From frown lines to fissures: Therapeutic uses for botulinum toxin

International Journal of Surgery (2005) 3, 141e146

www.int-journal-surgery.com

REVIEW

From frown lines to fissures: Therapeutic uses for botulinum toxin R.P. Sutcliffe*, N.A. Sandiford, H.T. Khawaja Department of Surgery, Queen Mary’s Hospital, Sidcup, Kent, UK

KEYWORDS Botulinum toxin; Neurotoxin; Clostridium botulinum

Abstract Introduction: Since the pharmacological mode of action of botulinum toxin (BTX) has been elucidated, its therapeutic potential has been increasingly recognised. The aims of this review were to summarize our current understanding of the pharmacological action of this agent and to review its therapeutic uses. Methods: An electronic literature search with Medline (January 1965 to December 2004) was carried out to identify articles related to the pharmacological mode of action and clinical uses for botulinum toxin using the keyword ‘‘botulinum toxin’’. Results and conclusion: Botulinum toxin A is emerging as a valuable clinical tool, both for diagnostic and therapeutic purposes in a wide variety of disorders, and is already the treatment of choice for selected conditions. Better understanding of its modes of action may identify alternative targets for pharmacological intervention, and may allow development of longer acting drugs with lower immunogenicity. Therapeutic uses of BTX-A must be assessed systematically in prospective studies, and the clinical role of other subtypes requires evaluation. ª 2005 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved.

Background Generalized paralysis with respiratory failure is the principal mode of death in patients infected with Clostridium botulinum, and is due to the systemic neurotoxic effects of botulinum toxin (BTX) which causes striated muscle paralysis.1 However, since the pharmacological mode of action of BTX has * Corresponding author. 100, Dartmouth Road, London, UK. Tel.: C44 2086993149. E-mail address: [email protected] (R.P. Sutcliffe).

been elucidated,2 its potential for therapeutic use in a wide spectrum of disorders associated with muscle overactivity has become appreciated.3 BTX exists as seven antigenically distinct subtypes (AeG), all of which are derived from C. botulinum, but subtype A is the only toxin currently manufactured for clinical use. BTX-A causes paralysis of striated muscles by its effect on cholinergic neurones: the toxin binds selectively to presynaptic cholinergic nerve terminals via its heavy chain, and is internalized by receptor-mediated endocytosis.4 The zinc-dependent light chain of BTX-A is then

1743-9191/$ - see front matter ª 2005 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.ijsu.2005.06.005

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R.P. Sutcliffe et al.

released into the cytoplasm,5 and cleaves SNAP-25, a cytoplasmic synaptosome-associated protein that is necessary for neurotransmitter release.6,7 Other BTX subtypes have similar modes of action, subtypes C and E also cleaving SNAP-25, and subtypes B, D and F cleaving synaptobrevin, also involved in vesicle release.2 More recently, an appreciation that BTX-A inhibits glandular secretion and induces paralysis of smooth muscle has resulted in a marked expansion of its potential therapeutic applications.3 Although the exact mechanisms by which BTX-A exerts its effects on smooth muscle have not been fully evaluated, in vitro work on internal anal sphincters suggests that it may work by inhibiting noradrenaline release from sympathetic neurones.8 Since being granted FDA approval for the treatment of strabismus and blepharospasm in 1989,9 BTX-A has been used to treat disorders that are characterized by overactivity of either (1) muscle (striated or smooth), or (2) exocrine glands (e.g. sweat and salivary) (see Table 1). A minute quantity of BTX-A injected locally into either muscle or glandular tissue causes neuromuscular blockade or reduced glandular function without systemic toxicity.3 Local side effects, including rash or excessive neuromuscular blockade (e.g. faecal Table 1

incontinence) are well recognised, while systemic paralysis is rare.10 Although BTX-A causes irreversible blockade of neurotransmission, its clinical effect is short-lived, with symptoms frequently recurring after only a few months.11 This transient effect of BTX-A has been attributed to expansion of motor end plates, growth of collateral axonal sprouts, and development of new neuromuscular junctions.11 Failure of BTX-A therapy may also be due to immunoresistance,12,13 the incidence of which may be reduced by developing toxin with lower immunogenicity.13 BTX-A may also exert pharmacological effects on other aspects of neuronal function, such as retrograde axonal transport, motoneuronal excitability and presynaptic inhibition,14 but their clinical relevance is unknown.

