2004, Vol.22, Issues 2, The Clinical Use of Botulinum Toxin

Dermatol Clin 22 (2004) ix
Preface
The clinical use of botulinum toxin
Arnold W. Klein, MD Guest Editor
The interest in botulinum toxin and its many uses has increased exponentially in recent years; especially since the approval of Botox Cosmetic for the treatment of glabellar lines. In fact, Botox, which was virtually unheard of to many just 5 years ago, has become a household name. This increased popularity has been a truly amazing process to behold. Facial wrinkles are frequently caused by repeated muscle contraction. Botulinum A exotoxin can produce weakness or paralysis of these muscles and offers a novel approach for the treatment of certain facial rhytides. The disappearance of wrinkles through the paralysis of these muscles, although temporary, is extremely popular with both patients and physicians. There is a very low incidence of side effects and it is a relatively easy technique to acquire. For these reasons, botulinum toxin A has gained rapid and enthusiastic acceptance. Experience since the worldwide approval of the first therapeutic botulinum-neurotoxin based product in 1989, Botox, has shown that this therapeutic agent is safe and effective for numerous indications, including movement disorders. Subsequently, another botulinum toxin type A complex, Dysport, was approved in the United Kingdom in 1991, but is not currently available in the United States. There is also a type B complex preparation, Myobloc, which is approved by the Food and Drug Administration for cervical dystonia patients.
In addition to its previously noted off-label cosmetic indication, Botox in all likelihood will be shown to be safe and effective in placebo-controlled studies for a wide range of medical conditions including achalasia, dysphonia, cervical dystonia, cerebral palsy, chronic anal fissures, migraines, and hyperhidrosis. There are numerous reasons for this phenomenal explosion of interest. The rapid thrust of Botox into the limelight has brought with it an influx of novice injectors, increasing the possibility of unwanted complications. It has also brought a plethora of new uses, which are being discovered everyday. I believe it is important to bring together many of the most experienced and knowledgeable people in the field to share their experience and knowledge with those who are just beginning to get involved with this material. This issue of Dermatologic Clinics comprises a comprehensive look at the subject. All of us, the novice user and the highly experienced, can increase our knowledge from reading these articles. Arnold W. Klein, MD David Geffen School of Medicine at UCLA 435 North Roxbury Drive Suite 204 Beverly Hills, CA 90210, USA E-mail address: awkmd1@aol.com
0733-8635/04/$ see front matter D 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.det.2004.01.001
Dermatol Clin 22 (2004) 131 133
Development of botulinum toxin therapy

Alan B. Scott, MD
Smith-Kettlewell Eye Research Institute, 2318 Fillmore Street, San Francisco, CA 94115, USA
Botulism occurs mostly from eating improperly preserved food. In the eighteenth and nineteenth centuries in Bavaria, botulism was caused by sausages that were preserved with inadequate boiling, smoking, and salting. Justinius Kerner collected data on 230 cases of botulism and published two important monographs in 1820 and 1822. Kerner gave a remarkably complete and accurate description of clinical botulism: its symptoms, time course, and physical findings, especially that the tear fluid disappears, the pupil dilates, the eye muscles are paralyzed, mucus and saliva secretion is suppressed, the skin is dry, the skeletal muscles and gut are paralyzed, and until the last, cognition is preserved. Finally, Kerner suggested the potential therapeutic use of toxin to block abnormal motor movements, such as chorea, and speculated on its use in other disorders with hypersecretion, for example. However, he stopped there. Kerner was an important romantic poet and a busy medical officer; lacking a university appointment, he went off in these directions at age 37, after remarkably insightful and creative research on botulism. His work is summarized in further detail by Smith [1] and more recently by Erbguth and Naumann [2]. Seventy-five years later, van Ermengem, professor of bacteriology and a student of Koch, correctly described the bacterial basis of botulism. Of 34 individuals who had attended a funeral and ate some raw, partially salted ham, 23 were paralyzed and three died. van Ermengem found extracts of the ham to be toxic to laboratory animals, producing a paralytic disease akin to botulism. The toxicity in the animals, as well as in those who had eaten the ham, was related to the amount consumed, with only a small amount needed.
Animals vary in their susceptibilityin particular, carrion eaters, such as dogs, are resistant. From the ham and from the spleen of a man who had died, van Ermengem isolated the anaerobic bacterium, grew it, named it, characterized its culture requirements, and described its toxin. Over the next three decades, food canning and botulism grew together. K.F. Myer, a Swiss veterinarian, developed a major focus of botulinum investigation at the Hooper Foundation in San Francisco. New strains of the organism and toxin were characterized. Techniques for reliably killing the spores in the canning process and knowledge of the correct pH (<4.0) and salt concentration to prevent organism growth and toxin production were defined. The requirements for toxin inactivation by heating were also defined. The California canning industry was saved, and knowledge of how to grow the organism and extract the toxin was developed. Type F toxin was recognized later in 1960 and type G in 1970.
Swords into plowshares The potential for botulinum toxin as a warfare agent was a second focus of investigation from the 1930s onward. The bacteria are remarkably easy to grow in culture, with tremendous toxin yields in a 5-gallon container after just 3 or 4 days. It is easy to concentrate (although not so easy to crystallize), and quantities to paralyze whole cities or armies have been made by several nationsthe United States, the United Kingdom, Russia, Iraq, and perhaps many others. But distribution for ingestion is not easy, as the toxin loses potency with time in dilute without protein-buffering solutions, as might occur in a water supply. Inhalation of the dried toxin as an aerosol is frightening to contemplate but was never developed.
E-mail address: abs@ski.org
0733-8635/04/$ see front matter D 2004 Elsevier Inc. All rights reserved. doi:10.1016/S0733-8635(03)00019-6
132
A.B. Scott / Dermatol Clin 22 (2004) 131133
Development of concentration and crystallization techniques at Fort Detrick by Lamanna and Duff in 1946 7, using acid precipitation techniques, became the basis of the clinical product. The breakup of the Armys Chemical Corps at Fort Detrick led to the move by Edward Schantz to the Food Research Institute in Wisconsin. There, he continued to manufacture toxin in concentrated form for experimental use and gave it out generously to the academic community. Among these experimenters was Drachman [3], at Johns Hopkins, who used small doses of toxin to paralyze the hind limb in chicks. At that time, techniques had been developed to accurately inject extraocular muscles with local anesthetics to assess their contribution to the eye movement performance. Because strabismus surgery had high reoperative rates in many categories, other alternatives to strabismus surgical treatment were being sought systematically by injecting various anesthetics, alcohol, enzymes, enzyme blockers, snake neurotoxins, and finally, motivated by Drachmans work, botulinum toxin. The effect was remarkable. An injection of a few picograms would induce paralysis confined to the target muscle, long in duration, and with no side effects whatsoever. The results of these animal experiments on strabismus were published in 1973, and an application was sent to the Food and Drug Administration (FDA) for human use after working out techniques for freeze-drying, buffering with albumin, and assuring sterility, potency, and safety. Human experimentation began first in strabismus in 1977. By 1982, the eye muscles were injected for strabismus and nystagmus, the lid muscles for retraction, hemifacial spasm, and blepharospasm, and the limbs and neck for dystonia, all as predicted in the 1973 study. It was astonishing that none of the local neurology, orthopedic, and rehabilitation physicians at the Childrens Hospital, University of California at San Francisco, Stanford, and the Shriners Hospital would try toxin for muscle contractures with stroke, dystonia, torticollis, or cerebral palsy. This strong aversion to the idea of toxin use makes it possible to grasp why no one in the century and a half since the time of Kerner had tried this. Without local support, I had no possibility of trying out the wide spectrum of toxin uses and, therefore, enlisted others. My cases of torticollis, the first three injected, were later published by Dr. Tsui of Vancouver [4], and many others undertook to expand the use in dystonia and muscular disorders. It was only in the late 1980s that Dr. Koman of Wake Forest University would pioneer the use of toxin in pediatric treatment of leg spasm and cerebral palsy. The use gradually expanded, because there was no adequate alternative treatment for many motility disorders. With active patient groups
and Internet access, blepharospasm patients rapidly disseminated information of good results. Torticollis patients likewise came soon to know that pain was markedly decreased by toxin injection, motility increased, head position improved a little, and tremor was not changed much. And so on through the range of motor and muscle disorders such as spasmodic dysphonia, spasm in various gastroenteric and urinary sphincters, muscle spasm in stroke, and pretty well every muscle, including those producing low back pain. With data from thousands of patients and 240 investigators, the FDA approved use in adult strabismus and blepharospasm in December 1989. The use to reduce hyperhidrosis came from the original and creative application of botulinum toxin by Drobic and Laskawi in 1994 [5] to treat Freys Syndrome, gustatory sweating usually occurring after parotid gland surgery with subsequent anomalous connection of nerves in that region. It was an easy transfer of this concept of blocking cholinergic innervation to sweat glands as a treatment for hyperhidrosis in the axilla, hands, and elsewhere. Remarkable in this application in Freys Syndrome is the extraordinary duration of toxin effect, sometimes more than 1 year, much longer than the typical 3 to 4 months seen after injection of muscles. An extension of this approach is the use to diminish salivation by parotid gland injection to ameliorate the poorly handled secretions in amyotrophic lateral sclerosis and to decrease excessive lacrimal gland secretion effects, which harkens directly back to clinical findings of dryness so prominent in Kerners patients of 1820. Cosmetic use of botulinum toxin, probably its greatest single application, is the creation of Alistair and Jean Carruthers. For many years, a few blepharospasm patients injected at intervals of 3 or 4 months around the eyes and upper face would mention as a joke upon return that they were back to get the wrinkles out. But only somebody working in aesthetic dermatology and ophthalmology could grasp the potential for this application of botulinum toxin. The Carruthers thoughtful and rational application of toxin to selective agonist-antagonistic muscle groups in the face, to lift the brow, flatten folds, is probably overtaken now by less discriminate use. The idea that toxin use in young people may prevent skin wrinkle development is an intriguing prospect. It is from widespread use around the face that the beneficial effect of toxin on headache has emerged. Direct release of muscle tension by the paralytic effect at neuromuscular junctions is the principal mechanism. Intriguing theories on toxin operating by effect on proprioceptors, thus altering centrally controlled muscle tonus in migraine, are speculative.
A.B. Scott / Dermatol Clin 22 (2004) 131133
133
An important historical event is the appearance of toxin type B, Myobloc. In choosing the toxin type to concentrate on in our original studies, we looked at epidemics and found that type A typically produced extensive muscle paralysis, and type B was often associated with autonomic disorders. This has been proved by the high degree of autonomic side effects of type B toxin, where use for torticollis brought about good paralytic effects, but in a sizable percentage also dryness of the mouth, difficulty in accommodation, reduced sweating, constipation, and so on [6]. If limited for muscle paralysis in higher doses because of side effects, type B toxin would seem superior for injection into lacrimal or salivary glands and in the GI tract. Type B is essential in those patients for whom type A toxin is impossible because of antibody development, although the development of resistance to type B toxin in five of 21 patients resistant to type A toxin is a high and troubling occurrence rate [7]. A drawback for cosmetic use of type B is the stinging of the current low pH solution when injected subcutaneously. This can be ameliorated by dilution with bicarbonate buffer, but then higher volume injection at each site is needed. Type C is under development in Italy, and types D, E, and G will certainly be future alternatives. Type F toxin developed in Japan and used in clinical experimental series had a shorter duration of effect than type A toxin and is not available. Antibodies to botulinum toxin should become increasingly less of a problem. The initial lot of type A (79-11) licensed to me by the FDA and later used by Allergan to formulate Botox in the United States had a relatively low potency, and thus a higher
antigenic protein content. This resulted in antibody production in doses > 200 U or even lesser doses at injection intervals of < 30 days. The lot used in Europe for Botox (88-4), had a much higher potency and probably fewer antibodies developed. Both of these have now been replaced by still higher potencies for the Allergan product, Botox. In the future, we might hope for cheaper toxin as competition develops, but high regulatory costs in the United States will prevent this.
References
[1] Smith Louis DS, Thomas Charles C. Botulism. Springfield (IL): Charles C. Thomas; 1977. [2] Erbguth FJ, Naumann M. Historical aspects of botulinum toxin: Justinus Kerner (1786 1862) and the sausage poison. Neurology 1999;53:1850 3. [3] Drachman DB. Neuropoisons. In: Simpson LL, editor. New York: Plenum Press; 1971. p. 315 39. [4] Tsui JK, Eisen A, Mak E, Carruthers J, Scott A, Calne DB. A pilot study on the use of botulinum toxin in spasmodic torticollis. Can J Neurol Sci 1985;12(4):314 6. [5] Drobik C, Laskawi R. Frey-Syndrom: Behandlung mit Botulinum-Toxin. HNO Aktuell 1994;2:142 4. [6] Dressler D, Benecke R. Initial experiences with clinical use of botulinum toxin type B. Nervenarzt 2002;73(2): 194 8. [7] Kumar R, Seeberger L. Long-term safety, efficacy, and dosing of botulinum toxin B (Myobloc) in cervical dystonia (CD) and other movement disorders. Mov Disord 2002;17(Suppl 5):S292 3.
Dermatol Clin 22 (2004) 135 136
Dilution, storage, and electromyographic guidance in the use of botulinum toxins

Alan M. Mantell, MD
1818 Verdugo Boulevard, Suite 304, Glendale, CA 91208-1403, USA
To use botulinim toxin A (BTX-A) successfully for cosmetic purposes, it is important to understand the basic principles of BTX-A therapy and the specific guidelines for its use, including dilution and storage. BTX-A is available commercially in two formulations, BOTOX, (Allergan Inc., Irvine, CA) and Dysport (Ipsen Limited, Berkshire, England). BOTOX is available in the United States, Canada, and many other countries, whereas Dysport is available in Britain, France, Germany, and other countries, but not in the United States or Canada. Both are sold in a lyophilized form and must be reconstituted with physiologic saline before use. Botulinim toxin type B, MYOBLOC, which is currently available only in the United States but may become available in Europe soon, is sold in an aqueous solution. The dosages of each of these vary greatly, and it is essential to use the correct dosage for the specific product used. Incorrect dosages are very likely to result in severe adverse effects. This is particularly significant when using BOTOX at Dysport or MYOBLOC dosages. The Dysport dosages are typically 3 to 6 times higher than the BOTOX dosages, and the MYOBLOC dosages are typically 50 to 100 times higher than the typical BOTOX dosages. Using Dysport or MYOBLOC at BOTOX dosages will result in inadequate therapeutic benefit.
Dilution and storage Although the manufacturers of both BOTOX and Dysport recommend that their products be reconsti-
E-mail address: dralan@pacbell.net
tuted using preservative-free solutions, recent studies [1] have shown that preservative-containing normal saline is just as effective and retains its potency when refrigerated for a week or more after reconstitution. When using preservative-free solutions, the botulinum toxin should be used within 4 hours of reconstitution. A significant number of patients have reported that injections with preservative-containing saline are less painful. Dr. Murad Alam performed a double-blind, randomized trial to validate the findings from a botulinum toxin study [1]. He concluded that botulinum toxin A that has been reconstituted with benzyl alcohol preserved saline maintains its potency for a week or more when refrigerated and appears to be just as effective in results and duration as preservative-free saline. He found no adverse effects associated with using preservative-containing saline. Most patients noted a significant reduction in the pain associated with the injection [1]. Depending on how the BTX-A is to be used, the dilution may vary. Two studies have shown that higher doses delivered in smaller volumes tend to keep the toxin and its effect more localized [2,3]. For BOTOX, dilutions range from 2.5 U/mL to 100 U/mL with most investigators using about 25 U/mL or 100 mL [4 10]. Higher concentrations allow for low-volume injections with more precise placement of the toxin and with little spread to other areas. Low concentrations may be useful in some cases, but increasing the concentration and decreasing the volume injected will limit the possibility of adverse effects resulting from the unintended spread of the toxins to other areas. The manufacturers guidelines should be adhered to for storage and handling of all botulinum products. When BTX-A has been diluted with preservative-free saline, it should be refrigerated at 2 Centigrade to
136
A.M. Mantell / Dermatol Clin 22 (2004) 135136
8 Centigrade for a maximum of 4 hours to ensure that it remains sterile [11].
Electromyographic guidance in the use of botulinum toxins Injection using electromyographic (EMG) guidance is helpful in achieving correct placement of BTX-A by locating the most active part of the muscle responsible for a particular facial line. For this purpose, a combined EMG injection needle (available through Allergan Inc., Irvine, CA) is used. The EMG-guided technique is helpful until a thorough understanding of the facial anatomy is attained. However, it requires the use of a larger needle, and many clinicians feel it has little benefit to the experienced physician except when dealing with patients who are difficult to treat or who have not had a satisfactory result. Some clinicians use EMG to increase the accuracy of the injections because the effect of BTX-A is muscular. Nevertheless, EMG is useful in locating the muscle, especially when injecting a patient for the first time because the pattern of muscle activity varies from patient to patient. Some clinicians feel that the anatomy of the glabela is so reliable that EMG guidance is not necessary. They use EMG guidance only for reinjection in cases where they have produced a partial response. It may be a better idea to use EMG guidance the first time so that the muscle is located more accurately, rendering reinjection unnecessary. Furthermore, the pattern of muscle activity is not uniform from patient to patient and EMG can obviate these variables. The EMG apparatus can be used to determine which muscles are contracting during the frowning process and contributing to the frown. The use of 0.5-inch, 30-gauge metal needles for patient comfort in place of the hollow-bore 27-gauge needles supplied with the EMG machine is highly recommended. Although the 30-gauge needles transmit electrical impulses from their entire length rather than only at needle tip, they are still more user friendly for both the physician and patient. Additionally, patients who fear the use of botulinum toxin may be calmed by the knowledge that the physician is locating the target muscles accurately [12]. The recommended technique for injecting using EMG guidance is to first cleanse the area with alcohol and allow the alcohol to evaporate completely. The target muscles should be at rest. The patient is directed
to frown, squint, or raise the eyebrows to activate the targeted muscle. One-half to one-third of a 0.5-inch metal hub needle, which is connected to the EMG unit, is placed in the muscle. After placement, if no sound is heard upon activation of the muscle, the needle is reinserted until a sound is heard from the EMG machine [12].
References
[1] Alam M. Pain associated with injection of botulinum toxin A exotoxin reconstituted using isotinic sodium chloride with and without preservative. Arch Dermatol 2002;138:510 4. [2] Borodic GE, Ferrante R, Pierce B, et al. Histologic assessment of dose related diffusion and muscle fiber response after therapeutic botulinum-A. toxin injection. Mov Disord 1994;9:31 9. [3] Shaari CM, Sander SI. Quantifying how location and dose of botulinum toxin injection affect muscle paralysis. Muscle Nerve 1993;16:964 9. [4] Blitzer A, Binder WJ, Aviv JE, et al. The management of hyperfunctional facial lines with botulinum toxin. Arch Otolaryngol Head Neck Surg 1997;123:389 92. [5] Lowe NJ, Maxwell A, Harper H. Botulinum a exotoxin for glabellar folds: a double blind, vehicle controlled study with an electromyographic injection technique. J Am Acad Dermatol 1996;35:569 72. [6] Carruthers A, Carruthers J. Cosmetic uses of botulinum A exotoxin. In: Klein AW, editor. Tissue augmentation in clinical practice. New York: Marcel Dekker; 1998. p. 207 36. [7] Klein AW. Dilution and storage of botulinum toxin. Dermatol Surg 1998;24:1179 80. [8] Pribitkin EA, Greco TM, Goode RL, et al. Patient selection in the treatment of glabellar wrinkles with botulinumtoxin type a injection. Arch Otolaryngol Head Neck Surg 1997;123:321 6. [9] Ahn K-Y, Park M-Y, Park D-H, et al. Botulinum toxin A for the treatment of facial hyperkinetic wrinkle lines in Koreans. Plast Reconstr Surg 2000;105: 778 84. [10] Guerrissi JO. Intraoperative injection of botulinum toxin A into orbicularis oculi muscle for the treatment of crows feet. Plast Reconstr Surg 2000;105:2219 28. [11] Carruthers A, Carruthers J. Botulinum toxin type A: history and current cosmetic use in the upper face. Semin Cutan Med Surg 2001;20(2):71 84. [12] Klein AW, Mantell A. Electromyographic guidance in injecting botulinum toxin. Am Soc Dermatol Surg 1998;24:1184 6.
Dermatol Clin 22 (2004) 137 144
Botulinum toxin type A for the treatment of glabellar rhytides

Alastair Carruthers, MDa,*, Jean Carruthers, MDb
b a Division of Dermatology, University of British Columbia, Vancouver, BC, Canada Department of Ophthalmology, University of British Columbia, Vancouver, BC, Canada
Since the introduction of botulinum toxin type A (BTX-A) more than 20 years ago, its use has expanded to include a wide range of clinical applications for the aging face. Although its use in facial rejuvenation initially provoked amazement in the general population, BTX-A injections have become an accepted part of cosmetic practice. Glabellar frown lines, which give the impression of anger, frustration, or general unhappiness, especially in women [1], were the focus of the initial cosmetic investigations and are still the most common site for BTX-A injections. This article reviews the start of this process (BTX-A for the treatment of glabellar lines) and reviews current clinical procedures and experience.
Initial clinical trials One of the authors (JC) was one of the early coinvestigators with Alan Scott of the management of blepharospasm with BTX-A. When patients pointed out that they were unable to frown as much as they had before as a result of treatment, we were intrigued and developed the first systematic study of BTX-A (Botox, Botox Cosmetic; Allergan, Irvine, CA) in treating glabellar lines. The first report was published in 1992 [2]; two small, double-blind, placebo-controlled trials followed, reporting benefits in 42 patients [3,4]. Trials continued until 2001, when the results of a large, randomized, placebo-controlled trial cemented
what clinicians already knew: that BTX-A was an impressively effective and safe treatment for facial rhytides. In this trial, 264 patients with moderate to severe glabellar lines at maximum frown received 20 U BTX-A or placebo into five glabellar sites and were followed for 120 days after injection [5]. Patients receiving BTX-A experienced a significantly greater reduction in glabellar line severity than patients receiving placebo, as measured by physician rating of glabellar line severity at maximum frown and rest and patient assessment of improvement. Clinical results lasted 3 to 6 months and were greater in magnitude and duration in patients less than 50 years of age. The cumulative result of these trials led to the official approval of BTX-A for the treatment of glabellar rhytides by Health Canada in 2001 and the US Food and Drug Administration in 2002.
Anatomy Mastering the use of BTX-A for any indication requires a thorough understanding of the relevant muscular anatomy (Fig. 1). Any discussion of anatomy, however, must be prefaced with a warning about the enormous variability in facial features and musculature. In addition, although each muscle functions individually, it is important to remember that most work in conjunction with others. Treatment of one muscle invariably affects others. Frontalis
* Corresponding author. 943 West Broadway, Suite 820, Vancouver, BC V5Z 4E1, Canada. E-mail address: alastair@carruthers.net (A. Carruthers).
Understanding the anatomy of the frontalis (a large, quadrilateral muscle that originates from the
138
A. Carruthers, J. Carruthers / Dermatol Clin 22 (2004) 137144
Glabellar complex The glabella is the smooth elevation of the frontal bone just above the bridge of the nose. The glabellar complex refers to a group of brow-associated muscles that are used primarily for facial expression, especially concern, anger, unhappiness, and pleasure. Muscles of the glabellar complex include the orbicularis oculi and corrugator muscles (which move the eyebrows medially or inferomedially), and the procerus and depressor supercilii muscles (which move the eyebrows inferiorly). The strength and size of the glabellar complex varies significantly from patient to patient, and cadaver dissection and forehead lift surgery show that there is variation of muscle mass between individuals. In general, men have a larger glabellar complex compared with women, and many patients with deeper wrinkles have a hypertrophic glabellar complex compared with those with fewer wrinkles. Glabellar frown lines (vertical creases seen adjacent to or in between the medial aspects of the eyebrows) arise naturally from the activity of the glabellar complex (Fig. 2).
Fig. 1. Facial anatomy.
Corrugator supercilii Corrugator supercilii muscles arise from the medial end of the superciliary arch and run at an angle to insert along and above the skin of the eyebrow, with most of the muscle passing through the fibers of the orbicularis oculi and the frontalis [7]. Hyperactivity of the corrugator supercilii, in conjunction with the lateral orbicularis oculi and the depressor supercilii, can antagonize the frontalis and facilitate the descent of the eyebrow and contribute to the formation of the oblique glabellar skin line [8].
galea aponeurotica and inserts inferiorly into the procerus, orbicularis oculi, corrugator supercilii, depressor supercilii, and the skin of the brow) is crucial. The frontalis muscle resting tone suspends the lateral eyebrow segment medial to the temporal fusion line of the skull [6]. Contraction of the frontalis produces a series of primarily horizontal forehead wrinkles, which appear in the late 20s to early 40s; thicker musculature contributes to increased, overlying, cutaneous rhytides. The frontalis, which has no bony attachments and is adherent to the superficial fascia, raises the eyebrows and skin over the root of the nose and draws the scalp forward. The lower 2 cm of the frontalis is thought to be largely responsible for elevation of the eyebrows. The paired frontalis muscles are described as forming a large quadrilateral muscle with a distinct mid-line separation. In the authors experience, many individuals do not have this mid-line separation. The superior margins of these muscles originate from the galea aponeurotica just anterior to the coronal suture line of the skull, with the lateral aspects extending more cephalad. Many fibrous septae pass from the muscle anterior surface up to the dermis. The lateral margin of the frontalis always ends or becomes severely attenuated at the temporal fusion line.
Fig. 2. Glabellar frown lines.
139
Procerus and depressor supercilii The procerus and depressor supercilii, which lie adjacent to one another and may be an extension of the frontalis, originate from the nasal bone and extend upward to insert into the skin of the brow intertwining with fibers of the orbicularis oculi and frontalis. The procerus draws the medial angle of the eyebrows down and produces transverse wrinkles over the nasal bridge. Orbicularis oculi The orbicularis oculi is the sphincter muscle of the eyelids. The palpebral portion of this muscle is thin and close to the skin, ringing around the palpebral opening and acting largely involuntarily, whereas the orbital portion is thicker, with horizontal and oblique fibers. Orbicularis oculi muscles move the brow inferomedially and run at an angle, penetrating the frontalis and orbicularis muscles to insert into the dermis above the middle third of the eyebrow, whereas the procerus and depressor supercilii pull the brow inferiorly, creating a frown or furrowed brow.
what treatments and indications are and are not officially approved by Health Canada or the Food and Drug Administration. Not all patients respond well to BTX-A injections, especially older patients with existing brow ptosis or extensive photodamage. BTX-A works by relaxing the underlying musculature that causes dynamic facial rhytides; nondynamic rhytides may improve from BTX-A treatment but rarely disappear completely. Before treatment, standardized, same-magnification, color photographs of the muscles at rest and maximum frown determine individual patient characteristics. Document each patients current anatomy with careful photographs that provide before and after comparisons and note any atypical features. Sites and dosages The type of brow arch, asymmetry, ptosis, and regional muscle mass can be important factors in determining injection sites and dosages. The male brow, associated with greater muscle bulk, requires more toxin to produce paresis (Fig. 3). A variety of injection sites and dosages have been reported in the literature, ranging from a single injection of 10 U into each corrugator to total doses of 20 to 50 U spread over seven sites [9]. For women, the authors current dose is a total of 25 to 40 U BTX-A. Although they previously reported lower total doses of 20 U [9], current dose-ranging studies suggest that higher doses of 30 and 40 U produce significantly greater responses with the longer duration on glabellar lines than 10 or 20 U [10]. Most patients injected with higher doses report benefits lasting 3 to 4 months; although some continue to benefit for as long as 6 to 8 months, these patients usually have experienced a series of injections over a year or more. In addition, the
Procedures Injections of BTX-A for glabellar rhytides are rapid, can be performed on an outpatient basis, and do not require a lengthy recovery period, unlike more invasive procedures [5]. The best outcomes arise from individualizing treatment sites and doses to match each patients needs [9]. Although there are currently two commercially available sources of BTX-A, all references in this article refer to the Botox, Botox Cosmetic, or Vistabel formulations, unless otherwise specified. The clinician should be aware, however, of the significant clinical differences between the sources of BTX-A, and adjust dosages accordingly. Patient assessment and education In preparing patients for treatment, it is important to address their safety concerns. Ensure that they understand the procedures, what to expect before and after treatment, potential side effects (including ptosis or bruising), the typical time course of the clinical effects, and the need for retreatment after 3 to 6 months. All of the authors patients sign an informed consent form, which outlines the treatment, the reasons for treatment, the expected outcomes, and the potential risks and benefits for the average patient. Informed consent forms also ensure that patients understand
Fig. 3. The male brow, associated with a greater muscle mass, often requires more toxin to produce paresis, compared with the female brow.
140
authors found that injecting total doses of 30 to 40 U leads to a significant lateral, central, and medial eyebrow elevation that peaks 12 weeks following injection [11,12]. Although few studies have been conducted in men, it is known that greater doses are required to produce a satisfactory response in the glabellar region, more than double the amount required in women. Data show that men injected with 60 and 80 U BTX-A achieve a better response rate and no increase in adverse effects than men injected with lower doses [13]. In the authors clinic, initial doses are 30 U (in women) and 60 U (in men). Simply halving the volume of saline used to reconstitute the vial is an easy method of doubling the injected dose for men. If patients fail to experience a sufficient response after the first treatment, the dose is increased to 40 and 80 U in women and men, respectively. Injection techniques Injection techniques vary by clinic and injecting physician. The following injection techniques are used in the authors clinic with the Botox or Botox Cosmetic formulations. 1. Follow all usual precautions of sterility and skin preparation before injection. 2. Reconstitute the BTX-A with sterile, preserved saline. The authors find that it is more efficient to apply low-volume, concentrated toxin (100 U/mL). 3. Use a bottle opener to remove the vials rubber stopper gently so that the injecting needle remains sharp. Draw up the appropriate dose of BTX-A into the syringe and express the air. The authors clinic uses the Becton-Dickinson UltraFine II short needle 0.3 insulin syringe (BectonDickinson Inc., Franklin Lakes, NJ), which has an integrated 30-gauge, silicon-coated needle to minimize patient discomfort [14]. The needle dulls after approximately six injections and should then be discarded. 4. Seat the patient with chin down and head slightly lower than the physicians. The authors always begin by injecting the central area (procerus), because that area is less painful and can be massaged. This helps the patient to become accustomed to the injection procedure. Five to 10 U are injected into the procerus at a point below a line joining the brows and above the crossing point of the X formed by joining the medial eyebrow to the contralateral inner canthus (Fig. 4).
5. Next, insert the needle directly in the medial corrugator above the caruncle of the inner canthus (at the bony supraorbital ridge) and inject 4 to 10 U. Always place the injection site above the bony supraorbital ridge, regardless of eyebrow position, at a point where it is possible to apply postinjection pressure if bleeding is encountered. Injectors should keep their nondominant thumb on the orbital rim to avoid injection within the orbit. 6. Partially withdraw the needle, keeping it beneath the skin, and reposition it until it angles superiorly. 7. Advance the tip until it is approximately 1 cm above the previous injection site in the orbicularis oculi; inject another 4 to 10 U. 8. Repeat the injection on the contralateral side to achieve a balanced look. 9. Finally, inject an additional 3 to 10 U into a point 1 cm above the supraorbital rim in the midpupillary line in those with horizontal brows. After the injections are complete, instruct the patient to remain vertical for the next 2 hours and frown as much as possible while the toxin is binding. Patients should not press or manipulate the injected areas. Typically, neuromodulation of the injected muscles begins to occur 1 to 2 days after injection, increasing in intensity during the first week [15]. At 2 weeks, patients are asked to return for a follow-up visit, at which time photographs are taken and treatment responses are assessed. Patients with deep furrows at 2 weeks may require the addition of a filler. BTX-A is used routinely as adjunctive therapy with soft tissue augmentation to achieve more effective, longer lasting results. BTX-A often eliminates or reduces the muscular activity responsible for the wrinkles, improves the response, and increases the longevity of the filling agent [16 18]. Injection intervals should be no more frequent than every 2 weeks, and injections should be performed using the optimum dose. Further injections at 3- to 4-month intervals over a period of 1 year in those with deep glabellar lines are recommended to keep the
Fig. 4. Injection sites for the treatment of glabellar rhytides.
141
musculature paralyzed and allow the furrows to drop out. After 1 year, patients return as desired.
Results The safety and efficacy of BTX-A as a treatment for glabellar lines have been well documented. In the authors first published study, glabellar rhytides in 18 patients were treated with BTX-A; 16 out of 17 patients showed improvement for periods ranging from 3 to 11 months [2]. In a much larger prospective, double-blind, randomized, placebo-controlled, clinical trial, 264 patients with moderate to severe glabellar lines at maximum frown received 20 U BTX-A or placebo into five glabellar sites and were followed for 120 days after injection [5]. Patients receiving BTX-A experienced a significantly greater reduction in glabellar line severity than patients receiving placebo, as measured by physician rating of glabellar line severity at maximum frown and rest and patient assessment of improvement (Fig. 5). These clinical effects lasted from 3 to 6 months, although the magnitude and duration of effect were somewhat lower in patients greater than or equal to 51 years than in patients younger than 50 years. In the authors experience, maximum clinical effects typically last around 3 to 4 months. Although some patients continue to benefit for as long as 6 to 8 months or longer, these patients usually have received a series of treatments over the period of a year or more.
Combination therapy with BTX-A and a filling agent provides superior benefits for severe glabellar rhytides than BTX-A alone. The authors reported a retrospective study of the improved treatment of combined BTX-A with hylan B (Hylaform) compared with BTX-A alone in patients with moderate or severe glabellar rhytides at rest [17]. After treatment, no patients treated with BTX-A alone achieved a reduction in rhytides to none or mild, whereas 94% of those treated with both BTX-A and hylan B achieved mild rhytides. In a prospective, randomized study of 38 patients with moderate-to-severe glabellar rhytides, BTX-A plus nonanimal stabilized hyaluronic acid led to a better response both at rest and on maximum frown than nonanimal stabilized hyaluronic acid (Restylane) alone (Fig. 6) [18]. In addition, combination therapy led to a longer duration of response: the median time for return to preinjection furrow status occurred at 18 weeks in the nonanimal stabilized hyaluronic acid alone or BTX-A alone groups, compared with 32 weeks in patients treated with BTX-A plus nonanimal stabilized hyaluronic acid.
Complications Most complications are relatively uncommon and are related to poor injection techniques [19]. The authors have used BTX-A for over 20 years, and none of their patients has suffered a serious, irreversible complication.
Fig. 5. Before (A) and after (B) treatment of glabellar rhytides with BTX-A.
