New Therapeutic Indications for Botulinum Toxins

Carla Cordivari, MD,1,2 V. Peter Misra, MD, FRCP,1 Santiago Catania, MRCP,1

and Andrew J. Lees, MD, FRCP2*

1Department of Clinical Neurophysiology, The National Hospital for Neurology and Neurosurgery, Queen Square,London, United Kingdom

2Reta Lila Weston Institute of Neurological Studies, Windeyer Building, University College of London, United Kingdom

Abstract: The efficacy of botulinum toxin (BTX) withoutsystemic effects has led to the rapid development of applica-tions in neuromuscular disorders, hyperactivity of sudomotorcholinergic-mediated glandular function, and pain syndromes.The successful use of BTX in conditions with muscle overac-tivity, such as dystonia and spasticity, has been established andnew areas in the field of movement disorders such as tics,tremor, myoclonic jerks, and stuttering has been explored withsatisfactory results. Strategies to temporarily inactivate musclefunction after orthopaedic or neurosurgery have also been de-veloped. BTX treatment of hyperhidrosis was followed by itsapplication in other hypersecretory conditions (hyperlacrima-tion and nasal hypersecretion) and in excessive drooling. Stud-ies are in progress, aimed at optimising the technique and

protocol of administration. Other applications for BTX havebeen proposed in gastroenterological and urogenital practice; itappears to be effective in replacing standard surgical proce-dures. Trials of BTX in painful conditions are ongoing mainlyon refractory tension headache, migraine, and backache as wellas dystonia-complex regional pain syndrome and myofascialpain with promising results. Recently, the fastest growing usefor BTX toxin has been in the cosmetic applications. Clearly,the indications for the use of BTX are expanding, but furtherclinical trials will be needed in many different areas. © 2004Movement Disorder Society

Key words: botulinum toxin; hypersalivation; hyperhidro-sis; dystonia; tremor; tic; myoclonus; parkinsonism; pain

Until recently, botulinum toxin (BTX) was most com-monly used for the treatment of conditions characterisedby excessive involuntary muscle activity such as dysto-nia and spasticity. The efficacy of local BTX injections,without systemic spread, has led to its empirical use in anever broadening range of medical disorders includingsome related to autonomic dysfunction. BTX is alsobeing intensively explored as a potential therapy forseveral pain syndromes, although the pathophysiologicalbasis for its beneficial action remains unclear.

NEW INDICATIONS

Recently, the efficacy of BTX for the treatment ofhyperhidrosis, such as palmar and axillary hyperhidrosis,

has been established in open1 and double-blind placebo-controlled studies.2–6 There are a few anecdotal reportsof the benefit of BTX for excessive sweating over theforehead, trunk, and soles. Gustatory sweating can occurafter parotid surgery (Frey’s syndrome) and is due to aninappropriate parasympathetic cholinergic innervation ofcutaneous sympathetic receptors. It is characterised byface and neck hyperemia and abundant sweating of thehyperemic skin in response to gustatory stimulation.Intradermal BTX/A injections over the affected areahave been shown to be highly effective in producingprolonged benefit from this condition.7,8

The initial success of BTX for the treatment of hyper-hidrosis was followed by its use for other hypersecretorysyndromes such as hyperlacrimation and nasal hyperse-cretion. Hyperlacrimation (crocodile tears), due to aber-rant regeneration of the facial nerve after facial palsy hasbeen shown to be successfully treated with injections ofBTX into the lacrimal gland.9 A recent report showedbenefit of BTX for nasal hypersecretion (allergic rhini-tis): 20 units of botulinum toxin A (BOTOX) were

*Correspondence to: Dr. Andrew J. Lees, Reta Lila Weston Instituteof Neurological Studies, Windeyer Building, 46 Cleveland Street,University College of London, London, UK W1T 4JF.E-mail: alees@ion.ucl.ac.uk

DOI 10.1002/mds.20071Published online in Wiley InterScience (www.interscience.wiley.

com).

