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Abbreviations
BTX

botulinum toxin

LUT

lower urinary tract

CISC

clean intermittent catheterization

DSD

detrusor-sphincter dyssynergia.

INTRODUCTION

  1. Top of page
  2. INTRODUCTION
  3. HISTORICAL ASPECTS
  4. PHARMACOLOGY OF BTX-A
  5. USE OF BTX IN THE LUT
  6. SUMMARY AND CONCLUSIONS
  7. CONFLICT OF INTEREST
  8. REFERENCES

Botulinum toxin (BTX) is a neurotoxin produced by the bacterium Clostridium botulinum and is one of the most poisonous substances known to man. It is estimated that 1 g of purified crystalline toxin, if evenly dispersed and inhaled, would kill ≈ 1 million people. The story of its discovery as an obscure cause of food poisoning, its procurement as a tool of biological warfare and eventual transformation into a medical therapeutic agent is fascinating. Herein we review the history and development of BTX and discuss its place in the current urological management of the lower urinary tract (LUT).

BTX is produced by the spore-forming obligate anaerobe C. botulinum (Fig. 1) of which there are four genetically distinct groups, between them producing seven different immunogenic toxins, labelled A–G. Types A, B and E are most commonly implicated in human cases of botulism. The toxins have a molecular weight of ≈ 150 kDa and consist of a 50-kDa light chain, which is the toxic unit, and which is non-covalently bound to a 100 kDa heavy chain. The latter provides protection from digestive enzymes and enables the bacterium to act so powerfully as a food poison.

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Figure 1. Clostridium botulinum, a spore-forming obligate anaerobe

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Human botulism is characterized by an acute, afebrile and symmetrical paralysis, associated with prominent cranial nerve and bulbar palsies. Dry mouth, blurred vision and constipation signify its marked anticholinergic effects. The severity may vary from mild weakness to coma and respiratory failure requiring ventilatory support. Recovery follows as re-innervation occurs over a period of months.

HISTORICAL ASPECTS

  1. Top of page
  2. INTRODUCTION
  3. HISTORICAL ASPECTS
  4. PHARMACOLOGY OF BTX-A
  5. USE OF BTX IN THE LUT
  6. SUMMARY AND CONCLUSIONS
  7. CONFLICT OF INTEREST
  8. REFERENCES

Christian Andreas Justinus Kerner (1786–1862, Fig. 2), a German physician and poet, was the first to publish an account of botulism as a food-borne disease in spoiled pork sausages [1]. However, the association had been recognized by doctors almost a century earlier, the first recorded outbreak being in 1735, when 13 people died after eating ‘schweinsmagen’, a sausage packed with pigs’ blood and offal. The aetiology of the condition mystified physicians, who implicated various poisonous agents, including prussic acid (because of the blue-black colour of the victim's blood), poisonous vegetable seeds and pyroligneous acid, a by-product of smoking food with certain types of wood. One of the more bizarre theories was that because of the slow and painful death suffered by the pig, a poison would be secreted in its saliva at the point of death, thus contaminating the meat in some way. Kerner undertook scientific experiments to elucidate the cause of botulism and noted that most incidents of poisoning occurred from sausages produced in the autumn, that had been subjected to alternate freezing and thawing. From such meat he isolated a fatty substance that was extremely toxic to animals and went on to isolate the same ‘fatty acid’ from the blood of postmortem human cadavers. This substance, Kerner suggested, might be used in the future as a therapeutic agent in patients with involuntary movements as a result of neurological disease. However, it would be 160 years before the first therapeutic use of BTX was reported in humans. The actual bacterium was isolated by Ermengem (Fig. 3) after an outbreak of sausage-related poisoning in 1894 in the small village of Ellezelles, in Holland [2].

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Figure 2. Christian Andreas Justinus Kerner (1786–1862)

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Figure 3. Emile Pierre-Marie van Ermengem (1851–1932)

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Outbreaks of botulism continued to occur during the early 1900s, originating mainly from tinned foods, although improved canning processes led to a decline in outbreaks, and there was little interest in botulism until the advent of the Second World War, when intelligence led to fears that biological agents such as BTX might be used against Allied Forces.

In 1944, military bacteriologists and physicians on both sides of the Atlantic were assigned to study and purify BTX, leading to the production of a crystalline form of type A BTX (BTX-A), one of the more common forms in human outbreaks. Of the more elaborate applications for the new agent was a plan instigated by the US Office of Strategic Studies in which Chinese prostitutes were to assassinate high-ranking Japanese officers, with whom they consorted, by using tiny toxin-containing gelatine capsules. The pinhead-sized capsules were to be concealed about their person and slipped into the officers’ food or drink. However, the plans were abandoned when field tests on mules were unsuccessful. It later transpired that the mule is one of the very few creatures to be immune to BTX-A [3].

