Clinics in Dermatology (2008) 26, 182–191

Advanced techniques against wrinkles in the upper Giovanni Salti, MDa, Ilaria Ghersetich, MDb,⁎ a“Florence” Surgical Center, Florence, Italy bInstitute of Dermosciences, University of Florence, Florence, Italy

Abstract The use of botulinum toxin type A for facial rejuvenation is one of the most common procedure in esthetic medicine. Overall clinical and study experience with botulinum toxin type A for facial enhancement has confirmed that it is effective and safe even in the long term. The different injection techniques, the starting doses, the sex, the dilution, and the storing of the product, nevertheless, may influence the final result of the treatment. In this article we propose some recommendations including general principles as well as information about its specific use. Perhaps one of the most important perspectives is that, based on a well-established knowledge of the technique, individualized esthetic planning is the key to success. This depends on a precise understanding of the underlying anatomy and physiology of the individual muscles and their interactions, as well as on individual patient's characteristics, including goals and expectations. © 2008 Elsevier Inc. All rights reserved.

Botulinum toxin basic science toxins,6,7 leading to a widespread acceptance of the technique after 1995. A large body of scientific articles and History of the cosmetic use of botulinum toxin textbooks are nowadays available for the cosmetic indication of botulinum toxins. In 1990, Jean and Alastair Carruthers1 published their first report on the cosmetic use of type A botulinum toxin. Basic pharmacology They discovered this new indication of the drug by serendipity while treating patients for blepharospasm. Botulinum neurotoxin is the exotoxin produced by Subsequently, they started expanding their research in the Clostridium botulinum. Seven distinct serotypes of the field and published further articles on the topic.2,3 Also, neurotoxin, designated type A to G, have been identified. Blitzer and his group4 published extensively on the cosmetic Type A is the most commonly toxin used for cosmetic use of the drug at the beginning of the 1990s. Later works purposes, although there are some reports about the use of widened the knowledge of the different commercial type B toxin in aesthetics. preparations of the drug5 and of the different types of The toxin is a protein molecule consisting of a 50-kd light chain and a 100-kd heavy chain, linked by a disulfide bonding.8 Botulinum toxin acts at the level of the neuromuscular ⁎ Corresponding author. Clinica Dermatologica, Villa Basilewski, via plate and of other cholinergic synapses by a 3-step 9 Lorenzo il Magnifico, 104, 50100 Firenze, Italy. mechanism : after injection, the heavy chain rapidly binds E-mail address: [email protected] (I. Ghersetich). to its target receptor on the cholinergic presynaptic

