Introduction

The discovery of ‘sausage poison’ and subsequent identification of Clostridium botulinum as the bacterium responsible has had an enormous and lasting impact on the field of cosmetic dermatology. As is often the case in medicine, a series of serendipitous discoveries – coupled with astute clinical observations – unlocked the potential of botulinum toxin (BoNT) and led to significant medical gains (Tables 3.1 and 3.2). Once hailed as a promising breakthrough for a handful of muscular disorders, BoNT has since become a veritable mainstay of the cosmetic practitioner, its popularity growing exponentially to become one of the most requested procedures in facial rejuvenation.

Table 3.1 Timeline of clinical discovery

Table 3.2 Timeline of therapeutic development and use

Serendipitous discovery

By the late 1980s, nearly 10 000 patients had received injections of BoNT type A (BoNT-A; then called ‘Oculinum’ and distributed to qualified injectors by Dr Alan Scott of the Smith Kettlewell Institute of Visual Sciences, San Francisco, CA) for the treatment of strabismus, benign essential blepharospasm, and hemifacial spasm (Smith Kettlewell 1990.) Many of these patients had received multiple injections with no evidence of antibody formation or systemic complications over 6 years of continued use. In Vancouver, British Columbia, ophthalmologist Dr Jean Carruthers noticed a remarkable and unexpected effect in the brow of a patient treated for blepharospasm: a noticeable reduction in the appearance of glabellar furrows, giving her a more serene, untroubled expression. Dr Carruthers discussed the observation with her dermatologist spouse, Dr Alastair Carruthers, who was attempting to soften the forehead wrinkles of his patients using soft-tissue-augmenting agents available in the eighties.

Case Study 1

Mrs. LW, 50-years-old, had suffered for 20 years from severe bilateral spasms and twitches of her eyelids on both sides. Despite her normal visual acuities, she was unable to drive her car and apprehensive about crossing the street. Her clerical job had become increasingly difficult to perform; her eyelids would spasm and close without warning, worsening toward the end of the working day. Treatment with 30 units of onabotulinumtoxinA (Botox^®) on each side resulted in almost complete symptom relief for approximately 3 months. In addition, she noticed that her brow and face appeared more relaxed, and her friends commented about how ‘fresh’ and attractive she looked. The deep frown lines between her brows appeared to efface, and her husband thought she looked less intense and angry. At her next appointment, Mrs. LW expressed concern when her doctor (JC) did not treat the medial ends of her eyebrows. When her doctor explained that she had not observed any spasm in those areas, Mrs. LW said: ‘Every time you treat me there, I get this beautiful, untroubled expression.’ It was the birth of the realization that onabotulinumtoxinA could be helpful in other patients with similar glabellar folds and medial brow ptosis.

Patient zero and the first clinical trials

Intrigued by the possibilities, the Carruthers injected a small amount of Scott’s BoNT-A between the brows of their assistant, Cathy Bickerton Swann – known as ‘patient zero’ – and awaited the results (Figure 3.1A–D). Seventeen more patients followed, aged 34 to 51, who would become part of the first report on the efficacy of BoNT-A, published in 1992. Subjects received injections directly into the glabellar furrow (10–12.5 U/furrow), as well as one or more subsequent injections into the corrugator muscles (10–20 U/furrow or per corrugator) 3 to 4 months following previous injections. One patient did not respond at all to injection, and one was lost to follow-up. The remaining patients experienced varying degrees of brow improvement, from complete line effacement (six of seventeen) (Fig. 3.2) to discernible brow creases that simply lessened in depth (eight subjects). The effects of the toxin lasted from 4 to 11 months, depending on the number of repeated injections and length of exposure. In general, subjects who received treatment over a longer period of time experienced a treatment persistence of 7–11 months. Side effects included one case each of brow and lid ptosis that resolved within 14 days, two cases of transient headache, and one subject who experienced transient numbness at the injection site. Although the authors conclude by saying that BoNT-A is safe and effective, ‘We do not believe at present that it is the treatment of choice’ except for ‘those who are collagen-allergic or who are disinclined to undergo surgery.’

