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I will now review selected promising developments and newer indications for treatment with BoNT, concentrating on autonomic disturbances and pain. There are many other indications, some of which are discussed in other chapters of this book. Table 7.1 in Section 7.2.4 provides an indication of the range of benefits.

7.2.1 Autonomic Indications: Glandular Hypersecretion

BoNT influences autonomic function by blocking sympathetic and parasympathetic ganglion cells and postganglionic parasympathetic and cholinergic sympathetic neurones. Kerner noted that patients with botulism experienced dry mouth, nose, and eyes, and did not produce earwax.1 In the right settings, any of these effects could be helpful. Hypersalivation

Although excessive production of saliva per se is rarely a clinical problem, many patients have difficulty controlling normal volumes of saliva. Any disorder that leads to dysphagia (difficulty swallowing) may cause aspiration of saliva, even when food and drink are given by some other means such as nasogastric or parenteral feeding. Diseases that produce poor control of throat, mouth, or tongue muscles can cause pooling of saliva in the back of the mouth, so the patient can only deal with even normal saliva volumes by spitting or drooling. Facial or lip muscle weakness may allow saliva to escape at any time, and particularly during eating or speaking.

Drooling requires constant attention from a patient or caregiver, may lead to breakdown of the skin, and is socially disastrous. It is common in cerebral palsy, stroke, and neurodegenerative diseases such as motorneurone disease (ALS) and Parkinsonism (PD). Patients with PD do not produce excessive saliva,15 but do experience reduced swallowing,16 The common forward head posture probably contributes to drooling. Systemic drugs such as anticholinergics may help but are often poorly tolerated, and a few patients undergo surgical denervation or parotid gland irradiation to reduce saliva production.

In initial studies with BoNT/A in children, in PD and bulbar ALS, up to two thirds of patients reported marked or moderate improvement. However, not all patients experienced relief from their symptoms even when saliva production demon-strably diminished. Clinicians usually injected the parotid glands, and sometimes the submandibular glands. The trials used a variety of injection techniques, BoNT/A preparations, and doses. Most investigators used ultrasound to ensure accurate injections and minimize the risk of injury to the facial nerve or to large blood vessels. Evidence from a small RCT indicated that freehand injections are less effective.17 Overall, the results were encouraging and evidence is now appearing from random ized, controlled trials that intraglandular injections of BoNT/A both reduce saliva production and produce significant clinical benefit.

For children, a controlled clinical trial in 45 patients with cerebral palsy and severe drooling compared transdermal scopolamine with single-dose BoNT/A injections in the submandibular glands under general anesthetic. Drooling severity was measured up to 24 weeks, using the Drooling Quotient (DQ), the Teacher Drooling Scale (TDS), and Visual Analog Scales (VAS). Both treatments produced clinically relevant reductions in drooling as measured by all three scales. After BoNT/A treatment, the best effect was at 2 to 8 weeks, but benefit was equally good in both groups up to 24 months. Therapy was successful (a two-point decrease on the TDS) in 62% of BoNT/A patients; 71% of the patients had moderate to severe side effects from scopolamine. Only mild or moderate incidental side effects were noted after BoNT/A.18

In adults, a RCT of BoNT/A in 20 patients with Parkinsonism and drooling showed that after treatment the average secretion of saliva in the BoNT/A group was significantly lower than in the placebo group. A dose of 450 U Dysport was split between the parotids and submandibular glands under ultrasound guidance. Compared to baseline and to placebo, drooling was significantly reduced (p = 0.005) in the active BoNT/A group at 1 week, benefits lasted approximately 1 month, and there was no residual treatment effect at 3 months.19 Previous small open label studies using 10 to 30 U Botox in a total of 25 patients reported treatment effects lasting 6 to 8 weeks20 and 4 to 7 months.21 Botulinum Toxin B

