Susan Holmes, PhD, BSc, SRN, FRSH.
Director of Research and Development and Professor of Nursing, Faculty of Health, Canterbury Christchurch University CollegeBotulinum toxin (BTX), the deadliest toxin known to humans, is produced by an anaerobic bacterium, Clostridium botulinum and causes botulism, a potentially fatal form of food poisoning. It lends itself particularly well to bioterrorism, since it can be inhaled. Iraq in the past deployed more than 11 000 litres of BTX in Scud missiles, while a Japanese cult had plans to use it in an attack in the Tokyo subway but, in the event, used the nerve toxin sarin (Shapiro et al, 1997; Zilinskas, 1997). The US Defense Department is so concerned about this type of activity that it funds research related to such uses (Delaney, 2002).
Botulinum toxin (BTX), the deadliest toxin known to humans, is produced by an anaerobic bacterium, Clostridium botulinum and causes botulism, a potentially fatal form of food poisoning. It lends itself particularly well to bioterrorism, since it can be inhaled. Iraq in the past deployed more than 11 000 litres of BTX in Scud missiles, while a Japanese cult had plans to use it in an attack in the Tokyo subway but, in the event, used the nerve toxin sarin (Shapiro et al, 1997; Zilinskas, 1997). The US Defense Department is so concerned about this type of activity that it funds research related to such uses (Delaney, 2002).
Inhalation of just one microgram of BTX can kill an adult; when injected into a muscle, it causes contraction, leading to paralysis or weakness. This prompted investigation into the possible therapeutic uses of BTX, and today its clinical benefits in managing many neurological and muscular disorders are increasingly recognised.
The toxin has been known since the early 19th century when Kerner (1817) published the first systematic description of food-borne botulism, falsely attributing it to a 'fatty acid' present in sausages (botulus is Latin for sausages) (Munchau and Bhatia, 2000). It was another 80 years before van Ermengem (1897) related botulism to a bacterial toxin and even longer before Burgen et al (1949) discovered that BTX blocks neuromuscular transmission and promotes muscle weakness. The latter laid the basis for the therapeutic uses of BTX.
Botulism most commonly occurs when contaminated food is ingested, from colonisation of the infant gastrointestinal tract or from wound infection. The former is the most common method and may occur in two ways:
- The toxin is consumed; it then enters the general circulation from the gut, from where it is distributed throughout the body
- The bacterium itself may colonise the gut. It will then produce the toxin that in turn enters the circulation. The neurotoxin is disseminated to the peripheral cholinergic motor nerve endings, where it binds irreversibly to the presynaptic terminals, blocking acetylcholine release at the neuromuscular junction (Markowitz, 1991).
Botulism is manifested by diplopia and ptosis followed by dyspnoea (progressing to respiratory arrest), constipation (progressing to ileus) and urinary retention (Davis, 1993); autonomic dysfunction and flaccid paralysis may lead to death (Simpson, 1997).
Treatments involving botulism toxin
Scott (1981) first reported successful use of small injections of BTX directly into overactive muscles in treating strabismus. After this, the use of focal injections was widely investigated in other conditions involving overactive muscle contraction (such as hemifacial spasm and blepharospasm). BTX has since been shown to be effective in treating many neurological and non-neurological diseases (Jankovic and Brin, 1991; Misra, 2002).
Injecting the toxin directly into overactive or abnormally contracting muscles (as occurs in hemifacial spasm, spasmodic torticollis, focal dystonias, including writer's cramp) causes chemodenervation, blocking neuromuscular activity, leading to relaxation and a reduction in excessive or uncontrollable spasms or movements (NIH, 1990).
BTX may help reduce abnormal glandular activity (Naumann and Lowe, 2001) and can ameliorate spasticity; it can also help relieve spasms after stroke or spinal injury and those associated with multiple sclerosis (Hallett, 1999), as it reduces muscle tone and improves movement (Simpson, 1997). It is effective in treating the spastic hypertonia of the calf muscles, which causes toe-walking in children with cerebral palsy (Flett et al, 1999).
Injection of BTX into the internal urethral sphincter can improve the detrusor-sphincter dyssynergia that accompanies spinal-cord injuries, while injection into the lower oesophageal sphincter reduces dysphagia associated with achalasia (Pasricha et al, 1995). It is also an effective non-surgical treatment for chronic anal fissure, when internal anal sphincter paralysis allows healing to occur (Brisinda et al, 1999).
