An Update on the Neurologic Applicationsof Botulinum Toxins

Virgilio Gerald H. Evidente & Charles H. Adler

Published online: 22 June 2010# Springer Science+Business Media, LLC 2010

Abstract Initially used to treat strabismus in the 1970s,botulinum toxin now has more than a hundred possiblemedical applications. Its utility in neurologic conditions haslargely involved treating movement disorders (particularlydystonia and conditions with muscle hyperactivity), al-though practically any hyperkinetic movement disordermay be relieved by botulinum toxin, including hemifacialspasm, tremor, tics, myoclonus, and spasticity. Althoughinitially thought to inhibit acetylcholine release only at theneuromuscular junction, botulinum toxins are now recog-nized to inhibit acetylcholine release at autonomic cholin-ergic nerve terminals, as well as peripheral release ofneurotransmitters involved in pain regulation. Thus, theiruse in neurology has been expanded to include headacheand other pain syndromes, as well as hypersecretorydisorders. This article highlights some of the commonneurologic conditions currently improved by botulinumtoxins and reviews the scientific evidence from researchstudies and clinical experience with these conditions.

Keywords Botulinum toxin . Botox .Myobloc . Xeomin .

Dysport . OnabotulinumtoxinA . AbobotulinumtoxinA .

RimabotulinumtoxinB . Spasticity . Hemifacial spasm .

Blepharospasm . Headache . Pain . Tics . Tremor . Spasmodicdysphonia . Cervical dystonia . Torticollis . Dystonia .

Writers’ cramp . Hypersalivation . Hyperhidrosis .

Oromandibular dystonia . Migraine

Introduction

Botulinum neurotoxin (BoNT) is the most poisonous sub-stance known to humans, with a median lethal dose (LD50)ranging from 0.1 to 1 ng/kg [1]. There are seven serotypes ofBoNT (A–G) produced by different strains of the bacteriumClostridium botulinum. Of these seven serotypes, onlyBoNT-A, -B, and -E (and possibly BoNT-C and -F) affecthumans. The core neurotoxin is produced as a single inactivepolypeptide chain of 150 kD, which is cleaved by tissueproteinases into an active di-chain molecule: a heavy (H)chain of approximately 100 kD and a light (L) chain ofaround 50 kD held together by a disulfide bond [2]. In thepreparation of the various commercial forms of BoNT,ancillary proteins (hemagglutinins and nontoxin nonhemag-glutinins) are included to protect the core neurotoxin fromdegradation [3]. Such protein complexes may vary in sizefrom 300 to 900 kD, with BoNT serotype A being the largest(900 kD). All BoNTs act by inhibiting the vesicle-dependentrelease of acetylcholine and other neurotransmitters fromsomatic and autonomic nerve terminals. BoNTs, once boundto the nerve cell membrane, are internalized into the cell, andthe L chain is translocated across the vesicular membraneand acts as a protease, cleaving one or more specific solubleN-ethylmaleimide–sensitive factor attachment protein recep-tors (SNAREs) [4]. The SNARE proteins includesynaptosome-associated protein 25, which is cleaved byBoNT-A, -C, and -E; synaptobrevin (also known as vesicle-associated membrane protein), which is cleaved by BoNT-B,-D, -F, and -G; and syntaxin, which is cleaved by BoNT-C.

Commercial Formulations of Botulinum Toxin

Currently, five major BoNT products are commerciallyavailable in different countries for various neurologic,

V. G. H. Evidente (*) : C. H. AdlerDepartment of Neurology, Mayo Clinic Arizona,13400 East Shea Boulevard,Scottsdale, AZ 85259, USAe-mail: evidente.virgilio@mayo.edu

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medical, and cosmetic indications. Four are BoNTserotype A:

1. Botox (Allergan, Irvine, CA)2. Dysport (Tercica, Inc., Brisbane, CA)3. Xeomin (Merz Pharma, Frankfurt, Germany)4. CBTXA (Lanzhou Biological Products Institute,

Lanzhou, China)

