql\li993\sb17\
sl-276\slmult0 \up0 \expndtw-3\charscalex100 \ul0\nosupersub\cf3\f4\fs24 2. Path
ophysiology of Tetanus Toxin \par\pard\qj \li993\ri797\sb252\sl-340\slmult0\fi28
8 \up0 \expndtw-3\charscalex100 \ul0\nosupersub\cf2\f3\fs24 By a mechanism simil
ar to that of botulinum toxin, tetanus toxin is taken up into nerve terminals of
\line \up0 \expndtw-4\charscalex100 lower motor neurons, the nerve cells that a
ctivate voluntary muscles \up0 \expndtw-4\charscalex100 [4-6]. Tetanus toxin i
s a \par\pard\qj \li993\ri635\sb0\sl-340\slmult0 \up0 \expndtw-1\charscalex100 z
inc-dependent metalloproteinase that targets a protein (synaptobrevin/vesicle-as
sociated membrane \line \up0 \expndtw0\charscalex102 protein\u8212?VAMP) that is
necessary for the release of neurotransmitter from nerve endings through \line
\up0 \expndtw0\charscalex103 fusion of synaptic vesicles with the neuronal plasm
a membrane [7]. The initial symptom of local \line \up0 \expndtw-3\charscalex100
tetanus infection may therefore be flaccid paralysis [8,9], caused by interfere
nce with vesicular release \line \up0 \expndtw0\charscalex103 of acetylcholine a
t the neuromuscular junction, as occurs with botulinum toxin. However, unlike \l
ine \up0 \expndtw-1\charscalex100 botulinum toxin, tetanus toxin undergoes exten
sive retrograde transport in the axons of lower motor \line \up0 \expndtw0\chars
calex103 neurons and thus reaches the spinal cord or brainstem [3,7]. Here, the
toxin is transported across \line \up0 \expndtw0\charscalex102 synapses and take
n up by nerve endings of inhibitory GABAergic and/or glycinergic neurons that \l
ine \up0 \expndtw-3\charscalex100 control the activity of the lower motor neuron
s [10,11]. Once inside inhibitory nerve terminals, tetanus \line \up0 \expndtw-2
\charscalex100 toxin cleaves VAMP [11], thereby inhibiting the release of GABA a
nd glycine. The result is a partial, \line \up0 \expndtw-3\charscalex100 functio
nal denervation of the lower motor neurons, which leads to their hyperactivity a
nd to increased \line \up0 \expndtw0\charscalex100 muscle activity in the form o
f rigidity and spasms. It is not clear to what extent tetanus toxin in the \line
\up0 \expndtw-4\charscalex100 spinal cord and brainstem is also taken up into e
xcitatory nerve endings, such as those originating from \line \up0 \expndtw0\cha
rscalex100 the upper motor neurons, or those that convey impulses from the muscl
e spindles and constitute the \line \up0 \expndtw-1\charscalex100 sensory part o
f the simple, monosynaptic reflex arc of the tendon reflexes. Experiments in cat
s have \line \up0 \expndtw-4\charscalex100 shown tetanus toxin to augment centra
l polysynaptic, but not monosynaptic, reflexes [12], suggesting a \line \up0 \ex
pndtw0\charscalex105 primary effect on inhibitory neurons. Studies \ul0\nosupers
ub\cf1\f2\fs24 in vitro\ul0\nosupersub\cf2\f3\fs24 and \ul0\nosupersub\cf1\f2\f
s24 in vivo\ul0\nosupersub\cf2\f3\fs24 point to an early inhibition of \line \u
p0 \expndtw-4\charscalex100 inhibitory nerve endings and a later, or dose-depend
ent, involvement of excitatory nerve endings [13-15]. \line \up0 \expndtw-1\char
scalex100 A temporary reduction in the number of GABAergic nerve terminals has b
een seen after injection of \line \up0 \expndtw-1\charscalex100 tetanus toxin in
to eye muscles of cats [16]; thus, the effect of tetanus toxin may be both bioch
emical \line \up0 \expndtw-2\charscalex100 and structural. \par\pard\ql \li993\s
b0\sl-276\slmult0 \par\pard\ql\li993\sb17\sl-276\slmult0 \up0 \expndtw-3\charsca
lex100 \ul0\nosupersub\cf3\f4\fs24 3. Symptomatology of Tetanus \par\pard\qj \li
993\ri796\sb252\sl-340\slmult0\fi288 \up0 \expndtw-4\charscalex100 \ul0\nosupers
ub\cf2\f3\fs24 Tetanus toxin causes hyperactivity of voluntary muscles in the fo
rm of rigidity and spasms. Rigidity \line \up0 \expndtw-1\charscalex100 is the t
onic, involuntary contraction of muscles, while spasms are shorter lasting muscl
e contractions \line \up0 \expndtw0\charscalex103 that can be elicited by stretc
hing of the muscles or by sensory stimulation; they are termed reflex \line \up0
\expndtw0\charscalex103 spasms. For instance, rigidity of the temporal and mass
eter muscles leads to trismus (lockjaw), a \par\pard\sect\sectd\fs24\paperw11900
\paperh16840\pard\sb0\sl-240{\bkmkstart Pg3}{\bkmkend Pg3}\par\pard\li993\sb0\sl
-276\slmult0\par\pard\li993\sb0\sl-276\slmult0\par\pard\li993\sb70\sl-276\slmult
0\fi0\tx10671 \up0 \expndtw-3\charscalex100 \ul0\nosupersub\cf1\f2\fs24 Toxins \
ul0\nosupersub\cf3\f4\fs24 2013\ul0\nosupersub\cf2\f3\fs24 , \ul0\nosupersub\cf1
\f2\fs24 5\tab \up0 \expndtw-3\charscalex100 \ul0\nosupersub\cf3\f4\fs24 75\par\
pard\ql \li993\ri792\sb282\sl-340\slmult0\tx1281 \up0 \expndtw0\charscalex105 \u
l0\nosupersub\cf2\f3\fs24 highly reduced ability to open the mouth. Attempts at
opening the mouth, e.g., during physical \line \up0 \expndtw-2\charscalex100 exa
mination, may induce spasms that cause the complete clenching of the jaws. \line
\tab \up0 \expndtw-2\charscalex100 Tetanus is categorized into generalized, neo
natal (which is a generalized form in children less than \line \up0 \expndtw0\ch
arscalex102 one month), local, and cephalic (which is tetanus is localized to th
e head region). Generalized and \line \up0 \expndtw-4\charscalex100 neonatal tet
anus affect muscles of the whole body and lead to opistotonus (the backward arch
ing of the \line \up0 \expndtw0\charscalex103 columna due to rigidity of the ext
ensor muscles of the neck and back) and may cause respiratory \line \up0 \expndt
w0\charscalex100 failure and death due to rigidity and spasms of the laryngeal a
nd respiratory muscles [1]. Local and \line \up0 \expndtw0\charscalex102 cephali
c tetanus account for only a minority of cases; however, they can de
velop into the \line \up0 \expndtw-5\charscalex100 generalized form. \par\pard
\qj \li993\ri796\sb0\sl-340\slmult0\fi288 \up0 \expndtw0\charscalex100 Depending
on whether it is local/cephalic or generalized/neonatal, tetanus typically mani
fests as \line \up0 \expndtw-2\charscalex100 trismus/lockjaw, risus sardonicus,
dysphagia, neck stiffness, abdominal rigidity, and opistotonus, \ul0\nosupersub\
cf1\f2\fs24 i.e.\ul0\nosupersub\cf2\f3\fs24 , \line \up0 \expndtw-2\charscalex10
0 hyperactivity of muscles of the head, neck, and trunk. The limbs tend to be le
ss severely affected, but \line \up0 \expndtw0\charscalex102 with full opistoton
us there is also flexion of the arms and extension of the legs, as in a decortic
ate \line \up0 \expndtw0\charscalex104 posture. Trismus is frequently the i
nitial symptom in both local/cephalic and generalized \line \up0 \expndtw-
2\charscalex100 tetanus [17,18], but the disease may present in any of the above
-mentioned ways. In addition, general \line \up0 \expndtw-2\charscalex100 muscle
ache, focal flaccid paralysis, and an array of unusual symptoms reflecting unus
ual patterns of \line \up0 \expndtw-2\charscalex100 neuronal inactivation, inclu
ding diplopia [19], nystagmus [20], and vertigo [21], may occur. \par\pard\qj \l
i993\ri795\sb0\sl-340\slmult0\fi288 \up0 \expndtw0\charscalex104 The action of t
etanus toxin is not confined to the motor system. Autonomic dysfunction with \up
0 \expndtw-1\charscalex100 episodes of tachycardia, hypertension, and sweating,
sometimes rapidly alternating with bradycardia \up0 \expndtw-3\charscalex100 and
hypotension are common, especially in generalized tetanus [18,22,23].