Studies of the effects of botulinum toxin B in cervical dystonia reported a higher incidence of autonomic side effects such as dry mouth than with type A toxin. This raised the possibility that type B toxin may be useful for autonomic disorders such as sialorrhea. A small open label study of BoNT/B suggested that it can be helpful to treat drooling in PD.22 A subsequent RCT of BoNT/B in 16 patients tested doses of 2500 U Neurobloc injected freehand, with no ultrasound guidance. Compared to placebo, BoNT/B improved scores at 1 month in several drooling scales, a visual analogue scale, and a global impression of change. Only mild adverse effects were noted and there was no worsening of dysphagia in this small, short-term study.23 Focal Hyperhidrosis (Excessive Sweating)

As many as 1 in 200 people may have focal hyperhidrosis and it can be extremely disabling both professionally and in private life; 60% of these have excessive sweating in the palms or soles of the feet, 30% in the axillae, and 10% in the face. The cause is usually unknown so that treatment is symptomatic. In Ross syndrome, large areas of skin cannot sweat, and compensatory excessive sweating occurs in the residual areas with functioning sweat glands. In gustatory hyperhidrosis (Frey's syndrome), the cheeks sweat excessively in anticipation of food or when salivation occurs.

The diagnosis is made on clinical grounds, and studies performed with indicator powder reveal the distribution and severity of resting hyperhidrosis and can document the integrity of normal thermoregulatory sweating. Clinicians can select from a range of treatments, depending on the severity of hyperhidrosis and the risks and benefits of therapy. In general, therapy begins with antiperspirants or anticholinergics. Iontophoresis may help palmar-plantar and axillary hyperhidrosis. Local excision and suction curettage are effective for isolated axillary hyperhidrosis not responsive to topical application of aluminum chloride. Endoscopic thoracic sympathectomy can correct palmar-axillary hyperhidrosis but is not risk-free. No single treatment of choice has emerged for craniofacial sweating.

After proof in healthy volunteers that BoNT/A can reduce physiological sweating, it was first used to treat a patient with palmar hyperhidrosis in 1997.24 Small open label studies were followed by large RCTs. Recent reviews generally support the use of BoNT in hyperhidrosis and attempt to define its position in the overall management of the disorder.25 Treatment is with multiple small doses of BoNT injected intradermally in a closely spaced grid drawn over the affected skin. This can be very painful in the palms or soles of the feet and needs a local anesthetic, for instance, a median and ulnar nerve block. Patients tolerate axillary and facial injections more readily. Adverse effects include pain on injection, bruising, infection, and local muscle weakness, for example, of small hand or facial muscles.

Because multiple injections are generally painful, other methods of application are being explored. It may be possible in future to deliver BoNT/A by iontophoresis, a painless technique that early reports suggest was effective in two patients with palmar hyperhidrosis.26 A small open study of BoNT/A injected into hyperhidrotic plantar skin in ten adults using a Dermojet device reported significantly less sweating in eight patients, seven of whom were symptom-free for up to 5 months.27

7.21.21 Hyperhidrosis as a Risk Factor

Sweaty skin predisposes to or exacerbates many other skin disorders. An interesting example of this revolves around the disorder of inguinal hyperhidrosis. Dermato-logical disorders such as tinea cruris, folliculitis, erythrasma, and seborrheic dermatitis, all common in the inguinal region, may be helped by reducing local sweating — perhaps by using botulinum toxin. The principle may extend to other areas afflicted by similar disorders. Axillary Sweating

Two large RCTs of BoNT/A in axillary sweating have shown clear benefit. In one trial enrolling 320 patients, response was defined as >50% reduction in sweating; 93.8% of patients receiving 50 U Botox per axilla responded at week 4 vs. 35.9% of the placebo group (p <0.0001). Patients receiving BoNT/A were significantly more satisfied. Open label follow up of up to three injection cycles per patient over 1 year found no diminution of benefit with repeated cycles, and the mean duration of benefit per cycle was 7.6 months. Patients reported marked improvement in their quality of life.28 A second RCT in 145 patients tested 100 and 200 U Dysport against placebo and found the two doses were equally effective, but did not provide any long-term follow-up data.29

Botulinum toxin B may become a useful alternative to BoNT/A in reducing axillary sweating. A small open study in 13 patients (13 axillae) reported that 5000 U BoNT/B (Neurobloc) produced a significant reduction in the hyperhidrotic area at follow-up compared to baseline. The mean percentage reductions in the hyper-

hidrotic area were 84, 87, and 81% at 4, 8, and 12 weeks (p = 0.001, paired t test). Patient satisfaction was 100% throughout.

