Eur. J. Epidemiol. 0392-2990 Vol. I, No.

3
September 1985, p. 193-201

NEUROPHYSIOLOGICAL ASPECTS OF TETANUS

TOXIN EFFECTS ON THE MOTOR SYSTEM

K. T A K A N O
Abteihmg PathoneurophysioIogie, Universitiit GOttingen,
Humboldtallee 23, D-3400 G6ttingen, West Germany

Key words: Tetanus toxin - Motor system - Central nervous system - Synaptic
transmission.

The action of tetanus toxin on the motor system in experimental tetanus

relaLing to the clinical one was reviewed. Special attention was paid to several
controversial results in recent years.

INTRODUCTION muscles, occurring stronger in antigrav,ity muscles,

The m o s t representative sign of the tetanus
intoxication in h u m a n s and animals 'is the hyper-
activity of the m o t o r system. Most of 'the patients
die, if not relaxed by adequate therapy, due to
a n ,apnea, which is caused by the hyperactive
spasms of the r e s p i r a t o r y musc'les.
L o c k j a w ( t r i s m u s ) a n d / o r so-called, local tet-
anus ,, ,are frequently the 'first s y m p t o m s ~o,f the
disease. The latter is characterized by rigidity or
painful m u s c u l a r spasm at the site of injury.
It .occurrence is not too unusual, especially in
light cases but m a n y of t h e m m a y remain unre-
cognized as tetanus by physicians, and some pa-
tients m a y even not visit 'the clinic. Local tetanus
can well be studied experimentally by injection
of tetanus toxin into either the muscle, a peri-
pheral nerve o r the spinal cord.
Fully developed cl,in~,c:al tetanus is r a t h e r well
characterized by gen<eralized hyperactivity of the
(e.g. in the extensor muscles of the legs) and in
the ~masseter (trismus). Experimental general 'tet-
anus c a n be induced by injecting tetanus toxin
in Lravenousty.
This review will describe the action of tetanus
toxin .on the m o t o r system in experimentM tetanus
.and relate it to the state .of clinical tetanus. Spe-
cial attention will be paid to several controversial
results reported in the last ten years. Fo.r recent
general reviews see H a b e r m a n n (24), Kryzhanov-
sky (36), Bizzin,i (4, 5), Takano (62), Mellanby
and .Green (44), Wellh6ner ,(73), Matsuda (41).
FATE OF THE TOXIN IN THE NERVOUS SYSTEM
B i n d i n g to c e n t r a l n e r v o u s s y s t e m . - It i.s well
k n o w n as Wass,ermann-Takaki p h e n o m e n o n (72),
that tetanus to~in has a strong affinity to the
tissue of the central nervous system but not to
other .organs. The gray m a t t e r is stronger m o r e

Corresponding author.

193
 Takano K.
in ,binding the toxin t h a n the white m a t t e r . Tet-
anus :toxin shows ,an o p t i m a l i n t e r a c t i o n w i t h l h e
gangliosid, es containing c e r e b r o s i d e (27, 28). In
s u b f r a c t i o n a t e d gangliosides the s y n a p t o s o m e
m e m b r a n e fraction b o u n d ten times the a m o u n t
of toxin b o u n d by the synaptic vesicles (45).
Dimpfel .et .al. (12) using .cell cultures found that
cereb,rosides w e r e not crucial f o r toxin binding.
Neuronal transport. - T h e r e are n u m b e r s .of stu-
dies showing h o w tetanus toxin reaches its .target
o r g a n w h e n it is :injected into the muscle. I t ,appe-
a r s :well e s t a b l i s h e d t h a t the ,toxin is mainly tran-
s p o r t e d retrograd.ely via the alpha m o t o r axons
to tbe .central n e r v o u s s y s t e m (35, 51, 25, 74). The
ascending axonal ' t r a n s p o r t of the toxin is accele-
r a t e d w h e n n e r v e activity is .increased (75). G r e e n
et al. (22) s h o w e d that the labelled ~2sI,tetanus
to.xin co,u~d be ,found only in a l p h a - m o t o r fibres
in t h e v e n t r a l ro.ot, b u t not in the gamma-fibres.
This finding has been one of the a r g u m e n t s to
.claim 'that .gamma h y p e r a c t i v i t y has ,only sear-
ce significance in tetanus ( h o w e v e r , ~see 65).