Such symptoms are \up0 \expndtw-3\charscalex100 paralleled by dramatic increas
es in circulating adrenaline and noradrenaline [22,24], which may cause \up0 \ex
pndtw0\charscalex100 myocardial necrosis [25]. Autonomic symptoms tend to occur
a week after the occurrence of motor \up0 \expndtw0\charscalex103 symptoms. They
have been interpreted to reflect an effect of tetanus toxin on the brainstem [2
4], \up0 \expndtw-2\charscalex100 although entry of tetanus toxin into pregangli
onic nerve terminals of the sympathetic nervous system \up0 \expndtw-3\charscale
x100 has been demonstrated in experimental animals [26]; an effect of tetanus to
xin on these neurons would \up0 \expndtw-1\charscalex100 be expected to cause au
tonomic dysregulation. With the advent of modern intensive care, which has \up0
\expndtw0\charscalex102 made tetanus-mediated respiratory insufficiency a treata
ble condition, autonomic dysfunction has \up0 \expndtw-5\charscalex100 become a
major cause of death in tetanus victims [2]. \par\pard\qj \li993\ri796\sb0\sl-34
0\slmult0\fi288 \up0 \expndtw-3\charscalex100 Sensory nerves may also become inv
aded by tetanus toxin [4,26], causing altered sensation, such as \up0 \expndtw0\
charscalex103 pain and allodynia [9,27]. It is unclear where this effect takes p
lace, since experimental evidence \up0 \expndtw-1\charscalex100 suggests that th
e toxin is unable to pass spinal sensory ganglia [3]. Therefore, a sensory effec
t of the \up0 \expndtw-2\charscalex100 toxin should be peripheral. However, the
vesicular release of neurotransmitters from sensory neurons \up0 \expndtw-1\char
scalex100 occurs centrally, in the spinal cord or brainstem [28]. This apparent
paradox may reflect the fact that \up0 \expndtw-1\charscalex100 altered sensatio
n in tetanus is predominantly seen in the region of the head [9,27], \ul0\nosupe
rsub\cf1\f2\fs24 i.e.\ul0\nosupersub\cf2\f3\fs24 , in the area of \up0 \expndtw0
\charscalex100 the (cranial) trigeminal nerve, the ganglion of which may differ
from those of spinal sensory nerves \up0 \expndtw-1\charscalex100 with respect t
o axonal transport of tetanus toxin. \par\pard\qj \li993\ri796\sb0\sl-340\slmult
0\fi288 \up0 \expndtw-2\charscalex100 It is not known whether tetanus toxin that
arrives in the brainstem spreads to structures involved in \line \up0 \expndtw0
\charscalex102 higher functions, such as cognition and mood regulation. Such sym
ptoms are rarely reported. In a \line \up0 \expndtw0\charscalex103 recent survey
of 68 patients from Ethiopia, altered mentation was noted at an early stage in
three \line \up0 \expndtw0\charscalex100 patients, but it was not stated whether
such symptoms could be attributed to the tetanus itself [18]. \line \up0 \expnd
tw-3\charscalex100 Sequelae of tetanus in the newborn include intellectual disab
ility [29], which may suggest an effect of \line \up0 \expndtw-3\charscalex100 t
etanus toxin on higher cerebral functions. Animal studies show clear effects of
tetanus toxin on \par\pard\sect\sectd\fs24\paperw11900\paperh16840\pard\sb0\sl-2
40{\bkmkstart Pg4}{\bkmkend Pg4}\par\pard\li993\sb0\sl-276\slmult0\par\pard\li99
3\sb0\sl-276\slmult0\par\pard\li993\sb70\sl-276\slmult0\fi0\tx10671 \up0 \expndt
w-3\charscalex100 \ul0\nosupersub\cf1\f2\fs24 Toxins \ul0\nosupersub\cf3\f4\fs24
2013\ul0\nosupersub\cf2\f3\fs24 , \ul0\nosupersub\cf1\f2\fs24 5\tab \up0 \expnd
tw-3\charscalex100 \ul0\nosupersub\cf3\f4\fs24 76\par\pard\qj \li993\ri796\sb282
\sl-340\slmult0 \up0 \expndtw0\charscalex100 \ul0\nosupersub\cf2\f3\fs24 neurona
l activity after focal application to the cerebral cortex [30], implying that if
the toxin reaches \up0 \expndtw0\charscalex100 the brain in tetanus victims, hi
gher cerebral functions may become affected. \par\pard\ql \li993\sb0\sl-276\slmu
lt0 \par\pard\ql\li993\sb17\sl-276\slmult0 \up0 \expndtw-3\charscalex100 \ul0\no
supersub\cf3\f4\fs24 4. Treatment of Tetanus \par\pard\qj \li993\ri797\sb252\sl-
340\slmult0\fi288 \up0 \expndtw0\charscalex100 \ul0\nosupersub\cf2\f3\fs24 Acute
treatment of tetanus is based on wound cleaning and antibiotic eradication of C
lostridium \line \up0 \expndtw-1\charscalex100 tetani, e.g., with intraven
ous metronidazole, \up0 \expndtw-1\charscalex100 500 mg three times da
ily, or penicillin, \par\pard\qj \li993\ri795\sb0\sl-340\slmult0 \up0 \expnd
tw-3\charscalex100 100,000-200,000 IU/kg/day [31,32]. Treatment is continued for
seven to ten days. The notion that one \line \up0 \expndtw-3\charscalex100 shou
ld avoid penicillin because of a possible inhibition of the GABAA receptor, whic
h could increase \line \up0 \expndtw0\charscalex105 muscle rigidity, does not se
em to be supported by studies [31]. Tetanus antitoxin is given once \line \up0
\expndtw-1\charscalex100 intramuscularly; doses of 500 IU, 3000 IU, or higher ha
ve been used, but it is debatable whether the \line \up0 \expndtw0\charscalex100
higher doses are more effective [33]. The antitoxin is given to inactivate any
free tetanus toxin. The \line \up0 \expndtw-2\charscalex100 toxin that has been
taken up into nerve terminals is probably not available to the antitoxin. Theref
ore, \line \up0 \expndtw-2\charscalex100 muscle symptoms may develop further, al
though the clostridia have been eradicated and antitoxin has \line \up0 \expndtw
-1\charscalex100 been given, because tetanus toxin continues to be transported a
xonally and trans-synaptically and to \line \up0 \expndtw0\charscalex103 cleave
VAMP. Intrathecal administration of antitoxin, e.g. via lumbar puncture, could i
nactivate \line \up0 \expndtw0\charscalex104 tetanus toxin during its trans-
synaptic transport; a meta-analysis indicated that intrathecal \line \up0
\expndtw-4\charscalex100 administration was superior to the intramuscular route
with respect to survival [34]. Because immunity \line \up0 \expndtw-4\charscalex
100 may not develop after an episode of tetanus, vaccination is included in the
treatment. \par\pard\qj \li993\ri796\sb0\sl-340\slmult0\fi288 \up0 \expndtw-3\ch
