Clinical Applications

Glabellar Frown Lines

Contraction of the muscles in the glabellar complex (corrugator supercilii, procerus, and depressor supercilii) causes vertical frown lines. Treatment of this area is the most common site for BTX-A injection and the only FDA-approved cosmetic indication for BTX-A.

Twenty to 35 U of BTX-A are placed using a five-point injection method (14-17). The authors typically start with the lower amount because our experience demonstrates that this effectively reduces muscle activity. Higher doses are used for male patients because of a larger muscle mass, with some studies demonstrating that 40 U may be the optimal dose for men (18). However, doses exceeding 50 U show no difference in efficacy (14). The patient should be seated upright and instructed to frown their brows; this helps identify the corruga-tors and ensure accurate placement (Fig. 1). Forty percent of the toxin is injected to each cor-rugator with two injections, one at the medial portion of the brow and the second at the mid-pupillary line (Fig. 2). To avoid adverse events resulting from diffusion, all injections should be placed at least 1 cm superior to the orbital rim. The remaining 20% of the toxin is placed midline in the procerus (Fig. 3). Maximum response occurs around 4 weeks after the injections and last approximately 12 to 16 weeks (Fig. 4; refs. 16-18).

Complications can often be avoided with proper technique, placement, and dosage. Adverse events in this area include bruising, diplopia, lower lateral lid drooping, or upper eyelid ptosis (19). If the toxin diffuses through the orbital septum into orbit, it can cause paralysis of the extraocular muscles resulting in diplopia. Diffusion can also affect the muscles responsible for elevating the upper eyelid, causing ptosis. Upper eyelid ptosis is most commonly seen within 2 to 14 days following treatment of the glabellar complex and can last up to 12 weeks (20). Early studies reported a ptosis rate of 3 to 6% (16,21); however, with improved injection techniques, the current rate is closer to 1% or less (15,22). The use of a-adrenergic agonist eyedrops, apraclonidine hyprochloride 0.5% (Iopidine®, Alcon Labs,

Fig. 1. Glabellar complex before treatment. The corrugator muscles become easily visible with furrowing of the brow.
Fig. 2. Injection of botulinum toxin type A into the corrugator muscle. Note how the physician isolates the muscle by grasping it between the thumb and forefinger.
Fig. 3. Injection of botulinum toxin type A into the midline of the procerus muscle.
Fig. 4. Four weeks after botulinum toxin type A treatment of the glabellar complex.

Forth Worth, TX), or phenylephrine hydrochloride 2.5% (Neo-synephrine®, Sanofi, Winthrop Pharmaceuticals, New York, NY) can stimulate Muller's muscles in the lid, providing some relief of eyelid ptosis until the effects of BTX-A disappear (19).

Horizontal Forehead Lines

The frontalis muscle elevates the brow and its contraction causes horizontal forehead rhytids (Fig. 5). Treatment of this brow elevator results in a reduction of muscle activity and decreased forehead lines. Care must be taken when treating this area and injections are generally limited to the upper half to two-thirds of the frontalis. This placement avoids total paralysis of the frontalis, which can cause brow ptosis and heaviness. Physicians will often treat this area with the glabellar brow depressors to help decrease the occurrence of brow ptosis.

Ten to 20 U of BTX-A are placed in four to nine injections across the upper two-thirds of the forehead (1,23,24). Slightly higher doses are sometimes required in men with larger muscles. Injections are placed along the rhytids, taking care to stay 2 to 3 cm above the orbital rim to avoid brow ptosis (Fig. 6; refs. 20 and 22). This distance depends on the size of the patient's forehead; thus, some physicians recommend using the first horizontal line above the eyebrows as a landmark and only injecting above this line. Maximum response occurs at 2 to 4 weeks and the duration is often longer than seen when treating the glabellar complex (Fig. 7). Retreatment intervals range from 3 to 6 months (1,25).

Another adverse event unique to treating the frontalis is raising the lateral eyebrow creating an elevated "quizzical" brow (20). In general, if the upper lateral fibers are not treated,

Fig. 5. Horizontal forehead rhytids, which are accentuated when the patient raises her eyebrows.

the unopposed muscle action will raise the lateral edge of the eyebrow. However, overtreatment of these fibers or inappropriate injections into the lower lateral fibers can cause significant ptosis that can partially cover the eye. As previously mentioned, mild ptosis can be improved with apraclonidine or phenylephrine eye drops.

Carruthers et al. performed a prospective blinded study comparing the safety and efficacy of BTX-A dosage in the treatment of horizontal forehead rhytids. Sixteen, 32, and 48 total

Fig. 6. For treatment of horizontal forehead wrinkles, botulinum toxin type A injections are placed into the frontalis muscle along the rhytids. Note that the injections are in the upper two-thirds of the forehead to avoid brow ptosis.
Fig. 7. Four weeks after treatment of horizontal forehead rhytids.
Fig. 8. Periocular rhytids (or "crow's feet") are easily identified when the patient squints the eyes.

units were administered over 8 injection sites into both brow depressors and elevators in 59 women, with 8, 16, and 24 U, respectively, into the frontalis muscle. A reduction in the severity of rhytids was noted in all three treatment groups, with the largest degree of response at the 48-U level. In addition, longer duration of response was associated with the higher doses of BTX-A, with some patients benefiting up to 24 weeks. However, although the percentage of adverse events was similar in all three groups, all six reports of eyebrow ptosis occurred in the 32- and 48-U groups (25).