Movement DisordersVol. 19, Suppl. 8, 2004, pp. S157–S161© 2004 Movement Disorder Society

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applied to each nostril using a small sponge in closecontact with the lower and middle turbinates.10

Excessive drooling can occur in neurological diseaseas a consequence of a reduced rate of spontaneous swal-lowing (such as in parkinsonism), weakness and incoor-dination of pharyngeal muscles (as in motor neurondisease, cerebral palsy, and after stroke), and in condi-tions with impaired alertness and cognitive dysfunction.The pooling of saliva in the mouth leads to embarrassingand unhygienic drooling and also presents risks of chok-ing with aspiration and hypostatic pneumonia. Systemicanticholinergic drugs, local irradiation of salivary glands,and surgical interventions produce only variable benefitand are often associated with systemic side effects aswell as those due to a dry mouth. Promising preliminaryresults have been reported with injections of BTX intothe parotid and submandibular glands (which are respon-sible for 90% of salivary production). BTX blocks ace-tylcholine release at the cholinergic neurosecretory junc-tion of salivary glands. Most of the published literaturedescribes open pilot studies with relatively small groupsof patients but the results are uniformly favourable.11–20

Different doses of BTX and different techniques of ad-ministration have been used (see Table 1). BTX admin-istration has usually been through injections deliveredpercutaneously, but there has been one pilot study ondirect retrograde injections to the Stenson’s duct andlingual ducts through a small catheter.21 This techniquewas associated with side effects (painful swelling inlingual gland and base of the tongue in 1 patient anddysphagia in the other). In some studies, percutaneousinjections have been administered blindly with basicanatomical knowledge of the topography of the salivaryglands, whereas in others, they have been guided by

ultrasound or electromyography. The parotid gland hasusually been injected at two or three sites (Fig. 1) and thesubmandibular gland in one site. The total dose of BTXinjected into each parotid gland has varied from 10 MUto 40 MU BOTOX and 10 to 20 MU Dysport. Thesubmandibular gland has been less frequently injected,using a lower dose of 5 to 15 MU BOTOX. Quantifica-tion of the degree of sialorrhea has been difficult, as theamount of drooling can vary greatly. Time of day, astooped posture, and level of alertness are some of thefactors involved in the amount of salivary production.Various methods, including weighing dental rolls beforeand after placement in different parts of the mouth for 5minutes, a drooling rating scale using a visual 1 to 10analogue scale based on patient and/or carer observationof severity and frequency of drooling, the number ofstandard sized handkerchiefs used per day, direct collec-tion of saliva over fixed time periods, and salivary glandscintigraphy have all been used. Generally, results havebeen encouraging with the reported duration of the ben-eficial response varying from 6 weeks to 6 months. Thereported adverse events include weakness of nearbymuscles producing difficulties chewing or dysphagia dueto BTX spreading to the masseter or bulbar muscles.Hematoma and infections at the site of injection anddental caries and gum disease due to an excessively drymouth are other potential hazards. Further studies are inprogress, aimed at optimising the technique and theprotocol of administration.

New uses of botulinum toxin are also being exploredin the field of movement disorders. There have been oneor two placebo controlled studies on limb tremor wherebotulinum toxin has been shown to produce a significanttremor amplitude reduction but with only mild functional

TABLE 1. Summary of studies on botulinum toxin in hypersalivation

AuthorNo. ofpatients Diagnosis BTX-A dose (MU) Side of injection Technique

Bhatia (1999)11 4 PD1; PSP1; Dy1;MND1

10–20 (Dysport) Each parotids Blind

Jost (1999)12 5 PD 10 (BOTOX) Each parotid BlindPal (2000)14 9 PD 7.5–15.5 (BOTOX) Each parotids BlindGiess (2000)18 5 MND 20 (BOTOX) Each parotid Blind

5 (BOTOX) Each submandibularPorta (2001)15 10 MND4; PD2; CP1;

PS1; SSPE115–40 (BOTOX) Each parotid USS

10–15 (BOTOX) Each submandibularFriedman (2001)16 11 PD 5 (BOTOX) Each parotid BlindSuskind (2002)19 22 CP (children) 40 (BOTOX) Each parotid US

30 (BOTOX) Each submandibularEllis (2002)20 4 CA, tracheostomy, PS 55–65 (BOTOX) in total Parotids,

submandibularsUS

CA, carcinoma; CP, cerebral palsy; Dy, dystonia; MND, motoneuron disease; PD, Parkinson–disease; PS, primary sialorrhea; PSP, progressivesupranuclear palsy; SSPE, subacute sclerosing panencephalitis; US, ultrasound.