142
Fig. 6. (A H) Severe glabellar rhytides before and after nonanimal stabilized hyaluronic acid alone (R306). Severe glabellar rhytides before and after BTX-A plus nonanimal stabilized hyaluronic acid (RB304). Both subjects photographed using Canfield photography at rest and on maximum frown before treatment and after treatment.
143
Brow ptosis One of the most undesirable adverse events, brow ptosis occurs when the injected toxin affects the frontalis during glabellar or brow treatment and is related to poor injection technique. Avoiding brow ptosis begins with proper patient selection and preinjecting the brow depressors in patients with low-set brows, mild brow ptosis, and patients over the age of 50 years [19]. Using a higher concentration allows for more accurate placement of injections, greater duration of effect, and fewer side effects, because of toxin spread of 1 to 1.5 cm (2 to 3 cm diameter) associated with each point of injection. Injecting the glabella and the whole forehead in one session is also more likely to produce brow ptosis [19]. Patients must be advised to remain upright for 2 hours, exercise the treated muscles as much as possible for the first 4 hours, and avoid rubbing or massaging the injected area for 2 hours following treatment. Mild brow ptosis responds to aproclonidine (Iopidine 0.5%) a-adrenergic agonist ophthalmic eye drops. Eyelid ptosis Ptosis of the upper eyelid occurs when the injected toxin migrates to the upper eyelid levator muscle, producing a weak paralytic effect as early as 48 hours or as late as 14 days after injection and persisting from 2 to 12 weeks. The incidence of ptosis in the authors clinic is low (0% to 1%). Accurate dose dilution and injecting the toxin no closer than 1 cm above the central eyebrow decreases the chances of ptosis, as does advising patients to remain upright for 2 to 3 hours following treatment and to refrain from manipulating the injection site. Bothersome ptosis can be treated with aproclonidine [19].
References
[1] Carruthers J, Carruthers A. Botox treatment for expressive facial lines and wrinkles. Curr Opin Otolaryngol Head Neck Surg 2000;8:357 61. [2] Carruthers JDA, Carruthers JA. Treatment of glabellar frown lines with C. botulinum-A exotoxin. J Derm Surg Oncol 1992;18:17 21. [3] Keen M, Blitzer A, Aviv J. Botulinum toxin A for hyperkinetic facial lines: results of a double-blind, vehicle-controlled study. Plast Reconstr Surg 1994;94: 94 9. [4] Lowe NJ, Maxwell A, Harper A. Botulinum A exotoxin for glabellar folds: a double-blind, vehicle controlled study with an electromyographic injection technique. J Am Acad Dermatol 1996;35:569 72. [5] Carruthers JA, Lowe NJ, Menter MA, et al. A multicenter, double-blind, randomized, placebo-controlled study of the efficacy and safety of botulinum toxin type A in the treatment of glabellar lines. J Am Acad Dermatol 2002;46:840 9. [6] Knize DM. An anatomically-based study of the mechanism of eyebrow ptosis. Plast Reconstr Surg 1996;97: 1321 33. [7] Isse NG, Elahi MM. The corrugator supercilii muscle revisited. Aesthetic Surg J 2001;21:209 15. [8] Knize DM. Muscles that act on the glabellar skin: a closer look. Plast Reconstr Surg 2000;105:350 61. [9] Carruthers A, Carruthers J. Botulinum toxin type A: history and current cosmetic use in the upper face. Semin Cutan Med Surg 2001;20:71 84. [10] Carruthers A, Carruthers J, Said S. Dose-ranging study of botulinum toxin type A in the treatment of glabellar lines. Presented at the 20th World Congress of Dermatology. Paris, France, July 1 5, 2002. [11] Carruthers A, Carruthers J. Botulinum toxin type A (BTX-A) in the treatment of glabellar rhytides: an objective analysis of treatment response. Presented at the American Academy of Dermatology 2002 Winter Meeting. New Orleans, LA, February 22 27, 2002. [12] Carruthers A, Carruthers J. Glabella BTX-A injection and eyebrow height: a further photographic analysis. Presented at the Annual Meeting of the American Academy of Dermatology. San Francisco, March 21 26, 2003. [13] Carruthers A, Carruthers J. Botulinum toxin type A for treating glabellar lines in men: a dose-ranging study. Presented at the Annual Meeting of the American Academy of Dermatology. San Francisco, March 21 26, 2003. [14] Flynn TC, Carruthers A, et al. Surgical pearl: the use of the Ultra-Fine II short needle 0.3-cc insulin syringe for botulinum toxin injections. J Am Acad Dermatol 2002; 46:931 3. [15] Product monograph. Botox cosmetic (botulinum toxin type A for injection) purified neurotoxin complex. Irvine, CA: Allergan; 2002. [16] Fagien S, Brandt FS. Primary and adjunctive use of botulinum toxin type A (Botox) in facial aesthetic
Summary Injections of BTX-A improve the appearance of glabellar rhytides by relaxing the underlying musculature in a quick and relatively painless procedure that can be performed over the lunch hour and causes few adverse effects. Alone or in combination with filling agents, BTX-A has become one of the most popular cosmetic procedures performed. Cosmetic facial aesthetics is a dynamic, rapidly evolving field, however, and producing the most optimal benefits means understanding the dynamics of facial musculature and principles of BTX-A therapy and remaining abreast of the latest clinical developments.
144
A. Carruthers, J. Carruthers / Dermatol Clin 22 (2004) 137144 (Botox) and non animal sourced hyaluronic acid (Nasha, Restylane) in combination compared to Nasha (Restylane) alone in severe glabellar rhytides in adult female subjects. Dermatol Surg, in press. [19] Klein AW. Complications and adverse reactions with the use of botulinum toxin. Dermatol Surg, in press.
surgery: beyond the glabella. Clin Plast Surg 2001;28: 127 48. [17] Carruthers J, Carruthers A, Maberley D. Deep resting glabellar rhytides respond to BTX-A and hylan B. Dermatol Surg 2003;29:1 6. [18] Carruthers J, Carruthers A. A prospective, randomized, parallel group study analyzing the effect of BTX-A
Dermatol Clin 22 (2004) 145 149
Botox for the eyes and eyebrows

Arnold W. Klein, MD
Department of Dermatology, David Geffen School of Medicine at UCLA, 435 North Roxbury Drive, Suite 204 Beverly Hills, CA 90210, USA
The forehead and crows-feet (periorbital wrinkles) are among areas where Botox has been quite helpful. This cosmetic use is not approved by the Food and Drug Administration and is considered offlabel. The effect, although temporary, is extremely popular with patients, has a very low incidence of side effects, and is a relatively easy technique to acquire. One of the primary tenets to remember when injecting botulinum toxin is that one is injecting muscles, not wrinkles. It is the underlying pull of the musculature that causes the wrinkles and it is the relaxation of those muscles that alleviates the wrinkles. It is incumbent on the injecting physician to understand thoroughly the musculature of the face and the interaction of these muscles (Fig. 1). The occipitofrontalis (frontal belly) raises the eyebrows and produces transverse wrinkles of the forehead. The orbicularis oculi functions as the sphincter of the eye. The orbital portion acts primarily to depress the eyebrow. The palpebral portion pertains to the eyebrow and the eyelid. The depressor supercilii depresses the eyebrow. The procerus pulls the forehead skin in an inferior direction and is determinant of medial eyebrow height [1]. Horizontal forehead lines are produced by the action of the frontalis. This is a large, vertically oriented muscle that inserts superiorly into the galea aponeurotica and inferiorly into procerus, orbicularis oculi, corrugator supercilii, depressor supercilli, and the skin of the brow. The brow is the aesthetic center of the upper face just as the lips are the aesthetic center of the lower face. The objective in treating this area is to lessen the forehead lines without causing brow ptosis or a com-
E-mail address: melissa.hollis@doctorklein.md
plete lack of expressiveness. The goal is to soften the forehead lines without eliminating them completely. Before injecting the forehead of a patient for the first time, it is best to determine the anatomic boundaries. Pre-existing or anatomic changes in the underlying musculature can alter the effects of Botox, and modifications in injection technique should be made. The width of the forehead and location of the temporal fusion line vary from patient to patient. Botulinum toxin treatment of the forehead needs to be individualized. The high-narrow forehead must be treated differently than the short and wide forehead. When treating the forehead, one must consider the aesthetic effects it will have on brow shape and position. For the forehead, six injections of 0.10 mL (3.3 U) are placed across the forehead in a uniform grid (using a 3-mL per vial dilution). Electromyogram assistance is used and in this area visible blebs are temporarily produced on injection. It must be remembered that the brow shape can be changed because the major muscles responsible for elevating the brow are being eliminated. The characteristics of a wellproportioned female eyebrow are well established. The medial aspect of the brow should begin at a point defined by a straight line drawn from the lateral nose upward. The eyebrow should arch maximally at a point defined by a line drawn from the lateral nose through the pupil. The eyebrow should end at a point defined by a line from the lateral nose through the lateral aspect of the eyeball (Fig. 2). John Pershing from Yale has shown that altering brow shape or position has a dramatic effect on others perception of mood. Thirty-five versions of facial images were viewed by 20 participants. Surprise, anger, sadness, disgust, happiness, and tiredness were evaluated. The greatest variable was found to be brow shape. The lateral-most injection should be vertically above the mid-pupil, although with wider foreheads
0733-8635/04/$ see front matter D 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.det.2004.02.001
146
A.W. Klein / Dermatol Clin 22 (2004) 145149
Fig. 1. Understanding facial anatomy is critical to the successful use of Botox.
this can be extended beyond the pupil to the iris. Lack of expressivity may be caused by injection of frontalis lateral to the mid-pupillary line. It must be remembered that the brow shape can be changed because one is relaxing the major muscle responsible for elevating the brow. If the patient has a low eyebrow, treatment of the forehead lines should be avoided, or limited to that portion of the forehead 4 cm or more above the brow. The glabella and the entire forehead should not be injected during the same session. This invariably produces brow ptosis. Frequently, only the upper half of the forehead should be injected to avoid the possibility of brow ptosis. The upper half of the forehead and the frown can be done at the same time. It is important always to remember the brow dynamics of the opposing muscles (Fig. 3). Injections in the forehead should always be above the lowest fold
Fig. 2. The feminine eyebrow. The well-proportioned eyebrow should begin at point A, maximally arch at point B, and end at point C.
produced when the subject is asked to elevate their forehead (frontalis). The beneficial effects typically last from 4 to 6 months. The lower 2.5 to 4 cm of the frontalis muscle moves cephalad to elevate the eyebrows. Older people use this to raise their eyebrows to see. One must always cautiously address the lower frontalis and stay 2 cm above the brow in all individuals. Weakening the frontalis muscle rather than completely immobilizing it can achieve the desirable goal of reducing the folds while maintaining some forehead movement. In individuals who have significant brow ptosis, the possible effects of frontalis injection should be discussed with the individual and injection of the brow depressors (the glabellar complex) performed. There is upward diffusion of toxin, which addresses the lower forehead lines. The frontalis muscle ends midway between the lateral and the mid-brow. The orbicularis oculi depresses the portion of the brow lateral to this. Injection of 3 U of Botox just below the lateral brow and lateral to the temporal fusion line can raise the lateral brow, giving the patient a chemical brow-lift of up to 2 mm [2]. Treatment of the brow depressors alone may be indicated. This can be accomplished without totally eliminating the frown. This produces brow elevation, especially medially, and a more open-eyed look. Treated individuals also frown less because of weak treatment of the brow opposers, but can frown if required. This form of treatment is more successful in women, especially those who do not have heavy horizontal brows.
147
Fig. 3. Brow dynamics.
Many of the complications that occur in the brow can be mitigated if, before injection, the full range of motion of the frontalis muscle is noted and the proposed injection sites are marked. Patients should also be reminded that most of the population (roughly 90%) has some degree of brow asymmetry and warned that this can be diminished or, conversely, may be accentuated by the treatment. An alternative method is the injection of large volumes of low-dose toxin to smooth crows-feet and brow area. This method works by weakening, but not paralyzing, underlying facial muscles. Many have found, however, that these large dilutions result in paralysis of unacceptably short duration [3]. Large dilutions have also, naturally, resulted in larger areas of paralysis as an associated side effect. In general, a higher concentration allows for more accurate placement and greater duration of effect and fewer side effects. Lower concentrations encourage the spread of the toxin. It should be remembered that there is an area of denervation associated with each point of injection because of toxin spread of about 2.5 to 3 cm. The concentration of the toxin is highest at the point of injection and the concentration gradient decreases rapidly with distance from this point. With higher dilutions and more volume of solution injected, this area of diffusion naturally increases and the concentration gradient is much less steep. The most significant complication of treatment of the frontalis is brow ptosis. Botox should not be injected above the middle brow so as to avoid brow ptosis. Injection should also be avoided within 1 cm of the bony superior orbital rim for the same reason.
Botox works best in younger female patients (20 45 years of age). In some older patients and in some male patients, redundant skin can be created under the brow (pseudoptosis), so these patients should be approached with caution. Treatment of the brow depressors may be necessary, however, after brow ptosis has become manifest. Untoward sequelae that can occur at any site because of percutaneous injection of Botox include pain, edema, erythema, ecchymosis, headache, and short-term hypesthesia. Discomfort can be decreased by use of topical anesthetics (EMLA, Astra Pharmaceuticals, Westborough, MA) before injection, and the use of smaller-gauge needles. Local anesthesia injections are also helpful in reducing pain. Ice applied immediately before and after injection further reduces the pain and the edema and erythema associated with an intramuscular injection. Ecchymosis can be minimized by avoiding aspirin, aspirincontaining products, and products that inhibit platelet function (nonsteroidal anti-inflammatory agents) for 7 to 10 days before injection. Limiting the number of injections and postinjection digital pressure without manipulation assists in reducing the number and severity of bruising Ecchymosis occurs easily in the soft eyelid tissue and can be minimized by applying pressure at the injection site immediately following needle withdrawal. More importantly, injecting superficially in this area greatly reduces this occurrence. An equally aesthetically unfavorable outcome is the brow that assumes a quizzical or cockeyed appearance [4]. That is, the lateral eyebrows may arch
148
upward to an excessive extent because of the unopposed pull of the frontalis. This occurs when the lateral fibers of the frontalis muscle have not been appropriately injected. This may be corrected by injecting 3 U about 2 cm above each brow medial to the temporal fusion line. For this reason most individuals have moved their lateral-most forehead injections laterally. Ptosis of the upper eyelid, although less likely, also can occur. This is secondary to downward diffusion of the injected material and often caused by poor technique. Eyelid ptosis is a significant risk if injections are placed at or under the middle of the eyebrows in the vicinity of the mid-pupillary line. Diffusion of the toxin downward can induce levator ptosis requiring correction by recurrent use of apraclonidine eye drops. The baseline rate of diffusion of botulinum toxin may be amplified by rapid or forceful injection, or excessively deep injection at the level of the periosteum, which can disperse botulinum toxin far from the injection site and may increase the risk of eyelid ptosis. Use of very dilute solutions of toxin may also result in diffusion of the material to areas distant from the injection site. The female brow is normally positioned above the bony orbital margin, rising in its central and lateral portions to resemble a wing. Ptosis of the brow occurs with photodamage and with the inherent and habitual use of the brows in thinking, working, and speaking. The resulting interpretation of this expression is one of fatigue, depression, frustration, or angerall negative emotions. The normal male brow is situated below the orbital margin but this is perceived as a vital part of masculine presentation. An injection directly under the lateral eyebrows into the lateral brow depressors can make the eye appear more open and create an aesthetically desirable eyebrow arch. Injections that are incorrectly placed too far medial to the lateral edge of the brow can result in brow ptosis or even lid ptosis. Small quantities should be used because diffusion from larger injections can further contribute to the risk of ptosis. Precautions can also be taken to reduce the likelihood of overcorrection in those who would benefit from this technique. Limiting the quantity of botulinum toxin injected and concurrently injecting the medial depressors in the glabellar complex to raise the medial brow may help avoid aesthetically displeasing overcorrection. Crows-feet in the lateral canthal area are produced by the action of the orbicularis oculi, whose fibers are arranged in a circular pattern around the eyes, and also by the elevators of the corner of the mouth, risorius, and zygomaticus. Contraction of
orbicularis is needed for forceful closure of the eyelids. The goal of treatment is to produce a weakening just in the area of the crows-feet lines. Treatment of the lateral orbital (crows-feet) areas with Botox produces satisfactory amelioration of wrinkling in this area. Younger individuals have no wrinkling in this area, so that if an individual just has the crows-feet area treated, this does not produce any detectable change apart from a more youthful appearance. This is distinct from treatment of the glabellar area, which produces an inability to frown. When treating this area it is important to treat only the area that shows wrinkling. In addressing the periocular area with botulinum toxin, it is possible to erase crows-feet, soften lateral oblique lines on the forehead, smooth the inferior oblique lines of the cheek, soften the suborbital area, and elevate the lateral eyebrow. To treat the periorbital wrinkles, measure 1.5 cm from the lateral canthus (or 1 cm lateral to the bony margin) and inject at this site. Again, the electromyogram should be used. The observance of such a boundary is more important if very dilute, largevolume injections are performed. Consequently, injection of large volumes should be avoided. Oculoplastic surgeons using small, concentrated volumes often inject right at the lateral canthus. This dose should be repeated 1 cm inferior and slightly medial to the first injection site. The dose should also be repeated 1 cm superior and slightly medial to the first injection site. These sites can be massaged gently, but firmly, away from the orbital rim. Some believe that this produces a more even result and reduces the bruising, which is more common in this location. Nevertheless, one should always stay above the zygomatic arch for the inferior injection. At each site, 0.1 mL (3.3 U) is used for a total of 3 3.3 or 9.9 U per side. A total dose of 6 to 18 U per side is satisfactory for most individuals but can be increased if necessary. Similarly, if the wrinkled area is larger, appropriately spaced injection sites can be used, bearing in mind that the effect of the toxin seems to spread at least 1 cm radius from the injection site in this area. Injection should follow the pattern of the wrinkling. There are four basic wrinkle patterns of crows-feet: (1) full fan from the upper eyelid to the upper cheek, (2) lower lid and upper eyelid to the upper cheek, (3) upward sweeping crows-feet, and (4) central zone of crows-feet at the lateral canthus only. These should be directed at the site of the wrinkles only. It is important to keep the periorbital injections as superficial as possible to avoid blood vessels around the eyes. This technique is best for lateral and upper crows-feet at rest.
149
If a patient has redundant skin, one should be careful because the skin can end up folding on the zygomatic arch, producing an undesirable cosmetic result. This technique is best for lateral and upper crows-feet at rest. Ecchymoses are common when treating periorbital wrinkles, so ice compresses are advised after each side is treated [5]. This can be almost totally avoided by injecting the Botox in a wheal or a series of continuous blebs with each injection at the advancing border of the previous injection to avoid hitting blood vessels. All Botox patients are told to stay upright for at least 4 hours. Immediately after injection, movement of the treated muscles is encouraged so that the toxin is taken-up by the involved neural end plates. Deeper zygomaticus lines often connect to the lower crows-feet lines. Treatment of the crows-feet can paradoxically worsen the zygomaticus lines because the redundant cheek skin gravitates downward. Anatomically, many facial muscles do not insert into bone (eg, the frontalis). When the treating physician has the patient smile to see the crows-feet, the lower crows-feet are really created by the zygomaticus major, not the obicularis oculi. If the crowsfeet are treated, one quite large lower crows-foot remains when the patient smiles. This is why Botox is best balanced by fillers in the lower areas. A more wide-eyed look can be obtained for the patient by injecting the lower eyelid at the lash margin. Two Units of Botox are injected at the midpupil and 2 U midway between the pupil and the outer canthus. Some injectors only use the single injection at mid-pupil. This procedure also helps to smooth out fine lines under the eyes. This must be approached cautiously and should not be attempted if the patient exhibits a significant degree of scleral show pretreatment; if the patient has had significant surgery under the eye previously; or if the patient has a great deal of redundant skin under the eye as exhibited by a snap test of the lower eyelid (ie, if the lid does not return to its previous position when manually pulled down). Lateral rounding of the eye, however, may result when 4 U or more are injected. Although many patients are delighted by the rounding, some may complain that it makes the pre-existing oval contour of their eyes rather too round.
Injections into the soft skin under the lateral eyes can cause ecchymoses. Tissue should be handled gently, and superficial vessels identified and avoided. Blebs should be placed immediately under the epidermis because the periocular muscles are extremely superficial at this site. Pressure should be applied immediately following injection in the event of incipient purpura to mitigate the risk of a fullfledged bruise. Reported complications in this area are bruising, diplopia, ectropion or a drooping lateral lower eyelid, and an asymmetric smile caused by the toxin diffusing to the zygomaticus major. To avoid these complications one should inject at least 1 cm outside the bony orbit or 1.5 cm lateral to the lateral canthus and not inject close to the inferior margin of the zygoma. Violating these boundaries has on occasion also resulted in diplopia caused by medial migration of Botox and resultant paralysis of the lateral rectus muscle. If diplopia occurs covering or patching the eye alleviates some of the double vision. Injecting below the lateral margin of the zygoma and deeply can affect the zygomaticus major. Strabismus can also occur. Both diplopia and strabismus are exceedingly uncommon side effects. If they manifest, referral to an ophthalmologist is imperative for appropriate management.
References
[1] Toledo LS. Facial rejuvination: technique and rationale. In: Fodor PB, Nicanor GI, Hengst TC, editors. Endoscopically assisted aesthetic plastic surgery. St. Louis: Mosby-Year Book; 1996. p. 91 105. [2] Fraenkel AS, Kamer FM. Chemical brow lift. Arch Otolaryngol Head Neck Surg 1998;124:321 3. [3] Guyuron B, Huddleston S. Aesthetic indications for botulinum toxin. Plast Reconstr Surg 1994;93:913 8. [4] Burns RL. Complications of botulinum exotoxin. Presented at the 25th Annual Clinical and Scientific Meeting of the ASDS. Portland, OR, May 13 17, 1998. [5] Keen M, Kopelman J, et al. Botulinum toxin A: a novel method to remove periorbital wrinkles. Facial Plast Surg 1994;10:141 6.
Dermatol Clin 22 (2004) 151 158
Botulinum toxin A in the mid and lower face and neck

Jean Carruthers, MDa,*, Alastair Carruthers, MDb
a
Department of Ophthalmology, University of British Columbia, 943 West Broadway, Suite 720, Vancouver, BC V5M 4E1, Canada b Division of Dermatology, University of British Columbia, Vancouver, BC V5M 4E1, Canada
Although once considered a novel concept, the use of botulinum neurotoxins, primarily botulinum types A (BTX-A) and B (BTX-B), to smooth hyperkinetic lines in the upper face has become an accepted and successful procedure in facial rejuvenation. In the mid and lower face and neck, botulinum toxin injections diminish rhytides and sculpt the face into more aesthetically pleasing lines. The doses used in the mid and lower face and neck differ greatly from those in the upper face, however, and only experienced clinicians with a detailed understanding of the underlying muscular anatomy and tissue relationships should inject in areas associated with more risk of potential complications. This article reviews current approaches to botulinum toxins as primary and adjunctive therapies in the mid and lower face and neck.
Botulinum toxins Botulinum neurotoxins derive from the bacterium Clostridium botulinum and include seven distinct serotypes, identified as A, B, C1, D, E, F, and G [1]. These serotypes share the ability to block neurotransmission at the neuromuscular junction by blocking acetylcholine release, producing denervation and atrophy of cholinergic skeletal muscles. Because the neurotoxin serotypes differ in their cellular mechanisms of action and in the size of the neurotoxin complex, however, they are not interchangeable and their clinical profiles vary. BTX-A is the most powerful toxin and was the first to be developed for clinical use.
* Corresponding author. E-mail address: drjean@carruthers.net (J. Carruthers).
At this time in North America there are two commercially available toxins: Botox (BTX-A) and Myobloc (BTX-B). Botox is the only botulinum toxin currently approved for cosmetic use in North America, although Dysport (BTX-A) is available in Europe and is under consideration for licensing by the US Food and Drug Administration. Because each preparation differs in terms of the C botulinum strain, potency, and manufacturing, the biologic behaviors of each are not interchangeable, and the dosages for each product vary. For most procedures, 1 U of Botox has efficacy equivalent to 3 to 5 U of Dysport. Botox is distributed in a crystalline form with approximately 100 U per vial. The package insert recommends reconstitution with sterile, nonpreserved saline [2]. Recent data, however, suggest that reconstitution with preserved saline does not impair the stability of BTX-A [3,4] and is less painful than nonpreserved saline [5]. The optimum concentration depends on the procedure. Although the package insert suggests that the reconstituted toxin should be used within 4 hours, evidence now indicates that the reconstituted product can be stored refrigerated for a week or longer without any loss of efficacy [6]. Myobloc is available in a liquid formulation containing BTX-B, 5000 U/mL, and is available in 0.5-, 1-, and 2-mL vials containing BTX-B, saline, human serum albumin, and sodium succinate, with a pH of approximately 5.6 (accounting for the stinging sensation reported on injection) [7]. Reconstitution is not required and is hampered by overfill of the vials. Clinicians with the desire to add saline are advised to do so in the syringe. The unopened vial is stable for months or years; once opened, the labeling is similar to BTX-A. Dysport is available as a lyophilized vial containing 500 U of BTX-A and sodium chloride, lactose,
152
J. Carruthers, A. Carruthers / Dermatol Clin 22 (2004) 151158
and human serum albumin [8]. In Europe, Dysport is labeled for transport at ambient temperature and storage at 2C to 8C, and the guidelines for reconstitution and use are similar to those for Botox.
Clinical application of botulinum type A Intramuscular injections of BTX-A have become the treatment of choice for most forms of focal dystonia. The ability of botulinum toxin to block acetylcholine release from autonomic nerve endings innervating glandular tissue or smooth muscle has led to investigation of its use for other indications including hyperhidrosis [9,10] and gastrointestinal disorders [11 14]. More recently, BTX-A has been reported to have beneficial effects in relieving myofascial pain [15,16] and tension and migraine headache [17 22], and for the treatment of obesity [23]. Because most of the authors clinical experience resides with Botox, all references hereafter refer to the Botox or Botox Cosmetic formulations, unless otherwise specified. Clinicians should be aware, however, of the significant clinical differences between the sources of BTX-A and adjust dosages accordingly.
Among cosmetic users, the average volume of dilutant has been reported to be 2.5 mL [3], but the authors typically dilute the vial in 1 mL. In general, higher doses of BTX-A delivered in smaller volumes keep the effects more localized and allow for the precise placement of the toxin with little diffusion, whereas smaller doses in larger volumes tend to cause more widespread effects [24]. One of the greatest concerns with the use of BTX-A is the formation of neutralizing antibodies. The total protein concentration and number of units injected are critical in determining potential immunogenicity, and some studies suggest that BTX-A injections at more frequent intervals or at higher doses may lead to a greater incidence of antibody formation [2]. The protein concentration in the current lots of Botox is significantly lower than in previous lots, however, and has been shown to be less antigenic than the original product. The overall risk of antibody formation using BTX-A at recommended doses for cosmetic applications is low, and injecting the lowest effective dose with the longest feasible intervals between injections minimizes the potential for immunogenicity.
Midface indications Contraindications Botulinum type A is contraindicated in patients with neuromuscular disease, such as myasthenia gravis and amyotrophic lateral sclerosis [2]. Experience with BTX-A in pregnant and lactating women is extremely limited, so caution is warranted in these cases (the authors believe that use in pregnancy is contraindicated). Other contraindications include infection at the injection site, or a known hypersensitivity to any of the product contents. The possibility of drug interactions exists, and patients taking aminoglycoside antibiotics should receive smaller doses. Hypertrophic orbicularis Widening the palpebral aperture is part of the new artistry of BTX-A in facial contouring and sculpting. Hypertrophy of the pretarsal portion of the orbicularis oculi can give a jelly roll appearance. In some patients, the act of smiling transiently diminishes the perceived size of the palpebral aperture, especially in Asian patients, who sometimes desire a more round-eyed appearance. Flynn et al [25] injected 2 U subdermally, 3 mm inferior to the lower pretarsal orbicularis, in addition to three injections of 4 U placed 1.5 cm from the lateral canthus, each 1 cm apart and found a mean palpebral aperture increase in 86% of patients of 1.8 mm at rest and 2.9 mm at full smile [25]. One must be careful, however, to select patients who have a good preinjection snap test and who have not had previous lower eyelid ablative resurfacing or infralash blepharoplasties without a coexisting canthopexy to support the normal position of the lower eyelid. Goldman [26] reports one case in which a patient developed festooning of the infraocular area 2 to 3 days following injections of 10 and 2 U BTX-A in the midlateral canthal region and 2 to 3 mm below the ciliary margin in the midpapillary line, respectively.
Dosing The effects of BTX-A injections begin to appear within 1 to 2 days and typically last for 3 or 4 months or longer. There is a tendency for repeated injections to show a longer duration of effect. Larger muscles require larger unit doses of BTX-A. The volume of the dose should be adjusted according to the desired diffusion of toxin: more concentrated doses diffuse less and should be used to target small muscles.
153
Bunny lines and nasal flare Contraction of the muscular fibers of the upper nasalis across the bony dorsum of the nose causes fanning rhytides (bunny lines) at the radix of the nose. Weakening of the underlying mimetic musculature with botulinum toxin effectively and dramatically softens these lines. The authors inject 2 to 4 U of botulinum toxin into the belly of the upper nasalis as it transverses the nasal bone. The injection should be given high on the lateral nasal wall, inferior to the angular vein. Care must be taken to give the injection well above the nasofacial groove to avoid relaxing the levator labii superioris and causing upper lip ptosis. Gentle massage should follow the injection to diffuse the toxin. Some individuals repeatedly dilate their nostrils in social situations, revealing the sides of the columella and septum. Injecting 5 to 10 U BTX-A bilaterally into the lower nasalis fibers draped over the lateral nasal ala, at the most active area of muscle contraction, can decrease involuntary nostril flare in some patients for 3 to 4 months [24]. Nasolabial folds Nasolabial (melolabial) folds extend from the lateral nasal ala to a point lateral to the external angle of the mouth. Older individuals who have sustained photodamage or who smile excessively develop a permanent, deep crevice. The most common treatment for these folds has been soft tissue fillers and laser resurfacing. Injecting BTX-A directly into the area of the fold is most likely to produce an asymmetric smile and upper lip ptosis. Weakening the lip elevator muscles and zygomaticus and risorius muscles, tempting although it may be, flattens the midface and elongates the upper lip. In patients who have a naturally shorter upper lip, however, very small doses (1 U) into each lip elevator complex in the nasofacial groove collapses the upper extent of the nasolabial fold but also elongates the upper lip. Because the effect is long lasting (F 6 months), one should select patients carefully and be sure to explain fully the aesthetic result of the procedure. Perioral rhytides The orbicularis oris is the sphincter muscle that encircles the mouth, lying between the skin and mucous membranes of the lips and extending upward to the nose and down to the region between the lower lip and chin. Sometimes called the kissing muscle, it causes the lips to close and pucker. Overactive
orbicularis oris causes vertical perioral rhytides that are commonly labeled as smokers lines but can also result from heredity, photodamage, playing a musical instrument that requires embouchure, or even whistling. Patients often are disturbed by the increased vertical length of the cutaneous lip and by the radial upper lip lines that can cause lipstick to bleed upward from the lip and blur the outline of the lip. Although multiple fine wrinkles of the upper lip can be treated effectively with fillers, such as collagen, or with ablative or nonablative resurfacing, deeper wrinkles may be resistant to these treatments. Tiny doses (1 to 2 U per lip quadrant) are usually sufficient to result in localized microparesis of the orbicularis oris, especially when used adjunctively with a soft tissue augmenting agent, such as collagen, hylaruronan, or Artecol, and can greatly improve the appearance of the lip without creating a paresis that might interfere with elocution and suction. To maintain competence of the mouth it is important to be conservative with dosing and to use superficial, rather than deep, injections [24]. Even low doses, however, may result in lip sphincter weakening that affects the ability of the individual to play musical instruments or whistle. Patients should be screened carefully; musicians who play wind instruments, professional singers or speakers, and patients with unrealistic expectations are not ideal candidates for this procedure.
Lower face indications Botulinum toxin should be used with caution for cosmetic indications in the area of the mouth. Dosages are much reduced in comparison with those used for the upper face, and the underlying muscular anatomy varies from patient to patient. Mouth frown and melomental fold The frowning expression created when the lateral corners of the mouth are permanently angled downward gives an impression of disapproval and unpleasantness, even in the absence of a discrete melomental fold or drool groove. The depressor anguli oris (DAO) pulls down the corner of the mouth in opposition to the zygomaticus major and minor muscles. BTX-A injections can weaken the DAO and reset the muscular balance, allowing the zygomaticus to elevate the corners of the mouth and return them to a horizontal position (Fig. 1) [24]. In the authors clinic, 2 to 3 U of botulinum toxin are injected .directly into the DAO on each side of the mouth
154
Fig. 1. Treatment of depressor anguli oris with botulinum type A.
Melomental folds (drool grooves or marionette lines) extending from the downturned corner of the mouth to the lateral mentum involuntarily produces a sad expression and reinforces the negative impression produced by the inverted smile. They also give the appearance of advancing age and decrepitude. Traditionally, soft tissue augmentation has been used alone to rebuild the soft tissue support of the lateral mouth corner and the melomental fold, but the effects are short term. Injections of BTX-A are useful adjuncts to soft tissue augmentation, relaxing the muscles and lengthening the duration of the filling-agent effect, such as Zyplast, Hylaform, Restylane, Perlane, or Artecol, by preventing the repeated molding of the implant [27]. BTX-A in combination with laser resurfacing produces the most satisfactory results. The authors inject 2 to 5 U BTX-A into each DAO immediately above the angle of the mandible and 1 cm lateral to the lateral oral commissure. Caution must be used when placing injections close to the mouth. Injections too medial can cause an ipsilateral weakness of the depressor labii and flattening of the lower lip contour when the mouth
attempts to form an O, and injections placed too high can interfere with the sphincter function of the orbicularis oris, leading to difficulties with speech and suction. Other possible complications include flaccid cheek, incompetent mouth, difficulty with elocution, and asymmetric smile. Injections are not recommended for singers or musicians, or for patients who use their perioral muscles with intensity. Mental crease and peau dorange chin Contraction of the mentalis produces a deep groove, or mental crease, between the lower lip and the prominence of the chin. Soft tissue augmentation in the mental crease leads to visible beading and poor results. Injections into the mentalis at the bony mentum softens the crease while avoiding an incompetent mouth, which can occur from BTX-A injections at the level of the crease. The authors usually inject 3 to 5 U BTX-A per mentalis band. The mentalis serves to raise and protrude the lower lip and wrinkles the skin of the chin, producing horizontal or multiple dimple rhytides called the
155
apple dumpling or peau dorange chin. Previously treated with soft tissue augmentation and laser resurfacing, chin dimpling responds well either to BTX-A plus soft tissue augmentation or BTX-A alone. The authors inject 5 to 10 U BTX-A into the mentalis at the most distal point from the orbicularis oris, the prominence of the chin. Following the injection, massage of the chin is recommended to aid in the diffusion of toxin. Smile lines Deep smile lines, produced by contraction of the zygomaticus and often connected to lower crows feet lines, are best treated with carbon dioxide laser resurfacing. One to 2 U BTX-A injected into each side of the zygomaticus before resurfacing, however, enhances the effects of the procedure [28]. Upper gum show In some patients, the levator labii superioris alaeque nasi retracts the upper lip and produces excessive upper gum exposure, revealing the gum line, upper incisors, and canines. Injecting 1 to 2 U BTX-A into the levator labii superioris on each side of the bony nasal prominence drops the upper lip enough to correct the upper gum show [27]. Because vertical elongation of the cutaneous lip can occur after injections (a process that occurs naturally with aging), treatment produces optimal results in younger patients. The best results are often obtained when BTX-A is used in combination with soft tissue augmentation in the lip margins. Facial asymmetry Correction of midfacial asymmetry, which may have bony tissue, soft tissue, or muscular etiology, is another artistic indication for BTX-A that requires a thorough knowledge of muscular anatomy and function. Physicians not comfortable with facial surface anatomy are advised to use the aid of an electromyography system for accurate placement of injections. In hemifacial spasm, in which repeated clonic and tonic facial movements draw the facial midline over toward the hyperfunctional side, relaxing the hyperfunctional zygomaticus, risorius, and masseter with BTX-A injections allows the face to be centered at rest. Likewise, hypofunctional asymmetry, such as Bells palsy, can be alleviated by small injections (1 to 2 U into the zygomaticus, risorius, and orbicularis and 5 to 10 U in the masseter) on the normofunctional side [29].
