SURGICAL TECHNIQUETreatment of Periorbital RhytidsWith Botulinum Toxin Type AMaximizing Safety and ResultsJeffrey H. Spieg...
plications (eg, headaches, flu symptoms, dysgeusia, anddysphagia) regardless of injection area (which may notactually be t...
sultant flaccid paralysis of the muscle. This stands in im-portant contradistinction to the effect of the tetanusneurotoxi...
orbital botulinum toxin type A administration place thetoxin in excessively close proximity to muscle groups,which can res...
domized, placebo-controlled study of the efficacy and safety of botulinum toxintype A in the treatment of glabellar lines....
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Treatment of periorbital_rhytids_with_botox[1]

  1. 1. SURGICAL TECHNIQUETreatment of Periorbital RhytidsWith Botulinum Toxin Type AMaximizing Safety and ResultsJeffrey H. Spiegel, MDBotulinum toxin type A is widely used for treatment of facial rhytids, often in an “off-label” fashion. Important mechanisms of action and safety concerns for such treat-ments are presented along with recommendations for treatment of periorbital rhytids.Arch Facial Plast Surg. 2005;7:198-202Injection of botulinum toxin type A (Bo-tox and BotoxCosmetic; Allergan Inc, Ir-vine, Calif) for the treatment of facialrhytids has become the most commonnonsurgical cosmetic procedure.1Themedication has been in use for more than30 years, and its popularity continues togrow. Botulinum toxin type A was first ap-proved by the Food and Drug Adminis-tration (FDA) in 1989 to treat strabismusand blepharospasm and was then ap-proved in 2000 for cervical dystonia. How-ever, for facial plastic surgeons, the mostsignificant milestone was probably April15, 2002, when the FDA approved botu-linum toxin type A for the cosmetic treat-ment of glabellar frown lines. The FDA ac-knowledged that clinical studies providedto them by Allergan Inc substantiated thatthe medication can safely attenuate gla-bellar frown lines for up to 120 days.Public safety is, of course, the primaryconcern of the FDA, and they note thatmedications such as botulinum toxin typeA, which are used for the treatment of con-ditions that are not life threatening or de-bilitating, “are subject to a greater level ofscrutiny because of the benefit-to-risk ra-tio.”2While the FDA has approved botu-linum toxin type A for the treatment ofglabellar lines, and more recently for hy-perhidrosis, the FDA remains concernedabout several ways that the drug is beingused and cautions patients that it is beingadministered in health spas, gyms, hotelrooms, at patient homes, and othernonmedical sites and by improperlytrained practitioners. The FDA expressesfurther concern about “Botox parties” be-cause botulinum toxin type A is licensedfor marketing and distribution only insingle-use vials, and as approved shouldbe used within 4 hours of reconstitution.As noted by the FDA, “Treating multiplepeople with one vial violates product la-beling, which is stated on the package in-sert, the vial and the carton.”2An additional area of concern for theFDA is that physicians are using botuli-num toxin type A for treatment of rhytidsin off-label areas such as the forehead, peri-oral area, neck, and periorbital area. TheFDA warns,Consumers should be aware . . . that this “off-label” use has not been independently re-viewed by the agency, and the safety and ef-fectiveness of Botox injections into otherregions of the face and neck, alone or in com-bination with the frown-lines region, have notbeen clinically evaluated.2Although not officially recognized as anapproved use by the FDA, treatment ofareas other than the glabella has becomecommonplace in many practices. In fact,detailed instructions for treatment of fore-head rhytids, crow’s feet, nasal flare, men-tal creasing, nasolabial folds, upper liprhytids, and neck rhytids are available toanybody with access to the Internet.3As noted by the FDA, appropriate useof a medication such as botulinum toxintype A is dependent on an appropriatelylow risk-benefit ratio. If we assume anoverall consistent rate of systemic com-Author Affiliations: Departments of Otolaryngology–Head and Neck Surgery andPlastic Surgery, Boston University School of Medicine, Boston, Mass.(REPRINTED) ARCH FACIAL PLAST SURG/VOL 7, MAY/JUNE 2005 WWW.ARCHFACIAL.COM198©2005 American Medical Association. All rights reserved.