Though the .main p a t h w a y of :the tox~in are the
m o t o r nerves, t r a n s p o r t is also possible in vagal
(26) s o m a t o s e n s o r y (19) nerve fibres in cats, and
s y m p a t h e t i c ones in rats (56). Recently K a n d a
and Takano. (31, 32) suggested that the p a r t o,f
the toxin which acts .on the e x c i t a t o r y postsynapti.c
potential ( E P S P ) seems to ascend in sensory fi-
bres b e y o n d the d o r s a l r o o t ganglia.
The speed of the toxin m i g r a t i o n ,in the peri-
pheral n e r v e has b e e n e s t i m a t e d in the r a t as
5-10 m m / h ,(24), or 7.5 m m / h (56) in the sciatic
ner~e .o.f ~he cat 7-9 m m / h '(66). In the b r a i n ,of
the cat it is a b o u t 1 m m / h (6, 9).
In the n a t u r a l disease the toxin p r o d u c e d
b y Clostridium tetani first spreads f r o m the w o u n d
into l y m p h a t i c s y s t e m and then passes into the
blood s t r e a m (25, 53).
H a b e r m a n n and Di.mpSel (25) have i n j e c t e d
i.v. ~2SIdab.ell.ed toxin in rats at doses 1.ower t h a n
LD:~0. They o b s e r v e d high radioactivity in the plas-
m a at the .first d a y a f t e r injection a n d r a p i d
decay in the following days, w h e r e a s the radio-
activity in the central n e r v o u s s y s t e m reached its
m a x i m u m at the second day, foil.owed b y a p.er~.o.d
of c o n s t a n t activity. After the 6th day, the .activity
declined slowly. I t is usuallv p o s t u l a t e d 't(~day
that the toxin first is a b s o r b e d ,at endplates o.f
the muscles and enters into the m o t o r nerve.
H o w e v e r , there are controversial reports, s o m e
showing the toxin within the e n d p l a t e s (76, 50)
while o t h e r s have failed to d e m o n s t r a t e this (20, 80).
A c u r r e n t view is, that general tetanus is the
integration of m u l t i p l e local tetanus .events, due
to u p t a k e o.f toxin f r o m the b l o o d by endplates
t h r o u g h o u t the body (24, 25, 44, 4). However,
this point will be discussed (see ,later).
194
Eur. J. Epidemiol.
Intraspinal and transsynaptic migration.
After i n t r a m u s c u l a r injection into the gastrocne-
mius at a dose several times higher t h a n one cat
m i n i m a l lethal dose (MLD), the first visible sign
(light hobbling of freely moving cat) could be
o b s e r v e d a f t e r 20-30 h, depending ,on the size of
the cat and tax, in doses. I.n the next 10 h the stiff
extension of the leg developed r a t h e r speedy up
to its m a x i m a l degree (66). In this stage it is a n
a l m o s t p u r e local tetanus and the toxin is localized
in the ipsilateral spinal s e g m e n t L7 and S~ (74).
Three to fiwe clays a f t e r toxin injection the
f.o,relegs a n d the c o n t r a l a t e r a l hind leg showed
the t e t a n u s signs, p r o v i d e d the doses w e r e suffi-
ciently high. Is this d e v e l o p m e n t of the *etanus
signs d u e to ,a,n intras,pinal m i g r a t i o n ,of the toxin?
If so, the ipsilateral m i g r a t i o n velocity in the di-
rection of the b o d y axis seems to b e a l m o s t as
high as .in the p e r i p h e r a l nerve while that in the
c o n t r a l a t e r a l side of the spinal cord a p p e a r s to
be one h u n d r e d times slower. T h e r e are a n u m b e r
of ex,p e r i m e n t s since the study of Meyer a n d Ran-
sore (46) which s u p p o r t ,the ,concept of ] n t r a s p i n a i
m i g r a t i o n of the toxin ( f o r review see 80, 44).
However, it is also. possible that the toxin is di-
s t r i b u t e d b y the b l o o d circulati,on .due to the lea-
kage f r o m the injection .site, b e c a u s e the onset
t i m e in all three legs is roughly the same. No ex-
p e r i m e n t concerning the i.ntraspinal migration is
av.ai,lable which employs m o d e r n so,phisticated me-
thods (using a label.led toxin etc.).