The fifth product, BoNT serotype type B, is manufacturedby Solstice Neurosciences (South San Francisco, CA) underthe nameMyobloc in the United States and NeuroBloc in Asiaand Europe. Starting in 2009, the US Food and DrugAdministration assigned generic names to three of thecommercially available formulations in the United States:Botox is onabotulinumtoxinA, Dysport is abobotulinumtox-inA, and Myobloc is rimabotulinumtoxinB. All these for-mulations of BoNT differ in their specific activity in humans.Because the current method for establishing units of measureis through mouse LD50 assays, all the toxins are marketedwith 1 U being equivalent to the mouse LD50. However, inhumans, the number of units needed to cause the samemagnitude of muscle weakness varies by formulation.Therefore, even though a toxin is BoNT serotype A, thepotency of individual products varies in humans. Similarly,the potency of BoNT-B differs from that of BoNT-A.Attempts to establish conversion factors for the number ofunits needed among the various forms of BoNT-A and -Bhave resulted in estimates but no clearcut recommendations.Thus, each specific brand needs to be considered separatelyand dosed according to the medical condition being treated.

Another difference among BoNT products is the process-ing. Xeomin is the only BoNT formulation free of complexingproteins (hemagglutinins and nonhemagglutinin proteins) [5].Immunization studies in animals have shown that hemag-glutinins can enhance antibody titers against BoNT or otherproteins [6]. However, only the neutralizing antibodies toprotein epitopes in the core neurotoxin molecule are the onesthat ultimately lead to secondary nonresponse or immunore-sistance. The clinical significance of lack of complexingproteins remains to be established.

Neurologic Indications for Botulinum Toxins

Currently, there are more than a hundredmedical conditions forwhich BoNTs are being used, and the list continues to expand.This review provides an update on some of the more commonneurologic conditions for which BoNT is being used [7••].

Cervical Dystonia

There are around 80 published studies of BoNT in thetreatment of cervical dystonia (CD); however, only 14 of

them are randomized controlled studies, including sevenclass I studies (four with BoNT-A, three with BoNT-B).Three class I studies investigated CD subjects naïve toBoNT treatment [8–10], whereas the other four enrolledsubjects with previous response to BoNT [11–14]. All theplacebo-controlled studies showed superiority of BoNTover placebo, whereas a comparator trial showed superior-ity of BoNT over trihexyphenidyl [10]. In BoNT-naïve CDpatients, a double-blind noninferiority study showed equiv-alent effects at 1 month of BoNT-A and BoNT-B, withsimilar median duration of effect (∼13 weeks) [15]. In CDpatients resistant to BoNT-A, BoNT-B has been shown tobe superior to placebo [13]. Compared with patients treatedwith BoNT-A, those receiving BoNT-B present with moremouth dryness and pain from injections [13, 15]. Comparedwith Botox, Dysport has been observed to cause moredysphagia, possibly as a result of a greater area of diffusion[16]. The longest longitudinal follow-up of CD patientsreceiving BoNT, up to 20 years, showed sustained efficacyand duration of response, as well as a low risk ofimmunoresistance [17]. BoNT-B (Myobloc) appears to behighly immunogenic, with as many as 44% of toxin-naïveCD patients developing neutralizing antibodies with chron-ic treatment [18]. In contrast, Jankovic et al. [19] comparedthe incidence of blocking antibodies in 130 CD patients, 42of whom were exposed only to the original batch of Botoxbefore 1998 (with 25 ng protein/100 U) and 119 of whomwere treated with the current batch of Botox (with 5 ng ofprotein/100 U). Blocking or neutralizing antibodies weredetected in 9.5% of patients treated with the original batch,versus no patients receiving the current batch of Botox.

Blepharospasm and Hemifacial Spasm

Extensive open-label and long-term clinical observationshave shown efficacy for BoNT in relieving blepharospasmand hemifacial spasm (HFS), such that attempts to performcontrolled clinical trials for these two indications have beenlimited. One class I noninferiority study compared Xeominwith Botox, using equivalent doses in 300 patients withblepharospasm, with no difference observed in efficacy atweek 3 using the Jankovic blepharospasm rating scale [20].Adverse reactions were similar between the two formula-tions, with ptosis being most common. One class IIcrossover study comparing Botox and Dysport at a 1:4dose ratio in 212 patients with blepharospasm showed asimilar duration of effect between the two formulations[21]. A multicenter randomized trial by the BenignEssential Blepharospasm Study Group studied the efficacyand safety of Dysport (40, 80, and 120 U per eye) versusplacebo in 119 patients with blepharospasm [22]. All threedoses of Dysport were superior to placebo, with the benefitbeing dose related. The benefit was maintained through

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week 12 for all doses, and through week 16 for the 80-Uand 120-U/eye groups. However, the rate of side effectswas highest in the 120-U/eye group, with the most commoneffects being ptosis, blurring of vision, and lagophthalmos.Thus, the best balance between efficacy and safety wasachieved with 80 U/eye of Dysport.

