Review Botulinum toxin: Clinical...

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Parkinsonism and Related Disorders 12 (2006) 331–355

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Review

Botulinum toxin: Clinical use

Daniel D. Truonga,�, Wolfgang H. Jostb

aThe Parkinson’s and Movement Disorder Institute, 9940 Talbert Avenue, Fountain Valley, CA 92708, USAbDepartment of Neurology, Deutsche Klinik fur Diagnostik, Wiesbaden, Germany

Received 12 April 2006; received in revised form 21 June 2006; accepted 21 June 2006

Abstract

Since its development for the use of blepharospasm and strabismus more than 2.5 decades ago, botulinum neurotoxin (BoNT) has

become a versatile drug in various fields of medicine. It is the standard of care in different disorders such as cervical dystonia,

hemifacial spasm, focal spasticity, hyperhidrosis, ophthalmological and otolaryngeal disorders. It has also found widespread use in

cosmetic applications. Many other indications are currently under investigation, including gastroenterologic and urologic

indications, analgesic management and migraine. This paper is an extensive review of the spectrum of BoNT clinical applications.

r 2006 Elsevier Ltd. All rights reserved.

Keywords: Botulinum toxin; Dystonia; Blepharospasm; Cervical dystonia; Spasmodic dysphonia; Writer’s cramp; Oromandibular dystonia;

Tourette’s syndrome; Spasticity; Hyperhydrosis; Cosmetic; Hyperreflexive bladder; Detrusor sphincter dyssynergia; Urethrism; Achalasia; Anal

fissure; Levator ani syndrome; Pain; Parkinson’s disease; Headache

Contents

0. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 332

1. Preparations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 332

2. Neurological disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 333

2.1. Cervical dystonia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 333

2.2. Blepharospasm . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 334

2.3. Hemifacial spasm (HFS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 334

2.4. Oromandibular dystonia (OMD) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 335

2.5. Writer’s cramp (WC). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 335

2.6. Other occupational cramps . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 336

2.7. Foot dystonia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 336

2.8. Axial dystonia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 336

2.9. Tardive dyskinesia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 336

2.10. Tourette’s syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 337

2.11. Tremor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 337

2.12. Spasticity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 337

3. Ophthalmology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 338

3.1. Strabismus and other ophthalmic disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 338

3.2. Protective ptosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 338

3.3. Crocodile tears (lacrimation) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 338

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ess: [email protected] (D.D. Truong).

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ARTICLE IN PRESSD.D. Truong, W.H. Jost / Parkinsonism and Related Disorders 12 (2006) 331–355332

4. Otolaryngology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 338

4.1. Spasmodic dysphonia (SD) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 338

4.2. Bruxism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 339

4.3. Rhinitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 339

4.4. Sialorrhea. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 340

5. Dermatology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 341

5.1. Wrinkles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 341

5.2. Hyperhidrosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 341

6. Urological disorders. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 343

6.1. Hyperreflexive bladder. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 343

6.2. Detrusor-sphincter dyssynergia (DSD) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 343

6.3. Spasticity of the vesical sphincter and urethrism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 343

6.4. Neobladder (artificial bladder) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 343

6.5. Benign prostatic hyperplasia (BPH) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 344

7. Gynecology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 344

8. Gastrointestinal and proctologic disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 344

8.1. Achalasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 344

8.2. Other gastrointestinal uses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 344

8.3. Anal fissure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 344

8.4. Further use of BoNT in proctology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 344

9. Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 344

10. Botulinum toxin applications in parkinsonism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 346

11. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 346

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 346

0. Introduction

In 1897, Emile van Ermengem investigated anepidemic in Ellezelles, Belgium, where several peoplewho had gathered at a funeral music festival developedbotulism after consuming raw ham [1]. After isolatingthe bacteria from the ham, van Ermengem produced thedisease in laboratory animals by injecting the toxinproduced by the organism. Botulism can develop notonly from ingestion of foods, but also as intestinalcolonization in infants or, rarely, adults. Woundbotulism or inadvertent botulism has also been docu-mented. Inadvertent botulism has been reported inpatients treated with intramuscular injections of botu-linum neurotoxin (BoNT), even in therapeutic doses ordoses below the maximum recommended doses [2,3]. Inthese reports, patients demonstrated moderate tomarked clinical weakness, autonomic nervous systemeffects or electrophysiological abnormalities consistentwith botulism [4].

In the late 1970s, the toxin was introduced astherapeutic agent for the treatment of strabismus [5].Since then, its therapeutic applications have expandedinto many different fields, often with innovative treat-ments and surprising results.

1. Preparations

A number of botulinum toxin preparations have beenapproved in different countries. Currently, there are five

different botulinum toxins available on the market inone or more countries. Four of them contain BoNTserotype A (Botoxs, Dysports, Xeomins and CBTXA)and the other contains BoNT type B (Myoblocs/NeuroBlocs). Approval procedures are very complexand vary from preparation to preparation and fromcountry to country. CBTXA is currently available onlyin China and there is little information about thisproduct. Xeomins was recently approved in Germany.The only approved BoNT/B preparation (Myoblocs)/NeuroBlocs) has only been licensed for cervicaldystonia (CD), and only in a few countries. Its use islimited to patients who develop neutralizing antibodiesto BoNT/A preparations. Botoxs has garnered themost approvals worldwide, followed by Dysports,although Dysports is not yet licensed in the US.

Doses of BoNT used for the treatment vary depend-ing on the particular brand of toxin used. Although twoof the widely available products contain type A (Botoxs

and Dysports), a unit of one product is not the same asa unit of the other. Various studies put the dose ratio(Botoxs). Dysports differently, with many in the rangeof 1:3 to 1:5 [6–9]. At the 1:3 ratio, Dysport has anadverse event profile different from Botoxs [8]. Thedose ratio for Botoxs:Xeomins is estimated as 1:1 [10];however, the US type A product (Botoxs) is estimatedto be about 50 times more potent than the type Bproduct [11–13]. It is therefore important to rememberthat the dose given for any particular toxin refers only tothat particular preparation and does not readily transferto doses of other products, even if they are of the same

ARTICLE IN PRESSD.D. Truong, W.H. Jost / Parkinsonism and Related Disorders 12 (2006) 331–355 333

toxin serotype. Furthermore, it should be emphasizedthat these ratios should be applied with extreme cautionbecause different preparations may have differentefficacy in different parts of the body.

Over the course of more than 20 years, the therapeuticspectrum of BoNT has been successively expanding. Inthe following sections, established and emerging appli-cations of BoNT are reviewed, grouped into thefollowing categories: neurological, otolaryngological,ophthalmological, urological disorders, cosmetics, gas-trointestinal/proctological disorders and pain. For thereaders of this journal, we include a section about theusefulness of botulinum toxin in the symptomatictreatment of Parkinson’s disease (PD).

2. Neurological disorders

2.1. Cervical dystonia

CD, or spasmodic torticollis, is a focal dystoniaarising from involuntary contraction of muscles in theneck and shoulders, causing turning, tilting, flexion orextension movements of the head, sometimes combinedwith elevation or anterior shifting of the shoulders. Painis present in up to 60% of patients [14]. CD is now theonly indication for which all botulinum toxins availableare licensed in one or more countries [15].

BoNT/A therapy of CD was first reported in 1985[16]. Currently, both commercially available serotypes,BoNT/A and BoNT/B have been evaluated in rando-mized controlled trials to demonstrate safety andefficacy for CD. Tsui et al. reported the first study ofBoNT for CD in 12 patients [16]. The study was single-blinded with a total maximum dose of 200U of BoNT/Aas Oculinums (Smith-Kettlewell, San Francisco, CA;the name Oculinums was later changed to Botoxs) [16].Improvement occurred in 92% of the patients and lasted4–8 weeks with 25% reporting transient neck weakness[16]. A subsequent double-blind, placebo-controlled,crossover study confirmed these early results [17]. Theeffect of BoNT was also confirmed by the efficacy of adifferent formulation of BoNT/A from the VaccineResearch and Production Laboratory, Porton Down,UK (the precursor of Dysports) in an open-label studyusing blinded video ratings [18].