When toxin was injected 'into a fast flexor
muscle, like tibialis anterior, initial strong t e t a n u s
signs did not o c c u r in this m u s c l e b u t in the ga-
strocnemi.us. The onset t i m e was 7-8 h o u r s longer
than in the case of injection into the gastrocne-
mius. T r a n s s e g m e n t a l m i g r a t i o n of the toxin f r o m
L 4 t o L 7 (,or L 5 t o S l ) w a s t h e r e f o r e a s s u m e d to
be 7-8 h (66).
Under e x p e r i m e n t a l conditions tetanus toxin
reaches to the r n o t o n e u r o n e s m o s t l y via mo*o.r
nerve fibres. The action of the toxin ,is presynaptic.
This implies that the toxin can r e a c h the presy-
naptic side a p a r t f r o m the m.otoneurone. Trans.sy-
napti.c m i g r a t i o n of the toxin into the ~.motoneu-
ro,ne was suggested b y Schwab and Thoenen (55).
Thev injected labelled toxin at a very high dose
(3.75 t~.g, high purified tox,in) into 'the unilateral
deltoideus muscle .of the rat. 7 or 14 h a f t e r the
injection the radioactivity could b.e r e c o r d e d at
the p r e s y n a p t i c side which was not tbe case in
the control .animal. ( T h e y have not investigated
the c o n t r a l a t e r a l .as a .control side). They f u r t h e r
o b s e r v e d a decrease .of the r o u n d synaptic vesicles
which p r o b a b l y are excitatory ones. The n u m b e r
of the inhibitory, flattened, vesicles was not chan-
ged. They discussed t h a t this .exhaustion of r o u n d
vesicles indicated a h y p e r a c t i v i t y of the e x c i t a t o r y
synapses due t.o disinhibition.
Vol. 1, 1985
ACTION ON T H E MUSCLE
On the s e n s o r y m u s c l e r e c e p t o r s . - There are
several .old studies declearing that the toxin acts
directly on the sensory recepto.rs in the muscle
(e.g. 38, 54; for o t h e r old studies see 80). This
interpretation suffers f r o m the lack of m o d e r n
knowledge in neurophysiology. ]'he a u t h o r s were
no.t aware .of tile efferent innervation .of the ,mus-
cle spindle :by the g a m m a m o t o r cells in the spi-
nal .cord ,(see 65). There 'is no convincing stu-
dy which indicates direct ,effects of this to~in
on the sensory receptors, neither in intra- or
e x t r a m u s c u l a r regions. However, a change of the
p a t t e r n of the muscle spindle discarges, which is
probab,ly ,due to an actio,n on the intrafusal fibres
in local ~etanus, was r e p o r t e d by .our group (49).
On the endplate. - Though the main feature
of tetanus is the hyperactivity of the m o t o r sy-
stem, there is a n u m b e r of observations that the
m a m m a l i a n endplate can be blocked u n d e r some
experimental conditions as well as in ,clinical te-
tanus (10, 48, 35).
Duchen and his group (13, 14, 15) f o u n d that
after .the functional ~, denervation ,, by tetanus
toxin there o c c u r r e d ,a sprouting f r o m moto.r ner-
ve terminals and subsequently the f o r m i n g of
new endplates.
K r e t z s c h m a r et al. (34) have clearly demon-
strated that tetanus toxin blocks the n e u r o m u -
scular :transmission of the pale fast (white phasic)
muscle m o r e strongly than that of the ired stow
(tonic) mus.cle. There was a controversial result
by Duchen and his group, which was .clarified by
our g r o u p (34) as an artifact resulting f r o m the
injection of too large volumes .o.f toxin solution.
Results similar to those of K r e t z s c h m a r et al.
(34), were obtain,ed by o t h e r groups (30, 57, 42, 43).
For f u r t h e r discuss.ion see (63).
A flaccid paralysis was observed when very
large d o s e s of toxin were injected (10, 48, 15,
34, 57). The paralysis was p r e c e d e d by a hyper-
activity of the intoxicated muscle (34).
D i r e c t and~or s e c o n d a r y a c t i o n on the s t r i a t e d
m u s c l e . - The ,early period of clinical as well as
of experimental local tetanus, the main,ta.ined short-
ening of the muscle ~is caused by a ,tonic activity
of the m o t o r units, and therefore a high activity
in the e l e c t r o m y o g r a m (EMG) can b e observed.
