Invited Review Paper

Therapeutics

Int. J. Oral Maxillofac. Surg. 2010; 39: 197–207doi:10.1016/j.ijom.2009.10.022, available online at http://www.sciencedirect.com

Clinical use of botulinum toxinsin oral and maxillofacial surgeryO. W. Majid: Clinical use of botulinum toxins in oral and maxillofacial surgery. Int. J.Oral Maxillofac. Surg. 2010; 39: 197–207. # 2009 International Association of Oraland Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.

Botulinum toxin (BTX) is a bacterial toxin that could be used as a medicine. Clinicalapplications of BTX have been expanding over the last 30 years and novelapplications reported. Its mechanism of inhibiting acetylcholine release atneuromuscular junctions following local injection is unique for the treatment offacial wrinkles. Other dose-dependent anti-neuroinflammatory effects and vascularmodulating properties have extended its spectrum of applications. Conditions suchas temporomandibular joint disorders, sialorrhea, headache and neuropathic facialpain, muscle movement disorders, and facial nerve palsy could also be treated withthis drug. Further applications of BTX are likely to be developed. This paperreviews the established and emerging applications of BTX in the field of oral andmaxillofacial surgery. An overview of the pharmacology, toxicity and preparationsof the agent is given.

0901-5027/030197 + 11 $36.00/0 # 2009 International Association of Oral and Maxillofacial Surge

O. W. MajidDepartment of Oral and Maxillofacial Surgery,College of Dentistry, University of Mosul,Mosul, Iraq

Keywords: botulinum; clinical use.

Accepted for publication 30 October 2009Available online 2 December 2009

Purified botulinum toxin (BTX) was thefirst bacterial toxin used as a medicine.Since its introduction into clinical use,over 30 years ago, it has become a versa-tile drug in various fields of medicine. Theclinical applications of BTX have beenexpanding and novel applications devel-oped.

BTX is widely used in cosmetic appli-cations for the treatment of facial wrinklesafter local injection, but conditions such astemporomandibular joint disorders, sialor-rhea, headache and neuropathic facialpain, muscle movement disorders, andfacial nerve palsy could be treated withthis drug. Many other indications areunder investigation, and further applica-tions for BTX are likely to be devel-oped220. In the maxillofacial region,most studies on the use of BTX are oflow quality (noncomparative, non-rando-

mized trials), but the overall results werepromising.

In this review, established and emergingapplications of BTX in the field of oral andmaxillofacial surgery are discussed.Emphasis is placed on the mechanism ofaction and outcome of treatment in differ-ent clinical situations. An overview of thepharmacology, toxicity and different pre-parations of the agent is given.

History

The idea of a possible therapeutic use forbotulinum toxin (BTX) was first devel-oped by the German physician and poetJustinus Kerner (1786–1862); he called it‘sausage poison’. In 1870, Muller, anotherGerman physician, coined the name botu-lism. The Latin form is botulus, whichmeans sausage66.

In 1897, Emile van Ermengem investi-gated an epidemic of botulism in Elle-zelles, Belgium, after the consumptionof raw ham. He isolated the bacteria fromthe ham and produced the disease inlaboratory animals by injecting the toxinproduced by the organism41.

BTX was developed as a biologicalweapon by many countries in the twenti-eth century50. Although many countriesstopped research related to biologicalweaponry after signing the Biologicaland Toxin Weapons Convention, purifica-tion of BTX for medical use continued222.

A therapeutic use for botulinum toxintype-A (BTX-A) was first studied in pri-mates by Scott et al in 1973187. In the late1970s, the toxin was introduced as a ther-apeutic agent for the treatment of strabis-mus186. Since then, its therapeuticapplications have expanded into many

ons. Published by Elsevier Ltd. All rights reserved.

198 Majid

different fields, often with innovativetreatments and surprising results.

BTX was first used for treating facialwrinkles and aging skin in 1988, but itswidespread cosmetic use did not occuruntil the mid-1990s148. There was muchspeculation about the storage, dilution,delivery methods and treatment doses. Inmaxillofacial surgical practice, Niamtureported on the cosmetic use of BTX forfacial rhytids and dynamic lines in 1999and 2000147,149. During the mid- andlate-1990s, BTX was used for lateralcanthal lines (crow’s feet), platysmalbanding, orbicularis oris injection, mass-eter muscle injection and the treatmentof temporomandibular disorders(TMDs). Later, there were manyattempts to use BTX for different clin-ical situations in oral and maxillofacialsurgery.

Bacteriology

Clostridium species bacteria are sporulat-ing, obligate anaerobic, Gram-positivebacilli. The spores of C. botulinum areubiquitous, distributed widely in soil andmarine sediments worldwide and oftenfound in the intestinal tract of domesticgrazing animals199,206.

Under appropriate environmental orlaboratory conditions, spores can germi-nate into vegetative cells that will producetoxin. C. botulinum grows and producesneurotoxin in the anaerobic conditionsfrequently encountered in the canning orpreservation of foods200,223.

Seven different strains of Clostridiumhave been described (designated A, B, C(1 and 2), D, E, F and G), and eachproduces a distinct neurotoxin identifiedby the corresponding letter of the bacterialstrain producing it, so, there are 7 distinctneurotoxins (BTX-A, -B, -C, -D, -E, -F, -G)100,216. Humans can be affected by thetoxins of 5 strains (A, B, E, F and G) andare not affected by the toxins of strains Cand D71,100. All 7 toxins may potentiallycause botulism in humans given a highenough exposure140. All 7 neurotoxins arestructurally similar but immunologicallydistinct92. There is some serum cross-reactivity among the serotypes becausethey share some sequence homology withone another as well as with tetanustoxin91.

Structure and Toxicity

Toxins produced by clostridial bacteriaare high-molecular-weight protein com-plexes that include 3 key proteins: a 150-kDa toxin, a non-toxin hemagglutinin

protein, and a non-toxin non-hemagglu-tinin protein. The 150-kDa toxin is com-posed of a 100-kDa heavy chain and a 50-kDa light chain. Disulfide and noncova-lent bonds link the heavy and light chains,and both chains are required for neuro-toxicity100.

BTX is the most toxic material known.It is 4 times more lethal in mice thantetanus toxin, 1 � 1010 more lethal thancurare, and 100 � 1010 more lethal thansodium cyanide33. The estimated humandose (assuming a weight of 70 kg) of typeA toxin lethal to 50% of an exposedpopulation (the LD50) is estimated, basedon animal studies, to be approximately0.09–0.15 mg by intravenous administra-tion, 0.7–0.9 mg by inhalation and 70 mgby oral administration76,96,180,188. Basedon findings from primate studies, humanLD50 for intramuscular BTX injection isestimated at 2500–3000 U for a 70-kgadult (35–40 U/kg).

Mechanism of Action

BTX is a protease that causes temporarychemical denervation of skeletal muscleby blocking the Ca+2-mediated release ofacetylcholine from nerve endings of alphaand gamma motor neurons (myoneuraljunction), producing a transient dose-dependent weakening of the muscle activ-ity rendering it nonfunctional without sys-temic effects23. This inhibition ofmuscular contraction is believed to befollowed by the sprouting of new axonterminals, which results in synaptic regen-eration and the reestablishment of neuro-muscular transmission15.

The 7 neurotoxins have different spe-cific toxicities,87,113,151 different durationsof persistence in nerve cells49,74, and dif-ferent potencies5. All BTX serotypes, ulti-mately, inhibit acetylcholine release.

The area of flaccidity produced may belarger than the area of muscle denervatedas a result of postulated paralysis ofgamma motor neurones, so the output ofthe muscle spindles is reduced leading toreduced muscular contraction at adjacentsites within the injected muscle150. Weak-ening of surrounding muscles not injectedmay also occur because of toxin diffusion.Animal studies have demonstrated thatBTX-A diffuses across fascial planes tosurrounding muscles193.

Clinical effect occurs within approxi-mately 3–7 days (typically seen after 1–3days) after administration, followed by 1–2 weeks of maximum effect, which thenlevels off to a moderate plateau until fullnerve recovery within 3–6 months (typi-cally at approximately 3 months)176.

Preparations

A number of BTX preparations have beenapproved in different countries. Currently,there are 6 different BTXs available on themarket, 5 contain BTX-A (Botox, Dys-port, Xeomin, Prosigne and PurTox) andthe other contains BTX-B (Myoblocs/NeuroBlocs). Approval procedures arecomplex and vary between preparationsand countries, but, in general, Botox hasgarnered the most approvals worldwide,followed by Dysport220.

Treatment doses of BTX vary depend-ing on the brand of toxin used. The dosegiven for any toxin refers only to thatparticular preparation and does not readilytransfer to doses of other products, even ifthey are of the same toxin serotype. Theseratios should be applied with extremecaution because different preparationsmay have different efficacy in differentparts of the body77.

BTX-A

Botox (Allergan Inc, USA): BTX-A (ori-ginally called ‘Oculinum’) was first usedin humans in 1968 to treat strabismus187.In 1991, Allergan Inc. purchased severalbatches of this purified BTX-A, and theagent was given the name Botox216.

Botox is the only available BTX pro-duct approved for cosmetic use in NorthAmerica. It is specifically approved for thetherapeutic treatment of strabismus, ble-pharospasm, cervical dystonia and axillaryhyperhidrosis. There are reports of Botoxspecifically improving patient self-percep-tion35,37,38,69,90,124,126,127.

Each vial of Botox contains 5 ng (100U) of air-dried toxin, with 1 unit (U) equalto the median amount necessary to kill50% of female Swiss-Webster miceweighing 18–20 g each after intraperito-neal injection (LD50)135,176,216. Each vialcontains 500 mg of albumin and 900 mg ofsodium chloride135.

Dysport (Ipsen Limited, UK) isanother BTX-A product approved forcosmetic use, which is marketed andsold in many European countries as wellas Russia, New Zealand, Mexico, Brazil,Argentina and Vietnam35. Each vial con-tains 12.5 ng (500 U) of air-dried toxin,125 mg of albumin, and 2.5 mg of lac-tose135. Dysport comes from a differenttype A strain of bacteria than Botox anddoses are not equivalent. Direct compar-isons of Botox and Dysport in animalstudies suggest that the equivalencedoses are 1 U Botox to 2.5–5 U Dysport,though in humans, this conversion islargely an estimate135.