There are 10 prospective, double-blind, randomized,controlled clinical trials meeting the criteria for classi-fication as class I evidence [11,12,19–26]. Four of themused BoNT/A and three used BoNT/B, separated intostudies of de novo CD patients and those in previouslytreated patients. Three studies compared differentpreparations of botulinum toxin [24–26]. The first studyin 55 de novo patients [19] compared BoNT/A (Botoxs)to placebo over a 12-week study period, reportedmaximal benefit following injection occurred at 6 weeks,

with significant improvement in functional capacity,head turning, pain and subjective assessment. Adverseevents included dysphagia and neck weakness. Asubsequent de novo study [22] compared 3 doses (250,500, 1000 U) of BoNT/A (Dysports) to placebo in 75 denovo CD patients using the Tsui scale. Significantimprovement was seen only at week 4 in the 500 and1000U dose groups. Adverse events include neckweakness and voice changes. The third study [20] of denovo CD patients compared 554U (range 74–880U)BoNT/A (Dysports) to 16.5mg (range 4–24mg) trihex-yphenidyl at 12 weeks following treatment. This studydemonstrated the superiority of BoNT/A over trihex-yphenidyl for the disability subscale of the TorontoWestern Spasmodic Torticollis Rating Scale (TWSTRS)(2 points), TSUI scale (5 points), TWSTRS pain (2points) and general health perception (6 points).Adverse events were significant higher in the trihex-yphenidyl group. Other controlled studies are listed inTable 1.

Responder rates in studies of CD have varied,probably due to the different rating scales used, thedefinition of response, the use of enrichment techniquein some studies (i.e., only including patients who hadresponded previously), and/or increased experienceinvestigators (e.g., injection skill, knowledge of doses)in later studies.

Of interest is a recent double-blind, randomized non-inferiority study, which compared NT 201(Xeomins;Merz Pharmaceuticals), a new BoNT/A that is free ofcomplexing proteins, to Botoxs [25]. Both formulationsof BoNT/A provided similar benefit. Whether there areadvantages to a complex protein-free formulation ofBoNT/A in preventing antibody formation can only beproven with longitudinal studies [27]. Two studiescompared the two serotypes of botulinum toxin (Aand B) in CD patients [24,26]. One used a randomized,double-blind, parallel-arm study design [26]. It com-pared these agents for efficacy, safety and responseduration in patients, with prior repeated exposure andresponsiveness to botulinum toxin type A. Patients wererandomized to receive either 250U of type A or10,000U of type B. In this study, improvement inTWSTRS score did not differ between serotypes. BoNT/A had a marginally longer duration of effect in subjectsshowing a clinical response. Dysphagia and dry mouthwere more frequent with BoNT/B [26]. The second studywas a multi-center, double-blind, randomized, non-inferiority comparison study in botulinum toxin naıveCD patients [24]. In this study, non-inferiority of type Bto type A was demonstrated in toxin-naıve subjects.Patients were randomized to receive either 150U of typeA or 10,000U of type B. It should be noted that whilethe dose of botulinum toxin A was less than in the studyconducted by Comella et al. [26], the dose of B was thesame. This may explain the slight advantage of duration

ARTICLE IN PRESS

Table 1

Studies 480 patients with BoNT in cervical dystonia

Study N Study design Responders (N or %) Dose (U)

Kessler [15] 616 Open 89 D: 778

Benecke [25] 420 DB, non-inferiority design Not given. Xeomins is not inferior

to BotoxsX: 140

B: 139

Jankovic [28] 205 Open 71% B: 209

Wissel [29] 180 Open 85 D: 594

Naumann [30] 133 Open 100 (known responders) B: 133

Truong [23] 80 DB 29 D: 500

Brashear [11] 109 DB Not given M: 5000 or 10,000

Lew [21] 122 DB 58% (2.500U) M: 2500, 5000, or 10,000

61% (5.000U)

77% (10.000U)

Pappert [24] 106 DB, non-inferiority design BoNT/A responders: 48/55 (87%) B: 150U; M: 10,000U

BoNT/B responders: 48/51 (94%)

Myoblocs is not inferior to Botoxs

Anderson [31] 107 Open 95% D: 1000

Jankovic [32] 195 Open 90% B: 100 neck or shoulder muscles

Jankovic [33] 115 Open Not given B: 218

Hsiung [34] 106 Retrospective 63% B: 222

B: Botoxs, D: Dysports, X: Xeomins, M: Myoblocs.

D.D. Truong, W.H. Jost / Parkinsonism and Related Disorders 12 (2006) 331–355334

of effect of type A in Comella’s study. The side effect,xerostomia was three times as common in the subjectsreceiving type B [24].

2.2. Blepharospasm

Blepharospasm is a focal cranial dystonia character-ized by excessive involuntary closure of the eyelids,usually bilateral, though it may sometimes be brieflyunilateral at onset [35]. BoNT/A has been usedsuccessfully in blepharospasm [36,37] for more than 20years, and is considered the treatment of choice.Favorable outcomes are even higher than with CD,with responder rates of approximately 90%.

Most of the studies of BoNT in blepharospasm [36–39] were small, with the exception of two recent studies[40,46] and two controlled trials that compared Botoxs

and Dysports, but without a placebo control group[9,41]. Both toxins improved the symptoms of blephar-ospasm with a mean duration of effect of 13.3 weeks inthe Dysports-treated group and 11.2 weeks in theBotoxs-treated group. A review of 55 open case-controlled studies with a total of more than 2500patients and data compiled by the American Society ofOphthalmology showed a success rate of approximately90% [42]. Furthermore, there is also an improvement inquality of life following treatment with BoNT [43–45].Recently, a newly developed BoNT type A (Xeomins)has been reported to be equally as effective as Botoxs inthe treatment of blepharospasm [46]. Common adverseside effects include dry eye, ptosis, lagophthalmos anddiplopia [47,48]. These symptoms are transient and

disappear after a few weeks. It is noteworthy that tearsecretion is already reduced in patients with blephar-ospasm even prior to treatment with BoNT comparedwith controls [49]. Table 2 summarizes a number ofstudies that have been published.

2.3. Hemifacial spasm (HFS)

HFS is most commonly caused by vascular compres-sion of the facial nerve at the root exit zone. Non-vascular origins of HFS occur and include cholesteato-ma, acoustic neuroma, facial nerve neuroma andadenoid cystic tumors [53]. Injections are appliedto the muscles primarily affected. There have onlybeen a few double-blind studies and with small numbersof patients [54,55]. Similarly favorable results areobtained in HSF spasm as with blepharospasm [56].The dose used is lower than in blepharospasm.Treatment with BoNT improves the quality of life ofthose suffering from HFS [57]. The mean beneficialeffect of BoNT injections is approximately 2.8 months[57].

Side effects of BoNT injections include erythema,ecchymosis of the region injected, dry eyes, mouthdroop, ptosis and lid edema and facial muscle weakness[54,55,58,59]. These are usually mild and short lived.Ptosis may result from local diffusion of the BoNT tothe levator palpabrea [56]. Injection either into thelateral [60] or into the pretarsal region of the orbicularisoculi [61] may result in lower incidence of ptosis. BoNThas also found a use in correcting facial asymmetry afterinjection for HFS [62].

ARTICLE IN PRESS

Table 2

Studies 450 patients with BoNT in blepharospasm

Study N Open/double blind Responders Dose (U)

Roggenkamper [46] 256 Double blind, non-

inferiority study

94% (known responders) X: Mean 40U, up to

35U per eye

Taylor [50] 235 Open 98 B: 2.5–5MU� 4–6 sites

Nussgens [41] 212 Double-blind B: 45.4

D: 182.1

Jankovic [32] 90 (70 came to follow-up) Open 66 of 70 (94%) Botulinum A: 20 per side

Grandas [51] 264 (151 treated with

BoNT)

Open 78.1% reached

significant improvement

Botulinum toxin A 0.4–

2.2 ng per side

Mezaki [52] 54 Double-blind 50 of 53 patients reported

subjective improvement

Botulinum toxin A and F

mixed 1:1 on one side

Botulinum toxin A or F

alone on the other side

10U per side

B: Botoxs, D: Dysports, X: Xeomins.