When the muscle nerve i.s ,cut the EMG disappears.
In the later period the rigid extension of the
hind leg can f u r t h e r be sustained even wi,thout
any EMG activity. When the muscle nerve 'is cut,
the rigidity persists. This now is a contracture.
Old investigators of tetanus were aware o,f this
fact (e.g. 46).
I n 1928 Ranson (52) showed an increase in
stiffness of the intoxi.caved muscle. The tens.ion-
extension curve of the intoxicated muscle was
195
Tetanus toxin: neurophysiological aspects
studied by (66, 61, 30). Takano and Henatsch (66)
have shown that in the passive tension-extension
relation the a-value (the slopes of the half-loga-
rithmic graph,
t=k.a ~
t tension, k constant, 1 length of stretch) increa-
sed in the slow muscle u n d e r toxin action. They
did not find any a-value change in the fast mu-
scle (60). A change of the a-value could also b.e
observed a f t e r long continuous nerve s~imulation
(unpublished data). These findings indicate that
the change of muscle mechanics 'can be the ~result
of prolcnged high activity of the n e u r o m u s c u l a r
units.
Ebisawa and M a t s u k u r a (16) e.g., f o u n d .by
a u t o p s y of tetanus patients pathological changes
in the striated muscles, a b n o r m a l bleeding, loss
of stripes, r u p t u r e and degenerative changes.
EFFECTS ON N E R V E F I B R E S
Many w o r k e r s have tried to detect effects of
the to~in on the excitable axon m e m b r a n e b u t
f o u n d no such signs in vivo (e.g. 77).
However, a small (but statistically sign~ificant,
p < 0.005) reduc,tion .of the axonal conduction v,e-
locitv of the m o t o r nerve was found by o u r group
(31) which is in accord with the increase .o.f con-
duction time of 'the m o t o r nerve, observed by
Mikhailov and Shvarts (47). In severe cases of
h u m a n tetanus, nerve conduction was also f o u n d
affected (39).
EFFECTS ON MONOSYNAPTIC R E F L E X
AND POSTSYNAPTIC I N H I B I T I O N
OF T H E SPINAL M,OTONEURONE
Brooks, Curtis and E ccles (7) r e p o r t e d no
virtual change in the m o n o s y n a p t i c reflex up to
43 h after toxin injection into the spinal cord
(0.4 or 10 mouse MLD) or into the sciatic nerve
7×106 mouse MLD of the cat. They investigated
five types of p o s t s y n a p t i c inhibition of the moto-
neurone and f o u n d that all of them were blocked
by tetanus toxin. There are several other studies
in s u p p o r t of this statement (e.g. 79, 21). I n these
studies the well k n o w n hypothesis was est,ab-
lished t h a t the .clinical picture, namely a Lgeneral
hyperactivi.ty .o,f the m o t o r system, reflects a di-
sinhibition within the spinal cord.
However, Sverdlov (58) r e p o r t e d depression
of the monosynap,tic reflex in the later preriod
of intoxication. Similar findings were obtained by
Mikhailov and Shvarts (47) with single motoneu-
tones. These russian studies remained unnoticed
by some reviewers (.e.g. 44, 5) or were misinter-
preted (80).
Results of our group (68, 71) clearly showed
partial or total depression of the m o n o s y n a p t i c
Takano K.
reflex after the injection of toxin into the triceps
surae .muscle of the cat at doses of 1 m o u s e
MLD/kg to 10,000 m o u s e MLD/kg. At the time
when the signs of local tetanus .could be .observed
we ,could always see the depression o.f the mono-
synaptic 'reflex.
We could never failed to r e c o r d responses of
alpha motoneuro.nes 'in experiments concerned
with R e n s h a w cells, w h e n a n t i d r o m i c stimulation
of the m o t o r nerve was p e r f o r m e d (1, 33). This
fact showed that the blocking effect of the toxin
was not directed on the mo.toneuronM soma b u t
r a t h e r on its .excitatory synapses. To s u p p o r t the-
se findings K a n d a and Takano r e c o r d e d I a I P S P s
and EPSPs f r o m micro.recorded indivfdual alpha
m o t o n e u r o n e s (31). Tetanus toxin at the dose o,f
100 m o u s e MLD/kg ( c o r r e s p o n d i n g to 0.0'5 cat
MLD/kg) was injected into the medial gastrocne-
mius of the cat. I,aIPSPs could only be prodtlced
up to 30 h after toxin .injection, thereafter they
had disappeared. I a E P S P s were depressed not ear-
lier than 4 days after the injection.
