A Goonetilleke, J B Harris
J Neurol Neurosurg Psychiatry 2004;75(Suppl III):iii35–iii39. doi: 10.1136/jnnp.2004.046102
See end of article for authors’
Dr A Goonetilleke,
Department of Neurology,
Newcastle General Hospital,
Centre, Newcastle upon Tyne,
NE4 6BE; ajith.goonetilleke@
marine and freshwater sediments. Many clostridial species produce medically important toxins
but the species of neurological interest (Clostridium tetani and Clostridium botulinum) produce
neurotoxins. The toxins responsible for these neurotoxic syndromes are tetanus toxin (sometimes
known as tetanospasmin) and the botulinum toxins.
he genus Clostridium comprises a number of spore forming Gram positive, rod shaped bacilli.
They are found in the intestines of numerous mammalian species including domestic
animals, horses, chickens, and humans. They are also widely distributed in the soil and in
Tetanus and botulinum toxins share several important features: they are produced as a single
polypeptide of 75 kb which undergoes post-translational cleavage to form a heavy (H) chain and
a lighter (L) chain of 100 kDa and 50 kDa, respectively, linked by a single disulfide bond. The H
chain facilitates binding to gangliosides on the plasma membrane of peripheral nerve terminals
before internalisation via receptor mediated endocytosis. Protonation of the endosome results in
the reduction of the disulfide bond. The H chain forms a transmembrane pore across the
endosome and the L chain then enters the nerve terminal cytosol. The L chains of both tetanus
and botulinum toxins are zinc activated proteases. Their targets are a number of specific proteins
involved in synaptic vesicle docking—synaptobrevin (also know as VAMP), SNAP-25, and
The toxins selectively target individual proteins (table 1), but the result is always the same—the
hydrolysis of the target protein, blockade of transmitter release, and a resultant flaccid paralysis.
While the botulinum toxins remain in the nerve terminal the tetanus toxin is transported by
retrograde axonal transport into the cell body and then by transynaptic exchange into the
terminals of inhibitory neurones in the spinal cord and brain stem. The resultant inhibition of
inhibitory transmission by the tetanus toxin results in the dominant clinical features of
hyperexcitability combined with clinical weakness between spasms and the paralysis of cranial
nerves (as seen in cephalic tetanus). Both tetanus and botulinum toxins affect both somatic and
autonomic nervous systems, but autonomic features (for example, labile hypertension and
tachycardia) are more common in tetanus.
C tetani form resilient spores capable of surviving household disinfectants and boiling in water for
several minutes. In conditions of low oxygen tension (for example, wounds) the spores germinate
and the resultant bacteria multiply and produce a neurotoxin responsible for the clinical features
Generalised tetanus is the most common presentation in which muscles throughout the body
are affected, with the head and neck being usually affected first followed by a caudal spread of
spasms. Tetanus following intramuscular injections of quinine has a particularly poor prognosis;
the low pH of quinine may facilitate the entry of tetanus toxin into nerves. Quinine is often mixed
with heroin as it has a bitter taste that resembles heroin. The effects of quinine may therefore also
explain the poorer prognosis of tetanus in drug abusers.
Localised tetanus occurs if the rigidity and pain remain localised to the site of injury, and is
usually associated with a better prognosis. An exception is cephalic tetanus following a head or
neck injury, and which is associated with a high mortality. A unilateral lower motor neurone
facial weakness is the most common involvement in cephalic tetanus, though other lower cranial
nerves and the oculomotor nerve may also be affected.
Tetanus neonatorum is rare in the developed world. The condition arises from poor umbilical
hygiene, and is prevalent in communities that employ traditional midwifery practices such as
cutting the cord with grass or dirty scissors, or rubbing manure on the umbilical stump. The
affected neonate presents within a week of birth with a failure to feed, vomiting, and
‘‘convulsions’’. The disease may be prevented by improved
hygiene and by maternal vaccination, even if the latter is
administered during the pregnancy.