Therapeutic uses Neurology Blepharospasm BTX-A is first line treatment for this condition, which is characterized by excessive involuntary

Clinical uses of botulinum toxin

Site

Condition

Head and neck Smooth muscle Smooth muscle Striated muscle Striated muscle Striated muscle Smooth muscle Gland Striated muscle Striated muscle

Intraocular muscles Levator palpebrae superioris Orbicularis oculi Corrugator superciliaris Neck musculature Vocal cords Salivary glands Cranial musculature Lateral pterygoid

Strabismus Lid retraction Blepharospasm Glabellar lines Dystonias, whiplash Tourette’s syndrome Sialorrhoea Migraine Recurrent TMJ dislocation

Limbs Striated muscle Gland Gland

Upper and lower limbs Axilla Hands

Gastrointestinal tract Smooth muscle Smooth muscle

Cerebral palsy Axillary hyperhidrosis Palmar hyperhidrosis Dystonia

Cricopharyngeus Lower oesophageal sphincter

Smooth muscle Smooth muscle

Sphincter of Oddi Internal anal sphincter

Urinary tract Smooth muscle

Cricopharyngeal dysphagia Achalasia Diffuse oesophageal spasm Sphincter of Oddi dysfunction Anal fissure Anismus Rectocoele

Detrusor muscle

Smooth muscle

Internal urethral sphincter

Detrusor instability Detrusor-sphincter dyssynergia Detrusor-sphincter dyssynergia Chronic prostatic pain

Therapeutic uses for botulinum toxin closure of the eyelids.15 Repeated injections of BTX-A into the orbicularis oculi muscle are highly effective, and are associated with less local toxicity than doxorubicin chemomyectomy.16 Failure to respond to BTX-A injection may be due to apraxia of lid opening, a condition that is effectively treated by surgical myomectomy.17 Spasticity BTX-A injection into lower limb musculature in patients with cerebral palsy or after traumatic brain injury significantly improves motor skill performance, and may be a useful adjunct to conventional treatments in the management of lower limb spasticity in these patients.18e20 Early data indicate that although muscle tone returns to baseline after an initial reduction following BTX-A, functional improvement of upper limb spasticity is sustained.21 Improved results may be achieved by using ultrasonography to guide BTX-A injections into appropriate muscles.22 Dystonias There is growing evidence that BTX-A is an effective treatment for dystonias, including cervical dystonia,23 myofascial pain,24 Piriformis syndrome25 and writer’s cramp.26 BTX-A is more efficacious than BTX-B for treating myofascial pain,24 and accurate identification of muscles by electromyography appears to be important.23 Migraine BTX-A has been used to treat migraine, and although its mechanism of action is currently unknown, symptomatic relief may be secondary to its antinociceptive effect, rather than due to neuromuscular blockade.27 Tourette’s syndrome In a recent uncontrolled study of 30 patients with Tourette’s syndrome and phonic tics, injection of botulinum toxin into bilateral vocal cords improved symptoms in 93%.28 This effect was sustained for a mean duration of 102 days, and was associated with an improved quality of life and no serious side effects, although hypophonia developed in 80%.28 Parkinson’s disease Anatomically guided injection of BTX-B into the salivary glands is a safe and effective method of reducing symptoms of sialorrhoea in patients with Parkinson’s disease, and does not appear to significantly worsen dysphagia.29

143 Whiplash The pathophysiology of whiplash, which is commonly associated with motor vehicle accidents, is poorly understood.30 Whiplash symptoms are thought to be secondary to aberrant cervical muscle spasms, and are treated either by physical therapies (e.g. manipulation, transcutaneous electrical nerve stimulation, ultraosonography and acupuncture) or pharmacological agents (e.g. muscle relaxants and nonsteroidal anti-inflammatory drugs). Preliminary studies have indicated that botulinum toxin injections may relieve pain and improve mobility in patients suffering from whiplash,31 and results of a prospective, randomized study are awaited.30