Crow's Feet

Crow's feet are periocular rhytids that radiate outward from the lateral canthus. These dynamic wrinkles are caused by contraction of the orbicularis oculi. However, natural aging and sun exposure add a static component. The primary function of the orbicularis oculi is the involuntary and voluntary closure of the eyelids to protect the globe. Thus, similar to the treatment of horizontal forehead wrinkles, the goal is to relax and not to immobilize the muscle. A close evaluation of the patient is also imperative before injection. For example, a patient with excessive lower eyelid skin or fat pads would not only be at increased risk for adverse events from BTX-A injections, but would also likely derive greater benefit from a blepharoplasty.

The authors routinely have the patient squint to identify the exact location of the rhytids, and then 8 to 12 U are used on each side (Fig. 8). Injections are placed approximately 1 cm

Fig. 9. Botulinum toxin type A is placed into the obicularis oculi, approximately 1 cm lateral to the orbital rim. Note the superficial bleb that is raised with injection.

lateral to the orbital rim. A superficial bleb is raised with a series of three injections on each side, followed by gentle massage to diffuse the toxin (Fig. 9). Care is taken to avoid any superficial veins that are frequently present in this location. In some patients, the orbicularis oculi may extend more than 3 cm laterally; in this case, an additional injection can be placed 1 cm distal to conventional injection points (9). An additional 2 to 4 U can be placed into the lower eyelid to minimize infraorbital rhytids and widen the eye. The dose is often divided between two injection sites, one at the midpupillary line and the second halfway between the midpupillary and the lateral canthus (26). The maximum response is seen approximately 4 weeks after the injection and the average duration is between 4 and 6 months (Fig. 10; refs. 27-29).

Lowe et al. performed a double-blind, randomized, placebo-controlled dose-response trial comparing placebo with 3, 6, 12, and 18 U BTX-A for the treatment of crow's feet (28). Improved efficacy and longer duration was achieved with higher doses, but no difference was seen between the 12- and 18-U dosing. This prompted the authors to recommend 12 U per side as the most appropriate dose (28).

Potential adverse events in this area include bruising, ectropion, upper lid ptosis, asymmetrical smile, strabismus, and dry eyes (20). The increased risk of bruising results from the many periocular superficial veins. Using proper lighting and stretching the skin can help the physician visualize these small veins. Ice and/or pressure immediately after the injections can also help. Limiting the number of injections can further decrease the incidence of bruising. If the patient has lower lid retraction at baseline or if a snap test reveals lower lid laxity, a high

Fig. 10. Two weeks after treatment of periocular rhytids.

risk of ectropion is associated with BTX-A treatment (1). The lower portion of the orbicularis oculi should not be injected in these patients. Strasbismus is caused by the diffusion of toxin into the ocular muscles, such as the lateral rectus. Tear formation can also be affected if diffusion around lacrimal glands occurs. Lip ptosis, a more distal adverse event, results from diffusion of the toxin into the zygomaticus major, which inserts near lateral aspect of orbicularis oculi and the levator labii superioris muscle (30). Weakening of these muscles causes an asymmetric smile. Although these complications can often be avoided with proper injection technique, they appear to be more common in patients who have had previous facial plastic surgery and/or vision correction surgery such as laser-assisted in situ keratomileusis (1,31).

"Bunny" Lines

Bunny lines are rhytids on the sides of the nose that result from contracting the transverse portion of the nasalis muscle, which runs from the maxilla diagonally across the bridge of the nose. These wrinkles radiate downward and should be distinguished from the transverse lines across the nasal bridge, which are caused by procerus contraction.

For treatment of bunny lines, a total of one to three injections are placed into the nasalis. Some authors recommend a single superficial injection into the midline of the muscle while some prefer injecting each side, placing the toxin into the lateral wall of nose anterior to the nasofacial groove. Still others combine the methods for a total of three sites. The recommended total starting dose is between 2 and 6 U, divided evenly if more than one injection is placed. A recent study of 250 patients with nasal rhytids injected 3 U to each side of the nose with 40% of the patients having satisfactory treatment (32). The authors went back and treated the persistent wrinkles (at the nasal root and between the eyes) for complete satisfaction. No complications were reported.

The adverse event unique to this area is drooping of the upper lip. Placing an injection into the nasofacial groove or a vigorous downward massage can affect the levator labii alaeque nasi and the levator labii superioris. As with other sites, injections should be kept superficial to avoid bruising, but in this area particular caution should be undertaken to avoid the angular vein. Of note, treatment may be less effective in patients who have undergone rhinoplasty (1).