Table 3

Studies of BoNT for the treatment of oromandibular disorder [67]

Author Year Design N Duration (weeks) Toxin type EMG guidance

Brin et al. [56] 1987 Open 4 Not given Botoxs Yes

Jankovic and Orman [37] 1987 Double 9 6.3 (mixed collective) Botoxs No

Blitzer et al. [64] 1989 Open 20 Injections needed every 2.5–4 months Botoxs Yes

Hermanowicz and Truong [65] 1991 Open 5 Not given Botoxs Yes

Van den Bergh et al. [73] 1995 Open 5 27.074.5 Dysports Yes

Tan and Jankovic [66] 1999 Open 162 16.477.1 Botoxs No

Laskawi and Rohrbach [70] 2001 Open 6 1479.2 Botoxs Yes

Wan et al. [75] 2005 Open 12 13.872.9 Myoblocs/NeuroBlocs No

D.D. Truong, W.H. Jost / Parkinsonism and Related Disorders 12 (2006) 331–355 335

2.4. Oromandibular dystonia (OMD)

OMD is a focal dystonia involving the masticatorymuscles causing jaw closing or opening, lateral devia-tion, protrusion, retraction or a combination of differentmovements. The symptoms of involuntary biting of thetongue, cheek or lips and difficulty speaking andchewing is often socially embarrassing and cosmeticallydisfiguring [63]. OMD can be subdivided into jawclosing, jaw opening, jaw deviation, lingual, pharyngealand mixed types.

BoNT has become the therapy of choice for OMD andits use in jaw-opening, jaw-closing, and jaw-deviationOMD has been well documented [37,64–66]; however,most of the reported literature on OMD has been openstudies as seen in Table 3 [67], but all have reportedimprovement with BoNT [32,65,66,68–74] . The bestresponse was obtained with jaw-closing OMD [66].

2.5. Writer’s cramp (WC)

WC was first reported amongst scribes in the 18thcentury under the term ‘‘occupational palsy,’’ wheresome workers had disabling spasms of their hands only

when performing their jobs [76,77]. When cramps aresimple, individuals are able to conduct most of theirnormal activities without difficulty [78]. BoNT has beenreported to be effective in WC and other occupationaldystonias [79,80].

The injection scheme used in the first reported studywas incremental doses administered into active musclesevery 2 weeks [81]. Three such sessions were carried outwith the BoNT/A preparation Oculinums in doses of20, 40 and 80U. Sixteen of the 19 patients studied had abenefit lasting 1–6 months, which was reproducible.Incremental dosing with booster injections is no longeradvocated to avoid antibody formation.

Several open and blinded studies have found morethan minimal improvement in 80% of patients on atleast 1 injection series. The onset of benefit startsapproximately 1 week after injection, peaks at 2 weeksand lasts approximately 3 months [32,82,83]. Despitean initial benefit, only about one-third of patientscontinued injections for more than 2 years [79]; however,recent studies have shown that more than halfof the patients with WC returned repeatedly forlonger follow-up periods [34,84]. In a quantitativeanalysis using the Writer’s Cramp Rating Scale

ARTICLE IN PRESS

Table 4

Studies of BoNT for writer’s cramp (modified from Das et al. [88])

Study No. of patients Sub-type of writer’s cramp Dosage Duration of improvement

Karp et al. [80] 53 Simple WC–21 Botoxs: 2672U (range 2.6–160U) Mean: 372 months

Dystonic WC–32 Range: 2 weeks–9 months

Flexor–29

Extensor–9

Both–15

Cohen et al. [81] 19 Simple WC–7 Oculinums: 20–80U Range: 1–6 months

Dystonic WC–12

Tsui et al. [87] 20 — Botoxs 30–50U —

Wissel et al. [85] 31 Simple WC–15 Dysports 133.2U (Range: 40–240U) Mean: 59.6 days

Dystonic WC–16 Range: 6–195 days

Localized–4

Generalized–27

Djebbari et al. [86] 47 Flexor–43% Botoxs 40–160U Not available

Extensor–13%

Pronators–14%

Shoulder–14%

Behari [89] 16 Not available Botoxs (n ¼ 8) (20–100U) Mean: 9.4775.34 weeks

Dysports (n ¼ 8) (200–250U) Range: 4–16 weeks


(WCRS), 76% of patients (n ¼ 31) had a good response[85].

In one study, women respond better than men,requiring a lower mean dosage of BOTOXs (1673versus 3075U) with a longer mean duration of benefit(3.270.2 versus 2.470.2 months) [79]. Patients withlocalized WC fared better and those with associatedtremor had the worst prognosis [79]. Patients with aflexion and pronation of the forearm and those withthumb extension had a significantly better response onthe Burke–Fahn–Marsden scale [86]. An earlier placebo-controlled, double-blind study by Tsui et al. also showeda better outcome in those with wrist deviation [87].Table 4 lists studies on WC that have been reported [88].

2.6. Other occupational cramps

BoNT has used to treat other occupational crampswith good results. Focal task-specific dystonia inmusicians presents as a loss of voluntary motor controlin extensively trained movements [90]. This disorder isquite rare but is seen with several instruments. Inpatients with string instruments, the main complaintsreported in one study were playing-related loss ofcontrol and involuntary movements affecting thefingering hand in most patients and to a lesser degreethe bowing arm in some patients [91]. In most patients,signs of abnormal posture could be detected by watch-ing them play their instrument. In selected patients,treatment includes BoNT injections or splinting devices.Treatment benefit is limited, and in more than half ofthe patients reported, dystonia led to the end of theirmusical career [91]. Despite this bleak outcome, more

than one-third of the patients reported long-term benefitwith BoNT and improvement in their playing ability[90]. Minor paralysis may have an impact on virtuosityleading to the inability to play for a living. There havebeen no controlled studies to date due to the complexityof the disorder.

2.7. Foot dystonia

Foot dystonias can be either idiopathic or sympto-matic as in PD. Numerous successful treatments withBoNT have been reported but currently there have beenno controlled studies [92–94]. Use of BoNT is recom-mended here since therapeutic alternatives are lacking.Higher doses may be given than in hand dystoniasbecause the expected functional impairment is less.

2.8. Axial dystonia

Although there are no controlled studies, many casereports point to the usefulness of botulinum toxin inaxial dystonia [95–98]. Patients’ satisfaction with treat-ment was high—the benefit was rated as good toexcellent. BoNT can provide substantial benefit withminimal side effects in the majority of patients with axialdystonia, particularly with pain relief and posturalimprovement.

2.9. Tardive dyskinesia

Tardive syndromes refer to a group of disorderscharacterized by predominantly late onset and some-times persistent abnormal involuntary movements


(or a sensation of restlessness that often causesinvoluntary movements) caused by exposure to adopamine receptor-blocking agent within 6 months ofthe onset of symptoms and persisting for at least 1month after stopping the offending drug [99]. The termtardive dystonia has been used to refer to the tardivesyndrome that presents with rapid, repetitive, stereo-typic movements involving the oral, buccal and lingualareas [100]. It has also been termed tardive stereotypybecause of its repetitive rather than random nature.Patients have been reported to develop tardive dystoniaeven after a relatively short duration of exposure todopamine antagonists (21% within 1 year) [101]. Somepatients improved after the drug was withdrawn.Although anticholinergics and dopamine-depletingdrugs frequently improved symptoms, treatment withthem only rarely led to a remission or satisfactorycontrol of symptoms. Truong et al. first reported thesuccessful use of botulinum toxin in tardive dystonia[102]. Although there are no controlled studies, itsusefulness has have been noted in many case reports andopen studies [98,103–109]. Laryngeal tardive dystoniamay resemble spasmodic dysphonia (SD)-like symptomsand treatment with botulinum toxin has been shown tobe useful [110].

2.10. Tourette’s syndrome

There are several reports of single case studies [111–113] and case series [114–116], which report a decrease inthe frequency and intensity of tics with BoNT.Improvement has also been reported in urge orpremonitory symptoms associated with the tics, orboth [111,115–117]. In an open study of 30 patientswith vocal tics, who received BoNT injections inboth vocal cords, vocal tics improved after treatmentin 93% patients, with 50% being tic free. Hypophoniawas the only side effect of note (80% of patients)[117]. A double-blind study with 18 patients alsoconcluded that BoNT reduced tic frequency and theurge associated with the tic [118]. Interestingly, despitethese improvements, patients did not report anoverall benefit from the treatment. Therefore, there isa need for careful consideration of the contribution ofthe target tic to the patient’s disability before deciding totreat it.