Clinical use of botulinum toxins in oral and maxillofacial surgery 199

Xeomin (NT-201; Merz Pharmaceuti-cals GmBH, Germany), packaged as afreeze-dried powder, is a purified BTX-A that is free of the accessory complexingproteins (hemagglutinin and nonhemag-glutinin) found in the other BTX-A pro-ducts229. It is reported to be lessimmunogenic than other BTX-A pro-ducts,107 making it useful when largeamounts of toxin are required for extendedperiods77. Animal studies support this, butreliable human immunogenicity data arenot available107.

Many studies have found that Botoxand Xeomin have similar dose-dependentparalytic effects and minimal diffusioneffects on surrounding musculature53,229.It has been suggested that conversion ofBotox and Xeomin doses can be per-formed in a 1:1 ratio allowing exchangeof both BTX drugs in a therapeutic set-ting.

Prosigne (Lanzhou Biological ProductsInstitute, China) is a BTX-A that is onlyapproved in China; it has been availablefor clinical use there since October1993215. Preliminary studies suggest thatProsigne may have therapeutic actionscomparable with Botox for some thera-peutic purposes168,215. Trials specificallyexamining Prosigne for cosmetic uses arelacking77.

PurTox (Mentor Corp, Santa Barbara,CA, USA) is a purified BTX-A that isundergoing trials to approve its efficacyin some therapeutic uses77.

BTX-B

BTX-B is available as Myobloc (SolsticePharmaceuticals, South San Francisco,CA, USA) and is marketed as Neurobloc(Elan Pharmaceuticals, Shannon, CountyClare, Ireland)135. Myobloc has shownefficacy in clinical trials for the treatmentof various movement disorders since 1995and was approved by the FDA for thetreatment of cervical dystonia and hemi-facial spasm in 2001163. Myobloc has notreceived cosmetic approval in any coun-try, but there are reports of its efficacy inthe treatment of lateral canthal, glabellarand forehead rhytides. It appears to offerversatility in cosmetic neuroblockade byexhibiting action in patients resistant toBTX-A products3,11,119,125,135,163,174–176.

Myobloc is preconstituted in vials con-taining 25 ng (2500 U)/0.5 cc, 50 ng (5000U)/1.0 cc and 100 ng (10,000 U)/2.0 cc ofproduct in solution with 0.05% albu-min135. Treatment of patients with cervi-cal dystonia with Botox and Myobloc ledto attempts at equivalency doses in manycosmetic studies (1 U Botox equals

approximately 50–100 U Myobloc), butthe optimal ratio has not been estab-lished77.

Studies comparing the cosmetic effi-cacies of BTX-A and BTX-B reportthat the latter causes more pain duringinjection, has shorter action and prob-ably a less predictable diffusion pat-tern70,73,125,135,163. BTX-B could beuseful in situations in which rapid onsetis desirable or in which there areconcerns about antibody production toBTX-A77.

Cosmetic Uses

Intramuscular injection of BTX to reducefacial wrinkles is the most common cos-metic procedure performed in many coun-tries. In conjunction with fillers, BTXsallow the practitioner to sculpt the facethrough alterations in the dynamics of thefacial muscles. The limited on-label usesof these drugs for hyperkinetic foreheadwrinkles and brow furrows belie its rangeof cosmetic applications.

Facial Wrinkles

Glabellar lines, also called frown lines,occur naturally with facial animation, as aresult of the pulling of the skin by theunderlying musculature, predominantlythe procerus muscle and the corrugatorsupercilii. With aging and chronic activityof the facial muscles, these lines becomemore prominent93. The cosmetic potentialof BTX-A was first explored in the mid1980s in the treatment of hyperfunctionalfacial lines. Since then, BTX-A has beenused to temporarily treat glabellar linesand other hyperfunctional facial linessuch as horizontal forehead lines, lateralcanthal lines ‘crow’s feet’, platysmabands and perioral lines68,75,147. The evi-dence for the effect of BTX in the treat-ment of facial wrinkles is level 2 evidence(evidence from randomized controlledtrials).

The technique for injecting BTX isgenerally simple and most patients toler-ate injections without anesthesia quitewell, although topical anesthetics are usedby some practitioners. Some have usedacid mantle cream mixed with lidocaine(4%) and Lidoderm patches (lidocaine5%)146. Many patients treated with topicalanesthesia elected not to use it for subse-quent treatments148.

Multiple injection techniques have beendescribed. Some authors describe amethod based on brow position36. Othersdescribe a method based on needle angu-lation and measurement147,149. All injec-

tions are now made perpendicular to theskin surface and are tailored to the specificanatomy, but they must be 10 mm awayfrom the bony orbit because the apparentdiffusion of BTA is approximately10 mm148.

Botox has only been approved offi-cially for the treatment of glabellar lines,but other uses have shown the samedegree of improvement for frontalis andlateral canthal regions. Botox has alsobeen used for the reduction of platysmalbands108,134. Several patients with men-talis wrinkling and lower eyelid orbicu-laris hypertrophy were treatedsuccessfully with Botox injections72,148.Other sites treated include the vertical liprhytids (lipstick lines) with minimalimprovement and good patient satisfac-tion but perioral muscular palsy wasreported in some cases148,186. Some havedescribed an improvement in patientswith excessive gingival exposure. Byweakening the lip elevators, the amountof movement decreases and the patientshows less gingiva on smiling34.

Masseteric and temporalis muscle

hypertrophy

Masseteric hypertrophy usually resultsfrom anatomical asymmetry of the jaw,habitual asymmetric use of the jaw,clenching during exercise or sleep, exces-sive chewing of gum or congenital mal-formations. It may be unilateral orbilateral. The early results of treatmentwith intramasseter injections of BTX havebeen encouraging and satisfying topatients, but the effect has not been wellquantified12,138,144,170.

Temporalis muscle hypertrophy is lesscommon but has been managed success-fully using BTX injection; there were noappreciable side effects103.

Therapeutic Uses

BTX has evolved from a poison to aversatile clinical tool for a growing listof conditions resulting from muscularhyperfunction. In the head and neck, thislist includes focal dystonias, vocal ticsand stuttering, cricopharyngeal achalasia,various manifestations of tremor, hemi-facial spasm, temporomandibular jointdysfunction, bruxism, masticatory myal-gias, sialorrhea, hyperhidrosis and head-ache80,220. Recently, it has been reportedfor clinical use in dental implantology forthe prophylactic reduction of masseterand temporalis muscle strength afterimplantation in immediate load proto-cols101.

200 Majid

Temporomandibular joint (TMJ)

Many reports on BTX-A treatment forTMJ disorders have dealt with TMJ andmasticatory muscle pain78,79, reduced jawopening capacity10,202, recurrent TMJ dis-locations143,195,235, and masticatoryhyperactivity225. Most of these studieswere case series (level 4 evidence).

Temporomandibular disorders (TMDs)are subgroups of musculoskeletal andrheumatologic disorders, and are consid-ered the major cause of pain in the orofa-cial region152. TMDs may be divided intothose related to the muscles acting on thejoint (myofascial) and those related to thejoint itself (arthrogenic). Joint noise, painand a restricted range of mandibularmotion are the most frequent symptomsof TMD58. Directing treatment at the mus-cular component of TMD, which in somepatients can be identified as non-spasticclenching or bruxism, could yield impor-tant therapeutic gains. BTX-A has beeneffective in the treatment of some patientswith TMD with high specificity as well astolerable side-effects82. Injections areusually performed under electromyo-graphic or ultrasonic control12,82.

The source of chronic myofascial painis not clear57,227. There is some consensusthat peripheral and central mechanismsare variably involved in the propagationof pain in TMD192,208. The injection ofBTX-A into the masseter and temporalismuscles of patients with TMD reducedsubjective pain and tenderness in somepatients coincident with the objectiveand subjective weakening of the mastica-tory muscles and not before81,83. Thisobservation was attributed to the pre-sumed action of BTX on nociceptors201

and the inhibitory effect of specific pro-tein-receptor binding within the intracel-lular compartment on the release ofneuropeptides and inflammatory mole-cules, such as calcitonin gene-related pep-tide, substance P, and glutamate56.

Most patients with restricted mouthopening experienced some degree ofimprovement in the maximal range ofvertical motion after BTX therapy. Mus-cular relaxation, reduction of inflamma-tion in the muscle and the TMJ, and theguarding response to pain may contributeto this finding81.

Earlier studies suggest that displace-ment of the articular disc may be caused,precipitated or maintained by lateral pter-ygoid activity or friction between thearticular surfaces of the disc and condylecausing clicking48,115,128. BTX injectioninto the lateral pterygoid muscle hasreduced the clicking associated with

TMD9,26,45,94,95,217. Clicking was perma-nently eliminated in some cases with asmall but distinctive positional improve-ment in the disc–condyle relationship9.

The term ‘bruxism’ is derived from theGreek word brychein, which means ‘togrind or gnash the teeth’141. When severe,this rhythmic grinding is associated withheadache, masseter hypertrophy, dysar-thria, TMJ destruction and dental wear165.Several studies have described the treat-ment of bruxism with BTX104,212,221.Some authors have found that BTX-Ainjection into the flexor muscles of themandible produced subjective and objec-tive reductions in the power of muscularvoluntary contraction in most subjects81.There have been no double-blind studiesto assess the effectiveness of BTX therapyin bruxism.

Arthrocentesis is a less invasive surgicalintervention than open arthrotomy torelieve the discomfort and dysfunctionassociated with chronic cases of internalderangement of TMJ85. Intramuscularinjection of BTX as an adjunct to arthro-centesis of the TMJ gave encouragingresults regarding duration of improve-ment, suggesting that there may besynergy between the two procedures78.

Dislocation of the TMJ occurs when themandibular condyle is displaced anteriorlybeyond the articular eminence. It repre-sents 3% of all reported dislocatedjoints123. There have been several anec-dotal reports of the use of BTX-A astreatment for TMJ dislocation45,143, buta controlled clinical trial is needed toprove evidence of its efficacy. BTX-Awas first used to treat surgical failuresand then used as initial treatment158.The muscle selected varies with each case,but the lateral pterygoid is that most com-monly reported. Treating only the lateralpterygoid muscle appears to be sufficientto prevent temporarily recurrent disloca-tion of the TMJ158, but, in some reports,the superficial part of the masseter at theangle of the mandible was also injected45.