Despite the World Health Organization’s intention of
eradicating tetanus by 1995 there are still 800 000 to 1
million deaths worldwide each year from tetanus, with half
these deaths caused by neonatal tetanus. Most fatal cases
occur in Africa and South East Asia, where the problem
remains endemic. In these regions mortality is related to
limited access to artificial ventilation—for neonatal tetanus
mortality is 65–90% without ventilation and drops to 10%
with ventilation. There are 12–15 cases in Britain and 50–70
cases of tetanus in the USA each year. In such countries with
access to assisted ventilation the mortality is negligible in
young adults, but increases to over 50% in patients over 60
years of age. The age related differences in mortality may be
caused by waning immunoprotection.2Death may occur due
to autonomic dysfunction or the complications (for example,
sepsis, thromboemboli) of prolonged critical illness. Although
tetanus is easily preventable by immunisation (the first
effective vaccine was produced over 100 years ago), it is tragic
that many people still remain unprotected.
Tetanus usually occurs following a deep penetrating wound
where anaerobic bacterial growth may occur, particularly if
the wound is contaminated by soil, manure or rusty metal. It
may also occur by other mechanisms such as in burns, ulcers,
septic abortions, circumcisions, intramuscular injections,
acupuncture, ear piercing, tattooing, poor dentition, chronic
otitis media, and following snakebites. In up to 30% of cases
the portal of entry cannot be identified.
The incubation period (time of inoculation to the first
symptom) is usually 7–10 days (range 1–60 days), and the
period of onset (time from first symptoms to the start of
spasms) is 1–7 days. The severer forms of the disease have
shorter incubation periods and periods of onset.
The clinical picture is dominated by muscle spasms,
rigidity, and autonomic disturbances.3 4Neck stiffness, sore
throat, and difficulty opening the mouth are the earliest
features. Masseter spasm causes trismus (‘‘lockjaw’’), with
the spasms extending to the facial muscles to cause a
characteristic facial expression (‘‘risus sardonicus’’). Muscle
spasms may lead to laryngeal obstruction as well as
decreased chest wall compliance, resulting in respiratory
compromise. Involvement of axial muscles leads to neck
extension, and truncal rigidity may lead to opisthotonus.
Back pain, trismus, muscle stiffness, and dysphagia are
common. The episodic spasms tend to be extremely painful
and affect agonist and antagonist muscle groups together,
and may be spontaneous or stimulus sensitive (triggered by
touch, visual, auditory, or emotional stimuli). These spasms
may appear convulsive in nature and be violent enough to
cause fractures or tendon avulsions. Rigidity is most
prominent in muscles adjacent to the portal of entry. The
autonomic disturbances can lead to labile hypertension,
tachycardia, pyrexia, profuse sweating, excessive bronchial
secretions, gastric stasis, and diarrhoea. The hypertension is
predominantly caused by increases in systemic vascular
resistance secondary to raised concentrations of circulating
catecholamines similar to those seen in phaeochromocytoma.
Increasing muscle spasms and rigidity characterise the first
week of illness. Autonomic disturbances usually start a few
days after the spasms and reach a peak during the second
week, and persist for 1–2 weeks. Spasms start to subside after
2–3 weeks, but the muscle rigidity may continue long after
the spasms and autonomic involvement have subsided.
Muscle rigidity may last up to 6–8 weeks in severe cases.
Various grading systems of severity of tetanus have been
described, one of the most commonly used being the Ablett
system (table 2). Other scoring systems (for example, Dakar
and Phillips scores) have also been devised to assess overall
The diagnosis is made clinically as there is no specific
confirmatory investigation. A positive culture of C tetani from
a wound would be supportive evidence for the diagnosis.
The differential diagnosis for tetanus may be diverse.
Intense muscle rigidity may be mistaken for acute dystonic
reactions. Rigidity of abdominal muscles may mimic an acute
abdomen. Poisoning by strychnine (a competitive antagonist
of glycine) may mimic tetanus. Cephalic tetanus may be
difficult to differentiate from other causes of cranial nerve
palsies—helpful clinical pointers include impaired mouth
opening and complaints of dysphagia which are commonly
seen in tetanus. The ‘‘spatula test’’ (stimulation of the
pharynx with a spatula provokes an intense spasm of the
masseters resulting in the patient biting the spatula) may aid
in diagnosis, though this should be performed with great care
as intense pharyngeal and laryngeal muscle spasm may occur
leading to respiratory arrest. Neonatal tetanus may need to be
differentiated from hypocalcaemia, hypoglycaemia, neonatal
seizures, and meningitis.