Similar to BoNT for blepharospasm, the frequent use ofBoNT in the treatment of HFS stems mainly from extensiveopen-label and clinical experience rather than from con-trolled trials. One class II prospective, blinded study of 11patients with HFS had four treatment arms: 2.5, 5, and 10 Uof Botox, and placebo [23]. Each subject cycled through thefour treatment arms in a random order. A clinical scale usedto rate videotapes and a patient subjective scale demon-strated that 79% of the patients had subjective benefitlasting a mean of 2.8 months with active treatment and 84%had objective improvement with at least one of the activedoses, with a trend toward increasing response with higherdoses. A class II single-blind, randomized, parallel-designstudy compared Botox and Dysport without placebo at adose ratio of 1:4 in 91 patients with HFS or blepharospasm[24]. Both products showed similar clinical efficacy andtolerability.

For patients with blepharospasm who become resistant toBotox, an open-label study showed that Myobloc at anaverage dose of 3633 U per treatment session may bebeneficial, with an average duration of effect of 7.3 weeks[25]. However, side effects were more common thantypically expected of BoNT-A, particularly pain on injection(100%), ptosis (32.3%), dry mouth (17.2%), and dry eyes(9.7%). The higher incidence of injection pain with Myobloclikely is a result of its acidic pH of 5.6 compared with theneutral pH of BoNT-A. Dilution of Myobloc with normalsaline results in an increase in pH and reduced pain frominjections. The high incidence of dryness of mouth and eyessuggests that BoNT-B has a greater effect than BoNT-A oncholinergic autonomic nerve terminals. For secondary non-responders to Botox, Dysport has been anecdotally reportedto potentially relieve HFS or blepharospasm, although thishas not been confirmed with controlled trials, and themechanism remains unexplained [26].

In patients with blepharospasm and HFS, one studyobserved that pretarsal injections of BoNT-A into theorbicularis oculi produced a significantly higher responserate and longer duration of maximum response comparedwith preseptal injections, with a lower frequency of majorside effects such as ptosis [27].

Oromandibular Dystonia and Spasmodic Dysphonia

Although most of the data on BoNT in the management oforomandibular dystonia (OMD) come from open-labelstudies, such uncontrolled reports provide compelling

evidence on the efficacy of both BoNT-A and BoNT-B inpatients with OMD [28, 29]. In particular, jaw-closingdystonia responds best to BoNT, particularly with injectionsto the anterior digastrics as an initial approach, and withfurther injections to the lateral pterygoid muscles ifinjections into the anterior digastrics do not offer sufficientrelief.

In one class I double-blind, randomized, parallel-groupstudy of Botox in 13 patients with adductor-type spasmodicdysphonia (ADSD), seven patients received Botox and sixreceived placebo [29]. Significant voice improvement wasfound in the BoNT-injected group, although excessivebreathiness of voice and dysphagia are potential side effects.A large retrospective study of 901 patients demonstrated thesafety and efficacy of Botox [30]. In a retrospective study of31 patients who had undergone five consecutive Dysportinjections for ADSD, unilateral injections to the thyroaryte-noids were just as effective as bilateral injections in terms ofvoice improvement and duration of action, with no post-treatment total voice loss observed with unilateral injections[31, 32]. BoNT-B (Myobloc) was found to be safe andeffective for ADSD in a class IV single-site, open-labelstudy in 13 patients [33].

With regard to abductor spasmodic dysphonia (ABSD),one class III prospective, randomized, crossover treatmentstudy involving 15 patients showed no objective benefit ofBotox, whether injected percutaneously or transnasally intothe posterior cricoarytenoid muscle [34]. Nevertheless,anecdotal experience of centers that frequently treat patientswith ABSD shows the efficacy of BoNT-A.

Focal Limb Dystonia and Writers’ Cramp

The literature contains published controlled trials of BoNTfor upper limb dystonia, but not for lower limb dystonia. Aclass I randomized, double-blind, placebo-controlled trial in40 patients with writers’ cramp treated with BoNT-A versusplacebo showed the superiority of BoNT-A based on thepatients’ subjective desire to continue injections, as well asthe visual analogue scale, symptom severity scale, writers’cramp rating scale, and writing speed [35]. A class IIdouble-blind, placebo-controlled, crossover study of BoNT-A in 10 patients with focal hand dystonia showedimprovement in subjective rating in eight patients and invideotape rating in six patients [36]. Weakness of injectedmuscles was noted in 80% of those who received activetreatment.