BTX injection is invasive, but it is arelatively conservative option. It is speci-fically indicated in patients for whom con-servative treatment of recurrent dislocationof the TMJ has failed and for whom surgerycarries major risks. BTX injection therapyis also an option in patients who sufferrecurrent dislocation of the TMJ as a resultof impaired muscle coordination secondaryto oromandibular dystonia, neurolepticallyinduced early and late dyskinesias, epilepsyand brain-stem syndromes45,158.

BTX treatment of protracted TMJ dis-location after medical conditions such asanoxic encephalopathy and stroke or cer-

ebrovascular event has also beenreported,6,45,143,191 which could lead toan increase in verbalization, masticationand improved quality of life.

Salivary secretory disorders

Xerostomia is one of the first manifesta-tions of botulism, which led to investiga-tions of its application for sialorrhea anddrooling. Topical injection of BTX-A as aminimally invasive option for the treat-ment of drooling has been used for manyyears in neurological diseases29,86,160. Itsgreatest limitation in this indication is itstransient effectiveness (3–4 months),requiring multiple and expensive admin-istrations32. The therapeutic effect is basedon the inhibitory action of the toxin at thecholinergic receptors of the salivary glandcells, shown in animal experiments60,63.An initial animal model showed a signifi-cant reduction in saliva production with-out direct toxicity to the acinar cells194.

Only pilot studies with relatively smallgroups of patients are available with abrief follow-up (level 4 evidence),although here are some studies on sialor-rhea associated with Parkinson’s disease[level 2 evidence (randomized clinicaltrials)]. The outcome of using BTX-A inthe treatment of drooling appears to beuniformly favorable; the preliminaryresults are promising, with rare reportsof serious complications. Up to two-thirdsof patients experienced a marked or mod-erate improvement in drooling after thetreatment of both parotid glands or parotidand submandibular glands com-bined18,106,122,179. Treatment is mostlyfocused on the parotid gland and to a lesserextent on the submandibular gland. Thesublingual gland is seldom injected220.

BTX has found application for sialor-rhea in Parkinson’s disease112,153,155,162,amyotrophic lateral sclerosis86,189,224,228,cerebral palsy160,207, and carcinoma of theupper digestive tract. It has also been usedfor accumulated saliva and droolingcaused by swallowing disorders aftertumor operations of the upper aerodiges-tive tract62 and for diseases of the gland-ular tissue such as posttraumatic andiatrogenic salivary sialoceles andcysts8,30,31,222 or salivary fistulas after sia-ladenectomy or oropharyngeal cancer sur-gery130–132 where the temporary stoppingof glandular secretory action is needed topromote healing. It has also been usedsuccessfully to treat auriculotemporal(Frey’s) syndrome32,54,111,116,167,190 as itreduces the skin area affected by gustatorysweating by inhibiting the sweat glandsabnormally re-innervated by the choliner-

Clinical use of botulinum toxins in oral and maxillofacial surgery 201

gic pathway55. BTX-A also has advan-tages in temporarily drooling statesbecause its effect is only temporary61. Inpatients with recurrent and chronic paro-titis, BTX injection resulted in a reductionin the number of episodes of parotid swel-ling32,59. BTX-B has also been successfulin some cases153,162.

With the exception of those with Frey’ssyndrome who are treated intracuta-neously, all of the injections are performedpercutaneously, either intraparenchymalor perilesional. In the case of sialoceles,the extravasation fluid should be drainedbeforehand32. Some authors still use BTXinjections under EMG control131,132 whentreating salivary secretory disorders.According to others, ultrasonographic-assisted intraparenchymal infiltration ispreferable and improves efficacy andsafety31,51,129,220. Others have found nodifference in undesired effects associatedwith the method of drug application133.

Facial pain (other than myofascial origin)

Chronic facial pain often presents difficultmanagement problems requiring interdis-ciplinary consultations and multipleattempts with different therapies. BTXinjections showed some advantages overexisting therapies regarding safety andefficacy18. The evidence provided by theliterature in this area lies in level 2 (ran-domized clinical trials).

Facial pain relief has been reported aftertreatment by BTX for other reasons; suchconditions include regional dystonias1,16,facial wrinkles148, and skull base surgery18.These observations led to the study of non-dystonic pain syndromes, such as myofas-cial pain and tension headache, these pro-duced beneficial results and were thenstudied in larger controlled trials84,171. Sev-eral studies have been conducted on the useof BTX-A in pain conditions such as tensionheadache, myofascial pain, migraine, tri-geminal neuralgia, bruxism and hemifacialcontracture after seventh cranial nerveinjury18,84,114,166,183,184,196,198,225,226.BTX-A was found promising in postopera-tive wound pain including reconstructivefacial and oral surgery, traditional andendoscopic sinus surgery, TMJ surgeryand blowout fracture repair17. Chronicfacial pain following post-dental proce-dures was associated with a poor results17.

Similar benefits have been reportedwith the use of BTX-B4. The ultimateefficacy of BTX in pain is difficult toassess and the data available do notpermit definitive conclusions. Other stu-dies did not show a beneficial effect ofBTX-A67,154,181,185,236.

Facial nerve palsy (FNP)

FNP is a disfiguring condition, differentaspects of which have been treated suc-cessfully using BTX. Most studies werecase series (level 4 evidence).

BTX injection, through an orbital routeor a skin crease, provides a good means ofinducing a protective ptosis by temporarilyparalyzing the levator palpebrae super-ioris64,177. This intentionally induced ptosismay be useful in intensive care patients toprevent desiccation of the cornea89.

Synkinesis is an involuntary uncoordi-nated muscle movement associated withvoluntary movement of the muscle. It issecondary to aberrant regeneration164.BTX-A is commonly used to relieve thesymptoms of synkinesis with markedimprovement19,42.

In patients with facial asymmetry,chemo-denervation of the normal sidewith BTX7,28,43,110,197 has been reportedto be an effective disguising tool. In thissetting, BTX reduces the relative hyper-kinesis of the contralateral side to theparalysis, resulting in a more symmetricalfunction of the face.

An aberrant connection of the salivarysceromotor fibres to the fibres of the lacri-mal gland may develop after a facial palsy,causing a hyperlacrimation whenever thepatient salivates (crocodile tears). Injec-tion of BTX into the lacrimal gland is asuccessful treatment for hyperlacrimationin these cases97,142,169.

Other nerve palsies

Trauma is a common cause of acquiredthird-nerve palsy in adults and chil-dren102,218. Such patients are less likelyto recover than those with palsies of othercauses121. There are few reports (level 4evidence) of BTX injection to the lateralrectus muscle for treatment of third-nervepalsy139,173,210. BTX injection decreasesthe likelihood of contracture of the lateralrectus muscle, thereby allowing return ofmedial rectus muscle function136.

The abducens nerve can be injured dur-ing a severe orbital trauma172. In suchcases, BTX injection of the medial rectusmuscle has been studied with variableimprovements99,109,161.

Muscle movement disorders

BTX has been used since 1977 as a ther-apeutic agent in the treatment of numerousneuromuscular disorders15. BTX-A injec-tions are considered a safe and efficientlocal treatment for focal dystonia andmuscle spasms105. Other serotypes havebeen used with comparable effects44,156.

Dystonia refers to the involuntary con-traction of specific muscles. Numerousstudies document the usefulness of BTXtherapy in the treatment of oromandibulardystonia14,95,213, cervical dystonia (spas-modic torticollis)22,27,44,203, hemifacialspasm26,157,211,232, tardive dyskine-sia205,219,231, and tardive tongue protru-sion dystona40,182. Many studies weredouble-blind randomized trials (level 2evidence).

A specific type in this category is hyper-kinesia of the platysma. In the literature,data on successful treatment of the pla-tysma with BTX are nearly always relatedto its use for aesthetic indica-tions13,21,108,134. BTX also provides afavorable therapeutic option117.

Perioperative use of botulinum toxins

In patients with movement disorders whorequire surgery, the presence of postopera-tive involuntary movements may be detri-mental to healing. BTX weakens themuscle and in so doing may improve post-operative recovery and healing. Woundhealing improves if the muscles involvedare injected with BTX prior to surgery2.

In maxillofacial surgery, patients under-going eyelid reconstructive surgery hadsuccessful wound healing after adjuncttreatment with BTX2. BTX was betterthan placebo in the wound healing offacial lacerations requiring surgery120.BTA has been used to immobilize musclesafter jaw fractures (level 4 evidence)137 toreduce the displacing forces on the frac-ture ends and obtain good immobilizationespecially if rigid internal fixation is notavailable or feasible.

BTX has also been beneficial during theinitial osseointegration phase for dentalimplants. This indication is mostly experi-mental, but some authors have found it tobe safe and effective in the prophylacticreduction of masseter and temporalis mus-cle strength after implantation in immedi-ate loading protocols101.

Complications

Botox has a large margin of safety216. Themost important side effects reported forcosmetic use of BTX include immuno-genicity, allergy and local complications.

Neutralizing antibodies to BTX-A tox-ins can lead to loss of treatment effect.Clinical resistance to BTX-A has beenestimated as high as 7%27, and BTX-Bis being investigated as an alternativetherapeutic agent22,27.

In theory, because human albumin isused in the preparation of Botox, a patient

202 Majid

could exhibit an allergic reaction,148 butno case has been reported.

Adverse effects such as pain, oedema,erythema, ecchymosis and short-termhypoesthesia may occur after injectionof BTX-A39,148. Other reported adverseevents are headache, blepharoptosis andperioral muscular palsy148,178,204.