Wounds from which the infection originated should be
surgically debrided and an antibiotic administered. Penicillin
has been the worldwide antibiotic of choice. However, the
structure of penicillin is similar to c aminobutyric acid
Clostridial neurotoxins and their target proteins
The Ablett classification of tetanus severity
IMild-moderate trismus; general spasticity; no spasms; no
respiratory embarrassment; little or no dysphagia
Moderate trismus; well marked rigidity; mild-moderate but
short spasms; moderate respiratory embarrassment with RR
.30/min; mild dysphagia
Severe trismus; generalised spasticity; reflex prolonged
spasms; RR .40/min; severe dysphagia; HR .120/min
Grade III and severe autonomic disturbances affecting
cardiovascular system (for example, severe hypertension and
tachycardia alternating with relative hypotension and
bradycardia, either of which may be persistent)
HR, heart rate RR; respiratory rate.
NEUROLOGY IN PRACTICE
(GABA); it therefore acts as a competitive GABA antagonist,
and in high doses may cause central nervous system (CNS)
hyperexcitability and convulsions. In tetanus this potential
side effect of penicillin may act synergistically with the toxin
to block GABA neuronal activity. Metronidazole is therefore
considered to be the antibiotic of choice in the treatment of
tetanus. Comparative studies in human tetanus have
demonstrated the superiority of metronidazole over peni-
cillin. Antibiotics should be administered for 7–10 days.
Alternative agents that may be used include erythromycin,
tetracycline, vancomycin, clindamycin, doxycycline, and
Passive vaccination with anti-tetanus immunoglobulin
shortens the course and may reduce the severity of the
illness. Anaphylactic reactions occur in approximately 20% of
cases receiving the equine antitoxin, and in 1% may be severe
enough to require the use of adrenaline (epinephrine),
steroids, and intravenous fluids; such reactions occur much
less frequently with the human antitoxin. For prophylaxis
against tetanus passive immunisation should be given as
soon as possible after an injury.
Active immunisation (that is, tetanus toxoid) also needs to
be given to add to the short term immunity provided by anti-
tetanus immunoglobulin, as well as providing longer term
humoral and cellular immunity. The toxoid and the anti-
tetanus immunoglobulin need to be given at different sites of
the body to prevent interaction at the injection site. Also, if
they are to be administered at the same time the dose of anti-
tetanus immunoglobulin needs to be modified, as higher
doses may neutralise the immunogenicity of the toxoid.
Reactions to the toxoid occur in approximately one in 50 000
of injections. Reactions include local tenderness, oedema, flu-
like illness, and a low grade fever. Severe reactions to the
toxoid are rare, and include a Guillain-Barre ´ type syndrome.
External stimuli provoke muscle spasms and may worsen
the autonomic disturbances in tetanus. Unnecessary stimuli
should therefore be minimised, and all patients should
therefore receive adequate sedation and be nursed in a
darkened and quiet room. The benzodiazepines (which
augment GABA activity) are the sedatives most commonly
used. Diazepam is given initially as intravenous boluses (total
daily doses of up to 200 mg are common) followed by oral
administration in the recovery phase. Midazolam is a suitable
alternative with a shorter half life. Parenteral boluses of
morphine can also prove beneficial for sedation. Morphine
also induces peripheral venous and arteriolar dilatation,
probably by reducing sympathetic discharge centrally, an
effect which can offset some of the autonomic disturbances
seen in tetanus.
If muscle spasms persist despite adequate sedation, muscle
relaxants may be required. Traditionally the long acting agent
pancuronium has been used to achieve muscular paralysis.
However, this agent inhibits catecholamine reuptake and
may therefore worsen autonomic instability and cause
hypertension and tachycardia in the more severe cases.
Pipercuronium and rocuronium are newer longer acting
agents with fewer cardiovascular effects, but are relatively
expensive. Vecuronium similarly has fewer cardiovascular
effects but is shorter acting. Baclofen and dantrolene tend
to be less effective agents in relieving muscle spasms in this
context. If muscle spasms are severe enough to require
such agents the patients also usually require assisted
Excessive bronchial secretions and hypersalivation result-
ing from autonomic overactivity, in conjunction with
laryngeal spasms and dysphagia, make aspiration a particular
complication that needs to be guarded against in tetanus.