Cosmetic surgery Facial rejuvenation The effect of botulinum toxin to reduce dynamic facial rhytids (wrinkles), such as glabellar lines, was first observed in patients being treated for blepharospasm. In a randomized, placebo-controlled study, BTX-A injection into corrugator superciliaris and/or procerus muscles was shown to significantly reduce the severity of frown lines for up to 120 days,32 and FDA approval for its cosmetic use was subsequently granted in 2002.

Gastroenterology Achalasia Achalasia is characterized by failure of lower esophageal sphincter (LES) relaxation, typically presents with progressive dysphagia, and has been traditionally treated by either balloon dilatation or surgical myotomy. Injection of BTX-A into the LES provides symptomatic relief in 90% of patients,33 but due to its short-lived effect, recurrence of symptoms is common, occurring in up to 70% of patients within two years.34e37 Improved results may be achieved by combining prograde and retrograde injection of toxin into the LES, although this must be confirmed in a randomized, controlled study.38 Due to limited duration of response, BTX-A is unlikely to supersede balloon dilatation or surgical myotomy in the management of achalasia, but provides a safe alternative in the elderly and patients unfit for general anaesthesia.39 BTX-A has also been applied to the treatment of diffuse oesophageal spasm40 and cricopharyngeal dysphagia41e43 although long-term benefits are unclear. Sphincter of Oddi dysfunction Injection of BTX-A into the sphincter of Oddi in patients with post-cholecystectomy pain was

144 associated with relief of symptoms in more than 50% in one study,43 and potentially avoids morbidity due to sphincterotomy.44 However, since its effects last for less than 6 months, its clinical role may be diagnostic, to aid selection of patients who will benefit from sphincterotomy, rather than therapeutic.39 Anal fissure Up to one-third of patients will develop faecal incontinence after surgical treatment of anal fissures (anal stretch or lateral anal sphincterotomy),45 while encouraging results with topical nitroglycerin or calcium channel blockers have prompted re-evaluation of most appropriate treatment for this condition.46 A single injection of BTX-A into the internal anal sphincter is effective, associated with long-term benefit,47 and may be superior to topical nitroglycerin,48 although cost may limit its availability.46 Recent in vitro data indicate that BTX-A may cause sphincteric paralysis by inhibition of sympathetic rather than parasympathetic neurones,8 although this requires confirmation in vivo. Pelvic floor dysfunction BTX-A injections may also relieve symptoms due to anismus (inappropriate contraction of anal sphincter on straining), anterior rectocoele and following surgery for Hirschsprung’s disease, although direct comparisons with conventional approaches are lacking, and the long-term benefits are unknown.49e51 Long-term results may be improved by using transrectal ultrasonography to direct injection of toxin.52

Ophthalmology Strabismus BTX-A may be used for both diagnostic and therapeutic purposes in patients with strabismus.53 After transient monocular vision loss, BTX-A injection permits selection of patients who have binocular cooperation and may benefit from surgery.3 Injection of BTX-A into ipsilateral antagonist muscles in patients with paralytic strabismus may prevent muscle contracture.53

Dermatology Hyperhidrosis Focal hyperhidrosis, which is characterized by profuse and frequently disabling sweating, is due to excessive secretion by eccrine sweat glands.54,55 Conventional treatments for hyperhidrosis have

R.P. Sutcliffe et al. important limitations, since unacceptable side effects develop commonly with oral anticholinergic drugs54 and compensatory hyperhidrosis occurs in the majority of patients after sympathectomy.56 Recently, BTX-A has been shown to be an effective alternative for axillary hyperhidrosis,57 and although it also appears to relieve palmar hyperhidrosis,58 injection of toxin at this site is painful, and may cause nerve injury and impaired motor function.59,60 Facial flushing Facial flushing, which is a common problem that may be severe and disabling in some patients, has been effectively treated by BTX-A in a patient after failed laser treatment.61