Bigalke (3) a n d Bergey et al. (2) f o u n d si-
milar .effects of tetanus toxin on 'the cultured cell.
They observed also that the blocking of IPSPs
was followed by that of the EPSPs.
H e t e r o n y m o u s EPSPs .remained n o r m a l when
the nerve to the lateral gastrocnemius and soleus
muscle was sectioned just before the toxin injec-
tion. This finding m i g h t be explained bv sugge-
sting that tetanus toxin acting on the EPSP does
not a s c e n d in m o t o r axons but in ,sensory fi,bres.
Wiegand and Wellh6ner (78) :as well as K a n d a
and Takano ,(31), have investigated m o t o n e u r o n e s
in the period of local tetanus, induced by intra-
m u s c u l a r injection o.f small doses of tetanus toxin.
While the rigidity was evident, they did not ob-
serve any change in the electrical pro,perties of
mo,toneurones, such as resting potential, after hy-
perp.olarisalion, m e m b r a n e resistance. However,
these were changed in the cultured cell (11).
POLYSYNAPTIC REFLEXES
AND SPINAL INTERNEURONES
P o I y s y n a p t i c reflex. - A n u m b e r of authors
observed great facilitations .of polysynaptic retie-
xes in the period when the spontaneous activity
of the muscle was increased after the intramus-
cular o r i n t r a n e u r o n . a l injection of the ~toxin
(e.g. 7, 10, 79). The potysynaptic reflexes were
nociceptive reflexes a n d / o r of undefined nature,
since these authors recorded f r o m whole ventral
roots consisting of nerve fibres to flexor as well
as extensor muscles. We have d e m o n s t r a t e d (64)
that the proprioceptive stretch reflex as wel,1 as
non-proprio,ceptive reflexes are facilitated during
tetanus.
196
Eur. J. Epidemiol.
S p i n a l i n t e r n e u r o n e s . - The facilitation o.f the
polysynaptic reflexes indicates hyperactivity of va-
rious interneurones. There are no reports about
the facilitation of particular interneurones, except
for the Renshaw cell and the Ia inhibitory inter-
neurone .( 1 ). When the micropipette .electrode was
iffserted into the spinal .cord to r e c o r d activities
o.f motoneur.ones (31, 32) or Renshaw cells (1, 33)
a highly increased spontaneous activity of unde-
fined interneurones was frequently observed in
the int,oxicated animal, as c o m p a r e d to the non-
intoxicated one.
First observations about 'the Renshaw cell du-
ring tetanus intoxication were made by Brooks
et al. (7). They r e p o r t e d that the ,toxin prevented
the r e c u r r e n t inhibitory action of the Renshaw
cell on the m o t o n e u r o n e , w i t h o u t altering the re-
sponse of the Kenshaw cells themselves. Curtis
and de Groat (8) demons'trated that tetanus toxin
reduced the a m o u n t of glycine, released f r o m in-
hibitory p r e s y n a p t i c terminals.
Benecke et al. (1), showed that the response
to a n t i d r o m i c m o t o r nerve stimulation as well as
the spontaneous activity o.f the Renshaw cell in-
creased during the development of local .tetanus.
Kircbn.er and Takano (33) observed .the Renshaw
cell activity for longer times after the intramus-
cular injection of the toxin. The a n t i d r o m i c re-
sponses as well as spontaneous activity of the
Renshaw cell r e t u r n e d to n o r m a l levels after a
while. The m u t u a l inhibition of Renshaw ceils,
however, disappeared in the local tetanus.
In c o n t r a s t to the fact that the toxin can
block the endplate, the .cholinergic syn,apses on
the Renshaw cell were always left intact in all
studies .on this subject (7, 1, 33).
Wellh6ner (73) w r o t e that the activation by
tetanus toxin of spinal c o r d functions m a y not
be due to an effect .on m o t o n e u r o n e s but on inter-
neurones adjacent to them. If so, one might be
able to prevent the spinal ,effects o~f the toxin b y
intrathecal ~injection of antitoxin. This has been
achieved by E r d m a n n et al..(18).