arscalex100 Treatment of the muscular rigidity and spasms in tetanus is of vital
importance, since this feature of \line \up0 \expndtw-2\charscalex100 the disea
se often interferes with respiration and is a likely cause of death [1,18]. Rigi
dity and spasms \line \up0 \expndtw0\charscalex100 also cause severe pain, which
stimulates muscle activity. Muscle relaxation is customarily achieved \line \up
0 \expndtw0\charscalex100 with benzodiazepines [35], which augment the effect of
GABA on the GABAA receptors of lower \line \up0 \expndtw0\charscalex105 motor n
eurons. Baclofen, which acts on GABAB receptors, may also be effective; when giv
en \line \up0 \expndtw0\charscalex103 intrathecally its sedative effect is avoid
ed [36]. In the setting of an intensive care unit, propofol, \line \up0 \expndt
w0\charscalex100 another GABAA receptor modulator, may be used [37], as may non-
depolarizing muscle relaxants \line \up0 \expndtw-1\charscalex100 (pancuronium,
pipecuronium) [38], which act directly on the muscle motor end plates by competi
ng \line \up0 \expndtw0\charscalex106 for the acetylcholine binding site. Magnes
ium, a calcium antagonist that acts both by reducing \line \up0 \expndtw-2\chars
calex100 acetylcholine release and by reducing the muscle response to acetylchol
ine [39-41], may be effective \line \up0 \expndtw-3\charscalex100 in relieving r
igidity and spasms [42]. Magnesium also seems to reduce autonomic dysfunction [4
2,43], \line \up0 \expndtw-1\charscalex100 which is of importance, because
anti-adrenergic drugs, especially beta-blockers, may produce \line \up0 \ex
pndtw-1\charscalex100 untoward effects, including cardiac arrest [24]. Dantrolen
e, which binds to the ryanodine receptor in \line \up0 \expndtw-1\charscalex100
muscle and reduces calcium mobilization and thereby muscle contraction, is also
in use [44,45]. \par\pard\qj \li993\ri795\sb0\sl-340\slmult0\fi288 \up0 \expndtw
0\charscalex102 Tetanus patients should be in a calm environment to avoid the tr
iggering of spasms by noise or \up0 \expndtw-1\charscalex100 other sensory sti
mulation. This objective must be balanced against the need to avoid s
ensory \up0 \expndtw-1\charscalex100 deprivation, which predisposes to delirium,
a condition that tetanus patients are prone to, given their \up0 \expndtw-2\cha
rscalex100 often lengthy stays in intensive care units with mechanical ventilati
on and treatment with neuroactive \up0 \expndtw-3\charscalex100 drugs such as be
nzodiazepines and propofol [46]. \par\pard\qj \li993\ri796\sb0\sl-340\slmult0\fi
288 \up0 \expndtw-2\charscalex100 Prophylaxis against tetanus consists of immuni
zation with formaldehyde-inactivated tetanus toxin \line \up0 \expndtw-2\charsca
lex100 (toxoid) and measures to achieve good hygiene. For instance contamination
of the umbilical stump of \line \up0 \expndtw-3\charscalex100 the newborn is a
primary cause of neonatal tetanus. These issues are interrelated: a good immuniz
ation \line \up0 \expndtw0\charscalex104 status in pregnant women leads to reduc
tion in the prevalence of neonatal tetanus [47], because \line \up0 \expndtw0\c
harscalex104 maternal anti-tetanus toxin antibodies are transferred across the p
lacenta to the child in utero [48]. \par\pard\sect\sectd\fs24\landscape\paperw16
840\paperh11900\pard\sb0\sl-240{\bkmkstart Pg5}{\bkmkend Pg5}\par\pard\li993\sb0
\sl-276\slmult0\par\pard\li993\sb0\sl-276\slmult0\par\pard\li993\sb135\sl-276\sl
mult0\fi0\tx15603 \up0 \expndtw-3\charscalex100 \ul0\nosupersub\cf1\f2\fs24 Toxi
ns \ul0\nosupersub\cf3\f4\fs24 2013\ul0\nosupersub\cf2\f3\fs24 , \ul0\nosupersub
\cf1\f2\fs24 5\tab \up0 \expndtw-3\charscalex100 \ul0\nosupersub\cf3\f4\fs24 77\
par\pard\li2809\sb0\sl-276\slmult0\par\pard\li2809\sb128\sl-276\slmult0\fi0 \up0
\expndtw-2\charscalex100 Table 1.\ul0\nosupersub\cf2\f3\fs24 Summary of case r
eports on the use of botulinum toxin against tetanus-induced muscle rigidity and
spasms.\par\pard\sect\sectd\sbknone\cols3\colno1\colw5982\colsr160\colno2\colw3
571\colsr160\colno3\colw6837\colsr160\ql \li3779\sb178\sl-253\slmult0 \up0 \expn
dtw-3\charscalex100 \ul0\nosupersub\cf11\f12\fs22 Cause/\par\pard\ql \li1108\sb4
7\sl-253\slmult0\tx3591 \up0 \expndtw0\charscalex103 Reference Age/sex\tab \u
p0 \expndtw-3\charscalex100 incubation\par\pard\ql \li3890\sb46\sl-253\slmult0 \
up0 \expndtw-3\charscalex100 time\par\pard\column \ql \li6142\sb0\sl-253\slmult0
\par\pard\ql \li20\sb225\sl-253\slmult0 \up0 \expndtw-3\charscalex100 Symptoms/
Ablett grade\par\pard\column \ql \li9863\sb0\sl-253\slmult0 \par\pard\ql \li20\s
b75\sl-253\slmult0\tx4088 \up0 \expndtw-3\charscalex100 Botulinum toxin: treatme
nt start \ul0\super\cf12\f13\fs21 a\ul0\nosupersub\cf11\f12\fs22 /dose\tab \up0
\expndtw-3\charscalex100 Time to onset/time\par\pard\ql \li1020\sb46\sl-253\slmu
lt0\tx4150 \up0 \expndtw-3\charscalex100 and injection sites\tab \up0 \expndtw-3
\charscalex100 to maximal effect\par\pard\sect\sectd\sbknone\cols4\colno1\colw33
42\colsr160\colno2\colw1323\colsr160\colno3\colw4798\colsr160\colno4\colw6777\co
lsr160\ql \li1396\sb0\sl-253\slmult0 \par\pard\ql \li1396\sb81\sl-253\slmult0\tx
2388 \up0 \expndtw-3\charscalex100 \ul0\nosupersub\cf13\f14\fs22 [49]\tab \up0 \
expndtw-3\charscalex100 33/male\par\pard\ql \li1396\sb0\sl-253\slmult0 \par\pard
\ql \li1396\sb0\sl-253\slmult0 \par\pard\ql \li1396\sb0\sl-253\slmult0 \par\pard
\ql \li1396\sb164\sl-253\slmult0\tx2388 \up0 \expndtw-3\charscalex100 [50]\tab \
up0 \expndtw-3\charscalex100 28/male\par\pard\ql \li1396\sb0\sl-253\slmult0 \par
\pard\ql \li1396\sb0\sl-253\slmult0 \par\pard\ql \li1396\sb0\sl-253\slmult0 \par
\pard\ql \li1396\sb0\sl-253\slmult0 \par\pard\ql \li1396\sb85\sl-253\slmult0\tx2
303 \up0 \expndtw-3\charscalex100 [45]\tab \up0 \expndtw-3\charscalex100 64/fema
le\par\pard\column \ql \li32\sb184\sl-253\slmult0 \up0 \expndtw-3\charscalex100
Nose wound/\par\pard\ql \li331\sb47\sl-253\slmult0 \up0 \expndtw-2\charscalex100
8 days\par\pard\ql \li240\sb173\sl-253\slmult0 \up0 \expndtw-3\charscalex100 I.