Urology Detrusor instability Preliminary data indicate that intravesical injection of BTX-A in patients with neurogenic detrusor instability is safe, improves bladder capacity and reduces urge incontinence.62,63 Detrusor-sphincter dyssynergia Transurethral or transperineal injection of BTX-A effectively produces a sustained reduction in external urethral sphincter pressure, voiding pressure and post-void residual volume in patients with multiple sclerosis and incomplete spinal cord injury.64e67 Chronic prostatic pain Injection of BTX-A into the external urethral sphincter has been reported to improve chronic prostatic pain, presumably by reducing sphincter hyperactivity.68 Large prospective studies are required to clarify the role of BTX-A injections in neuro-urologic disorders.

Miscellaneous conditions Injection of BTX-A into the lateral pterygoid muscle has been used to treat recurrent temporomandibular joint dislocation with some success,69 while a sustained improvement of upper lid retraction due to dysthyroidism was demonstrated in 5 out of 6 patients in a recent study.70

Conclusions Botulinum toxin A is emerging as a valuable clinical tool, both for diagnostic and therapeutic purposes in a wide variety of disorders, and is already the

Therapeutic uses for botulinum toxin treatment of choice for selected conditions. Careful dosage, radiologic guided injection and restricted use by appropriately trained individuals are important in achieving clinical efficacy, and to avoid local and systemic toxicity. Better understanding of the modes of action of botulinum toxin A may identify alternative targets for pharmacological intervention, and may facilitate development of neurotoxins with prolonged duration of action and reduced immunogenicity. Therapeutic applications of botulinum toxin A must be assessed systematically in prospective studies, and the clinical role of other subtypes requires evaluation.

References 1. Cherington M. Clinical spectrum of botulism. Muscle Nerve 1998;21:701e10. 2. Coffield JA, Considine RV, Simpson LL. The site and mechanism of action of botulinum neurotoxin. In: Jankovic J, Hallet M, editors. Therapy with botulinum toxin. New York, NY: Marcel Dekker Inc.; 1994. p. 3e13. 3. Munchau A, Bhatia KP. Uses of botulinum toxin injection in medicine today. BMJ 2000;320(7228):161e5. 4. Black JD, Dolly JO. Interaction of 125I-labeled botulinum neurotoxins with nerve terminals. II. Autoradiographic evidence for its uptake into motor nerves by acceptormediated endocytosis. J Cell Biol 1986;103(2):535e44. 5. Lebeda FJ, Hack DC, Gentry MK. Theoretical analyses of the functional regions of the heavy chain of botulinum neurotoxin. In: Jankovic J, Hallett M, editors. Therapy with botulinum toxin. New York, NY: Marcel Dekker, Inc.; 1994. p. 51e61. 6. Simpson LL, Maksymowych AB, Park JB, Bora RS. The role of the interchain disulfide bond in governing the pharmacological actions of botulinum toxin. J Pharmacol Exp Ther 2004;308(3):857e64. 7. Blasi J, Chapman ER, Link E, Binz T, Yamasaki S, De Camilli P, et al. Botulinum neurotoxin A selectively cleaves the synaptic protein SNAP-25. Nature 1993;365(6442):160e3. 8. Jones OM, Brading AF, Mortensen NJ. Mechanism of action of botulinum toxin on the internal anal sphincter. Br J Surg 2004;91(2):224e8. 9. Schantz EJ. Historical perspective. In: Jankovic J, Hallet M, editors. Therapy with botulinum toxin. New York, NY: Marcel Dekker Inc.; 1994. p. xxiiiexxvi. 10. Coletti Moja M, Dimanico U, Mongini T, Cavaciocchi V, Gerbino Promis PC, Grasso E. Acute neuromuscular failure related to long-term botulinum toxin therapy. Eur Neurol 2004;51(3):181e3. 11. Alderson K, Holds JB, Anderson RL. Botulinum-induced alteration of nerveemuscle interactions in the human orbicularis oculi following treatment for blepharospasm. Neurology 1991;41(11):1800e5. 12. Atassi MZ. Basic immunological aspects of botulinum toxin therapy. Mov Disord 2004;19(Suppl. 8):S68e84. 13. Dressler D. Clinical presentation and management of antibody-induced failure of botulinum toxin therapy. Mov Disord 2004;19(Suppl. 8):S92e100. 14. Gracies JM. Physiological effects of botulinum toxin in spasticity. Mov Disord 2004;19(Suppl. 8):S120e8. 15. Hallett M. Blepharospasm: recent advaces. Neurology 2002; 59(9):1306e12.

