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History and Use of the 21st Centuries’ Fountain of Youth

Sharon Giese, MD

Botox injections are the most commonly performed cosmetic procedures in the United States. More than 1.6 million procedures are performed annually and the number is expected to rise this year following a 2002 FDA approval for cosmetic use. (Final figures are projected to reflect nationwide statistics and are based on a survey of doctors certified by American Board of Medical Specialties recognized boards, including, but not limited to, the American Board of Plastic Surgery. The survey portion of this research has a standard error of +/-3.79% at a 95% level of confidence.) This article will detail Botox’s history, use, hint at reasons for its dramatic rise in popularity, and help you advise patients desiring treatment.

Botulinum toxin type A, more commonly known as Botox, can create a chemodenervation, selectively and temporarily paralyzing facial muscles, thereby diminishing fine lines and wrinkles. Botulinum toxin is a potent neurotoxin produced by the bacterium Clostridium botulinum and has been known for centuries. Therapeutic use for weakening skeletal muscles dates back to the 1920s. In 1946, Schantz and colleagues prepared a batch of the crystalline toxin.¹ Later in the 1960s and 1970s, Allen B. Scott, MD, a pediatric ophthalmologist, produced transient weakness of extraocular muscles and permanent changes in ocular alignment with botulinum toxin type A.² The FDA allowed the use of the toxin in human trials in 1978. In 1989, botulinum toxin A (named as Oculinum at the time), was FDA approved for the use in strabismus and blepharospasm, and then cervical dystonia in 2000 to decrease the severity of neck pain. Botox Cosmetic was FDA approved for the treatment of glabellar frown lines in 2002. In 1997, the commercially available product, Botox, became available worldwide. The bacteria Clostridium botulinum produces eight immunologically distinguishable exotoxins.³ Type A toxin is the most easily produced in culture and the first one obtained in a highly purified, stable, and crystalline form.

The mechanism of action of the chemodenervation by Botox is by inhibition of the release of acetylcholine at the neuromuscular junction. The peak effect of the toxin occurs at 5 to 7 days after injection. The denervated muscle shows some atrophy and axonal nerve sprouting, which may diminish noticeable clinical muscular atrophy over time.

ANATOMY

The cosmetic uses of Botox are based simply on the anatomy of the facial muscles. Many facial muscles of expression insert onto the undersurface of the skin. Following contraction, including baseline muscle tone, a visible line or wrinkle will develop in the skin that will deepen permanently over time. This type of wrinkle cannot be removed by any type or superficial skin treatment, but can only be treated at the source: the muscle itself. Botox is the preventive treatment of choice to avoid deepening of these wrinkles.

FDA approval has been given for treatment of the “frown lines,” which refer to the lines between the eyebrows (Figure 1). The frown gesture is created by drawing the brows together, which connotes the expression of anger or distress. Most people view these as unpleasant expressions and are happy to “hide” that feeling. The two muscles that draw the brows together are the depressor supracilii (DSC) and the corrugators (Figure 2). The transverse or horizontal furrow is created by the procerus muscle, which also aids in the downward pull of the brows medially. The origins of the DSC and the corrugators are the bony attachment and they insert at the undersurface of the skin at the base of the brow. The procerus originates at the nasal bones and inserts at the medial edges of the frontalis muscle and forehead skin. Paralysis of these muscles relaxes the skin wrinkle.

FIGURE 1 and FIGURE 3. Unretouched clinical photos taken while frowning before and after Botox Cosmetic treatment. (Source: Allergan, Inc.)

Another common but not FDA approved use of Botox is in the frontalis muscle of the forehead. Generally, the lateral portions of the frontalis muscle are spared from treatment, allowing for the persistence of some lateral brow elevation. When artfully performed, the combined treatment of the glabella and frontalis muscles maintain a more natural appearance and balance to the upper third of the face. A “nonsurgical brow-lift” can be achieved in some individuals by selectively altering the agonist-antagonist action of the muscles about the brows. This can also create a rejuvenative effect on the eyes by maintaining the upward lift of the frontalis muscle laterally, thereby lifting subtle skin excess of the upper eyelid (lateral hooding). The shape of the brow can also be manipulated, for example, by dropping the medial portion (DSC, corrugators, and medial frontalis paralysis) and lifting the lateral portion by preservation of the lateral frontalis muscle, creating a more dramatic arched brow. Selective paralysis of portion of the obicularis oculi (subbrow portion) can further effect brow position. The treatment to change the appearance of the eye and brow area must be individualized since muscle patterns and strengths vary from person to person.