0738-081X/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.clindermatol.2007.09.008 Advanced botulinum toxin techniques against wrinkles in the upper face 183 membranes, being internalized by endocytosis. Then, the In general, high concentrations (low dilutions) mean low disulfide bond is cleaved, and the light chain is liberated. The volume injections, with a more precise placement of the light chain acts as an endopeptidase with proteolytic activity, toxin and scarce diffusion, whereas low concentrations (high being able to cleave different plasma membrane proteins dilutions) may be helpful when a certain grade of diffusion is responsible for the exocytosis of acetylcholine. Serotype A needed (eg, in the frontalis muscle). Using low concentra- leads to the cleavage of SNAP-25 (25-kd synaptosome tions, and hence small volumes, also reduces pain at the associated protein), whereas serotype B cleaves VAMP injection site. Because the range of transient denervation due (Vesicle Associated Membrane Protein). When these pro- to the spreading of the toxin is proportional to its dilution, teins are lacking, no acetylcholine can be released and thus lower dilutions reduce the risk of unwanted effects. the synapse is blocked. The final effect is the clinical Most authors use concentrations of 40 or 50 U/mL, but a denervation of the muscle or of the innervated structure. skilled use implies a fine tuning of dilutions and concentra- Drug's effect starts within 24 to 72 hours after injection, and tions to perfectly treat each single muscle, in accordance with its action is completed in about 2 weeks. The area of the desired degree of efficacy and toxin diffusion. Using functional denervation depends on drug's dosage and varying concentrations of the toxin in different patients and/ volume.10 To get a uniform and even effect, multiple or in the same patient is the way to achieve the best results.19 injections over the target muscle are recommended. The Once reconstituted, the drug must be stored at a effects of botulinum toxin on facial muscles persist for temperature of 2°C to 8°C. After reconstitution, the drug approximately 12 to 16 weeks. Because the blockade is not should be used within 4 hours, as recommended by the reversible, the remission of the effect occurs after regenera- manufacturer. This recommendation is for sterility purposes tion (nerve sprouting) of motor axons and final reactivation and not because of a loss of efficacy. The general practice of the blocked end plate.11,12 indeed suggests that the drug still maintains its efficacy even over such a limited period. A study showed that no Dosage and toxicity, dilution and concentration, statistical differences were observed about toxin efficacy storage and duration of the effect in vials reconstituted at the time of injection, or at 2, 4, and 6 weeks before use.20 Any Type A is the most commonly available serotype of remaining solution must be inactivated by a 0.5% sodium botulinum toxin. Several preparations are commercially hypochlorite solution. available, although only one is presently approved for cosmetic use (Botox Cosmetic/Vistabel/Vistabex; Allergan, Injection technique Irvine, CA), which we will refer to in this article. When reading dosage data in the literature, it is mandatory There is no standard injection technique. Each patient's to note which commercial preparation the dosing is referring individual characteristics must be taken into account because to. The dosage is based on the biologic potency of the toxin individualization of the treatment is the key to success. and is expressed in units (1 U is the median lethal dose of the Independently of the technique chosen, any given region to toxin when injected intraperitoneally in the rat). The lethal be treated with botulinum toxin should be perfectly studied oral dose in humans is estimated at 3000 to 30,000 U. When in its anatomical, static, and dynamic aspects. maintaining an interval between doses of at least 10 weeks, a Some rules apply when using botulinum toxin for cumulative effect after repeated injections is not expected.13 cosmetic purposes. As with any drug, it is recommended to A 100-U vial of the preparation contains 5 ng of toxin as use the lowest efficacious dose tailored to every single lyophilized powder. patient to provide an effect lasting at least 12 weeks. Because the preparation is in powder form, it needs to be The right selection of drug concentration with respect to reconstituted before the injection. The recommended diluent the area to be treated is mandatory to foresee efficacy and is 0.9% saline without preservatives.13,14 It is usually diffusion. The concentration also determines the volume of recommended to gently inject the diluent into the vial, the injection. avoiding the formation of foam in the complex, which could Depending on the volume of reconstituted drug to inject, result in toxin denaturation.15 More recent articles, however, different types of syringes can be used. have found no difference in efficacy between botulinum The most commonly used syringes are 1-mL insulin toxin not shaken and botulinum toxin shaken and foamed syringes with removable 30-gauge, 13-mm needles. These during reconstitution.16 Some authors proposed to add syringes are marked with a 100-unit scale, allowing for a adrenaline to the solution to reduce the diffusion of the precise assessment of the number of units injected. drug once in the tissues.17 The expert will often use the 0.3-mL Ultra-Fine II syringe Toxin concentration may vary depending on the medical equipped with a 30-gauge, 8-mm incorporated needle. This and aesthetic goal. In the medical literature, concentrations of syringe allows for the best precision even with low volumes 100 U/mL (10 U/0.1 mL) to 10 U/mL (1 U/0.1 mL) are and very concentrated toxin; it is also provided with a fine, encountered, but there is a general consensus that 40 U/mL less painful needle and is discarded after only few injections, (4 U/0.1 mL) is the most versatile and useful concentration.18 due to the small volume of solution loaded.21 184 G. Salti, I. Ghersetich

Fig. 1 Balance between elevator and depressor muscles. Fig. 3 Reshaping of the eyebrows. Deep treatment of the glabellar complex: elevation of the medial eyebrow, before. Apart from personal preferences, consensus exists about some general technical issues: Generally, the injection is not painful; however, some – Always examine the patient closely, when at rest authors treat the target area with ice before treatment to and during mimics, taking pictures of him or her in prevent pain and bruising. both situations. Botulinum toxin is usually injected intramuscularly. – Always mark out with a pencil every injection point Subcutaneous or intradermal injections are also effective, before treatment. although needing more injection sites to obtain maximum – Always use nonalcoholic antiseptics because alcohol absorption. Intramuscular placement stings less and produces could be responsible for toxin inactivation. less local erythema but carries a higher risk of bruising. – Always treat the patient in a sitting or semi-reclined Some of the different injection techniques will be position. This allows for a better visualization of the reviewed hereafter. anatomy of the muscles to treat. – Always inject into relaxed muscles. Contraindications, systemic effects, – Always think in units and not volumes, to reduce and immunogenicity confusion and possible over- or underdosing. – Always note down treatment's data (date of treatment, Botulinum toxin should not be used in patients with dilution of the drug, batch number of the drug, number neuromuscular transmission disorders (myasthenia gravis, of total units, units per point, pattern of injection). Eaton-Lambert syndrome). Concomitant use of aminoglyco- – Always ask the patient not to manipulate the treated area side antibiotics and spectinomycin should be avoided because for some hours after the injection.