Subjective mean percentage reductions in sweat production were 98, 96, and 90 at 4, 8, and 12 weeks. Side effects were minimal.30 Subsequent studies include an RCT reported in a review31 but not yet published that tested 2500 U BoNT/B against placebo in 20 subjects. BoNT/B had a rapid onset of action, over 5 to 7 days in most subjects, with a mean duration of action of 5 months (range 2.2 to 8.1). A single-blind RCT comparing BoNT/A with BoNT/B found that they were equally effective.32 Adverse effects may limit doses of BoNT/B. The higher dose of BoNT/B tested was 4000 U, and this produced more mouth dryness, visual accommodation difficulties, and corneal irritation than a 2000 U dose. Palmar Sweating

Several open studies, a small single-blind RCT, and a small double-blind RCT33 support the use of BoNT/A for palmar sweating. Doses are typically larger than for axillary hyperhidrosis (120 to 220 U Botox). Sweating diminished for 4 to 12 months. Transient side effects included weakness of the small muscles of the hands.

Reduction of palmar sweating may also be helpful in dyshidrotic hand eczema, as suggested in a controlled clinical pilot study of BoNT/A (Botox 100 U) plus topical steroids in six patients. The mean Dyshidrotic Eczema Area and Severity Index score changed from 28 to17 with topical steroid therapy alone and from 36 to 3 with adjuvant BoNT/A (p <0.01). Itching and vesiculation subsided earlier when using the combination of steroids and BONT/A. There was one relapse in the steroid group and none in the BoNT/A group.34 The antipruritic effect of BoNT/A raised the possibility that it reduced the release of substance P.

Compensatory sweating elsewhere — a major problem in many patients who have undergone transthoracic endoscopic sympathectomy for hyperhidrosis — has only rarely been reported after botulinum toxin use. One open study in 17 patients over 6 months showed that successful treatment of palmar hyperhidrosis with BoNT/A does not evoke compensatory hyperhidrosis in nontreated skin territories.35

As in axillary hyperhidrosis, botulinum toxin type B (Myobloc) has been used off-label to treat palmar hyperhidrosis. One double-blind RCT evaluating safety and efficacy in bilateral palmar hyperhidrosis tested Myobloc 5000 U per palm against saline control injections in 20 patients. It found significant improvement with BoNT/B at day 30, with benefit commencing in the first week and lasting 2.3 to 4.9 months, with a mean duration of 3.8 months. Eighteen of 20 participants reported dry mouth or throat. Other adverse effects included indigestion (60%), excessively dry hands (60%), muscle weakness (60%), and decreased grip strength (50%).36 Frey's Syndrome and Crocodile Tears

Gustatory sweating occurs on the cheek due to missprouting of cholinergic nerves after parotid gland lesions, and crocodile tears can occur for the same reasons after facial nerve paralysis or head trauma. A number of small open studies suggest that BoNT/A can be very effective in suppressing both disorders. It seems to exert a particularly long effect in gustatory sweating, with benefit lasting from 11 to 36 months, making it possibly a treatment of choice.37 Rhinorrhea (Runny Nose) and Allergic Rhinitis

Autonomic cholinergic fibers also control nasal secretions. Rhinorrhea is a common disorder, so the results of early studies are of great interest. One double-blind RCT tested BoNT/A in 60 patients with intrinsic rhinitis, using 4 U Botox injected into the middle and inferior turbinates bilaterally. BoNT/A reduced rhinorrhea significantly for 4 weeks without any adverse effects. A second RCT in 34 patients with allergic rhinitis reported that rhinorrhea, nasal obstruction, and sneezing scores were significantly lower in the active BoNT/A treatment group than in the placebo group and improved symptom control for up to 8 weeks.38

7.2.2 Autonomic Indications: Urological Bladder Hyperreflexia

The bladder is in essence an expandable muscular bag whose activity is controlled mainly by autonomic sympathetic and parasympathetic fibers that pass from the micturition center in the pons via the sacral spinal cord. The detrusor muscle makes up much of the body of this bag and is the main muscle involved in actively expelling urine. In bladder hyperreflexia, detrusor overactivity produces urinary frequency, urgency, incontinence, and nocturia. It is common in spinal cord diseases such as multiple sclerosis or traumatic injury. As the bladder fills, spontaneous or provoked involuntary contractions ensue that may be difficult to suppress using oral medication or intermittent self-catheterization. The next level of treatment has been surgery such as augmentation cystoplasty, and an intermediate therapy has long been needed.