  2. 2. plications (eg, headaches, flu symptoms, dysgeusia, anddysphagia) regardless of injection area (which may notactually be the case), then for cosmetic use, the most im-portant consideration will be the incidence of poor aes-thetic outcome, most commonly due to ptosis or otherundesired malposition of facial structures. In other words,botulinum toxin type A is a reasonable treatment forrhytids if it is effective and only rarely causes an unde-sirable outcome.This guideline has led many practitioners to avoid en-tirely or to discontinue the use of botulinum toxin typeA for perioral and nasolabial fold rhytids. Of necessity,the muscles that must be weakened to provide attenua-tion of rhytids in these areas are those that when para-lyzed create the undesirable appearance of facial paraly-sis and potential functional problems with speaking ororal sphincter competence. It is possible with finesse andexperience to improve rhytids in these areas, to narrowan undesirably wide smile, or to reduce the alveolar showwith smiling, but the relatively high risk of a poor resulthasledmanyexperiencedaestheticsurgeonstoavoidtheseareas.The periorbital area is different. Crow’s feet resultlargely from hyperkinetic muscle function of the orbi-cularis oculi, and experience has shown that chemode-nervation of the lateral aspect of this muscle can greatlyattenuate the appearance of lateral orbital rhytids with-out impairing the ability to squint and protect the eyesfrom foreign bodies or bright light.RISKSAs it is for the FDA, patient safety is the primary con-cern of ethical physicians. Thus, for off-label applica-tions of pharmaceuticals and other medical technolo-gies, it is imperative that the physician be cognizant ofthe potential for adverse outcomes because widely ac-cepted treatment guidelines may not be available.Apart from the obvious risks of bruising and bleed-ing that result from the application of botulinum toxintype A with a syringe and needle, the most commonlyrecognized and feared complication has been upper lidptosis. Published reports have determined an average in-cidence of 6.5% for this complication, although some re-ported incidences have been much higher.4The cause isaccepted to be contact of the levator palpebrae musclewith the toxin, presumably through diffusion from anappropriately distant injection site. Some researchersbelieve that older patients or those with loose skin or aweak orbital septum are particularly susceptible to thiscomplication, while others believe that in some casesthe problem may result from the weakening of a fronta-lis muscle that was compensating for a preexisting de-gree of ptosis.In addition to upper eyelid ptosis, lower eyelid ectro-pion can result. As with surgical treatments such asblepharoplasty, a lower eyelid “snap-test” can providevaluable guidance regarding the risk for development ofthis complication. Similarly, in patients with a weak or-bital septum, flaccid paralysis of the orbicularis oculiover the lower lid can lead to pseudoherniation of infra-orbital fat.5Nonobstructive vision problems can also develop. Theocular muscles insert relatively close to the anterior as-pect of the orbit; therefore, strabismus due to lateral rec-tus weakness can occur following treatment of crow’s feet.Another potential complication is disruption of tear for-mation. Whether from direct injection, diffusion into arelevant orbital muscle, or direct involvement of the lac-rimal gland, disruption of tear formation can occur alongwith an abnormal findings on a Schirmer test.6Cosmetic procedures are of course intended to im-prove the patient’s appearance, and so any result that pro-duces a less desirable appearance should rightfully be con-sidered a significant adverse outcome. Malposition of theeyebrow has long been recognized as a potential com-plication