Spasticity

Of the 11 class I trials in adult upper-extremity spasticity,10 used BoNT-A and one used BoNT-B [37••]. Reductionin muscle tone, the primary outcome measure in all but one

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of the studies, was demonstrated in a dose-dependentfashion with BoNT treatment. Despite improvement inglobal satisfaction of subjects, family members, or clini-cians, improvement in active function (defined as activitiesthe subject could perform voluntarily with the spastic limb)was not demonstrated in any of the studies. For lower-limbspasticity, there are three class I trials reporting improve-ment in muscle tone post injections [37••], but not inwalking speed [38]. In children with cerebral palsy, fourclass I studies demonstrated the efficacy of BoNT injectionsinto the gastrocnemius in improving spastic equinus gaitover 1 to 3 months [37••]. One class I study injecting BoNTinto the thigh adductors and medial hamstrings of childrenwith adductor spasticity showed significant improvement inknee-to-knee distance as well as adductor muscle tone [39].

Tremor

There are no class I studies investigating the effects ofBoNT on tremor. A class II placebo-controlled studyrandomly assigned 25 patients with hand tremor to receive50 U of Botox or placebo into the wrist flexors and flexorsof the dominant upper limb [40]. One month post injection,75% of the BoNT-treated patients versus 27% of placebo-treated patients reported mild to moderate improvement,although the functional rating scales did not show anyimprovement. Accelerometry showed a 30% reduction intremor amplitude in 9 of 12 BoNT-treated subjects and inone placebo-treated patient. All patients who receivedBoNT had finger weakness. Another class II studyrandomly assigned 133 patients with essential hand tremorto receive low-dose Botox (50 U), high-dose Botox(100 U), or placebo [41]. Injections were made into thewrist flexors and extensors. Both doses of Botox resulted inimprovement of postural tremor on clinical rating scalesafter 4 to 16 weeks, although kinetic tremor was signifi-cantly reduced only at 6 weeks. Measures of motor tasksand functional disability, however, were not consistentlyimproved with BoNT-A treatment. The main adversereaction was dose-dependent hand weakness. One class IIstudy involving 10 patients with head tremor did not showsignificant improvement [42]. A class IV open-label studyof Botox in 13 subjects with isolated vocal tremor with nospasmodic dysphonia showed a beneficial effect in allpatients assessed at 6 weeks post injection [43].

Tics

One class II double-blind, crossover study of 18 patientswith simple motor tics demonstrated a 39% reduction in thenumber of tics per minute on evaluation 2 weeks afterinjections with BoNT, compared with a 6% increase in theplacebo-treated patients [44]. Interestingly, the urge associ-

ated with tics also improved in the BoNT-treated group, butnot in the placebo-treated patients. A class IV open-labelstudy of 15 patients with simple motor tics showed long-term efficacy of BoNT-A [45], with similar reduction ofpremonitory urge in all patients reporting such symptoms.

Hypersalivation and Hyperhidrosis

Five class I studies (three in BoNT-A and two in BoNT-B)investigated the effect of BoNT on sialorrhea in patientswith Parkinson’s disease (one study also included patientswith amyotrophic lateral sclerosis) [46•, 47]. All studiesshowed significant reduction in saliva production afterinjections into the parotid/submandibular glands, with nosignificant subjective worsening of any baseline dysphagia.A study of oropharyngeal swallowing dynamics based onswallowing videofluoroscopy showed no difference beforeor 30 days after injections of BoNT-A into the parotids inParkinson’s patients [48].

Two class I and several class II studies showed areduction in sweat production after intradermal BoNTtreatment in patients with axillary hyperhidrosis [46•].Two class II and several class III studies also showedefficacy of BoNT in reducing sweat production in patientswith palmar hyperhidrosis, without significant hand weak-ness [46•].

There are no controlled studies of BoNT-A versus BoNT-B in hypersalivation or hyperhidrosis. However, in patientswith cervical dystonia, BoNT-B appears to have a higherincidence of dryness of mouth compared with BoNT-A,thus suggesting a greater effect on autonomic nerves. Oneclass IV open-label study of BoNT-A and BoNT-B in 30children with hypersalivation from cerebral palsy or someother neurodegenerative disorder showed no difference inefficacy or side effects between the two types of BoNT[49].