In therapeutic applications, complica-tions were mostly local and relativelymild, such as pain, erythema, ecchymosisof the region injected, dry eyes, mouthdroop, ptosis and lid edema, facial muscleweakness, asymmetry of facial expressionduring dynamic facial movements, xeros-tomia, transient dysphagia, restrictedmouth opening, nasal regurgitation andnasal speech, headache, blurred vision,dizziness, upset stomach, infection, neckweakness, voice changes, difficulties inchewing and breathing risk of aspiration,recurrent jaw dislocation, dysarthria, sali-vary duct calculi and local injuries of thecarotid arteries or branches of the facialnerve14,18,24–26,44,45,61,65,79,94,98,129,153,155,

157,159,162,207,214,228,232.Systemic side effects are rarely

reported, generally not dose related, andcan include transient weakness, fatigue,nausea and pruritis14. Flu-like syndromeshave been reported, but they are generallyof brief duration12.

Some adverse effects such as xerosto-mia and dysphagia are more frequentlyseen after treatment with BTX-B thanBTX-A22,27,52,118.

Contraindications

Contraindications to BTX-A are generallyfew. In many studies, no complaints werereceived about systemic problems asso-ciated with cosmetic injection. Allerganlists Botox contraindications as pregnancyand breastfeeding, disorders of the neuro-muscular junction (myasthenia gravis,amyotrophic lateralizing sclerosis, myo-pathies) and theoretical drug interactions(aminoglycoside antibiotics, quinidine,calcium channel blockers, magnesium sul-fate, succinylcholine, and polymyxin)20.Other reported contraindications areEaton–Lambert syndrome and hypersen-sitivity to BTX or one of its ingredients100.

Potential Therapeutic Uses

Topical Formulations

Because intradermal BTX injection hasbeen successful in treating focal hyperhi-drosis of the palms, soles, axillae and facialareas47,145,209, investigators have consid-ered the potential for a topical formulation.

Topical BTX has been used for axillaryhyperhidrosis with promising results88.

Keloid and Hypertrophic Scar

Clinical observations indicate that BTX-Acan improve the appearance of hyper-trophic scar and inhibit its growth46,120,234.Evidence supporting this potential usearise from BTX’s ability to prevent exces-sive muscle contraction of the skin nearkeloid tissue33, and its reported influenceon cellular apoptosis and cellular prolif-eration230,233.

Funding

None.

Competing interests

None declared.

Ethical approval

Not required.

References

1. Acquadro M, Borodic GE. Treatmentof myofascial pain with botulinum toxin.Anesthesiology 1994: 80: 705–706.

2. ADLER C. Perioperative Use Of Botuli-num Toxins. Abstracts Toxins 2008;Toxicon 51: 44.

3. Alster T, Lupton J. Botulinum toxintype B for dynamic glabellar rhytidesrefractory to botulinum toxin type A.Dermatol Surg 2003: 29: 516–518.

4. ALVAREZ M, GROGAN P: Efficacy andsafety of Myobloc in headache prophy-laxis: A retrospective observation.Abstracts Toxins 2008/Toxicon 51: p. 44.

5. Aoki KR, Guyer B. Botulinum toxintype A and other botulinum toxin ser-otypes: a comparative review of bio-chemical and pharmacological actions.Eur J Neurol 2001: 8(suppl 5):21–29.

6. Aquilina P, Vickers R, Mckellar G.Reduction of a chronic bilateral tempor-omandibular joint dislocation with inter-maxillary fixation and botulinum toxinA. Br J Oral and Maxillofac Surg 2004:42: 272–273.

7. Armstrong MW, Mountain RE,Murray JA. Treatment of facial synkin-esis and facial asymmetry with botuli-num toxin type A following facial nervepalsy. Clin Otolaryngol Allied Sci 1996:21: 15–20.

8. Arnaud S, Batifor D, Goudot P.Nonsurgical management of traumaticinjuries of the parotid gland and ductusing type A botulinum toxin. PlastReconstr Surg 2006: 117: 2426–2430.

9. Bakke M, Møller E, Werdelin LM,Dalager T, Kitai N. Treatment of

severe temporomandibular joint click-ing with botulinum toxin in the lateralpterygoid muscle in two cases of ante-rior disc displacement. Oral Surg OralMed Oral Pathol Oral Radiol Endod2005: 100: 693–700.

10. Bakke M, Werdelin LM, Dalager T,Fuglsang-Frederiksen A, Prytz S,Møller E. Reduced jaw opening fromparadoxical activity of mandibular ele-vator muscles treated with botulinumtoxin. Eur J Neurol 2003: 10: 695–699.

11. Baumann L, Stezinger A, Vujevich

J, Halem M, Bryde J, Black L. Adouble-blinded, randomized, placebo-controlled pilot study of the safety andefficacy of Myobloc (botulinum toxintype B)-purified neurotoxin complexfor the treatment of crow’s feet: A dou-ble-blinded, placebo- controlled trial.Dermatol Surg 2003: 29: 508–515.

12. Bentsianov B, Francis A, Blitzer A.Botulinum toxin treatment of temporo-mandibular disorders, masseteric hyper-trophy, and cosmetic masseterreduction. Oper Tech Otolaryngol HeadNeck Surg 2004: 15: 110–113.

13. Blitzer A, Binder WJ, Aviv JE. Themanagement of hyperfunctional faciallines with botulinum toxin: A collabora-tive study of 210 injection sites in 162patients. Arch Otolaryngol Head NeckSurg 1997: 123: 389–392.

14. Blitzer A, Brin MF, Greene PE, Fahn

S. Botulinum toxin injection for the treat-ment of oromandibular dystonia. AnnOtol Rhinol Laryngol 1989: 98: 93–97.

15. Blitzer A, Sulica L. Botulinum toxin:basic science and clinical uses in otolar-yngology. Laryngoscope 2001: 111:218–226.

16. Boghen D, Flanders M. Effectivenessof botulinum toxin in the treatment ofspasmodic torticollis. Eur Neurol 1993:33: 199–203.

17. Borodic G, Acquadro M. Manage-ment of facial pain with botulinum toxinin a tertiary pain clinic. Naunyn Schmie-debergs Arch Phannacol 2002:365(Suppl 2):R14.

18. Borodic GE, Acquadro MA. The Useof Botulinum Toxin for the Treatment ofChronic Facial Pain. J Pain 2002: 3: 21–27.

19. Borodic GE, Pearce LB, Cheney M.Botulinum A toxin for treatment of aber-rant facial nerve regeneration. PlastReconstr Surg 1993: 91: 1042–1045.

20. BOTOX PACKAGE INSERT. Irvine, CA,Allergan, Inc.

21. Brandt FS, Bellman B. Cosmetic useof botulinum toxin Aexotoxin for theaging neck. Dermatol Surg 1998: 24:1232–1234.

22. Brashear A, Lew MF, Dykstra DD,Comella CL, Factor SA, Rodnitzky

RL. Safety and efficacy of NeuroBloc(botulinum toxin type B) in type A-responsive cervical dystonia. Neurology1999: 53: 1439–1446.

Clinical use of botulinum toxins in oral and maxillofacial surgery 203

23. Brin MF. Botulinum toxin therapy:basic science and overview of othertherapeutic applications. In: Blitzer

A, ed: Management of facial lines andwrinkles. Philadelphia: Lippincott,Williams and Wilkins 2000 p : 279–302.

24. Brin MF, Blitzer A, Herman S. Oro-faciomandibular and lingual dystonia.In: Moore AP, ed: Handbook of Botu-linim Toxin Treatment. Oxford, Eng-land: Blackwell Scientific 1995 : 151–163.

25. Brin MF, Blitzer A, Herman S. Oro-mandibular dystonia: Treatment of 96patients with botulinum toxin. In: Jan-

kovic J, Hallett M, eds: Therapy WithBotulinum Toxin.. New York, NY: Mar-cel Dekker 1994: 429–435.

26. Brin MF, Fahn S, Moskowitz C.Localized injections of botulinum toxinfor the treatment of focal dystonias andhemifacial spasm. Mov Disord 1987: 2:237–254.

27. Brin MF, Lew MF, Adler CH,Comella CL, Factor SA, Jankovic

J. Safety and efficacy of NeuroBloc(botulinum toxin type B) in type A-resistant cervical dystonia. Neurology1999: 53: 1431–1438.

28. Bulstrode NW, Harrison DH. Thephenomenon of the late recovered Bell’spalsy: treatment options to improvefacial symmetry. Plast Reconstr Surg2005: 115: 1466–1471.

29. Bushara KO. Sialorrhea in amyo-trophic lateral sclerosis: a hypothesisof a new treatment-botulinum toxin Ainjections of the parotid glands. MedHypotheses 1997: 48: 337–339.

30. Capaccio P, Cuccarini V, Benicchio

V. Treatment of iatrogenic submandib-ular sialocele with botulinum toxin.Case report. Br J Oral Maxillofac Surg2007: 45: 415–417.

31. Capaccio P, Paglia M, Minorati Det al. Diagnosis and therapeutic manage-ment of iatrogenic parotid sialocele.Ann Otol Rhinol Laryngol 2004: 113:562–564.

32. Capaccio P, Torretta S, Osio M,Minorati D. Botulinum toxin therapy:a tempting tool in the management ofsalivary secretory disorders. Am J Otol –Head and Neck Medicine and Surgery2008: 29: 333–338.

33. Carruthers A, Carruthers J. Botu-linum toxin type A: History and currentcosmetic use in the upper face. SeminCutan Med Surg 2001: 20: 71–84.

34. CARRUTHERS A: Facial aestheticenhancement educational initiative.Chicago, IL, Faculty Training, July2001; 13-15.

35. Carruthers J, Carruthers A. Theevolution of botulinum neurotoxin typeA for cosmetic applications. J CosmetLaser Ther 2007: 9: 186–193.

36. Carruthers J, Carruthers A. Treat-ment of glabellar frown lines with C.

botulinum-A exotoxin. J Dermatol SurgOncol 1992: 18: 17–21.

37. Carruthers JA, Lowe NJ, Menter

MA, Gibson J, Nordquist M, Mor-

daunt J. A multicenter, double-blind,randomized, placebo-controlled study ofthe efficacy and safety of botulinumtoxin type A in the treatment of glabellarlines. J Am Acad Dermatol 2002: 46:840–849.

38. Carruthers SJ, Fagien S, Matarasso

SL. Consensus recommendations on theuse of botulinum toxin type A in facialaesthetics. Plast Reconstr Surg 2004:114(6 Suppl):1S–22S.