2.11. Tremor

Tremor is one of the most common kinetic disorders.Satisfactory results have been reported with BoNTin essential and dystonic tremor in the neck [119,120].Both open-label and controlled studies in patientswith essential tremor have shown improvement withBoNT [121–125]. It significantly improved postural,but not kinetic, hand tremor [125]. Hand weakness is a

dose-dependent significant side effect of treatment.In palatal tremor, local injections of BoNT into thetensor veli palatini muscle have been reported toimprove the ear clicks [126]. There have been reportedimprovements with injection into the levator velipalatini but not with injections into the tensor velipalatine [127].

2.12. Spasticity

BoNT has been studied in spasticity and rigidity[128]. BoNT/A has received approval in several coun-tries for the indication of spasticity. Table 5 lists studiesthat have been conducted with BoNT in upper-limb spasticity. All these studies [128–143] reportedpositive outcomes, except the study performed byBrashaer et al. using Myoblocs [133]. Reduction oftonus, pain relief, prevention of contractures andfunctional improvement are listed among the therapeu-tic objectives.

In the management of calf spasticity and equinus gait,intramuscular injection of BoNT/A is associated withonly a modest increase in direct medical costs per childper year compared with serial casting [144]. Anotherstudy compared the cost-effectiveness and outcomes oforal therapy versus BoNT/A treatment strategies inpatients with flexed wrist/clenched fist spasticity [145].Thirty-five percent of patients receiving oral therapyshowed an improvement in pretreatment functionaltargets, which would warrant continuation of therapy,compared with 73% and 68% of patients treated withBoNT/A as first- and second-line therapy, respectively.BoNT/A treatment was more cost-effective than oraltherapy with the ‘‘cost-per-successfully-treated month’’[145]. When BoNT was compared with phenol injectionin a double-blind study with 20 patients to relieveankle plantar flexor and foot invertor spasticity afterstroke, both BoNT/A and tibial nerve blockade withphenol were effective in plantar flexor spasticity.The changes were more significant in the group thatreceived BoNT/A at weeks 2 and 4, but there was nosignificant difference between the two groups at weeks 8and 12 [146].

A recent double-blind placebo-controlled study re-ported three parallel treatments to determine whetherserial casting combined with BoNT reduced the devel-opment of lower limb spasticity after severe head injuryin adults. Twenty-eight patients completed the trial,which consisted of: current physical treatment, lower legcasting plus injections with either saline, or with BoNTinto gastrocnemius and soleus muscles. Cast and BoNTpatients demonstrated significant improvement in theModified Ashworth Scale scores and Glasgow OutcomeScale. Casting alone in these patients was sufficient, butfurther improvement was seen when combined withadditional BoNT [143].

ARTICLE IN PRESS

Table 5

Studies 450 patients with BoNT in arm spasticity

Study Year Cause of spasticity Treated areas N Open/double-blind Toxin Dose (U)

Baker [129] 2002 Cerebral palsy Leg 125 Double-blind Dysports 10–30U/kg

Brashear [130] 2002 Stroke Arm 126 Double-blind Botoxs 200–240

Bakheit [131] 2000 Stroke Arm 82 Double-blind Dysports 500–1500

Bakheit [132] 2001 Stroke Arm 59 Double-blind Dysports 1000

Brashear [147] 2003 Stroke Arm Double-blind, single

center

Myoblocs 10,000

Burbaud [134] 1996 Stroke Foot 23 Double-blind Botoxs

Childers [135] 2004 Stroke Arm 91 Double-blind Botoxs 90–360

Grazko [128] 1995 Stroke and

Parkinson’s disease

? 20 Double-blind, cross-

over

Botoxs ?

Hyman [136] 2000 MS Hip adductor 74 Double blind Botoxs 5–1500

Mall [137] 2006 Cerebral palsy Adductor

spasticity

61 Double-blind Dysports 30U/kg body weight

or max 1500U

Mancini [138] 2005 Stroke Spastic foot 45 Double-blind From 166.7 to 540

Simpson [139] 1996 Stroke Spastic arm 39 Double-blind, dose

ranging

Botoxs 75–300

Smith [140] 2000 Stroke, head injury Spastic arm 21 Double-blind, dose

ranging

Dysports 500–1500

Snow [141] 1990 Multiple sclerosis Hip adductor 9 Crossover, double-blind

design

Botoxs 400

Pittock et al. [142] 2003 Stroke Calf spasticity 234 Double-blind, placebo-

controlled, dose-ranging

Dysports 500–1500

Verplancke [143] 2005 Head injury Calf

contracture

253 Double-blind placebo-

controlled trial of three

parallel treatments

Botoxs 200

B: Botoxs, D: Dysports, X: Xeomins.


3. Ophthalmology

3.1. Strabismus and other ophthalmic disorders

BoNT was first used by Alan Scott to treat strabismus[5,148]. Although a recognized treatment, it is not widelyused for this indication. A small study with short follow-up also reported beneficial results in infants and children[149]. Other conditions such as endocrine orbitopathy,oscillation nystagmus, and abducens paralysis have beenstudied using open-label designs [150–152], but formalstudies have not been conducted.

3.2. Protective ptosis

Ptosis is a side effect of treatment for blepharospasm.However, intentional induction of ptosis produced byinjection into the m. levator palpebrae may be useful inintensive care patients to prevent desiccation of the cornea[153]. Only limited data are available for this use [154].The drawback is that the paralysis will persist for manyweeks beyond the time needed and may also interfere withneurological evaluation in patients suffering from trauma.

3.3. Crocodile tears (lacrimation)

Secretomotor fibres of the facial nerve innervate thelacrimal gland through the greater superficial petrosal

nerve. An aberrant connection of the visceromotorfibres, originally innervating the salivatory gland to thefibres of the lacrimal gland may develop after a facialpalsy, causing a hyperlacrimation whenever the patientsalivates (crocodile tears). Hyperlacrimation after facialpalsy has been shown to be successfully treated withinjections of BoNT into the lacrimal gland [155–159].The onset of effect of the BoNT was typically 24–48 hafter the initial injection and lasted 4–5 months.Injection of BoNT into the lacrimal gland can minimizeor even suppress the secretion of tears [156]. Injectioncan be performed either transcutaneously or transcon-junctivally. In the latter technique, a smaller amountof toxin is needed. The lacrimal gland is located in thelateral angle of the upper eyelid of the eye. Table 6summarizes the results of published case reports andstudies.

4. Otolaryngology

4.1. Spasmodic dysphonia (SD)

SD is a focal dystonia characterized by task-specific,action-induced spasm of the vocal cords. It adverselyaffects the patient’s ability to communicate. It can occurindependently, as part of Meige’s syndrome, or in otherdisorders such as in tardive dyskinesia. Initially reported

ARTICLE IN PRESS

Table 6

Studies of BoNT for gustatory hyperlacrimation

Authors Design N Region Dose per side (U) Duration (months)

Botoxs

Reimann et al. [158] Open 1 Tconjunctival 2.5 6

Open 2 Transcutaneous 15 5

Hofmann [159] Open 2 Tconjunctival 5 9

Kyrmizakis et al. [160]

Dysports

Boroojerdi et al. [155] Open 7 Tcutaneous 20 (total) 2

Open 4 Tcutaneous 3

Keegan et al. [156] Open 4 Tconjunctival 20 (total) 3.5–6

Montoya et al. [157] 20

Tconjunctival: transconjunctival; Tcutaneous: transcutaneous.

D.D. Truong, W.H. Jost / Parkinsonism and Related Disorders 12 (2006) 331–355 339

by Blitzer et al., the beneficial effects of BoNT on SD[161] were quickly confirmed by double-blind studies[162]. Meta-analysis of 30, mostly single-blind studiesindicated moderate overall improvement as a result ofBoNT treatments [163]. The Cochrane Collaborationreviewed the use of BoNT for SD [164] and foundsimilar results in the length of treatment effect, degree ofimprovement, patient satisfaction and observed sideeffects from nearly 77 open reports, although there isonly one double-blind study [162,164].