145 16. Wirtschafter JD, McLoon LK. Long-term efficacy of local doxorubicin chemomyectomy in patients with blepharospasm and hemifacial spasm. Ophthalmology 1998;105(2):342e6. 17. Andersson KE. New pharmacologic targets for the treatment of the overactive bladder: an update. Urology 2004;63 (3 Suppl. 1):32e41. 18. Gaebler-Spira D, Revivo G. The use of botulinum toxin in pediatric disorders. Phys Med Rehabil Clin N Am 2003;14(4): 703e25. 19. Papadonikolakis AS, Vekris MD, Korompilias AV, Kostas JP, Ristanis SE, Soucacos PN. Botulinum A toxin for treatment of lower limb spasticity in cerebral palsy: gait analysis in 49 patients. Acta Orthop Scand 2003;74(6):749e55. 20. Fock J, Galea MP, Stillman BC, Rawicki B, Clark M. Functional outcome following botulinum toxin A injection to reduce spastic equinus in adults with traumatic brain injury. Brain Inj 2004;18(1):57e63. 21. Wallen MA, O’flaherty SJ, Waugh MC. Functional outcomes of intramuscular botulinum toxin type A in the upper limbs of children with cerebral palsy: a phase II trial. Arch Phys Med Rehabil 2004;85(2):192e200. 22. Berweck S, Schroeder AS, Fietzek UM, Heinen F. Sonographyguided injection of botulinum toxin in children with cerebral palsy. Lancet 2004;363(9404):249e50. 23. Walker FO. Botulinum toxin therapy for cervical dystonia. Phys Med Rehabil Clin N Am 2003;14(4):749e66. 24. Lang AM. A preliminary comparison of the efficacy and tolerability of botulinum toxin serotypes A and B in the treatment of myofascial pain syndrome: a retrospective, open-label chart review. Clin Ther 2003;25(8):2268e78. 25. Lang AM. Botulinum toxin type B in piriformis syndrome. Am J Phys Med Rehabil 2004;83(3):198e202. 26. Karp BI. Botulinum toxin treatment of occupational and focal hand dystonia. Mov Disord 2004;19(Suppl. 8):S116e9. 27. Ashkenazi A, Silberstein SD. Botulinum toxin and other new approaches to migraine therapy. Annu Rev Med 2004;55: 505e18. 28. Porta M, Maggioni G, Ottaviani F, Schindler A. Treatment of phonic tics in patients with Tourette’s syndrome using botulinum toxin type A. Neurol Sci 2004;24(6):420e3. 29. Ondo WG, Hunter C, Moore W. A double-blind placebocontrolled trial of botulinum toxin B for sialorrhea in Parkinson’s disease. Neurology 2004;62(1):37e40. 30. Juan J. Use of botulinum toxin-A for musculoskeletal pain in patients with whiplash associated disorders. BMC Musculoskelet Disord 2004;5(1):5. 31. Freund BJ, Schwartz M. Treatment of whiplash associated neck pain [corrected] with botulinum toxin-A: a pilot study. J Rheumatol 2000;27(2):481e4. 32. Carruthers JA, Lowe NJ, Menter MA, Gibson J, Nordquist M, Mordaunt J, et al. BOTOX Glabellar Lines I Study Group. A multicenter, double-blind, randomized, placebo-controlled study of the efficacy and safety of botulinum toxin type A in the treatment of glabellar lines. J Am Acad Dermatol 2002; 46(6):840e9. 33. Pasricha PJ, Ravich WJ, Hendrix TR, Sostre S, Jones B, Kalloo AN. Intrasphincteric botulinum toxin for the treatment of achalasia. N Engl J Med 1995;332(12):774e8. 34. Katz P. Achalasia: two effective treatment options e let the patient decide. Am J Gastroenterol 1994;89(7):969e70. 35. Malthaner RA, Tood TR, Miller L, Pearson FG. Long-term results in surgically managed esophageal achalasia. Ann Thorac Surg 1994;58(5):1343e6. 36. Pasricha PJ, Rai R, Ravich WJ, Hendrix TR, Kalloo AN. Botulinum toxin for achalasia: long-term outcome and predictors of response. Gastroenterology 1996;110(5):1410e5.