Botulinum type A can be used to relax the jaw and relieve discomfort in patients who experience asymmetric jaw movements. Injections (10 to 15 U) are placed intraorally into the internal pterygoid on the hyperfunctional side. Surgical cutting or traumatic lesion of the orbicularis oris or the risorius muscle can result in an offcentered mouth caused by the unopposed action of the partner muscles in the normally innervated side. Correction can be achieved by treatment of the risorius immediately lateral to the corner of the mouth on the normally innervated side. In patients with congenital or acquired unilateral weakness, who cannot depress the corner of one side of the mouth, BTX-A injected into the partner muscle restores functional balance. Masseteric hypertrophy Preliminary investigations show that BTX-A may be a simple alternative with a short recovery period for facial contouring in patients with masseteric hypertrophy. To et al [30] injected 200 to 300 U of Dysport per side in five patients with unilateral and bilateral hypertrophy of the masseter. All five patients showed a good response, with the maximal effect of a 31% reduction in muscle bulk 3 months after treatment. Three out of nine hypertrophic muscles needed a secondary injection within 1 year to maintain atrophy. Von Lindern et al [31] reported a reduction of the masseter muscles by half in seven patients with unilateral and bilateral hypertrophy of the masseter and temporalis muscles treated with an average of 100 U of Dysport. Four patients considered the result satisfactory after a single injection. More recently, Park et al [32] injected 25 to 30 U BTX-A per side in five to six sites in 45 patients. Masseter thickness was gradually reduced during the first 3 months following injection (average change in masseter thickness, 1.5 to 2.9 mm, equivalent to 17% to 19% of the original muscle thickness). Clinical effects lasted 6 to 7 months following injection before the muscle thickness retreated to its initial size; at 10 months, 36 patients expressed satisfaction with the results. Main transient side effects included mastication difficulty, muscle pain, and verbal difficulty during speech and lasted from 1 to 4 weeks.
Cervical indications The platysma is a large muscle arising from upper parts of pectoralis major and deltoid that slants upward along the full length of the neck. Some platysmal
156
fibers extend to the mandible, whereas others insert into the skin and subcutaneous tissue of the lower part of the face or blend into the muscles of expression above the angle and lower corner of the mouth and lower lip. As with all facial muscles, there is enormous variability from one individual to another. Two types of lines can be produced from the platysma: horizontal necklace lines (transverse lines in the neck that run perpendicular to the contraction of the platysma) and vertical platysmal bands. Horizontal neck lines Horizontal necklace lines of skin indentation, caused by the superficial musculoaponeurotic system attachments in the neck, often grace the chubbier neck. To treat with BTX-A, the authors dance along the lines, injecting small doses over multiple sites, for a total of 15 to 20 U per treatment session. Gentle massage following treatment helps alleviate potential bruising. Physicians are advised to use deep dermal, rather than subcutaneous, injections because of deeper venous perforators that can bleed and underlying muscles of deglutition that can be affected. Vertical platysmal bands When cervical skin loses its elasticity, the anatomy of the submental space changes: more submental fat becomes visible, and the platysma separates into two diverging vertical bands [33]. These bands tighten and become prominent when the patient speaks or otherwise animates the neck. Botulinum type A injections can soften vertical platysmal bands in some patients [24,34]; however, careful patient selection of those with obvious platysmal bands, good cervical skin elasticity, and minimal fat descent are essential. In necks with jowl formation and bone resorption, treatment with BTX-A may worsen the appearance of the bands. To some, traditional rhytidectomy surgery remains the gold standard treatment for most aging necks [35]. Used as an adjunct to rhytidectomy, BTX-A reduces the residual muscular banding that becomes apparent in the postoperative phase. In addition, some patients may prefer to use botulinum toxin treatment as a kind of rehearsal for regular surgery. Because the platysma is external to the muscles of deglutition and neck flexion, large doses of BTX-A (ie, 75 or 100 U) have been known to cause profound dysphagia [24] and must be used cautiously. The authors typically inject 5 U in three sites for each band (with sites that are 1 to 1.5 cm apart) and no
more than 25 to 30 U over multiple sites per treatment session. It is far better to undertreat; additional touchup treatments can always be given if necessary during a subsequent treatment session.
Side effects and complications Side effects that may occur with BTX-A injections include transient swelling or bruising at the injection site, mild headache, and flulike symptoms. To minimize ecchymosis, patients are instructed to avoid aspirin, nonsteroidal anti-inflammatory drugs, and vitamin E. Smaller doses of BTX-A are less likely to cause problems than larger doses, which supports a conservative approach in most patients. Most complications are relatively uncommon and are related to poor injection techniques [36]. Most side effects result from undesired muscle weakening caused by diffusion of the toxin to adjacent muscles and can be avoided by using concentrated doses. No long-term adverse effects have been reported, and no other systemic safety problems have been associated with botulinum toxin treatment. Studies of the lower face report complications, such as effects on muscle function and facial expression, usually caused by overenthusiastic use of BTX-A in large doses [36]. Starting with low doses and injecting more superficially rather than deeply limits the potential for complications (such as drooling and asymmetry), and injections should be symmetric to ensure uniform postinjection movement. Avoid injections in singers, musicians, or other patients who use their perioral muscles with intensity. When injecting the DAO, avoid areas too close to the mouth, injection into the mental fold, and interaction with the orbicularis oris, all of which can result in a flaccid cheek, incompetent mouth, or asymmetric smile. Large doses (> 100 U) of BTX-A in the platysma have resulted in reports of dysphagia and weakness of the neck flexors.
Summary Botulinum toxins have been smoothing hyperkinetic lines in the upper face for over 15 years. More recently, their use has widened to include applications in the mid and lower face and neck to smooth, shape, and sculpt, blurring the line between science and art. Their use in the lower face, however, requires a thorough and detailed knowledge of not only facial and cervical anatomy, but also the complex interac-
157
tions of muscles and the aesthetic and implications of a misplaced injection. Although proper patient selection and injection techniques do not guarantee optimal results, poor selection and techniques almost certainly guarantee disappointing results. In addition to its use as primary procedure, botulinum toxin is also an effective adjunct to other cosmetic procedures, enhancing and prolonging the benefits of surgery, soft tissue augmentation, and laser resurfacing.
References
[1] Jankovic J, Hallett M, editors. Therapy with botulinum toxin. New York: Marcel Dekker; 1994. [2] Botox (botulinum toxin type A) purified neurotoxin complex: advanced toxin technology [product monograph]. Irvine, CA: Allergan; 1998. [3] Klein AW. Dilution and storage of botulinum toxin. Dermatol Surg 1998;24:1179 90. [4] Huang W, Foster JA, Rogachefsky AS. Pharmacology of botulinum toxin. J Am Acad Dermatol 2000;43: 249 59. [5] Alam M, Dover JS, Arndt KA. Pain associated with injection of botulinum A exotoxin reconstituted using isotonic sodium chloride with and without preservative: a double-blind, randomized controlled trial. Arch Dermatol 2002;138:510 4. [6] Klein AW. Botulinum toxin: beyond cosmesis. Arch Dermatol 2000;136:539 41. [7] Myobloc (botulinum toxin type B) injectable solution [package insert]. San Francisco: Elan Pharmaceuticals; 2001 [8] Dysport: Clostridium botulinum type A toxin-haemagglutinin complex [package insert]. Maidenhead, Berkshire, UK: Ipsen Limited; 2001. [9] Naumann M, Hofmann U, Bergmann I, Hamm H, Toyka KV, Reiners K. Focal hyperhidrosis: effective treatment with intracutaneous botulinum toxin. Arch Dermatol 1998;134:301 4. [10] Naver H, Swartling C, Aquilonius S-M. Palmar and axillary hyperhidrosis treated with botulinum toxin: oneyear clinical follow-up. Eur J Neurol 2000;7:55 62. [11] Brisinda G, Maria G, Bentivoglio AR, Cassetta E, Gui D, Albanese A. A comparison of injection of botulinum toxin and topical nitroglycerin ointment for the treatment of chronic anal fissure. N Engl J Med 1999; 341:65 9. [12] Albanese A, Bentivoglio AR, Cassetta E, Viggiano A, Maria G, Gup D. Review article: the use of botulinum toxin in the alimentary tract. Aliment Pharmacol Ther 1995;9:599 604. [13] Wollina U, Konrad H. Botulinum toxin A in anal fissures: a modified technique. J Eur Acad Dermatol Venereol 2002;16:469 71. [14] Brant C, Moraes-Filho JP, Siqueira E, et al. Intrasphincteric botulinum toxin injection in the treatment of chagasic achalasia. Dis Esophagus 2003;16:33 8.
[15] Porta M. A comparative trial of botulinum toxin type A and methylprednisolone for the treatment of myofascial pain syndrome and pain from chronic muscle spasm. Pain 2000;85:101 5. [16] Foster L, Clapp L, Erickson M, Jabbari B. Botulinum toxin A and mechanical low back pain. Neurology 2000;54(suppl 3):A178 9. [17] Carruthers A, Langtry JAA, Carruthers J, Robinson G. Improvement of tension-type headache when treating wrinkles with botulinum toxin A injections. Headache 1999;39:662 5. [18] Klapper JA, Klapper A. Use of botulinum toxin in chronic daily headaches associated with migraine. Headache Q 1999;10:141 3. [19] Silberstein S, Mathew N, Saper J, Jenkins S. Botulinum toxin type A as a migraine preventive treatment. Headache 2000;40:445 50. [20] Barrientos N, Chana P. Efficacy and safety of botulinum toxin type A (Botox) in the prophylactic treatment of migraine [abstract]. Presented at the American Headache Society 44th Annual Scientific Meeting. Seattle, Washington, June 21 23, 2002. [21] Mauskop A. Long-term use of botulinum toxin type A (Botox) in the treatment of episodic and chronic migraine headaches. Presented at the American Headache Society 44th Annual Scientific Meeting. Seattle, Washington, June 21 23, 2002. [22] Blumenfeld A. Botulinum toxin type a as an effective prophylactic treatment in primary headache disorders. Headache 2003;43:853 60. [23] Gui D, de Gaetano A, Spade PL, et al. Botulinum toxin injected in the gastric wall reduces body weight and food intake in rats. Aliment Pharmacol Ther 2000;14: 829 34. [24] Carruthers A, Carruthers J. Botulinum toxin type A: history and current cosmetic use in the upper face. Semin Cutan Med Surg 2001;20:71 84. [25] Flynn TC, Carruthers JA, Carruthers JA. Botulinum A toxin treatment of the lower eyelid improves imfraorbital rhytides and widens the eye. Dermatol Surg 2001; 27:703 8. [26] Goldman MP. Festoon formation after infraorbital botulinum A toxin: a case report. Dermatol Surg 2003;29:560 1. [27] Carruthers J, Carruthers A. Botox treatment for expressive facial lines and wrinkles. Curr Opin Otolaryngol Head Neck Surg 2000;8:357 61. [28] Carruthers J, Carruthers A. The adjunctive usage of botulinum toxin. Dermatol Surg 1998;24:1244 7. [29] Carruthers JDA, Carruthers JA. Botulinum toxin in clinical ophthalmology. Can Ophthalmol 1996;31: 389 400. [30] To EW, Ahuja AT, Ho WS, et al. A prospective study of the effect of botulinum toxin A on masseteric muscle hypertrophy with ultrasonographic and electromyographic measurement. Br J Plast Surg 2001;54: 197 200. [31] von Lindern JJ, Niederhagen B, Appel T, Berge S, Reich RH. Type A botulinum toxin for the treatment
158
J. Carruthers, A. Carruthers / Dermatol Clin 22 (2004) 151158 Botulinum A exotoxin for the management of platysma bands. Plast Reconstr Surg 1999;103:643 52. [35] Kane MAC. Nonsurgical treatment of platysmal bands with injection of botulinum toxin A. Plast Reconstr Surg 1999;103:656 63. [36] Klein AW. Complications, adverse reactions, and insights with the use of botulinum toxin. Dermatol Surg 2003;29:549 56.
of hypertrophy of the masseter and temporal muscle: an alternative treatment. Plast Reconstr Surg 2001; 107:327 32. [32] Park MY, Ahn KY, Jung DS. Application of botulinum toxin A for treatment of facial contouring in the lower face. Dermatol Surg 2003;29:477 83. [33] Hoefflin SM. The platysma aponeurosis. Plast Reconstr Surg 1996;97:1080. [34] Matarasso A, Matarasso SL, Brandt FS, Bellman B.
Dermatol Clin 22 (2004) 159 166
Botulinum toxin for the treatment of neck lines and neck bands
Fredric S. Brandt, MDa,b,*, Andres Boker, MDb
Department of Dermatology, University of Miami School of Medicine, 4425 Ponce de Leon Boulevard, Suite 200, Coral Gables, FL 33146, USA b Clinical Research, Frederic S. Brandt, MD, PA, 4425 Ponce de Leon Boulevard, Suite 200, Coral Gables, FL 33146, USA
a
The recent upheaval caused by the new wonder drug, in part prompted by the Food and Drug Administrations (FDA) recent approval of botulinum toxin type A for cosmetic purposes, has sent the popularity and use of this remedy soaring. Botulinum toxin type A (BOTOX, Allergan, Inc., Irvine, CA) has become a household name, and the procedure is now part of virtually every cosmetic and general dermatology practice in the nation. With an ever-increasing demand for the procedure and the number of treated patients steadily growing, so are the experience and knowledge of the physicians administering the drug. The resulting better understanding of its mechanism of action, clinical effectiveness, and potential side effects is gradually helping establish the cosmetic use of botulinum toxin as a safer, better, and more predictable practice. Nowadays, the importance of health maintenance and beauty preservation is higher than ever before, and as a result, cosmetic procedures have become a perfectly acceptable means of rejuvenation. The advent of botulinum toxin injections as an outpatient quick fix for the temporary treatment of facial wrinkles has unquestionably changed the concept of cosmetic procedures and the way people perceive them.
The aging neck As the human body ages, the vitality of all organs and tissues decreases, and there is a progressive loss of optimal function throughout. In the skin, these changes are especially apparent and are therefore a common complaint of the aging population. This process is the result of the combination of two distinct pathophysiologic phenomena. Chronologic (intrinsic) aging affects the skin in a manner similar to other organs in which a reduced collagen deposition resulting from diminished biosynthesis and reduced proliferative capacity of fibroblasts yields an atrophy and apparent tissue volume loss in the dermal layer of the skin [1]. Furthermore, the coexisting loss of elastin fibers, the oxidative stress imposed upon the lipid bilayer of cell membranes and dermal proteins, the nonenzymatic glycosilation of proteins, and the reduced repair capacity to resynthesize both collagen and elastin fibers all contribute to and accelerate the degenerative changes occurring in the senescent skin [2,3]. Superimposed on this inherent process is the injury resulting from environmental factors, mainly ultraviolet-induced photodamage to the dermal connective tissue of the exposed skin from sunlight [4,5]. This may be the most important contributing factor responsible for the premature senescence of the skin and is therefore the main target of preventive measures for cutaneous health preservation. In the neck, the aging process is no different and in the long run is manifested by increased laxity, thinning, and loss of elasticity of the cervical skin. Furthermore, the downward pull exerted by the platysma
* Corresponding author. Department of Dermatology, University of Miami School of Medicine, 4425 Ponce de Leon Boulevard, Suite 200, Coral Gables, FL 33146. E-mail address: dermbrandt@aol.com (F.S. Brandt).
160
F.S. Brandt, A. Boker / Dermatol Clin 22 (2004) 159166
Fig. 1. Age-related changes of the human face and neck. (A) Physical effects of age on facial structures. (B) Topographic changes in the cervical region related to advancing age.
161
muscle complex and the ptosis of the facial portion of the muscle itself creates jowls, with loss of definition of the chin and jawline. Gravity, too, has a profound effect on the thin, lax, and dehydrated skin of the aged neck and contributes to the accentuation of horizontal and radial neck lines (Fig. 1). All facial soft tissue descends and pushes down on the cervical structures, bringing the skin, soft tissue, and even the hyoid bone and larynx caudally and more visibly noticeable [6]. The vertical fibrous bands classically noted in a senescent neck are the result of a persistently active platysma muscle trying to support the sagging deeper neck and floor of the mouth structures. In addition, the anterior edges of the muscle separate over time, lose tone, and protrude anteriorly, creating the anterior banding or turkey neck deformity. These changes become particularly apparent in people who use this muscular complex habitually during facial animation and expression. In addition, the loss of tone of the platysma muscle allows for a large subplatysmal fat pad to herniate through the free borders of the muscle and create a central fullness of the neck [7]. Until recently, the only treatment options people had to rejuvenate their necks involved an invasive surgical procedure (eg, liposuction, superficial musculoaponeurotic system (SMAS) facelift), which was often highly risky and required a prolonged recuperation time [8,9]. In addition, numerous potential candidates are precluded from surgical procedures because of medical problems, psychological instability, or suboptimal previous rhytidectomy results. The recent application of botulinum toxin injections to the neck to help reduce both rhytids and prominent banding has given a myriad of patients the chance to look better quickly with virtually no down time.
neck and continue upward in a decussated fashion (Fig. 2). Cadaver studies have identified three different variants of the platysma muscle based on the decussation of its fibers (Table 1). The most common variant, or type I, seen in f 75% of patients, is where the platysma fibers interface with those of the opposite side 1 to 2 cm below the chin. In the second category, or type II, found in f 15% of the patients, the decussation of fibers occurs at the level of the thyroid cartilage and covers the submental region confluently in one band. In the third variant (type III), the do not interdigitate with those of the opposite side and run as two separate muscle sheets toward their insertions in the mandible and the skin. This is the least common presentation and occurs in only f 10% of patients [10] (Fig. 3). After descussation, some fibers are then inserted into the mandibular bone below the oblique line, others into the skin and subcutaneous tissue of the lower part of the face. Many of these fibers blend in with the perioral muscles at the angle and lower part of the mouth (Fig. 2) [11]. Above the mandible the fibers continue cephalically as the SMAS. When the entire platysma complex is contracted, it produces a slight wrinkling of the skin of the neck in an oblique
Relevant anatomy When injecting the neck with botulinum toxin, it is important to keep in mind the necks intricate anatomic composition, thereby avoiding injury to important blood vessels, nerves, and deeper cervical structures and minimizing complications. The platysma complex is a broad muscular sheet that stretches over the anterolateral aspect of the neck. It has its origin on the fascia covering the upper parts of the pectoralis major and deltoid muscles including clavicular and acromial subcutaneous insertions on each side. Its fibers arise as two separate sheets and cross the clavicle and proceed obliquely upward and medially along the side of the neck. Both muscular sheets are joined at the anterosuperior portion of the
Fig. 2. Schematic representation of the superficial and middepth anatomic relations of the neck. (1) Platysma muscle. (2) External jugular vein. (3) Sternocleidomastoid muscle. (4) Orbiculris oris muscle. (5) Depressor anguli oris muscle.
162
Table 1 Anatomical variants of the platysma muscle complex Type I Description The medial fibers of the platysma muscle are separated in the suprahyoid region. They interlace with those of the opposite side below the chin. The medial fibers of the platysma muscle decussate at the level of the thyroid cartilage, forming a single muscular layer covering the submental region. Fibers do not interlace, they run separately toward their cutaneous and body insertions in the chin.
II
III
Data from Cardoso de Castro C. The changing role of platysma in face lifting. Plast Reconstr Surg 2000;105:764 75.
such, patients with submental fullness classified as the type II anatomic variant, with the platysma covering the entire submental region, will respond almost completely with botulinum toxin treatment, as relaxation of the protruded anterior bands will tighten the muscular fibers overlying the fat pad and push it back into place. Conversely, if the submental platysma muscle is absent as seen in the third anatomic variant of the muscle (type III), a herniated fat pad will be especially noticeable, and injections with botulinum toxin alone will not suffice to correct the abnormality. In these cases, liposuction can be performed to enhance the cosmetic outcome.
Classification direction. Its anterior portion, the thickest part of the muscle, depresses the lower jaw and also serves to depress slightly the lower lip and angle of the mouth. The platysma muscle receives its innervation from the cervical motor branch of the facial nerve. The sensory component of the nerve surfaces at the junction of the sternocleidomastoid and platysma muscles at Erbs point. The major blood vessels in the cervical area are the two anterior jugular veins, running in a cephalocaudal manner on each side lateral to the thyroid cartilage, and the external jugular veins, also running cephalocaudally along the anterior edge of the sternocleidomastoid muscles. There are two distinct fat depositions that play an important role in the aging pathophysiology of the neck: the submental fat pad, which lies directly anterior to the platysma muscle, and the subplatysmal fat pad, which lies deep and posterior to the muscle. Depending on the anatomic variant of the platysma muscle, the protrusion of the subplatymsal herniated fat pad becomes more or less clinically evident. As The aging neck can be classified into four distinct categories (Table 2). Category I describes the earliest phase of cervical cutaneous degeneration and category IV the most severe [12].
Injection technique Patients are treated in an upright sitting position, and the cervical skin is cleansed with a rubbing alcohol swab. To identify properly the platysmal bands, patients are asked to forcefully contract their necks by clenching their teeth. Each band is grasped individually and held firmly between the thumb and index fingers. Injections are placed directly into the platysmal band at 1.0- to 1.5-cm intervals along the band, starting at the jawline and descending all the way to the clavicular border (Figs. 4, 5). Injections should be placed into the deep dermis and not subcutaneously as the risk of hitting deep venous perforations or
Fig. 3. Schematic representation of the three anatomic variants of the platysma muscle complex. (A) Type I. (B) Type II. (C) Type III.
F.S. Brandt, A. Boker / Dermatol Clin 22 (2004) 159166 Table 2 Categories of age-related neck degeneration Category I Description Platysmal bands only detectable with neck contraction Subtle horizontal neck rhytides No laxity of the skin No submental fat pads Thin platysmal bands at rest Mild horizontal neck rhytides Mild laxity of the skin Minimal jowls Moderate platysmal bands at rest Moderate horizontal neck rhytides Moderate laxity of the skin Moderate jowls Submental fat pads Severe hyperthrophy of platysmal bands Deep horizontal neck rhytides Severe laxity of the skin Prominent jowls and loss of the mandibular contour Prominent submental fat pads/drooping of the chin
163
II
III
Fig.5. Treating physicians perspective of platysmal band injection.
IV
From Brandt FS, Bellman B. Cosmetic use of botulinum A exotoxin for the aging neck. Dermatol Surg 1998;24: 1232 4; with permission.
other cervical muscles increases as injections are situated in more profound planes. Our technique using botulinum toxin type A at a dilution of 2.0 cc per 100-U vial involves placing 3 to 10 U into each injection point using a 0.5-inch, 30-gauge metal
Fig. 4. Schematic representation of the approximate injection points of botulinum toxin into the platysma muscle.
hubbed needle. The decision on how many U to inject depends on the thickness of the band at the injection site. Upon injection, one can feel the resistance of the platysma muscle, indicating the correct injection depth. Although the total injected dose of botulinum toxin type A has occasionally been as high as 200 U per treatment session, most patients need a total of 50 to 100 U to achieve optimal correction, depending on the category of their age-related neck degeneration. Immediately after the injection of the toxin, one can observe relaxation of the platysma muscle and elevation of the SMAS complex. The onset of striated muscle weakness usually begins 3 to 5 days after the treatment session and continues to improve over the next couple of weeks. Most of our experience treating the aged neck has been using botulinum toxin type A. However, recent experience using botulinum toxin type B (MYOBLOC, Elan Pharmaceuticals, San Diego, CA) for this particular indication has shed some light on some of the differences between the two formulations. Whereas the doses for botulinum toxin type A are well established and the results quite predictable, the doses needed for botulinum toxin type B still need to be established. However, a recent clinical trial comparing three different dose groups of botulinum toxin type B (2500, 5000, and 7500 U) showed that the best results were obtained when using the highest doses. Furthermore, as a general rule, botulinum toxin type B has an earlier onset of action and clinical results can be observed 2 to 3 days after injection. Also, the botulinum toxin type B appears to diffuse more extensively, and care must be exercised when placing the injections so that they are not too close to each other and there is not too much overlap between the treated regions. Gentle massage and icing the skin after the injections will prevent the skin from bruising
164
Results An acceptable cosmetic result when treating the aged neck with botulinum toxin can be achieved after a singe treatment session. Most patients treated with the botulinum toxin type A exotoxin report the onset of a favorable cosmetic result f 5 to 7 days after injections, whereas patients treated with botulinum toxin type B notice the changes occurring f 3 to 5 days after being treated. The duration of effect is also variable, even when the appropriate dose and injection technique are used, and depends on several factors, including the individuals age and biological catabolism of the toxin. It is likely that gradually increasing doses of botulinum toxin type A will yield exponentially better subjective results in the majority of patients. However, the fixed number of SNARE-complex receptors in the neuromuscular junction and their saturation with maximal doses of exotoxin make very high doses unlikely to be beneficial after a certain point, also increasing the risk of prompting unwanted adverse reactions. Thus, as mentioned before, dosing of the toxin should be
estimated individually and according to the thickness of the bands and degree of sagginess of the overlying skin. As such, patients with very thick hypertrophied bands obtain significant improvement after injection of up to 30 U of botulinum toxin type A per band, whereas patients with thinner, less fibrous bands respond well with doses up to 15 to 20 U per band (Figs. 6, 7). Younger patients yield noticeably better results than their older counterpart, as do older patients with previous facelift surgery.
Complications Treating platysma muscle banding and horizontal lines of the neck with botulinum toxin is a fairly safe procedure. Complications are minimal and, as a general rule, technique dependent. It is therefore paramount to have a complete understanding of the toxins pharmacologic properties and the anatomic relations of the neck to perform the therapy optimally and minimize complications. Commonly observed and expected side effects include transient edema and
Fig. 6. Frontal view of the cervical region before (A, B) and after (C, D) treatment with botulinum toxin type A.
165
Fig. 7. Frontal view of the cervical region before (A, B) and after (C, D) treatment with botulinum toxin type B.
ecchymoses, both of which usually resolve within 1 to 2 days. Other less common adverse reactions include muscle soreness or neck discomfort, difficulty lifting the head off a pillow from the decubital position, and headaches. Rare complications include hoarseness and difficulty swallowing. The latter must be prevented at all costs by exercising care during injection to not place the toxin too deeply where it can affect other cholinergic muscular structures. As mentioned earlier, the experience with botulinum toxin type B is somewhat limited in treating this area in part because the optimal doses have yet to be determined correctly. This also makes the true and objective description of commonly observed side effects more challenging. But generally speaking, some common complaints observed in a fair amount of patients being treated with botulinum toxin type B are dry mouth and headache. The dry mouth can last up to 3 weeks after injection, and the headaches usually disappear after 1 or 2 days. So far, no reports have been made of allergic reaction to any type of botulinum toxin preparations, and although the incidence of antibody formation to the botulinum protein complex has been reported to be
between 3% and 5%, when treating the neck region alone we have not observed resistance to botulinum toxin secondary to antibody neutralization [13]
Summary Rejuvenation of the aging neck with botulinum toxin injections is a minimally invasive, safe, and effective treatment modality with a very high patient satisfaction rate. Treatments are usually started early in the aging process of the neck to prevent further degenerative changes and are performed thereafter at 4- to 6-month intervals. It is the ideal alternative to rhytidectomy when the patient is too young for facelift surgery or for patients unwilling to take recuperation time. Furthermore, botulinum toxin therapy can be used to correct jowl and platysmal band asymmetry occurring after suboptimal rhytidectomy. Botulinum exotoxin should not be used in pregnant or lactating women or in patients with a known sensitivity to human albumin or with a history of neuromuscular disorders.
166
F.S. Brandt, A. Boker / Dermatol Clin 22 (2004) 159166 [7] Vistnes LM, Souther SG. The anatomical basis for common cosmetic anterior neck deformities. Ann Plast Surg 1979;2:381 8. [8] Morrison W, Salisbury M, Beckham P, Schaeferle 3rd M, Mladick R, Ersek RA. The minimal facelift: liposuction of the neck and jowls. Aesthetic Plast Surg 2001;25:94 9. [9] Owsley JQ. Face lifting: problems, solutions, and an outcome study. Plast Reconstr SurgJan 2000;105: 302 13. [10] Cardoso de Castro C. The changing role of platysma in face lifting. Plast Reconstr Surg 2000;105:764 75. [11] Hoefflin SM. Anatomy of the platysma and lip depressor muscles. A simplified mnemonic approach. Dermatol Surg 1998;24:1225 31. [12] Brandt FS, Bellman B. Cosmetic use of botulinum A exotoxin for the aging neck. Dermatol Surg 1998;24: 1232 4. [13] Zuber M, Sebald M, Bathien N, de Recondo J, Rondot P. Botulinum antibodies in dystonic patients treated with type A botulinum toxin: frequency and significance. Neurology 1993;43:1715 8.
References
[1] Uitto J. Connective tissue biochemistry of the aging dermis. Age-related alterations in collagen and elastin. Dermatol Clin 1986;4:433 46. [2] Uitto J, Bernstein EF. Molecular mechanisms of cutaneous aging: connective tissue alterations in the dermis. J Investig Dermatol Symp Proc 1998;3:41 4. [3] Goukassian D, Gad F, Yaar M, Eller MS, Nehal US, Gilchrest BA. Mechanisms and implications of the age-associated decrease in DNA repair capacity. FASEB J 2000;14:1325 34. [4] Krutmann J. Ultraviolet A radiation-induced biological effects in human skin: relevance for photoaging and photodermatosis. J Dermatol Sci 2000;1(Suppl): S22 6. [5] Yaar M, Gilchrest BA. Aging versus photoaging: postulated mechanisms and effectors. J Investig Dermatol Symp Proc 1998;3:47 51. [6] Zimbler MS, Kokoska MS, Thomas JR. Anatomy and pathophysiology of facial aging. Facial Plast Surg Clin North Am 2001;9:179 87.
Dermatol Clin 22 (2004) 167 175
Botulinum neurotoxin for the treatment of migraine and other primary headache disorders
Andrew M. Blumenfeld, MDa,*, David W. Dodick, MD, FRCP(C), FACPb,c, Stephen D. Silberstein, MD, FACPd
Department of Neurology, Kaiser Permanente, 4405 Vandever Avenue, San Diego, CA 92120, USA b Department of Neurology, Mayo Medical School, USA c Department of Neurology, Mayo Clinic, 13400 East Shea Boulevard, Scottsdale, AZ 85259, USA d Jefferson Headache Center, Thomas Jefferson University Hospital, 111 South 11th Street, Suite 8130, Philadelphia, PA 19107, USA
a
Migraine is a chronic neurovascular disorder that afflicts 2% to 15% of the worlds population. In the United States there are an estimated 28 million migraine sufferers, with women being affected three times as often as men [1]. It is characterized by severe headaches and is often associated with nausea, vomiting, and heightened sensitivity to sound and light at the peak of the attack. Migraine is considered to cause more disability than epilepsy, and severe migraine has been judged by the World Health Organization to be as disabling as quadriplegia, psychosis, and dementia [2]. Most sufferers are in their most socially active and productive years (25 to 55) [1]. Not only is migraine painful and disabling for the sufferer, but it exerts a significant economic burden on society. It causes 112 million bedridden days each year and costs $14 billion in reduced productivity and missed workdays [3]. The economic burden of migraine is comparable with that of diabetes [4] and higher than that of asthma [5]. Even among migraineurs who consult a physician, many are not satisfied with their therapy and report that prescribed medications are not always optimal. Triptan medications, the most effective therapy for acute migraine attacks, are only effective in improving the pain and associated migraine symptoms, such as photophobia and nausea, in up to two thirds of patients
* Corresponding author. E-mail address: Andrew.m.Blumenfeld@kp.org (A.M. Blumenfeld).