PRESYNAPTIC INHIBITION
The depolarisation of p r i m a r y afferent fibres
t h r o u g h axo-axonal synapses reduces the ampli-
tude of their terminal action potentials, .resulting
in .a decrease .of t r a n s m i t t e r release f r o m the pre-
synaptic terminals on motoneurones. Consequen-
tly the excitatory p o s t s y n a p t i c potential of the
m o t o n e u r o n e is depressed. This action is k n o w n
as presynaptic ,inhibition. The electronic spread
of depolarizati,on of the p r i m a r y afferent endings
can be recorded f r o m the dorsal root surface of
the spinal cord, which is called ,, .dorsal root po-
tential ,,. Presynaptic inhibition ,is .characterized
by its ,delayed appearance ,and prolonged duration
Vol. 1, 1985
(for f u r t h e r i n f o r m a t i o n see textbooks of neuro-
physiology).
Sverdloaz a n d Aleks.eeva (59) r e p o r t e d that ap-
p a r e n t p r e s y n a p t i c inhibition of gastrocnemius ,mo-
toneurones was decreased in local tetanus after to-
xin injection at doses of 500-1000 mo.use MLD/kg in-
to the g a s t r o c n e m i u s muscle, but that ,the dorsal
roo.t potential was not changed.
Curtis and his coworkers (9) f o u n d neither
dorsal root potentials n o r presynaptic inhibition
nine hours after they had injected tetanus toxin
at doses .of 6000 m o u s e MLD/kg tinto the lateral
aspect of the ventral h o r n at $1-$2 junction of
the cat.
On the other h a n d K r y z h a n o v s k y and Lut-
senko (37) f o u n d an increase of the dorsal root
potential after i n t r a m u s c u l a r injecti,on of toxin at
the dose of 5 rat MLD. We, too, observed that
the presynaptic inhibition was prolonged up to
2000 ms or m o r e u n d e r the toxin action.
T,o study presynaptic inhibition, we ,i,njected
tetanus toxin ,at doses of 2-2000 m o u s e MLD/kg
into the gastrocnemius of the left bind leg of the
cat. Acute experiments were p e r f o r m e d at various
later times when the intoxicated hind leg was
strongly extended. An inhibition of p r e s u m e d pve-
synaptic ,type of the m o n o s y n a p t i c reflex of ga-
strocnemius m o t o n e u r o n e s was elicited by single
electrical stimuli to the antagonistic deep pero-
neal nerve. I n d e p e n d e n t of the doses used, the
typical long lasting inhibition (up to 2000 m s )
c o u l d be observed as long as the m o n o s y n a p t i c
reflex could be r e c o r d e d (71).
Considering the different m e t h o d s o.f toxin
application in the experiments of the groups on
presynaptic .inhibit:ion, we come to the foil.owing
conclusions: Tetanus toxin at a high local con-
centration blocks or reduces b o t h the p r e s y n a p t i c
inhibition a n d the dorsal root potential, p r o b a b l y
by depressing the t r a n s m i t t e r release at the axo-
axonal Synapses as shown in .the study of Curtis
et ,al. (9). When the local c o n c e n t r a t i o n is consi-
derably lower, like in the studies of S~¢erdlov and
Alekseeva (59), .of K r y z h a n o v s k y and Lutsenko
(37) and of ,ours ,(71), the m e c h a n i s m ,of presy-
nap,tic inh,ib.ition seems to remain intact, or m i g h t
even be a u g m e n t e d for so,me time.
In h u m a n ~e.tanus intoxication, which com-
m o n l y shows s y m p t o m s of general tetanus, the
toxin c o n c e n t r a t i o n within the spinal segments is
far lower than can be achieved in most experi-
ments with local tetanus. Therefore it ~s highly
probable that p r e s y n a p t i c inhibition is left intact
in clinical tetanus.
GENERAL (,OR GENERALIZED) TETANUS
AFTER TOXIN INJECTION
Though the experimental generalized tetanus
after intravenous injection of tetanus toxin, ,is a
197
Tetanus toxin: neuro.physiologicaI aspects
better s.imulation of the clinical tetanus than the
experimental local tetanus, there .are only few
neurophysiologieal experiments on the m o t o r sy-
stem after i.v. injection of the toxin.