Fig. 4 Reshaping of the eyebrows. Deep treatment of the Fig. 2 Balance between elevator and depressor muscles. glabellar complex: elevation of the medial eyebrow, after. Advanced botulinum toxin techniques against wrinkles in the upper face 185

Fig. 7 Arched brow. Fig. 5 Reshaping of the eyebrows. Superficial treatment of the glabellar complex: rebalancing of the eyebrow, before. formation after injection for cosmetic purposes; it is these drugs may potentiate the effect of the toxin. Patients recommended to use the lowest effective dose of the drug, with dysphagia should not be treated either. Because of a to avoid treatment repetition before 12 weeks have elapsed, 18,26 limited experience in the field, botulinum toxin therapy should and to avoid short-term booster injection. be avoided during pregnancy and lactation, even if there are some anecdotal reports about its nonharmfulness. It should Patient evaluation also not be injected in case of infection in the proposed site. Relative contraindications are coagulation disorders and When approaching a cosmetic patient, the physician anticoagulant therapy. should be aware that a good result means a pleased patient, Electromyographic studies revealed minor variations in and that a patient is pleased when the physician meets her or nontarget muscles, suggesting that low amounts of the drug his expectations. The physician should not simply under- enter the systemic circulation, without exerting a clinically stand patient's needs and suggest the best option to address relevant effect.22,23 the problem, but he should also identify unrealistic Neurologic patients can develop neutralizing antibo- expectations. Each target area should be discussed in detail dies.24 It seems that these antibodies are mainly produced with the patient to share with her or him a common idea for in response to the injection of the toxin at high dosage and/or an optimal correction. at frequent intervals.25 The latest batches of drug contain a In particular, the degree of paralysis should be carefully purer toxin and are less prone to induce antibody's clarified with the patient for the determination of treatment production.18 To date, there are no reports of antibody dosage. The glabellar area evokes mostly negative feelings (anger, worry, thoughtfulness) and can be completely

Fig. 6 Reshaping of the eyebrows. Superficial treatment of the glabellar complex: rebalancing of the eyebrow, after. Fig. 8 Arched brow, before. 186 G. Salti, I. Ghersetich

Fig. 9 Arched brow, after. Fig. 11 Flared brow, before. paralyzed, whereas other areas express positive feelings from classic wrinkle patients because they are usually and need to keep their ability to move. So, in these areas, younger and do not ask for a rejuvenation treatment but for it is important to obtain only a partial effect, eliminating a pure cosmetic effect. wrinkles at rest while leaving a residual mimic capacity. The ideal patient for this type of treatment is young, with Probably the most important cosmetic preoperative good skin elasticity, and with no static wrinkles because the evaluation is the analysis of preexisting asymmetries. Almost range of brow elevation that can be achieved with botulinum nobody is perfectly symmetrical, and all asymmetries, even toxin is limited to 1 to 3 mm.18,27,28 A pretreatment minor, should be pointed out to the patient because after the evaluation should take into account some important features, treatment, she or he will look at her or his face almost such as the shape of the eyebrow, the presence of preexisting constantly, finding out any asymmetry and considering the asymmetries, the presence of a supraciliar wrinkle, and the treatment responsible for it. desired modifications. The original shape of the eyebrow must be respected, thus limiting the chances to modify its aspect. A supraciliar wrinkle is another important limiting Advanced concepts in botulinum toxin factor because the elevation of the brow tail could worsen it. In this case, a complete elevation of the eyebrows is better treatment of the upper face than a rebalancing of the shape. The balance between elevator and depressor muscles Browlift and brow reshaping should be studied before performing any treatment because only the frontalis muscle elevates the eyebrows, whereas the Besides classic indications, browlift is the first most corrugator supercilii, procerus, and orbicularis ones move requested treatment. Browlift patients are often different

Fig. 10 Flared brow. Fig. 12 Flared brow, after. Advanced botulinum toxin techniques against wrinkles in the upper face 187