[6]. There is a significant need to develop more effective therapies for migraine prevention because 35% of migraineurs suffer from two to three severe attacks per month, whereas 25% suffer from more than four attacks per month [6]. Furthermore, more than 4% of the United States population suffers from chronic daily headache [7]. Patients with frequent, disabling, or refractory migraine should be considered for prophylactic treatment. Current United States guidelines recommend preventive therapy in one or more of the following situations: (1) frequent headaches; (2) recurring migraines that significantly interfere with daily routine; (3) failure of, a contraindication to, overuse of, or adverse events (AEs) with acute migraine therapies; (4) cost of acute and preventive therapies; (5) patient preference; and (6) the presence of uncommon migraine conditions, including hemiplegic migraine, basilar migraine, migraine with prolonged aura, or migrainous infraction [8]. Although numerous therapies are currently available for the prevention and treatment of migraine, most of these agents have significant side effects. Commonly used agents for migraine prophylaxis include b-adrenergic blockers, calcium channel blockers, tricyclic antidepressants, and anticonvulsants (Table 1). Moderate to severe AEs are not uncommon with all available prophylactic medications. b-Blockers are known to produce a wide array of AEs, including drowsiness, fatigue, lethargy, sleep disorders, and depression. AEs typically associated with the calcium channel blockers include constipa-
168
A.M. Blumenfeld et al / Dermatol Clin 22 (2004) 167175
Table 1 Preventive therapeutics commonly prescribed for migraine Quality of Scientific Clinical Evidencea Effectb Impressionc Anticonvulsants Divalproex sodium A Topiramate A Gabapentin B Antidepressants Amitriptyline A Fluoxetine B b-blockers Propranolol A Metoprolol B Timolol A Atenolol B Calcium channel blockers Verapamil B Nimodipine B
a
+++ +++ ++ +++ + ++ ++ +++ ++ + +
+++ +++ ++ +++ + +++ +++ ++ ++ + +
A, Multiple well-designed randomized clinical trials, directly relevant to the recommendation, yielded a consistent pattern of findings; B, some evidence from randomized clinical trials supported the recommendation, but scientific support was not optimal. b +, Effect of medication is either statistically or not clinically significant; ++, effect of medication is statistically significant and exceeds the minimally clinically significant benefit; +++, effect is statistically significant and far exceeds the minimally clinically significant benefit. c +, Somewhat effective: few people get clinically significant improvement; ++, effective: some people get clinically significant improvement; +++, very effective: most people get clinically significant improvement. Adapted from Silberstein SD, Goadsby PJ. Migraine: Preventive treatment. Cephalalgia 2002;22:491 512.
the treatment of glabellar lines [11]. Although not currently indicated, it has also been safely used for spasticity; hyperkinetic disorders, such as tremor; autonomic disorders, such as hyperhidrosis; and cosmetically troublesome hyperfunctional facial lines (crows feet, forehead lines) [12,13]. The analgesic effect of BoNT-A has long been observed in the treatment of dystonia and spasticity [14,15]. This led to further investigation of the efficacy of BoNT-A for other painful conditions, including migraine and tension-type headaches. Because most clinical experience with the use of BoNT for the treatment of headache has been with BoNT-A, this article describes the potential antinociceptive mechanism of action of BoNT-A, summarizes the clinical evidence to date for BoNT-A as effective migraine prophylactic therapy, and reviews the injection technique and strategies used in treating headache and cervical myofascial pain.
Mechanism of action Botulinum toxins are exotoxins of the anaerobic bacterium Clostridium botulinum. This bacterium has eight serotypes: A, B, C-alpha, C-beta, D, E, F, and G. Seven serologically separate exotoxins are produced. The intracellular targets of each of these toxins vary; however, their biologic activity at the neuromuscular junction is similar [16]. Injection of BoNT-A directly affects neuromuscular signaling processes. On injection, the toxin enters the nerve terminals by endocytosis; interacts with intracellular proteins (snare proteins); and inhibits the vesicular release of the acetylcholine neurotransmitter at the neuromuscular junction. Inhibition of acetylcholine produces chemical denervation and paralysis of the striated muscles. Paralysis usually peaks 2 weeks postinjection. Because of molecular turnover within the neuromuscular junction and neuronal sprouting, neuronal activity begins to return at 3 months, with complete function at approximately 6 months [17]. Although neuromuscular activity inhibition may alleviate a portion of the pain associated with headache disorders, it does not fully explain the pain relief mechanisms mediated by BoNT-A. Intensive research on BoNT-A has begun to suggest that this toxin may interact with several other neuronal signaling pathways, although the exact mechanisms remain elusive. Current data suggest that BoNT-A modifies the sensory feedback loop to the central nervous system by blocking intrafusal fibers, resulting in decreased activation of muscle spindles. This effectively alters the
tion, peripheral edema, and weight gain [9], whereas the tricyclic antidepressants commonly are associated with a variety of AEs, including sedation, weight gain, dry mouth, constipation, dizziness, mental confusion, palpitations, blurred vision, and urinary retention. The AEs associated with antiepileptic drugs are unique to each medication, but the most common AEs include nausea, vomiting, and gastrointestinal distress [9]. Because of the AE profile and limited efficacy of currently available preventive therapies, there is a need for novel and improved prophylactic therapies. Recently, the potent neurotoxin botulinum toxin type-A (BoNT-A) has been under intensive clinical investigation for the treatment of migraine and other types of headache. Over the last 20 years, BoNT-A has been used to treat a variety of disorders characterized by inappropriate and involuntary muscle contraction [10]. BNT-A is currently approved for blepharospasm, strabismus, cervical dystonia, and, more recently, for
169
sensory afferent system by reducing the traffic along Ia spindle afferent fibers [18]. This toxin also seems to inhibit the release of glutamate from primary afferent nociceptive fibers, reduce the firing of wide dynamic range neurons within the dorsal horn of the spinal cord, and reduce the activity of central nociceptive neurons as measured by a reduction in the expression of immediate early genes (c-Fos) after nociceptor stimulation [19]. A reduction in afferent sensory activity coming from pericranial and cervical muscles, and inhibition of peripheral and central trigeminal sensitization, may represent the potential mechanisms by which BoNT-A exerts its therapeutic effect in migraine, tension-type headache, and other primary headache disorders [20].
Clinical efficacy: retrospective reviews and openlabel trial Historically, while conducting the initial clinical trials of BoNT-A for the treatment of hyperfunctional facial lines, Binder et al [21] noted a correlation between pericranial BoNT-A injections and alleviation of migraine headache symptoms. Based on these initial findings, the authors conducted a combined, multicenter, open-label trial that evaluated the efficacy of
Fig. 2. Injection site: temporalis and masseter muscles.
Fig. 1. Injection sites: glabellar and frontal regions.
Fig. 3. Injection site: occipital, suboccipital, and trapezius muscles.
170
Table 2 Retrospective/open-label and placebo-controlled trials of botulinum toxin A treatment for migraine Study Design (N) and Patient Typea Dose Mean dose 31 units (range 5 110 units) Injection site Fixed injection sites Glabellar Frontal Temporal Fixed injection sites (frontalis, glabellar, and temporalis) Some patients received a combination of fixed injections and follow-the-pain injections Follow-the-pain protocol Primary result reported 51% of migraine patients reported complete response
Retrospective Reviews/Prospective Open-label Trials Binder et al (2000) Retrospective chart review (N=77)
Mauskop and Basedo (2000)
Retrospective chart review (N=27)
25 100 units
85% (23 of 27) of patients reported significant reduction in frequency and intensity
Mauskop (2002)
Miller and Denny (2002)
Retrospective chart review (N=78) Episodic migraine, N=32 Chronic migraine, N=46 Retrospective chart review (N=48) All patients were chronic headache patients who had failed previous therapy Retrospective chart review (N=271) Headache types includeb Chronic daily Episodic-tension Episodic-migraine Mixed Retrospective chart review (N=112) All patients diagnosed with chronic migraine
Varying dose from 25 200 units Varying dose from 50 300 units
Blumenfeld (2002)
Average dose 63.2 units
Fixed injection site (frontalis, corrugator, temporalis, splenius captis) with follow-the-pain as needed Injection sites were either fixed or follow-the-pain
Most patients reported partial to complete response (no percentage improvement given in this study) 86% of patients treated with BTX-A reported nominal benefit with 35% reporting good and 27% very good benefits
25% reduction in headache intensity ( P < .001) 56% reduction in headache days per month ( P < .0001) 85.6% of patients reported symptomatic improvement
Mathew et al (2002)
50 100 units
Combination of fixed injection sites (frontal/ glabellar/ temporal/ occipital/ suboccipital) and follow-the-pain
Three months after third injection a significant decrease in the number of headache days ( P < .05) and a decrease in mean MIDAS scores ( P < .01) were observed
Smuts and Barnard (2000)
Prospective, open-label (N=19) Prospective, open-label (N=73) Episodic migraine, N=12 Chronic migraine, N=36
100 units
Eross and Dodick (2002)
25 units If required based on pain, 25 75 additional units injected into cervical paraspinals 50 units
Variable sites (no specific protocol mentioned in abstract) Fixed injection sites Frontalis Temporalis Procerus Corrugator Fixed injection sites Glabellar Frontal Temporal Procerus Trapezius Splenium capitis Fixed injection sites Glabellar Frontal Temporal Fixed injection sites Frontal Temporal Individual injection choice using followthe-pain protocol
68% (13 of 19) of migraine patients reported positive response Of patients who responded > 50% reported an improvement in disability 61% of responders reported decrease in headache frequency and 27% reported decrease in headache severity Significant reduction in frequency (P < .001), severity (P < .02), and adjunct medications (P < .001) compared with placebo
Placebo-Controlled Trials Barrientos and Chana (2002)
Placebo-controlled (N=30)
Silberstein et al (2000)
Placebo-controlled/ double-blind (N=123)
25 units (low dose) 75 units (high dose)
45% of patients in low-dose group (25 units) reported a >50% decrease in frequency
Brin et al (2000)
Placebo-controlled/ double-blind (N=56) Placebo-controlled/ double-blind (N=60) Chronic migraine, N=19 Chronic tension headache, N=22 Features of both types of headache, N=19
Dose not given in study 200 units
BTX-A was superior than placebo in reducing severity (P=.04) 10% of patients reported a dramatic improvement and 24% a marked improvement. Significant reduction in the number of headache days (weeks 8 12) compared with placebo (P < .05)
Ondo et al (2002)
a b
Unless specified, patient population consists of migraine headache. Number of patients in each headache not specified.
171
172
BoNT-A for migraine management. Efficacy was categorized as either complete response with total symptom elimination, partial response with greater than 50% reduction in headache severity and frequency, or no beneficial response. In this study, 51% of patients treated with BoNT-A as migraine prophylaxis reported a complete response to localized head and neck BoNT-A injections with a mean duration of 4.1 months. An additional 38% reported partial improvement with a mean response period of 2.7 months [21]. Since then, many researchers have reported their experience with BoNT-A. Mauskop and Basedo [22] reviewed chart records of 27 patients treated with BoNT-A for migraine prophylaxis by injections in the pericranium. A decrease in headache frequency and severity was reported in 85% (N = 23) of patients. Rather than focusing solely on the end point of severity and frequency of headache, Eross and Dodick [23] evaluated the effect of BoNT-A (25 to 100 units) on reducing disability in 47 patients with either episodic or chronic migraine. Using a well-validated tool to assess migraine-related disability (the MIDAS questionnaire), 58% of all patients reported a decrease in migraine-associated disability. Episodic migraine patients (N = 12) seemed to show the most benefit, with 75% reporting a decrease in migraine frequency compared with 53% of chronic migraine patients [23]. Other retrospective reviews [24 28] further support the beneficial role of BoNT-A for the preventive treatment of episodic migraine, chronic tension-type headache, and treatment-refractory chronic migraine headaches. Aside from the obvious limitation of a retrospective review or open-label design, the weaknesses of many of these study reports include small patient number; poorly defined end points; and often heterogeneous patient populations (episodic-chronic migraine, tension-type or chronic headaches).
Clinical efficacy: placebo-controlled trials Currently, few well-conducted clinical trials of BoNT-A in migraine prevention exist. The first double-blind, placebo-controlled, randomized clinical trial was published by Silberstein et al [8]. In this study, 123 patients who had experienced between two to eight moderate-to-severe migraine headaches over a 3-month period were randomized to receive a single injection of either placebo, low-dose (25 units), or high-dose (75 units) BoNT-A. This single dose was injected into multiple sites of pericranial muscles during the injection visit. Injections were performed anteriorly, in the frontalis, glabellar region, and tem-
poralis muscle. At the end of the 3-month follow-up period postinjection, the low-dose BoNT-A group experienced a mean decrease of 1.88 moderate-tosevere migraines compared with the placebo group (P = .042). Furthermore, patients in the low-dose group had a significant reduction in the incidence of migraine-associated vomiting compared with placebo (P = .012). The high-dose BoNT-A group, however, did not have a significant effect on migraine pain and associated symptoms. In fact, at the higher dose, there was an increase in AEs. The authors suggest that the lack of BoNT-A activity at this higher concentration may actually be caused by a lower number of migraine headaches at baseline compared with the low-dose BoNT-A group [8]. In this trial, BoNT-A was well tolerated with no AEs observed in the low-dose group compared with placebo. Barrientos and Chana [29] also conducted a randomized, placebo-controlled trial (no indication of being double-blinded) that evaluated the efficacy and tolerability of BoNT-A as prophylaxis for episodic migraine. Thirty patients with a history of two to eight migraine attacks per month were enrolled and randomized to receive placebo or 50 units of BoNT-A injected in 15 pericranial muscle sites. During the 3-month study, when compared with baseline, patients treated with BoNT-A experienced fewer attacks at day 30 (3.7 versus 5.8, P < .02); day 60 (3.2 versus 5.8, P < .2); and day 90 (2.5 versus 5.8, P < .01). In comparison, no significant reduction from baseline was observed in the placebo group. Severity and duration of migraine attacks also were significantly reduced in the BoNT-A group compared with placebo. At the end of the 3-month study, the BoNT-A treated group reported a significant decrease in the use of nonsteroidal anti-inflammatory drugs and triptan medications for acute headache treatment compared with placebo. This supports the previous clinical data that BoNT-A is effective and well tolerated for preventive migraine treatment. A small, double-blind, placebo-controlled study of BoNT-A conducted by Brin et al [30] further supports the efficacy of BoNT-A in migraine. In this trial, 56 subjects with a history of two to six migraines per month were randomized into four groups receiving (1) BoNT-A in frontal-temporal regions, (2) BoNT-A in frontal and placebo in temporal, (3) placebo in frontal and BoNT-A in temporal, and (4) placebo in frontaltemporal regions. Migraine frequency was reduced by a median of 1.8 headaches per month in BoNT-A treated groups (groups 1 to 3) compared with a median reduction of 0.2 headaches per month in the placebo group (group 4). This study is limited, however, by its small population size.
173
Recently, Ondo et al [31] conducted a randomized, double-blind, placebo-controlled, parallel clinical trial that examined the effect of BoNT-A treatment on patients with chronic daily headache, including chronic tension-type headache and chronic migraine. Sixty patients who experienced chronic headache more than 15 days each month were enrolled and randomized to receive, based on the follow-the-pain rationale, either 200 units of BoNT-A or matching placebo and at 12 weeks, if patient consented, a second open-label BoNT-A injection. Following the first injection, patients treated with BoNT-A had significantly fewer headache days from week 8 to 12 compared with placebo. In addition, 10% of patients treated with BoNT-A reported a dramatic improvement and 24% reported a marked improvement compared with 3% and 7%, respectively, in the placebo-treated group. At week 24, patients who had received two BoNT-A injections had significantly fewer headache days over the second 12-week period than those receiving one injection (40 versus 19 days, P < .05).
Use of botulinum toxin A: dosage and administration The most common sites of injections include the glabellar (procerus and corrugators), frontal, temporal, and sometimes the occipital regions (Figs. 1 3). BoNT-A is administered either at fixed injection sites; at sites of pain or tenderness (follow the pain); or a combination of both. The total dosage of toxin, the number of units per site of injection, dilution of toxin, and sites of injection varied widely, however, between studies (Table 2). The total dosage ranged from 25 to 300 units over several injection sites. The fixed-site approach consists of bilateral injections, even if the patient has strictly unilateral headaches. The muscles injected are the procerus, corrugators, frontalis, and temporalis. Follow-the-pain injection sites are identified by history (Where does it hurt when you have a headache? and Show me with your hands where the pain is) and by examination of the cervical-shoulder girdle and temporomandibular musculature. These sites include the frontalis, temporalis, occipitalis, trapezius, splenius capitus, suboccipital, and cervical paraspinal muscles. For patients with migraine or migrainous headache features by history, treatment with a fixed-site approach may be required for successful results. When only a follow-the-pain approach is used in patients with migraine or migrainous headache, two problems arise: first, a poor cosmetic outcome; and second, the headaches often shift to the previously unaffected side.
For patients with only tension-type headaches, the follow-the-pain approach is used. Even in these cases, cosmetic effects in the frontal region need to be obtained, but asymmetric injections can be given in the temporalis, occipitalis, splenius capitus, cervical, and subcervical paraspinal muscles. The doses injected in the cervical-shoulder girdle muscles are low to prevent any possible weakness, which could cause headache. Patients need to be assessed carefully for associated cervical dystonia, which requires injection of the dystonic muscles. Current available data do not seem to indicate a dose response-benefit [8,21,23,24]. There is need for further randomized, placebo-controlled clinical trials to identify the optimal dosing regimen and injection sites for BoNT-A. Some data, however, report greater efficacy with repeated dosing. In the Ondo et al [31] trial, patients who received a repeat BoNT-A injection reported better improvement than patients who received only a single BoNT-A injection [31]; these data are also supported by results from retrospective chart reviews [26,28]. Until results of large, well-conducted trials are available, optimal method of BoNT-A delivery remains unresolved.
Tolerability The clinical dose of BoNT-A commonly used for migraine therapy is between 25 and 100 units, which is 30 to 120 times below the toxic limit [17]. Most published trials have reported minimal to no AEs. In a placebo-controlled, double-blind trial, Silberstein et al [8] found that although no serious AEs occurred, some patients receiving BoNT-A injections experienced transient minor AEs, including blepharoptosis, diplopia, and injection site weakness. The authors also found that injection of high doses of BoNT-A (75 units) resulted in a dose-dependent increase in the side effect profile of BoNT-A. In an open-label study, Binder et al [21] also reported only minimal and transient AEs, including brow ptosis, local injection discomfort, and ecchymosis at the injection site. Overall, clinical studies and retrospective reviews confirm the tolerable side effect profile of BoNT-A and that associated AEs are typically mild and transient.
Summary Clinical data and experience to date have demonstrated that BoNT-A is an effective and well-tolerated therapy for the prevention of migraine and other headache disorders. It has a long duration of action
174
A.M. Blumenfeld et al / Dermatol Clin 22 (2004) 167175 Evidence-based medicine: botulinum toxin A in migraine and tension type headache. J Neurol 2001; 248(suppl 1):34 8. Allergan Pharmaceuticals. BOTOX (botulinum toxin type A) prescribing information. Irvine, CA: Allergan Pharmaceuticals. Heckmann M, Ceballos-Baumann AO, Plewig G. Botulinum toxin A for axillary hyperhidrosis (excessive sweating). N Engl J Med 2001;344:488 93. Carruthers J, Carruthers A. Botulinum toxin (Botox) chemodenervation for facial rejuvenation. Facial Plast Surg Clin North Am 2001;9:197 204. Tsui JKC, Eisen A, Stoessl AJ, Calne DB. Double-blind study of botulinum toxin in spasmodic torticollis. Lancet 1986;2:245 7. Dunne JW, Heye N, Dunne SL. Treatment of chronic limb spasticity with botulinum toxin A. J Neurol Neurosurg Psychiatry 1995;58:232 5. Klein AW. Complications and adverse reactions with the use of botulinum toxin. Dis Mon 2002;48:336 56. Brin MF. Botulinum toxin: chemistry, pharmacology, toxicity, and immunology. Muscle Nerve 1997; 20(suppl 6):S146 68. Rosales R, Arimura K, Takenaga S, Osame M. Extrafusal and intrafusal muscle effects in experimental botulinum toxin-A injection. Muscle Nerve 1996;19: 488 95. Aoki R. The antinociceptive mechanism of action of botulinum toxin A. Presented at the American Headache Society 44th Annual Scientific Meeting. Seattle, WA, June 21 23, 2002. Burstein R, Yarnitsky D, Goor-Aryeh I, Ransil BJ, Bajwa ZH. An association between migraine and cutaneous allodynia. Ann Neurol 2000;47:614 24. Binder WJ, Brin MF, Blitzer A, Schoenrock LD, Pogoda JM. Botulinum toxin type A (BOTOX) for treatment of migraine headaches: an open-label study. Otolaryngol Head Neck Surg 2000;123:669 76. Mauskop A, Basdeo R. Botulinum toxin A is an effective prophylactic therapy for migraines. Cephalalgia 2000;20:422. Eross EG, Dodick DW. The effects of botulinum toxin type A on disability in episodic and chronic migraine [abstract S108]. Presented at the American Headache Society 44th Annual Scientific Meeting. Seattle, WA, June 21 23, 2002. Blumenfeld A. Botulinum toxin type A (BOTOX) as an effective prophylactic treatment in headache [abstract 81]. Presented at the 6th headache congress: European Headache Federation. Istanbul, Turkey, June 26 30, 2002. Mauskop A. The use of botulinum toxin in the treatment of headaches. Curr Pain Headache Rep 2002a;6: 320 3. Mauskop A. Long-term use of botulinum toxin type A (BOTOX) in the treatment of episodic and chronic migraine headaches [abstract S105]. Presented at the American Headache Society 44th Annual Scientific Meeting. Seattle, WA, June 21 23, 2002.
that may last over 4 months with no systemic or serious AEs. Several issues remain to be defined, however, including dosing, location, and number of injections; optimal dilution of BoNT-A; specific headache types that respond best to BoNT-A; and long-term efficacy and safety. Data from ongoing well-designed trials that include a larger patient population investigating these issues may confirm a role for BoNT-A as a first-line agent for migraine prevention. Neurotoxin therapy is part of a broader headache management approach. Because the injection techniques for headache are unique and vary depending on the primary headache disorder being treated and the location and pattern of pain referral, the use of BoNT-A for headache is not simply an extension of its use for cosmesis. The use of BoNT-A in the overall management of primary headache disorders should be reserved for medical practitioners who not only have experience with BoNT-A injections, but possess the expertise in the diagnosis and management of complex headache disorders. Educating patients and addressing headache triggers and optimizing acute treatment improve the outcome of any preventive program.
[11]
[12]
[13]
[14]
[15]
[16] [17]
[18]
[19]
References
[1] Lipton RB, Stewart WF, Diamond S, Diamond ML, Reed M. Prevalence and burden of migraine in the United States: data from the American Migraine Study II. Headache 2001;41:646 57. [2] Menken M, Munsat TL, Toole JF. The global burden of disease study: implications for neurology. Arch Neurol 2000;57:418 20. [3] Hu XH, Markson LE, Lipton RB, Stewart WF, Berger ML. Burden of migraine in the United States: disability and economic costs. Arch Intern Med 1999;159:813 8. [4] Thom TJ. Economic costs of neoplasms, arteriosclerosis, and diabetes in the United States. In Vivo 1996;10: 255 9. [5] Weiss KB, Gergen PJ, Hodgson TA. An economic evaluation of asthma in the United States. N Engl J Med 1992;326:862 6. [6] Goadsby PJ, Lipton RB, Ferrari MD. Migraine: current understanding and treatment. N Engl J Med 2002;346: 257 70. [7] Scher AI, Stewart WF, Liberman J, Lipton RB. Prevalence of frequent headache in a population sample. Headache 1998;38:497 506. [8] Silberstein S, Mathew N, Saper J, Jenkins S. Botulinum toxin type A as a migraine preventive treatment. Headache 2000;40:445 50. [9] Silberstein SD, Goadsby PJ. Migraine: preventive treatment. Cephalalgia 2002;22:491 512. [10] Gobel H, Heinze A, Heinze-Khun K, Jost WH. [20]
[21]
[22]
[23]
[24]
[25]
[26]
A.M. Blumenfeld et al / Dermatol Clin 22 (2004) 167175 [27] Mathew NT, Kallasam J, Kaupp A, Meadors L. Disease modification in chronic migraine with botulinum toxin type A: long-term experience [abstract S107]. Presented at the American Headache Society 44th Annual Scientific Meeting. Seattle, WA, June 21 23, 2002. [28] Miller T, Denny L. Retrospective cohort analysis of 48 chronic headache patients treated with botulinum toxin type A (BOTOX) in a combination fixed-injection-site and follow the pain protocol [abstract S138]. Presented at the American Headache Society 44th Annual Scientific Meeting. Seattle, WA, June 21 23, 2002. [29] Barrientos N, Chana P. Efficacy and safety of botulinum toxin type A (BOTOX) in the prophylactic treat-
175
ment of migraine [abstract S106]. Presented at the American Headache Society 44th Annual Scientific Meeting. Seattle, WA, June 21 23, 2002. [30] Brin MF, Binder WJ, Blitzer A, Schenrock L, Pogoda JM. Botulinum toxin type A for pain and headache. In: Brin MF, Hallett M, Jankovic J, editors. Scientific and therapeutic aspects of botulinum toxin. New York: Lippincott Williams & Wilkins; 2002. p. 233 50. [31] Ondo WG, Vuong KD, Derman HS. Botulinum toxin A (BOTOX) for chronic daily headache: a randomized placebo-controlled, parallel design study [abstract S131]. Presented at the American Headache Society 44th Annual Scientific Meeting. Seattle, WA, June 21 23, 2002.
Dermatol Clin 22 (2004) 177 185
Treatment of hyperhidrosis with botulinum toxin

Richard G. Glogau, MD
Department of Dermatology, University of California at San Francisco, 350 Parnassus Avenue, Suite 400, San Francisco, CA 94117 3685, USA
Focal idiopathic and episodic eccrine sweating of the axillae, palms, soles, and face troubles afflicted individuals with a social curse that can only be imagined by those whose hands or underarms dampen only occasionally. Although there is no accurate incidence in the epidemiology literature, it seems that about half of the patients who have presented to the author with this condition have at least one first-degree relative similarly affected. Social stigma, lack of understanding on the part of medical providers as to the cause and nature of the problem, and lack of effective therapy keeps most of these patients from seeking medical care. A larger social sampling is needed to measure accurately both the number of patients per 100,000 population who have the condition, and the exact nature of the genetic influence. Gravimetric measurements of palmar sweating show that patients with hyperhidrosis easily exceed 12 to 30 times normal rates of eccrine secretion from the palmar surface of the hands and fingers, and often the distal dorsal aspects of the fingers and sides of the hand and digits. Diagnostic rates are arbitrarily defined. In some patients perspiration may exceed 50 mg of sweat per minute in the axillae and 30 mg of sweat per minute on the palms [1 5]. Although many patients sweat on a more or less continuous basis, even while asleep, many if not most of the patients report that they suffer from sudden, inexplicable increases in sweating. These sweating attacks can be brought on by emotional stressors, such as public speaking or meeting new social contacts at work or leisure; high ambient temperature; and ingestion of stimulants like coffee. But they also report that they can be sitting relatively calm and cool and without situational stress
E-mail address: drglogau@sfderm.com
and notice that suddenly and inexplicably their hands, underarms, soles, or faces begin to drip. Many patients have covered this affliction up by resorting to elaborate behavior rituals, repetitively wiping their palms on clothes, wearing underarm absorbent pads, carrying towels and handkerchiefs at all times, and avoiding the dreaded handshake at all costs. Traditional therapies, such as topical aluminum chlorides salts in antiperspirants, anticholinergic drugs, and glutaraldehyde tinctures, are irritating, rife with side effects, and generally impractical for patients with this condition [6 8]. Direct excision of the affected skin has been proposed for treating axillary sweating [9,10] but cannot be performed on the palms. Liposuction curettage has been advocated for axillary hyperhidrosis [11 16], but is of no value in palmar sweating. The standard surgical approach for palmar and facial sweating has been focused on neurosurgical techniques with elective thoracic sympathectomies at the T2-T3 level, performed with endoscopic approaches and minimal incisions, popular for some time [17 22]. The procedure provides unpredictable partial relief for axillary sweating and carries the risk of some significant postoperative complications, including Horners syndrome, pneumothorax, and partial or incomplete response [23 26]. Worse, significant portions of patients treated by sympathectomy develop some degree of compensatory hyperhidrosis [27 29]. This condition affects the skin from the areolas caudally. The patients, although dry over the entire hand, arm, shoulder, neck and head, paroxysmally sweat profusely from mid-chest down. This is a highly distressing and irreversible condition and no known algorithm to predict its occurrence preoperatively has yet been described. When compensatory hyperhidrosis occurs, the result is that one intolerable sweating problem is traded for another.
0733-8635/04/$ see front matter D 2004 Elsevier Inc. All rights reserved. doi:10.1016/S0733-8635(03)00072-X
178
R.G. Glogau / Dermatol Clin 22 (2004) 177185
Botulinum toxin for sweating There has been considerable interest in using selective, focal chemodenervation with botulinum neurotoxin to control problems of localized but severe sweating [30 36]. There are two commercially available forms of the A serotype complex: BOTOXR (Allergan, Irvine, CA) and Dysport (Speywood Pharmaceuticals, Maidenhead, Berkshire, UK). A third commercially approved product, a B serotype, was recently approved by the Food and Drug Administration for cervical dystonia and is marketed in the United States under the name Myobloc (Elan Pharmaceuticals, South San Francisco, CA) and in Europe as Neurobloc. The A serotypes have accumulated more clinical experience in treatment of hyperhidrosis. For the balance of this article, reference is made to BOTOXR unless otherwise specifically indicated. Unlike the case with sympathectomy, the focal areas treated with BOTOXR are confined to the palms or axillae or the soles, and the total body surface area treated is less than 3%. In contrast the surgical section of the sympathetic chain at the T2-T3 level renders at least 20% of the bodys surface anhidrotic. Thermoregulatory stress then creates the compensatory sweating, which has not been reported with focal chemodenervation with BOTOXR.
Fig. 2. Minor starch-iodine test of axilla 2 weeks after treatment with 50 U intradermal BOTOXR at a dilution of 2.5 mL/100 U.
Documentation of problem There are two methods used to document the magnitude and distribution of abnormal palmar sweating: gravimetric measurement and the Minor starchiodine test [37]. Gravimetric testing uses filter paper that is held in contact with the palm for a fixed period
Fig. 1. Minor starch-iodine test of axilla before treatment with BOTOXR.
of time and then weighed. This technique is useful largely as a research tool to document the magnitude of sweat reduction and identify the therapeutic dose range. The Minor starch-iodine test is performed by first wiping the skin with a colored iodine tincture (eg, an antibacterial iodine solution available in pharmacies). The iodine solution must be brown-orange in color. Decolorized iodine solution does not perform the colorimetric conversion properly. Several seconds are given to allow the iodine solution to dry. A small fan is useful for this purpose. The palm is then lightly dusted with ordinary baking cornstarch powder, available in any food store. As the eccrine sweat exits the skin onto the palmar surface a chemical reaction takes place between the iodide molecule and the starch present in the powder producing a colorimetric reaction as the powder turns deep purple in a matter of a couple of seconds (Figs. 1, 2). The exact location of the active sweating is then mapped and outlined with a marking pen before beginning injections. One should take care to perform the starch-iodine test before applying any regional nerve blocks or before application of topical anesthetics like prilocaine or eutectic mixtures of lidocaine (EMLA) in wide use today. The vasoconstrictive effect of the topical anesthetics and the hyperemic response in the skin seen after regional wrist blocks both interfere with the amount of sweating and can give misleading results in the Minor starch-iodine test. The author has found it useful to take a digital photograph of the starch-iodine test for the medical record and a Polaroid picture to give to patients. They can easily perform a starch-iodine test themselves in follow-up and ascertain the fractional response to therapy (Figs. 3 5). The photographs also help
179
Fig. 3. By injecting through the starch-iodine, the small amount of moisture at each injection site readily demonstrates the scattered pattern of injections.
Fig. 5. Minor starch-iodine test. Two weeks after treatment of both palms with BOTOXR. (From Glogau RG. Treating palmar sweating with neurotoxins. Semin Cutan Med Surg 2001; 20:104; with permission.)
patients visualize the degree of the problem and their response to therapy after the BOTOXR injections are performed. Patients are psychologically traumatized by hyperhidrosis, and most are exquisitely sensitive to any persisting sweat after treatment. They are often reassured by comparing the before and after starch test pictures (Fig. 6). It reinforces their understanding of the effect of the drug and the therapy.
Anesthesia Treating the axillary skin with intradermal injections of BOTOXR through a 30-gauge hypodermic needle can be accomplished easily without anesthesia, although topical anesthetics may be used after marking
the area to be treated using the Minor starch-iodine test. Similarly, forehead or facial sweating can be treated without anesthetic. A few stoic patients with palmar or plantar sweating may opt for simple topical anesthesia, such as ice, EMLA, ELA-MAX, and so forth, but few can tolerate the discomfort of 60 to 70 needle sticks per palm or sole without anesthesia. Most patients require regional nerve block anesthesia, such as wrist or ankle blocks, before undergoing palmar injection [38,39]. The occasional patient may require twilight anesthesia [40] or tourniquet limb anesthesia (Bier block) [41]. For palmar anesthesia 1% to 2% lidocaine plain, without epinephrine, is placed by superficial, subcutaneous injections at the wrist to produce blocks of the
Fig. 4. Minor starch-iodine test. Right hand untreated. Left hand 2 days after treatment with BOTOXR. Notice areas of diffusion with anhidrosis developing circumferentially around injection sites. (From Glogau RG. Treating palmar sweating with neurotoxins. Semin Cutan Med Surg 2001; 20:103; with permission.)
Fig. 6. Minor starch-iodine test. Right hand treated 2 weeks previously. Left hand untreated. (From Glogau RG. Treating palmar sweating with neurotoxins. Semin Cutan Med Surg 2001;20:105; with permission.)
180
median, ulnar, and radial nerves. The median nerve is blocked by injecting between the palmaris longus tendon and the flexor carpi radialis tendon at the proximal flexion crease of the wrist. Injecting between the ulnar artery and the flexor carpi ulnaris tendon blocks the ulnar nerve. The superficial radialis is blocked by injecting in the anatomic snuff box on the dorsal-medial aspect of the base of the thumb. Once the injections are placed, usually a half-hour wait ensues to allow for the diffusion of anesthetic into the nerves to produce sufficient anesthesia. The disadvantage of using wrist blocks is that the patients reactive hyperemia that develops increases the tendency to bleed from each small injection site, which may increase loss of material from the injection site and decrease the relative effectiveness of each injection. Warning patients off aspirin before treatment is probably wise for the same reason. For plantar anesthesia, adequate anesthesia of the sole of the foot can be achieved with two injections [39]. The first is a medial ankle block of the tibial nerve at the level of the medial malleolus posterior to the posterior tibial artery, in-between the Achilles tendon and the medial malleolus. The second injection is a lateral ankle block of the sural nerve, between the Achilles tendon and the superior border of the lateral malleolus with the needle pointed perpendicular to the skin. Wrist and ankle blocks are usually performed without significant trauma if 30-gauge needles are used and if injection pressure is kept slow and steady. Occasional reflex neuropathy can be encountered as a rare complication.