39. Cather JC, Cather JC, Menter A.Update on botulinum toxin for facialaesthetics. Dermatol Clin 2002: 20:749–761.

40. Charles PD, Davis TL, Shannon KM,Hook MA, Warner JS. Tongue protru-sion dystonia: treatment with botulinumtoxin. South Med J 1997: 90: 522–525.

41. Cherington M. Botulism: update andreview. Semin Neurol 2004: 24: 155–163.

42. Chua CN, Quhill F, Jones E. Treat-ment of aberrant facial nerve regenera-tion with botulinum toxin A. Orbit 2004:23: 213–218.

43. Clark RP, Berris CE. Botulinumtoxin: a treatment for facial asymmetrycaused by facial nerve paralysis. PlastReconstr Surg 2005: 115: 573–574.

44. Comella CL, Jankovic J, Shannon

KM, Tsui J, Swenson M, Leurgans S.Comparison of botulinum toxin sero-types A and B for the treatment ofcervical dystonia. Neurology 2005: 65:1423–1429.

45. Daelen B, Thorwirth V, Koch A.Treatment of recurrent dislocation ofthe temporomandibular joint with typeA botulinum toxin. Int J Oral MaxillofacSurg 1997: 26: 458–460.

46. David A, Sherris M, Holger G. Botu-linum toxin to minimize facial scarring.Facial Plast Surg 2002: 18: 35–39.

47. De Almeida AT, Marques E, De

Almeida J, Cunha T, Boraso R. Pilotstudy comparing the diffusion of twoformulations of botulinum toxin typeA in patients with forehead hyperhidro-sis. Dermatol Surg 2007: 33(1 SpecNo.):S37–S43.

48. De Bont LG, Stegenga B. Pathologyof temporomandibular joint internalderangement and osteoarthrosis. Int JOral Maxillofac Surg 1993: 22: 71–74.

49. De Paiva A, Meunier FA, Molgo J,Aoki KR, Dolly JO. Functional repairof motor endplates after botulinum neu-rotoxin type Apoisoning: biphasicswitch of synaptic activity betweennerve sprouts and their parent terminals.Proc Natl Acad Sci U S A 1999: 96:3200–3205.

50. Dembek ZF, Smith LA, Rusnak JM.Botulinum Toxin (chapter 16). In: Dem-

bek ZF, ed: Medical Aspects of Biolo-

gical Warfare. Virginia: Office of TheSurgeon General 2007: 337–353.

51. Dogu O, Apaydin D, Sevim S, Talas

DU, Aral M. Ultrasoundguided versusblind intraparotid injections of botuli-num toxin- A for the treatment of sialor-rhoea in patients with Parkinson’sdisease. Clin Neurol Neurosurg 2004:106: 93–96.

52. Dressler D, Benecke R. Autonomicside effects of botulinum toxin type Btreatment of cervical dystonia andhyperhidrosis. Eur Neurol 2003: 49:34–38.

53. DRESSLER D, MANDER GJ, FINK K.Equivalent potency of Xeomin andBOTOX. Abstracts Toxins 2008/Toxi-con 51: 10.

54. Drobik C, Laskawi R. Frey’s syn-drome: treatment with botulinum toxin.Acta Otolaryngol Stockh 1995: 115:459–461.

55. Drummond P. Mechanism of gustatoryflushing in Frey’s syndrome. Clin AutonRes 2002: 12: 144–146.

56. Durham PL, Cady R, Cady R. Regula-tion of calcitonin gene-related peptidesecretion from trigeminal nerve cells bybotulinum toxin type A: implications formigraine therapy. Headache 2004: 44:35–42.

57. Dworkin SF. A model for pain mechan-isms in myogenous temporomandibulardisorders. Pain Forum 1997: 6: 166–169.

58. Dworkin SF, Leresche L. Researchdiagnostic criteria for temporomandib-ular disorders Review criteria examina-tions and specifications critique JCraniomandib Disord Facial Oral Pain6301-55 1992.

59. Ellies M, Gottstein U, Rohrbach-

Volland S. Reduction of salivary flowwith botulinum toxin: extended reporton 33 patients with drooling, salivaryfistulas, and sialadenitis. Laryngoscope2004: 114: 1856–1860.

60. Ellies M, Laskawi R, Gotz W. Immu-nohistochemical and morphometricinvestigations of the influence of botu-linum toxin on the submandibular glandof the rat. Eur Arch Otorhinolaryngol1999: 256: 148–152.

61. Ellies M, Laskawi R, Rohrbach-

Volland S, Arglebe C. Up-todatereport of botulinum toxin therapy inpatients with drooling caused by differ-ent etiologies. J Oral Maxillofac Surg2003: 61: 454–457.

62. Ellies M, Laskawi R, Rohrbach-

Volland S. Botulinum toxin to reducesaliva flow: Selected indications forultrasound guided toxin application intosalivary glands. Laryngoscope 2002:112: 82–86.

63. Ellies M, Laskawi R, Tormahlen G.The effect of local injection of botuli-num toxin A on the parotid gland of therat: An immunohistochemical and mor-phometric study. J Oral Maxillofac Surg2000: 58: 1251–1256.

204 Majid

64. Ellis MF, Daniell M. An evaluationof the safety and efficacy of botulinumtoxin type A (BOTOX) when used toproduce a protective ptosis. Clin ExpOphthalmol 2001: 29: 394–399.

65. Elston JS. Botulinum toxin A in clin-ical medicine. J Physiol (Paris) 1990:84: 285–289.

66. Erbguth FJ, Naumann M. Historicalaspects of botulinum toxin: JustinusKerner (1786–1862) and the ‘‘sausagepoison’’. Neurology 1999: 53: 1850–1853.

67. Evers S, Vollmer-Haase J, Schwaag

S, Rahmann A, Husstedt IW, Frese

A. Botulinum toxin A in the prophylac-tic treatment of migraine—a rando-mized, double-blind, placebo-controlled study. Cephalalgia 2004:24: 838–843.

68. Fagien S, Brandt FS. Primary andadjunctive use of botulinum toxin typeA (Botox) in facial aesthetic surgery:beyond the glabella. Clin Plast Surg2001: 28: 127–148.

69. Fagien S, Cox SE, Finn JC, Wersch-

ler WP, Kowalski JW. Patient-reported outcomes with botulinum toxintype A treatment of glabellar rhytids: Adouble-blind, randomized, placebo-con-trolled study. Dermatol Surg 2007: 33(1Spec No.):S2–S9.

70. Flynn TC. Myobloc. Dermatol Clin2004: 22: 207–211.

71. Flynn TC. Update on botulinum toxin.Semin Cutan Med Surg 2006: 25: 115–121.

72. Flynn TC, Carruthers J, Car-

ruthers A. Botulinum-A toxin treat-ment of the lower eyelid improvesinfraorbital rhytides and widens theeye. Dermatol Surg 2001: 27: 703–708.

73. Flynn TC, Clark RE. Botulinum toxintype B (MYOBLOC) versus botulinumtoxin type A (BOTOX) frontalis study:rate of onset and radius of diffusion.Dermatol Surg 2003: 29: 519–522.

74. Foran P, Mohammed N, Lisk G. Eva-luation of the therapeutic usefulness ofbotulinum neurotoxins B, C1, E, and Fcompared with the long lasting type A.Basis for distinct durations of inhibitionof exocytosis in central neurons. J BiolChem 2003: 278: 1363–1371.

75. Frampton JE, Easthope SE. Botuli-num toxin A (Botox cosmetic): a reviewof its use in the treatment of glabellarfrown lines. Am J Clin Dermatol 2003:4: 709–725.

76. Franz DR, Pitt LM, Clayton MA,Hanes MA, Rose KJ. Efficacy of pro-phylactic and therapeutic administrationof antitoxin for inhalation botulism. In:DasGupta BR, ed: Botulinum and Teta-nus Neurotoxins: Neurotransmissionand Biomedical Aspects. New York,NY: Plenum Press 1993: 473–476.

77. Freeman SR, Cohen JL. New Neuro-toxins on the Horizon. Aesthetic Surg J2008: 28: 325–330.

78. Freund B, Schwartz M. Intramuscu-lar injection of botulinum toxin as anadjunct to arthrocentesis of the tempor-omandibular joint: preliminary observa-tions. Br J Oral Maxillofac Surg 2003:41: 351–352.

79. Freund B, Schwartz M. Temporalrelationship of muscle weakness andpain reduction in subjects treated withbotulinum toxin A. J Pain 2003: 4: 159–165.

80. Freund B, Schwartz M, Symington

JM. Botulinum toxin: new treatment fortemporomandibular disorders. Br J Oraland Maxillofac Surg 2000: 38: 466–471.

81. Freund B, Schwartz M, Symington

JM. The Use of Botulinum Toxin for theTreatment of Temporomandibular Dis-orders: Preliminary Findings. J OralMaxillofac Surg 1999: 57: 916–920.

82. Freund BJ, Schwartz M. The use ofbotulinum toxin for the treatment oftemporomandibular disorder. OralHealth 1998: 88: 32–37.

83. Freund BJ, Schwartz M. Relief oftension-type headache symptoms in sub-jects with temporomandibular disorderstreated with botulinum toxin-A. Head-ache 2002: 42: 1033–1037.

84. Freund BJ, Schwartz M. Treatmentof chronic cervical-associated headachewith botulinum toxin A: A pilot study.Headache 2000: 40: 231–236.

85. Frost De. Kendell BD. Part II. Theuse of arthrocentesis for treatment oftemporomandibular joint disorders. JOral Maxillofac Surg 1999: 57: 583–587.

86. Giess R, Naumann M, Werner E.Injections of botulinum toxin A intothe salivary glands improve sialorrhoeain amyotrophic lateral sclerosis. J Neu-rol Neurosurg Psychiatry 2000: 69: 121–123.

87. Gill DM. Bacterial toxins: a table oflethal amounts. Microbiol Rev 1982: 46:86–94.

88. Glogau RG. Topically applied botuli-num toxin type A for the treatment ofprimary axillary hyperhidrosis: Resultsof a randomized, blinded, vehicle-con-trolled study. Dermatol Surg 2007: 33(1Spec No.):S76–S80.