v. drug\par\pard\ql \li335\sb47\sl-253\slmult0 \up0 \expndtw-3\charscalex100 abu
se/\par\pard\ql \li206\sb47\sl-253\slmult0 \up0 \expndtw-2\charscalex100 unknown
\par\pard\ql \li151\sb47\sl-253\slmult0 \up0 \expndtw-2\charscalex100 incubation
\par\pard\ql \li420\sb47\sl-253\slmult0 \up0 \expndtw-3\charscalex100 time\par\p
ard\qj \li20\ri51\sb9\sl-299\slmult0\tx216 \up0 \expndtw-3\charscalex100 Hand wo
und/ \line\tab \up0 \expndtw-2\charscalex100 unknown\par\pard\ql \li151\sb39\sl-
253\slmult0 \up0 \expndtw-2\charscalex100 incubation\par\pard\ql \li420\sb47\sl-
253\slmult0 \up0 \expndtw-3\charscalex100 time\par\pard\column \ql \li312\sb184\
sl-253\slmult0 \up0 \expndtw-3\charscalex100 Trismus, dysphagia, ptosis. Cephali
c tetanus/\par\pard\ql \li1672\sb47\sl-253\slmult0 \up0 \expndtw-3\charscalex100
Ablett grade 3\par\pard\ql \li5311\sb0\sl-253\slmult0 \par\pard\ql \li5311\sb0\
sl-253\slmult0 \par\pard\ql \li356\sb117\sl-253\slmult0 \up0 \expndtw-3\charscal
ex100 Trismus, progressing to generalized tetanus/\par\pard\ql \li1672\sb47\sl-2
53\slmult0 \up0 \expndtw-3\charscalex100 Ablett grade 3\par\pard\qj \li5045\sb0\
sl-299\slmult0 \par\pard\qj \li5045\sb0\sl-299\slmult0 \par\pard\qj \li90\ri224\
sb11\sl-299\slmult0\tx451 \up0 \expndtw-3\charscalex100 Generalized tetanus, inc
luding diffuse rigidity and \line\tab \up0 \expndtw-3\charscalex100 pain, trismu
s, risus sardonicus, dysphagia/\par\pard\ql \li1672\sb39\sl-253\slmult0 \up0 \ex
pndtw-3\charscalex100 Ablett grade 3\par\pard\ql \li20\sb197\sl-253\slmult0 \up0
\expndtw-3\charscalex100 Generalized tetanus, including rigidity, opistotonus,\
par\pard\column \ql \li20\sb184\sl-253\slmult0 \up0 \expndtw-3\charscalex100 15
days: Botox\ul0\super\cf14\f15\fs21 \ul0\nosupersub\cf13\f14\fs22 50 IU in each
masseter.\par\pard\ql \li4115\sb0\sl-198\slmult0 \up0 \expndtw0\charscalex100 3-
4 days/2 weeks\par\pard\ql \li432\sb0\sl-198\slmult0 \up0 \expndtw-3\charscalex1
00 Two injection sites per muscle.\par\pard\ql \li10032\sb0\sl-253\slmult0 \par\
pard\ql \li129\sb126\sl-253\slmult0 \up0 \expndtw-2\charscalex100 >3 weeks: Dysp
ort\ul0\super\cf14\f15\fs21 \ul0\nosupersub\cf13\f14\fs22 into left biceps +\pa
r\pard\ql \li174\sb47\sl-253\slmult0\tx4389 \up0 \expndtw-3\charscalex100 brachi
oradialis + both gastrocnemius\tab \up0 \expndtw-3\charscalex100 1 day/1 day\par
\pard\ql \li551\sb47\sl-253\slmult0 \up0 \expndtw-3\charscalex100 muscles, total
dose 1000 IU.\par\pard\ql \li10243\sb0\sl-253\slmult0 \par\pard\ql \li10243\sb0
\sl-253\slmult0 \par\pard\ql \li340\sb141\sl-253\slmult0 \up0 \expndtw-4\charsca
lex100 3 weeks: Botox\ul0\super\cf14\f15\fs21 \ul0\nosupersub\cf13\f14\fs22 30
IU into each\par\pard\ql \li4267\sb0\sl-198\slmult0 \up0 \expndtw-2\charscalex1
00 2 days/1 week\par\pard\ql \li198\sb0\sl-198\slmult0 \up0 \expndtw-3\charscale
x100 cricopharyngeal muscle with EMG \ul0\super\cf14\f15\fs21 b\par\pard\ql \li1
396\sb0\sl-253\slmult0 \par\pard\ql \li340\sb150\sl-253\slmult0 \up0 \expndtw-4\
charscalex100 \ul0\nosupersub\cf13\f14\fs22 3 weeks: Botox\ul0\super\cf14\f15\fs
21 \ul0\nosupersub\cf13\f14\fs22 30 IU into each\par\pard\sect\sectd\sbknone\c
ols4\colno1\colw2148\colsr160\colno2\colw2761\colsr160\colno3\colw4732\colsr160\
colno4\colw6599\colsr160\ql \li1396\sb0\sl-198\slmult0 \up0 \expndtw-3\charscale
x100 [45]\par\pard\column \ql \li20\sb0\sl-198\slmult0 \up0 \expndtw0\charscalex
102 68/female Leg wound/3\par\pard\ql \li1608\sb0\sl-198\slmult0 \up0 \expndt
w-3\charscalex100 days\par\pard\ql \li1375\sb127\sl-253\slmult0 \up0 \expndtw-2\
charscalex100 Unknown\par\pard\ql \li1397\sb47\sl-253\slmult0 \up0 \expndtw-2\ch
arscalex100 entry and\par\pard\column \ql \li450\sb0\sl-198\slmult0 \up0 \expndt
w-3\charscalex100 trismus, risus sardonicus, dysarthria,\par\pard\ql \li952\sb0\
sl-253\slmult0 \up0 \expndtw-3\charscalex100 dysphagia/Ablett grade 3\par\pard\q
l \li5219\sb0\sl-253\slmult0 \par\pard\ql \li20\sb118\sl-253\slmult0 \up0 \expnd
tw-3\charscalex100 Throat pain, dysphonia, neck rigidity, trismus.\par\pard\colu
mn \ql \li4089\sb0\sl-198\slmult0 \up0 \expndtw-2\charscalex100 2 days/1 week\pa
r\pard\ql \li20\sb0\sl-198\slmult0 \up0 \expndtw-3\charscalex100 cricopharyngeal
muscle with EMG \ul0\super\cf14\f15\fs21 b\par\pard\ql \li1396\sb0\sl-253\slmul
t0 \par\pard\ql \li162\sb24\sl-253\slmult0 \up0 \expndtw-4\charscalex100 \ul0\no
supersub\cf13\f14\fs22 8 weeks: Botox\ul0\super\cf14\f15\fs21 \ul0\nosupersub\cf
13\f14\fs22 75 IU into each\par\pard\sect\sectd\sbknone\cols4\colno1\colw3473\
colsr160\colno2\colw1256\colsr160\colno3\colw4644\colsr160\colno4\colw6867\colsr
160\ql \li1396\sb0\sl-198\slmult0\tx2303 \up0 \expndtw-3\charscalex100 [51]\tab
\up0 \expndtw-3\charscalex100 80/female\par\pard\ql \li1450\sb0\sl-253\slmult0 \
par\pard\ql \li1450\sb0\sl-253\slmult0 \par\pard\ql \li1450\sb0\sl-253\slmult0 \
par\pard\ql \li1450\sb15\sl-253\slmult0\tx2303 \up0 \expndtw-2\charscalex100 [9]
\tab \up0 \expndtw-3\charscalex100 82/female\par\pard\column \ql \li20\sb47\sl-2
53\slmult0 \up0 \expndtw-2\charscalex100 incubation\par\pard\ql \li289\sb47\sl-2
53\slmult0 \up0 \expndtw-3\charscalex100 time\par\pard\ql \li75\sb71\sl-253\slmu
lt0 \up0 \expndtw-3\charscalex100 Forehead\par\pard\ql \li45\sb47\sl-253\slmult0
\up0 \expndtw-3\charscalex100 wound/11\par\pard\ql \li283\sb47\sl-253\slmult0 \
up0 \expndtw-3\charscalex100 days\par\pard\column \ql \li821\sb47\sl-253\slmult0
\up0 \expndtw-3\charscalex100 Cephalic tetanus/ Ablett grade 3\par\pard\ql \li5
039\sb0\sl-253\slmult0 \par\pard\ql \li5039\sb0\sl-253\slmult0 \par\pard\ql \li2
0\sb15\sl-253\slmult0 \up0 \expndtw-3\charscalex100 Bell\u8217?s paresis, facial
pain, trismus, tongue spasms.\par\pard\ql \li848\sb47\sl-253\slmult0 \up0 \expn
dtw-3\charscalex100 Cephalic tetanus/Ablett grade 3\par\pard\column \ql \li118\s
b0\sl-198\slmult0\tx4225 \up0 \expndtw-3\charscalex100 sternocleidomastoideus, 2
5 IU into right\tab \up0 \expndtw-2\charscalex100 \u8220?responded well\u8221?\p
ar\pard\ql \li20\sb0\sl-253\slmult0 \up0 \expndtw-3\charscalex100 trapezius, 50
IU into each levator scapulae\par\pard\ql \li9903\sb0\sl-253\slmult0 \par\pard\q
l \li90\sb118\sl-253\slmult0 \up0 \expndtw-4\charscalex100 5 days: Botox\ul0\sup
er\cf14\f15\fs21 \ul0\nosupersub\cf13\f14\fs22 25 IU into each masseter\par\pa
rd\ql \li4315\sb0\sl-198\slmult0 \up0 \expndtw-3\charscalex100 3 days/3 weeks\pa
r\pard\ql \li194\sb0\sl-198\slmult0 \up0 \expndtw-3\charscalex100 and 10 IU into
each temporalis muscle \par\pard\sect\sectd\sbknone \li1555\sb97\sl-230\slmult0
\fi0\tx2283\tx13818 \up0 \expndtw-2\charscalex100 \ul0\nosupersub\cf10\f11\fs20
a: time\tab \up0 \expndtw-1\charscalex100 (days or weeks) after admission
to the hospital. b: injections into the cricopharyngeal muscles were d
one with electromyographic\tab \up0 \expndtw-2\charscalex100 (EMG) guidance.\
par\pard\sect\sectd\sbknone \li1555\sb70\sl-230\slmult0\fi0 \up0 \expndtw-1\char
scalex100 I.v.: intravenous. Please observe that Dysport\ul0\super\cf15\f16\fs19
\ul0\nosupersub\cf10\f11\fs20 and Botox\ul0\super\cf15\f16\fs19 \ul0\nosupersub\
cf10\f11\fs20 cannot be compared directly with respect to dosage [52].