Injection technique Each syringe then holds 0.5 mL of solution that is 20 U; it is relatively easy to read the graduations on the syringe and place either 2 U (0.05 mL) or 4 U (0.1 mL) in each site. With practice, one can generate about 10 to 12 injections with each syringe. To treat the axillae, one bottle of 100 U of BOTOXR is diluted with 2.5 mL of sterile saline with preservative and then divided into five 0.5-mL insulin syringes. Following a spiral pattern, 50 U of BOTOXR are injected in 0.05 mL to 0.01 mL (2 to 4 U) amounts intradermally raising tiny wheals spaced approximately 1.5 to 2.0 cm apart, beginning at the periphery of the hair-bearing skin and circling into the center of the axillary vault (see Fig. 3). The skin being rather thin in this area, care is taken to avoid injecting the material subcutaneously where it could go beyond the targeted glands. Keeping the needle bevel up and more parallel to the skin surface and advancing the needle 2 mm before injecting helps prevent backflow of the BOTOXR from the injection tract, which minimizes any loss of the toxin. The technique for palmar injections is similar, but injections must be spaced closer together because of the smaller zone of radial diffusion produced in palmar skin (Fig. 7). The needle must enter the palmar skin at an oblique angle. Mechanical needle flanges have been advocated, which provide a method for assisting the depth of the injection [38,45]. But if the needle enters perpendicular to the skin surface, there is usually a significant amount of backflow of material that leaks out of the injection tract. Because the volumes of
Injection syringes The dosage of drug used and injection method has not been standardized. There are a variety of dosages reported in the literature [35,38,42 44]. For all areas to be treated, the authors technique is to use a dilution of 2.5 mL per 100 mouse units, dividing the whole bottle among five Ultrafine II 50-U insulin syringes (Becton-Dickinson Franklin Lakes, New Jersey). Each syringe holds 0.5 mL and has the 30-gauge needle swaged directly into the chamber of the syringe, eliminating the dead space that occurs with a needle hub. This minimizes the waste of expensive botulinum toxin. The syringes are filled by popping the metal cap and rubber stopper from the bottle and drawing up the BOTOXR by aspirating with the needle inside the bottle. This is done to avoid needlessly dulling the 30gauge needle passing through the rubber stopper.
Fig. 7. Minor starch-iodine test. Immediately after placing injections in the right palm. Note how minimal backflow was achieved in most, but not all, injection sites. (From Glogau RG. Treating palmar sweating with neurotoxins. Semin Cutan Med Surg 2001;20:105; with permission.)
181
BOTOXR are typically small, this backflow significantly impacts the effectiveness of the injections. In axillary skin each injection is placed to produce a wheal. The palmar skin is comparatively stiffer, however, and usually a wheal cannot be raised under any circumstances. It is desirable, however, to produce a small zone of visible blanching, indicating that the material is in the deep dermis. One should take care with each injection to remove the thumb from the plunger and allow a second or two for the pressure to normalize before withdrawing the needle from the skin or else the fluid flows back out the injection tract directly.
Injection pattern and dosage A representative sample of the dosage regimens, pattern of injection, and indications for the botulinum toxin are presented in Table 1. Injection of the axilla usually involves placement of 10 to 20 individual intradermal injections of BOTOXR about 2.5 cm apart to cover the area of the axillary vault that stains darkly with Minor starch-iodine test. These can be performed quickly with minimal discomfort and virtually no sequelae.
Sweating of the upper forehead and anterior crown can be approached in a similar fashion, by injecting 2 to 4 U of BOTOXR every 2 cm along the anterior hair line from sideburn to sideburn, and an additional shorter row in the anterior crow about 2 cm behind the anterior hairline, and another horizontal row in the upper third of the forehead skin. These are also performed easily without anesthesia and well tolerated (Figs. 8, 9). In the authors technique palmar injections are placed approximately every 1.5 cm across the palmar surface. On the fingers the volar pad of each phalanx receives its individual dose. The fingertips usually receive two: one in mid pad and another at the very tip, because this is a very problematic sweating area for people with hyperhidrosis. The dominant or writing hand also receives an extra row of injections along the ulnar side, midway between the palm and dorsal surface, to provide maximum dryness for writing. Occasionally extra injections can be placed on the distal dorsal fingers or in the webs depending on the patients complaints. The goal is to place the injections in a pattern so that diffusion provides overlapping coverage for the entire palmar surface. One needs to minimize the number of injections that arrive subcutaneously because this increases the likelihood of diffusion of drug into the intrinsic muscles of the hand.
Table 1 Sample of dosage regimens and patterns of injections for treatment of hyperhidrotic conditions with botulinum toxins Author Odderson, 2002 [57] Heckmann 2002 [73] Naumann and Hamm, 2002 [52] Salmanpoor and Rahmanian, 2002 [58] Naumann and Lowe, 2001 [53] De Almeida et al, 2001 [38] Heckmann et al, 2001 [48] Dulguerov et al, 2000 [72] Karamfilov et al, 2000 [50] Naver et al, 2000 [54] Solomon and Hayman, 2000 [44] Birch et al, 1999 [70] Laccourreye et al, 1999 [74] Schnider et al, 1999 [59] Glogau, 1998 [32] Heckmann et al, 1998 [49] Naumann et al, 1998 [42] Odderson, 1998 [56] Shelley et al, 1998 [43] Schnider et al, 1997 [35] Bushara et al, 1996 [30] Cheshire, 1996 [31] Drobik et al, 1995 [71] Dilution mL/100 U 2 4 4 ? 4 2 5 2 1 ? 2 4 Dose BOTOXR unless otherwise labeled 50 per axilla 50 per axilla 50 per axilla 125 per axilla Dysport 50 (3 5 per site) 5 per site 200 (Dysport) 5 per site 200 per axilla 2 per site 2 4 per site 7.5 per site 2.5 per site 33.3 per axilla 2 per site 400 (Dysport) 3 100 (BOTOXR) 2 20 U 20 50 1U 0.5 U Distance or total sites per area treated 7 10 sites/axilla 2.5 per site 10 per axilla 10 per axilla 10 15 sites/axilla 1 cm 10 sites/axilla 1 Single dose 4 cm2 1 cm 6 cm2 1 cm2 2 3 cm 1.5 cm 1 cm 2 cm 1 cm 6 sites Single dose 1.5 cm 1 cm Diagnosis Axillary Axillary Axillary Axillary Axillary Palmar Axillary Freys Axillary Axillary/palm Palmar Freys Freys Axillary Axillary Axillary Axillary, palm Axillary Palmar Palmar Axillary Forearm Freys
182
Fig. 8. Minor starch-iodine test on upper forehead showing broad area of excessive sweating.
The total amount of drug used per hand is dependent on the surface area of the hand. Patients with large shoe sizes have correspondingly larger hands and require more injections and larger total dosage. A man with a size 13 shoe (US) requires up to 150 U per palm, whereas a woman with a size 6 shoe (US) requires as little as 75 U to cover the palm. The average dose in the authors patients was about 120 U per palm. Injection of the soles of the feet follows the same technique and pattern as the palms. The difficulty arises from the necessity of treating a much larger surface area, so doses usually exceed those of the palms. Using the Minor starch-iodine test as a guide, and relying on ankle blocks for anesthesia, the same satisfactory outcome can be achieved. Duration of effect seems to be identical to that achieved in the palms.
axillary skin. On average, patients seem to require treatment about twice a year to maintain reasonable control of the palmar sweating. Patients are usually expecting complete anhidrosis as an end point, at least with their initial treatment. It may take several treatments before they recognize less than total response as successful. They are generally unfamiliar with normal palmar moisture, and at least initially are intolerant of anything but a totally dry hand as a measure of success. With time and release from the mental anguish of unreliable palmar sweating, many do seem to change their therapeutic end point goals, and are comfortable with control as opposed to total ablation of palmar sweating. This changes the treatment intervals and dosages, but further work on patient acceptance needs to be undertaken. There have been no known reports of compensatory hyperhidrosis from the focal use of botulinum toxin in the palms or axillae. This is an important theoretical and practical advantage of the botulinum toxins in the management of hyperhidrosis. The downside relates to the fact that the botulinum effect is neither permanent nor inexpensive. Properly informed patients may elect to pursue the surgical alternative, however, and referral should be made to neurosurgical or thoracic surgical practices with expertise in this method.
Scheduling palmar treatments Almost every patient who undergoes this treatment develops a transient period of weakness and instability
Duration of effect Reported response times for duration of anhidrosis in the axillae range from 4 months to 10 months in numerous studies depending on dosage and technique [1,30,32,42,46 62]. Similar responses are seen in treatment of forehead sweating [51,63 65]. There is a broader range of responses to palmar treatment, varying from about 3 months to 12 months [34,35,42 44,48,54,66]. The average in the authors hands is about 6 months. Interestingly, the effect does not seem as long as it is with axillary hyperhidrosis. Speculative reasons for this may be the problem with backflow, the smaller diffusion distance in thicker palmar skin, the higher number of cholinergic nerve endings in the palmar skin, or a differential recovery rate between the nerves of the palm and those in the
Fig. 9. Minor starch-iodine test after treatment with 60 U of BOTOXR. Note that only the upper portion of the forehead was treated to avoid inactivation of lower frontalis and secondary disturbance of normal brow elevation. Treatment also was extended back into the anterior hairline where some of the most intense staining was visualized before treatment.
183
of the lumbrical muscles of the hand, which is predictably spontaneously reversible [2,34,35,43, 44,54,66]. Such tasks as shoving a button through a tight button hold, holding heavy objects with chop sticks, or opening a stuck lock with a key, become problematic about 5 to 7 days after treatment and remain so for 3 to 5 weeks. Patients can write, type, and eat without difficulty, but opening up a tight jar lid, for example, poses problems for a few weeks. For this reason, if the patient has ready geographic access to the treating physician, it may be wise to offer to stagger the treatments apart. Beginning with the right hand on the first visit, the author often waits a couple of weeks and then treats the left hand with any needed touch up injections of the right hand on the second visit, and schedules a third visit to touch up the left hand. By doing so, one can stagger the time line of weakness to make it easier on the patient. Multiple visits often are logistically impossible, however, and the author has no objection to treating both palms simultaneously as long as the patient is aware of the implications. One successful strategy has been to offer to treat the hands separately the first time, but depending on the muscle weakness, let the patient choose to schedule future treatments together or staggered according to their own experience.
[3]
[4]
[5] [6]
[7] [8]
[9]
[10] [11]
[12] [13]
Future directions Further work is needed to optimize the dilution and units per square centimeter. Introduction of a botulinum toxin of the B serotype (Myobloc, Neurobloc, Elan Pharmaceuticals, Dublin, Ireland) may present an alternative molecule to the A serotypes currently in use. No data exist on the behavior of this molecule in the hyperhidrosis model [67,68]. Work on injection delivery devices has stimulated some investigators and further enhancements to the delivery system [38,69] may optimize the treatment for many patients. Further investigation of the genetic pattern of the disorder may give clues to possible therapies. Until then the patients can benefit from truly life-altering therapy with this amazing molecule.
[14]
[15]
[16]
[17]
[18]
[19]
References
[1] Heckmann M, Breit S, Ceballos-Baumann A, et al. Sidecontrolled intradermal injection of botulinum toxin A in recalcitrant axillary hyperhidrosis. J Am Acad Dermatol 1999;41:987 90. [2] Naumann M, Bergmann I, Hofmann U, et al. Botulinum toxin for focal hyperhidrosis: technical considera[20] [21]
tions and improvements in application. Br J Dermatol 1998;139:1123 4. Reinauer S, Neusser A, Schauf G, et al. Iontophoresis with alternating current and direct current offset (AC/ DC iontophoresis): a new approach for the treatment of hyperhidrosis. Br J Dermatol 1993;129:166 9. Sato K, Kang WH, Saga K, et al. Biology of sweat glands and their disorders. J Am Acad Dermatol 1989; 20:713 26. Sato K, Ohtsuyama M, Samman G. Eccrine sweat gland disorders. J Am Acad Dermatol 1991;24:1010 4. Sheean GL. Botulinum treatment of spasticity: why is it so difficult to show a functional benefit? Curr Opin Neurol 2001;14:771 6. Shelley WB, Hurley HJ. Axillary hyperhidrosis [letter]. JAMA 1975;233:1257. Shelley WB, Hurley HJ. Studies on topical antiperspirant control of axillary hyperhidrosis. Acta Derm Venereol 1975;55:241 60. Bisbal J, del Cacho C, Casalots J. Surgical treatment of axillary hyperhidrosis. Ann Plast Surg 1987;18: 429 36. Cilliers PH. Surgical management of patients with hyperhidrosis. S Afr Med J 1987;72:538 9. Christ JE. The application of suction-assisted lipectomy for the problem of axillary hyperhidrosis. Surg Gynecol Obstet 1989;169:457. Coleman WD. Noncosmetic applications of liposuction. J Dermatol Surg Oncol 1988;14:1085 90. Lillis PJ, Coleman WD. Liposuction for treatment of axillary hyperhidrosis. Dermatol Clin 1990;8:479 82. Shenaq SM, Spira M, Christ J. Treatment of bilateral axillary hyperhidrosis by suction-assisted lipolysis technique [published erratum appears in Ann Plast Surg 1990;24:212]. Ann Plast Surg 1987;19:548 51. Swinehart JM. Treatment of axillary hyperhidrosis: combination of the starch-iodine test with the tumescent liposuction technique. Dermatol Surg 2000;26:392 6. Tofield JJ. Re: Shenaq and Spir: treatment of bilateral axillary hyperhidrosis by suction-assisted lipolysis technique [letter]. Ann Plast Surg 1988;21:99. Kao MC. Endoscopic thoracic sympathectomy (ETS) is a simple, safe, and effective method for treating palmar hyperhidrosis. Surg Laparosc Endosc Percutan Tech 2000;10:338 9. Lau W, Lee J, Dang C, et al. Improvement in quality of life after bilateral transthoracic endoscopic sympathectomy for palmar hyperhydrosis. Hawaii Med J 2001; 60:126 7. Lin TS, Kuo SJ, Chou MC. Uniportal endoscopic thoracic sympathectomy for treatment of palmar and axillary hyperhidrosis: analysis of 2000 cases. Neurosurgery 2002;51:84 7. Patel NP. Uniportal and biportal endoscopic thoracic sympathectomy. Neurosurgery 2002;51:79 83. Reisfeld R, Nguyen R, Pnini A. Endoscopic thoracic sympathectomy for hyperhidrosis: experience with both cauterization and clamping methods. Surg Laparosc Endosc Percutan Tech 2002;12:255 67.
184
R.G. Glogau / Dermatol Clin 22 (2004) 177185 regional anaesthesia for treatment of palmar hyperhidrosis with botulinum toxin type A. Br J Dermatol 2001;144:632 3. Blaheta HJ, Vollert B, Zuder D, et al. Intravenous regional anesthesia (Biers block) for botulinum toxin therapy of palmar hyperhidrosis is safe and effective. Dermatol Surg 2002;28:666 72. Naumann M, Hofmann U, Bergmann I, et al. Focal hyperhidrosis: effective treatment with intracutaneous botulinum toxin. Arch Dermatol 1998;134:301 4. Shelley WB, Talanin NY, Shelley ED. Botulinum toxin therapy for palmar hyperhidrosis. J Am Acad Dermatol 1998;38:227 9. Solomon B, Hayman R. Botulinum toxin type A therapy for palmar and digital hyperhidrosis. J Am Acad Dermatol 2000;42:1026 9. Zaiac M, Weiss E, Elgart G. Botulinum toxin therapy for palmar hyperhidrosis with ADG needle. Dermatol Surg 2000;26:230. Akdeniz S, Harman M, Aluclu U, et al. Axillary hyperhidrosis treated with botulinum toxin A exotoxin. J Eur Acad Dermatol Venereol 2002;16:171. Filosto M, Bertolasi L, Fincati E, et al. Axillary injection of botulinum A toxin in a patient with muscle cramps associated with severe axillary hyperhidrosis. Acta Neurol Belg 2001;101:121. Heckmann M, Ceballos-Baumann A, Plewig G. Botulinum toxin A for axillary hyperhidrosis (excessive sweating). N Engl J Med 2001;344:488 93. Heckmann M, Schaller M, Ceballos-Baumann A, et al. Follow-up of patients with axillary hyperhidrosis after botulinum toxin injection. Arch Dermatol 1998; 134:1298. Karamfilov T, Konrad H, Karte K, et al. Lower relapse rate of botulinum toxin A therapy for axillary hyperhidrosis by dose increase. Arch Dermatol 2000; 136:487 90. Naumann M. Evidence-based medicine: botulinum toxin in focal hyperhidrosis. J Neurol 2001; 248(suppl 1):31. Naumann M, Hamm H. Treatment of axillary hyperhidrosis. Br J Surg 2002;89:259 61. Naumann M, Lowe N. Botulinum toxin type A in treatment of bilateral primary axillary hyperhidrosis: randomised, parallel group, double blind, placebo controlled trial. BMJ 2001;323:596 9. Naver H, Swartling C, Aquilonius SM. Palmar and axillary hyperhidrosis treated with botulinum toxin: one-year clinical follow-up. Eur J Neurol 2000;7: 55 62. Odderson IR. Axillary hyperhidrosis: treatment with botulinum toxin A. Arch Phys Med Rehabil 1998; 79:350. Odderson IR. Hyperhidrosis treated by botulinum A exotoxin. Dermatol Surg 1998;24:1237. Odderson IR. Long-term quantitative benefits of botulinum toxin type A in the treatment of axillary hyperhidrosis. Dermatol Surg 2002;28:480 3.
[22] Swan MC, Paes T. Quality of life evaluation following endoscopic transthoracic sympathectomy for upper limb and facial hyperhydrosis. Ann Chir Gynaecol 2001; 90:157 9. [23] Gossot D, Kabiri H, Caliandro R, et al. Early complications of thoracic endoscopic sympathectomy: a prospective study of 940 procedures. Ann Thorac Surg 2001;71:1116 9. [24] Heckmann M. Complications in patients with palmar hyperhidrosis treated with transthoracic endoscopic sympathectomy. Neurosurgery 1998;42:1403 4. [25] Kao MC. Complications in patients with palmar hyperhidrosis treated with transthoracic endoscopic sympathectomy. Neurosurgery 1998;42:951 2. [26] Lai YT, Yang LH, Chio CC, et al. Complications in patients with palmar hyperhidrosis treated with transthoracic endoscopic sympathectomy. Neurosurgery 1997; 41:110. [27] Adar R. Compensatory hyperhidrosis after thoracic sympathectomy. Lancet 1998;351:231 2. [28] Collin J. Compensatory hyperhidrosis after thoracic sympathectomy. Lancet 1998;351:1136. [29] Shuster S. Compensatory hyperhidrosis after thoracic sympathectomy. Lancet 1998;351:1136. [30] Bushara KO, Park DM, Jones JC, et al. Botulinum toxin: a possible new treatment for axillary hyperhidrosis. Clin Exp Dermatol 1996;21:276 8. [31] Cheshire WP. Subcutaneous botulinum toxin type A inhibits regional sweating: an individual observation. Clin Auton Res 1996;6:123 4. [32] Glogau RG. Botulinum A neurotoxin for axillary hyperhidrosis: no sweat BOTOXR. Dermatol Surg 1998;24: 817 9. [33] Heckmann M, Schaller M, Ceballos-Baumann A, et al. Botulinum beyond wrinkles [letter]. Dermatol Surg 1997;23:1221 2. [34] Naumann M, Flachenecker P, Brocker E, et al. Botulinum toxin for palmar hyperhidrosis. Lancet 1997; 349:252. [35] Schnider P, Binder M, Auff E, et al. Double-blind trial of botulinum A toxin for the treatment of focal hyperhidrosis of the palms. Br J Dermatol 1997; 136:548. [36] Schnider P, Binder M, Berger T, et al. Botulinum A toxin injection in focal hyperhidrosis [letter]. Br J Dermatol 1996;134:1160. [37] Minor V. A new procedure for the clinical investigation of sweat discharges. Dtsch Z Nervenheilkd 1928;101: 301 6. [38] de Almeida A, Kadunc B, de Olivieria EM. Improving botulinum toxin therapy for palmar hyperhidrosis: wrist block and technical considerations. Dermatol Surg 2001;27:34 6. [39] Fujita M, Mann T, Mann O, et al. Surgical pearl: use of nerve blocks for botulinum toxin treatment of palmar-plantar hyperhidrosis. J Am Acad Dermatol 2001; 45:587 9. [40] Vollert B, Blaheta H, Moehrle E, et al. Intravenous
[41]
[42]
[43]
[44]
[45]
[46]
[47]
[48]
[49]
[50]
[51]
[52] [53]
[54]
[55]
[56] [57]
R.G. Glogau / Dermatol Clin 22 (2004) 177185 [58] Salmanpoor R, Rahmanian MJ. Treatment of axillary hyperhidrosis with botulinum-A toxin. Int J Dermatol 2002;41:428 30. [59] Schnider P, Binder M, Kittler H, et al. A randomized, double-blind, placebo-controlled trial of botulinum A toxin for severe axillary hyperhidrosis. Br J Dermatol 1999;140:677. [60] Schnider P, Moraru E, Kittler H, et al. Treatment of focal hyperhidrosis with botulinum toxin type A: long-term follow-up in 61 patients. Br J Dermatol 2001;145:289. [61] Whatling P, Collin J. Botulinum toxin injection is an effective treatment for axillary hyperhidrosis. Br J Surg 2001;88:814. [62] Wollina U, Karamfilov T, Konrad H. High-dose botulinum toxin type A therapy for axillary hyperhidrosis markedly prolongs the relapse-free interval. J Am Acad Dermatol 2002;46:536. [63] Boger A, Herath H, Rompel R, et al. Botulinum toxin for treatment of craniofacial hyperhidrosis. J Neurol 2000;247:857. [64] Kinkelin I, Hund M, Naumann M, et al. Effective treatment of frontal hyperhidrosis with botulinum toxin A. Br J Dermatol 2000;143:824. [65] Tan SR, Solish N. Long-term efficacy and quality of life in the treatment of focal hyperhidrosis with botulinum toxin A. Dermatol Surg 2002;28:495. [66] Holmes S, Mann C. Botulinum toxin in the treatment of palmar hyperhidrosis. J Am Acad Dermatol 1998; 39:1040.
185
[67] Carruthers A. Update on botulinum toxin. Skin Therapy Lett 1999;4:1. [68] Carruthers A, Carruthers J. Update on the botulinum neurotoxins. Skin Therapy Lett 2001;6:1. [69] Grimalt R, Moreno-Arias G, Ferrando J. Multi-injection plate for botulinum toxin application in the treatment of axillary hyperhidrosis. Dermatol Surg 2001; 27:543. [70] Birch JF, Varma SK, Narula AA. Botulinum toxoid in the management of gustatory sweating (Freys syndrome) after superficial parotidectomy. Br J Plast Surg 1999;52:230 1. [71] Drobik C, Laskawi R, Schwab S. Therapy of Frey syndrome with botulinum toxin A: experiences with a new method of treatment [see comments]. HNO 1995; 43:644. [72] Dulguerov P, Quinodoz D, Cosendai G, et al. Frey syndrome treatment with botulinum toxin. Otolaryngol Head Neck Surg 2000;122:821 7. [73] Heckmann M. Hyperhidrosis of the axilla. In: Kreyden OP, Bo ni R, Burg G, editors. Hyperhidrosis and botulinum toxin in dermatology, vol. 30. Basel, Switzerland: Karger; 2002. p. 149 55. [74] Laccourreye O, Akl E, Gutierrez-Fonseca R, et al. Recurrent gustatory sweating (Frey syndrome) after intracutaneous injection of botulinum toxin type A: incidence, management, and outcome. Arch Otolaryngol Head Neck Surg 1999;125:283 6.
Dermatol Clin 22 (2004) 187 195
Noncosmetic uses of botulinum toxin

Craig Zalvan, MDa, Boris Bentsianov, MDb,c, Omar Gonzalez-Yanes, MDd, Andrew Blitzer, MD, DDSe,f,*
Department of Otolaryngology, New York Medical College, 1055 Saw Mill River Road, Ardsley, NY 10502, USA b Department of Otolaryngology, State University of New York Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, NY 11203, USA c Division of Laryngology, Voice and Swallowing Disorders, State University of New York Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, NY 11203, USA d Department of Otolaryngology, 525 Roosevelt Avenue, Suite 811, Plaza de les Americas, San Juan, 00918-8058 Puerto Rico e Clinical Otolaryngology, Columbia University, New York, NY, USA f New York Center for Voice and Swallowing Disorders, 425 West 59th Street, New York, NY 10019, USA
a
Since the introduction of botulinum toxin as a therapeutic tool in the 1970s, the number of uses for this drug has increased exponentially. The mechanism of action of the toxin is to degrade the SNARE (soluble NSF attachment protein receptor) proteins blockading the release of acetylcholine into the neuromuscular junction. In many body systems, decrease of contractility, strength, and tension of certain muscle groups results in improved clinical outcomes. Applications now include cosmetic, gastroenterologic, otolaryngologic, genitourinary, neurologic, and dermatologic use. In fact, in any situation with inappropriate or exaggerated muscle contraction, botulinum toxin can be considered as a potential treatment. The toxins effect on SNARE proteins may also inhibit the release of pain mediators and block autonomic nervous system effects such as in hyperhidrosis. Currently, the Food and Drug Administration (FDA) has licensed botulinum toxin A (BOTOX) for the treatment of glabelar lines, blepharospasm, strabismus, hemifacial spasm, cervical dystonia, and spasticity. With the recent addition of cosmetic applications to the FDAs approval list, the use of botulinum toxin has dramatically increased. Review of the literature now shows hundreds of
articles with novel ideas for the use of botulinum toxin. However, the vast majority of these articles are anecdotal, with few randomized, controlled, and blind studies (Box 1).
Neurologic disorders Perhaps the most widely used neurologic application of botulinum toxin is in patients with dystonia. Patients with cervical dystonia (CD) constitute one of the largest subgroups of this disorder. Characterized by abnormal movement and posture of the neck, CD is the most common form of focal dystonia. Also known as spastic torticollis, it is characterized by turning and flexion or extension of the neck. Many patients eventually suffer from associated muscular hypertropy. The majority of patients report a moderate to complete relief of symptoms often lasting 3 to 4 months after injection [1]. Similarly, botulinum toxin has been useful in treating oromandibular dystonia [2], lingual dystonia [3], hemifacial spasm [4], and blepharospasm [5]. Benign cramp-fasciculation syndrome is an inherited disease that results in continuous, involuntary, widespread muscle contractions. Treatment is usually pharmacologic; however, botulinum toxin has recently been shown to provide substantial relief. In one study, injection of botulinum toxin into the calf muscles and small flexor muscles of the foot resulted in a markedly decreased symptom severity score, de-
* Corresponding author. Clinical Otolaryngology, Columbia University, New York, NY, USA. E-mail address: Ab1136@aol.com (A. Blitzer).
188
C. Zalvan et al / Dermatol Clin 22 (2004) 187195
Box 1. Noncosmetic therapeutic uses of botulinum toxin Neuromuscular disorders Focal dystonias Blepharospasm Cervical dystonia Occupational dystonias (writers cramp) Spasmodic dysphonia Oromandibular dystonia Facial dystonia Lingual dystonia Meiges syndrome Benign cramp - fasciculation syndrome Essential tremor Hemifacial spasm Mental retardation cerebral palsy Spasticity Myokymia Neurogenic muscle hypertrophy Palatal myoclonus Spinal myoclonus Synkinesis/VII nerve disorders Ophthalmological diseases Essential blepharospasm Strabismus Esotropia Exotropia Duannes eye-retraction syndrome Nystagmus Therapeutic ptosis for corneal protection Oscillopsia Laryngeal disorders Spasmodic dysphonia Granuloma Puberophonia Posterior glottic stenosis Rebalancing Stutter Tracheoesophageal puncture failure Essential voice tremor Vocal tics Cricopharyngeus Oromandibular disorders Bruxism Masseter hypertrophy Temporomandibular disorders Gastrointestinal disorders Achalasia Anal fissure (chronic)
Anismus Intractable hiccups Severe constipation Anorectal pain Gastroparesis (pyloric) Benign anal disorders Esophageal diverticulosis Sphincter of Oddi Salivary disorders Crocodile tears Sialocele Sialorrhea Drooling Parotid fistula Freys syndrome Ptyalism Genitourinary disorders Detrusor-sphincter dyssynergia Overactive bladder Vaginismus Urinary retention Pain Syndromes Back pain Headache Tension Migraine Cervicogenic pain Myofascial pain Other disorders Apraxia of eyelid opening Hemifacial spasm Synkinesis secondary to facial nerve palsy Stuttering with glottal blocks Hyperhydrosis (axillary, palmar, gustatory) Body odor/sweat Intrinsic rhinitis Surgical applications Perisurgical and postsurgical muscle immobilization (aspiration)
creased fasciculations, and minimal weakening of the muscle groups. Symptomatic relief was achieved for 3 to 4 months [6]. Writers cramp is a focal occupational dystonia that can prevent a person from writing by causing physical discomfort and difficulty with control of hand movements. Traditional pharmacologic and surgical therapy has yielded marginal results. Botulinum toxin injections into the affected muscle groups of the hand and wrist have provided significant relief [7]. Although
189
this treatment is not effective for all people, significant improvement in writing and reduction of pain is seen in at least two-thirds of those treated [8]. Another use of botulinum toxin has been in the treatment of spasticity in stroke patients as well as patients with mental retardation cerebral palsy. Plagued by inability to control contractions of various muscle groups, these patients often have nonfunctional limbs and fingers. Often these muscular contractions can result in permanent contractures, pain, and hypertrophy. In one study, decreasing spasticity and improving upper limb function of young children with cerebral palsy with normal cognition were found after injection of the affected muscle groups with botulinum toxin [9]. Another study addressing poststroke spasticity of the wrist and fingers found greater flexibility, subjective improvement, and no adverse effects of botulinum toxin injection [10]. Continuous facial myokymia is an involuntary undulating movement that spreads across the muscles of the face. It is often seen in patients with intrinsic brainstem lesions, particularly in multiple sclerosis. Although usually lasting only a few weeks, in some patients symptoms can persist. Botulinum toxin was used in two of these patients with abrupt and prolonged cessation of their facial movements [11]. Additionally, orbicularis oris myokymia is a similar disorder that frequently occurs in young, otherwise healthy individuals. These patients are troubled by continuous, rhythmic movements of the orbicularis muscle. Traditionally treated with surgical myectomy and muscle relaxants, botulinum toxin has been shown to be very effective and well tolerated in these individuals [12]. Botulinum toxin has also been used to decrease the size of hypertrophied muscle in patients with spasticity and complex repetitive discharges. These injections effectively decreased the size of the hypertrophied muscle, helping decrease the pain often associated with the repetitive movements [13]. Palatal myoclonus is characterized by rhythmic involuntary movements of the soft palate and occasionally other muscles of the upper aerodigestive tract. When associated with eye movements, it is called oculopalatal myoclonus, and a clicking sound is commonly heard. Injection of botulinum toxin into the levator veli palatini and tensor veli palatini muscles has been shown to weaken the soft palate, prevent the repetitive movements, and stop the clicking noise [14]. In addition, botulinum toxin therapy has been shown to be useful in patients with spinal cord injuries and associated spinal myoclonus [15]. Synkinesis occurring after facial nerve paralysis is a problem that is difficult to manage. Mass facial movements, exaggerated response, and inappropriate
segmental movement are commonly seen in patients who develop synkinesis. Botulinum toxin injection into the abnormally functioning muscles on the side of facial paralysis has been shown to decrease the cosmetic disfigurement synkinesis creates. In addition, better control of oral and ocular motility helps the patient to be more functional [16]. Occasionally, botox is given to the uninvolved side to weaken the normal musculature and make the bilateral movement symmetrical.
Laryngeal applications Botulinum toxin has been found useful in the treatment of laryngopharyngeal disorders [17]. Popularized initially in the treatment of spasmodic dysphonia, botulinum toxin can effectively treat a number of disorders related to dysphagia and dysphonia. Perhaps the most popular use of botulinum toxin in the larynx has been with the treatment of spasmodic dysphonia. Spasmodic dysphonia (SD) is a focal laryngeal dystonia. Spasmodic dysphonia may further be classified into abductor or adductor types. The adductor type of SD is more common and manifests itself during speaking with a strained or strangled voice The abductor type of SD manifests itself during the speaking with voiceless or hypophonic breaks in phrases such as Harrys hat. Both types can be highly debilitating, resulting in social, economic, and personal hardship. The injections can be given percutaneously using electromyographic (EMG) guidance into the thyroarytenoid muscle or the posterior cricoarytenoid muscle with doses of 0.1 to 10 U per vocal cord. [18]. Onset of action is usually within 48 hours and lasts for an average of 4 months. Up to 90% of adductor SD patients and up to 70% of abductor SD patients have significant relief of their symptoms. Another innovative use in the larynx has been in the prevention and treatment of granuloma formation. By injection into the thyroarytenoid muscle with diffusion to the lateral cricoarytenoid muscle, forceful closure of the glottis is prevented. In one study, six patients had resolution of their laryngeal granulomas after injection of botulinum toxin [19]. In another study, two patients who failed medical therapy with proton pump inhibitors showed resolution of their granulomas after injection of botulinum toxin [20]. Puberophonia, or mutational dysphonia, is a failure of the vocal pitch to lower in males at puberty. This disorder is primarily treated with vocal therapy. Botulinum toxin has been injected into the cricothyroid muscle of these patients, resulting in normal vocalization after failure of voice therapy [21].
190
Posterior glottic stenosis is a challenging problem encountered by the otolaryngologist. Trauma, surgical manipulation, reflux, and congenital deformity can result in fusion of the posterior glottic tissue, arytenoids, and posterior vocal folds. The result can range from aphonia to respiratory distress. The traditional modality of treatment is surgical, including the use of the CO2 laser. This approach is often met with failure and recurrence of the stenosis because of repeated trauma from vocalization, coughing, and other laryngeal movements. To overcome this problem, one group has used botulinum toxin injections into the interarytenoid and thyroarytenoid muscles after laser excision of posterior glottic scar tissue. These patients experienced complete healing of the interarytenoid area and resolution of their stenosis [22]. Bilateral vocal fold paralysis or paresis with synkinesis can be a devastating disorder, resulting in respiratory insufficiency and often tracheotomy. A unique approach to alleviating airway obstruction in this patient group has been the use of botulinum toxin injection into the thyroarytenoid and lateral cricoarytenoid muscles. By weakening these vocal cord adductors, the abductors can now function with less opposition and effectively increase the caliber of the airway [23]. Stuttering is a speech disorder with involuntary, action-induced utterances of short speech segments. Many of these patients have interrupted speech due to intermittent glottal block. Speech therapy has been the gold standard of treatment. However, some patients often have difficulty attaining normal speech. Botulinum toxin injection into the thyroarytenoid muscle has been shown to be helpful in alleviating the severity of stuttering by decreasing the duration of glottal block and increasing fluency of speech. This therapy is useful in refractory cases or as an adjunct to traditional speech therapy [24]. Laryngectomy, most often performed for squamous cell carcinoma, leaves a patient aphonic with little means of oral communication. Tracheoesophageal puncture (TEP) is a technique in which a catheter is inserted through the tracheastoma into the esophagus. Inspired air is then redirected into the esophagus, and the patient is able to create sound in the pharynx that is then used to propagate speech through the oral cavity. In some patients, hypertonicity of the cricopharyngeus muscle or the upper pharyngoesophageal segments can result in aphonia after the insertion of the TEP device. Treatment usually consists of surgical division of these muscle segments or abandoning the use of the TEP. Botulinum toxin has been shown to be very useful in weakening these muscle segments to allow for continued phonation [25,26].
