Clinical review

Uses of botulinum toxin injection in medicine today

A Münchau, research fellow,  K P Bhatia, senior lecturer. 

University Department of Clinical Neurology, Institute of Neurology, London WC1N 3BG

Correspondence to: K P Bhatia K.Bhatia{at}ion.ucl.ac.uk

Botulinum neurotoxin is produced by the anaerobic bacterium Clostridium botulinum. It is the most poisonous biological substance known. Very small amounts of botulinum toxin can lead to botulism, a descending paralysis with prominent bulbar symptoms and often affecting the autonomic nervous system. Botulism can occur in two ways. It can result from infection with bacterial spores that produce and release the toxin in the bodyas in enteric infectious botulism, when the bacteria grow in the intestine, and in wound botulism, when the wound becomes infected. Alternatively, botulism occurs after ingestion of the toxin (food borne botulism).¹

Botulism has been recognised since the early 19th century, and there was speculation about what caused the condition. In 1822 it was suggested that a "fatty acid" in sausages was the culprit,² and this led to the term botulism (botulus being the Latin word for sausage). In 1897, Van Ermengen related botulism to a bacterial toxin.³

The discovery that botulinum toxin blocks neuromuscular transmission⁴ and thereby causes weakness laid the foundation for its development as a therapeutic tool. In 1981, the ophthalmologist Alan Scott pioneered treatment with botulinum toxin when he used it to treat strabismus.⁵ He paved the way for clinical research in many specialties.

	Methods

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This review was prompted by an increasing number of publications on the therapeutic uses of botulinum neurotoxin. For the literature review we used standard textbooks^6-9 and a Medline search for the years 1981 to 1999.

	Mode of action

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Strains of Clostridium botulinum produce seven antigenically distinct neurotoxins designated as serotypes A-G. All seven serotypes have a similar structure and molecular weight, consisting of a heavy (H) chain and a light (L) chain joined by a disulphide bond.¹⁰ They all interfere with neural transmission by blocking the release of acetylcholine (fig 1), which is the principal neurotransmitter at the neuromuscular junction. After synaptic transmission is blocked by botulinum toxin, the muscles become clinically weak and atrophic. The affected nerve terminals do not degenerate, but the blockage of neurotransmitter release is irreversible. Function can be recovered by the sprouting of nerve terminals and formation of new synaptic contacts; this usually takes two to three months.

View larger version (37K): [in this window] [in a new window]   Action of botulinum toxin at cholinergic nerve terminals. The heavy (H) chain of the toxin binds selectively and irreversibly to high affinity receptors at the presynaptic surface of cholinergic neurones, and the toxin-receptor complex is taken up into the cell by endocytosis. The disulphide bond between the two chains is cleaved (by an unknown mechanism), and the toxin escapes into the cytoplasm. The light (L) chains of the seven serotypes interact with different proteins (synaptosomal associated protein (SNAP) 25, vesicle associated membrane protein (VAMP) and syntaxin) in the nerve terminals to prevent fusion of acetylcholine vesicles with the cell membrane and thereby impede its release. (Adapted from Moore,6 with permission)

	Rationale for treatment with botulinum neurotoxin

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Botulinum toxin induces weakness of striated muscles by inhibiting transmission of alpha motor neurones at the neuromuscular junction. This has led to its use in conditions with muscular overactivity, such as dystonia. Transmission is also inhibited at gamma neurones in muscle spindles, which may alter reflex overactivity.¹¹

The toxin also inhibits release of acetylcholine in all parasympathetic and cholinergic postganglionic sympathetic neurones. This has fuelled interest in its use as a treatment for overactive smooth muscles (for example, in achalasia) or abnormal activity of glands (for example, hyperhidrosis).

	Preparations of botulinum neurotoxin

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Serotype A is the only one commercially available for clinical use, although experience is emerging with serotypes B, C, and F.¹² Two preparations exist: Dysport, which is most widely used in the United Kingdom, and Botox, which is used in the United States and elsewhere. Unfortunately, there has been much confusion over the doses and units of potency of the two preparations. Although doses are quoted in mouse units (which is the amount of toxin that kills 50% of a group of 18-20 g female Swiss-Webster mice), implying some standardisation, Botox seems to be more potent. A recent study comparing the two preparations found that a unit of Botox is three times as potent as a unit of Dysport.¹³

	Practical aspects of botulinum toxin injection treatment

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Botulinum toxin has to be injected into affected muscles or glands. Doses have to be tailored according to the mode of use and individual patients. Generally, the effective dose depends on the mass of muscle being injected: the larger the muscle the higher the dose required. However, susceptibility to the toxin varies. Lower doses may be required in patients with preexisting weakness and in women and lighter patients.

Overactive muscles are identified by muscular hypertrophy, stiffness, tenderness, and visible abnormal muscular activity. In addition, clinical observation of abnormal movements or postures may help identify an overactive muscle. Electromyography can also be usefulfor example, in writer's cramp. Hollow Teflon coated needles are used to target toxin injections into affected muscles. In conditions with very localised muscle overactivity in delicate places, such as strabismus, the injections are usually guided by electromyography.

The weakness induced by injection with botulinum toxin A usually lasts about three months. Patients will then need further injections at regular intervals, although the interval varies widely depending on the dose and individual susceptibility. Patients usually experience relief after each injection and then gradually deteriorate to a point where further injections are required. Response after the injections should be assessed both by using patient reported benefit in terms of pain relief and improvement of disability, and by objective measures on clinical examination.