{\shp {\*\shpinst\shpleft995\shptop1989\shpright9670\shpbottom2009\shpfhdr0\shpb
xpage\shpbypage\shpwr3\shpwrk0\shpfblwtxt1\shpz76\shplid0
}
}}
}
}}
}
}}
}
}}
{\shp {\*\shpinst\shpleft981\shptop9522\shpright2163\shpbottom9542\shpfhdr0\shpb
xpage\shpbypage\shpwr3\shpwrk0\shpfblwtxt1\shpz383\shplid4
}
}}
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}}
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}}
}
}}\par\pard\sect\sectd\fs24\paperw11900\paperh16840\pard\sb0\sl-240{\bkmkstart P
g6}{\bkmkend Pg6}\par\pard\li993\sb0\sl-276\slmult0\par\pard\li993\sb0\sl-276\sl
mult0\par\pard\li993\sb70\sl-276\slmult0\fi0\tx10671 \up0 \expndtw-3\charscalex1
00 \ul0\nosupersub\cf1\f2\fs24 Toxins \ul0\nosupersub\cf3\f4\fs24 2013\ul0\nosup
ersub\cf2\f3\fs24 , \ul0\nosupersub\cf1\f2\fs24 5\tab \up0 \expndtw-3\charscalex
100 \ul0\nosupersub\cf3\f4\fs24 78\par\pard\ql \li993\sb0\sl-276\slmult0 \par\pa
rd\ql\li993\sb58\sl-276\slmult0 \up0 \expndtw-2\charscalex100 5. The Use of Botu
linum Toxin against Tetanus-Induced Rigidity and Spasms \par\pard\ql \li1281\sb0
\sl-276\slmult0 \par\pard\ql\li1281\sb28\sl-276\slmult0\tx8166 \up0 \expndtw-2\c
harscalex100 \ul0\nosupersub\cf2\f3\fs24 Botulinum toxins enter nerve termin
als of lower motor neurons \tab \up0 \expndtw-1\charscalex100 [6,7]. The t
oxins are zinc \par\pard\qj \li993\ri796\sb12\sl-340\slmult0 \up0 \expndtw-2\c
harscalex100 metalloproteinases that attack synaptic vesicle proteins, but they
do so differentially: botulinum toxin \up0 \expndtw0\charscalex103 A cleaves syn
aptosomal-associated protein (SNAP-25), botulinum toxins B, D, F, and G cleave
\up0 \expndtw0\charscalex102 synaptobrevin (which is also attacked by tetanus to
xin); botulinum toxin C cleaves SNAP-25 and \up0 \expndtw-2\charscalex100 syntax
in [7]. Compared to tetanus toxin, the botulinum toxins undergo less axonal and
trans-synaptic \up0 \expndtw0\charscalex100 transport, although some transport d
oes seem to occur [53,54]. Therefore, the effects of botulinum \up0 \expndtw0\ch
arscalex103 toxins remain fairly confined to the nerve terminals of lower motor
neurons, inhibiting release of \up0 \expndtw-4\charscalex100 acetylcholine and a
ctivation of voluntary muscles. For this reason they may have a role in reducing
the \up0 \expndtw-5\charscalex100 muscular hyperactivity in tetanus patients. \
par\pard\qj \li993\ri796\sb0\sl-340\slmult0\fi288 \up0 \expndtw0\charscalex100 I
n six reported cases of tetanus, all with symptom severity that amounted to grad
e 3 in the Ablett \line \up0 \expndtw-3\charscalex100 symptom severity grading s
ystem, botulinum toxin A was used successfully to control muscle rigidity \line
\up0 \expndtw0\charscalex105 and spasms [9,45,49-51]. In three cases the tetanu
s was cephalic or fairly local; in three it was \line \up0 \expndtw0\charscalex1
02 generalized (Table 1). In all cases beneficial effects of treatment were seen
. However, only in one \line \up0 \expndtw-2\charscalex100 patient was the treat
ment given within the first week after admission to the hospital; in the remaind
er, \line \up0 \expndtw0\charscalex105 botulinum toxin was given two to eight we
eks after admission, although symptom severity was \line \up0 \expndtw0\charscal
ex104 greatest in the earlier phase of the disease. Therefore, one cannot rule o
ut the possibility that the \line \up0 \expndtw-2\charscalex100 improvement seen
after treatment with botulinum toxin to some extent reflected the natural histo
ry of \line \up0 \expndtw-3\charscalex100 tetanus, including spontaneous resolut
ion of muscle rigidity. In some cases [45,50,51] botulinum toxin \line \up0 \exp
ndtw0\charscalex104 was used to treat residual muscle rigidity tha
t proved especially resistant to other \line \up0 \expndtw-5\charscale
x100 muscle-relaxing therapies. \par\pard\qj \li993\ri796\sb0\sl-340\slmult0\fi2
88 \up0 \expndtw-4\charscalex100 In the four reports that give details on onset
of action, improvement of rigidity was noted within one \line \up0 \expndtw0\cha
rscalex104 to four days. Maximal effect was reached after one to three weeks, ex
cept in one case, in which \line \up0 \expndtw0\charscalex106 maximal effect was
seen one day after injection of botulinum toxin (Table 1). The activity of \l
ine \up0 \expndtw0\charscalex100 botulinum toxin is reported to be increased by
neuronal activity [55,56]. Theoretically, the action of \line \up0 \expndtw0\cha
rscalex100 botulinum toxin could be more rapid in tetanus, in which the activity
of the lower motor neurons is \line \up0 \expndtw0\charscalex100 much increased
. \par\pard\qj \li993\ri796\sb0\sl-340\slmult0\fi288 \up0 \expndtw-1\charscalex1
00 Dosage varied somewhat (Table 1), but resembled those commonly used to treat
dystonia [57]. It \up0 \expndtw-3\charscalex100 should be noted that the two pre
parations of botulinum toxin A that were used, Botox\ul0\super\cf8\f9\fs23 \ul0\n
osupersub\cf2\f3\fs24 and Dysport\ul0\super\cf8\f9\fs23 \ul0\nosupersub\cf2\f3\f
s24 , \up0 \expndtw-4\charscalex100 are not equipotent and somewhat difficult t
o compare [52]. \par\pard\qj \li993\ri796\sb0\sl-340\slmult0\fi288 \up0 \expndtw
0\charscalex103 Only in one patient was treatment repeated (two months after the
initial injection) [51]. In the \up0 \expndtw-1\charscalex100 remaining cases,
the effect of botulinum toxin apparently outlasted the symptoms of tetanus. Only
in \up0 \expndtw0\charscalex103 one case was a side effect noted: a certain atr
ophy of the masseter muscles after botulinum toxin \up0 \expndtw-3\charscalex100
injection for trismus [49]. \par\pard\ql \li993\sb0\sl-276\slmult0 \par\pard\ql
\li993\sb17\sl-276\slmult0 \up0 \expndtw-2\charscalex100 \ul0\nosupersub\cf3\f4\
fs24 6. Advantages and Disadvantages of Botulinum Toxin Treatment in Tetanus \pa
r\pard\qj \li993\ri796\sb252\sl-340\slmult0\fi288 \up0 \expndtw-3\charscalex100
\ul0\nosupersub\cf2\f3\fs24 Trismus and dysphagia are early and common symptoms