In 1998, Schurch et al. tested the idea that wide infiltration of the detrusor muscle with BoNT/A might be helpful. They selected patients with spinal cord injury and intractable neurogenic detrusor overactivity, and used a rigid cystoscope to spread 200 to 400 U Botox between 20 to 30 points in the detrusor muscle, avoiding the trigone. They reported major urodynamic and clinical improvement lasting up to 9 months39 and recently supported these open label findings in a randomized controlled trial.40

Further open label studies and case series using Botox or Dysport also supported the observation, with quoted success rates of 80 to 100%. Some centers simplified the technique using flexible cystoscopy, which can be performed under local anesthetic in outpatients and avoids the need for hospital admission. The procedure is quick and well tolerated and appears to be just as effective, with significant improvements in urinary urgency, incontinence, bladder capacity, and end-filling detrusor pressures. Clinical benefit may last 7 to 12 months.41 One RCT tested Botox, 200 or 300 U, in 59 patients with urinary incontinence caused by neurogenic detrusor overactivity and found a significant reduction in episodes of incontinence with both doses of BoNT/A compared to placebo (p <0.05). There were significant improvements in urodynamic indices and in patient quality of life. There were some benefits from week 2 to the end of the 24 week study.42

So far, repeat injections with BoNT/A seem to be as effective as the first one, so that it is reasonable to give repeat treatment with BoNT/A when the symptoms of bladder overactivity recur.43

Urodynamic studies after treatment with BoNT/A typically showed increased bladder capacity, decreased voiding pressure, increased postvoid residual urinary volume, decreased voiding efficiency, and increased bladder neck opening time. Voiding pressure remained low and bladder neck opening time remained increased at 3 months, although the postvoid residual volume and voiding efficiency may have returned to baseline levels.44

Side effects are generally minor and include transient hematuria, urinary tract infection and flu-like symptoms. Because of the reduced ability to empty their bladders, patients commonly need to employ clean intermittent self-catheterization (CISC) for some while after the injections.

Overall there appears to be a favorable risk-to-benefit ratio for this treatment. However, it remains an unlicensed use of BoNT/A and more RCT evidence would be valuable. Detrusor Sphincter Dyssynergia (DSD)

Normally, when the detrusor muscle contracts to empty the bladder, the main bladder sphincter (vesical sphincter) relaxes to allow urine to pass. DSD involves poor relaxation plus uncoordinated active contraction of the vesical sphincter just as the detrusor muscle is contracting. High pressures in the bladder during attempted voiding may cause ureteric reflux and renal damage. DSD can occur in a variety of spinal cord disorders such as multiple sclerosis and traumatic injury. Drugs, bladder training, and intermittent self-catheterization may help. Patients need full neurological, urological, and urodynamic investigations before treatment proceeds further with surgery or botulinum toxin injections. BoNT/A injections into the urethral sphincter to treat detrusor sphincter dyssynergia have been successfully used for some years.45 Initial studies in 198846 were promising, and were supported by a double-blind RCT in 199047 and additional open label studies.

The toxin is injected endoscopically or under EMG control or with image guidance such as ultrasound, depending on the available facilities and the clinician's expertise. Injection into the sphincter usually weakens both the smooth muscle internal and the striated muscle external sphincters, with effects commencing within the first week and benefit for 2 to 6 months. A major aim is to reduce residual urine after micturition. A wide range of published doses is cited in the literature and it can be difficult to assess the optimum doses for individual patients. Success seems less certain than with detrusor injections, with benefit in studies or more than 10 patients of the order of 58 to 88%48 achieving reduction in residual urine of >50%. Local temporary adverse effects include local bleeding, hematoma, or infection following the needle pass, and sphincter hematoma can reduce urinary flow. Transient urinary incontinence can occur in about one-third of treatments. Urethrospasm