FIGURE 2. Periorbital motor nerves. FM = frontalis muscle; CSM = corrugator supercilii muscle; DSM = depressor supercilii muscle; PM = procerus muscle; ZM = zygomatic major muscle; TB = temporal branch; ZB = zygomatic branch

Other uses of Botox include around the eyes to diminish the appearance of “crow’s feet” or radial wrinkles around the eyes. These lines are apparent secondary to the skin insertion of the obicularis oculi muscle. Treatment of this area diminishes, but does not completely eliminate the ocular wrinkles because other powerful facial muscles lift the cheek pad, forcing redundancy of the skin about the eyes, during a full smile or squint. Other, albeit, less common uses of Botox are in the platysma muscle, at the anterior neck to lessen the appearance of the anterior vertical neck bands, a sign of aging; the zygomaticus major muscle, to lessen the appearance of the nasolabial fold (smile fold); and the obicularis oris muscle to diminish perioral vertical wrinkles at the vermilion border (“smokers’ wrinkles”).

Botox can also be used in the axilla and the palms of the hands to decrease excessive perspiration or “sweaty hands.” The toxin temporarily inhibits eccrine glands via acetycholine receptors to decrease perspiration. More recently, Botox injections to the glabella have been shown to shorten and decrease the intensity of migraine headaches for some patients.⁵ Other clinical, non-FDA approved, application of Botox include its use in treatment of bruxism (grinding teeth), stuttering, temporomandibular joint syndrome, lumbosacral pain and back spasms, spastic bladder, aberrant regeneration of facial nerve after Bell’s palsy, and acquired nystagmus.

Treatment

Prior to the elective use of Botox, patients should be advised to temporarily discontinue the use of nonsteroidal anti-inflammatory medications to decrease the risk of bruising. The patient’s pattern of facial wrinkles and desires are assessed. The site of injection is made to the presumed belly or muscle mass of the selected muscle of facial expression and not typically at the site of the maximal skin depression. Electromyographic guidance may be employed, however, the location of the muscle is generally revealed by the wrinkle pattern. Injections are administered with a 1.0 mL syringe and a 30-gauge needle. Typically four injection sites at a dose of 2.5 to 5 units per site are satisfactory to eliminate voluntary action of the corrugators and DCS in the glabella. The forehead is treated in a similar fashion, generally with 8 to 12 dispersed injections. The “crow’s feet” are treated with two to five more superficial injections.

Patients experience minimal pain from the needle piercing the skin followed by a mild burning sensation as the toxin is injected into the muscle. The pain from both, and potential bruising is diminished by prior application of an ice pack to the area being treated. The effect of the paralysis is seen 1 to 4 days following treatment with peak effect at 5 to 7 days after injection. Paralysis lasts an average of 4 months (2 to 8). Serial treatments obtained as muscle activity returns may prolong the time between treatments as the habitual contraction of the muscle decreases.

ALTERNATIVE AND ADJUNCTIVE TREATMENTS

The alternative correction for brow wrinkling is the surgical removal of the corrugators and DSC either through an upper eyelid incision, generally during blepharoplasty (eyelift surgery) or an open or endoscopic brow lift. Surgical removal generally results in a more permanent paralysis. However, some activity usually returns. Very deep wrinkles require some deep volume enhancement in addition to the blocking of muscle activity. This author preferred filler is autologous, including a slip of obicularis oculi muscle or autologous fat placed under the released wrinkle (Figure 3). Silicone, collagen, Fascian, or other similar soft tissue filler’s can be used.