Fig. 13 Horizontal brow. Fig. 15 Horizontal brow, after. downward and medially the eyebrows (Figs. 1 and 2). Corrugator supercilii and depressor supercilii muscles are concentrated in the medial and central area of the brow. attached to the periosteum in the glabellar region under the Leaving the lateral brow untreated helps to create the frontalis muscle, deep in the medial aspect. The muscles then downward slope at the lateral edge of the brow, accentuating continue laterally and superficially to insert in the skin above the arch. A single toxin injection in the orbicularis reduces its the eyebrows. The corrugator is usually treated in 2 points: action in the central brow area and leaves the frontalis medially at its attachment, and laterally at its skin unopposed. To evaluate this injection site, it is useful to place insertion.29,30 The medial corrugator injection can be a finger under the brow in the midpupillary line, asking the performed deeply or superficially; a deep plane injection patient to squeeze the eyes as hard as she or he can. The acts only on the corrugator muscle, whereas a superficial outer edge of the orbicularis will pull down the finger, injection acts on the frontalis too. The consequence is that a indicating the point where the brow depressor has to be deep injection leaves the frontalis unaffected and able to weaken (Figs. 7-9). elevate, whereas a superficial injection targets also the Nowadays, a flared brow is widespread considered very frontalis, causing a relaxation of the head of the eyebrow. fashionable. To obtain this type of shape, we inject the lateral Thus, to achieve a rebalancing effect, the exotoxin should be section of the orbicularis oculi starting from the midpupillary applied also superficially in the medial aspect of the line and we also treat the crow's-feet area to release the corrugator muscle; whereas to obtain a medial elevation of pulling force of the orbicularis at the lateral brow edge. We the glabellar complex, it should be applied only deeply do not treat the procerus because our objectives are a medial (Figs. 3-6). Sometimes it is useful to obtain only a lowering and a lateral lifting. rebalancing of the shape by using the bascule movement of For a stronger flare, as preferred by fashion models, the brow when the medial part is depressed and the lateral we may also consider to treat the frontalis in the central part is elevated by the upward traction of the frontalis. The arched brow is the classic feminine eyebrow shape. To create or enhance this shape, the injections should be

Fig. 14 Horizontal brow, before. Fig. 16 Patterns of periocular wrinkles, diffuse. 188 G. Salti, I. Ghersetich

Fig. 17 Patterns of periocular wrinkles, mostly superior. Fig. 19 Patterns of periocular wrinkles, diffuse fine. forehead area to further drop the medial brow and but later they become fixed and present even at rest. These accentuate the lateral arch. It is also possible to give more lines are caused by the contraction of the lateral aspect of or less elevation to the brow tail depending on the dosage the orbital portion of orbicularis oculi muscle. This is a very of the drug. For a softer flare with a downward lateral superficial muscle constituted by fibers originating infer- edge, we suggest not to treat the crow's-feet area iorly on the anterior aspect of the infraorbital rim and (Figs. 10-12). superiorly on the supraorbital rim, and inserting in the The horizontal brow is the natural shape of the brows in lateral canthal tendon.31 Because there are different patterns most of the women who have not cosmetically correct them. of periocular wrinkles (diffuse, mostly superior, mostly Injecting the brow symmetrically at the medial and lateral inferior, and diffuse fine) (Figs. 16-19), different techniques edges and concomitantly releasing the procerus muscle will of injection can be used in this area. The same patient produce a “more open-eyed look.” The objective is an can have one or multiple patterns of wrinkles so the unopposed elevation at the medial and lateral ends of the treatment should be individualized for each single perio- brow (Figs. 13-15). cular area. Dynamic wrinkles respond well while static wrinkles are not completely amenable to botulinum toxin Periocular techniques injections, although repeated treatments greatly reduce static wrinkles too. The lateral canthal lines begin to appear around 20 to 25 The classic 3-spot technique can be reserved to a diffuse years of age. These lines are firstly only dynamic wrinkles, pattern of lines.

Fig. 18 Patterns of periocular wrinkles, mostly inferior. Fig. 20 Wheal-and-mash technique. Advanced botulinum toxin techniques against wrinkles in the upper face 189

Fig. 21 Multspot technique. Fig. 23 Single injection technique.

In case of localized lines (superior or inferior), the wheal- requires the maintenance of a constant cutaneous plane and-mash technique may be more indicated (Fig. 20). This is as well as a constant pressure on the plunger (Figs. 23 a very simple way to administer the drug. One or two wheals and 24).32 of drug are gently massaged upward, downward, and laterally, resulting in a diffuse spreading of the drug without the risk of injuring the numerous vessels in this area using Avoiding mephisto repeated injections. In case of diffuse fine lines, a multispot technique (up to The frontalis muscle is the only elevator muscle in the 8 injections) may be indicated (Fig. 21). For this type of upper face. Its complete treatment causes a flaccid paralysis injections, a strictly intradermic puncture is mandatory to with brow ptosis: it is therefore necessary to avoid injecting obtain a limited shift of the pharmacologic solution and to some areas of this muscle to leave some mobility, useful to avoid bruising. get a lifting effect. Sometimes, when too much lateral In case of mostly inferior lines, a single injection may also activity is left, the tail of the eyebrows is excessively pulled be used (Fig. 22). This technique of “kebabing” the upward, resulting in an unnatural look that has been well orbicularis muscle with a single tangential puncture causes described as “mephisto.” less discomfort to the patient, but it should be carried out by a The lateral extension of the frontalis muscle ends at the skilled and experienced operator because the use of a longer level of the temporal fusion line33 (Fig. 25) so that it is not needle is suggested and the continuous retrograde injection necessary to inject laterally to it.

Fig. 22 Single injection technique. Fig. 24 Single injection technique. 190 G. Salti, I. Ghersetich

References

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