On average, patients treated for adductor SD withBoNT experienced a 97% improvement in voice[165]. Mild breathiness occurred in 35% and chokingin 15% of patients treated [166]. The duration ofbenefit has been reported as 15.1 weeks [167]. Theinjection can be performed with laryngoscopic orEMG guidance or both [162,168]. Other techniquesinclude the transoral [169], transnasal [170] and point-touch technique [171]. Although transnasal and transor-al techniques may demonstrate lower failure ratesthan percutaneous EMG-guided methods, they are lesswell tolerated [163,170,172,173]. There is also thedisadvantage of an unacceptable amount of wastedtoxin due to the length of the dead volume from thesyringe to the needle in the transnasal or transoraltechniques.

4.2. Bruxism

Bruxism refers to tooth clenching or grinding. Whensevere, it is associated with headache, dysarthria,temporomandibular joint destruction and dental wear.Bruxism can be treated with BoNT quite easily andvery successfully. Studies have been published [174,175]over the past 15 years, but to date, there have beenno double-blind studies to assess the effectiveness ofBoNT therapy in bruxism. Clinical effects were reportedto appear a few days after injection of BoNT intothe masseter muscles bilaterally and lasted for 6–78

weeks, with a significant reduction in the severity ofsymptoms [175].

4.3. Rhinitis

Because rhinorrhea is under parasympathetic control,blocking cholinergic parasympathetic neurotransmis-sion may be a useful strategy for rhinitis. In an animalstudy, BoNT soaked into sterile gauze packed into onenasal cavity for 1 h was compared with saline-soakedgauze similarly introduced into the opposite nasal cavity[176]. Rhinorrhea was produced by inserting a bipolarneedle electrode into the sphenopalatine ganglion, whichwas electrically stimulated. Nasal secretions collectedwith suction catheter showed a decrease in rhinorrheawith BoNT over placebo. Rhinitis, of allergic origin forinstance, can be treated either by injecting BoNT or byapplying a sponge impregnated with BoNT [177,178].

In a double-blind, placebo-controlled study compar-ing 25 patients who received 4U of Botoxs into eachnasal cavity and 18 patients who received saline, a 30%improvement in the severity of rhinorrhea and a 50%reduction in paper tissue were noted in the BoNT-treated group when compared with the control group.Positive outcomes have been documented in anothercontrolled study [179]. As some secretion is mediated bynon-cholinergic neurotransmitters such as vasoactiveintestinal peptide, topical application of an anticholi-nergic substance has limitations; however, because allthe nasal parasympathetic nerves appear to originatefrom cholinergic synapses in the sphenopalatine gang-lion, direct injections of toxin into this ganglion maypossibly allow complete blockade of all cholinergicallymediated rhinorrhea. This indication invites criticaldiscussion. There should be substantial subjectivepathology, i.e. considerable rhinorrhea that is refractoryto standard treatment before botulinum toxin is used.The disadvantage of using a sponge soaked with toxin isthe toxin-associated cost.


4.4. Sialorrhea

Sialorrhea, or excessive salivation and drooling,occurs in many neurological conditions and is oftenthe result of swallowing disturbances or excessive salivaproduction. Botulinum toxin has found application forsialorrhea in PD, amyotrophic lateral sclerosis (ALS),cerebral palsy, carcinoma of upper digestive tract, etc.[180,181]. The treatment of hypersalivation has beenestablished in many centers, although this is not anapproved indication. The treatment of sialorrhea is donefor cosmetic, social and medical reasons.

In one study, BoNT/A was injected into the salivarygland of five patients with bulbar ALS and sialorrhea[181]. The effect was measured by the number of paperhandkerchiefs used and by salivary gland scintigraphy.The mean total dose injected into the parotid glands was46U (SD 16.9) of Botoxs (range 30–72U). Reduction ofsialorrhea was first noticed 3–5 days after injection [181].A pronounced reduction in sialorrhea was found 4weeks after the injection. BoNT/A also improvedquality of life without major adverse effects [181]. Thisfinding is in line with the reduced radiotracer uptake inboth parotid glands in salivary gland scintigraphy. In adouble-blind, randomized, placebo-controlled studyevaluated excessive drooling, 32 PD patients wereinjected with either 50U Botoxs or placebo into eachparotid gland without ultrasound guidance [182]. Sub-

Table 7

Summary of selected studies on BoNT in sialorrhea (NX5) (modified from

Authors Design Technique N, diagnosis

Botoxs

Ellies et al. [180] Open U/S 13, carcinoma, neuro-

degenerative, stroke

Bothwell et al.

[196]

Open Blind 9, CP

Pal et al. [192] Open Blind 9, PD

Giess et al. [181] Open U/S 5, ALS

Porta et al. [197] Open U/S 10, ALS, PD, CP, SSPE

encephalopathy

Suskind et al. [191] Open U/S 22, CP

Jongerius et al.

[183]

Controlled U/S 45, CP

Jost [193] Open Blind 5, PD

Dogu et al. [198] Open U/S, Blind 15, PD

Lagalla et al. [182] Controlled Blind 32, PD

Dysports

Mancini et al.

[189]

Controlled U/S 20, PD, MSA

Lipp et al. [184] Controlled Blind 32, ALS, PD, CBD, MS

Myoblocs

Racette et al. [185] Open Blind 9, Parkinsonism

Ondo et al. [186] Controlled Blind 16, PD

U/S: ultrasound; CP: cerebral palsy; PD: Parkinson’s disease; ALS: amyotro

system atrophy; SSPE: subacute sclerosing panencephalitis.

jects treated with BoNT experienced a reduction in bothdrooling frequency and social disability, as well as insaliva production. There was a striking improvement inalmost all subjective measures of drooling [182] withoutany adverse events. Two other blind studies alsoreported favorable results [183,184].

Encouraging results of BoNT/B in sialorrhea haverecently been reported in two studies involving 25patients with parkinsonism [185,186]. Indeed, BoNT/Bmay prove to be a particularly effective treatment forsialorrhea due to an apparent predilection of thisserotype for autonomic neurons [187]. Table 7 sum-marizes selected studies on BoNT in sialorrhea [188].

The reported duration of the beneficial response ofBoNT in sialorrhea varies from 7 weeks to 7 months.Most of the studies of BoNT for sialorrhea have notreported any significant adverse events, except forlocal pain, infection, dry mouth, transient dysphagiaand weakness of mouth opening and closure[180,185,186,189–193]. Recurrent jaw dislocation,marked deterioration of dysphagia and local infectionof the gland have been reported in ALS patients[194,195]. Most other studies have used ultrasoundguidance to direct injections.

BoNT doses used in this indication are relatively highcompared to what is being used in increased muscleactivity, i.e. up to one vial in individual cases,distributed to the salivary glands. Treatment is mostly

Bhidayasiri and Truong) [188]

Region Dose per side (U) Duration (months)

Parotid, SM 50–65 (total) 3

Parotid 5 2

Parotid 7.5–15 2 (approx)

Parotid 6–20 43

, Parotid, SM 15–40 4–7

Parotid, SM 20–40 N/A

SM 20–25 Up to 6

Parotid 10 4–7

Parotid 15 2–6

Parotid 50

Parotid, SM 450–500 (total) 1

A Parotid 18.75–75 3

Parotid 1000 3.5

Parotid, SM 250–1000 41

phic lateral sclerosis; CBD: corticobasal degeneration; MSA: multiple


focused on the parotid gland and to a lesser extent onthe submandibular gland. The sublingual gland is rarelyever injected. The patient should be advised regardingdental and oral care due to reduced salivation.

Overall, the results of these studies suggest that BoNTtherapy may be useful for the treatment of sialorrhea,with a low risk of side effects. The highest safeindividual dose is not known and may be very low insome patients, particularly in patients suffering fromALS, who may be unusually sensitive to BoNT. The riskcan be minimized by cautiously increasing the dose andlimiting the treatment initially in the parotid glands.