This related disorder involves staccato and sometimes painful voiding caused by repetitive involuntary contractions of the external urethral sphincter, and sphincter EMG can confirm the diagnosis. BoNT/A injections, given as in DSD, are probably now the treatments of choice.48 Potential adverse effects are the same as in DSD. Artificial Bladders and Other Urological Procedures

When an artificial bladder is constructed, the nerve supply to the new bladder is not normal and poor coordination often occurs between the detrusor and the urethral sphincter. BoNT-induced weakening of the external sphincter may be helpful. Similarly, increased muscle tone following pubovaginal sling operations may improve after BoNT injections. Experience is very limited, but this is a logical extension of the use of BoNT.48 Vaginismus

Vaginismus is narrowing of the vaginal introitus due to involuntary contraction of the pelvic musculature in response to a real or imagined attempt to introduce an object into the vagina. There may be additional adduction of the thighs and other involuntary spasms. It is important to distinguish it from fear of coitus without vaginal spasm. Diagnosis requires full gynecological and usually psychological evaluations. If appropriate conventional treatment fails, injections of BoNT into muscles of the pelvic floor and vagina may have a useful direct effect from the induced weakness for 3 to 4 months. Sometimes much longer benefit ensues if the experience allows healing of psychological or physical scars. Treatment with several BoNT injections into the affected area may be unpleasant and stressful for women with vaginismus and they may experience transient urinary incontinence.49 Prostate Disorders

Long-term nonbacterial inflammation of the prostate can cause pain, local muscle spasms, and difficulty with micturition. In 1998, Maria described the use of BoNT/A to relieve voiding dysfunction due to prostatitis.50 That study along with other open label studies51 in small numbers of patients provided accumulating evidence that transurethral or transperineal infiltration of BoNT/A around the external urethral sphincter can reduce pain and spasms and improve the voiding dysfunction as measured by urodynamic studies.

Benign prostatic hypertrophy is extremely common in elderly men, and is often only benign in the sense that it is not cancerous. It causes considerable discomfort and may lead to significant bladder and renal problems. Current medical and surgical treatment options all have disadvantages. Patients often comply poorly with medical treatments.

Prostate hypertrophy may shrink after intralobar injections of BoNT/A, as demonstrated in a double-blind RCT in 30 patients comparing 200 U Botox against saline. At 1 month, symptom scores, prostate-specific antigen, prostate volume, and residual volume all improved by 50% or more, and peak urinary flow rate almost doubled. After 2 months, 13 patients in the treated group and 3 in the control group had subjective symptomatic relief (p = 0.0007). No local complications or systemic side effects were noted. The report suggested that prostate injections of botulinum toxin appeared straightforward, safe, and well tolerated, and pointed out that the benefit is not related to a patient's willingness to complete treatment.52

Overall, there seems to be a favorable risk-benefit ratio for many neurogenic and nonneurogenic disorders within urology. These do, however, remain unlicensed indications and more RCTs are needed before BoNT use is fully accepted.45,53

7.2.3 Autonomic Indications: Gastrointestinal

Kerner was well aware of the gastrointestinal effects of botulinum toxin and its ability to paralyze gut motility. BoNT blocks cholinergic nerve terminals throughout the gut, thereby providing a selective mechanism for damping contractions mediated by acetylcholine release rather than nitrous oxide (NO) or many other excitatory neurotransmitters and hormonal influences. The relative influence of cholinergic, noradrenergic, sympathetic, and parasympathetic neurones varies at different gut locations, and a complex mix of extrinsic neurones interacts with intrinsic gut neurones. In general, a deficiency of gut cholinergic neuronal activity inhibits contractility and reduces motility.