Protection of the airway may require percutaneous tracheos-
tomy. Assisted ventilation may be required if there is any
respiratory impairment. Autonomic disturbances (for exam-
ple, labile hypertension, tachycardia, vasoconstriction, excess
sweating) may need to be corrected. The routine use of agents
that block autonomic transmitters and receptor blockers (for
example, magnesium, a blockers, b blockers, atropine) have
not shown consistent benefits in tetanus; therefore, auto-
nomic functions should be monitored and any specific
complications treated as they arise.
Most adults start to recover once the muscle spasms have
subsided. In most cases recovery is complete. Some of the
long term sequelae of tetanus include limb contractures, bed
sores, seizures, myoclonus, and sleep disturbances. The
prognosis is generally worse in neonates, especially if
prolonged hypoxic periods had occurred during the illness.
Overall the prognosis is dependent on disease severity and
the medical facilities available, with particular regard to
access to ventilation.
Human botulism occurs in a variety of forms. Food-borne
botulism occurs after the ingestion of food contaminated
with C botulinum containing the pre-formed toxin. This form
typically occurs when susceptible foods are exposed to room
temperatures for prolonged periods. Wound botulism occurs
in wounds contaminated with C botulinum spores. Increasing
numbers of cases of wound botulism have been reported in
drug addicts in the USA following the subcutaneous injection
of black tar heroin (‘‘skin popping’’).5 6Infant/adult intestinal
botulism occurs when spores are ingested and then germi-
nate in the intestinal tract. Infants less than 1 year of age
(95% of infants being younger than 6 months) and adults
with a history of gastrointestinal abnormalities or antibiotic
use may contract this form. Infant botulism is the most
reported form of botulism. In the USA approximately 110
cases of botulism are reported annually, with infant botulism
accounting for 72% of cases compared to 25% caused by food
borne botulism. The caecum is thought to be the initial site of
activity, and paralysis of the ileocaecal valve may allow the
colonising bacteria to extend into the terminal ileum. Soil
and the ingestion of honey are the two well recognised
sources of spores in infant botulism.7C botulinum may be
present in 10% of honey supplies in the USA where it has
been linked with 20–35% of known cases of infant botulism.
As a preventative measure honey should not be fed to infants
younger than 12 months of age. The infant’s intestinal tract
lacks the protective bacterial flora of the adult, allowing
colonisation by C botulinum. Once colonisation occurs the
toxin produced is absorbed through the intestinal tract.
The role of breastfeeding in infant botulism is unclear.
Breastfeeding occurs in 70–90% of infants with botulism, and
in a prospective case–control study was found to be a risk
factor for the development of the disease in infants younger
than 2 months of age.7However, breast feeding may delay the
disease such that infants reach medical attention in time for
supportive care, and may therefore be a protective feature.8
Inhalational botulism occurs from the absorption of a man
made aerosolised version of the toxin from the lung mucosa,
and may occur in the context of a bioterrorist attack.9
NEUROLOGY IN PRACTICE
Inadvertent/iatrogenic botulism occurs in patients being
treated with botulinum toxin.
Of the seven distinct serotypes of botulinum toxin (types
A–G), most forms of human poisoning are caused by types A,
B, E, and F. Food borne botulism results from the absorp-
tion of toxins A, B, E, and F, whereas intestinal and wound
botulism results from toxin type C originating from dead
tissue. Infant botulism is caused by types A and B. Type A
toxin is typically found in home preserved and canned
foods that have not been heated to the correct tempera-
ture. Home preserved vegetables, fish, and meat are
recognised sources of infection. Type A toxin is usually
associated with more severe disease and a higher mortality
rate than type B or E toxin. Type E toxin is often associated
with the ingestion of contaminated seafood, but can occur
with other foods.
All forms of botulism produce similar effects, and should
always be considered in afebrile and alert patients presenting
with a descending flaccid paralysis with intact sensation. The
incubation period and time to onset of symptoms is
determined by the amount of toxin absorbed. In food borne
botulism the time to onset of neurological symptoms varies
from 2–36 hours, but can be up to eight days.