Common adjunctive therapies include the multitudes of skin resurfacing modalities. Removing the top layers of the skin directly compliments the effects of Botox by further diminishing the appearance of facial wrinkles. Commonly available superficial resurfacing agents include microdermabrasion, mild to moderate depth chemical peels, and some lasers. Newer modalities that target the collagen and deeper layers of the skin include intense-pulse light, radio and ultrasonic applications. The appearance of deeper wrinkles will continue to improve over time with ongoing relaxation of the muscle and resultant wrinkle, but adjunctive skin treatment certainly helps the natural process.

Some patients may be resistant to the Botox treatment secondary to toxin immunity. Such patients will have minimal to no paralysis following injection and may successfully be treated with an alternative agent, Myobloc. Monobloc is botulinum toxin type B.

PRECAUTIONS, COMPLICATIONS AND SIDE EFFECTS

Side effects cited by the manufacturer include headaches (13.3%), respiratory infection (3.5%), temporary eyelid droop (3.2%), nausea (3%), and flu syndrome (2%).⁶ In the hands of an experienced practitioner, the most common side effects are temporary redness or bruising at the injection site, both of which are self-limiting.

The most feared temporary side effect of upper lid droop or ptosis can be avoided with careful injection technique and the diagnosis of pre-existing ptosis, which is being compensated by a hyperactive frontalis muscle. If the forehead-lifting muscle is blocked, it can no longer aid in the accessory lifting of the upper lid, which may be misinterpreted as a new event rather than the uncovering of a pre-existing condition. Again, a practitioner skilled in the diagnosis and treatment of ptosis will note this on pretreatment examination. Such patients receive lower doses in multiple treatments until satisfactory result is obtained. Otherwise, upper lid ptosis can occur by direct injection or spreading of the toxin to the levator palpebrae muscle, which lifts the upper lid open. If transient ptosis results from paralysis of the levator muscle, the lid can be lifted by the use of eye drops containing adrenergic agents (Naphcon A, Vasocon A, Opcon A). These ocular decongestants contract Mullers muscle, resulting in elevation of the upper eyelid margin position but have an annoying side effect of dilating the pupil.

PREGNANT AND NURSING WOMEN

Animal reproduction studies have not been conducted with Botox. It is not known whether Botox can cause fetal harm when administered to a pregnant woman. Therefore, Botox should be administered to pregnant women only if clearly needed. It is also not known if Botox is excreted in human milk. Since many drugs are excreted in human milk, the use of Botox is not recommended for nursing women unless clearly necessary.

The halflife of Botox is 10 hours. Intramuscular injections do not enter the circulation and it is not known to prevent or impair fertilization. Therefore, its use is not contraindicated prior to pregnancy.

CONCLUSION

The use of Botox for hyperactive facial muscles and the resultant wrinkles is an effective treatment or adjunctive therapy for patients desiring facial rejuvenation. The temporary, selective paralysis of facial muscle diminishes the appearance of unwanted wrinkles and displeasing facial expressions. Undesirable side effects of Botox can be minimized by proper patient selection and a thorough understanding of the facial soft-tissue anatomy.

REFERENCES

1. Schantz EJ, Scott AB. Use of crystalline type a Botulinum toxin in medical research. In: GE Lewis (ed.), Biomedical Aspects of Botulism. New York, NY: Academic Press; 1981: 143-149.
2. Scott AB, Rosenbaum A, Collins CC. Pharmocologic weakening of extraocular muscles. Invest Ophthalmol. 1973;12(12):924-927.
3. Osako M, Keltner JL. Botulinum a toxin (oculinum) in ophthalmology. Survey Ophthalmol. 1991;36(1):28-46.
4. Knize DM. Muscles that act on glabellar skin: a closer look. Plast Reconstr Surg. 2000;105(1):350-361.
5. Guyuron B, Tucker T, Davis J. Surgical treatment of migraine headaches. Plast Reconstr Surg. 2002;109(7):2183-2189.
6. Botox [package insert]. Irvine, Calif: Allergan Inc; 2002.

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