Essential voice tremor generally affects older individuals. It is often characterized by an activationinduced tremor with a frequency of 3 to 7 Hz. Voicing is marked by decreased fluency, voice breaks, and occasional voice arrests. Tremor is commonly seen in patients with a variety of neurologic disorders, such as Parkinsons disease, dystonia, and cerebellar disorders. Voice therapy has provided some relief but often with limited success. Recently, botulinum toxin injections into the thyroarytenoid or sternothyroid muscles have resulted in modest improvement in voicing. Identification of tremor is confirmed by EMG and used to guide the injection into the appropriate musculature. In some cases, extralaryngeal muscular tremor can contribute to the vocal tremor [27]. Vocal tics, a common manifestation of Gilles de la Tourettes syndrome, can be psychologically and socially devastating. The vocal tics are often accompanied by repetitive tics of the muscles of the head and neck. Vocal tics can include simple and complex utterances, grunting, loud talking, and coprolalia. Treatment is traditionally a combination of psychotropic medication and behavioral therapy. Recently a number of patients have found relief with botulinum toxin injections into the thyroarytenoid muscle. Although not completely understood, a decrease in vocal tics, outbreaks, and grunting has been demonstrated [28]. Cricopharyngeal dysfunction can be a debilitating and painful disorder resulting in severe dysphagia. Patients typically have increased tone to the cricopharyngeal muscle with inability to relax the upper esophageal sphincter during a swallow. These patients can have severe pain from cricopharyngeal spasm, aspiration secondary to pooling of hypopharyngeal contents, and malnutrition. Past treatments have included mechanical dilation and endoscopic as well as transcervical cricopharyngeal myotomy. Recent reports in the literature indicate that botulinum toxin treatment of the cricopharyngeal muscle may be efficacious [29]. The injection of this muscle may be accomplished endoscopically or percutaneously under EMG guidance.
Pain syndromes Over the past decade, botulinum toxin has been found to be very useful in reducing a variety of pain syndromes. The exact mechanism of this action is unknown; however, the effect appears to be mediated by both a decrease in muscular tension and a central modulation of the afferent pathways. There is evidence that the effect on the SNARE proteins also decreases the release of pain mediators such as substance P,
191
GCRP, and glutamate. Research to understand this mechanism is currently underway. Another common disorder affecting millions of patients yearly is headache. Reduction in headache complaints was noted incidentally during a clinical trial of botulinum toxin injections for cosmetic use. Migraine headaches have traditionally been treated with pharmacologic means. A recent study demonstrated that botulinum toxin injections in the glabelar, temporal, frontal, or suboccipital regions of the head and neck can provide a moderate to complete reduction of migraine symptoms in up to 90% of patients treated [30]. Another study addressed the use of botulinum toxin for prophylaxis against migraine headaches. The results of this double-blind, randomized, controlled study demonstrated that there were significantly fewer migraine attacks per month, a decreased severity of migraine pain and discomfort, a decreased usage of migraine medications, and reduced incidence of associated vomiting [31]. Low back pain is a ubiquitous problem affecting the middle-aged and elderly populations. Discomfort, disability, and financial hardships are often the outcome of this disorder. Recently, botulinum toxin injected into the paravertebral lumbar area has been shown to provide up to 73% of patients with a greater than 50% reduction in their pain and discomfort with no adverse affects. These patients enjoyed decreased disability and improved function in their daily lives [32]. Botulinum toxin has also been used to treat headache of musculoskeletal origin. These cervicogenic headaches are usually associated with significant strain and discomfort along the neck, back, and shoulders, frequently associated with decreased range of motion. In a randomized, controlled study, botulinum toxin injections into affected muscle groups demonstrated a significant reduction in pain and a greater increase in range of motion than did placebo injection [33].
BOTOX has been reported to promote healing by causing protective temporary ptosis [39]. Corneal protection and symptomatic relief in patients with severe dry eyes have been achieved by injecting the medial portion of the lower eyelid and reducing lacrimal drainage [40]. Essential blepharospasm is a focal dystonia of the orbicularis oculi muscles. Management algorithms now incorporate botulinum toxin injections and limited myectomy as first-line treatment, reserving complete myectomy for BOTOX failures [41]. Even with a full myectomy, patients who were undergoing BOTOX before surgery may need to continue injections after surgery [42,43]. Duane retraction syndrome is a congenital disorder that affects horizontal or vertical eye movements, resulting in restriction of the affected eye. Standard management, when indicated, involves surgery, but BOTOX can be used to lessen the restrictive changes of the medial rectus muscle [44]. Nystagmus or involuntary, rapid, rhythmic movement of the eye can be congenital or acquired. Botulinum toxin injections into the medial or lateral rectus muscles or retrobulbar space improve visual acuity in patients with acquired nystagmus [45 48]. Furthermore, patients with oscillopsia [49] and congenital nystagmus [34] also benefited from injections.
Salivary disorders Hyperlacrimation due to gustatory lacrimation, best known as crocodile tears, is secondary to aberrant regeneration of seventh nerve fibers. BOTOX injection into the lacrimal gland has been used successfully for this application [50]. Facial hyperhidrosis due to gustatory sweating or Freys syndrome is secondary to aberrant regenerated parasympathetic fibers of the auriculotemporal nerve, which inappropriately reinnervate sweat glands of the skin. Intradermal BOTOX injection has been used to decrease sweat production significantly for a period of 6 months to 2 years [51 53]. Botulinum toxin injections directly into the salivary gland or into the salivary duct can be used effectively to treat sialoceles [54] or to improve sialorrhea [55,56]. Postparotidectomy salivary fistulas can also be controlled with decreased salivary production after BOTOX injection [57]
Ophthalmologic disorders Strabismus was the first disorder treated by Alan Scott with BOTOX. Strabismus or misalignment of the eyes can have the presentation of exotropia or esotropia. Injections of BOTOX into the extraocular muscles or at the retrobulbar space improved conjugate gaze and vision [34 37]. Technical considerations such as inadvertent ptosis, diffusion into surrounding muscles, and compliance are greater issues in children, limiting the use of BOTOX in this patient group [38]. Corneal protection is of paramount importance in the healing process of patients with corneal epithelial defect.
Genitourinary disorders Urinary retention due to detrusor sphincter dyssynergia can be seen in patients with spinal cord injury,
192
multiple sclerosis, and other voiding dysfunctions. Transperineal BOTOX injections can improve clinical symptoms and urethral hypertonia in this population [58,59]. Patients who are on maximal doses of anticholinergic medication and perform self-catheterization receive the greatest benefit from the injections, which may last up to 9 months [60]. Botulinum toxin injections of the anterior vaginal wall muscles have also been used to treat vaginismus, which is a form of CNS dysfunction noted by inappropriate vaginal, periannal, and levator ani muscle spasm that prevents penile penetration during intercourse and can affect one in 200 women [61].
Oromandibular disorders Overall botulinum toxin has been reported to provide relief in f70% of patients with oromandibular dystonias. These hyperfunctional movements of the mandible can manifest as a jaw-opening dystonia, in which toxin injection into the anterior digastric and lateral or external pterygoid muscles may provide relief [62]. More commonly hyperfunctional movement of the mandible creates the spectrum of symptoms associated with jaw-closing dystonias. Bruxism is a condition in which patients audibly grind their teeth, wearing down tooth enamel and creating difficulty with speech, swallowing, and mastication. This condition can be successfully treated with botulinum toxin injection into bilateral masseter, temporalis, and internal pterygoid muscles [63]. Injection of the masseter muscle in patients with masseter muscle hypertrophy has been effective in symptomatic improvement and reduction of muscle bulk up to 30% [64]. There has been great excitement with the use of botulinum toxin to treat the spectrum of temporomandibular disorders (TMD) of the face and jaw. Early results have demonstrated significant improvement in pain, overall function, mouth opening, and decreased tenderness [65]. Multicenter, randomized studies are currently underway to confirm these promising results in this difficult patient group.
fissures, injections of toxin into the internal anal sphincter and below the fissure have been shown to decrease anal pain, bleeding, and defactory difficulty without permanent effects on anal incontinence previously seen with surgery [68,69]. Botulinum toxin has also shown early success in the treatment of chronic constipation [70,71], anorectal pain [72], and anismus [73] through the injection of selected muscle groups within the perineum. Botulinum toxin injection into the pylorus in patients with idiopathic and diabetic gatroparesis has been shown to improve gastric emptying and associated postprandial symptoms [74,75]. Endoscopic injection of botulinum toxin into the papilla of vater has been proven safe and effective in relief of symptoms in patients with sphincter of Oddi dysfunction. These early studies also suggest that toxin may have a role in predicting which patients will derive long-term benefit from endoscopic sphincterotomy [76,77]. Botulinum toxin may also prove efficacious in the treatment of esophageal diverticulosis [78] and has been suggested for use in the debilitating condition of intractable hiccups.
Miscellaneous disorders Patients with autonomic disorders such as hyperhidrosis have shown excellent results with botulinum toxin injection. Use of toxin in the axillary region has demonstrated relatively complete anhidrosis for periods of 4 to 7 months [79,80]. Toxin has shown similar success rates in palmer and gustatory hyperhidrosis [81]. Another promising use for toxin lies in its ability to block intrinsic rhinitis. Early animal work in this field has been promising [82,83], and randomized human trials are in progress to address this common disorder. Toxin may also have a use in patients with pathologic body sweating and odor disorders [84]. Botulinum use has also improved facial function in patients with synkinesis occurring after idiopathic, traumatic, and iatrogenic facial nerve injury [85].
Gastrointestinal disorders Uses of botulinum toxin outside the head and neck region are also gaining popularity. Treatment of the lower esophageal sphincter in patients with achalasia has shown success rates of 70% [66,67]. Classically, surgical myotomy has been the treatment of choice in patients with nonhealing anal fissures. In chronic anal
Summary In conclusion, botulinum toxin usage over the past 2 to 3 decades has expanded exponentially. Almost every discipline in medicine has found some therapeutic use for this toxin. Botulinum toxin has been shown to be safe, effective, and relatively easy to administer with proper training.
193
References
[1] Braun V, Richter HP. Selective peripheral denervation for spasmodic torticollis: 13-year experience with 155 patients. J Neurosurg 2002;97(Suppl 2):207 12. [2] Blitzer A, Brin MF, Greene PE, Fahn S. Botulinum toxin injection for the treatment of oromandibular dystonia. Ann Otol Rhinol Laryngol 1989;98(2):93 7. [3] Blitzer A, Brin MF, Fahn S. Botulinum toxin injections for lingual dystonia. Laryngoscope 1991; 101(7 Part 1):799 803. [4] Defazio G, Abbruzzese G, Girlanda P, et al. Botulinum toxin A treatment for primary hemifacial spasm: a 10-year multicenter study. Arch Neurol 2002;59(3): 418 20. [5] Taylor JD, Kraft SP, Kazdan MS, et al. Treatment of blepharospasm and hemifacial spasm with botulinum A toxin: a Canadian multicentre study. Can J Ophthalmol 1991;26(3):133 8. [6] Bertolasi L, Priori A, Tomelleri G, et al. Botulinum toxin treatment of muscle cramps: a clinical and neurophysiological study. Ann Neurol 1997;41(2):181 6. [7] Tsui JK, Bhatt M, Calne S, Calne DB. Botulinum toxin in the treatment of writers cramp: a double-blind study. Neurology 1993;43(1):183 5. [8] Wissel J, Kabus C, Wenzel R, et al. Botulinum toxin in writers cramp: objective response evaluation in 31 patients. J Neurol Neurosurg Psychiatry 1996; 61(2):172 5. [9] Wong V, Ng A, Sit P. Open-label study of botulinum toxin for upper limb spasticity in cerebral palsy. J Child Neurol 2002;17(2):138 42. [10] Brashear A, Gordon MF, Elovic E, et al. Intramuscular injection of botulinum toxin for the treatment of wrist and finger spasticity after a stroke. N Engl J Med 2002; 347(6):395 400. [11] Sedano MJ, Trejo JM, Macarron JL, et al. Continuous facial myokymia in multiple sclerosis: treatment with botulinum toxin. Eur Neurol 2000;43(3):137 40. [12] Jordan DR, Anderson RL, Thiese SM. Intractable orbicularis myokymia: treatment alternatives. Ophthalmic Surg 1989;20(4):280 3. [13] Nix WA, Butler IJ, Roontga S, et al. Persistent unilateral tibialis anterior muscle hypertrophy with complex repetitive discharges and myalgia: report of two unique cases and response to botulinum toxin. Neurology 1992;42(3 Part 1):602 6. [14] Srirompotong S, Tiamkao S, Jitpimolmard S. Botulinum toxin injection for objective tinnitus from palatal myoclonus: a case report. J Med Assoc Thai 2002; 85(3):392 5. [15] Lagueny A, Tison F, Burbaud P. Stimulus-sensitive spinal segmental myoclonus improved with injections of botulinum toxin type A. Mov Disord 1999;14(1): 182 5. [16] Laskawi R, Damenz W, Roggenkamper P. Botulinum toxin treatment in patients with facial synkinesis. Eur Arch Otorhinolaryngol 1994;4:S195 9. [17] Blitzer A, Zalvan C, Gonzalez-Yanes O, Brin M. Botu-
[18]
[19]
[20] [21]
[22]
[23]
[24]
[25]
[26]
[27]
[28]
[29]
[30]
[31]
[32]
[33]
linum toxin injections for the management of the hyperfunctional larynx. In: Brin MF, Jancovic J, Hallett M, editors. Scientific and therapeutic aspects of botulinum toxin. Philadelphia: Lippincott Williams & Wilkins; 2002. p. 207 17. Blitzer A, Brin MF, Stewart C. Botulinum toxin management of spasmodic dysphonia (laryngeal dystonia): a 12-year experience in more than 900 patients. Laryngoscope 1998;108(10):1435 41. Nasri S, Sercarz JA, McAlpin T, Berke GS. Treatment of vocal fold granuloma using botulinum toxin type A. Laryngoscope 1995;105(6):585 8. Wani MK, Woodson GE. Laryngeal contact granuloma. Laryngoscope 1999;109(10):1589 93. Woodson GE, Murry T. Botulinum toxin in the treatment of recalcitrant mutational dysphonia. J Voice 1994; 8(4):347 51. Nathan CO, Yin S, Stucker FJ. Botulinum toxin: adjunctive treatment for posterior glottic synechiae. Laryngoscope 1999;109(6):855 7. Ptok M, Schonweiler R. Botulinum toxin type Ainduced rebalancing in bilateral vocal cord paralysis. HNO 2001;49(7):548 2. Brin MF, Stewart C, Blitzer A, Diamond B. Laryngeal botulinum toxin injections for disabling stuttering in adults. Neurology 1994;44(12):2262 6. Zormeier MM, Meleca RJ, Simpson ML. Botulinum toxin injection to improve tracheoesophageal speech after total laryngectomy. Otolaryngol Head Neck Surg 1999;120(3):314 9. Blitzer A, Komisar A, Baredes S, Stewart C, Brin MF. Voice failures after tracheoesophageal puncture: management with Botulinum toxin. Otolaryngol Head Neck Surg 1995;113:668 71. Warrick P, Dromey C, Irish JC, Durkin L, Pakiam A, Lang A. Botulinum toxin for essential tremor of the voice with multiple anatomical sites of tremor: a crossover design study of unilateral versus bilateral injection. Laryngoscope 2000;110(8):1366 74. Salloway S, Stewart CF, Israeli L, et al. Botulinum toxin for refractory vocal tics. Mov Disord 1996;11: 746 8. Blitzer A, Brin MF. Use of botulinum toxin for diagnosis and management of cricopharyngeal achalasia. Otolaryngol Head Neck Surg 1997;116(3):328 30. Binder WJ, Brin MF, Blitzer A, et al. Botulinum toxin type A (BOTOX) for treatment of migraine headaches: an open-label study. Otolaryngol Head Neck Surg 2000; 123(6):669 76. Silberstein S, Mathew N, Saper J, Jenkins S. Botulinum toxin type A as a migraine preventive treatment. For the BOTOX Migraine Clinical Research Group. Headache 2000;40(6):445 50. Foster L, Clapp L, Erickson M, Jabbari B. Botulinum toxin A and chronic low back pain: a randomized, double-blind study. Neurology 2001;56(10):1290 3. Freund BJ, Schwartz M. Treatment of chronic cervicalassociated headache with botulinum toxin A: a pilot study. Headache 2000;40(3):231 6.
194
C. Zalvan et al / Dermatol Clin 22 (2004) 187195 [51] Dulguerov P, Qinodoz D, Cosendal G, et al. Frey syndrome treatment with botulinum toxin. Otol Head Neck Surg 2000;122:821 7. [52] Laccourreye O, Gutierrez-Fonseca R, et al. Recurrent gustatory sweating (Frey Syndrome) after intracutaneous injection of botulinum toxin type A: incidence, management and outcome. Arch Otol Head Neck Surg 1999;125:283 6. [53] Arad-Cohen A, Blitzer A. Botulinum toxin treatment for symptomatic Freys syndrome. Otolaryngol Head Neck Surg 2000;122(2):237 40. [54] Vargas H, Galati LT, Panes SM. A pilot study evaluating the treatment of postparotidectomy sialoceles with botulinum toxin type A. Arch Otol Head Neck Surg 2000;126:421 4. [55] Gless R, Nauman M, Werner B, et al. Injections of botulinum toxin A into the salivary glands improve sialorrhea in amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry 2000;69:121 3. [56] Suskind DL, Tilton A. Clinical study of botulinum-A toxin in the treatment of sialorrhea in children with cerebral palsy. Laryngoscope 2002;112(1):73 8. [57] Guntinas-Lichius O, Sittel C. Treatment of postparotidectomy salivary fistula with botulinum toxin. Ann Otol Rhinol Laryngol 2001;110(12):1162 4. [58] Akkoc Y, Kirazli Y, Ozyurt C, et al. Effects of botulinum toxin on detrusor-sphincter dyssynergia in patients with multiple sclerosis. BJU Int 2000;86(6):754 6. [59] Phelan MW, Franks M, Somogyi GT, et al. Botulinum toxin urethral sphincter injection to restore bladder emptying in men and women with voiding dysfunction. J Urol 2001;165(4):1107 10. [60] Schurch B, Stohrer M, Krainer G, et al. Botulinum-A toxin for treating detrusor hyperreflexia in spinal cord injured patients: a new alternative to anticholinergic drugs? J Urol 2000;164(3):692 7. [61] Brin MF, Vapnek JM. Treatment of vaginismus with botulinum toxin injections. Lancet 1997; 349(9052):656. [62] Tan EK, Jankovic J. Tardive and idiopathic oromandibular dystonia: a clinical comparison. J Neurol Neurosurg Psychiatry 2000;68:186 90. [63] Tan EK, Jankovic J. Treating severe bruxism with botulinum toxin. J Am Dent Assoc 2000;131:211 6. [64] To EW, Ahuja AT, Ho WS, King WW, Pang PC, Hui AC. A prospective study of the effect of botulinum toxin on masseteric muscle hypertrophy with ultrasonographic and electromyographic measurement. Br J Plast Surg 2001;54(3):197 200. [65] Freund B, Schwartz M, Symington JM. Botulinum toxin: new treatment for temporomandibular disorders. Br J Oral Maxillofac Surg 2000;38(5):466 71. [66] Neubrand M, Scheurlen C, Schepke M, Sauerbruch T. Long term results and prognostic factors in the treatment of achalasia with botulinum toxin. Endoscopy 2002;34(7):519 23. [67] DaSilveira EB, Rogers AI. Treatment of achalasia with botulinum toxin. Am J Ther 2002;9(2):157 61. [68] Minguez M, Melo F, Espi A. Therapeutic effects of
[34] Carruthers JDA. The treatment of congenital nystagmus with Botox. J Pediatr Ophthalmol Strabismus 1995;32: 306 8. [35] Scott AB. Botulinum toxin injection of the eye muscles to correct strabismus. Trans Am Ophthalmol Soc 1981; 79:734 70. [36] Harris G, Dawson E, Lee J. Botulinum toxin to the lateral rectus for the treatment of esotropia with paradoxical diplopia. Strabismus 2001;9(2):79 82. [37] Dawson EL, Marshman WE, Adams GG. The role of botulinum toxin A in acute-onset esotropia. Ophthalmology 1999;106(9):1727 30. [38] Chalzislefanov KI, Mills MD. The role of drug treatment in children with strabismus and amblyopia. Pediatr Drugs 2000;2:91 100. [39] Wuebolt GE, Drummond G. Temporary tarsorrhaphy induced with type A botulinum toxin. Can J Ophthalmol 1991;26(7):383 5. [40] Sablin S, Chen E, Kaugesnar T, et al. Effect of eyelid botulinum tosin injection on lacrimal drainage. Am J Ophthalmol 2000;129:481 6. [41] Chang LB, Tsai CP, Liao KK, et al. Use of botulinum toxin A in the treatment of hemifacial spasm and blepharospasm. Zhongua Yi Xue Za Shi (Taipei) 1999; 62(1):1 5. [42] Barklley GB, Walker RR, et al. Follow-up of patients with essential blepharospasm who underwent eyelid protractor myectomy at the Mayo Clinic from 1980 through 1995. Ophthal Plast Reconstr Surg 1999;15: 106 10. [43] Mezaki T, Kaji R, Brin MF, et al. Combined use of the A and B botulinum toxins for blepharospasm: a doubleblind controlled trial. Mov Disord 1999;14:1017 20. [44] Campos E. Strabismus and ocular motility disorders. In: Proceedings of the Sixth Meeting of the International Strabismological Association. Surfers Paradise, Australia: MacMillan Press; 1990. p. 221 35. [45] Lennerstrand G, Nordbo OA, Tian S, et al. Treatment of strabismus and nystagmus with botulinum toxin type A. An evaluation of effects and complications. Acta Ophthalmol Scand 1998;76(1):27 7. [46] Ruben ST, Lee JP, ONeil D, et al. The use of botulinum toxin for treatment of acquired nystagmus and oscillopsia. Ophthalmology 1994;101(4):783 7. [47] Helveston EM, Pogrebniak AE. Treatment of acquired nystagmus with botulinum toxin A. Am J Ophthalmol 1988;106(5):584 6. [48] Repka MX, Savino PJ, Reinecke RD. Treatment of acquired nystagmus with botulinum neurotoxin A. Arch Ophthalmol 1994;112(10):1320 4. [49] Lawson JM, Kousoulides L, Lee JP. Long term results of botulinum toxin in consecutive and secondary exotropia: outcome in patients initially treated with botulinum toxin. J AAPOS 1998;2(4):195 200. [50] Keegan DJ, Geerling G, Lee JP, et al. Botulinum toxin treatment for hyperlacrimation secondary to aberrant regenerated seventh nerve palsy or salivary gland transplantation. Br J Ophthalmol 2002;86(1): 43 6.
C. Zalvan et al / Dermatol Clin 22 (2004) 187195 different doses of botulinum toxin in chronic anal fissure. Dis Colon Rectum 1999;42:1016 21. Maria G, Brisinda G, Bentivoglio AR. Botulinum toxin injections in the internal anal sphincter for the treatment of chronic anal fissure: long-term results after two different dosage regimens. Ann Surg 1998;228:664 9. Minkes RK, Langer JC A prospective study of botulinum toxin for internal anal sphincter hypertonicity in children with hirschsprungs disease. J Pediatr Surg 1999;35(12):1733 6. Maria G, Brisinda G, Bentivoglio AR, Cassetta E, Albenese A. Botulinum toxin in the treatment of outlet obstruction constipation caused by puborectalis syndrome. Dis Colon Rectum 2000;43(3):376 80. Hawley HP. Botulinum toxin for severe anorectal pain. J Pain Symptom Manage 2002;24(1):11 2. Ron Y, Avni Y, Lukovetski A, Wardi J, Geva D, Birkenfeld S, et al. Botulinum toxin type-A in the therapy of patients with anismus. Dis Colon Rectum 2001; 44(12):1821 26. Miller LS, Szych GA, Kantor SB, Bromer MQ, Knight AH, Maurer AH, et al. Treatment of idiopathic gastroparesis with injection of botulinum toxin into the pyloric sphincter muscle. Am J Gastroenterol 2002;97(7): 1653 60. Ezzeddine D, Jit R, Katz N, Gopalswamy N, Bhutani MS. Pyloric injections of botulinum toxin for the treatment of diabetic gastroparesis. Gastrointest Endosc 2002;55(7):920 3. Wehrman T, Schmitt TH, Arndt A, Lembcke B, Caspary WF, Seifert H. Endoscopic injection of botulinum toxin in patients with recurrent acute pancreatitis due to
195
[69]
[77]
[70]
[78]
[79]
[71]
[80] [81]
[72] [73]
[82]
[74]
[83]
[75]
[84] [85]
[76]
pancreatic sphincter of oddi dysfunction. Aliment Pharmacol Ther 2000;14(1):1469 77. Wehrman T, Seifert H, Seipp M, Lembcke B, Caspary WF. Endoscopic injection of botulinum toxin for biliary sphincter of Oddi dysfunction. Endoscopy 1998; 30(8):702 7. Devault KR. Dysphagia from esophageal diverticulosis responding to botulinum toxin injection. Am J Gastroenterol 1997;92(5):895 7. Whatling PJ, Collin J. Botulinum toxin injection is an effective treatment for axillary hyperhidrosis. Br J Surg 2001;88(6):814 5. Glogau RG. Botulinum A neurotoxin for axillary hyperhidrosis. Dermatol Surg 1998;24(8):817 9. Glogau RG. Treatment of palmer hyperhidrosis with botulinum toxin. Semin Cut Med Surg 2001;20(2): 101 8. Rohrbach S, Olthoff A, Laskawi R, Giefer B, Gotz W. Botulinum toxin type A induces apoptosis in nasal glands of guinea pigs. Ann Otol Rhinol Laryngol 2001;110(11):1045 50. Shaari CM, Sanders I, Wu BL, Biller HF. Rhinorrhea is decreased in dogs after nasal application of botulinum toxin. Otolaryngol Head Neck Surg 1995;112(4): 566 71. Bushara MA, Bushara K. Botulinum toxin, sweating, and body odor. N Engl J Med 2002;347(8):620 1. Boroojerdi B, Fergert A, Schwartz M, Herath H, Noth J. Botulinum toxin treatment of synkinesis and hyperlacrimation after facial palsy. J Neurol, Neurosurg Psychiatry 1998;65(1):111 4.
Dermatol Clin 22 (2004) 197 205
Complications with the use of botulinum toxin

Arnold W. Klein, MD
Department of Dermatology, David Geffen School of Medicine at UCLA, 435 Roxbury Drive, Suite 204, Beverly Hills, CA 90210, USA
The treatment of hyperfunctional facial lines with botulinum A exotoxin injection is safe, effective, and without serious side effects. Properly used, the incidence of complications is low and their severity mild. Millions of individual clinical doses have been delivered without major complications. Indeed, cosmetic use of botulinum A exotoxin has become routine within dermatology. Initiated during the 1980s, and refined by leaders in dermatologic surgery during the past decade [1 5], botulinum toxin injections have become commonplace. The bacterium Clostridium botulinum has eight serotypes, which produce seven serologically distinct exotoxins. With lethal doses approximating 109 g/ kg body weight, these neurotoxins represent some of the most toxic naturally occurring substances [6]. Not all, however, are associated with botulism in humans. Although the different serotypes are structurally and functionally similar, specific differences in neuronal acceptor binding sites, intracellular enzymatic sites, and species sensitivities suggest that each serotype is its own unique pharmacologic entity. Neutralizing antibodies developed against one serotype have not been reported to block the biologic activity of another serotype [7]. Although the intracellular targets of the toxins are variable, they all ultimately prevent release of membrane-bound acetylcholine at the neuromuscular junction of striated muscles and produce chemical denervation and paralysis of the muscles [8]. This chemical denervation is effective for both striated muscle and eccrine glands. This action may not be complete for 2 weeks and effectively destroys the
E-mail address: awkmd1@aol.com
affected neuromuscular junction, causing muscular paralysis. There is an ongoing turnover of neuromuscular junctions, however, such that muscular function begins to return at approximately 3 months and is usually complete by 6 months. Botulinum toxins exist as large protein complexes consisting of the neurotoxin moiety (approximately 150 kd) and one or more nontoxic proteins, which are stabilized through noncovalent bonds and that function to protect the toxin molecule [9]. Botulinum toxin type B serotype associates with the nontoxic proteins to form a complex with a total molecular weight of approximately 700 kd, whereas the type A complex is estimated to be approximately 900 kd [10]. These large botulinum toxin complexes are most stable in the pH range of 5 to 7 [11]. At pH values above 7, the protein subunits dissociate [12]. The mode of measuring strength of this toxin is paralytic activity in the mouse. One unit is defined as that amount of the toxin that kills 50% (LD50) of a standardized mouse model when injected intraperitoneally. This is affected by many factors: strain of mouse, housing conditions, and so forth. Theoretically, specific activity can be reduced by the presence of contaminating proteins or inactive, aggregated toxin that may have been carried through in the purification procedures [13]. The peripheral blockade of neuromuscular activity causes muscular weakness, which produces the therapeutic effect. There has been no evidence to suggest any permanent degeneration or atrophy of muscles in those patients treated for dystonic or spastic disorders who have been injected with highdose, repetitive injections of botulinum toxin over an extended period. Muscle biopsies that were taken from patients after injections of botulinum toxin type A two to five times those used for aesthetic improve-
198
ment failed to show any long- term evidence of permanent degeneration or atrophy [14]. Purified toxin complexes have found a niche in the treatment of clinical disorders involving muscle hyperactivity. Botox (Allergan, Irvine, CA) is a toxin type A approved for use in the United States (for treatment of cervical dystonia, blepharospasm, and glabellar lines) and Dysport (Speywood Pharmaceuticals, London, United Kingdom) is also botulinum toxin type A but is not approved in the United States. Dysport is primarily used in Europe. It should be noted that all doses in this article are of Botox unless otherwise stated. A highly concentrated type B toxin (Myobloc) developed by Athena Neurosciences (Foster City, CA) and manufactured by Elan Pharmaceuticals (San Francisco, CA) is approved by the Food and Drug Administration (FDA) for use in the treatment of cervical dystonia [15].
single reported case of systemic spread of botulinum toxin A. The patient had one set of injections for blepharospasm. After the second set, the patient immediately went into acute myasthenic crisis. This was a motor end plate problem. Botox should not be used in any patient with motor neuron disease. The main complications of treatment of strabismus with botulinum toxin are ptosis and vertical deviations [23 25]. Rare instances of ciliary ganglion injury, retrobulbar hemorrhage, and scleral perforation have been reported [25]. Transient ptosis, tearing, and dry eye are the most frequently encountered complications with the use of botulinum toxin in the treatment of blepharospasm, hemifacial spasm, and Meiges syndrome. Diplopia and facial weakness are seen more rarely.
Resistance to botulinum toxin Conditions caused by muscle spasms Local injections of botulinum toxin type A (Botox) directly into excessively contracting muscles have been successful in treating dystonia, spasticity, and other conditions characterized by inappropriate muscle spasm [16,17]. Botox is considered a safe therapy for these inappropriate muscle spasms and is generally well tolerated, with adverse effects being typically self-limited [18]. Effects of a localized injection of botulinum toxin to nearby or adjacent muscles are believed to be a result of local diffusion of toxin to that muscle (eg, ptosis following facial injections) [19]. There is an area of denervation associated with each point of injection because of toxin spread of about 2.5 to 3 cm. Although there are reversible and, rarely, irreversible histologic changes in muscles that are denervated after Botox treatment, there have been no irreversible clinical effects reported. There have been few reports of clinically relevant paresis in muscles distant from the site of injection. Subclinical effects, however, such as increased jitter and changes in the single fiber electromyography (EMG), have been described [20]. The clinical significance and duration of this effect have yet to be determined [21]. Generalized reactions that have idiosyncratically occurred include nausea, fatigue, malaise, flulike symptoms, and rashes at sites distant from the injection. A report documenting three cases of generalized muscular weakness associated with the use of botulinum toxin type A (Dysport) in patients with dystonia reinforces the concern about the possible spread of botulinum toxin induced effects [22]. There has been a The possibility of antibody production with resulting immunoresistance has always been a concern with the use of Botox [26]. Hypersensitivity reactions to the injection of the substance do not occur. The only consequence is that Botox no longer is effective as a treatment. With the original Allergan batch [27], it was recommended that not greater than 100 U be used at treatment sessions that occur at not less than monthly intervals. Antigenicity of a foreign material, however, is almost uniformly proportional to protein load and the vastly decreased amount of protein present in the currently used batches of Botox may allow the application of larger doses of the product per treatment session without fear of immunogenicity. Indeed, animal studies have supported the decreased formation of neutralizing antibodies with these new batches [28]. Prevalence of Botox resistance is less than 5% [29] and is associated with dose and frequency of treatment sessions but not by duration of overall treatment regimen [30]. The intramuscular injection of botulinum toxin type A into affected muscles is used as therapy for the treatment of cervical dystonia. After repeated use, however, some patients receiving high doses, as are often required in cervical dystonia, develop secondary resistance to type A therapy, possibly related to the development of neutralizing antibodies. The incidence of clinical resistance to type A treatment in cervical dystonia has been estimated to be as high as 6.5% [31]. Some of these patients have benefited from different preparations of Botox [32] or from other types of botulinum toxin [33,34]. Although there have been reports in the literature of treated patients developing resistance after a
199
mean cumulative dose of 192 U of Botox [32], communication with Allergan indicated that only 1% to 2% of treated patients evidenced resistance (neutralizing antibodies). Furthermore, the company could not unequivocally say that this was caused by size or frequency of dose. The factors that predispose patients to the development of antibodies are unknown, but experience has shown that the risk is increased with repetitive dosages above 300 U [33,34]. It should be noted that most of these data are based on older batches of Botox that had greater amounts of protein load than the newer toxin. Dosages for individual sites treated for the purpose of minimizing hyperfunctional facial lines usually require no more than 20 to 40 U per site. To further minimize the dose and increase the accuracy of toxin placement, an EMG-guided technique can be used. In regards to frequency of injection sessions, many authorities using Botox for cosmetic indications do additional treatment, when indicated, 2 weeks post initial treatment. With the small doses (< 100 U) used for almost all cosmetic procedures, the limitation of injection interval does not seem to be crucial.