Perioral Lines

Perioral rhytids radiate vertically outward from the vermillion border. They primarily result from the purse string-like contraction of the orbicularis oris muscle. Although predominately associated with smokers, these wrinkles also result from photodamage, expression, and aging. In addition to softening the rhytids, BTX-A injection also gives the appearance of fuller lips as weakening of the muscles results in slight eversion (33,34). Injections can weaken the orbicularis oris muscle and reduce rhytids. Care must be taken to avoid weakness, which can interfere with speech and mouth function.

Injections are placed into the muscle adjacent to each visible crease either along or just above (<5 mm) the vermillion border. If the lines are not apparent, have the patient pucker the lips, and then mark the areas of muscle contraction adjacent to the rhytids. Usually 1 to 4 U are placed per lip with no more than 2 U per lip quadrant (34,35). The average total dosing is 5 to 6 U spread over six to eight injection sites.

Potential adverse events resulting from the treatment of perioral lines are both cosmetic and functional. Even small doses of BTA in this area can decrease the patient's ability to purse his or her lips, making it difficult to whistle, use a straw, or play a musical instrument. Patients may also have speech difficulties, specifically with pronouncing "b" and "p" sounds. Treatment of the lower lip is more likely to affect function, thus some authors recommend treatment of the upper lip only (1). The midline of the upper lip should be avoided during treatment to prevent flattening of cupid's bow. One should also not inject into the corners of mouth because weakening of these muscles can cause drooling and/or drooping as well as an asymmetrical smile (20). Injections placed too far above the vermillion border can cause the upper lip to invert or evert (33).

Mental Crease and Dimpled Chin

The mental crease is the groove between the lower lip and prominence of the chin. It is accentuated by the contraction of the mentalis muscle during expression. The mentalis muscle runs from mandible across the chin and inserts below the upper lip. Contraction in addition to loss of dermal collagen and subcutaneous fat also causes wrinkling and dimpling of the chin giving a peau d'orange appearance.

To soften the mental crease, 3 to 5 U BTX-A is placed into each mentalis band just lateral to midline on both sides and anterior to the bony mentum (33). To treat the dimpled chin, one injection is typically placed midline into the mass of muscle on the prominence of the chin. The starting dose is usually 5 to 6 total units but can be increased to 12 U depending on response (1,35).

Adverse events in this area most commonly involve inadvertent weakening of the orbicularis ori or the depressor labii, which result in lower lip incompetence and drooling (20). Conservative dosing regimens, proper placement of injection low on the chin, and avoidance of injection into the mental crease can help avoid complications.

Mouth Frown

Contraction of the depressor anguli oris (DAO) pulls down the lateral corners of the mouth, producing a permanent frown. Weakening this muscle allows for the upward pull of zygomaticus major and minor to elevate the corners of the mouth. The DAO extends superiorly from the lateral surface of the mandible to insert into the modiolus at the angle of the mouth and lays directly over the depressor labii inferioris. Some authors recommend injecting 2 to 3 U BTX-A directly into each DAO, while others place 3 to 5 U at the level of the mandible to avoid inadvertent asymmetrical weakening of the depressor labii inferioris (33,35). In addition to an asymmetrical appearance, other adverse events include flaccid cheeks, mouth incompetence/drooling, and difficulty with speech (20).

Platysmal Bands

The platysmal is a large sheet arising from the pectoralis and deltoid fascia, crossing the clavicle, and extending along the sides of the neck. The anterior fibers spread widely to insert into the mandible or interdigitate with the opposite platysma and the muscles of the lower part of the face. Platysmal bands occur with age as the cervical skin loses its elasticity, submental fat descends, and the platysma separates to form two vertical bands (33).

Patient selection and education is critical because BTX-A will not correct skin laxity or fat deposits, and injections can worsen the appearance of platysmal banding in patients who have jowl formation. These patients would have greater benefit with a traditional rhytidectomy rather than BTX-A injection. BTX-A has the best results in patients with obvious banding and good skin elasticity (36,37). Injections can also be used as an adjuvant therapy to liposuction of the neck or as post-surgical treatment for residual bands after a rhytidectomy.

Contraction of the platysma allows the bands to "pop out" of the neck and they are easily grasped with the physician's non-dominant hand. Injections are placed along the band into the belly of the muscle approximately 1 cm apart. Anywhere from 2 to 12 injection sites per band are placed for a 10- to 40-U total starting dose (1). Excessive or misplaced toxin, such as injecting into the strap muscles of the neck, can result in dysphagia, dysphonia, and neck weakness (20).

Horizontal Neck Lines

Horizontal or "necklace" lines are indentations in the skin caused by the attachment of the superficial musculoaponeurotic system in the neck. Treatment usually consists of deep intradermal injections of 1 to 2 U at 1-cm intervals along the horizontal lines for a total of 10 to 20 U (33).

The most common adverse event is bruising. This area is especially prone to bruising because of deep venous perforators, which can easily bleed. A gentle massage immediately after injection can diminish bruising. The deglutition muscles are also located in this area and are cholinergic; thus diffusion of toxin could potentially cause difficulty swallowing.

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