BTX is used in cosmetic therapy: facial wrinkles can be eliminated by small injections of BTX (Fagien and Brandt, 2001). Frown lines and crow's feet are the most responsive (Benedetto, 1999).
There is evidence that BTX can be effective in controlling pain from headaches, including tension headache and migraine (Blitzer and Silica, 2001) and pain from other sources (Childers, 2001), particularly those of muscular origin (Lang, 2003). For example, in patients with spasmodic torticollis it not only significantly reduces the incidence of pain but also improves motor function (Greene et al, 1990; Brefel-Courbon et al, 2000).
Mechanism of action
There are seven serologically distinct, but structurally similar, botulinum neurotoxins (serotypes A-G). Each interferes with neural transmission by binding at the neuromuscular junction, entering the neuronal cytoplasm and inhibiting acetylcholine release (Munchau and Bhatia, 2000) (Figure 1). Most clinical experience centres on botulinum toxin A, but there is interest in the other serotypes, not least because about 10% of patients develop antibodies to type A, making them resistant to further treatment. Botulinum toxins B and F may be effective in such patients (Hallett, 1999).
All serotypes induce weakness in striated muscle by inhibiting transmission of alpha motor neurons at the neuromuscular junction (Munchau and Bhatia, 2000). BTX may also alter overactivity by inhibiting gamma neurons in muscle spindles (Priori et al, 1995). Its effects on parasympathetic and cholinergic postganglionic sympathetic nerves may reduce overactivity in smooth muscles and glandular tissue (Munchau and Bhatia, 2000).
But in most cases the effects are short-lived - although blockage of neurotransmitter release is irreversible, the affected nerve terminals do not degenerate. Function is restored by formation of new neuromuscular junctions and synaptic contacts owing to 'sprouting' from the unmyelinated terminal axon (Borodic and Ferrante, 1992). Meunier et al (2002) suggest this effect is transitory and a second distinct rehabilitation phase brings a return of synaptic activity in the original nerve terminals.
Clinically significant responses have been reported to last from months to over a year. Therapeutic reversal generally takes two to three months (Simpson, 1997; Munchau and Bhatia, 2000). Continuing symptom relief can thus be achieved only by repeated injection.
Dosage and administration
The toxicity of BTX is described in mouse units (MU), a unit of potency rather than of weight or volume, which varies between serotypes. One MU is equivalent to the dose that is lethal to 50% of female Swiss-Webster mice after intraperitoneal injection; this is also described as the LD50 (lethal dose 50) (Erbguth, 1999). The human LD50 for a 70kg 'reference' adult has been calculated to be around 40MU per kg bodyweight (a total dose of 2500-3000MU) (Benedetto, 1999).
Therapeutic doses range from 1:100 to 1:5 of human LD50, so the margin of safety appears wide and systemic effects unlikely, provided the drug is injected intramuscularly or subcutaneously. By preventing acetylcholine release BTX causes functional neuromuscular denervation, temporarily paralysing the muscles and preventing overactivity without blocking voluntary control, as the more active neuromuscular junctions are more likely to be affected than the less active (Chen et al, 1999).
BTX must be injected directly into the endplate zone of a hyperactive muscle (Figure 1), which is identified by muscular hypertrophy, stiffness and tenderness. Electromyography and clinical observation of abnormal muscle activity, abnormal movements and postures may also be helpful (Munchau and Bhatia, 2000). The dose is tailored to the individual and carefully titrated to ensure maximal benefit (Hallett, 1999).
However, the effects of treatment are not as predictable as with surgery, so this largely depends on the clinician's experience and judgement. The effective dose generally depends on the mass of muscle to be treated: the greater the mass the higher the dose (Munchau and Bhatia, 2000).
The major disadvantages of BTX therapy are the need for repeated injections and cost (Gordon, 1999). For example, although BTX significantly reduces pain and improves quality of life for those with spasmodic torticollis, it also markedly increases the costs of care (Brefel-Courbon et al, 2000).
BTX should not be used in isolation but must be part of the patient's overall management.
Side-effects and contraindications
BTX is highly selective in acting on cholinergic cells so, provided it is carefully administered, side-effects are uncommon. Where they occur they many result in, for example, transitory weakness of the treated muscle (Hesse and Mauritz, 1997) and there may be pain at the injection site.