Cosmetic use of botulinum toxin Facial wrinkles are frequently caused by repeated muscle contraction. Botulinum A exotoxin can produce weakness or paralysis of these muscles and offers a novel approach for the treatment of certain facial rhytides. Botulinum toxin type A weakens the overactive underlying muscle contraction, causing a flattening of the facial skin and an improved cosmetic appearance [35]. The effect, although temporary, is extremely popular with patients, has a very low incidence of side effects, and is a relatively easy technique to acquire. For these reasons, botulinum toxin A (Botox) has gained rapid and enthusiastic acceptance [36,37]. Botulinum toxin injections have revolutionized the cosmetic approach to rejuvenation of the aging face. There have been no long-term adverse effects or health hazards related to the use of Botox for any cosmetic indication thus far [38]. Botox treatments have not been associated with any permanent clinical effects, although histologically there are reversible and, rarely, irreversible histologic changes in muscles that have been injected. In general, a higher concentration allows for more accurate placement and greater duration of effect and fewer side effects. Lower concentrations encourage the spread of the toxin. One should re-
member that there is an area of denervation associated with each point of injection because of toxin spread of about 2.5 to 3 cm. Large dilutions have also resulted in larger areas of paralysis. Botulinum toxin works best when delivered into the muscle belly. By limiting injections to the immediate subcutis, injection-related pain and risk of bruising is lessened, and effect is maintained. Injecting into the periosteum on the forehead or glabella is painful. Around the eyes the skin is extremely thin and injections need not be deep to reach muscle. Seldom are botulinum injections too superficial because the toxin easily penetrates muscle and even fascia. Pre-existing or anatomic redistribution or realignment of underlying musculature can alter the effects of Botox, and modifications in injection technique should be made. Exclusion criteria include pregnancy or active nursing and pre-existing neuromuscular conditions. Patients with neuromuscular diseases (myasthenia gravis, Eaton-Lambert syndrome) are not suitable candidates for Botox. Women who have inadvertently been treated with Botox during pregnancy have had uneventful deliveries, and no teratogenicity has been attributed to Botox. Nevertheless, Botox is classified as a pregnancy category C drug. Sequelae that can occur at any site because of injection of Botox include pain, edema, erythema, ecchymosis, headache, and short-term hypesthesia. Some unwanted effects are idiosyncratic, but spontaneously resolving. Upper eyelid swelling after forehead injection, lower lid swelling after injection at this site, bruising at the injection site, mild headache, and flulike symptoms can persist for several days to a few weeks after treatment with botulinum toxin [39]. Ice applied immediately after injection reduces the pain and the edema and erythema associated with an intramuscular injection. Ecchymosis can be minimized by avoiding aspirin, aspirin-containing products, and nonsteroidal anti-inflammatory agents for 7 days before injection. Although the onset of headaches has been initiated with Botox injections, they are alleviated with standard over-the-counter analgesics. It is, however, more common for patients to report that chronic tension headaches have been improved following injections of Botox. Pain associated with injections can be minimized by infusing slowly with a 30- or 32-gauge needle, by injecting small volumes of relatively concentrated solutions, and by reconstituting the toxin in preserved rather than preservative-free saline (Alam et al, 2002). New patients should be told of potential undesired effects, and their low likelihood and essentially benign nature.
200
There are, admittedly, patients who do not achieve their desired goal and are able to contract treated facial musculature. Combining Botox with adjunctive therapy is often necessary to appropriately address the aging anatomy. There are also patients who perceive that the Botox was a failure and are dissatisfied. In one instance, the muscles treated are, in fact, immobilized, but in an attempt to contract their muscles they recruit adjacent muscles. Although this can occur anywhere, it is particularly apparent in the glabellar area. Additionally, some patients do not recognize the improvement caused by the Botox and express disappointment as residual nondynamic rhytides persist. Demonstrating muscle immobility with a hand-held mirror or before- and after-injection Polaroid photographs is often necessary to convince these patients. All Botox patients are told to stay upright for at least 4 hours. There is some controversy as to the necessity of this, but it is a precaution that is used almost universally. Immediately after injection, movement of the treated muscles is encouraged so that the toxin is taken-up by the involved neural end plates. Patients are to repeat this muscle movement 10 times per hour for the first 90 minutes. After that the toxin has all been taken-up.
Glabella The most common complication in treatment of the glabellar complex is ptosis of the upper eyelid. Eyelid ptosis is a significant risk if injections are placed at or under the middle of the eyebrows in the vicinity of the mid-pupillary line. This is cause by diffusion of the toxin through the orbital septum, where it affects the upper eyelid levator muscle. This can occur as early as 48 hours or as late as 7 to 10 days following injection when the aesthetic effect is beginning to appear and can persist for 2 to 4 weeks. With proper technique, the ptosis rate is very close to zero. Ptosis, should it occur, can be treated with eyedrops to the affected side. a-Adrenergic agonists ophthalmic eyedrops apraclonidine 0.5% (Iopidine) and phenylephrine hydrochloride 2.5% (NeoSynephrine) are mydriatic agents. This causes contraction of an adrenergic muscle (Mu llers muscle), which is situated beneath the levator muscle of the upper eyelid. This treatment causes 1 to 2 mm of elevation of the eyelid, which is usually sufficient to make the individual symmetric. The treatment is symptomatic and 1 to 2 drops three times a day must be continued until the ptosis resolves [40].
To avoid eyelid ptosis, it is prudent to be conservative when treating elderly patients who may have a reduced or absent orbital septum. Injecting the Botox accurately and with low volume can also decrease the risk for ptosis. Increasing the volume injected increases the spread of the toxin from the injection site and increases the possibility of affecting unwanted muscles, and decreasing the volume allows more accurate placement of the toxin. To avoid ptosis, injections should be 1 cm above the eyebrow and for more precise intramuscular injection, EMG guidance can be helpful [35,41]. The site of deposition of the toxin, not the approach to it, is important. After injection of the procerus, one should massage this site horizontally across the upper nasal bridge to massage the toxin toward the depressor supercilii. Complications have not followed the massaging of this area. In the glabellar area, digital pressure at the border of the supraorbital ridge while injecting the corrugator also reduces the potential for extravasation of Botox, avoiding inadvertent weakening of the levator muscle and resulting eyelid ptosis. It is important that this injection site be 1 cm above the bony rim because lower placement of the toxin in this site is the most likely cause of ptosis. In Allergans multicenter FDA study, ptosis occurred in 12 (5.4%) of 263 patients, most of whom were in one center where the injecting physician had little experience with the technique. Individuals treated in the glabellar area are more likely to complain of an inadequate response than those treated in other areas. The usual cause is inadequate dosage.
Brow The most significant complication of treatment of the frontalis is brow ptosis. Botulinum A exotoxin should not be injected above the middle brow so as to avoid brow ptosis. Injection should also be avoided within 1 cm of the bony superior orbital rim for the same reason. Botox works best in younger female patients (20 to 45 years of age). In some older patients and in some male patients, redundant skin can be created under the brow (pseudoptosis), so such patients should be approached with caution. Treatment of the brow depressors may be necessary, however, after brow ptosis has become manifest. Lack of expressivity may be caused by injection of frontalis lateral to the mid-pupillary line. One should remember that the brow shape can be changed because of relaxing the major muscle responsible for
201
elevating the brow. If the patient has a low eyebrow, treatment of the forehead lines should be avoided, or limited to that portion of the forehead 4 cm or more above the brow. The lower 2.5 to 4 cm of the frontalis muscle moves cephalad to elevate the eyebrows. Older people use this to raise their eyebrows to see. One must always cautiously address the lower frontalis and stay 2 cm above the brow in all individuals. One should never try to inject the glabella and the entire forehead during the same session. This invariably produces brow ptosis. The upper half of the forehead and the frown, however, can be done at the same time. Not rendering the frontalis muscle completely immobile and paralyzed but weakened can achieve the comparable goal of reducing the folds while maintaining some forehead movement. In individuals who have significant brow ptosis, the possible effects of frontalis injection should be discussed with the individual and injection of the brow depressors (the glabellar complex) performed. The brow depressors should also be treated in individuals with low-set brows or mild brow ptosis. There is upward diffusion of toxin, which addresses the lower forehead lines. Brow elevation is usually achieved during treatment of the glabella or may be necessary to prevent or correct brow ptosis caused by treatment of horizontal forehead lines (frontalis) and hence unopposed action of the brow depressors. Chemodenervation of all the brow depressors, corrugator supercilii, depressor supercilii, procerus, and orbicularis oculi (the glabellar complex) with Botox alone (ie, no surgery) can elevate the brow from 1 to 2 mm [42]. An equally aesthetically unfavorable outcome is the brow that assumes a quizzical or cockeyed appearance [40]. That is, the lateral eyebrows may arch upward to an excessive extent because of the unopposed pull of the frontalis. This occurs when the lateral fibers of the frontalis muscle have not been appropriately injected. This may be corrected by injecting 3 U about 2 cm above each brow medial to the temporal fusion line. Ptosis of the upper eyelid (levator ptosis), although less likely, can also occur. This is secondary to downward diffusion of the injected material and often caused by poor technique. Before injecting the forehead of a patient for the first time, it may be best to clarify the anatomic boundaries. The width of the forehead and location of the temporal fusion line vary from patient to patient, and botulinum toxin treatment of the forehead needs to be individualized. The high-narrow forehead must be treated differently than the short and wide forehead.
Crows-feet Reported complications in this area are bruising, diplopia, ectropion, or a drooping lateral lower eyelid and an asymmetric smile caused by injection of zygomaticus major. To avoid these complications, one should inject at least 1 cm outside the bony orbit or 1.5 cm lateral to the lateral canthus, and not inject close to the inferior margin of the zygoma. Just as it is important not to inject too close to the eye, injections should not be placed too far below it or too deep, because the orbicularis oculi are very superficial muscles. Lip ptosis can occur if botulinum toxin is delivered below the zygoma and deeply into the zygomaticus major, an important elevator of the upper lip and mouth. Paralyzing the zygomaticus major can cause an appearance similar to a Bells palsy. Resolution is gradual and often slower than that of toxin-induced eyelid ptosis. Medial movement of the toxin from the lateral canthus can result in diplopia caused by lateral rectus muscle paralysis. Strabismus can also occur. Both diplopia and strabismus are exceedingly uncommon side effects. If they manifest, referral to an ophthalmologist is imperative for appropriate management. If a patient has redundant skin, one should be careful because the skin can fold on the zygomatic arch, producing an undesirable cosmetic result. Ecchymoses have been common in the past when treating periorbital wrinkles. This can be almost totally avoided by injecting the Botox in a wheal or a series of continuous blebs with each injection at the advancing border of the previous injection to avoid hitting blood vessels with resultant bruising. Injection of 2 to 4 U under the eye, especially when combined with treatment of the crows feet, can increase the aperture of the eye in a cosmetically pleasing manner. Tissue should be handled gently, and superficial vessels identified and avoided. Blebs should be placed immediately under the epidermis because the periocular muscles are extremely superficial at this site. Injections under the eye must be approached cautiously and should not be attempted if the patient exhibits a significant degree of scleral show pretreatment; if the patient has had significant surgery under the eye previously; or if the patient has a great deal of redundant skin under the eye as exhibited by a snap test of the lower eyelid (ie, if the lid does not return to its previous position when manually pulled down). Deeper zygomaticus lines often connect to the lower crows feet lines. Treatment of the crows feet can paradoxically worsen the zygomaticus lines because the redundant cheek skin gravitates downward.
202
If a patient has redundant skin, one should be careful because the skin can fold on the zygomatic arch, producing an undesirable cosmetic result.
Nasolabial folds Some physicians have treated levator labii superioris alaeque nasi to soften the superomedial part of the nasolabial fold. They have used relatively low doses (2 to 3 U of Botox per side) including EMG localization of the site but report unimpressive response. In those individuals who did get softening of the folds, some showed lengthening of the upper lip, which of itself is aging. Initially, several nasolabial injections were given. Although they reduced the nasolabial groove, they also diminished the elevation of the lip for smiling, which was not an acceptable cosmetic outcome for most patients. This procedure has mostly been abandoned.
Injecting the lower face and neck Many of the muscles in the lower central face, especially those used in facial expression, are also involved in the functions of the mouth and cheeks. An asymmetric smile, biting the inside of a flaccid cheek, or incompetence of the mouth manifest by drooling and dribbling are possible complications of the overly enthusiastic use of Botox in the lower face. Small doses, however, can be used satisfactorily (eg, into mentalis, nasalis, and levator labii superioris alaeque nasi). More recently Botox has been used for depressor anguli oris and upper lip wrinkles. For the upper lip lines, some injectors are using small doses of Botox, 1 to 3 U per wrinkle to a total of two to three wrinkles. They claim surprising effectiveness in the treatment of this annoying condition. Because of the importance of the competence of the mouth, however, it is necessary to be extremely gentle with the Botox, injecting more superficially rather than deeply. Although techniques vary, it is imperative to inject small quantities and maintain symmetric spacing relative to the facial midline. Failure to adhere to these rules can result in asymmetry. The mouth may appear lopsided at rest, and talking and chewing may accentuate this unattractive appearance. Functional deficits may include inability to sip from a straw, pucker, put on lipstick, clearly enunciate Ps and Ss, whistle, kiss with passion, or play a wind or brass instrument. In severe cases, drooling may be seen.
A common concern is a downturn at the corner of the mouth producing a dejected appearance. This is often treated by the use of fillers, such as injectable collagen. Brandt and Bellman [43] have suggested that injection of platysma may produce improvement in this area. Botulinum toxin may also be used to correct downward curl in the corners of the lip. For this, injections of 3 U per side are given into the depressor anguli oris at the jaw edge lateral to the first fold. Injecting within the obicularis oris causes unusual lip movement. Some practitioners inject depressor anguli oris directly to achieve improvement. They maintain that 2 to 3 U of Botox weaken this muscle and allow the elevators of the corner of the mouth to act with less opposition. The treatment may be repeated to increase the effect. One must be extremely cautious using Botox close to the mouth, however, because of the danger of producing a flaccid cheek, an incompetent mouth, or an asymmetric smile. On the chin, a prominent mentalis muscle can cause a horizontal crease or a cobblestoned appearance, which may be reduced by a single injection of 5 to 10 U directly into the point of the chin with massage. It is important to keep well away from the mental fold, although this may be softened by the injection. Injection into the mental fold area easily can produce an incompetent mouth. Massage after this injection is important. Prominent hypertrophic vertical bands and fine horizontal lines of the neck may develop with the aging of the underlying platysma muscles. This muscle is large, originating in the upper chest, and inserts and blends variably with muscles on the mandible, face, and ultimately the submusculoaponeurotic system. Botox has been injected into platysma for some years to alleviate these platysmal bands and horizontal neck lines. The use of larger doses also to improve the lower face and perhaps postpone a surgical rhytidectomy is more controversial. This technique has not produced any significant complications but the use of larger doses (75 to 100 U) can produce weakness of the neck flexors and dysphagia. In the neck, the platysma muscle bands can be reduced by a series of Botox injections into the anterior aspects of the platysma muscle bands. A total of 21 U of Botox is injected into the offending platysmal band at four separate sites: 3 U 1 cm below the mandibular margin and then three injections of 6 U each spaced 2.5 cm apart along the band. Usually 2 to 4 bands are injected per treatment session for a total dose of 42 to 84 U. This technique has not produced any significant complications, but the use of larger doses can produce weakness of the
203
neck flexors and dysphagia. It is advised that no more than 100 U be injected into these bands in total. Brandt and Bellman [43] have expanded this use to treat platysma more widely and with doses up to 200 U Botox per treatment session. Injection of large quantities or inadvertent injection or diffusion into the adjacent sternocleidomastoid and laryngeal muscles can, however, precipitate dysphagia and neck weakness, which is more apparent when an attempt is made at raising the head from a supine position. By affecting the strap muscles, botulinum toxin may cause singers to have difficulty reaching high notes, and doses should be limited in this case. Severe overtreatment of the neck can result in patients having trouble holding their heads erect.
Treatment of migraine headaches In a double-blind clinical study of migraine headache treatment conducted by Silberstein et al [45], there were no reported cases of true eyelid ptosis, diplopia, facial nerve or expression problems, keratopathy, or idiosyncratic or allergic reactions attributable to Botox treatment. Two subjects reported transient brow ptosis; other adverse effects were limited to transient local pain and ecchymosis at the injection site [45]. In another double-blind clinical study conducted by Brin et al [46], the 75-U Botox group had a higher incidence of treatment-related adverse events than the vehicle group (50% versus 24%, P = .02), whereas the 25-U Botox and vehicle groups were similar in adverse event incidence. All adverse events were transient and included blepharoptosis, diplopia, and injection site weakness.
Complications in treating hyperhidrosis Chronically sweaty palms are uncomfortable and socially debilitating. Superficial injection of botulinum toxin can provide dramatic relief from this disorder. Injections should be at the level of the superficial dermis and no deeper. Given the ability of Botox to diffuse radially in the axillary skin in a 1.5-cm radius, the physician must first identify the surface area of involvement using the starch-iodine test. Intercurrent doses of intradermal botulinum toxin can then be placed spaced at intervals to allow overlap of the diffusion patterns. This serves to maximize the paralytic effect on the eccrine units while minimizing the total dose needed to achieve dryness. A total dose of 50 U per axilla is normal in treating axillary hyperhidrosis. In treating palmar hyperhidrosis, a total dose of 100 U per hand is common. A degree of weakness in the hands is a common consequence of this therapy [44]. Because of the large quantities injected and the proximity of the small muscles of the hand, undesired outcomes can also be seen, particularly if the injections are too deep. Some impairment of fine motor function is common, and this may occasionally be clinically significant. Firm gripping with the distal digits and rotational motions of the whole hand may be difficult. This weakness is temporary and resolves after a few weeks. Because of this weakness in grip strength, however, it is advisable to only treat one hand per treatment session. It is also common to have to do touch-ups on areas of the axillae or palms that are still sweating after treatment. These touch-ups can be done 2 weeks after initial treatment. Informed consent In the informed consent, it must be brought to the patients attention that Botox has been approved by the FDA as a safe and effective therapy since 1989 for use in blepharospasm, strabismus, and hemifacial spasm and since 1992 for glabellar lines. The National Institutes of Health consensus conference of 1990 also included Botox as safe and effective therapy for the treatment of adductor spasmodic dysphonia, oromandibular dystonia, and cervical dystonia. The treatment of facial wrinkles other than the glabellar lines is considered an off-label use. Other offlabel uses include the treatment of Meiges syndrome, sphincter dysfunction, migraine headaches, hyperhidrosis, tremor disorders, and juvenile cerebral palsy and other spasticity disorders for which patients are currently receiving benefit from Botox.
References
[1] Carruthers A, Carruthers J. History of the cosmetic use of botulinum A exotoxin. Dermatol Surg 1998; 24:1168 70. [2] Carruthers A, Carruthers J. Clinical indications and injection technique for the cosmetic use of botulinum A exotoxin. Dermatol Surg 1998;24:1189 94. [3] Klein AW, Mantell A. Electromyographic guidance in injecting botulinum toxin. Dermatol Surg 1998;24: 1184 6. [4] Binder WJ, Blitzer A, Brin MF. Treatment of hyperfunctional lines of the face with botulinum toxin A. Dermatol Surg 1998;24:1198 205.
204
A.W. Klein / Dermatol Clin 22 (2004) 197205 [23] Lingua RW. Sequelae of botulinum toxin injection. Am J Ophthalmol 1985;100:305 7. [24] Burns CL, Gammon JA, Gemmill MC. Ptosis associated with botulinum toxin treatment of strabismus and blepharospasm. Ophthalmology 1986;93:1621 7. [25] Scott AB. Botulinum toxin treatment of strabismus (Focal Points 1989 Clinical Modules for Ophthalmologists, No. 7). San Francisco: American Academy of Ophthalmology; 1989. [26] Jankovic J, Schwartz K. Response and immunoresistance to botulinum toxin injections. Neurology 1995;45:1743 6. [27] Gonnering RS. Negative antibody response to longterm treatment of facial spasm with botulinum toxin. Am J Ophthalmol 1988;105:313 5. [28] Mezaki T, Kaji R, Kohara N, et al. Comparison of therapeutic efficacies of type A and F botulinum toxins for blepharospasm: a double-blind, controlled study. Neurology 1995;45:506 8. [29] Ludlow CL, Hallett M, Rhew K, et al. Therapeutic use of type F botulinum toxin [letter]. N Engl J Med 1992;326:349 50. [30] Sankhla C, Jankovic J, Duane D. Variability of the immunologic and clinical response in dystonic patients immunoresistant to botulinum toxin injections. Mov Disord 1998;13:150 4. [31] Brin MF, Lew MF, Adler CH, et al. Safety and efficacy of NeuroBloc (botulinum toxin type B) in type Aresistant cervical dystonia. Neurology 1999;53:1431. [32] Go schel H, Wohlfaqrth K, Frevert J, et al. Botulinum A toxin therapy: neutralizing and nonneutralizing antibodiestherapeutic consequences. Exp Neurol 1997; 147:96 102. [33] NIH. Clinical use of botulinum toxin. National Institutes of Health Consensus Development Conference. NIH Consens Statement, November 12 14, 1990; 8:1 20. [34] Borodic G, Johnson E, Goodnough M, et al. Botulinum toxin therapy, immunologic resistance and problems with available materials. Neurology 1996;46:26 9. [35] Klein A. Cosmetic therapy with botulinum toxin: anecdotal memoirs. Dermatol Surg 1996;22:757 9. [36] Blitzer A, Brin MF, et al. Botulinum toxin for the treatment of hyperfunctional lines of the face. Arch Otolaryngol Head Neck Surg 1993;119:1018 22. [37] Carruthers JDA, Carruthers JA. Treatment of glabellar frown lines with C. botulinum-A exotoxin. J Dermatol Surg Oncol 1992;18:17 21. [38] Hambleton P, Moore AP. Botulinum neurotoxins: origin, structure, molecular actions, and antibody. In: Moore P, editor. Handbook of botulinum toxin treatment. Oxford: Blackwell Science; 1995. p. 16 27. [39] Alam M, Arndt KA, Dover JS. Severe, intractable headache following injection with botulinum A exotoxin. J Am Acad Dermatol 2002;46(1):62 5. [40] Burns RL. Complications of botulinum exotoxin. Presented at the 25th Annual Clinical and Scientific Meeting of the ASDS. Portland, OR, May 13 17, 1998. [41] Foster JA, Barnhorst D, Papay F, et al. The use of
[5] Klein AW, Glogau RG. Botulinum toxin: beyond cosmesis. Arch Dermatol 2000;136:539 41. [6] Lamanns C. The most poisonous poison. Science 1969; 130:763 72. [7] Dertzbaugh MT, West MW. Mapping of protective and cross-reactive domains of the type A neurotoxin of Clostridium botulinum. Vaccine 1996;16:1538 44. [8] Keen M, Blitzer A, Aviv J, et al. Botulinum toxin A therapy for hyperkinetic facial lines: results of a double-blind, placebo-controlled study. Plast Reconstr Surg 1994;94:94 9. [9] Somers E, DasGupta BR. Clostridium botulinum type A, B, C1 and E produce proteins with or without hemagglutinating activity: Do they share common amino acid sequences and genes? J Protein Chem 1991;10: 415 25. [10] Sakaguchi G. Clostridium botulinum toxins. Pharmacol Ther 1983;19:165 94. [11] Bonventre PF, Kempe LL. Physiology of toxin production by Clostridium botulinum types A and B. III. Effect of pH and temperature during incubation on growth, autolysis, and toxin production. Appl Microbiol 1959; 7:374 7. [12] Townsend CT, Yee L, Mercer WA. Inhibition of the growth of Clostridium botulinum by acidification. Food Res 1954;19:1 7. [13] Baffi RA, Garnick RL. Quality control issues in the analysis of lyophilized proteins. Dev Biol (Basel) 1991; 74:181 4. [14] Borodic GE, Ferranter R. Orbicularis muscle histology after repetitive injections of botulinum A toxin. Presented at the annual meeting of American Academy of Ophthalmology. Atlanta, Georgia, October 28 November 1, 1990. [15] Sloop RR, Cole BA, Escutin RO. Human response to botulinum toxin injection: type B compared with type A. Neurology 1999;49:189 94. [16] Jankovic J, Brin MF. Botulinum toxin: historical perspective and potential new indications. Muscle Nerve 1997;20(Supp 6):S129 45. [17] Brin MF. Botulinum toxin: new and expanded indications. Eur J Neurol 1997;4:59 66. [18] Mahant N, Clouston PD, Lorentz IT. The current use of botulinum toxin. J Clin Neurosci 2000;7:389 94. [19] Lange DI, Brin MF, Warner CL, et al. Distant effects of local injection of botulinum toxin. Muscle Nerve 1987;10:552 5. [20] Olney RK, Aminoff MJ, Gelb DJ, et al. Neuromuscular effects distant from the site of botulinum neurotoxin injection. Neurology 1988;38:1780 3. [21] Report of the Therapeutics in Technology Assessment Subcommittee of the American Academy of Neurology. Assessment: the clinical usefulness of botulinum toxin A in treating neurologic disorders. Neurology 1990;40:1332 6. [22] Bhatia KP, Mu nchau A, Thompson PD, et al. Generalised muscular weakness after botulinum toxin injections for dystonia: a report of three cases. J Neurol Neurosurg Psychiatry 1999;67:90 3.
A.W. Klein / Dermatol Clin 22 (2004) 197205 botulinum A toxin to ameliorate facial kinetic frown lines. Ophthalmology 1996;103:618 22. [42] Fraenkel AS, Kamer FM. Chemical brow lift. Arch Otolaryngol Head Neck Surg 1998;124:321 3. [43] Brandt FS, Bellman B. Cosmetic use of botulinum A exotoxin for the aging neck. Dermatol Surg 1998;24: 1232 4. [44] Bushara KO, Jones JW, Park DM, et al. Botulinum toxin and sweating [abstract]. Mov Disord 1995;10:391.
205
[45] Silberstein S, Mathew N, Saper J, et al. Botulinum toxin type A as a migraine preventive treatment. Headache 2000;40:445 50. [46] Brin MF, Swope DM, Abassi S, et al. Botulinum toxin type A (Botox) for migraine: double blind, placebo controlled, region specific evaluation [poster 1196]. Poster presented at the Headache World 2000. London, September 3 7, 2000.
Dermatol Clin 22 (2004) 207 211
Myobloc
Timothy Corcoran Flynn, MDa,b,*
a
Department of Dermatology, University of North Carolina, Chapel Hill, NC 27514, USA b Cary Skin Center, PO Box 5129, Cary, NC 27519, USA
Botulinum toxins have been a major contribution to the field of cosmetic dermatology. These compounds improve facial wrinkles in the skin by relaxing overactive mimetic facial muscles producing a reversible improvement of the rhytides. Treatment with botulinum toxin is a minimally invasive procedure, and is currently ranked as the number one cosmetic procedure performed in the United States. All the botulinum toxins are naturally occurring compounds produced by the bacterium Clostridium botulinum [1]. There are seven antigenically different strains of toxin [2]. The human nervous system is affected by five toxin subtypes: A, B, E, F, and G. All botulinum toxins are high molecular weight complexes composed of the neurotoxin plus additional nontoxic proteins. The toxins affect striated muscle by creating a chemical denervation that is temporary and reversible [3]. They act first by binding to specific membrane receptors on the presynaptic cholinergic neurons. The toxin is then internalized by endocytosis, and the toxin acts to prevent the release of acetylcholine from the inside of the cell. Each of the toxins binds to a specific binding protein on the cell membrane and has unique target proteins within the cell [4]. All affect the soluble N-ethylmaleimide sensitive factor attachment protein receptor complex. This complex is necessary to allow the presynaptic motor neuron to release acetylcholine.
The most commonly used botulinum toxins, the type A toxins (Botox and Dysport), affect the SNAP-25 protein, whereas the type B toxin (Myobloc) affects vesicle-associated membrane protein, also known as synaptobrevin. Both type B and type A are antigenically distinct.
The product Myobloc (Elan Pharmaceuticals, San Diego, CA) is the commercial formulation of type B botulinum toxin. Baumann and Black [5] provide a nice review of the product. Released in the United States in 2000, it has a Food and Drug Administration approved indication for the treatment of cervical dystonia. The toxin is a highly purified liquid formulation prepared by fermenting the type B strain of C botulinum. A series of chromatography and salt precipitations are used to purify the product [6]. The process does not involve lyophilization, and it contains very little contaminating protein or inactive aggregated toxin. This is desirable because of the theory that extrasuperfluous proteins could increase the risk for antibody formation. Myobloc is formulated as slightly acidic liquid with a pH of 5.6. This ensures that the integrity of the complex is maintained and that the product is very stable. At this pH, the complex retains its integrity as an approximately 700-kd whole complex containing the active 150-kd toxin. It is interesting to note that experiments done by Elan have shown that when the pH was adjusted to a pH of 7.8, complex dissociation occurred within 12 hours releasing some of the free toxin [6]. The product may be purchased in multiple-use, rubber-stopper, aluminum-crimped vials containing different quantities of product. The sizes are 2500,
Dr. Flynn has served as a consultant to Allergan Incorporated and Elan Pharmaceuticals. He has received funding for research from Elan Pharmaceuticals and unrestricted grants from Allergan Incorporated. He is a research participant with Inamed, and holds stock in Allergan Incorporated. * Cary Skin Center, PO Box 5129, Cary, NC 27519. E-mail address: flynn@caryskincenter.com
208
T.C. Flynn / Dermatol Clin 22 (2004) 207211
5000, and 10,000 U each at a concentration of 5000 U/ mL. Each vial is slightly overfilled [5], so that the 2500-U vial now contains 4100 U (0.82 mL); the 5000-U vial contains 6800 U (1.36 mL); and the 10,000-U vial contains 12,650 U (2.53 mL). The long-term stability of Myobloc has been well documented. The botulinum type B preparation was stable for more than 30 months when stored at refrigerated temperatures and for 9 months when stored at room temperature. Dilution of the toxin with normal saline does not result in any loss of total activity [6].
How is Myobloc different than type A toxins? The use of botulinum toxins in cosmetic dermatology should be thought of as a precise surgical placement of a locally acting compound. Botulinum toxins do diffuse through tissue and musculature. This has the beneficial effect of spreading the effect over a certain radius, and the radius of diffusion must be considered when selecting injection points. Diffusion can have a detrimental effect. For example, instances of lid ptosis are thought to have occurred because of diffusion of the toxin into the levator palpebrae muscle. Myobloc has a different diffusion or spread than type A toxins. In clinical practice, Myobloc is believed to have an increased radius of diffusion when compared with Botox. The authors study [7] compared the direct effect of Myobloc versus Botox in the frontalis muscle. A single blinded paired comparison study injecting both types of toxin each into one side of the frontalis muscle was done. A dose of 5 U of Botox was used compared with 500 U of Myobloc on the contralateral side in eight volunteers. Intramuscular injections were placed in the midpupillary line halfway between the brow and the hairline. Serial controlled photographs of the patients were taken approximately daily and the images digitized to map out the area of effect. The area of effect was calculated and expressed in real centimeters squared. In every case the area of diffusion of Myobloc was greater than that of Botox. These were clinical data looking at the visible reduction in wrinkles and did not involve the use of electromyography. It is known, however, that the toxins do not affect all mammals equally. There are some intriguing data suggesting increased spread of botulinum A over botulinum B using a monkey hand model [6,8]. In the studies of Arezzo [8], one muscle in the monkey hand was injected with either Botox or Myobloc and muscular activity in other adjacent muscles was recorded using electromyography. The spread to adjacent muscles of botulinum type B could be compared
with botulinum type A. In the monkeys at doses of both 5 and 25 times the minimal effective electromyography dose, changes in the adjacent musculature were increased with botulinum type A as compared with botulinum type B. The differences were statistically significant. These data suggested that botulinum type B exhibited a significantly less spread to adjacent and distant noninjected muscles compared with botulinum type A. The rate of onset of Myobloc is increased over Botox. The authors direct comparison study showed that the rate of onset of Myobloc was slightly faster. Photographic analysis showed that the rate of onset of type B toxin preceded type A by approximately 1 day. Other scientific studies have documented the rate of onset of Myobloc as just slightly faster than that of Botox. Matarasso [3] observed this in his study. In 10 patients whose crows feet were treated, the average onset of Myobloc was 2.3 days with average onset of Botox being 3.7 days. Lowe et al [9] compared Myobloc with Botox injection in the glabellar complex. The rate of onset of Myobloc was at 2 to 3 days, whereas the onset for Botox was 3 to 7 days. Sadick [10] injected the glabella of 39 patients with either 2400 or 3000 U of Myobloc and followed them daily until onset of action. Most subjects showed improvement within 2 days, and all subjects responded by day 3. All experimental findings are consistent with the clinically observed phenomenon among patients who use Myobloc that the rate of reduction of wrinkles is more rapid than with Botox. Certain patients comment that they like the more complete effect and also appreciate the quick onset of action. The duration of effect has not been shown to be equivalent or longer than that of the type A toxins. It is important to keep in mind, however, that duration of effect can be dose dependant. In comparison studies, Matarassos [3] 10 crows feet subjects had an average duration of 6.4 weeks with 750 U of Myobloc, and 12.7 weeks with 15 U of Botox. Baumann et al [11] studied 20 volunteers in a double-blinded, placebocontrolled trial using Myobloc. Subjects crows feet were injected with 1500 U of Myobloc and photographed monthly. Investigator assessment of the photographs showed that the Myobloc began to wear off at an average of 68 days. Lowe et al [9] in their glabellar comparison showed a duration of effect of 6 to 8 weeks with the use of 1000 U of Myobloc in the glabellar complex and duration of 10 to 12 weeks with use of 2000 U. Duration of greater than 16 weeks was seen when 20 U of Botox was used. Sadicks [12] publication using only Myobloc in the glabella showed a duration of 8 weeks using a total dose of 1800 U. He
209
further increased the dose [10] and showed duration of effect of 9.6 weeks using 2400 U and 10.4 weeks using 3000 U. Sadicks data show a nice dose versus duration curve and suggests that higher doses may produce an increased duration. The duration of effect has been addressed in animal studies. In mice, 1 U of Myobloc is equal to 1 U of Botox. To evaluate duration of effect, mice were injected with either type A or type B toxin, and digit abduction score assessed [13]. The duration of effect was 36 days in mice treated with Botox and 14 days in mice treated with Myobloc.
Equivalency studies What is the ratio of equivalency between Myobloc and the other botulinum toxins for use in cosmesis? It is the opinion of the author that for wrinkle reduction, the final rate of equivalency is not yet known. Botulinum toxins affect individual species differently. In mice, 1 U of Botox equals 1 U of Myobloc, but in monkeys there is a ratio of 1:5. Many cosmetic dermatologists started with a ratio of 1 U of Botox to 50 U of Myobloc. This ratio was derived from patients suffering from cervical dystonia, in whom doses of 5000 to 10,000 U of Myobloc were found to be effective [14]. The corresponding effective dose of Botox was 100 to 300 U [3]. In practical use for cosmesis, it was quickly found that this ratio was too low, and many dermatologists began working with a ratio of 1:100. Many patients reported that the effect of the product dosed at 1:100 did not last as long as Botox. The data of Sadick and others suggest that to achieve an equal duration of effect to that of Botox, a ratio of greater than 1:100 or 1:125 needs to be surpassed. Even if an increased ratio is used, there are no data to date to show that Myobloc has an equal or increased duration over that of Botox.