An initial involvement of cranial nerves (resulting in
blurred vision, diplopia, dysarthria, dysphonia, or dysphagia)
is usually followed by an acute, symmetric, descending
flaccid paralysis that may lead to respiratory failure. Enlarged
or sluggishly reactive pupils are common. There are no
sensory or autonomic features, and the central nervous
system is rarely involved. In food borne botulism gastro-
intestinal effects (for example, nausea, vomiting, abdominal
cramps, diarrhoea, and constipation) may occur in up to half
the cases, and may precede the neurological features. Infant
botulism typically presents with lethargy, poor feeding,
and loss of head control. Constipation is a classical presenta-
tion,andmay precede weakness
Hypotension, neurogenic bladder, and other autonomic
features may occur early. Weakness typically starts with
cranial nerve involvement and loss of head control. The
infant may also have a weak cry, poor sucking ability,
impaired gag responses, pooling of secretions, and decreased
The diagnosis is predominantly a clinical one, and is
confirmed by testing for the toxin or organism. Toxin
isolation from serum occurs in 35% of cases, but this figure
drops if the sample is collected more than two days after
ingestion. Only 35% of stool cultures are positive after three
days.10The most reliable test for the C botulinum toxin is the
mouse inoculation test, whereby mice exposed and non-
exposed to type specific botulinum anti-toxin are injected
with the patient’s serum. A test is deemed positive if the non-
exposed mice die within 24–48 hours. Neurophysiological
investigations may aid in the diagnosis and show features of
a pre-synaptic neuromuscular junction deficit, with reduced
amplitude compound muscle action potentials (CMAPs) but
with normal motor conduction velocities and completely
normal sensory studies. A diagnostic triad of (1) decreased
amplitude of CMAPs in at least two muscle groups, (2)
tetanic or post-tetanic facilitation (defined by a CMAP
amplitude of more than 120% of baseline) after at least
10 seconds of tetanic stimulation at 50 Hz, and (3) pro-
longed post-tetanic facilitation of more than 120 seconds
and absence of post-tetanic exhaustion has been described
for diagnosis.11As studies may be normal in the early
stages repeat testing after an interval of 7–10 days may be
The differential diagnosis for botulism includes acute inflam-
matory demyelinating polyneuropathy (that is, Guillain-Barre ´
syndrome), porphyria, poliomyelitis, diphtheria, tick paraly-
sis, myasthenia gravis, and magnesium toxicity. Onset with
a bulbar weakness followed by a descending paralysis in a
patient with sluggish pupillary reactions and intact sensa-
tion is suggestive of botulism. Diagnosis of infant botulism
may be delayed because of the relatively non-specific
symptoms that may occur in this condition at onset. Tick
paralysis tends to occur in older and more mobile children
than in botulism.
Treatment is mainly supportive. As respiratory muscles may
be involved rapidly, patients suspected of botulism should
be initially managed in an intensive therapy unit. In patients
at risk of respiratory failure elective intubation and venti-
lation should be undertaken. Gastric lavage or induced
emesis should be considered if contaminated food was
ingested recently. The early use of antibiotics and surgical
debridement should be considered in wound botulism.
Neuromuscular junction blocking agents (for example,
aminoglycosides, magnesium containing compounds) should
Clostridial neurotoxins: key points
c Tetanus is easily preventable by active immunisation with
the tetanus toxoid
c The clinical picture in tetanus is dominated by muscle
spasms, rigidity, and autonomic disturbances
c The diagnosis in tetanus is made clinically as there is no
specific confirmatory investigation. A positive culture of
Clostridium tetani from a wound would be supportive
evidence for the diagnosis
c Wounds from which the infection causing tetanus
originated should be surgically debrided. Metronidazole
is considered to be the antibiotic of choice in the treatment
of tetanus, but penicillin is a suitable alternative. Passive
vaccination with anti-tetanus immunoglobulin shortens the
course and may reduce the severity of the illness. Active
immunisation (that is, tetanus toxoid) also needs to be
given to add to the short term immunity provided by anti-
tetanus immunoglobulin, as well as providing longer term
humoral and cellular immunity
c All forms of botulism produce a flaccid paralysis with
c In food borne and infant botulism gastrointestinal effects
often precede the neurological features
c The diagnosis in botulism is predominantly a clinical one,
and is confirmed by testing for the toxin or organism.