Most side-effects appear to arise from toxin diffusion and action on nearby cells, causing unanticipated but transitory problems for some patients (Delaney, 2002), such as paresis of nearby muscles (Mahant et al, 2000); some of those treated for facial wrinkles may develop new wrinkles adjacent to the treated area (The Times, 2003).
Bhutani (1997) reports that some patients treated with BTX for gastrointestinal disorders developed heartburn, owing to relaxation of the lower oesophageal sphincter, and faecal incontinence may follow treatment of anal fissures. He also shows that oropharyngeal dysphagia may accompany treatment of cervical or oromandibular dystonias; significant reduction in gall bladder emptying may occur for 8-15 days after injection.
Overall, BTX is an effective therapy requiring very small doses of toxin, comparing favourably with many drugs (Erbguth, 1999). However, there are clear contraindications to its use (Box 1).
Implications for nursing
Although BTX therapy is primarily an outpatient procedure, nurses may encounter patients in a range of specialties, so they need to be knowledgeable about its use. BTX is not an isolated therapy, but must be integrated into the patient's total management plan: it is simply an addition to the therapeutic armoury in managing many otherwise intractable conditions. The care required will depend on the nature of the primary disease.
In some situations nurses may administer BTX - for example, in ophthalmology (Northern and Yorkshire Regional NHS Modernisation Programme, 2001) and in managing dystonia, where a trained outreach practitioner, administering it in the patient's home, has been shown to provide a service that was as good as and, in some cases, better than that offered by a hospital outpatient clinic (Whitaker et al, 2001). Since many of the conditions for which BTX is used are highly visible and often distressing and/or embarrassing, this offers nurses the chance to provide effective therapy and enhance quality of life for many patients.
BTX is an invasive and expensive treatment, necessitating considerable skill in administration. However, its potency, relative safety and reversible clinical effects make it an attractive option for managing a range of distressing conditions that respond poorly to medical treatments.
Despite this, its use remains controversial, not least because of the limited data on its long-term effects (Misra, 2002), making it crucial to weigh up the potential benefits and risks before using it as part of a patient's treatment.
Benedetto, A.V. (1999)The cosmetic uses of botulinum toxin type A. International Journal of Dermatology 38: 641-655.
Bhutani, M.S. (1997)Gastro-intestinal uses of botulinum toxin. American Journal of Gastroenterology 92: 6, 929-933.
Blitzer, A., Silica, L. (2001)Botulinum toxin: basic science and clinical uses in otolaryngology. Laryngoscope 111: 2, 218-226.
Borodic, G.E., Ferrante, R. (1992)Effects of repeated botulinum toxin injections on orbicularis oculi muscle. Journal of Clinical Neuro-ophthalmology 12: 121-127.
Brefel-Courbon, C, Simonetta-Moreau, M., More, C. et al. (2000)A pharmacoeconomic evaluation of botulinum toxin in the treatment of spasmodic torticollis. Clinical Neuropharmacology 23: 4, 203-207.
Brisinda, G., Maria, G., Bentivoglio, A.R. et al. (1999)A comparison of injections of botulinum toxin and topical nitroglycerin ointment for the treatment of chronic anal fissure. New England Journal of Medicine 341: 65-69.
Burgen, A.S.V., Dickens, F., Zatman, L.J. (1949)The action of botulinum toxin on the neuromuscular junction. Journal of Physiology 109: 10-24.
Chen, R., Karp, B.I., Goldstein, S.R. et al. (1999)Effect of muscle activity immediately after botulinum toxin injection for writer's cramp. Movement Disorders 14: 307-312.
Childers, M.K. (2001)Botulinum toxin in pain management. emedicine.com May 16. Available at: www.emedicine.com/pmr/topic218.htm.
Davis, L.E. (1993)Botulinum toxin: from poison to medicine. Western Journal of Medicine 158: 25-29.
Delaney, N. (2002)Botox: miracle or deadly drug? Chemistry and Industry 24: (December 16), 10-11.
Erbguth, F.J. (1999)Botulinum toxin, a historical note. Lancet 351: 1820.
Fagien, S., Brandt, F.S. (2001)Primary and adjunctive use of botulinum toxin type A (Botox) in facial aesthetic surgery: beyond the glabella. Clinics in Plastic Surgery 28: 1, 127-248.
Flett, P.J., Stern, L.M., Waddy, H. et al. (1999)Botulinum toxin A versus fixed cast stretching for dynamic calf tightness in cerebral palsy. Journal of Paediatric Child Health 35: 71-77.