H a b e r m a n n and Dimpfel (25) injected 12sI-
labelled tetanus toxin i.v. in rats. After a few
hours they could find some radioactivity in the
brain stem and spinal cord, but not in the fore-
brain and cerebellum. Less than 1% of the radio-
activity injected was fo.und in the structures of
central nervous system. They concluded that the
blood-brain b a r r i e r was practically impermeable
for tetanus toxin. After m o r e detailed study Erd-
m a n n and H a b e r m a n n (1.7) pushed f o r w a r d s the
hypothesis that generalized tetanus is a multiple
local tetanus.
When Huck et al. (29) injected tetanus toxin
( 2 x 1 0 s m o u s e LD~0)i.v. in rabbits, a r h y t h m i c
electrical activity was recorded in the cerebellum
and in the spinal cord. More than 50% of alpha-
and g a m m a - m o t o n e u r o n e s to the extensor muscle
and o,f Renshaw cells in the L 7 spinal segment
discharged =in correlation with the :cerebellum wa-
ves. Cooling of the surface of cerebellum suppres-
sed the r h y t h m i c activity in the cerebellum as
well as in the spinal cord. After spinal transection
at T 2 the r h y t h m i c .activity could be r e c o r d e d in
the cerebellum but no longer in the spinal cord.
F r o m these results we concluded that ~h.e
main source of the r h y t h m i c hyperactivity o.f the
spinal cord, as observed in the generalized tetanus,
lies no,t in the spinal c o r d itself but in the supra-
spinal structures, possibly in the brain stem.
In severe cases o,f general tetanus of the cat we
could totally inhibit the ,stretch reflex using severa,1
types .of postsynaptic inhibition .(e.g. an~tagonistic
and Ib .inhibition) as well as presynaptic tinhib.ition
(69). Also the m u t u a l inhibition o,f Renshaw cells
in rabbits could always be observed during this
stage in contrast to local tetanus. (Kirchner, un-
publ,ished observation).
In view o.f these results a critical reconside-
ration of the hypothesis that the general tetanus
is ran :integration of the multiple local tetanus is
needed. R e m e m b e r that b o t h types of synapses
can be blocked in local tetanus when toxin dose
is low.
GAMMA MOTOR SYSTEM
The ~importance of the g a m m a m o t o r system
in the m o t o r control functions is well establ, ish.ed
(see text books of neurop.hysio!ogy). The possible
contri,bution of the g a m m a m o t o r ,system ,in tet-
anus :disease was discussed by m a n y reviewers.
My point of view, based on a series of specific
experiments, is that the g a m m a m o t o r system
plays an ,important role in clinical as well as in
refevant experimental tetanus. One m a y be remin-
Takano K.
ded that the first t h e r a p e u t i c a l choice of m o s t
physicians in .cases of tetanus is the a p p l i c a t i o n
of d i a z e p a m or o t h e r b.enzodiazepines (.e.g. 40)
which act p a r t i c u l a r l y on the g a m m a s y s t e m (70).
For f u r t h e r details see a s e p a r a t e review special
on that subject which a p p e a r s e l s e w h e r e (65).
ACTION OF TETANUS TOXIN INJECTED
INTO THE BRAIN
Many a u t h o r s have injected the toxin directly
at definite sites of the brain. I n m o s t o.f these
studies a b n o r m a l m o t o r activities like seizures and
forced turning m o v e m e n t s could be observed. Wel-
lhSn.er (73) has p r e s e n t e d an extensive table of
the effects o b t a i n e d in such studies.
PRESYNAPTIC ACTION OF TETANUS TOXIN
Many a u t h o r s have suggested or d e m o n s t r a -
ted that the action of tetanus toxin .on the end-
plate is located p r e s y n a p t i c a l l y (see for review 73).
T e t a n u s ,toxin can b l o c k the n e u r o m u s c u l a r tran-
smission b u t does not block the r e c e p t o r s for the
t r a n s m i t * e r at the .postsynaptic .membrane. The
thesis of p r e s y n a p t i c action of the toxin on the
e n d p l a t e was s u p p o r t e d by m o r p h o l o g i c a l stu-
dies (50, 76).