Botulinum toxin can serve as a long-lasting, readily focused anticholinergic agent in gut as well as in somatic muscle. It can reduce normal motility and relieve pathological muscle activity at many levels within the gut. Gastroenterologists are beginning to combine their own techniques and ability to deliver agents anywhere in the gut with their increasing pathophysiological understanding of gastrointestinal tract (GIT) disorders to generate a new range of clinical uses for botulinum toxins. This development is at an early stage involving much speculation, and inevitably some of the suggestions will not "pass muster" after formal testing. Studies have mainly used BoNT/A, but there is no reason why BoNT/B would not also work. Its reported propensity to produce autonomic adverse effects in other arenas might translate to a useful edge over type A toxin in the gut. It may also be that the success or failure of BoNT in these indications will help clarify the underlying pathophys-iology, as has happened in many other situations.

I will discuss some of the possibilities starting with the upper GIT. Esophageal Spasm

Cricopharyngeal spasms can be primary gut disorders or secondary to various neurological illnesses such as stroke, dystonia, or motor neurone disease. They may be very painful and provoke significant proximal dysphagia or lead to pharyngeal diverticulae. Current treatments include drugs, myotomy, dilatation, or neurectomy, each with its own disadvantages. Botulinum toxin injections can be given endoscop-ically or percutaneously under EMG control and may usefully diminish these spasms, but experience is limited. One open label prospective study in 13 outpatients with dysphagia and significant postcricoid pooling of fluids tested 100 U Botox injected under EMG control. Twelve patients showed overall improvements in their ability to take oral diets safely as evidenced by the penetration-aspiration scale. Of the 12 patients who were on nonoral or nearly nonoral diets, 9 resumed normal oral diets.54 Diffuse esophageal spasm is also painful, and a small study suggests that BoNT injections into the esophageal wall can reduce dysphagia and pain. Achalasia

This condition involves functional obstruction of the lower esophagus due to failure to relax the lower esophageal sphincter because of loss of the inhibitory VIP- and NO-containing neurones in the local myenteric plexus. Cholinergic innervation persists and acts unopposed to increase sphincter pressure. This produces a mixture of severe retrosternal pain, dysphagia, and respiratory complications from inhalation of pooled esophageal contents. There may be an underlying paraneoplastic or other autoimmune disorder, or achalasia may occur due to Chagas' disease. Current treatments help in 65 to 90% of patients and include drugs, dilatation, or myotomy, but with significant complication risk, and patients may be too ill to be treated with these methods.

Endoscopic injection of the lower esophageal sphincter with BoNT/A has now been tested in a number of open label studies and RCTs. In an early RCT of 21 patients with achalasia, the mean decrease in the symptom score (0 to 9 scale) at 1 week was 5.4 points for the patients treated with botulinum toxin and 0.5 point for the placebo group (p = 0.001). Lower esophageal sphincter pressure fell by 33% (p = 0.02), and the mean increase in the width of the opening of the lower esophageal sphincter was 204% in the treatment group (p = 0.02). Nineteen of the 21 patients treated with botulinum toxin initially showed symptomatic improvement; after 6 months, 14 patients were still in remission.55 There were no serious adverse effects.

Achalasia remains an unlicensed indication for BoNT/A. Several trials compared BoNT/A with pneumatic dilatation in a variety of clinical situations. As experience has grown, the consensus56 suggests medium-term symptomatic relief in 70 to 100% of patients including children. The early success rates are about the same as for classical surgical or dilatation techniques. BoNT/A does not provide the same immediate relief that the traditional techniques offer, and the injections do not last as long. Repeat injections occasionally do not work. BoNT/A is more expensive than pneumatic dilatation, which can also be repeated, but it may be safer in some situations. It seems likely that BoNT/A will find its place in the therapeutic strategy for achalasia, particularly for elderly or frail patients and others who may not tolerate the traditional options. Gastric and Pyloric Uses

Gastroparesis is a chronic disorder of gastric motility that causes delayed gastric emptying, and may occur in diabetes or collagen vascular disorders or be idiopathic. In some settings such as diabetes, increased pyloric tone and pyloric spasm impeding the stomach outflow may be present. Several small open label studies57 58 suggest that endoscopic BoNT/A injections may relax the pylorus and improve gastric emptying. No side effects were reported, and this area now needs RCT evidence to take matters forward.