Most patients treated with botulinum toxin require repeated injections over many years. Some patients who respond well initially develop tolerance to the injections. This can be caused by the development of neutralising antibodies to the toxin. Patients who receive higher individual doses or frequent booster injections seem to have a higher risk of developing antibodies. Injections should therefore be given at the lowest effective dose and as infrequently as possible.

Several types of antibody assay are available.¹⁴ The most widely used is the in vivo mouse neutralisation assay. In clinical trials patients resistant to botulinum A have benefited from injections with other serotypes, including B, C, and F. The duration of effect may differ widely with different serotypesfor example, the effect of botulinum F toxin lasts for only about two months in patients with torticollis, even when higher doses are used.¹⁵

	Side effects

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Injections with botulinum toxin are generally well tolerated. After injection the toxin diffuses into the muscles and other tissues. Its effect diminishes with increasing distance from the injection site, but spread to nearby muscles is possible, particularly when high volumes are injected. Patients receiving injections into the neck muscles for torticollis may therefore develop dysphagia because of diffusion of the toxin into the oropharynx. Distant effects shown by specialised electromyographic tests can also occur, but weakness of distant muscles or generalised weakness, possibly due to the toxin spreading in the blood, is very rare. ^{16 17} However, botulinum toxin should be used only under close supervision in patients with disturbed neuromuscular transmissionfor example, in myasthenia gravis or Lambert-Eaton myasthenic syndrome¹⁸ or during treatment with aminoglycosides. Other systemic side effects include an influenza-like illness and, rarely, brachial plexopathy, which may be immune mediated.¹⁹ No severe allergic reactions have been reported. Gallbladder dysfunction attributed to autonomic side effects of the toxin and a case of necrotising fasciitis in an 80 year old immunosuppressed woman with blepharospasm have been noted. ^{20 21} Botulinum toxin is contraindicated in pregnancy and while breast feeding. Careful monitoring is important when the toxin is used in children as it might alter cell functions such as axonal growth.⁶

	Indications for treatment

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Over the past 15 years botulinum toxin has been shown to be useful in many conditions, especially strabismus and various movement disorders (box). Encouraging clinical reports have generated an abundance of ideas for other uses, but many of these observations are anecdotal. Nevertheless, its potency, relative safety, and the reversibility of its effects have made botulinum toxin an attractive option for some chronic conditions that respond only partially to medical treatment. Sometimes it can be used as an alternative to surgical intervention. In the following section we will focus on established indications of botulinum toxin.

Strabismus and other ocular motility disorders
The idea behind using botulinum toxin A in disorders of ocular motility is to shorten the non-injected antagonist muscle in order to align the visual axes.⁶ In patients with concomitant strabismus, who have compromised or absent binocular fusion, treatment is cosmetic as permanent ocular realignment cannot be expected. In secondary strabismus resulting from transient monocular vision loss (such as posttraumatic cataract), toxin injections can help to establish whether binocular cooperation is still present. If so, the patient would be a candidate for surgery to restore ocular function. Botulinum toxin has also proved useful when surgery has over or under corrected strabismus.²²

Movement disorders
The effectiveness of botulinum toxin A in spasmodic torticollis was first shown in 1986,²³ and it is now the treatment of choice for this condition. Some improvement in pain relief, head position, and disability occurs in 90% of patients, and about three quarters achieve considerable improvement.²⁴ Injections are given into neck muscles, depending on the muscular activity and head position. Patients with severely restricted head movements usually respond less well to the injections. The most common side effect (occurring in 5-9% of patients) is dysphagia, but this is usually transient.

Spasticity
Botulinum toxin has been evaluated in various spastic disorders.³⁰ It was shown to improve gait pattern in patients with cerebral palsy with progressive dynamic equinovarus or equinovalgus foot deformities. Treatment of children with cerebral palsy during the key early years when functional skills in walking are being developed improves the outcome and may help to avoid surgery for contracture and bony torsion.³¹ In multiple sclerosis the toxin can relieve contractions of thigh adductors that interfere with sitting, positioning, cleaning, and urethral catheterisation. It can also reduce muscle tone and increase range of movement in upper extremity spasticity or in spastic foot drop after a stroke. Whether this translates into functional improvement has yet to be substantiated.³²

Other indications
Botulinum toxin has been tried in numerous other conditions (box). The list of possible new indications is rapidly expanding. It seems to be a promising alternative to sphincterotomy in patients with chronic anal fissures³³ and is effective in achalasia.³⁴ Some autonomic disorders resulting in hypersecretion of glands like excessive palmar hyperhidrosis, ptyalism, or gustatory sweating, which often occurs after surgery to the parotid gland, respond well to botulinum toxin.^35-37 Surprisingly, the response seems to last much longer than in conditions caused by overactivity of striated or smooth muscles.³⁶

	Acknowledgments

We thank Professor Niall P Quinn and Dr Cathy Chuang for critical review of the manuscript.

	Footnotes

Funding: AM was supported by the Ernst Jung-Stiftung für Wissenschaft und Forschung in Hamburg, Germany.

Competing interests: KPB and AM have been supported by Ipsen, the manufacturer of Dysport, to attend an international symposium.

	References

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(Accepted 16 August 1999)