of glabellar botulinum toxin type A treatment,typically resulting in a “confused” appearance due to ex-cessive medial elevation of the brow. Similarly, exces-sive elevation of the lateral brow can occur following treat-ment of lateral periorbital rhytids. This can result in an“angry” or “sinister” appearance as the brows slope in-feriorly toward the nose. Lateral perioral rhytids are causedby the sphincteric action of the orbicularis oculi as itsqueezes the eyelids together. That aspect of the musclesuperior to a line through the medial and lateral canthilogically has a downward force, which serves in part tobalance the upward pull of the frontalis thus maintain-ing brow position. Release of this inferior force leads tounopposed upward displacement of the lateral skin anda superior displacement of the lateral brow. When cre-ated as part of an intentional treatment, this upward dis-placement can provide a nonsurgical temporal brow-liftor what some refer to as a “chemical browlift.”7,8Complications from treatment with botulinum toxintype A can manifest at fairly distant sites when the drugis used in large doses. For example, treatment of cervi-cal dystonia has dysphagia as a recognized complica-tion.9However, in the appropriately low doses used forparalysis of facial muscles, relatively distant complica-tions can result from the close proximity of facial musclesto one another. In the treatment of periorbital rhytids,there is a risk for lip ptosis due to inadvertent weaken-ing of the zygomaticus major and levator labii superi-oris muscle groups.10It has been suggested that this com-plication is most likely to occur in patients who havepreviously had blepharoplasty or other facial plastic sur-gery, although these same authors would appear to re-fute the idea of abnormal anatomy as the primary risk.Rather, the risk is present in all patients owing to the in-sertion of the zygomaticus major near the lateral aspectof the orbicularis oculi.11,12ANATOMY AND PHARMACOLOGYMaximizing results and minimizing complications areboth achieved by a thorough understanding of how botu-linum toxin type A works and a detailed knowledge ofthe muscular anatomy in the areas being treated. Botu-linum toxin type A is 1 of 7 known serotypes of botuli-num toxin produced by the bacterium Clostridium botu-linum, and 1 of 2 serotypes clinically available (A and B).This potent neurotoxin blocks the release of acetylcho-line at the presynaptic neuromuscular junction with re-(REPRINTED) ARCH FACIAL PLAST SURG/VOL 7, MAY/JUNE 2005 WWW.ARCHFACIAL.COM199©2005 American Medical Association. All rights reserved.
  3. 3. sultant flaccid paralysis of the muscle. This stands in im-portant contradistinction to the effect of the tetanusneurotoxin from Clostridium tetani, which prevents therelease of neurotransmitters in the spinal cord, thus re-sulting in spastic paralysis. Botulinum toxin (1) stays lo-cal in the presynaptic neuromuscular junction and (2)provides a flaccid paralysis, both of which permit its usefor the safe attenuation of rhytids.Clearly, effective use of botulinum toxin type A re-quires careful placement of the medication. Diffusion ofthe medication can occur and depends on tissue char-acteristics, placement, and dilution. There is little evi-dence to suggest that the doses used for facial muscula-ture allow for distant diffusion, although it is known thatthis can occur in the higher doses used for other appli-cations such as the treatment of muscle spasms in largemuscle groups.9,13Exactly how far the medication in fa-cial application diffuses is not clear: some authors sug-gest 1 cm,14whereas others advise that it can travel 3 cmor more.15These larger distances for diffusion seem un-likely: radio-labeled botulinum toxin type A studies haveshown minimal movement. In any case, the total num-ber