5. Dermatology

5.1. Wrinkles

Aging and chronic activity of the facial muscles causefacial wrinkles [199]. The treatment of wrinkles may beseen as one of the most common indications for usingBoNT [200]. The excellent results in the treatment offurrows and frown lines on the forehead have beenconfirmed by several open and controlled studies [200–208]. The toxin has an influence on muscular activityalone. When injected into hyperactive corrugator and/orprocerus muscles that predominantly control frowning,BoNT produces a localized muscle weakness, resultingin a temporary improvement in glabellar frown lines(‘‘brow furrows’’). The peak effect is seen on days 14–30postinjection when the severity of the lines at maximumfrown reduces to mild or none [200,206].

Table 8

Studies of BoNT for cosmetic use

Authors Design EMG N

Botoxs

Carruthers [202] OP 18

Guyuron [211] OP 9

Foster et al. [212] OP EMG guided 11

Pribitkin [213] OP 80

Blitzer et al. [214] OP 162

Hankins et al. [208] OP escalat 46

Lowe et al. [215] DB 30

Carruthers et al. [201] DB 264



Dysports

Becker-Weigerich et al. [210] Open 5

Ascher et al. [200] DB 119

Myoblocs

Bauman et al. [205] DB 20

Injections of multiple sites in the frontalis muscleeliminate horizontal lines in the forehead and into thelateral orbicularis oculi reduce the lateral wrinkles(‘‘crow’s feet’’). Platysma muscle bands can result inhorizontal wrinkles in the neck and decollete wrinkles inthe chest, improved with BoNT injection into theplatysma [209,210].

Table 8 lists the studies that have been reported in theliterature.

5.2. Hyperhidrosis

Hyperhidrosis refers to excessive sweating and may befocal or generalized. Focal hyperhidrosis usually affectspalms or soles of the feet (60%), axillae (40%), and theface (10%) [217]. Rarely, other areas are involved. Focalhyperhidrosis is most often essential or idiopathic.Sweat is produced by the eccrine sweat gland and is aclear hypotonic, odorless fluid [218]. In response tonerve impulses, acetylcholine is released from thepresynaptic nerve endings and then binds to postsynap-tic cholinergic receptors. This activates a complex in-and efflux of electrolytes, creating the hypotonic sweat.Only about 5% of sweat glands are active at the sametime, indicating the enormous potential for sweatproduction.

The development of BoNT as a treatment ofhyperhidrosis came from the initial observation ofhypo- or anhidrosis in patients with botulism. Injectionof BoNT/A leads to temporary chemodenervation withthe loss or reduction of activity of the target organ.Swartling et al. [219] demonstrated that the sweat glands

Region Dose per side (U) Duration (months)

Glabella 10–20 4

Glabella 12.5 2

Glabella 40 3

Glabella 10 2–4

Glabella 5–20 3–6

Forehead 5–25 312

Crow’s feet 5–15 4

Glabella 12.5–20 4

Crow’s feet 10 4

Glabella 20 4–5

Glabella 20

Glabella 16–48

Frontalis

Decollete wrinkles 15 Dysports per site Not given

Glabella 25–75 Dysports 6

Crow’s feet 1500 3–4


were structurally normal before the BoNT therapy, butthat the lumen diminished after subsequent injections,suggesting the mechanism of denervation.

In addition to several small controlled studies, thebenefits of BoNT/A on patient quality of life andobjective sweating in primary axillary and palmarhyperhidrosis have been documented in large-scale,randomized, controlled trials [220–236]. Results showedthat up to 94% of patients in the BoNT/A group wereresponders, in contrast to 36% of patients in the placebogroup [220]. The duration of action of BoNT variedbetween 4 and 12 months with a mean duration of 7months after a single treatment session.

In axillary hyperhidrosis, the injection is given intothe axilla, which is a simple procedure. Its duration ofaction is significantly longer—up to 9 months—thanseen in other indications. The injection is administeredintra- or subcutaneously in the hairy region. An iodinestarch test can be used in areas of unclear delimitation.Recently, there had been a report of possible delivery of

Table 9

Selection of controlled and large open studies of BoNT injection of focal axilla

from Bhidayasiri and Truong [188])

Authors Design N

Botoxs

Naver et al. [230] Open 55

Solomon, Hayman [234] Open 20

Naver et al.[230] Open 94

Saadia et al. [250] Single-blind 24

Wollina, Karamfilov [251] Open 10

Swartling et al. [236] Open 58

Vadoud-Seyedi [252] Open 10

Glogau [229] Open 12

Naumann et al.[220] Controlled 320

Naumann et al. [253] Follow-up, Open 207

Odderson [254] Double-blind 18

Wollina et al. [255] Open 47

Karamfilov et al. [235] Open 24

Kinkelman et al. [256] Open 10

Naumann et al.[246] Open 45

Laccourreye et al.[257] Open 33

Beerens, Snow [258] Open 13

Bjerkhoel and Trobbe [259] Open 15

Dysports

Heckmann et al. [233] Controlled 145

Boger et al. [260] Open 15

Guntinas-Lichius Open 40

Heckman et al. [238] Open 37

Schnider et al. [226] Double-blind 13

Schnider et al. [222] Double-blind 11

Myoblocs

Dressler et al. [13] Single blind comparing

BooNT/A and BoNT/

B

19

Baumann et al. [261] Double-blind 23

Birklein et al. [262] Open, dose study 15

BoNT/A with iontophoresis allowing delivery of BoNTin sensitive areas such as the hand [237]. High doses ofBoNT do not seem to increase the efficacy or durationmore than low doses [238]. Unlike transthoracicendoscopic sympathectomy, which may induce compen-satory sweating and is a major problem in manypatients, successful treatment of palmar hyperhidrosiswith BoNT/A does not evoke compensatory hyperhi-drosis in non-treated skin territories [239]. BoNT/A hasalso been reported to be effective in the control ofchromhidrosis (dark-colored sweat) [240].

BoNT/B has also shown beneficial effects in severalstudies in the treatment of hyperhidrosis; however,systemic side effects such as visual accommodationdifficulties and dry mouth, as well as pain at the injectionsite, limit its widespread use [13,187,241,242]. Theconversion factor for BoNT type A to B in hyperhidrosisis suggested as 1:40 [13]. Using the conversion factor of1:4, the efficacy in hyperhidrosis between Botoxs andDysports according to a double-blind study was similar

ry or palmar hyperhidrosis (n420 except for BoNT/B study) (modified

Region Dose per side Duration

(months)

Axilla 32–100U 3–14

Palmar 165U 4–9

Palmar 120–220U 3–14

Palmar 50–100 6

Palmar 400U 3–22

Palmar, Axilla 1U/cm2 44.5

Plantar 50U 5

Axilla 50U 7

Axilla 50U 44

Axilla 50U 7

Axilla 100U 5

Axilla 200U 419

Axilla 200U 10

Frontalis 60–90U 5

Gustatory 21 46

Gustatory 25–175 12–36

Gustatory 100 11

Gustatory ? ?

Axilla 100–200 46

Craniofacial

hyperhidrosis

Axilla 148–248U 16

Axilla 100–200U 12

Axilla 200U ?

Palmar 120U ?

Axilla 100U BoNT/A

vs. 2000–4000U

44

Palmar 2500U 45

Lower leg 2–1000U 6


[243]; however, there was a trend towards a greaterimprovement after Dysports treatment but with ahigher incidence of adverse effects.

Intradermal injection of BoNT/A has been shown tobe effective in patients with gustatory sweating (Frey’ssyndrome) [244–246] in open studies, with a duration ofeffect up to 17 months. BoNT is also effective in Rosssyndrome [247], a rare form of focal hyperhidrosis ofunknown etiology, characterized by progressive anhi-drosis due to degeneration of sudomotor fibers, asso-ciated with compensatory hyperhidrosis in areas inwhich sudomotor fibers remain intact [247]. Interruptionof sweating by BoNT/A improves the outcome andreduces relapses in patients with dyshidrotic handeczema. It is also antipruritic [248,249]. Table 9 listsstudies that have been reported [188].

6. Urological disorders

6.1. Hyperreflexive bladder

BoNT injections into the detrusor muscle maybecome useful for the treatment of hyperreflexicbladder. This treatment is a possible new therapeuticoption in patients with severe detrusor hyperreflexiarefractory to anticholinergic medication. Schurch andco-workers were the first to report bladder injection ofBoNT/A in adult patients with neurogenic detrusoroveractivity (NDO) of spinal origin who emptied thebladder by clean intermittent catheterization [263].Botoxs was injected in different locations above thetrigone, resulting in detrusor paresis in about 2 weekslater. Urodynamic evaluation revealed a significantincrease in bladder capacity at 6 weeks and a significantdecrease in maximum detrusor voiding pressures lastingup to 36 weeks. All 17 patients became completelycontinent and episodes of autonomic dysreflexia alsodisappeared.