In 1968 Edward Schantz, an American army officer, working with the type A toxin, was approached by Alan Scott, an ophthalmic surgeon. Schantz and Scott collaborated in developing BTX-A and used it successfully in correcting strabismus in experimental monkeys. Progress in humans was slowed by a treaty in 1972 banning research into biological weapons, and it was not until some years later that USA Food and Drug Administration approval was given for civilian research on human volunteers. The first publication on the use of BTX-A in humans was in 1980 [4]. Over the last two decades, the use of BTX-A has become widespread in the treatment of various disorders of muscle overactivity. It is now licensed in the UK to treat strabismus, spasmodic torticollis, blepharospasm, hemifacial spasm and paediatric cerebral palsy spasticity. However, numerous other unlicensed applications have been reported, including oesophageal spasm, sphincter of Oddi dysfunction and anismus in the gastrointestinal tract, cosmetic facial wrinkle reduction, palmar hyperhydrosis and hypersalivation, to name but a few.

PHARMACOLOGY OF BTX-A

  1. Top of page
  2. INTRODUCTION
  3. HISTORICAL ASPECTS
  4. PHARMACOLOGY OF BTX-A
  5. USE OF BTX IN THE LUT
  6. SUMMARY AND CONCLUSIONS
  7. CONFLICT OF INTEREST
  8. REFERENCES

Medical grade BTX-A is isolated as white needle-shaped crystals and its toxicity is measured in mouse units (mU), the definition of which is ‘the amount fatal to 50% of a batch of Swiss Webster mice’. It is marketed as BOTOX® in the USA (Allergan Ltd) and as Dysport® in the UK (Ipsen Ltd). BOTOX is still supplied from the original 200 mg batch produced in 1979, which has retained most of its potency and remains the only batch currently approved by the Food and Drug Administration. An important point is the differing relative potencies of the British and American products. It is generally accepted that one unit of BOTOX is equivalent to 3–4 units of Dysport.

BTX-A is initially formed within the bacterium as a single 150 kDa polypeptide chain which requires activation by cleavage before release as a neurotoxin. Cleavage results in the formation of a light and a heavy chain joined by a single disulphide bond (Fig. 4). The light chain is a toxic zinc protease-containing unit, the heavy chain being a haemagglutinin. The haemagglutinin provides a stabilizing role and is essential for entry by endocytosis into the nerve terminal, where a second step required for toxicity occurs. This involves cleavage of the disulphide bond connecting the light and heavy chains, the latter promoting translocation through the endosomal membrane. The active light chain, by cleavage of a protein called SNAP-25 on the presynaptic membrane, interrupts fusion of vesicles containing acetylcholine to the plasma membrane. Release of acetylcholine at the end plate is therefore prevented, resulting in flaccid paralysis (Fig. 5). Clinical effects appear at 24–72 h after injection, the reason for this delay being unknown.

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Figure 4. Simplified molecular structure of BTX-A. Light and heavy chains are joined by a single disulphide bond. The light chain contains the toxic zinc endopeptidase moiety.

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Figure 5. Mechanism of action of BTX at the neuromuscular junction. The light chain zinc endopeptidase interferes irreversibly with the function of SNAP 25 protein on the presynaptic membrane. This prevents fusion of acetylcholine-containing vesicles, resulting in flaccid paralysis.

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The effects of long-term exposure to BTX-A have been studied in the orbicularis oculi muscle after treatment for blepharospasm. Re-innervation appears to occur by sprouting from the nodes of Ranvier and unmyelinated distal portion of preterminal axons. Indeed, some end plates appear to be segmented and muscle fibres may have more than one endplate. This process of re-innervation has been shown to continue for up to 12 months after injection of the thyroarytenoid muscle.

Side-effects of BTX-A after intramuscular injection are surprisingly uncommon, considering its extreme toxicity. However, the minute amounts required to relieve localized muscular overactivity are less than 1/1000 of the presumed fatal human dosage in a 70-kg male. Therefore, even though a small proportion of the injected dose inevitably reaches the systemic circulation, this is unlikely to cause systemic toxicity.