of units injected in any 1 area is relatively low, and ifthe medication were to diffuse over a 3-cm radius, its clini-cal effect, if any, would probably be small.13Additionally, authors do not agree on where to injectthe material for maximal efficacy. Some have suggestedthat injection into the belly of the muscle is the best ap-proach to minimize diffusion and maximize effect,16whereas others propose that a subcutaneous injection isboth safe and effective.17For treatment of periorbital rhytids, the primary muscleof concern is the orbicularis oculi. This sphincteric musclesits circumferentially around the eye and has the impor-tant function of providing deliberate closure of the eye-lids to protect the globe. The muscle has been consid-ered to have 3 distinct subparts: the orbital, palpebral,and lacrimal portions. The lacrimal portion of the muscletravels deep to the lacrimal sac and inserts on the upperand lower eyelids at the tarsal plates. Contraction of thispart of the muscle draws the eyelids against the globeand compresses the lacrimal sac, thus assisting tearflow. The palpebral portion passes into the eyelid su-perficial to the septum from the bifurcation of the me-dial palpebral ligament to the lateral palpebral raphe.The palpebral portion is considered to have a preseptaland a pretarsal part, depending on which portion of theeyelid the muscle is superficial to. Contraction of thispart of the muscle provides less forceful closure of theeyelid, as with blinking.The orbital portion of the muscle is that portion of themuscle over the bony aspect of the orbit and beyond. Thismuscle is near the surrounding musculature and can beseen to blend into the frontalis, corrugator, and zygo-maticus major muscles at its margins. In addition to pro-viding forceful eye closure and eyebrow depression, thisaspect of the muscle creates the lateral orbital rhytidsby its pull on the overlying skin. Typically it is this areathat is treated with botulinum toxin type A, although,the preseptal aspect of the inferior palpebral portion ofthe orbicularis oculi can be treated in some situations(Figure 1).It is evident that the muscle groups are in continuitywith one another in these areas, and knowledge of thespecific muscle relationships may help reduce the inci-dence of complications such as lip droop due to inad-vertent treatment of the zygomaticus major or levator la-bii superioris muscle groups. An analysis of the relativemuscle positions observed during cadaver dissections pro-vides some guidance by describing specific muscle rela-tionships in 48 facial sides.10The relationship between theorbicularis oculi and lip elevators was determined rela-tive to clinically useful landmarks, including the midpu-pillary line, the lateral canthus, and then at 1 and 2 cmdirectly lateral to the lateral canthus. It was observed thatat 2 cm lateral to the lateral canthus, the orbicularis oculiwas superficial to the zygomaticus major but was only anaverageof0.5cmsuperficialtothelipelevator,withwomenhaving a deeper zygomaticus major than men. At 1 cm lat-eraltothelateralcanthus,awidelyusedlandmarkforbotu-linum toxin type A injections in this area, the zygomati-cus major muscle interdigitated with the orbicularisoculi an average of 1.4 cm inferior to the Frankfort hori-zontal line. However, in 29% of cases, the zygomaticuswas less than 1 cm from the Frankfort line in this area.In the midpupillary dissection, the orbicularis oculi wassignificantly less than 1 cm superficial to the levator la-bii superioris.10RECOMMENDATIONSIt would appear based on anatomic studies that many ofthe conventionally touted anatomic landmarks for peri-Figure 1. Muscular anatomy of the periorbita.(REPRINTED) ARCH FACIAL PLAST SURG/VOL 7, MAY/JUNE 2005 WWW.ARCHFACIAL.COM200©2005 American Medical Association. All rights reserved.