BoNT/A may also be combined with surgery. For instance, it may improve gastric emptying if the pylorus is preserved and overactive after procedures such as duodenopancreatectomy.59 However, two infants with hypertrophic pyloric stenosis showed no response to BoNT/A.60 Obesity

Following the same principle that induced urologists to weaken the detrusor muscle to reduce bladder contractions, gastroenterologists interested in helping patients to lose weight are exploring the possibility of reducing gastric motility to delay gastric emptying, induce feelings of satiety or uncomfortable fullness after eating, and thereby decreasing appetite to allow weight loss. The rationale fits with current fashions in bariatric surgery. Early rat studies showed significantly less eating, with associated weight loss after BoNT/A injections into the gastric antrum.61 Early human studies appear promising and have not revealed any adverse effects.62 In one pilot study in 12 morbidly obese patients, all the patients reported feeling full after eating small meals.63 Several centers are planning more thorough trials of this concept (Cardoso-Junior, A., personal communication). Spasm of Sphincter of Oddi

This sphincter controls the outflow of bile and pancreatic digestive juices into the duodenum. Spasm of the sphincter may cause abdominal pain, for instance after cholecystectomy. Theoretically, BoNT may reduce the strength of such spasms. This effect could be used as a test for this condition to select patients for sphincterotomy or repeated injections of BoNT might prove to be treatments in their own right. Preliminary reports of open label BoNT/A injections in patients with frequent attacks of acute pancreatitis and proven spasms of the sphincter are promising. Twelve of the 15 patients were asymptomatic for 3 months, although 11 relapsed, on average, after 6 months.64

BoNT may also prove helpful in reducing complications such as pancreatitis after endoscopic biliary sphincterotomy. One small open study showed a trend towards less risk of postsphincterotomy pancreatitis if BoNT/A was injected into the sphincter during the endoscopy.65 Anal Fissure

These cracks in the anal canal or anal verge rarely heal spontaneously, and often produce severe pain for minutes to hours after defecation. Bright red blood may appear on the toilet paper. Fissures probably arise from a combination of minor trauma during defecation, other stressful situations such as childbirth, or poor local circulation. Fissure is usually associated with spasm of the internal anal sphincter, which in itself is painful and in turn promotes more local ischemia and impairs or prevents healing. In some patients, the sphincter spasm may be the primary initiating agent, again acting through the induced ischemia. Some patients have other abnormalities such as supersensitivity to beta-agonists. Increased adrenergic or cholinergic activity may produce anal fissure. The rectal spasms promote hemorrhoids and aggravate constipation.

Conventional treatment is by controlling constipation, or using anal dilators or surgical sphincterotomy. The latter heals and relieves symptoms in nearly all patients, but carries a risk of fecal incontinence in up to 30% of patients. Recently, local application of nitroglycerin has been shown to relax the anal sphincter and allow healing in many patients. Adverse effects include headaches.

Injection of BoNT/A into the anal sphincter under ultrasound or EMG guidance is becoming an established, though not yet licensed, treatment for anal fissure. The effects are dose-dependent. Injections are usually given into the involuntary internal sphincter, but with sufficient dose the effect spreads to the voluntary muscle of the external sphincter and vice versa. The toxin reduces resting anal pressures, a function mainly of the internal sphincter, and with spread to the external sphincter it may also reduce maximum voluntary contraction and squeeze pressure. Physical healing and symptom control may be related to the baseline maximum anal resting pressure and baseline fissure score.66 Despite the rationale above, manometric studies suggest that healing may not depend entirely on the reduction in maximum anal resting pressure.67

Studies in many hundreds of patients, including some RCTs against placebos,68 established that single sets of BoNT/A injections to the internal anal sphincter effect healing of the fissure and symptom control in around 70% (45 to 95%) of patients. Transient incontinence may occur. These cure rates are reinforced by the findings of RCTs testing BoNT/A against a variety of other treatments.