USE OF BTX IN THE LUT

  1. Top of page
  2. INTRODUCTION
  3. HISTORICAL ASPECTS
  4. PHARMACOLOGY OF BTX-A
  5. USE OF BTX IN THE LUT
  6. SUMMARY AND CONCLUSIONS
  7. CONFLICT OF INTEREST
  8. REFERENCES
  • Urologists are now beginning to realise the potential benefits of BTX in LUT dysfunction. This section will review publications about the injection of BTX-A into the external urethral rhabdosphincter and most recently, into the detrusor muscle.

Detrusor-sphincter dyssynergia (DSD)

There have been several studies of the use of BTX-A injected into the external urethral sphincter in DSD, but most have involved few patients, with only three publications describing more than five. Sphincteric injection of BTX-A for DSD was first described by Dykstra et al.[5], who carried out a double-blind placebo-controlled trial in five men. Urethral pressure profiles, postvoid residuals and voiding pressures were reported to be significantly reduced (on sphincter electromyography), confirming denervation, and the effects lasted ≈ 2 months. Schurch et al.[6] reported an improvement in voiding variables in 21 of 24 patients with DSD secondary to spinal cord injury after injection with BTX-A either transurethrally or transperineally. The effects lasted for 3–9 months after a single dose of 100 units. Phelan et al.[7], in 2001, injected the external sphincters of 21 patients with incomplete emptying of various causes (12 DSD, eight pelvic floor spasticity and one detrusor hypocontractility). They recorded a mean reduction in the postvoid residual of 71% and reported that all but one of those requiring catheterization before treatment (whether indwelling or intermittent) were able to do without. Recently, de Seze et al.[8] compared BTX with lignocaine in a randomized study of 13 patients. A single dose of 100 units of BTX was significantly more effective than 4 mL 0.5% lignocaine.

Injection of the external sphincter in conditions other than DSD

There are few firm data on the injection of BTX-A into the external urethral sphincter for indications other than DSD. Fowler et al.[9] injected the sphincters of six women with idiopathic chronic urinary retention but found no overall improvement in symptoms, despite transient stress incontinence in three. Maria et al.[10] reported improvements in urinary symptoms in men with prostatitis who received sphincteric injections of 200 units BTX-A and Zermann et al.[11] reported improved symptoms after perisphincteric injections in 11 men with chronic prostatitis associated with proven pelvic floor dysfunction.

Intradetrusor injections for the overactive bladder

Many patients with intractable overactivity, despite the maximal doses of oral therapy, are either unsuitable or unwilling to undergo a major operative procedure such as ileocystoplasty, and until recently there has been little else to offer them. Initially, attempts at denervation of hyper-reflexic bladders with instillations of capsaicin, the vanilloid compound extracted from chilli peppers, were promising [12].

The ultrapotent capsaicin analogue resiniferatoxin is less painful than capsaicin and has produced good outcomes [13], but results have been variable because of the adsorption of the drug to plastic dispensers, and it is now only available as a research tool. Atropine and oxybutynin have been used as instillations, but neither has found widespread acceptance.

In 2000, Schurch et al.[14] published their results in 21 patients with spinal cord injury and neurogenic bladders who had intradetrusor injections with BTX-A. They hypothesized that if injected directly into the muscle the powerful cholinergic blockade produced by BTX would effectively paralyse the detrusor, abolishing the overactivity.

All patients in their study were already using clean intermittent self-catheterization (CISC) for incomplete emptying and were injected via rigid cystoscopy with 200–300 units of BTX-A over 20–30 separate points, sparing the trigone. Continence was reported to be completely restored in 17 of 19 patients who were followed, with continuing improvement in all urodynamic variables, and significant increases in mean cystometric capacity and postvoid residual volume. The two patients who had a less satisfactory outcome received the lower dose of 200 units and therefore the 300 unit dose was recommended for this category of patient. Interestingly, the duration of the effect was longer (at least 9 months) in those receiving detrusor injections than in those whose external sphincters were injected for DSD (3–4 months), perhaps highlighting a difference in response between smooth and skeletal muscle. Subsequently, other authors using the proposals of Schurch et al. have reported similar findings, including a multicentre study of 184 patients from nine European centres [15]. The use of BTX-A in patients with idiopathic detrusor overactivity is less well studied, but early reports suggest that similar benefits can be achieved [16].