89. Gusek-Schneider GC, Erbguth F.Protective ptosis by botulinum A toxininjection in corneal affectations. KlinMonatsbl Augenheilkd 1998: 213: 15–22.

90. Hallett M. One man’s poison—Clin-ical applications of botulinum toxin. NEngl J Med 1999: 341: 118–120.

91. Halpern JL, Smith LA, Seamon KB,Groover KA, Habig WH. Sequencehomology between tetanus and botuli-num toxins detected by an antipeptideantibody. Infect Immun 1989: 57: 18–22.

92. Hatheway CL. Clostridium botulinumand other clostridia that produce botuli-num neurotoxins. In: Hauschild AHW,Dodds KL, eds: Clostridium botuli-num—Ecology and Control in Foods.

New York, NY: Marcel Dekker, Inc1992: 3–10.

93. Hegedus F, Diecidue R, Taub D,Nyirady J. Non-surgical treatmentmodalities of facial photodamage: prac-tical knowledge for the oral and max-illofacial professional. Int J OralMaxillofac Surg 2006: 35: 389–398.

94. Hennings JMH, Krause E, Botzel K,Wetter TC. Successful treatment oftardive lingual dystonia with botulinumtoxin: Case report and review of theliterature. Progress in Neuro-Psycho-pharmacology & Biological Psychiatry2008: 32: 1167–1171.

95. Hermanowicz N, Truong DD. Treat-ment of oromandibular dystonia withbotulinum toxin. Laryngoscope 1991:101: 1216–1218.

96. Herrero BA, Ecklung AE, Streett

CS, Ford DF, King JK. Experimentalbotulism in monkeys—Aclinical patho-logical study. Exp Mol Pathol 1967: 6:84–95.

97. Hofmann RJ. Treatment of Frey’ssyndrome (gustatory sweating) and‘crocodile tears’ (gustatory epiphora)with purified botulinum toxin.Ophthalmic Plast Reconstr Surg2000: 16: 289–291.

98. Hogan P, Charles D, Watts MW,Massey JM. Severity and Impact ofXerostomia in Patients Treated withBotulinum Toxin Type B for CervicalDystonia: Observations on the Qualityof Life of Patients with Xerostomia.Curr Ther Res Clin Exp 2004: 65:161–171.

99. Holmes JM, Beck RW, Kip KE,Droste PJ, Leske DA. Botulinum toxintreatment versus conservative manage-ment in the acute traumatic sixth nervepalsy or paresis. J AAPOS 2000: 4: 145–149.

100. Huang W, Foster JA, Rogachefsky

AS. Pharmacology of botulinum toxin. JAm Acad Dermatol 2000: 43(2 Pt1):249–259.

101. Stefan KA, Konstantinovic VS. Thetherapeutic use of botulinum toxin incervical and maxillofacial conditions:an evidence-based review. Oral SurgOral Med Oral Pathol Oral RadiolEndod 2007: 104: e1–e11.

102. Ing EB, Sullivan TJ, Clarke MP,Buncic JR. Oculomotor nerve palsiesin children. J Pediatr Ophthalmol Stra-bismus 1992: 29: 331–336.

103. Isaac AM. Unilateral temporalis musclehypertrophy managed with botulinumtoxin type A. Br J Oral Maxillofac Surg2000: 38: 571–572.

104. Ivanhoe CB, Lai JM, Francisco GE.Bruxism after brain injury: successfultreatment with botulinum toxin- A. ArchPhys Med Rehabil 1997: 78: 1272–1273.

105. Jankovic J, Orman J. Botulinum Atoxin for cranial–cervical dystonia: adouble-blind, placebo-controlled study.Neurology 1987: 37: 616–623.

Clinical use of botulinum toxins in oral and maxillofacial surgery 205

106. Jongerius PH, Van Den Hoogen F,Van Limbeek J, Gabreels FJ, Van

Hulst K, Rotteveel JJ. Effect of botu-linum toxin in the treatment of drooling:a controlled clinical trial. Pediatrics2004: 114: 620–627.

107. Jost Wh. Blumel J, Grafe S. Botuli-num neurotoxin type A free of complex-ing proteins (XEOMIN) in focaldystonia. Drugs 2007: 67: 669–683.

108. Kane MA. Nonsurgical treatment ofplatysmal bands with injection of botu-linum toxin A. Plast Reconstr Surg1999: 103: 656–663.

109. Kerr NC, Hoehn MB. Botulinum toxinfor sixth nerve palsies in children withbrain tumors. J AAPOS 2001: 5: 21–25.

110. Krohel GB, Cipollo CI, Gadipatti K.Contralateral botulinum toxin injectionsimprove drinking ability and facial sym-metry in patients with facial paralysis.Am J Ophthalmol 2005: 135: 540.

111. Laccourreye O, Muscatelo L,Naude C. Botulinum toxin type A forFrey’s syndrome: a preliminary prospec-tive study. Ann Otol Rhinol Laryngol1998: 107: 52–55.

112. Lagalla G, Millevolte M, Capecci

M, Provinciali L, Ceravolo MG.Botulinum toxin type A for droolingin Parkinson’s disease: a double-blind,randomized, placebo-controlled study.Mov Disord 2006: 21: 121–125.

113. Lamanna C. The most poisonous poi-son. Science 1959: 130: 763–772.

114. Lang AM. Botulinum toxin type Atherapy in chronic pain disorders. ArchPhys Med Rehabil 2003: 84(3 Suppl1):S69–73 [quiz S4–5].

115. Larheim Ta. Westesson Pl. Sano T.Temporomandibular joint disk displace-ment: comparison in asymptomaticvolunteers and patients. Radiology2001: 218: 428–432.

116. Laskawi R, Drobik C, Schonebeck C.Up-to-date report of botulinum toxintype A treatment in patients with gusta-tory sweating (Frey’s syndrome). Lar-yngoscope 1998: 108: 381–384.

117. Laskawi R, Rohrbach S, Rodel R,Surgical. Nonsurgical TreatmentOptions in Patients With MovementDisorders of the Platysma. J Oral Max-illofac Surg 2002: 60: 157–162.

118. Lew MF, Adornato BT, Duane DD.Botulinum toxin type B: A double-blind,placebo-controlled, safety and efficacystudy in cervical dystonia. Neurology1997: 49: 701–707.

119. Lew MF, Brashear A, Factor S. Thesafety and efficacy of botulinum toxintype B in the treatment of patients withcervical dystonia: Summary of threecontrolled clinical trials. Neurology2000: 55(12 Suppl 5):S29–S35.

120. Lger G, Anthoy E, Brisse T. Botuli-num toxin to improve facial woundhealing: a prospective, blinded, pla-cebo-controlled study. Mayo Clin Proc2006: 81: 1023–1028.

121. LIESEGANG TJ, SKUTA GL, CANTOR LB.Special forms of strabismus. In: SIMON

JW, BUCKLY EG, DRACK AV, et al, (eds.)Pediatric Ophthalmology and Strabis-mus. San Francisco (CA): AmericanAcademy of Ophthalmology; 2004–2005. p. 140–41.

122. Lipp A, Trottenberg T, Schink T,Kupsch A, Arnold G. A randomizedtrial of botulinum toxin A for treatmentof drooling. Neurology 2003: 61: 1279–1281.

123. Lovely FW, Copeland RA. Reductioneminoplasty for chronic recurrent luxa-tion of the temporomandibular joint. JCan Dent Assoc 1981: 3: 179–184.

124. Lowe NJ, Maxwell A, Harper H.Botulinum A exotoxin for glabellarfolds: A double-blind, placebo-con-trolled study with an electromyographicinjection technique. J Am Acad Derma-tol 1996: 35: 569–572.

125. Lowe NJ, Yamauchi PS, Lask GP,Patnaik R, Moore D. Botulinum tox-ins types A and B for brow furrows:Preliminary experiences with type Btoxin dosing. J Cosmet Laser Ther2002: 4: 15–18.

126. Lowe P, Patnaik R, Lowe N. Compar-ison of two formulations of botulinumtoxin type A for the treatment of gla-bellar lines: A double-blind, randomizedstudy. J Am Acad Dermatol 2006: 55:975–980.

127. Lowe PL, Patnaik R, Lowe NJ. Acomparison of two botulinum type Atoxin preparations for the treatment ofglabellar lines: Double-blind, rando-mized, pilot study. Dermatol Surg2005: 31: 1651–1654.

128. Lundh H, Westesson PL. Clinicalsigns of temporomandibular joint inter-nal derangement in adults. An epidemio-logic study. Oral Surg Oral Med OralPathol Oral Radiol Endod 1991: 72:637–641.

129. Mancini F, Zangaglia R, Cristina S,Sommaruga MG, Martignoni E,Nappi G, Pacchetti C. Double-blind,placebo-controlled study to evaluate theefficacy and safety of botulinum toxintype A in the treatment of drooling inparkinsonism. Mov Disord 2003: 18:685–688.

130. Marchese-Ragona R, De Filippis C,Staffieri A. Parotid gland fistula: treat-ment with botulinum toxin. PlastReconstr Surg 2001: 107: 886–887.

131. Marchese-Ragona R, Galzignato

PF, Marioni G. Endoscopic diagnosisof rhino-parotid fistula and successfultreatment with botulinum toxin. Laryn-goscope 2005: 115: 2062–2064.

132. Marchese-Ragona R, Marioni G,Restivo AD. The role of botulinumtoxin in postparotidectomy fistula treat-ment. A technical note. Am J Otolaryn-gol 2006: 27: 221–224.

133. MARINA S, VASIC M, PEKMEZOVIC T, KOS-

TIC V. Botulinum toxin in the treatment

of sialorrhea. Abstracts Toxins/Toxicon2008; 51: 50.

134. Matarasso A, Matarasso SL, Brandt

FS. Botulinum A exotoxin for the man-agement of platysma bands. PlastReconstr Surg 1999: 103: 645–652.

135. Matarasso SL. Comparison of botuli-num toxin types A and B: A bilateral anddouble-blind randomized evaluation inthe treatment of canthal rhytides. Der-matol Surg 2003: 29: 7–13.