of tetanus, both generalized and cephalic. \line \up0 \expndtw0\charscalex103 Th
ey constitute major hazards for the patient, irrespective of the threats of resp
iratory failure and \line \up0 \expndtw-2\charscalex100 autonomic dysfunction de
scribed above. Normal salivation predisposes to aspiration in a patient who \lin
e \up0 \expndtw0\charscalex102 cannot swallow normally or evacuate the mouth, wh
erefore aspiration and pneumonia commonly \line \up0 \expndtw0\charscalex102 occ
ur in tetanus [58,59]. Trismus further interferes with eating and with oral hygi
ene, which is an \par\pard\sect\sectd\fs24\paperw11900\paperh16840\pard\sb0\sl-2
tw-3\charscalex100 \ul0\nosupersub\cf3\f4\fs24 79\par\pard\ql \li993\ri797\sb282
\sl-340\slmult0\tx1281 \up0 \expndtw0\charscalex100 \ul0\nosupersub\cf2\f3\fs24
important issue, because the condition may last for many weeks, endangering dent
al health. Lastly, \line \up0 \expndtw-4\charscalex100 trismus is associated wit
h involuntary tongue biting, which may be very painful [9]. \line \tab \up0 \exp
ndtw0\charscalex105 The use of botulinum toxin to ameliorate tetanus-induced tri
smus must be considered a safe \line \up0 \expndtw0\charscalex104 procedure, giv
en that the masseter and temporalis muscles are at some distance from the larynx
; \line \up0 \expndtw0\charscalex100 injection into the cricopharyngeal
muscles to alleviate dysphagia, in contrast, requires \line \up0 \ex
pndtw0\charscalex100 electromyographic guidance [45]. Treatment of trismus and d
ysphagia with botulinum toxin should \line \up0 \expndtw0\charscalex102 probably
be considered at an early stage in tetanus, because it may contribute to a more
favorable \line \up0 \expndtw0\charscalex105 course of the disease, reducing th
e risk of aspiration and pneumonia, allowing dental care, and, \line \up0 \expnd
tw-5\charscalex100 possibly, food intake. \par\pard\qj \li993\ri795\sb0\sl-340\s
lmult0\fi288 \up0 \expndtw0\charscalex100 Injections into the trapezius, spleniu
s capitis, levator scapulae and sternocleidomastoid muscles \up0 \expndtw-1\char
scalex100 may alleviate painful neck rigidity; care must be taken to avoid neigh
boring vital structures, such as \up0 \expndtw-2\charscalex100 the carotid arter
y, and spread of botulinum toxin to the larynx. \par\pard\qj \li993\ri795\sb0\sl
-340\slmult0\fi288 \up0 \expndtw-3\charscalex100 No information exists on the us
e of botulinum toxin on large truncal muscles in tetanus, such as the \up0 \expn
dtw0\charscalex100 abdominal and erector spinae muscles, which are affected in g
eneralized tetanus. Successful use of \up0 \expndtw-2\charscalex100 botulinum t
oxin to treat hyperactivity of abdominal muscles has been reported in
Parkinson\u8217?s \up0 \expndtw-3\charscalex100 disease [60] and dystonia [61].
Botulinum toxin has been used for back pain syndromes with injection \up0 \expn
dtw-1\charscalex100 of the toxin into several levels of the erector spinae muscl
es in the L1-L5 area [62]. The total dose of \up0 \expndtw-3\charscalex100 botul
inum toxin A (Botox\ul0\super\cf8\f9\fs23 \ul0\nosupersub\cf2\f3\fs24 ) in these
cases was 240-500 IU. From such reports it seems feasible to use \up0 \expndtw-1
\charscalex100 botulinum toxin in large truncal muscles affected by tetanus, alt
hough it must be emphasized that no \up0 \expndtw-2\charscalex100 clinical exper
ience with such treatment has been published. \par\pard\qj \li993\ri796\sb0\sl-3
40\slmult0\fi288 \up0 \expndtw-1\charscalex100 Additional advantages of botulinu
m toxin in the treatment of tetanus include the reduced need for \line \up0 \exp
ndtw-2\charscalex100 muscle relaxants that affect consciousness \up0 \expndtw-2\
charscalex100 [63] and the long lasting effect of botulinum toxins \par\pard\ql
\li993\sb53\sl-276\slmult0 \up0 \expndtw-3\charscalex100 (>3 months) [64], which
in most cases outlasts that of tetanus toxin. \par\pard\qj \li993\ri797\sb12\sl
-340\slmult0\fi288 \up0 \expndtw0\charscalex103 Disadvantages of the botulinum t
oxin approach to tetanus include the difficulty of treating all \line \up0 \expn
dtw0\charscalex103 affected muscle groups in generalized tetanus. Even so, botul
inum toxin should be considered in \line \up0 \expndtw0\charscalex102 generalize
d tetanus, in which the rigidity of certain muscle groups may pose a special the
rapeutic \line \up0 \expndtw-3\charscalex100 challenge. The slow onset of action
and gradual increase in effect over one to three weeks necessitates \line \up0
\expndtw-2\charscalex100 simultaneous treatment with other muscle-relaxing drugs
. The possibility of overdosing, the evidence \line \up0 \expndtw-2\charscalex10
0 of which may become manifest days after injection of botulinum toxin, makes it
important to monitor \line \up0 \expndtw-3\charscalex100 patients closely. The
protracted effect of botulinum toxin [64] implies that such side effects may be
of \line \up0 \expndtw-1\charscalex100 some duration. A main obstacle to the use
of botulinum toxin for tetanus may prove to be the cost of \line \up0 \expndtw-
3\charscalex100 treatment, especially in generalized tetanus, in which large dos
es may be needed to reduce rigidity and \line \up0 \expndtw-4\charscalex100 spas
ms of large muscles. \par\pard\ql \li993\sb0\sl-276\slmult0 \par\pard\ql\li993\s
b17\sl-276\slmult0 \up0 \expndtw-5\charscalex100 \ul0\nosupersub\cf3\f4\fs24 7.
Conclusions \par\pard\qj \li993\ri793\sb252\sl-340\slmult0\fi288 \up0 \expndtw-3
\charscalex100 \ul0\nosupersub\cf2\f3\fs24 There is limited experience with the
use of botulinum toxin for the treatment of muscle rigidity and \line \up0 \expn
dtw0\charscalex100 spasms in tetanus. However, from a few published case reports
it would seem that such treatment is \line \up0 \expndtw0\charscalex100 useful.
This may be especially true for trismus, which constitutes a major
problem in itself, \line \up0 \expndtw-2\charscalex100 predisposing to pulmona
ry aspiration, painful, involuntary tongue biting, anorexia, and dental caries.