Similar results were also obtained by Reitz and co-workers in a retrospective review of data from a differentEuropean study with Botoxs with 200 severely incon-tinent adult patients with spinal cord injury, multiplesclerosis, spina bifida or myelomeningocele [264]. Of 180incontinent patients, 132 reported complete continenceafter treatment, while 48 patients reported improvementbut some level of continuing incontinence. Most of thepatients still experienced significant urodynamic andclinical improvement at 9 months. Of the 163 patientswho were on anticholinergic drugs prior to treatment, 45were able to discontinue treatment and 118 were able toconsiderably reduce treatment.

Repeat treatments are needed due to the relapse ofoveractive bladder symptoms. Repeat injections withBoNT/A are as effective as the first one [265]. The dosesof Botoxs used range from 200 to 300U [266].

BoNT/B (Myoblocs/Neuroblocs) has been reportedto improve detrusor overactivity [267,268]. In a double-blind, placebo-controlled, crossover study of Myo-blocs/Neuroblocs in 20 patients using 5000U in thetreatment of overactive bladder, the duration of effectwas reported to be only 6 weeks [269]. Autonomic sideeffects were observed in 4 patients. The short durationof action may limit the use of Myoblocs/Neuroblocs topatients who have developed immunity to BoNT/A.

BoNT/A (Botoxs) has shown good results in childrenwith NDO [270–272]. The toxin increased bladder capacityand decreased maximal detrusor pressure. The duration ofimprovement after each treatment is similar to thatobserved in adults, ranging from 6 to 9 months [270–272]. BoNT/A can be reinjected if necessary. BoNT hasalso shown to improve non-NDO as well [273]. The toxinwas injected into the suburothelial space.

BoNT/A has been used in a small number of patientswith NDO of supraspinal origin, caused by stroke,cerebrovascular accident (CVA) or PD [274,275]. In astudy of 24 patients (n ¼ 12 CVA, n ¼ 12 suprasacral cordlesions), Botoxs increased bladder capacity and improvedincontinence in 91.6% of the patients with spinal cordlesions, but only 50% of the patients with CVA.

6.2. Detrusor-sphincter dyssynergia (DSD)

BoNT has been studied in DSD since 1988 [276].Subsequent published studies reported encouraging results[277–279], but these were difficult to interpret because theydid not include enough patients and used differentoutcome measures such as patients’ reports, residual urinevolume or urodynamic test parameters [280]. In themajority of patients DSD was significantly improved,with a decrease in postvoid residual volumes [276,278,281].BoNT/A effects lasted 3–9 months, making reinjectionsnecessary [278]. BoNT/A injections, which aim at suppres-sing DSD but not bladder neck dyssynergia, appear to bea valid alternative for patients who do not desire surgeryor are unable to perform self-catheterization.

6.3. Spasticity of the vesical sphincter and urethrism

Damage to the upper motor neuron may causespasticity of the striated muscles of the pelvic floor,which can be attenuated by injections of BoNT. To date,only case reports have been published.

Urethrism is defined as involuntary contraction of thevoluntary sphincter on micturition, or—in some cases—even at rest. Injection of BoNT is a possible therapeuticoption for this disorder [280].

6.4. Neobladder (artificial bladder)

The installation of an artificial bladder eliminatesreflex contraction and coordination between detrusor


contraction and sphincter relaxation; the sphincter thusfails to relax, with the result of increased residual urine.BoNT may help by weakening the sphincter muscle. Sofar only one abstract has been published [280].

6.5. Benign prostatic hyperplasia (BPH)

Prostate injection of botulinum A toxin is an effectivealternative treatment with minimal adverse effects forpatients with BPH. Patients were injected with 200Ubotulinum A toxin into the transition zone of theprostate. All patients noted an improvement in sponta-neous voiding. Voiding pressure and postvoid residualvolume were significantly decreased. The total prostatevolume was significantly reduced, and the maximal flowrate was significantly increased after treatment. Themaximal effects of botulinum A toxin appeared at about1 week and were maintained at 3 and 6 months aftertreatment [282]. The author reported no adverse effects.In an earlier study, the serum prostate-specific antigenconcentration was also decreased after treatment [283].

7. Gynecology

Vaginismus is an uncommon condition, and dystonicvaginismus an even rarer phenomenon. Treatment withBoNT may be beneficial [284,285]. Psychogenic causesshould be ruled out.

8. Gastrointestinal and proctologic disorders

8.1. Achalasia

Achalasia is a well-known indication for BoNT ingastroenterology [286,287]. It is characterized by inade-quate relaxation of the lower esophageal sphincter.Clinical symptoms include dysphagia, retrosternal pain,nocturnal regurgitation, non-cardiac chest pain andsecondary weight loss. Conventional treatment is withHeller’s myotomy or pneumatic dilatation, with itsattendant risk of perforation. More than 30 studygroups have replicated Pasricha’s excellent results in thetreatment of achalasia with BoNT. The toxin-treatedgroups, however, had the disadvantage of a higherrelapse rate [288]. BoNT may be more useful in tortuousesophagus [289].

8.2. Other gastrointestinal uses

Other rare indications for BoNT include esophagealdisorders such as diffuse esophageal spasm [290,291],insufficient relaxation of the upper esophagus [292],cricopharyngeal dystonia [293], sphincter Oddi dysfunc-tion [294,295], obesity [296], gastroparesis (injection into

the pyloric sphincter) [297,298] and undiagnosed non-cardiac chest pain [290].

8.3. Anal fissure

BoNT has been used in the treatment of anal fissuressince 1990. Multiple studies with positive results havebeen published [299]. BoNT is more than a symptomaticapproach in anal fissures, as the toxin decisivelyinterferes with the pathogenic mechanisms causingchronic fissure. It reduces sphincter tone in the viciouscycle of inflammation—pain—increased sphincter tone,and is likely to have a positive effect on pain. Successrates range between 60% and 80% [299]. It is not knownwhether injections into the internal sphincter are super-ior to injections into the external sphincter [300].

There are 13 studies in the literature reportingBoNT/A in the therapy of chronic anal fissure, withdata from 632 patients in total [301]. One month aftertreatment, the studies reported a healing rate of 21.7–88%, the lowest with BoNT/A (5U) injected into theinternal anal sphincter (half the dose on each side of thefissure), and the highest with 20 U injected into theinternal anal sphincter (each side of the anterior midline,two different studies). Two months after treatment,healing was observed in 43.5–96% of cases [301].

8.4. Further use of BoNT in proctology

Other disorders of the anal canal such as anismus[302], spasticity of the anal sphincter and insufficientrelaxation of the sphincter muscles with straining ondefecation (paradoxical puborectal syndrome) are alsoamenable to BoNT treatment [303]. Use of BoNT in thetreatment of constipation is restricted to outlet con-stipation [300,303].

9. Pain

Botulinum Toxin type A does not only inhibit therelease of acetylcholine, but also the release of substanceP from trigeminal nerve endings [304]. Substance P is apotent neurotransmitter in the activation of inflamma-tion [305]. Through inactivation of transport proteinsSNAP-25 and VAMP, the light chain of botulinumtoxin type A not only inhibits the release of acetylcho-line but also numerous neurotransmitters and neuropep-tides, including substance P, CGRP, VIP andneuropeptide Y [305–308]. These peptides are knownto be involved in the mechanism of pain. Furthermore,current pathophysiological models of migraine assumethat the generation of an excessive input in thetrigeminovascular system results in migraine attacks[309]. Durham et al. [310] showed that botulinum toxincan block the release of CGRP from sensory trigeminal


neurons. The triptans, which are highly effective inmigraine acute therapy, inhibit the release of CGRP intrigeminal afferents through presynaptic inhibition of 5-HT1B/D-receptors [311]. In vivo, CGRP can precipitateheadache and migraine attack in migraine patients[312,313]. Sumatriptan inhibits the CGRP release andthereby stops migraine headache [314]. Pretreatmentwith botulinum toxin could theoretically prevent therelease of CGRP by activated trigeminal neurons and itcould also prevent the vascular and inflammatoryconsequences.