Neurophysiological investigations may aid in the diag-
nosis and show features of a pre-synaptic neuromuscular
c Specific treatment in botulism historically consists of the
early use of a trivalent antitoxin that neutralises toxin
serotypes A, B, and E
c The early use of antibiotics and surgical debridement
should be considered in wound botulism
NEUROLOGY IN PRACTICE
Specific treatment historically consists of the early use of a Download full-text
trivalent antitoxin that neutralises toxin types A, B, and E.
Significant side effects to the antitoxin may occur in more
than 20% of cases. The equine derived antitoxin has now
been superseded by a human derived antitoxin. A repeat dose
of antitoxin may be given 2–4 hours later, with doses
repeated at 12–24 hour intervals if required. The antitoxin is
traditionally thought to be relatively ineffective against infant
botulism as the type A toxin implicated in this form of
botulism is rarely found in the blood of the infant affected.
However, a recent five year study of human derived antitoxin
in infant botulism showed a reduction in the time spent in
hospital and the need for assisted ventilation and tube
feeding.12Benefits from anti-toxin are most likely with type E
botulism. A heptavalent antitoxin is available to the US Army
in the event of a bioterrorist attack.
With improved supportive care the overall mortality rates
in botulism have dropped to less than 10%, with rates of less
than 2% in infant botulism and higher rates in patients above
60 years of age. Recovery typically takes place over a period of
weeks to months, and is dependent on re-innervation
following the growth of new motor neuronal sprouts.
Respiratory support may therefore be required for months,
and weakness and autonomic dysfunction may persist for
more than one year.
A Goonetilleke, Department of Neurology, Newcastle General Hospital,
Regional Neurosciences Centre, Newcastle upon Tyne, UK
. . . . . . . . . . . . . . . . . .
J B Harris, School of Neurology, Neurobiology & Psychiatry, University
of Newcastle upon Tyne, Newcastle upon Tyne, UK
1 Meunier FA, Herreros J, Schiavo G, et al. Molecular mechanisms of action of
botulinal neurotoxins and the synaptic remodelling they induce in vivo at the
skeletal neuromuscular junction. In: Massaro EJ, ed. Handbook of
neurotoxicology, vol I. Totowa, New Jersey: Humana Press, 2002:305–47.
c An excellent review on the mechanisms of action of the neurotoxins
2 Gergen PJ, McQuillan GM, Kiely M, et al. A population-based serologic
survey of immunity to tetanus in the United States. N Engl J Med
3 Farrer JJ, Yen LM, Cook T, et al. Tetanus. J Neurol Neurosurg Psychiatry
c Excellent review article containing information on the structure and
action of the tetanus toxin, the clinical features of tetanus, and useful
details on the management of the condition.
4 Thwaites CL. Tetanus. Practical Neurology 2002;2(3):130–7.
c Recent article containing useful information on the clinical features and
management of tetanus.
5 Passaro DJ, Werner SB, McGee J, et al. Wound botulism associated with
black tar heroin among injecting drug users. JAMA 1998;279:859–63.
6 Werner SB, Passaro D, McGee J, et al. Wound botulism in California, 1951–
1998: recent epidemic in heroin injectors. Clin Infect Dis 2000;31:1018–24.
7 Spika JS, Schaffer N, Hargrett-Bean N, et al. Risk factors for infant botulism in
the United States. Am J Dis Child 1989;143:828–32.
8 Schmidt RD, Schmidt TW. Infant botulism: a case series and review of the
literature. J Emerg Med 1992;10:713–8.
9 Coleman EA, Yergler ME. Botulism. Am J Nursing 2002;102(9):44–7.
c A good introductory article for the reader interested in the bioterrorist
aspects of botulinum toxin.
10 Cherington M. Clinical spectrum of botulism. Muscle Nerve 1998;21:701–10.
11 Guiterrez AR, Bodensteiner J, Gutmann L. Electrodiagnosis of infant botulism.
J Child Neurol 1994;9:362–5.
12 American Academy of Pediatrics. Clostridial infections. In: Pickering LK, ed.
2000 Red book: report of the Committee on Infectious Diseases, 25th ed. Elk
Grove Village, Illinois: Academy of Pediatrics, 2000:212–4.
NEUROLOGY IN PRACTICE