Figure 3.1 ‘Patient zero’ before (A, B) and after (C, D) injection of BoNT into the glabella: (A, C) resting, (B, D) frowning.

From Carruthers JDA, Carruthers JA 1992 Treatment of glabellar frown lines with C. botulinum-A exotoxin. Journal of Dermatologic Surgery and Oncology 18:17-21. Reprinted with permission of Dermatologic Surgery.

Figure 3.2 The first clinical trial of BoNT in the glabellar furrow and corrugator muscles demonstrated varying degrees of improvement to the appearance of the brow. (A) Pre-treatment. (B) Here, treatment led to complete line effacement.

The publication of their findings drew a flurry of interest among other clinicians, some of whom had already begun their own off-label experiments. Clark & Berris restored symmetry in a post-surgical patient with unilateral frontal nerve paralysis and one-sided frown lines and brow elevation on animation by injecting BoNT-A into the opposite functioning frontalis muscle. Blitzer and colleagues had used BoNT-A to treat focal dystonia since 1984. By the late eighties, they had noticed a loss of hyperfunctional lines in subjects treated with the toxin for a number of disorders, including blepharospasm, Meige’s syndrome, hemifacial spasm, and post-Bell’s palsy facial synkinesis. In order to study the phenomenon further, 26 patients aged 3–84 years with hyperfunctional lines and dystonia received aliquots of 1.2–10 U BoNT-A via electromyography (EMG) guidance into the frontalis and corrugators muscles, nasolabial fold, lateral canthus, or platysma. The effect of the BoNT-A occurred within the first 24–72 hours, peaked at 2–3 weeks, when follow-up injections were performed, if necessary, and lasted from 3 to 6 months. Minimal adverse effects included ptosis of the eyelid and, in the case of nasolabial fold injections, droop of the upper lip. All patients experienced substantial benefit from treatment.

Recognizing the need for trials of longer duration, Keen and colleagues devised the first double-blind, placebo-controlled study to assess the efficacy and safety of BoNT-A for the treatment of facial rhytides in a group of twelve healthy subjects (one of whom was lost to follow-up) aged from 32 to 62 years. Nine patients with hyperfunctional forehead rhytides and two patients with prominent crow’s feet received injections of either 0.2 mL normal saline or BoNT-A (eight injection sites with 10 U in the forehead, two sites with 5 U in the periorbital wrinkles) on both sides of the face via EMG guidance. Before and after photographs documented the treatment effect (determined by blind self-assessment and investigator grading) 2 and 6 weeks after injection, and patients were followed for a minimum of 1 year. BoNT-A treatment led to a significant (p <0.01) improvement in facial rhytides. All patients requested the toxin after 6 weeks on the untreated side of their face to ‘even out’ the results. There were no serious complications; side effects included slight brow ptosis (two patients), change in eyebrow shape (one), forehead ‘heaviness’ (one), and pain on injection (three). Ten of eleven subjects requested further treatment after the effect from the initial injections dissipated (4–6 months).

Lowe and colleagues found similar results in a double-blind, placebo-controlled study of 30 subjects who received 10 U BoNT-A or normal saline into each corrugator muscle under EMG guidance for the treatment of glabellar rhytides. Treatment with BoNT-A led to a statistically significant reduction in glabellar frown line depth and length compared to placebo control at 12 weeks post-injection.

Results of these trials indicated that BoNT-A was indeed a novel – and promising – treatment for unsightly facial rhytides. Clinicians began to investigate other potential cosmetic applications, such as crow’s feet, horizontal forehead lines, and platysmal bands, all of which were considered off-label, non-approved uses.