Exactly how BTX works in the bladder is as yet unclear. Our initial observations in such patients were surprising in that although, as expected, flaccid paralysis of the detrusor was produced, patients also reported a marked reduction in their sensation of urge. Cholinergic blockade at the neuromuscular junction would not explain such sensory effects and BTX-A is not known to be toxic to the afferent C-fibres, which are thought to be responsible for bladder sensation. Other mechanisms may therefore be involved. BTX-A is known to improve certain chronic pain conditions of a neurological origin and therefore afferent mechanisms may be affected by some, as yet unknown, pathway, possibly involving muscle spindles. The existence of a suburothelial layer of myofibroblasts or so-called interstitial cells has been proposed [17] and recent work by Sui et al.[18] showed that these cells have extensions projecting deep into the suburothelium and are interconnected by connexin43-containing gap junctions. Possibly therefore the interstitial cells act together as a functional syncytium, akin to that known to exist in vascular tissue and the bowel, sensing bladder fullness and perhaps other stimuli.

There is understandable excitement about this particular indication for BTX and certainly there are many patients who could potentially benefit. However, more clinical and experimental data are required before widespread use can be recommended. In particular, the long-term effects of denervating the detrusor in this manner are unclear. As progressive re-innervation will inevitably occur, there are hypothetical concerns that repeated injections over several years may eventually enhance the pathological innervation in these patients and lead not only to tolerance but exacerbation of regional symptoms. However, there is no evidence from the last 20 years of BTX-A usage in other conditions to suggest that this is the case, but published long-term studies specifically assessing this issue are not available.

Patients undergoing intradetrusor injection of BTX-A should be warned about the possibility of incomplete emptying after treatment. Those who do not already use CISC as part of their bladder regimen should be prepared to do so, as marked hypocontractility may ensue. The ideal dose for an individual patient is not yet known and therefore at present most studies are administering 300 units, the dose shown by Shurch et al. to be effective. This issue may not be crucial to patients with neurogenic bladders, many of who will already be using CISC, but for those with idiopathic overactivity the prospect of catheterizing may be more than they are prepared to countenance. In these patients it would probably be preferable to stage treatment, beginning with a lower dose (e.g. 200 units) and injecting further at a later date if the need arises. We expect that the intractable overactive bladder will become the main urological indication for BTX-A. with patients being offered regular re-injection. At present, most urologists administer the toxin via rigid cystoscopy under general or spinal anaesthesia.

However, a significant group of patients with intractable neurogenic incontinence may have advanced progressive neurological disease and be deemed unsuitable for general anaesthesia. The inconvenience of such techniques of administration may now be avoidable. New technology has recently led to ultra-fine needles, which are suitable for use with standard flexible cystoscopes. In our department we have been using disposable sheathed 27 G flexible injection needles, with a working length of 1050 mm and a needle length of 4 mm (Fig. 6a,b). Injecting BTX-A through these needles appears to cause only minimal discomfort to the patient and in most cases we are able to perform the procedure quickly and efficiently with only intraurethral lignocaine gel [19].

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Figure 6. A, A flexible injection needle, suitable for use with a standard flexible cystoscope, and B, intradetrusor injection of BTX as a local anaesthetic outpatient procedure using the flexible injection needle and standard flexible cystoscope.

Side-effects of BTX-A in the urological patient are very rarely reported. All patients should be warned of the possibility of a reaction to the drug in the form of either a rash or mild transient ‘flu-like illness. The latter may occur 1–2 weeks after injection and will tend to decline after a similar interval. There has been one case report of unexplained distal muscular weakness in two patients with neurogenic detrusor overactivity [20].

SUMMARY AND CONCLUSIONS

  1. Top of page
  2. INTRODUCTION
  3. HISTORICAL ASPECTS
  4. PHARMACOLOGY OF BTX-A
  5. USE OF BTX IN THE LUT
  6. SUMMARY AND CONCLUSIONS
  7. CONFLICT OF INTEREST
  8. REFERENCES

Botulinum toxins have come a long way since their discovery in rancid sausages. Their potential for use in biological warfare remains a concern but, as predicted by Kerner in his initial descriptions over 180 years ago, much good has been harnessed from their medicinal properties and undoubtedly many more indications for their use will arise in the future. At present the use of BTX-A in urology is unlicensed, but its relative availability and ease of application will inevitably tend towards widespread use. As with any new treatment it is important that initially BTX-A should be used judiciously, within studies and in a manner that will enable a core of high-quality knowledge to be gained and with which to direct its future use.

REFERENCES

  1. Top of page
  2. INTRODUCTION
  3. HISTORICAL ASPECTS
  4. PHARMACOLOGY OF BTX-A
  5. USE OF BTX IN THE LUT
  6. SUMMARY AND CONCLUSIONS
  7. CONFLICT OF INTEREST
  8. REFERENCES