\line \up0 \expndtw-2\charscalex100 The treatment of trismus with botulinum toxi
n is probably a fairly safe procedure, since injection into \line \up0 \expndtw-
4\charscalex100 the masseter and temporalis muscles can be achieved without enda
ngering neighboring vital structures. \line \up0 \expndtw-4\charscalex100 Howeve
r, the possibility of complications caused by distant spread of the toxin must b
e kept in mind. \par\pard\sect\sectd\fs24\paperw11900\paperh16840\pard\sb0\sl-24
\sb0\sl-276\slmult0\par\pard\li993\sb70\sl-276\slmult0\fi0\tx10671 \up0 \expndtw
-3\charscalex100 \ul0\nosupersub\cf1\f2\fs24 Toxins \ul0\nosupersub\cf3\f4\fs24
2013\ul0\nosupersub\cf2\f3\fs24 , \ul0\nosupersub\cf1\f2\fs24 5\tab \up0 \expndt
w-3\charscalex100 \ul0\nosupersub\cf3\f4\fs24 80\par\pard\qj \li993\ri797\sb282\
sl-340\slmult0 \up0 \expndtw0\charscalex107 \ul0\nosupersub\cf2\f3\fs24 There is
a general lack of randomized clinical trials with respect to both antibiotic [
31,32] and \up0 \expndtw0\charscalex100 muscle-relaxing therapies [35] in tetanu
s. It is to be hoped that the potential usefulness of botulinum \up0 \expndtw0\c
harscalex100 toxin in the treatment of tetanus will lead to its evaluation in cl
inical trials. \par\pard\ql \li993\sb0\sl-276\slmult0 \par\pard\ql\li993\sb17\sl
-276\slmult0 \up0 \expndtw-3\charscalex100 \ul0\nosupersub\cf3\f4\fs24 Conflict
of Interest \par\pard\ql \li1281\sb0\sl-276\slmult0 \par\pard\ql\li1281\sb28\sl-
276\slmult0 \up0 \expndtw-3\charscalex100 \ul0\nosupersub\cf2\f3\fs24 The author
declares no conflict of interest. \par\pard\ql \li993\sb0\sl-276\slmult0 \par\p
ard\ql\li993\sb28\sl-276\slmult0 \up0 \expndtw-3\charscalex100 \ul0\nosupersub\c
f3\f4\fs24 References \par\pard\li993\sb0\sl-276\slmult0\par\pard\li993\sb35\sl-
276\slmult0\fi0\tx1454 \up0 \expndtw0\charscalex101 \ul0\nosupersub\cf2\f3\fs24
1.\tab \up0 \expndtw0\charscalex102 Bleck, T.P. \ul0\nosupersub\cf1\f2\fs24 Clos
tridium tetani\ul0\nosupersub\cf2\f3\fs24 (Tetanus). In \ul0\nosupersub\cf1\f2
\fs24 Principles and Practice of Infectious Diseases\ul0\nosupersub\cf2\f3\fs24
,\par\pard\li993\sb64\sl-276\slmult0\fi460 \up0 \expndtw0\charscalex102 6th ed.;
Mandell, G.L., Bennett, J.E., Dolin, R., Eds.; Elsevier: Amsterdam, The Netherl
ands,\par\pard\li993\sb64\sl-276\slmult0\fi460 \up0 \expndtw0\charscalex101 2005
; pp. 2817-2822.\par\pard\li993\sb64\sl-276\slmult0\fi0\tx1454 \up0 \expndtw0\ch
arscalex101 2.\tab \up0 \expndtw0\charscalex102 Thwaites, C.L.; Farrar, J.J. Pre
venting and treating tetanus. \ul0\nosupersub\cf1\f2\fs24 BMJ \ul0\nosupersub\cf
3\f4\fs24 2003\ul0\nosupersub\cf2\f3\fs24 , \ul0\nosupersub\cf1\f2\fs24 326\ul0\
nosupersub\cf2\f3\fs24 , 117-118.\par\pard\li993\sb64\sl-276\slmult0\fi0\tx1454
\up0 \expndtw0\charscalex101 3.\tab \up0 \expndtw0\charscalex102 Blencowe, H.; L
awn, J.; Vandelaer, J.; Roper, M.; Cousens, S. Tetanus toxoid immunization to\pa
r\pard\li993\sb64\sl-276\slmult0\fi460 \up0 \expndtw0\charscalex102 reduce morta
lity from neonatal tetanus. \ul0\nosupersub\cf1\f2\fs24 Int. J. Epidemiol\ul0\no
supersub\cf2\f3\fs24 . \ul0\nosupersub\cf3\f4\fs24 2010\ul0\nosupersub\cf2\f3\fs
24 , \ul0\nosupersub\cf1\f2\fs24 39\ul0\nosupersub\cf2\f3\fs24 , i102-i109.\par\
pard\li993\sb64\sl-276\slmult0\fi0\tx1454 \up0 \expndtw0\charscalex101 4.\tab \u
p0 \expndtw0\charscalex102 Meyer, H.; Ransom, F. Researches on tetanus\u8212?Pre
liminary communication. \ul0\nosupersub\cf1\f2\fs24 Proc. Royal Soc.\par\pard\li
993\sb64\sl-276\slmult0\fi460 \up0 \expndtw0\charscalex101 Lond\ul0\nosupersub\c
f2\f3\fs24 . \ul0\nosupersub\cf3\f4\fs24 1903\ul0\nosupersub\cf2\f3\fs24 , \ul0\
nosupersub\cf1\f2\fs24 72\ul0\nosupersub\cf2\f3\fs24 , 26-30.\par\pard\li993\sb6
4\sl-276\slmult0\fi0\tx1454 \up0 \expndtw0\charscalex101 5.\tab \up0 \expndtw0\c
harscalex102 Fishman, P.S.; Carrigan, D.R. Motoneuron uptake from the circulatio
n of the binding fragment of\par\pard\li993\sb64\sl-276\slmult0\fi460 \up0 \expn
dtw0\charscalex101 tetanus toxin. \ul0\nosupersub\cf1\f2\fs24 Arch. Neurol\ul0\n
osupersub\cf2\f3\fs24 . \ul0\nosupersub\cf3\f4\fs24 1988\ul0\nosupersub\cf2\f3\f
s24 , \ul0\nosupersub\cf1\f2\fs24 45\ul0\nosupersub\cf2\f3\fs24 , 558-561.\par\p
ard\li993\sb64\sl-276\slmult0\fi0\tx1454 \up0 \expndtw0\charscalex101 6.\tab \up
0 \expndtw0\charscalex102 Blum, F.C.; Chen, C.; Kroken, A.R.; Barbieri, J.T. Tet
anus toxin and botulinum toxin A utilize\par\pard\li993\sb64\sl-276\slmult0\fi46
0 \up0 \expndtw0\charscalex102 unique mechanisms to enter neurons of the central
nervous system. \ul0\nosupersub\cf1\f2\fs24 Infect. Immun\ul0\nosupersub\cf2\f3
\fs24 . \ul0\nosupersub\cf3\f4\fs24 2012\ul0\nosupersub\cf2\f3\fs24 , \ul0\nosup
ersub\cf1\f2\fs24 80\ul0\nosupersub\cf2\f3\fs24 ,\par\pard\li993\sb64\sl-276\slm
ult0\fi460 \up0 \expndtw0\charscalex101 1662-1669.\par\pard\li993\sb64\sl-276\sl
mult0\fi0\tx1454 \up0 \expndtw0\charscalex101 7.\tab \up0 \expndtw0\charscalex10
2 Schiavo, G.; Matteoli, M.; Montecucco, C. Neurotoxins affecting neuroexocytosi
s. \ul0\nosupersub\cf1\f2\fs24 Physiol. Rev\ul0\nosupersub\cf2\f3\fs24 .\par\par
d\li993\sb64\sl-276\slmult0\fi460 \up0 \expndtw0\charscalex101 \ul0\nosupersub\c
f3\f4\fs24 2000\ul0\nosupersub\cf2\f3\fs24 , \ul0\nosupersub\cf1\f2\fs24 80\ul0\
nosupersub\cf2\f3\fs24 , 717-766.\par\pard\li993\sb64\sl-276\slmult0\fi0\tx1454
\up0 \expndtw0\charscalex101 8.\tab \up0 \expndtw0\charscalex102 Mayo, J.; Berci
ano, J. Cephalic tetanus presenting with Bell\u8217?s palsy. \ul0\nosupersub\cf1
\f2\fs24 J. Neurol. Neurosurg.\par\pard\li993\sb64\sl-276\slmult0\fi460 \up0 \ex
pndtw0\charscalex101 Psychiatry\ul0\nosupersub\cf2\f3\fs24 \ul0\nosupersub\cf3\
f4\fs24 1985\ul0\nosupersub\cf2\f3\fs24 , \ul0\nosupersub\cf1\f2\fs24 48\ul0\nos
upersub\cf2\f3\fs24 , 290.\par\pard\qj \li993\ri795\sb5\sl-340\slmult0\tx1454\tx
1454 \up0 \expndtw-3\charscalex100 9. \tab \up0 \expndtw-3\charscalex100 Herrman
, H.; Brkhus, A.; Aaserud, O.; Aukrust, P.; Stubhaug, A.; Hassel, B. Early treatm
ent of \line\tab \up0 \expndtw-3\charscalex100 tetanus-induced trismus with botu
linum toxin A. \ul0\nosupersub\cf1\f2\fs24 Anesth. Analg\ul0\nosupersub\cf2\f3\f
s24 . \ul0\nosupersub\cf3\f4\fs24 2008\ul0\nosupersub\cf2\f3\fs24 , \ul0\nosuper
sub\cf1\f2\fs24 106\ul0\nosupersub\cf2\f3\fs24 , 1591. \par\pard\ql \li993\ri796
\sb0\sl-340\slmult0\tx1454\tx1454\tx1454 \up0 \expndtw-3\charscalex100 10. \tab
\up0 \expndtw0\charscalex104 Schwab, M.E.; Thoenen, H. Electron microscopic evid
ence for a transsynaptic migration of \line\tab \up0 \expndtw0\charscalex100 tet
anus toxin in spinal cord motoneurons: An autoradiographic and morphometric stud
y. \ul0\nosupersub\cf1\f2\fs24 Brain \line \tab \up0 \expndtw-1\charscalex100 Re
s\ul0\nosupersub\cf2\f3\fs24 . \ul0\nosupersub\cf3\f4\fs24 1976\ul0\nosupersub\c
f2\f3\fs24 , \ul0\nosupersub\cf1\f2\fs24 105\ul0\nosupersub\cf2\f3\fs24 , 213-22
7. \par\pard\qj \li993\ri797\sb0\sl-340\slmult0\tx1454\tx1454 \up0 \expndtw-3\ch
arscalex100 11. \tab \up0 \expndtw-1\charscalex100 Gonzlez-Forero, D.; Morcuende,
S.; Alvarez, F.J.; de la Cruz, R.R.; Pastor, A.M. Transynaptic \line\tab \up0 \
expndtw-1\charscalex100 effects of tetanus neurotoxin in the oculomotor system.