As pain is frequently present in CD and focalspasticity, it can be alleviated by treatment with BoNT.This led to the conclusion that BoNT may be used tomanage pain related to hyperactive muscles. Further-more, the treatment of wrinkles had shown that manypatients also reported improvement in pre-existingheadaches. Several studies were subsequently conductedon the use of BoNT in various pain syndromes.

The efficacy of BoNT in pain is difficult to assess atpresent. Single studies have been published on low-backpain [315] and myofascial pain [316], but these do notpermit definitive conclusions. Piriformis syndrome is apainful musculoskeletal condition with signs and symp-toms that resemble sciatic nerve compression but thatare thought to involve the piriformis muscle. In an openstudy, the piriformis muscle was injected under electro-myographic guidance with 5000U of BoNT/B [317].There was a significant reduction in mean visual analogscale scores for buttock and hip pain, low-back pain,pain radiating into lower limbs, and tingling. A total of95% of patients reported fair to excellent improvementin pain.

In the treatment of musculoskeletal pain, BoNT/A istypically used as part of a multimodal therapeuticprogram [318]. BoNT therapy may improve pain byreducing muscle tone and overactivity, perhaps enabling

Table 10

Controlled studies of BoNT in headache disorders (modified from Schulte-M

Year Type of headache No. of

Ondo et al. [336] 2004 CDH 60

Padberg et al. [326] 2004 TTH 40

Schmitt et al. [324] 2001 TTH 60

Silberstein et al. [327] 2000 M 123

Barrientos and Chana [332] 2003 M 30

Evers et al. [329] 2004 M 60

Rollnik et al. [325] 2000 TTH 21

Schulte-Mattler et al. [323] 2004 TTH 112

Gwynn et al. [337] 2003 CDH 39

CDH: chronic daily headache, M: migraine, TTH: tension-type headache,

injection sites.

�: negative, i.e. prospectively defined criterion not met.�Significant only in the 25U, no correction for multiple hypothesis testing��No outcome criterion was defined prospectively.��Preliminary results, published as abstract only.

greater benefit from physical therapy [318]. Given thisconception of the role of BoNTs in musculoskeletalpain, studies that include a multimodal regimen may bemore likely to produce positive results with BoNTtherapy.

The data on headaches and migraine are significantlybetter. In tension headache, the results of most openstudies are contradictory. There are two with negative ormixed results [319,320] and two with positive reports[321,322]. The results, however, were not confirmed indouble-blind clinical trials [323–326] (Table 10).

Due to the pain relief experienced by patients treatedwith BoNT for other reasons, the application of BoNTin migraine was studied [327]. An initial randomizedplacebo-controlled study on BoNT in episodic migraineyielded ambiguous results [327]. Formal statisticalsignificance was barely attained, with a p-value of0.046 [327]. Different results in one or two patientswould have rendered the result non-significant [328].Other studies did not show a beneficial effect of BoNT/A in migraine [329–331]. Silberstein et al. reported thatthe low-dose (25U) group of BTX was superior toplacebo in reducing migraine attacks after 3 months[327]. However, the higher dose (75U) did not result in asignificant improvement of migraine. Although theresults of other controlled studies have been published[332] (Table 10), they do not permit valid conclusions, asthe number of patients included was rather small(n ¼ 30).

One recent retrospective study examined the effects ofBoNT/A on various types of headache disorders in 271patients [333]. In this study, patients were injected intoeither fixed sites or the sites of pain, and outcomes weremeasured as the number of headache days per month,headache intensity (0–3 scale), or both. BoNT/Atreatment significantly reduced the number of headachedays per month from approximately 19 to 8, headache

attler et al. [328])

patients Toxin Dose (U), distribution Result

A (Botoxs) 200 B; FTP �

A (Botoxs) 100 B; FTP �

A (Botoxs) 20 B; FS �

A (Botoxs) 25 B, 75 B; FS +/��

A (Botoxs) 50 B, FS ��

A (Botoxs) 16 B, 100 B; FS �

A (Dysports) 200 D; FS �

A (Dysports) 500 D; FS �

B (Myoblocs) 5000 M, 7500 M; FS ��

FTP: variable injection sites, ‘‘follow the pain approach’’, FS: fixed


intensity from a mean of 2.4 to 1.8 points. Of 263patients surveyed, 225 (85.6%) reported improvement inheadache frequency and intensity.

A controlled study examined the effects of BoNT/A(Botoxs) for the treatment of chronic daily headache[334]. Patients in this study (N ¼ 355) were treated with3 cycles of BoNT/A or placebo at 90-day intervals (totaldose 105–260U). Among patients identified as placebonon-responders in the initial placebo run-in phase,BoNT/A did not significantly improve headache-freedays compared with placebo. However, significantlymore patients treated with BoNT/A than placebo had a50% or greater reduction in headache frequency at theprimary endpoint of day 180, as well as day 210.

In a subanalysis of this study that included onlypatients with chronic daily headache who were nottaking concurrent prophylactic medications [228,335],BoNT/A significantly decreased the number of head-ache-free days compared with placebo at the primaryendpoint of 180 days [335]. In this subanalysis, BoNT/Asignificantly reduced the frequency of headache episodesand acute medication use at multiple time points. Otherstudies of chronic daily headache have reported mixedor negative results [336,337].

The reason that some studies failed to detect benefitsof BoNT injections remains unknown. Based on theavailable literature, it appears that patients with chronicdaily headache may represent a more responsivepopulation than those with episodic migraine, at leastunder the conditions studied. Given the large placeboeffect noted in many headache studies, psychologicalvariables may play a role. The known inhibition ofacetylcholine release alone does not suffice to explain theprophylactic effect observed in some migraine studies. Afinal conclusion cannot yet be drawn.

10. Botulinum toxin applications in parkinsonism

Hypersialorrhea is frequently reported in patientswith idiopathic PD. Although both treated and un-treated PD patients exhibit lower salivary flow thancontrols, with no relation with age or sex [338],treatment with botulinum toxin benefits PD patients[192].

Constipation is one of the most common autonomicdysfunctions observed in PD. In one study, botulinumtoxin injections into the puborectalis muscle, underultrasonographic guidance, reduce constipation in pa-tients with PD affected by outlet-obstruction constipa-tion [339].

Another potential application is freezing of gait inPD. It is a common, very disabling and poorly under-stood symptom, which is poorly understood and doesnot respond to medical treatment. Seven of 10 patientsinjected with up to 300U of Botoxs into the gastro-

cnemius and soleus of one or both legs, reporteddifferent rates of improvement of freezing of gaitseverity. Some of these patients also had foot dystonia.The mean duration of improvement was 6 weeks(range 1–12 weeks) with definite deterioration afterward[340]. These findings were not confirmed later in double-blind studies with either Myobloc/Neuroblocs) [341] orBotoxs [342].

Flexion contracture may develop in patients withadvanced PD and treatment with botulinum toxin maybe beneficial [343]. Contractions at knee level improvewith manipulation under anesthesia and injections ofbotulinum toxin type A into the hamstring andgastrocnemius muscles, in conjunction with a staticprogressive extension orthosis and aggressive physicaltherapy. Other applications of botulinum toxin in PDpatients include lower-limb fixed dystonic posturingafter immobilization [344], adductor spasticity [345],dystonic clenched fist [346], ‘‘Off’’ painful dystonia [94]and camptocormia [347].

11. Conclusion

Since the introduction of BoNT into clinical use, itsclinical applications have been steadily expanding andnovel applications reported. Its mechanism of inhibitingacetylcholine release following local injection is unique,especially when combined with its tendency to remainmostly localized. As long as BoNT remains localized atthe site of action, systemic side effects are rare. Thediscovery of clinical use of BoNT may set a milestone inmedical therapy, the beginning of interventional neurol-ogy, and perhaps approaching those of antibiotics andanesthesia in the therapeutic armamentarium. It seemsentirely likely that further applications for BoNT will bedeveloped in the future.

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Review Botulinum toxin: Clinical...

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