One RCT tested BoNT/A in 34 patients against lidocaine in 28 patients; 71% of the BoNT/A group and 21% of the lidocaine group showed complete epitheliza-tion at 2 months (p = 0.006). After BoNT/A, all the patients with nocturnal pain became symptom-free, compared to four after lidocaine. Pain following defecation disappeared in 24 patients in the BoNT/A group and in 20 patients after lidocaine (p = 0.96).69

Another RCT70 in 50 patients compared BoNT against 0.2% nitroglycerin ointment applied twice daily for 6 weeks. After 2 months, the fissures were healed in 96% of the BoNT group and in 60% of the nitroglycerin group (p = 0.005). No patient had fecal incontinence. Five patients in the nitroglycerin group had transient, moderate-to-severe headaches related to treatment. None of the patients in the BoNT group reported adverse effects. Ten patients who did not have responses to the assigned treatment — 1 in the botulinum-toxin group and 9 in the nitroglycerin group — crossed over to the other treatment; the fissures subsequently healed in all 10 patients. No relapses occurred during an average of about 15 months of follow-up. Despite the absence of a placebo control group, the authors concluded that both treatments were effective and perhaps more justifiably that BoNT/A was the more effective treatment.

Surgical sphincterotomy is probably more effective than BoNT/A but carries a higher risk of long-term complications. For instance, in an early RCT71 testing BoNT/A against sphincterotomy as definitive management for chronic anal fissure, complete healing was noted in 45 of the 61 (74%) BoNT/A patients at month 2. After 10 of the remaining patients received BoNT/A, the overall healing rate was 87% at 6 months, falling to 75% at 1 year after 7 patients relapsed. After sphinc-terotomy, good healing was noted at 2 months in 49 of 50 (98%) patients (p <0.0001), 94% at 1 year (p = 0.008). Healing was slower with BoNT/A, but patients returned to full activities more quickly. The complication rate was significantly higher after sphincterotomy, with eight cases of anal incontinence vs. none in the botulinum toxin group (p <0.001).

A nonrandomized controlled trial in 21 patients reported fissure healing in 70% of patients after BoNT/A and 82% after surgery (p >0.05). No relapses were found during the 14 months of follow-up.72 A larger RCT73 in 80 patients reported overall healing in 93% after open sphincterotomy and 45% after BoNT/A (p <0.001). After 3 years of follow-up, 5% were incontinent after sphincterotomy and none after BoNT/A (p >0.05). Patients with fissures for more than 12 months with sentinel piles or certain manometric features were more likely to relapse. One RCT found no difference between Botox and Dysport.74

Once intervention is required, the optimum place of BoNT injections in the overall treatment strategy for anal fissure is gradually becoming clearer. The choice for an individual will depend on the experience of his or her surgeon, with a bias toward surgery if certainty of cure is top priority and toward medical treatment with GTN or BoNT/A in older patients when risk factors for incontinence are present or it is essential to avoid long-lasting adverse effects. Pelvic Floor Dysfunction

Patients with chronic idiopathic constipation may have slow bowel transit times or pelvic floor dysfunction. The latter condition may involve poor relaxation or paradoxical contraction of the puborectalis muscle during defecation, sometimes combined with spasm of the sphincter muscles. The anorectal angle is increased. After successful use of BoNT/A injection to the puborectalis muscle in a patient with this kind of outlet constipation due to Parkinson's disease, a number of studies suggested it is possible to improve the anorectal angle and reduce anal tone during straining, with symptomatic improvement in up to 75% of patients.56

Similarly, excessive contraction of the puborectalis may contribute to the formation of a rectocele, a hernia of the anterior rectal wall into the vagina. Surgical repair does not always work, and early studies suggest that some women may be helped by injection of BoNT into the puborectalis muscle.75 Rectal Pain

Apart from pain of anal fissures, rectal pain occurs in a variety of other situations such as perioperatively, for instance, after hemorrhoidectomy. It may be possible to diminish the pain by treatment with BoNT. In one RCT of 50 patients, those who received BoNT/A had significantly less pain toward the end of the first week after surgery.76 The authors assumed that BoNT/A acted by reducing spasm within the internal sphincter, but there are other possible mechanisms, as discussed below. It may also be more logical to pretreat with BoNT/A to allow it to take full effect before surgery proceeds.

Chronic idiopathic anal pain that shows no abnormalities on examination or investigation is often constant, intense, and resistant to conventional treatments. An open study of four patients reported improvement after BoNT/A injections to the anal sphincter and/or the puborectalis muscle.77

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