\ul0\nosupersub\cf1\f2\fs24 Brain\ul0\nosupersub\cf2\f3\fs24 \ul0\nosupersub\cf
3\f4\fs24 2005\ul0\nosupersub\cf2\f3\fs24 , \ul0\nosupersub\cf1\f2\fs24 128\ul0\
nosupersub\cf2\f3\fs24 , 2175-2188. \par\pard\qj \li993\ri797\sb0\sl-340\slmult0
\tx1454\tx1454 \up0 \expndtw-3\charscalex100 12. \tab \up0 \expndtw-1\charscalex
100 Brooks, V.B.; Curtis, D.R.; Eccles, J.C. The action of tetanus tox
in on the inhibition of \line\tab \up0 \expndtw-2\charscalex100 motoneurones
. \ul0\nosupersub\cf1\f2\fs24 J. Physiol\ul0\nosupersub\cf2\f3\fs24 . \ul0\nosup
ersub\cf3\f4\fs24 1957\ul0\nosupersub\cf2\f3\fs24 , \ul0\nosupersub\cf1\f2\fs24
135\ul0\nosupersub\cf2\f3\fs24 , 655-672. \par\pard\ql \li993\ri797\sb0\sl-340\s
lmult0\tx1454\tx1454\tx1454 \up0 \expndtw-3\charscalex100 13. \tab \up0 \expndtw
0\charscalex100 Bergey, G.K.; Bigalke, H.; Nelson, P.G. Differential effects of
tetanus toxin on inhibitory and \line\tab \up0 \expndtw0\charscalex102 excitator
y synaptic transmission in mammalian spinal cord neurons in culture: A presynapt
ic \line \tab \up0 \expndtw-4\charscalex100 locus of action for tetanus toxin. \
ul0\nosupersub\cf1\f2\fs24 J. Neurophysiol\ul0\nosupersub\cf2\f3\fs24 . \ul0\nos
upersub\cf3\f4\fs24 1987\ul0\nosupersub\cf2\f3\fs24 , \ul0\nosupersub\cf1\f2\fs2
4 57\ul0\nosupersub\cf2\f3\fs24 , 121-131. \par\pard\ql \li993\ri798\sb0\sl-340\
slmult0\tx1454\tx1454\tx1454 \up0 \expndtw-3\charscalex100 14. \tab \up0 \expndt
w-1\charscalex100 Gonzalez-Forero, D.; de la Cruz, R.R.; Delgado-Garcia,
J.M.; Alvarez, F.J.; Pastor, A.M. \line\tab \up0 \expndtw0\charscalex100 Fun
ctional alterations of cat abducens neurons after peripheral tetanus neurotoxin
injection. \ul0\nosupersub\cf1\f2\fs24 J. \line \tab \up0 \expndtw0\charscalex10
0 Neurophysiol\ul0\nosupersub\cf2\f3\fs24 . \ul0\nosupersub\cf3\f4\fs24 2003\ul0
\nosupersub\cf2\f3\fs24 , \ul0\nosupersub\cf1\f2\fs24 89\ul0\nosupersub\cf2\f3\f
s24 , 1878-1890. \par\pard\sect\sectd\fs24\paperw11900\paperh16840\pard\sb0\sl-2
tw-3\charscalex100 \ul0\nosupersub\cf3\f4\fs24 81\par\pard\ql \li993\ri794\sb282
\sl-340\slmult0\tx1454\tx1454\tx1454 \up0 \expndtw-3\charscalex100 \ul0\nosupers
ub\cf2\f3\fs24 15. \tab \up0 \expndtw-2\charscalex100 Shin, M.C.; Nonaka, K.; Wa
kita, M.; Yamaga, T.; Torii, Y.; Harakawa, T.; Ginnaga, A.; Ito, Y.; \line\tab \
up0 \expndtw0\charscalex100 Akaike, N. Effects of tetanus toxin on spontaneous a
nd evoked transmitter release at inhibitory \line \tab \up0 \expndtw0\charscalex
100 and excitatory synapses in the rat SDCN neurons. \ul0\nosupersub\cf1\f2\fs24
Toxicon\ul0\nosupersub\cf2\f3\fs24 \ul0\nosupersub\cf3\f4\fs24 2012\ul0\nosupe
rsub\cf2\f3\fs24 , \ul0\nosupersub\cf1\f2\fs24 59\ul0\nosupersub\cf2\f3\fs24 , 3
85-392. \par\pard\ql \li993\ri797\sb0\sl-340\slmult0\tx1454\tx1454\tx1454 \up0 \
expndtw-3\charscalex100 16. \tab \up0 \expndtw-1\charscalex100 Gonzlez-Forero, D
.; Pastor, A.M.; Delgado-Garca, J.M.; de la Cruz, R.R.; Alvarez, F.J. \
line\tab \up0 \expndtw-1\charscalex100 Synaptic structural modification followin
g changes in activity induced by tetanus neurotoxin in \line \tab \up0 \expndtw-
2\charscalex100 cat abducens neurons. \ul0\nosupersub\cf1\f2\fs24 J. Comp. Neuro
l\ul0\nosupersub\cf2\f3\fs24 . \ul0\nosupersub\cf3\f4\fs24 2004\ul0\nosupersub\c
f2\f3\fs24 , \ul0\nosupersub\cf1\f2\fs24 471\ul0\nosupersub\cf2\f3\fs24 , 201-21
8. \par\pard\ql \li993\sb53\sl-276\slmult0\tx1454 \up0 \expndtw-3\charscalex100
\ul0\nosupersub\cf10\f11\fs20 17. \tab \up0 \expndtw-2\charscalex100 \ul0\nosupe
rsub\cf2\f3\fs24 Weng, W.C.; Huang, W.Y.; Peng, T.I.; Chien, Y.Y.; Chang, K.H.;
Ro, L.S.; Lyu, R.K.; Wu, C.L. \par\pard\qj \li1454\ri797\sb12\sl-340\slmult0 \up
0 \expndtw-3\charscalex100 Clinical characteristics of adult tetanus in a Taiwan
medical center. \ul0\nosupersub\cf1\f2\fs24 J. Formos. Med. Assoc\ul0\nosupersu
b\cf2\f3\fs24 . \ul0\nosupersub\cf3\f4\fs24 2011\ul0\nosupersub\cf2\f3\fs24 , \u
p0 \expndtw-4\charscalex100 \ul0\nosupersub\cf1\f2\fs24 110\ul0\nosupersub\cf2\f
3\fs24 , 705-710. \par\pard\qj \li993\ri795\sb0\sl-340\slmult0\tx1454\tx1454 \up
0 \expndtw-3\charscalex100 18. \tab \up0 \expndtw0\charscalex100 Amare, A.; Melk
amu, Y; Mekonnen, D. Tetanus in adults: Clinical presentation, treatment and \li
ne\tab \up0 \expndtw0\charscalex100 predictors of mortality in a tertiary hospit
al in Ethiopia. \ul0\nosupersub\cf1\f2\fs24 J. Neurol. Sci\ul0\nosupersub\cf2\f3
\fs24 . \ul0\nosupersub\cf3\f4\fs24 2012\ul0\nosupersub\cf2\f3\fs24 , \ul0\nosup
ersub\cf1\f2\fs24 317\ul0\nosupersub\cf2\f3\fs24 , 62-65. \par\pard\qj \li993\ri
799\sb0\sl-340\slmult0\tx1454\tx1454 \up0 \expndtw-3\charscalex100 19. \tab \up0
\expndtw0\charscalex104 Meienberg, O.; Burgunder, J.M. Saccadic eye movement d
isorder in cephalic tetanus. \ul0\nosupersub\cf1\f2\fs24 Eur. \line\tab \up0 \ex
pndtw-3\charscalex100 Neurol\ul0\nosupersub\cf2\f3\fs24 . \ul0\nosupersub\cf3\f4
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