Headache

Two class I and two class II studies of BoNT in patientssuffering from episodic migraines used a fixed-site injectionapproach [46•]. None showed a significant differencebetween BoNT and placebo, although the lack of demon-strable efficacy was thought to be from the fixed dosing. Aclass IV open-label study attempted to explore neurologicmarkers that might identify migraine patients who wouldbenefit from BoNT-A treatment (100 U divided into 21injections across the pericranial and neck muscles) [50].The authors observed that imploding headaches (headseems to be crushed, clamped, or stubbed by externalforces) and ocular headaches (eye-popping pain) were morelikely to respond to BoNT than exploding headaches(buildup of pressure inside the head).

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Four class II studies of BoNT were performed in patientswith chronic daily headache (CDH); all included a largenumber of patients with transformed migraine. Three of thestudies used a follow-the-pain strategy, whereas one used afixed-site approach. The primary outcome measure for allCDH studies was the mean change in headache-free daysper month. Only one study demonstrated a significant effectof BoNT on the primary outcome measure [51].

Four randomized, placebo-controlled studies—two classI, one class II, and one class III—investigated BoNT forchronic tension headaches; none of the studies showed anysignificant benefit of BoNT [46•].

The antinociceptive effect of BoNT in headache wasinitially thought to be a result of relief of muscle spasms.However, in vitro studies have shown that BoNT blocks theperipheral release of pain and inflammatory neurotransmit-ters, including substance P, as well as glutamate [52].Furthermore, from animal studies, it has been inferred thatBoNT-A exerts its antinociceptive effects through retro-grade transport and involvement of the central nervoussystem (CNS) [53].

Central Action of Botulinum Toxin

Several neurophysiologic studies have shown evidence forpossible central effects of BoNT-A [54]. There are at leastthree possible mechanisms by which BoNT-A may affectcentral circuits: 1) BoNT-mediated blockade of gammamotor endings with reduction of spindle afferent input fromthe injected muscle, 2) plastic changes following BoNT-mediated blockade of neuromuscular transmission, and 3)retrograde transport and transcytosis of BoNT-A followinguptake at the neuromuscular junction. In fact, radiolabeledBoNT-A injected intramuscularly in animals can bedetected in the ventral roots and adjacent spinal cordsegments, thus suggesting its retrograde axonal transportinto the CNS. Its direct central effect has also beendemonstrated in animal experiments, especially at highdoses. Whether BoNT truly exerts some of its therapeutic(or adverse) effects by reaching and influencing the CNSremains to be proven, and currently is an area of researchbeing actively pursued.

Conclusions

There is strong evidence from controlled studies demon-strating the efficacy of BoNT in the treatment of cervicaldystonia, blepharospasm, spasticity (to relieve muscle tonebut not limb function), hypersalivation, and axillaryhyperhidrosis. Largely from open-label experience as wellas non-class I trials, BoNT is most likely effective for

hemifacial spasm, focal upper limb dystonia, adductorspasmodic dysphonia, and oromandibular dystonia. Thereare very limited studies showing possible efficacy of BoNTin treating tremor and tics. Although no controlled studieshave shown unequivocal effectiveness of BoNT in treatingheadache syndromes, subanalyses and anecdotal experiencehave shown potential benefits in patients with implodingheadaches and ocular pain, as well as in those who areinjected according to the follow-the-pain approach. Patientswho become resistant to BoNT-A with chronic injectionsmay respond to BoNT-B. Anecdotally, patients whodevelop immunoresistance to one form of BoNT-A mayrespond to another form of BoNT-A, although this has notbeen confirmed in controlled trials. BoNT-B has beenobserved to have a greater influence than BoNT-A onautonomic cholinergic terminals, although the superiority ofBoNT-B over BoNT-A in treating hypersecretory condi-tions remains to be proven in controlled trials.

Disclosure Dr. Evidente has served on Allergan advisory boards,has received speaking honoraria from Ipsen and GlaxoSmithKline,and has received research support from Allergan and Merz. Dr. Adlerhas been a consultant to Allergan, Biogen Idec, Ipsen, GlaxoSmithK-line, Eli Lilly, and Merck Serono and has received research supportfrom Allergan.

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