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improvement and associated unwanted limb weak-ness.22,23 Better outcome is observed with studies per-formed on head tremor.24 BTX is the treatment of choicein alleviating the ear click associated with idiopathicpalatal tremor. Small amounts of BTX are injected intothe tensor veli palatini muscle.25–27 There has also beenan encouraging recent study on the effect of BTX onfreezing of gait in parkinsonism by Giladi and col-leagues. Injection of BTX into the calf muscles was ableto reduce start hesitation with no significant adverseevents.28

Encouraging results on BTX treatment for vocal andmotor tics have also been published, and there are reportsof a significant reduction of tics premonitory sensationand tic frequency.29–31 The use of BTX is also beingexplored in myoclonic jerks, stiff-person syndrome,32

and stuttering.27 Encouraging anecdotal and preliminaryresults have been reported in all these indications, butfurther work is required.

Botulinum toxin has been used in prevention of con-tractures related to prolonged immobilization in spastic-ity and akinetic rigid syndrome (Parkinson’s disease,corticobasal degeneration). Rigidity and immobilizationcause shortening of muscle, reduce the numbers of sar-comeres, and produce rheological changes of plasticityand viscoelasticity of soft structures.33

These unwanted changes produce further reduction inmuscle compliance, which exacerbates increased muscletone and leads to increased contracture formation.34 Inthe hand, this causes a clenched fist with excessiveflexion at the third, fourth, and fifth metacarpophalan-geal, proximal, and distal interphalangeal joints, andthumb adduction.

The treatment of clenched fist with BTX improvesmuscle relaxation, reduces pain, improves hygiene, andprevents skin maceration and infection. Passive stretch-ing, serial plastering, or splinting after the BTX treat-ment is necessary to obtain the best results.35

BTX has been used recently as a treatment for pain.36

Trials of BTX in refractory tension headache, mi-graine,37,38 backache, post-whiplash injury,39 as well asdystonia-complex regional pain syndrome35 and myofas-cial pain40 are being carried out. Results are promising,but unfortunately, to date the data are insufficient toprovide concrete recommendations for any of these con-ditions. Use of BTX for preoperative treatment (cervicalspine fixation) has also been reported and as a strategy totemporarily inactivate muscle function after orthopaedicor neurosurgical intervention.41

BTX treatment of nerve entrapment conditions such asin piriformis syndrome where the sciatic nerve is com-pressed by the piriformis muscle42 and in that of the ulnar

FIG. 1. Semischematic representation of the anatomy of salivary glands. Lines point to the preferred sites of botulinum toxin injections.

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nerve at the elbow and peroneal nerve at the fibula headare all possible future indications. The anterior scalenusmuscle has also been a target for injection in the thoracicoutlet syndrome.43

Other applications for BTX have been proposed ingastroenterological and urogenital practice. It has beenreported to successfully replace standard surgical proce-dures in condition such as anal fissures,44 achalasia of thecardia,45 biliary dyskinesias, and detrusor sphincter dys-sinergia leading to an unstable urinary bladder.46

Perhaps the fastest growing use for BTX is in the fieldof cosmetic surgery where it is particularly effective forfrown lines (overactive frontalis) and crows feet.47,48

Recent reports also claim benefit for hyperkinetic facialwrinkles of mouth and neck,49 masseter hypertrophy, andblushing.50

CONCLUSION

Proposed clinical indications for the use of botulinumtoxin are rapidly expanding. Further controlled clinicaltrials are needed in many areas, but for some conditionsthat are distressing, rare, and untreatable, it seems likelythat widespread use of BTX will occur without the rein-forcement of good quality evidence of efficacy.

Acknowledgment: This study has been supported by Ipsen,the manufacturer of BTX/A Dysport.

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