FDA approval

Good news spreads fast: between 1992 and 1997, the popularity of off-label use of BoNT-A grew so rapidly that Allergan’s supply temporarily ran out. By 2002, investigators had established an excellent efficacy and safety profile for therapeutic doses of BoNT-A, which was used for a host of disorders, including strabismus, blepharospasm, hemifacial spasm, cervical dystonia, cerebral palsy, poststroke spasticity, hyperhidrosis, headache, and back pain. Moreover, the safety and efficacy of BoNT-A in reducing the appearance of hyperfunctional facial rhytides had been demonstrated in numerous open-label studies totaling more than 800 subjects. In the United States, the FDA had approved BoNT-A for strabismus, blepharospasm, hemifacial spasm, and cervical dystonia. Additional approvals had been granted in the United Kingdom for axillary hyperhidrosis, and in Canada for axillary hyperhidrosis, focal muscle spasticity, and for the cosmetic treatment of glabellar wrinkles.

Two large, double-blind, placebo-controlled, randomized, multicenter clinical trials in 2002 and 2003 cemented BoNT-A’s position as a safe and effective treatment for facial rhytides and would pave the way for FDA approval and future cosmetic applications. The first involved 264 patients with moderate-to-severe glabellar rhytides who received 20 U BoNT-A (n = 203) or placebo (n = 61) into five glabellar sites (one in the procerus muscle and two in each corrugator supercilii) and were followed for 120 days post-injection. Results were assessed by patient and investigator at days 7, 30, 60, 90, and 120 after treatment. BoNT-A led to a significantly greater reduction in glabellar line severity compared with placebo across all measures at every follow-up visit (p <0.022). Response to treatment was noted at first follow-up and peaked at day 30, although clinical effect was still apparent in over half of the subjects at day 90 and over one quarter at day 120. Treatment was well tolerated; side effects included transient headache (15.3%) and mostly unilateral blepharoptosis (5.4%) that resolved by day 20 (in 8 cases) and day 40 (in 4 cases).

The second large trial was identical in design to the first and comprised 273 patients injected with BoNT-A (n = 202) or placebo (n = 71). As in the first trial, response to BoNT-A peaked at day 30 for both physician- and patient-assessment and was significantly greater than for placebo at every follow-up visit (p <0.001) (Fig. 3.3). No treatment-related serious complications were reported; the most common adverse events in the BoNT-A group were headache (11.4%) and unilateral blepharoptosis (1%).

Figure 3.3 Response to BoNT peaked at day 30 and was significantly greater than for placebo at every follow-up visit.

Data from Carruthers JA, Carruthers JDA, Lowe NJ, et al 2004 One year, randomized, multicenter, two period study of the safety and efficacy of repeated treatments with botulinum toxin type A in patients with glabellar lines. Journal of Clinical Research 7:1–20.

In April of 2002, the FDA approved BoNT-A for the non-surgical reduction of glabellar furrows. The rest, as they say, is history.

The face of BoNT

The world of facial rejuvenation changed after the formal FDA approval of BoNT, which is now used to treat a variety of hyperkinetic facial lines in the upper face, including crow’s feet, horizontal forehead lines, and glabellar rhytides, as well as folds and lines in the lower face, neck, and chest with a high level of efficacy and patient satisfaction. Moreover, BoNT-A is used to sculpt and shape the face, can prolong the effects of other cosmetic modalities, particularly for the treatment of deeper, more static rhytides and folds, and is used during surgery to prolong or enhance the aesthetic results or as an aid in wound healing and minimizing scars.

More tellingly, surveys and statistics paint a convincing portrait of rising popularity: between 2005 and 2007, the use of BoNT and soft-tissue-augmenting agents increased by 130% and accounted for nearly half of all nonsurgical cosmetic procedures in 2008. Other formulations of BoNT-A have joined the original BOTOX, which has gone on to receive approval for 20 indications in more than 75 countries.

It is interesting to note that what once began as a potential – rather daring – treatment for a single disorder has translated into a worldwide phenomenon. BoNT has made remarkable advances since its initial discovery as a therapeutic agent over thirty years ago, becoming the treatment of choice for smoothing hyperkinetic lines and shaping the face, with an ever-expanding array of indications and formulations.