136. Mazow ML. Third cranial nerve palsy:Diagnosis and management strategies.In: Rosenbaum AL, Santiago AP,eds: Clinical Strabismus Management:Principles and Surgical Technique. Phi-ladelphia (PA): W.B. Saunders 1999 :251–258.

137. Mckellar G, Lorentz I. The use ofbotulinum-toxin in the treatment of oro-mandibular dystonias and fractures ofthe mandibular condyle. Aust N Z JMed 1992: 22: 428.

138. Metai M. Morphological and func-tional-changes in masseter after admin-istration of botulinum toxin fortreatment of masseteric hypertrophy. JDent Res 1996 May: 75: 1164.

139. Metz HS, Mazow M. Botulinum toxintreatment of acute sixth and third nervepalsy. Graefes Arch Clin Exp Ophthal-mol 1988: 226: 141–144.

140. Middlebrook JL, Franz DR. Botuli-num toxins. In: Sidell FR, Takafuji

ET, Franz DR, eds: Textbook of Mili-tary Medicine, Part I: Warfare, Weap-onry, and the Casualty—MedicalAspects of Chemical and Biological War-fare. Washington, DC: Department of theArmy, Office of The Surgeon General,Borden Institute 1997: 643–654 Chap 33.

141. Miller SC, Firestone JM. Psychoso-matic factors in the aetiology of period-ontal diseases. Am J Orthodont OralSurg 1947: 33: 675–680.

142. Montoya FJ, Riddell CE, Caesar R,Hague S. Treatment of gustatory hyper-lacrimation (crocodile tears) with injec-tion of botulinum toxin into the lacrimalgland. Eye 2002: 16: 705–709.

143. Moore AP, Wood CG. Medical treat-ment of recurrent temporomandibularjoint dislocation using botulinum toxinA. Br Dent J 1997: 183: 415–417.

144. Moore AP, Wood GD. The MedicalManagement of Masseteric HypertrophyWith Botulinum Toxin Type A. Br JOral Maxillofac Surg 1994: 32: 26–28.

145. Moreau MS, Cauhepe C, Magues JP,Senard JM. A double-blind, randomized,comparativestudyofDysport vs.BOTOXin primary palmar hyperhidrosis. Br JDermatol 2003: 149: 1041–1045.

146. Niamtu J, Campbell RL. The anes-thetic skin patch for topical cutaneousanesthesia. J Oral Maxillofac Surg 1984:42: 839–840.

147. Niamtu J. Aesthetic uses of botulinumtoxin A. J Oral Maxillofac Surg 1999:57: 1228–1233.

206 Majid

148. Niamtu J. Botulinum Toxin A: AReview of 1,085 Oral and MaxillofacialPatient Treatments. J Oral MaxillofacSurg 2003: 61: 317–324.

149. Niamtu J. Cosmetic facial surgery. OralMaxillofac Surg Clin North Am 2000:12: 595.

150. O’day J. Use of botulinum toxin inneuro-opthalmology. Curr Opin Opthal-mol 2001: 12: 419–422.

151. Ohishi I. Oral toxicities of Clostridiumbotulinum type Aand Btoxins from dif-ferent strains. Infect Immun 1984: 43:487–490.

152. Okeson JP. Orofacial Pain: Guidelinesfor Assessment, Diagnosis and Manage-ment. Chicago: Quintessence Co. 1996:p. 45–52.

153. Ondo WG, Hunter C, Moore W. Adouble-blind placebocontrolled trial ofbotulinum toxin B for sialorrhea in Par-kinson’s disease. Neurology 2004: 62:37–40.

154. PadbergM, De BruijnSF, De Haan RJ,Tavy DL. Treatment of chronic tension-type headache with botulinum toxin: adoubleblind, placebo-controlled clinicaltrial. Cephalalgia 2004: 24: 675–680.

155. Pal PK, Calne DB, Calne S, Tsui JK.Botulinum toxin A as treatment fordrooling saliva in PD. Neurology2000: 54: 244–247.

156. Pappert E, Leong M, Royal M. Botu-linum toxin type B compared with type Ain the treatment of patients with cervicaldystonia: results from a randomized, dou-ble-blind non-inferiority study. Neurol-ogy 2006: 66(Suppl):A252.

157. Park YC, Lim JK, Lee DK, Yi SD.Botulinum a toxin treatment of hemifa-cial spasm and blepharospasm. J KoreanMed Sci 1993: 8: 334–340.

158. Perez DM, Espiga PG. Recurrent Tem-poromandibular Joint Dislocation Trea-ted With Botulinum Toxin: Report of 3Cases. J Oral Maxillofac Surg 2004: 62:244–246.

159. Poewe W, Deuschl G, Nebe A, Feifel

E, Wissel J, Benecke R. What is theoptimal dose of botulinum toxin A in thetreatment of cervical dystonia? Resultsof a double blind, placebo controlled,dose ranging study using Dysport. Ger-man Dystonia Study Group. J NeurolNeurosurg Psychiatry 1998: 64: 13–17.

160. Porta M, Gamba M, Bertacci G.Treatment of sialorrhea with ultrasoundguided botulinum toxin type A injec-tions in patients with neurological dis-orders. J Neurol Neurosurg Psychiatry2001: 70: 538–540.

161. Quah BL, Ling YL, Cheong PY,Balakrishnan V. A review of 5 years’experience in the use of botulinium toxinA in the treatment of sixth cranial nervepalsy at the Singapore National EyeCentre. Singapore Med J 1999: 40:405–409.

162. Racette BA, Good L, Sagitto S,Perlmutter JS. Botulinum toxin B

reduces sialorrhea in Parkinsonism.Mov Disrod 2003: 18: 1059–1061.

163. Ramirez AL, Reeck J, Maas CS. Botu-linum toxin type B (MyoBloc) in themanagement of hyperkinetic faciallines. Otolaryngol Head Neck Surg2002: 126: 459–467.

164. RAMIREZ OM, MAILLARD GF, MUSOLAS

A. The extended subperiosteal face lift:a definitive soft-tissue remodeling forfacial rejuvenation. Plast Reconstr Surg88:227–36, discussion 1991; 237–8.

165. Redding GR, Rubright WC, Zimmer-

man SO. Incidence of brnxism. J DentRes 1966: 45: 1198–1204.

166. Relja M, Telarovic S. Botulinumtoxin in tension-type headache. J Neurol2004: 251(Suppl 1):I12–I14.

167. Restivo DA, Lanza S, Patti F.Improvement of diabetic autonomic gus-tatory sweating by botulinum toxin typeA. Neurology 2002: 59: 1971–1973.

168. Rieder CR, Schestatsky P, Socal

MP, Monte TL, Fricke D, Costa J.A double-blind, randomized, crossoverstudy of prosigne versus botox inpatients with blepharospasm and hemi-facial spasm. Clin Neuropharmacol2007: 30: 39–42.

169. Riemann R, Pfennigsdorf S, Rie-

mann E. Successful treatment of croco-dile tears by injection of botulinum toxininto the lacrimal gland: a case report.Ophthalmology 1999: 106: 2322–2324.

170. Rijsdijk BA. Botulinum toxin Type Atreatment of cosmetically disturbingmasseteric hypertrophy (DUT). NedTijdschr Geneeskd 1998: 142: 529–532 (Abstract).

171. Rollnik JD, Tanneberger O, Schu-

bert M, Schneider U, Dengler R.Treatment of tension-type headachewith botulinum toxin type A: A dou-ble-blind, placebo-controlled study.Headache 2000: 40: 300–305.

172. Rowe NL, Williams LI. Fracture of thezygomatic complex and orbit. 2nd editionIn: Williams LI, ed: Rowe and Wil-liams’ Maxillofacial injuries, Vol. 1.Churchill Livingstone 1994: 515.

173. Saad N, Lee J. The role of botulinumtoxin in third nerve palsy. Aust N Z JOphthalmol 1992: 20: 121–127.

174. Sadick N. Prospective open-label studyof botulinum toxin type B (Myobloc) atdoses of 2,400 and 3,000 U for thetreatment of glabellar wrinkles. Derma-tol Surg 2003: 29: 501–507.

175. Sadick NS. Botulinum toxin type B forglabellar wrinkles: A prospective open-label response study. Dermatol Surg2002: 28: 817–821.

176. Sadick NS, Matarasso SL. Compari-son of botulinum toxins A and B in thetreatment of facial rhytides. DermatolClin 2004: 22: 221–226.

177. Sadiq SA, Downes RN. A clinical algo-rithm for the management of facialnerve palsy from an oculoplastic per-spective. Eye 1998: 12(Pt 2):219–223.

178. Said SZ, Meshkinpour A, Car-

ruthers A, Carruthers J. Botulinumtoxin A: its expanding role in dermatol-ogy and esthetics. Am J Clin Dermatol2003: 4: 609–616.

179. Savarese R, Diamond M, Elovic E,Millis SR. Intraparotid injection ofbotulinum toxin A as a treatment tocontrol sialorrhea in children with cere-bral palsy. Am J Phys Med Rehabil2004: 83: 304–311.

180. Schantz EJ, Johnson EA. Propertiesand use of botulinum toxin and othermicrobial neurotoxins in medicine.Microbiol Rev 1992: 56: 80–99.

181. Schmitt WJ, Slowey E, Fravi N,Weber S, Burgunder JM. Effect ofbotulinum toxin A injections in the treat-ment of chronic tension-type headache:a double-blind, placebo-controlled trial.Headache 2001: 41: 658–664.

182. Schneider SA, Aggarwal A, Bhatt

M, Dupont E, Tisch S, Limousin P.Severe tongue protrusion dystonia —clinical syndromes and possible treat-ment. Neurology 2006: 67: 940–943.

183. Schulte-Mattler WJ, Krack P.Treatment of chronic tension-type head-ache with botulinum toxin A: a rando-mized, double-blind, placebo-controlledmulticenter study. Pain 2004: 109(1–2):110–114.

184. Schulte-Mattler WJ, Wieser T,Zierz S. Treatment of tensiontype head-ache with botulinum toxin: a pilot study.Eur J Med Res 1999: 4: 183–186.

185. Schwaag S, Vollmer-Haase J, Rah-

man A, Frese A, Husstedt Iw. Evers

S. Botulinum toxin A in the prophylactictreatment of migraine—a randomized,double-blind, placebo-controlled study.Cephalalgia 2004: 24: 838–843.