  4. 4. orbital botulinum toxin type A administration place thetoxin in excessively close proximity to muscle groups,which can result in undesired aesthetic outcomes. Forexample, the malar eminence is frequently considered auseful landmark for periorbital botulinum toxin type Atreatments, and the practitioner is cautioned to not gobelow the malar eminence. However, in the anatomicdissections described, the lip elevators were commonlyless than 1 cm from the orbicularis oculi at the Frank-fort line, which is at the superior edge of the malar emi-nence. If one accepts that botulinum toxin type A candiffuse 1 or even 3 cm, the malar eminence is clearly toofar from the periorbital area to serve as an appropriateguideline.Similarly, 1 cm from the bony orbital ridge is oftenconsidered an appropriate guideline for safety.18Thisguideline strives to avoid the complications of strabis-mus or blepharoptosis that can occur as described by stay-ing beyond the 1-cm accepted diffusion for botulinumtoxin. Clinical experience would suggest that this is a prac-tical landmark, since the incidence of these complica-tions is low. However, the zygomaticus major muscle canbe less than 1 cm from the orbicularis in areas com-monly treated for crow’s feet, and the levator labii supe-rioris is found less than 1 cm from the orbicularis in themidpupillary line, as might be used to treat lower lidrhytids. Many articles show pictures with recom-mended injection sites too close to adjacent muscle groupsor in areas where no facial muscle is present.7,14Carefulstudy of the relevant facial anatomy and relative musclepositions will allow for a more informed choice of treat-ment sites.In treatment of glabellar rhytids, particularly near themedial clubhead of the eyebrow, injection into the bodyof the muscle may be the safest and most effective treat-ment approach.19,20However, in the treatment of peri-orbital rhytids, a superficial injection is more appropri-ate. Injection just deep to the dermis provides effectivetreatment of those aspects of the orbital portion of theorbicularis oculi that pull on the temporal and lateral peri-orbital skin while maximizing distance from the sur-rounding musculature.Like many practitioners, I routinely dilute Botox with4 mL of preservative-free isotonic sodium chloride (nor-mal saline) solution into each 100-U vial for a final con-centration of 2.5 U/0.1 mL. However, unlike many whoroutinely inject 15 U or more per side, I have found that5 to 7.5 U divided into 2 or 3 treatment sites, all morethan 1.5 cm lateral to the lateral canthus, superficial, andsuperior to the Frankfort line, provides effective resolu-tion of rhytids with no perioral or periorbital complica-tions attributable to the toxin yet observed (Figure 2).Some practitioners suggest reconstituting the botuli-num toxin with either a local anesthetic with epineph-rine, or with epinephrine added to the saline dilu-tion.20,21These authors propose that this further reducesthe chance of diffusion from the injection site and, if alocal anesthetic is used, may provide some immediate in-dication of the expected results.Other commonly touted guidelines include keepingthe patient elevated for 4 hours after treatment, recom-mending repeated muscle contraction in the treated area,and advising the patient not to touch the face for severalhours after treatment. While these make some intuitivesense to minimize diffusion and target a specified muscle,it is my belief that careful placement and avoiding over-dilution are far more important. Thus, I do not advisemy patients of these additional restrictions and have notedno ill effects as a result.CONCLUSIONSAlthough technically an off-label application, treatmentof lateral periorbital rhytids with botulinum toxin typeA can be safely performed if strict attention is given tothe pharmacology of reconstituted botulinum toxin andthe anatomy of periorbital muscles. Physicians who de-sire to treat periorbital rhytids are advised to stay supe-rior to the Frankfort line, avoid overdilution, and limitthe overall number of units of botulinum toxin injectedto this area. A superficial injection just subcutaneous pro-vides effective treatment while minimizing exposure ofthe nearby lip elevators.Correspondence: Jeffrey H. Spiegel, MD, Departmentsof Otolaryngology–Head and Neck Surgery and PlasticSurgery, Boston University School of Medicine, 88 E New-ton St, Suite D-616, Boston, MA 02446 ( American Academy of Facial Plastic and Reconstructive Surgery. 2002 Mem-bership survey: trends in facial plastic surgery [news release]. Alexandria, Va:American Academy of Facial Plastic and Reconstructive Surgery; April 2003.2. US Food and Drug Administration. FDA Consumer Magazine. July-August 2002..3. Hauser RA, Wahba M. Botulinum toxin type A injections. Available at: Accessed November 26, 2004.4. Carruthers JA, Lowe NJ, Menter MA, et al. A multicenter, double-blinded, ran-Figure 2. Important landmarks for treatment of lateral periorbital rhytids.The horizontal line represents the Frankfort line; the red X is the mostprominent part of the malar eminence (note its position very inferior to theFrankfort line). The vertical line is drawn approximately 1 cm from the lateralcanthus at the bony margin of the orbit. The green oval designates the areafor safe and effective injection of botulinum toxin type A.(REPRINTED) ARCH FACIAL PLAST SURG/VOL 7, MAY/JUNE 2005 WWW.ARCHFACIAL.COM201©2005 American Medical Association. All rights reserved.