146 37. Martinek J, Siroky M, Plottova Z, Bures J, Hep A, Spicak J. Treatment of patients with achalasia with botulinum toxin: a multicenter prospective cohort study. Dis Esophagus 2003; 16(3):204e9. 38. Martinek J, Spicak J. A modified method of botulinum toxin injection in patients with achalasia: a pilot trial. Endoscopy 2003;35(10):841e4. 39. Qureshi WA. Gastrointestinal uses of botulinum toxin. J Clin Gastroenterol 2002;34(2):126e8. 40. Cassidy MJ, Schiano TD, Adrain AL, et al. Botulinum toxin injection for the treatment of symptomatic diffuse oesophageal spasm [abstract]. Am J Gastroenterol 1996;91: 1881. 41. Blitzer A, Brin MF. Use of botulinum toxin for diagnosis and management of cricopharyngeal achalasia. Otolaryngol Head Neck Surg 1997;116(3):328e30. 42. Chiu MJ, Chang YC, Hsiao TY. Prolonged effect of botulinum toxin injection in the treatment of cricopharyngeal dysphagia: case report and literature review. Dysphagia 2004; 19(1):52e7. 43. Wehrmann T, Seifert H, Seipp M, Lembcke B, Caspary WF. Endoscopic injection of botulinum toxin for biliary sphincter of Oddi dysfunction. Endoscopy 1998;30(8):702e7. 44. Sherman S, Ruffolo TA, Hawes RH, Lehman GA. Complications of endoscopic sphincterotomy. A prospective series with emphasis on the increased risk associated with sphincter of Oddi dysfunction and nondilated bile ducts. Gastroenterology 1991;101(4):1068e75. 45. Weaver RM, Ambrose NS, Alexander-Williams J, Keighley MR. Manual dilatation of the anus vs. lateral subcutaneous sphincterotomy in the treatment of chronic fissure-in-ano. Results of a prospective, randomized, clinical trial. Dis Colon Rectum 1987;30(6):420e3. 46. Lindsey I, Jones OM, Cunningham C, Mortensen NJ. Chronic anal fissure. Br J Surg 2004;91(3):270e9. 47. Maria G, Cassetta E, Gui D, Brisinda G, Bentivoglio AR, Albanese A. A comparison of botulinum toxin and saline for the treatment of chronic anal fissure. N Engl J Med 1998; 338(4):217e20. 48. Brisinda G, Maria G. Botulinum toxin for spastic GI disorders. Gastrointest Endosc 2003;58(3):472e3. 49. Maria G, Brisinda G, Bentivoglio AR, Albanese A, Sganga G, Castagneto M. Anterior rectocele due to obstructed defecation relieved by botulinum toxin. Surgery 2001; 129(5):524e9. 50. Langer JC, Birnbaum E. Preliminary experience with intrasphincteric botulinum toxin for persistent constipation after pull-through for Hirschsprung’s disease. J Pediatr Surg 1997;32(7):1059e61. 51. Hallan RI, Williams NS, Melling J, Waldron DJ, Womack NR, Morrison JF. Treatment of anismus in intractable constipation with botulinum A toxin. Lancet 1988;2(8613):714e7. 52. Maria G, Sganga G, Civello IM, Brisinda G. Botulinum neurotoxin and other treatments for fissure-in-ano and pelvic floor disorders. Br J Surg 2002;89(8):950e61. 53. Scott AB, Magoon EH, McNeer KW, Stager DR. Botulinum treatment of childhood strabismus. Ophthalmology 1990; 97(11):1434e8.