186. Scott AB. Botulinum toxin injection ofeye muscles to correct strabismus. TransAm Ophthalmol Soc 1981: 79: 734–770.

187. Scott AB, Rosenbaum A, Collins

CC. Pharmacologic weakening ofextraocular muscles. Invest Ophthalmol1973: 12: 924–927.

188. Scott AB, Suzuki D. Systemic toxicityof botulinum toxin by intramuscularinjection in the monkey. Mov Disord1988: 3: 333–335.

189. Scott KR, Kothari MJ, Venkatesh

YS, Murphy T, Simmons Z. Parotidgland injections of botulinum toxin Aare effective in treating sialorrhea inamyotrophic lateral sclerosis. J ClinNeuromuscul Dis 2005: 7: 62–65.

190. Sen P, Papesch M. Botulinum Toxin Afor the Management of GustatorySweating. Otolaryngol Head and NeckSurg 2008: 139: 126.

191. Senno RG, Marciniak CM, Olsson

AB, Esposito N, Duraski SA. Botuli-num Toxin Type A in the Treatment ofTemporomandibular Joint Dislocationin an Adult With Anoxic Brain Injury:A Case Report. (Abstract). Arch PhysMed Rehabil 2003: 84: E8.

Clinical use of botulinum toxins in oral and maxillofacial surgery 207

192. Sessle BJ. Neural mechanisms andneuroplasticity related to deep cranio-facial pain. Pain Forum 1997: 6: 173–175.

193. Shaari CM. Quantifying the spread ofbotulinum toxin through muscle fascia.Laryngoscope 1991: 101: 960–963.

194. Shaari CM, Bei-Lian WU, Biller HF,Chuang S-K, Sanders I. Botulinumtoxin decreases the salivation from caninesubmandibular glands. Otolaryngol HeadNeck Surg 1998: 118: 452–457.

195. Shorey CW, Campbell JH. Disloca-tion of the temporomandibular joint(Review). Oral Med Oral Pathol OralRadiol Endod 2000: 89: 662–668.

196. Silberstein S, Mathew N, Saper J,Jenkins S. Botulinum toxin type A as amigraine preventive treatment. Head-ache 2000: 40: 445–450.

197. Smet-Dieleman H, Van De Heyning

PH, Tassignon MJ. Botulinum A toxininjection in patients with facial nervepalsy. Acta Otorhinolaryngol Belg1993: 47: 359–363.

198. Smith HS, Audette J, Royal MA.Botulinum toxin in pain managementof soft tissue syndromes. Clin J Pain2002: 18(suppl):S147–S154.

199. Smith LDS. The occurrence of Clostri-dium botulinum and Clostridium tetaniin the soil of the United States. HealthLab Sci 1978: 15: 74–80.

200. Sobel J, Tucker N, Sulka A. Food-borne botulism in the United States,1900–2000. Emerg Infect Dis 2004:10: 1606–1611.

201. Song PC, Schwartz J, Blitzer A. Theemerging role of botulinum toxin in thetreatment of temporomandibular disor-ders. Oral Dis 2007: 13: 253–260.

202. Spillane KS, Shelton JE, Hasty MF.Stroke-induced trismus in a pediatricpatient: Long-term resolution with botu-linum toxin A. Am J Phys Med Rehabil2003: 82: 485–488.

203. Stell R, Coleman R, Thompson P,Marsden CD. Botulinum toxin treat-ment of spasmodic torticollis. BMJ1988: 297: 616.

204. Stern RS. Clinical practice. Treatmentof photoaging. N Engl J Med 2004: 350:1526–1534.

205. Stip E, Faughnan M, Desjardin I,Labrecque R. Botulinum toxin in acase of severe tardive dyskinesia mixedwith dystonia. Br J Psychiatry 1992:161: 867–868.

206. Sugiyama H. Clostridium botulinumneurotoxin. Microbiol Rev 1980: 44:419–448.

207. Suskind DL, Tilton A. Clinical studyof botulinum-A toxin in the treatment ofsialorrhea in children with cerebralpalsy. Laryngoscope 2002: 112: 73–81.

208. Svenson P. Pain mechanisms in myo-genous temporomandibular disorders.Pain Forum 1997: 6: 158–165.

209. Talarico-Filho S, Mendonca DO,Nascimento M, Sperandeo DE,

Macedo F, Sanctis DE. A double-blind, randomized, comparative studyof two type A botulinum toxins in thetreatment of primary Axillary hyperhi-drosis. Dermatol Surg 2007: 33(1 SpecNo.):S44–S50.

210. Talebnejad MR, Sharifi M, Now-

roozzadeh MH. The role of Botulinumtoxin in management of acute traumaticthird-nerve palsy. J AAPOS 2008: 12:510–513.

211. Tan EK, Fook-Chong S, Lum SY, Lim

E. Botulinum toxin improves quality oflife in hemifacial spasm: validation of aquestionnaire (HFS-30). J Neurol Sci2004: 219(1–2):151–155.

212. Tan EK, Jankovic J. Treating severebruxism with botulinum toxin. J AmDent Assoc 2000: 131: 211–216.

213. Tan EK, Jankovic J. Botulinum toxinA in patients with oromandibular dysto-nia: long-term follow-up. Neurology1999: 53: 2102–2107.

214. Tan EK, Lo YL, Seah A, Auchus AP.Recurrent jaw dislocation after botuli-num toxin treatment for sialorrhoea inamyotrophic lateral sclerosis. J NeurolSci 2001: 190: 95–97.

215. Tang X, Wan X. Comparison of Botoxwith a Chinese type A botulinum toxin.Chin Med J (Engl) 2000: 113: 794–798.

216. Ting PT, Freiman A. The story ofClostridium botulinum: From food poi-soning to BOTOX. Clin Med 2004: 4:258–261.

217. Titner R, Jankovic J. Botulinum toxintype A in the management of oroman-dibular dystonia and bruxism. In: Brin

MF, Hallet M, Jankovic J, eds: Scien-tific and therapeutic aspects of botuli-num toxin. Philadelphia: Lippincott:Williams and Wilkins 2002: 343–356.

218. Tokuno T, Nakazawa K, Yoshida S,Matsumoto S, Shingu T, Sato S.Primary oculomotor nerve palsy due tohead injury: analysis of 10 cases. NoShinkei Geka 1995: 23: 497–501.

219. Truong DD, Hermanowicz N, Ron-

tal M. Botulinum toxin in treatment oftardive dyskinetic syndrome. J Clin Psy-chopharmacol 1990: 10: 438–439.

220. Truong DD, Jost WH. Botulinumtoxin: Clinical use (Review). Parkinson-ism and Related Disorders 2006: 12:331–355.

221. Van Zandijcke M, Marchau MM.Treatment of bruxism with botulinumtoxin injections. J Neurol NeurosurgPsychiatry 1990: 53: 530.

222. Vargas H, Galatti LT, Parnes SM. Apilot study evaluationing the treatmentof postparotidectomy sialoceles withbotulinum toxin type A. Arch Otolaryn-gol Head Neck Surg 2000: 126: 421–424.

223. Varma JK, Katsitadze G. Moiscra-fishvili. Signs and symptoms predictiveof death in patients with foodborne botu-lism—Republic of Georgia, 1980–2002.Clin Infect Dis 2004: 39: 357–362.

224. Verma A, Steele J. Botulinum toxinimproves sialorrhea and quality of livingin bulbaramyotrophic lateral sclerosis.Muscle Nerve 2006: 34: 235–237.

225. Von Lindern JJ, Niederhagen B,Berge S, Appel T. Type A botulinumtoxin in the treatment of chronic facialpain associated with masticatory hyper-activity. J Oral Maxillofac Surg 2003:61: 774–778.

226. Watanabe Y, Bakheit A, Mclellan

D. A study of the effectiveness of botu-linum toxin type A (Dysport) in themanagement of muscle spasticity. Dis-abil Rehabil Int Multidiscip J 1998: 20:62–65.

227. Widmer CG. Idiopathic masticatorymuscle pain. Pain Forum 1997: 6:170–172.

228. Winterholler MG, Erbguth FJ,Wolf S, Kat S. Botulinum toxin forthe treatment of sialorrhoea in ALS:serious side effects of a transductalapproach [comment]. J Neurol Neuro-surg Psychiatry 2001: 70: 417–418.

229. Wohlfarth K, Muller C, Sassin I,Comes G, Grafe S. Neurophysiologi-cal double-blind trial of a botulinumneurotoxin type a free of complexingproteins. Clin Neuropharmacol 2007:30: 86–94.

230. Yao C-C, Chao C-H, Hong Y-K. Novelaction of botulinum toxin on the stromaland epithelial components of the pros-tate gland. J Urol 2006: 175: 1158–1163.

231. Yasufuku-Takano J, Sakurai M,Kanazawa I, Nagaoka M. Successfultreatment of intractable tardive dyskine-sia with botulinum toxin. J Neurol Neu-rosurg Psychiatry 1995: 58: 511–512.

232. Yoshimura DM, Aminoff MJ, Tami

TA, Scott AB. Treatment of hemifacialspasm with botulinum toxin. MuscleNerve 1992: 15: 1045–1049.

233. Zhibo X, Miaobo Z. Botulinum toxintype A affects cell cycle distribution offibroblasts derived from hypertrophicscar. J Plast Reconstr Aesthet Surg2008: 61: 1128–1129.

234. Zhibo X, Miaobo Z. Potential therapeu-tical effects of botulinum toxin type A inkeloid management. Medical Hypoth-eses 2008: 71: 623.

235. Ziegler CM, Haag C, Muhling J.Treatment of recurrent temporomandib-ular joint dislocation with intramuscularbotulinum toxin injections. Clin OralInvest 2003: 7: 52–55.

236. Zwart JA, Bovim G, Sand T, Sjaas-

tad O. Tension headache: botulinumtoxin paralysis of temporal muscles.Headache 1994: 34: 458–462.

Address:O.W. MajidDepartment of Oral and Maxillofacial SurgeryCollege of DentistryUniversity of MosulMosul, IraqE-mail: omerw_majid@yahoo.co.uk