  5. 5. domized, placebo-controlled study of the efficacy and safety of botulinum toxintype A in the treatment of glabellar lines. J Am Acad Dermatol. 2002;46:840-849.5. Paloma V, Samper A. A complication with aesthetic use of botulinum toxin typeA: herniation of the orbital fat. Plast Reconstr Surg. 2001;107:1315.6. Matarasso SL. Decreased tear expression with an abnormal Schirmer’s test fol-lowing botulinum toxin type A for the treatment of lateral canthal rhytides. Der-matol Surg. 2002;28:149-152.7. Ahn MS, Catten M, Maas CS. Temporal brow lift using botulinum toxin A. PlastReconstr Surg. 2000;105:1129-1135.8. Frankel AS, Kamer FM. Chemical browlift. Arch Otolaryngol Head Neck Surg. 1998;124:321-323.9. Zesiewicz TA, Stamey W, Sullivan KL, Hauser RA. Botulinum toxin A for the treat-ment of cervical dystonia. Expert Opin Pharmacother. 2004;5:2017-2024.10. Spiegel JH, Derosa J. The atomic relationship between the obicularis oculi muscleand the levator labii superioris and zygomaticus muscle complexes. Plast Re-constr Surg. In press.11. Matarasso SL, Matarasso A. Treatment guidelines for botulinum toxin type A forthe periocular region and a report on partial upper lip ptosis following injectionsto the lateral canthal rhytids. Plast Reconstr Surg. 2001;108:208-214.12. Fagien S. Discussion: treatment guidelines for botulinum toxin type A for the peri-ocular region and a report on partial upper lip ptsosis following injections to thelateral canthal rhytids by Seth L. Matarasso, M.D., and Alan Matarasso, M.D. PlastReconstr Surg. 2001;108:215-217.13. Tang-Liu DD, Aoki KR, Dolly JO, et al. Intramuscular injection of 125I-botulinumneurotoxin-complexversus125I-botulinum-freeneurotoxin:timecourseof tissue distribution. Toxicon. 2003;42:461-469.14. Niamtu J III. Botulinum toxin A: a review of 1,085 oral and maxillofacial patienttreatments. J Oral Maxillofac Surg. 2003;61:317-324.15. Borodic GE, Ferrante R, Pearce LB, et al. Pharmacology and histology of the thera-peutic application of botulinum toxin. In: Janckovic J, Hallett M, eds. TherapyWith Botulinum Toxin. New York, NY: Marcel-Dekker; 1994:119-157.16. Carruthers J, Fagien S, Matarasso SL; Botulinum Toxin Type A Consensus Group.Consensus recommendations on the use of botulinum toxin type A in facialaesthetics. Plast Reconstr Surg. 2004;114(6 suppl):1S-22S.17. Shaari CM, George E, Wu BL, Biller HF, Sanders I. Quantifying the spread of botu-linum toxin through muscle fascia. Laryngoscope. 1991;101:960-964.18. Carruthers JD, Carruthers A. Botulinum toxin in clinical ophthalmology. Can JOphthalmol. 1996;31:389-400.19. Macdonald MR, Spiegel JH, Raven RB, Kabaker SS, Maas CS. An anatomical ap-proach to glabellar rhytids. Arch Otolaryngol Head Neck Surg. 1998;124:1315-1320.20. Gassner HG, Sherris DA. Addition of an anesthetic agent to enhance the predict-ability of the effects of botulinum toxin type A injections: a randomized con-trolled study. Mayo Clin Proc. 2000;75:701-704.21. Redaelli A, Forte R. Botulinum toxin dilution: our technique. J Cosmet Laser Ther.2003;5:218-219.(REPRINTED) ARCH FACIAL PLAST SURG/VOL 7, MAY/JUNE 2005 WWW.ARCHFACIAL.COM202©2005 American Medical Association. All rights reserved.