Gordon, N. (1999)The role of botulinum toxin type A in treatment with special reference to children. Brain and Development 21: 1, 147-151.
Greene, P., Kang, U., Fahn, S. (1990)Double-blind, placebo-controlled trial of botulinum toxin injections for treatment of spasmodic torticollis. Neurology 40: 8, 1213-1216.
Hallett, M. (1999)One man's poison: clinical applications of botulinum toxin. New England Journal of Medicine 341: 118-129.
Hesse, S., Mauritz, K.M. (1997)Management of spasticity. Current Opinion in Neurology 10: 489-501.
Jankovic, J., Brin, M. (1991)Therapeutic uses of botulinum toxin. New England Journal of Medicine 324: 1186-1194.
Kerner, J. (1817)Vergiftung durch verdorbene Würst. Tübinger Bl[ap6]tter Für Naturwissenschafen und Arzneykunde 3: 1-25.
Lang, A.M. (2003)Botulinum toxin type A in chronic pain disorders. Archives of Physical and Medical Rehabilitation 84: (suppl 1), 69-73.
Mahant, N., Clouston, P.D., Lorentz, I.T. (2000)The current use of botulinum toxin. Journal of Clinical Neurosciences 7: 5, 389-394.
Markowitz, S.M. (1991)Other clostridial infections. In: Strickland, G.T. (ed.). Hunter's Tropical Medicine. Philadelphia, Pa: W.B. Saunders.
Meunier, F.A., Schiavo, G., Molgó, J. (2002)Botulinum neurotoxins: from paralysis to recovery of functional neuromuscular transmission. Journal of Physiology - Paris 96: 103-113.
Misra, V.P. (2002)The changed image of botulinum toxin: its unlicensed use is increasing dramatically, ahead of robust evidence. British Medical Journal 325: 1188.
Munchau, A., Bhatia, K.P. (2000)Uses of botulinum toxin injection in medicine today. British Medical Journal 320: 161-165.
National Institutes of Health. (1990)Clinical use of botulinum toxin. NIH Consensus Statement. NIH November 12-14; 8: 8, 1-20. Available at: www.consensus.nih.gov/cons/ 083/083_statement.htm
Naumann, M., Lowe, M.J. (2001)Botulinum toxin type A in treatment of bilateral primary axillary hyperhidrosis: randomised parallel groups, double blind, placebo controlled trial. British Medical Journal 325: 1-4.
Northern and Yorkshire Regional NHS Modernisation Programme. (2001)Nurse-led botulinum toxin clinic. Improving Practice Articles, October. Available at: www. nyx.org.uk/modernprogrammes/patientaccess/goodpractice/oct2001/botulinum.html
Pasricha, P., Ravich, W., Hendrix, T. et al. (1995)Intrasphincteric botulinum toxin for the treatment of achalasia. New England Journal of Medicine 332: 772-778.
Priori, A., Berardelli, A., Mercuri, B. et al. (1995)Physiological effects produced by botulinum toxin treatment of upper limb dystonia, changes in reciprocal inhibition between forearm muscles. Brain and Development 118: 801-807.
Scott, A.B. (1981)Botulinum toxin injection of eye muscles to correct strabismus. Transactions of the American Ophthalmological Society 79: 734-770.
Shapiro, R.L., Hatheway, C., Becher, J., Swerdlow, D.L. (1997)Botulism surveillance and emergency response: a public health strategy for a global challenge. Journal of the American Medical Association 278: 433-435.
Simpson, D.M. (1997)Clinical trials of botulinum toxin in treatment of spasticity. Muscle and Nerve 20: S6, 169-175.
The Times. (2003)Botox may create new wrinkles (News). The Times February 18, 7.
van Ermengem, E.P. (1897)[Up6]ber einen neuen anaeroben Bacillus und seine Beziehungen zum Botulismus. Zeitschrift fur Hygiene und Infectionskrankheiten 26: 1-56.
Whitaker, J., Butler, A., Semlyen, J.K., Barnes, M.P. (2001)Botulinum toxin for people with dystonia treated by an outreach nurse practitioner: a comparative study between a home and a clinic treatment service. Archives of Physical Medicine and Rehabilitation 82: 4, 480-484.
Zilinskas, R.A. (1997)Iraq's biological weapons: the past as future? Journal of the American Medical Association 278: 418-424.