Curtis a n d de G r o a t (8) f o u n d t h a t tetanus
toxin blocks the synaptic inhibition by the Ren-
shaw cell w i t h o u t affecting the inhibitory action
of glycine. Glycine is a s s u m e d to be the t r a n s m i t -
ter o,f the inhibitory synapses f o r m e d b y the Ren-
s h a w cell at m o t o n e u r o n e s as well .as in o t h e r ty-
pes of p o s t s y n a p t i c ,inhibition. They suggested t h a t
t e t a n u s toxin exerts its action by reducing the
a m o u n t of glycine released f r o m the inhibitory
terminals. F u r t h e r Curtis et al. (9) d e m o n s ' t r a t e d
t h a t the inhibitory action of the P u r k i n j e cell was
totally d e p r e s s e d by tetanus toxin. The P u r k i n j e
.cell could be d e p r e s s e d by electrophoretic appli-
cation .of GABA. This s t u d y also suggests that the
toxin dimin, ished the synaptic release o.f GABA
r a t h e r t h a n 'its p o s t s y n a p t i c .effect. The s a m e con-
clusion was m a d e by Gushkin et al. (23), w i t h
respect to the m o t o n e u r o n e .
GENERAL DISCUSSION
Discrepancies of the results of various inve-
stigations r e p o r t e d ,above, seem to be due m o s t l y
to different toxin applications and o t h e r varia-
tions of e x p e r i m e n t a l conditions (e.g. animal spe-
cies, t i m e a f t e r injection). H a b e r m a n n (24), as
well as o u r group (67), have distinguished two
types .of ,experimentation: one a i m e d at the m o d e
.of action of the toxin w i t h o u t being i n t e r e s t e d
in the clinical relevance, the o t h e r was designed
198
Eur. J. Epidemiol.
to elucidate the pathogenesis and t h e r a p y of te-
tanus. In m o s t cases of m o d e r n .animal experi-
ments, the local c o n c e n t r a t i o n of tetanus tox,in
at the investigated site was far higher t h a n in
the case o.f the .clinical disease.
Let us r e t u r n to the principal question: W h a t
is the ,origine o.f the h y p e r a c t i v i t y of the m o t o r
s y s t e m in tetanus a p p e a r i n g as convulsions and
rigidi.ty? The e x p e r i m e n t a l finding t h a t the moto-
n e u r o n e s of the spinal c o r d .or o t h e r nerve cells
in the central nervous s y s t e m are ,disinhibited in
the early period a f t e r local injection of toxin, was
e x t r a p o l a t e d to the situation in clinical tetanus.
Under the .assumption that the general tetanus
m i g h t be a multiple local tetanus, one t r i e d to
explain the prevailing h y p e r a c t i v i t y b y an overall
general disinhibition of all p a r t s of m o t o r system.
However, we have seen t h a t in the later pe-
riod of 1.ocal tetanus the excitatory .transmission
to mo.toneurones is also d e p r e s s e d at low toxin
doses, the endplate can be blocked and the muscle
itself r e m a i n s in a rigid state w i t h o u t any elec-
trical ,activity .(contracture). Therefore, the disin-
hibition of the spinal m o t o n e u r 0 n e s ~is obviously
p r e d o m i n a n t only in the early d e v e l o p m e n t of
,the iocM tetanus as already described. We ,co-
uM also .observe the intact functioning .many
types of inhibition in the spinal ,cord u n d e r ge-
neral tetanus. T,o m a i n t a i n the state which causes
co,n~vulsions a n d rigidity, excitation as well ,as in-
hibition of the m o t o n e u r o n e s m u s t be r a t h e r intact.
I t could be suggested t h a t the .origin of general
m o t o r h y p e r a c t i v i t y lies in higher central n e r v o u s
structures, including s u p r a s p i n a l g a m m a mo.tor
,activation, and not in the spinal cord. I t is an open
question w h e t h e r such higher centres a r e solely
responsible for the state of general tetanus, or
w e t h e r ~it also needs s o m e s u p p l e m e n t a r y actions
of the toxin at the spinal m o t o r level.
~eknowledgement
This study is dedicated to Prof. Dr. H.D. Henatsch
on occasion of his 65th aniversary. The author thanks
Prof Dr. H.D. Henatsch and Dr. F. Kirchner for
reading the manuscript.
Vol. 1, 1985
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