R.P. Sutcliffe et al. 54. White Jr JW. Treatment of primary hyperhidrosis. Mayo Clin Proc 1986;61(12):951e6. 55. Hashmonai M, Kopelman D, Assalia A. The treatment of primary palmar hyperhidrosis: a review. Surg Today 2000; 30(3):211e8. 56. Lin CL, Yen CP, Howng SL. The long-term results of upper dorsal sympathetic ganglionectomy and endoscopic thoracic sympathectomy for palmar hyperhidrosis. Surg Today 1999; 29(3):209e13. 57. Naumann M, Lowe NJ. Botulinum toxin type A in treatment of bilateral primary axillary hyperhidrosis: randomised, parallel group, double blind, placebo controlled trial. BMJ 2001;323(7313):596e9. 58. Naumann M, Flachenecker P, Brocker EB, Toyka KV, Reiners K. Botulinum toxin for palmar hyperhidrosis. Lancet 1997;349(9047):252. 59. Hayton MJ, Stanley JK, Lowe NJ. A review of peripheral nerve blockade as local anaesthesia in the treatment of palmar hyperhidrosis. Br J Dermatol 2003;149(3):447e51. 60. Shelley WB, Talanin NY, Shelley ED. Botulinum toxin therapy for palmar hyperhidrosis. J Am Acad Dermatol 1998;38(2 Pt 1): 227e9. 61. Yuraitis M, Jacob CI. Botulinum toxin for the treatment of facial flushing. Dermatol Surg 2004;30(1):102e4. 62. Schurch B, Stohrer M, Kramer G, Schmid DM, Gaul G, Hauri D. Botulinum-A toxin for treating detrusor hyperreflexia in spinal cord injured patients: a new alternative to anticholinergic drugs? Preliminary results. J Urol 2000; 164(3 Pt 1):692e7. 63. Dykstra D, Enriquez A, Valley M. Treatment of overactive bladder with botulinum toxin type B: a pilot study. Int Urogynecol J Pelvic Floor Dysfunct 2003;14(6):424e6. 64. Dykstra DD, Sidi AA. Treatment of detrusor-sphincter dyssynergia with botulinum A toxin: a double-blind study. Arch Phys Med Rehabil 1990;71(1):24e6. 65. Schurch B, Hauri D, Rodic B, Curt A, Meyer M, Rossier AB. Botulinum-A toxin as a treatment of detrusor-sphincter dyssynergia: a prospective study in 24 spinal cord injury patients. J Urol 1996;155(3):1023e9. 66. Schurch B, Hodler J, Rodic B. Botulinum A toxin as a treatment of detrusor-sphincter dyssynergia in patients with spinal cord injury: MRI controlled transperineal injections. J Neurol Neurosurg Psychiatry 1997;63(4):474e6. 67. Gallien P, Robineau S, Verin M, Le Bot MP, Nicolas B, Brissot R. Treatment of detrusor sphincter dyssynergia by transperineal injection of botulinum toxin. Arch Phys Med Rehabil 1998;79(6):715e7. 68. Zermann D, Ishigooka M, Schubert J, Schmidt RA. Perisphincteric injection of botulinum toxin type A. A treatment option for patients with chronic prostatic pain? Eur Urol 2000;38(4):393e9. 69. Martinez-Perez D, Garcia Ruiz-Espiga P. Recurrent temporomandibular joint dislocation treated with botulinum toxin: report of 3 cases. J Oral Maxillofac Surg 2004; 62(2):244e6. 70. Chuenkongkaew W. Botulinum toxin treatment for upper lid retraction of dysthyroidism. J Med Assoc Thai 2003;86(11): 1051e4.