Other published clinical studies A study by Ramirez et al [15] documented the effectiveness in treating facial lines. The glabellar frown lines, crows feet, and forehead wrinkles all responded to treatment with Myobloc. At the doses used, the drug significantly improved facial wrinkles but duration was shorter than expected. All facial wrinkles had returned to baseline by week 12, and glabellar lines had returned to baseline by 2 months. Lowe et al [9] compared doses of 1000 and 2000 U of Myobloc with 20 U of Botox injected into the
glabellar complex. They observed a more rapid onset of action with both doses of Myobloc (2 to 3 days) as compared with Botox (3 to 7 days). In duration of effect of 16 weeks or greater, the duration of the 1000-U dose was 6 to 8 weeks and the 2000-U dose 10 to 12 weeks. The study by Baumann et al [11] on crows feet injections using 1500 U of Myobloc has raised interesting questions regarding side effects. In 20 Myobloctreated subjects, 55% reported flulike symptoms, 45% reported dry mouth, and 25% reported dry eyes. There was a peak in influenza activity in the United States during that time, but this does not account for the dry mouth or dry eye symptoms. Using the glabellar frown lines as a model, Flynn, Carruthers, Carruthers, and Klein have participated in a phase 1, randomized, double-blind, placebo-controlled, safety and efficacy study sponsored by Elan Pharmaceuticals. In this study, cohorts of patients were injected with 250, 500, 1000, 1500, 2500, or 3000 U of Myobloc in the glabellar complex. The injections were placed in five equally divided doses in standard sites. An excellent safety profile was shown with no ptosis or dry mouth reported. Duration of effect rose proportionately with increasing dose. All subjects treated with the 3000-U dose of active drug reported substantial effect at the primary end point (4 weeks) and persistent efficacy was demonstrated in some, but not all, of these subjects at 12 weeks. These safety profile and efficacy results suggest that additional dose groups (eg, 3500 U) should be studied. The proper dose necessary to give an equivalent duration obtainable from the type A toxins needs to be determined. Alster and Lupton [16] studied the use of botulinum type B for dynamic glabellar rhytides believed to be refractory to type A toxin. Their patients were selected by having shown a less than 50% reduction in contraction of the corrugator muscles when injected with 25 U of Botox. Their patients all responded to 2500 U total glabellar dose with a 78% drop in wrinkle scores at 1 month. Duration was markedly shorter than usually seen when 25 U of Botox is injected in the glabellar complex.
Practical use Several practical comments regarding the clinical use of Myobloc are warranted. Because of the pH of 5.6, there is an increased amount of pain noticed with Myobloc injections compared with Botox, which is reconstituted to a more physiologic pH. This increased stinging or burning sensation often elicits
210
comments from patients. All patients have differing reactions to pain and some have commented that the increasing pain was a significant hurt. Multiple authors have noted the increased pain with Myobloc treatment. Baumann [5] has reported that mixing preservative containing normal saline with Myobloc reduces the pain on injection. The use of topical anesthetics reduces the pain of the needle stick but does not completely eliminate the burning sensation from Myobloc. Myobloc has a remarkably long half-life when stored in the refrigerator [6]. This ameliorates the need for concern about the stability of the product because no reconstitution is needed and no decrease in effectiveness is seen long-term. Furthermore, the product is remarkably stable even at room temperature, so should a vial be left out of the refrigerator overnight, there is no cause for concern. No decrease in effectiveness is seen. The rapid action of Myobloc makes it helpful for certain situations. Many clinicians have had patients who present with wrinkles wanting botulinum toxin and have an important upcoming social event in less than a week. These patients may be treated with Myobloc because the patient has a good clinical result within 3 days. The effect of Myobloc particularly in the glabella and the forehead is a very diffuse and uniform effect, most likely the result of the increased diffusion of Myobloc over Botox. Baumann [5] has described this as a hard freeze. Although the author favors an aesthetic result where a significant reduction in muscular effect occurs with some retention of movement to allow for expression, certain patients desire to have no muscular movement of the treated areas. These people often prefer to be treated with Myobloc and come more often to maintain the Myobloc effect. The issue of the side effects of dry mouth and dysphagia are interesting. These were seen when Myobloc was used in randomized, double-blind, placebo-controlled clinical trials for the treatment of cervical dystonia. It is important to note that doses ranged from 2500 to 10000 U and that the side effects increased in higher doses. These side effects were selflimited and resolved but were reported in up to 16% of patients [11]. Baumann also noted dry mouth in her crows feet study. The author has not had any patients report dysphagia or dry mouth when Myobloc has been used in cosmetic dermatology for treatment of rhytides or for hyperhidrosis. The current cost of the product is $185 for the 2500-U vial, $370 for the 5000-U vial, and $740 for the 10,000-U vial. It may be ordered directly from the manufacturer. It must be emphasized that the final
doses of Myobloc for cosmesis are not yet fully known. Many cosmetic dermatologists are now working at ratios of 1 U of Botox to 125 U of Myobloc. It is known that duration of effect is dose-dependent, and the ultimate length of effect depends on the dose used. Will Myobloc have the same duration of Botox? Only further use and carefully conducted studies can tell.
References
[1] Huang W, Foster JA, Rogachefsky AS. Pharmacology of botulinum toxin. J Am Acad Dermatol 2000;43: 249 59. [2] Spencer JM. Cosmetic uses of botulinum toxin type B. Cosmetic Dermatol 2002;15:11 4. [3] Matarasso SL. Comparison of botulinum types A and B: a bilateral and double-blind randomized evaluation in the treatment of canthal rhytides. Dermatol Surg 2003;29:7 13. [4] Setler P. The biochemistry of botulinum toxin type B. Neurology 2000;55(suppl 5):22 8. [5] Baumann L, Black L. Botulinum toxin type B (Myobloc). Dermatol Surg 2003;29:496 500. [6] Callaway JE, Arezzo JC, Grethlein AJ. Botulinum toxin type B: an overview of its biochemistry and preclinical pharmacology. Semin Cutan Med Surg 2001; 20:127 36. [7] Flynn T, Clark R. Botulinum toxin type B (Myobloc) versus botulinum toxin type A (Botox) frontalis study: rate of onset and radius of diffusion. Dermatol Surg 2003;29:519 22. [8] Arezzo JL, Litwals MS, Caputo FA, et al. A comparison of the spread of biologic activity of Neurobloc botulism toxin (type B) and Botox (botulinum toxin type A) in a monkey model. Mov Disord 2002;15:159. [9] Lowe NJ, Yamauchi PS, Lask GP, et al. Botulinum toxins types A and B for brow furrows: preliminary experiences with type B toxin dosing. J Cosmet Laser Ther 2003;4:15 8. [10] Sadick N. Prospective open-label study of botulinum toxin type B (Myobloc) at doses of 2400 and 3000 units for the treatment of glabellar wrinkles. Dermatol Surg 2003;29:501 7. [11] Baumann L, Stezinger A, Vujevich J, Halem M, Bryde J, Black L, et al. A double-blind, randomized, placebocontrolled pilot study of the safety and efficacy of Myobloc (botulinum toxin type B) purified neurotoxin complex for the treatment of crows feet: a double-blinded placebo-controlled trial. Dermatol Surg 2003;29:508 15. [12] Sadick NS. Botulinum toxin type B for glabellar wrinkles: a prospective open-label response study. Dermatol Surg 2002;28:817 21. [13] Aoki KR. A comparison of the safety margins of botulinum neurotoxins serotypes A, B, and F in mice. Toxicon 2001;39:1815 20.
T.C. Flynn / Dermatol Clin 22 (2004) 207211 [14] Lew MF, Brashear A, Factor S. The safety and efficacy of botulinum toxin type B in the treatment of patients with cervical dystonia: summary of three controlled clinical trials. Neurology 2000;55:S29 35. [15] Ramirez AL, Reeck J, Maas CS. Botulinum toxin type B (Myobloc) in the management of hyperkinetic
211
facial lines. Otolaryngol Head Neck Surg 2002;126: 459 67. [16] Alster T, Lupton J. Botulinum toxin type B for dynamic glabellar rhytides refractory to botulinum toxin type A. Dermatol Surg 2003;29:516 8.
Dermatol Clin 22 (2004) 213 219
Dysport
Andrew C. Markey, MD, FRCPa,b,*
a
St. Johns Institute of Dermatology, St. Thomas Hospital, London, SE17EH, UK b The Lister Hospital, Chelsea Bridge Road, London SW1W 8RH, UK
Although the introduction of botulinum toxin A (BTX-A) for medical and cosmetic therapy in the United States has been well documented [1,2], such reviews have dealt with the BOTOX product produced by Allergan Inc., California, USA. In Europe, however, a different BTX-A product, Dysport, manufactured by Ipsen Limited (formerly Speywood Pharmaceuticals) has been introduced and used over a similar period of time. In 1981, Elston working at the National Hospital for Nervous Diseases, London, pioneered the clinical use of BTX-A in the UK for patients with blepharospasm and strabismus [3]. Elston sourced the supplies of toxin from the Centre of Applied Microbiology and Research (CAMR), Porton Down, which is part of the government Public Health Laboratory Service in the UK. The toxin was released by the government to Elston and other interested clinicians on a clinical trial basis in a vial containing 50 ng or 2000 mouse U of BTX-A. Throughout the 1980s, this form of BTX-A was used for successfully treating focal movement disorders such as hemifacial spasm, spasmodic torticollis, as well as the initial ocular indications [4]. In 1985, Speywood Pharmaceuticals, (now Ipsen Ltd), formed an agreement with CAMR to commercially market their BTX-A in a new formulation. CAMR would be responsible for the primary manufacture of the BTX-A, and Speywood would carry out the secondary manufacturing processes of purification and formulation at its plant in Wrexam, North Wales.
This new formulation named Dysport was produced as a 12.5-ng or 500 BTX-A unit vial (as it is today). In 1989, a formal product license application was submitted to the regulatory authorities in the UK for the use of Dysport in treating blepharospasm and hemifacial spasm. The product license was granted in 1990, and Dysport was commercially launched in the UK in 1991. Throughout the 1990s, other licensed indications for Dysport were approved, including spasmodic torticollis and pediatric cerebral palsy spasticity. Dysport is currently licensed for use in 49 countries worldwide and for a variety of indications, including cosmesis in some markets (Brazil and Argentina). The Inamed Corporation in the USA has recently acquired the rights to develop, market, and distribute Dysport for cosmetic indications in the United States, Canada, and Japan.
Manufacturing Although both contain BTX-A, Dysport and BOTOX are subject to their own individual processes of manufacture and potency assessment: strains of toxin-producing organisms used in fermentation, methods of purification, excipients, and formulation. Such manufacturing and assay differences have a bearing on potency, diffusion, and antigenicity of any biologic product, so Dysport and BOTOX should be regarded as individual BTX-A products with their own individual characteristics rather than as generic equivalents. Dysport is produced via fermentation of the bacterium Clostridium botulinum. The toxin complex is recovered through a series of steps, including chromatography, precipitation, dialysis, and filtration. The toxin complex is then dissolved in an aqueous solution
The author has no significant connection with commercial products or companies mentioned in this article. * The Lister Hospital, Chelsea Bridge Road, London SW1W 8RH, UK. E-mail address: markeyoffice@aol.com
214
A.C. Markey / Dermatol Clin 22 (2004) 213219
of human serum albumin and lactose, after which it is filtered and freeze-dried. The lactose acts a bulking agent and allows the product to be seen in the vial as a small cake of white powder, facilitating reconstitution.
Dilution As with BOTOX (but unlike NeuroBloc/MyoBloc, which is provided as a solution), Dysport is provided in a glass vial as an air-dried powder, though unlike BOTOX, the Dysport powder is clearly visible in the vial. The air-dried powder allows for various dilutions of Dysport to meet clinical requirements. As the Dysport vial does not contain a vacuum, the insertion of a needle before introducing the diluent via a second, separate needle will facilitate the introduction of the salinethis consideration is irrelevant if the bung is removed before preparation. Dilution is with normal saline; quoted volumes of diluent recommended in the product package insert are 1.0 to 2.5cc saline per vial, however, this can be varied to suit requirements. Interestingly, biologic availability of Dysport has been reported to be enhanced by supplementing with albumin, lowering its concentration and increasing injection volume [8,9].
Immunogenicity An important area for concern in ongoing BTX therapy is the issue of neutralizing antibody formation. Factors contributing to antibody formation may be the quality (purity) and quantity of protein injected per treatment, the frequency of such injection, the antigenicity of the injected molecule, the route of administration (IM, SC), and the genetic predisposition of the patient to develop antibodies. In the largest study of its kind [5], looking for neutralizing antibodies in a condition requiring repeat, high-dose BTX-A injections, 616 patients undergoing long-term treatment of cervical dystonia using high dose (800+ U per treatment) Dysport, 1.5% to 2.5% of patients developed neutralizing antibodies to BTX-A but only after a minimum of six injection sessions spaced 3monthly. Clearly, this is a low rate of treatment failure due to serum neutralizing antibodies to Dysport, even in a repeat high dosage setting. Greater frequency of injections and high mean dose per treatment were a feature of the antibody-positive group, but neither total cumulative Dysport dose nor total number of treatment sessions correlated with a higher risk. Interestingly, some patients who became nonresponders did not have neutralizing antibodies, and the incidence of neutralizing antibodies in patients who continued to respond was not documented. There is evidence that where formed, neutralizing antibodies to BTX-A may eventually decrease (over years) when BTX-A therapy is withdrawn [6] and that some treatment failures can be overcome by increasing doses of the BTX-A toxin without further increasing neutralizing antibodies [7]. There are no prospective antibody studies with Dysport. In the Dysport manufacturing specification, the protein content per 500 U Dysport vial is noted at 12.5 ng, though according to the company this is a manufacturing upper limit and current batches are claimed to be significantly lower than this. BOTOX was reformulated several years ago and now has a protein content per 100 U BOTOX vial of approximately 5 ng. Clearly, total protein delivered per treatment will depend on dosage of the particular BTX-A molecule used and the protein content of the individual manufacturing batch. There are no published antibody studies comparing Dysport with the currently formulated BOTOX.
Biologic activity As described earlier, individual preparations of BTX-A will have product-specific unit efficacy, and the units of Dysport and BOTOX are not, therefore, directly comparable. Using different bioassay techniques and in vivo animal diffusion models to establish unit equivalence, a range of values of 1 U BOTOX to 2 to 4 U Dysport has been described [10 12]. Extrapolation of these laboratory and animal data to evolve a fixed conversion ratio between the products for use clinically assumes a linear relationship with increasing dosage between the two BTX-A products, which may not necessarily be the case. However, in clinical practice, conversion ratios of units of BOTOX to Dysport of 1:4 [13 15] or increasingly recently of 1:3 [16 20] have been widely reported and discussed, though there have been reports outside of these commonly used ratios ranging from 1:1 [21] to 1:6 [22]. Practitioners are best advised to be cognizant of publications using their preferred BTX-A product in specific clinical situations and the documented doses used.
Clinical results Noncosmetic usage Because of the extensive use of Dysport by European neurologists and other nonaesthetic practitioners, much of the early experience relating to
215
efficacy and safety of the product is contained in noncosmetic literature. Striated and smooth muscle disorders There is an extensive literature documenting the use of Dysport in the successful treatment of a number of disorders involving striated and smooth muscle, including blepharospasm, cervical dystonia, torticollis, and hemifacial spasm [7,16 18,23 35]. Also, stroke-associated spasticity [36 44], neurologic disease associated spasticity [45,46], pediatric cerebral palsy [26,47 50], brachial plexus birth palsy [51,52], writers cramp [53,54], and dystonic clenched fist [55] have all been reported to have responded with gratifying outcomes. Treatment of sphincteric and smoothmuscle disorders, such as achalasia [56 59], laryngeal dysphonia [60,61], laryngeal aspiration [62,63] and detrusor-sphincter dyssynergia [64,65], has been documented. Positive impact in headache and migraine is likewise well established [66], though not always with universal success [67]. Throughout these studies, positive clinical outcomes with a good safety profile have been routinely observed
Hyperhidrosis In 1996, as part of a report on sweat reduction after localized injections of BTX-A, Bushara et al [68] documented Dysport producing relative anhidrosis at the site of subcutaneous injection into the skin of the dorsum of the hand, whereas BOTOX was used successfully, in the same study, to treat the axillae. Shortly afterward, Schneider reported a double-blind, placebo-controlled study in 11 patients using Dysport (120 U per palm) for treating palmar hyperhidrosis [69] with an excellent outcome and low incidence of side effects (mainly minor weakness of selected small muscles of the hands in three patients). Heckmann et al then initially reported in the German [70] and English literature [71] dramatic reductions in sweat production in patients with primary axillary hyperhidrosis after Dysport therapy. The initial, open study was followed by a multicenter, double-blind, placebocontrolled, crossover study of 145 patients with primary axillary hyperhidrosis [72]. Sweat production was objectively quantified by gravimetry. All patients had been unresponsive to the usual topical therapies and had pretreatment sweat output >50 mg per minute. In the first part of the study, 200 U Dysport were injected into one axilla, with placebo placed in the contralateral axilla. Two weeks later, the treatment codes were broken and the axilla that had previously
received the placebo received a lower 100 U Dysport treatment. Mean pretreatment sweat production was 192 mg per minute, and at 2 weeks in the original 200-U Dysport treated axilla, this was reduced to 24 mg per minute, with the placebo axilla at 144 mg per minute. In the later axilla, after the 100-U Dysport injection, sweating was reduced to 32 mg per minute. At 24 weeks after the 100-U injection (26 weeks after the 200-U injection), sweating was still reduced from baseline at 67 mg per minute in the 200-U treated axilla and 65 mg per minute in the 100-U treated axilla. All these reductions in sweat production were highly significant statistically and led to an almost universal (98%) recommendation of the treatment by the patients in the study. Meanwhile, Schneider et al who had initially reported on palmar hyperhidrosis [69] documented the groups experience in treating axillary hyperhidrosis with Dysport [73] as part of a double-blind, randomized trial of 13 patients. A 200-U injection of Dysport in a single axilla was found to produce a dramatic reduction in sweating as measured by digitized, ninhydrin-stained sheets. In a subsequent open label study of 61 patients [74] undergoing repeat intradermal injections of Dysport for more than 3 years with either axillary (400 U total to axillae pretreatment) or palmar hyperhidrosis (460 U total to palms per treatment), repeat injections were found to be as effective as initial injections in reducing sweat production. Four weeks after initial injections, mean sweat production had fallen by 71% compared with baseline (in axillae) and 42% (in palms) with a mean time interval between treatments of 34 weeks (axillary hyperhidrosis) and 25 weeks (palmar hyperhidrosis). Again, nine of the 21 patients treated for palmar hyperhidrosis complained of minor hand muscle weakness. Whatling and Collin recently reported their experience in treating 16 patients with axillary hyperhidrosis using 240 U of Dysport per axillae with a mean response duration of 9 months [75]. In a case report of prolonged muscle cramps presumed to be caused by electrolyte imbalance secondary to axillary hyperhidrosis, Dysport injections not only resolved the hyperhidrosis, but also gave long-lasting relief from the muscle cramps [76]. In idiopathic craniofacial hyperhidrosis, Dysport has been reported to dramatically decrease facial sweating with only a minor impact on frowning being noted by patients [77]. To better quantify the effects of BTX-A on reduction in sweat volumes, a number of methods of measurement have been used, and most recently the sudomotor axon reflex test has been described for this
216
purpose [78], although some of the difficulties inherent in the interpretation of sweat reduction studies have been discussed [79]. Other assorted medical applications von Lindern et al [80] have described the novel of use of Dysport injections (500 U) directly into the parotid gland in situations where a salivary fistula has arisen due to trauma or a complication from parotid gland surgery. By interrupting cholinergic salivary gland innervation, a new noninvasive approach to salivary gland therapy is possible. Similarly, in gustatory tearing, or hyperlacrimation, Dysport has been effective in reducing tear output [81]. In thyroid eye disease, patients with eyelid retraction will often develop overactivity of the accessory muscles that facilitate eyelid closure, giving rise to a particular thyroid look. In 14 patients, Olver [82] injected 40 U of Dysport into each corrugator muscle mass, with or without a similar dose into the procerus muscle, and produced dramatic softening of the facies, which lasted 4 to 6 months after each injection session. Heckmann et al have recently reported an open pilot study of Dysport injections in three patients with lichen simplex in whom all pruritus and visible lesions cleared with no recurrences over a 4-month period. They hypothesize an ameliorative effect of the BTX-A injections on acetylcholine sensitive C-fibers [83]. Certainly, Dysport has been found to have pain-relieving actions via a number of proposed effects on the nociceptive pathways [84]. Cosmetic usage Following on previous reports by the Carruthers [85,86] who used BOTOX in the treatment of cosmetically troublesome, movement-associated lines, Ascher et al [87] in 1995 described their cosmetic experiences using Dysport in the glabella and crowsfeet areas in 19 patients. They introduced the idea of documenting effectiveness of BTX-A therapy by using computer analysis of casts of the treated sites. Patients were followed monthly over a 12-month to 24-month period with significant decreases in wrinkling being noted. After each injection, the effects lasted between 3 and 4 months, with longer periods of action being noted with repeated injections sessions. In 1998 Le Louarn [88] used varying concentrations of Dysport and differing injection depths in an attempt to limit BTX-A diffusion to adjacent muscles, aiming to reduce the incidence of ptosis and other
unwanted effects on nontarget muscles in aesthetic treatments, an approach that he later expanded on by using both Dysport and BOTOX [89]. Lowe reported his experience [15] using both Dysport and BOTOX in cosmetic practice and gave treatment guidelines based on an approximate dose conversion ratio of 1 U BOTOX: 4 U Dysport. As with BOTOX, Dysport has also been used in combination with intradermal and subcutaneous fillers in patients who needed a combination approach to obtain the desired cosmetic results [90]. A further study [91] of 13 patients undergoing Dysport treatment for glabellar, crows-feet or platysmal changes were assessed according to subjective criteria. Patients received a mean dose of 70 U (glabella area, seven injection points), 40 to 60 U (crows-feet area, four to six injection sites), and 80 U (platysma, eight sites). Most patients were satisfied with their treatment; median score for treatment efficacy was 2 (where 1 equaled totally satisfied and 5 equaled not at all satisfied), although four of 11 patients treated in the glabella reported temporary headache. Heckmann and Schon-Hupka [92] have used digital image analysis of pretreatment and post-treatment photographs to quantify the effects of treatment with Dysport in the glabella and forehead areas. This approach to quantification has demonstrated a longer time course in both onset and wearing off of BTX-A effects than previously reported and has emphasized the contribution of tissue elasticity (which declines with age) to smoothening of facial expression lines.
Summary Since the commercial launch of Dysport in 1991, after 10 years of clinical studies on its predecessor formulations, this BTX-A product has shown great therapeutic promise with a good safety profile and low incidence of treatment failures. As with all BTX products, Dysport should not be seen as a generic equivalent but as a specific product with individual unit dosing requirements and side effect profiles. Its role as an important BTX-A molecule looks set to expand as new indications for botulinum toxin arise, and as the cosmetic usage of Dysport is approved in countries outside of South America.
References
[1] Carruthers A, Carruthers J. History of the cosmetic use of Botulinum A exotoxin. Dermatol Surg 1998;24: 1168 70.
A.C. Markey / Dermatol Clin 22 (2004) 213219 [2] Markey AC. Botulinum A exotoxin in cosmetic dermatology. Clin Exp Dermatol 2000;25:173 5. [3] Elston JS. The clinical use of botulinum toxin. Semin Ophthalmol 1988;3:249 60. [4] Marsden CD, Quinn NP. The dystonias. BMJ 1990;300: 139 44. [5] Kessler KR, Skutta M, Benecke R. Long term treatment of cervial dystonia with botulinum toxin A: efficacy, safety and antibody frequency. J Neurol 1999;246: 265 74. [6] Dressler D, Bigalke H. Botulinum toxin antibody type A titres after cessation of botulinum toxin therapy. Mov Disord 2002;17(1):170 3. [7] Dressler D, Munchau A, Bhatia KP, Quinn NP, Bigalke H. Antibody-induced botulinum toxin therapy failure: can it be overcome by increased botulinum toxin doses? Eur Neurol 2002;47(2):118 21. [8] Rollnik JD, Matzke M, Wohlfarth K, Dengler R, Bigalke H. Low-dose treatment of cervical dystonia, blepharospasm and facial hemispasm with albumindilute botulinum toxin type A under EMG guidance. An open label study. Eur Neurol 2000;43(1):9 12. [9] Bigalke H, Wohlfarth K, Irmer A, Dengler R. Botulinum A toxin: Dysport improvement of biological availability. Exp Neurol 2001;168(1):162 70. [10] Hambleton P, Pickett AM. Potency equivalence of botulinum toxin preparations. J R Soc Med 1994;87:719. [11] Pickett AM, Hambleton P. Dose standardisation of botulinum toxin. Lancet 1994;344:474 5. [12] Aoki KR. A comparison of the safety margins of botulinum neurotoxin serotypes A, B, and F in mice. Toxicon 2001;39(12):1815 20. [13] Nussgens Z, Roggenkamper P. Comparison of two botulinum-toxin preparations in the treatment of essential blepharospasm. Graefes Arch Clin Exp Ophthalmol 1997;235(4):197 9. [14] Sampaio C, Ferreira JJ, Simoes F, Rosas MJ, Magalhaes M, Correia AP, et al. DYSBOT: a single-blind, randomized parallel study to determine whether any differences can be detected in the efficacy and tolerability of two formulations of botulinum toxin type A Dysport and BOTOX assuming a ratio of 4:1. Mov Disord 1997;12(6):1013 8. [15] Lowe NJ. Botunlinum toxin type A for facial rejuvenation. United States and United Kingdom perspectives. Dermatol Surg 1998;24:1216 8. [16] Ranoux D, Gury C, Fondarai J, Mas JL, Zuber M. Respective potencies of BOTOX and Dysport: a double blind, randomised, crossover study in cervical dystonia. J Neurol Neurosurg Psychiatry 2002;72(4): 459 62. [17] Odergren T, Hjaltason H, Kaakkola S, Solders G, Hanko J, Fehling C, et al. A double blind, randomised, parallel group study to investigate the dose equivalence of Dysport and BOTOX in the treatment of cervical dystonia. J Neurol Neurosurg Psychiatry 1998;64(1): 6 12. [18] Poewe W. Respective potencies of BOTOX and Dysport: a double blind, randomised, crossover study in
217
[19] [20]
[21]
[22]
[23]
[24]
[25]
[26]
[27]
[28] [29]
[30]
[31]
[32]
[33]
[34]
cervical dystonia. J Neurol Neurosurg Psychiatry 2002; 72(4):430. Van den Bergh P, Lison DF. Dose standardization of Botulinum Toxin. Adv Neurol 1998;78:231 5. Marion MH, Sheehy M, Sangla S, Soulayrol S. Dose standardisation of botulinum toxin. J Neurol Neurosurg Psychiatry 1995;59:102. Wohlfarth K, Goschel H, Frevert J, Dengler R, Bigalke H. Botulinum A toxins: units versus units. Naunyn Schmiedebergs Arch Pharmacol 1997;355(3):335 40. Durif F. Clinical bioequivalence of the current commercial preparations of Botulinum toxin. Eur J Neurol 1995;2:17 8. Bhaumik S, Behari M. Botulinum toxin A injection for cervical dystonia. J Assoc Physicians India 1999; 47(3):267 70. Sheean GL, Lees AJ. Botulinum toxin F in the treatment of torticollis clinically resistant to botulinum toxin A. J Neurol Neurosurg Psychiatry 1995;59(6):601 7. Brans JW, Lindeboom R, Snoek JW, Zwarts MJ, van Weerden TW, Brunt ER, et al. Botulinum toxin versus trihexyphenidyl in cervical dystonia: a prospective, randomized, double-blind controlled trial. Neurology 1996;46(4):1066 72. Lagueny A, Burbaud P. Mechanism of action, clinical indication and results of treatment of botulinum toxin. Neurophysiol Clin 1996;26(4):216 26. Finsterer J, Fuchs I, Mamoli B. Quantitative electromyography-guided botulinum toxin treatment of cervical dystonia. Clin Neuropharmacol 1997;20(1):42 8. Duran E, Chacon JR. Spasmodic torticollis and vertebral hemangioma. Rev Neurol 2001;32(1):60 2. Poewe W, Deuschl G, Nebe A, Feifel E, Wissel J, Benecke R, et al. What is the optimal dose of botulinum toxin A in the treatment of cervical dystonia? Results of a double blind, placebo controlled, dose ranging study using Dysport. German Dystonia Study Group. J Neurol Neurosurg Psychiatry 1998;64(1):13 7. Laubis-Herrmann U, Fries K, Topka H. Low-dose botulinum toxin-a treatment of cervical dystoniaa doubleblind, randomized pilot study. Eur Neurol 2002;47(4): 214 21. Wissel J, Kanovsky P, Ruzicka E, Bares M, Hortova H, Streitova H, et al. Efficacy and safety of a standardised 500 unit dose of Dysport (clostridium botulinum toxin type A haemaglutinin complex) in a heterogeneous cervical dystonia population: results of a prospective, multicentre, randomised, double-blind, placebo-controlled, parallel group study. J Neurol 2001;248(12):1073 8. Jitpimolmard S, Tiamkao S, Laopaiboon M. Long term results of botulinum toxin type A (Dysport) in the treatment of hemifacial spasm: a report of 175 cases. J Neurol Neurosurg Psychiatry 1998;64(6):751 7. Wissel J, Masuhr F, Schelosky L, Ebersbach G, Poewe W. Quantitative assessment of botulinum toxin treatment in 43 patients with head tremor. Mov Disord 1997;12(5):722 6. Brans JW, de Boer IP, Aramideh M, Ongerboer DV, Speelman JD. Botulinum toxin in cervical dystonia:
218
A.C. Markey / Dermatol Clin 22 (2004) 213219 low dosage with electromyographic guidance. J Neurol 1995;242(8):529 34. Van den BP, Francart J, Mourin S, Kollmann P, Laterre EC. Five-year experience in the treatment of focal movement disorders with low-dose Dysport botulinum toxin. Muscle Nerve 1995;18(7):720 9. Hesse S, Reiter F, Konrad M, Jahnke MT. Botulinum toxin type A and short-term electrical stimulation in the treatment of upper limb flexor spasticity after stroke: a randomized, double-blind, placebo-controlled trial. Clin Rehabil 1998;12(5):381 8. Bhakta BB, Cozens JA, Chamberlain MA, Bamford JM. Impact of botulinum toxin type A on disability and carer burden due to arm spasticity after stroke: a randomised double blind placebo controlled trial. J Neurol Neurosurg Psychiatry 2000;69(2):217 21. Johnson CA, Wood DE, Swain ID, Tromans AM, Strike P, Burridge JH. A pilot study to investigate the combined use of botulinum neurotoxin type A and functional electrical stimulation, with physiotherapy, in the treatment of spastic dropped foot in subacute stroke. Artif Organs 2002;26(3):263 6. Bakheit AM, Thilmann AF, Ward AB, Poewe W, Wissel J, Muller J, et al. A randomized, double-blind, placebo-controlled, dose-ranging study to compare the efficacy and safety of three doses of botulinum toxin type A (Dysport) with placebo in upper limb spasticity after stroke. Stroke 2000;31(10):2402 6. Bakheit AM, Pittock S, Moore AP, Wurker M, Otto S, Erbguth F, et al. A randomized, double-blind, placebocontrolled study of the efficacy and safety of botulinum toxin type A in upper limb spasticity in patients with stroke. Eur J Neurol 2001;8(6):559 65. van Kuijk AA, Geurts AC, Bevaart BJ, van Limbeek J. Treatment of upper extremity spasticity in stroke patients by focal neuronal or neuromuscular blockade: a systematic review of the literature. J Rehabil Med 2002; 34(2):51 61. Bhakta BB, Cozens JA, Bamford JM, Chamberlain MA. Use of botulinum toxin in stroke patients with severe upper limb spasticity. J Neurol Neurosurg Psychiatry 1996;61(1):30 5. Hesse S, Brandi-Hesse B, Bardeleben A, Werner C, Funk M. Botulinum toxin A treatment of adult upper and lower limb spasticity. Drugs Aging 2001;18(4): 255 62. Hesse S, Jahnke MT, Luecke D, Mauritz KH. Shortterm electrical stimulation enhances the effectiveness of Botulinum toxin in the treatment of lower limb spasticity in hemiparetic patients. Neurosci Lett 1995; 201(1):37 40. Hyman N, Barnes M, Bhakta B, Cozens A, Bakheit M, Kreczy-Kleedorfer B, et al. Botulinum toxin (Dysport) treatment of hip adductor spasticity in multiple sclerosis: a prospective, randomised, double blind, placebo controlled, dose ranging study. J Neurol Neurosurg Psychiatry 2000;68(6):707 12. Heinen F, Wissel J, Philipsen A, Mall V, Leititis JU, Schenkel A, et al. Interventional neuropediatrics: treatment of dystonic and spastic muscular hyperactivity with botulinum toxin A. Neuropediatrics 1997;28(6): 307 13. Deleplanque B, Lagueny A, Flurin V, Arnaud C, Pedespan JM, Fontan D, et al. Botulinum toxin in the management of spastic hip adductors in non-ambulatory cerebral palsy children. Rev Chir Orthop Reparatrice Appar Mot 2002;88(3):279 85. Ubhi T. Treatment of paediatric cerebral palsy with Dysport. Hosp Med 2000;61(10):718 21. Bakheit AM, Severa S, Cosgrove A, Morton R, Roussounis SH, Doderlein L, et al. Safety profile and efficacy of botulinum toxin A (Dysport) in children with muscle spasticity. Dev Med Child Neurol 2001;43(4): 234 8. Rasmussen LN. Botulinum toxin. Use in the treatment of spasticity in children. Ugeskr Laeger 2000;162(48): 6557 61. Desiato MT, Risina B. The role of botulinum toxin in the neuro-rehabilitation of young patients with brachial plexus birth palsy. Pediatr Rehabil 2001;4(1):29 36. Hierner R, Rollnik JD, Berger AC, Dengler R. Botulinum toxin type A for the treatment of biceps/triceps co-contraction in obstetrical brachial plexus lesions preliminary results after a follow-up of 18 months. Eur J Plastic Surg 2001;24:2 6. Wissel J, Kabus C, Wenzel R, Klepsch S, Schwarz U, Nebe A, et al. Botulinum toxin in writers cramp: objective response evaluation in 31 patients. J Neurol Neurosurg Psychiatry 1996;61(2):172 5. Koelman JH, Struys MA, Ongerboer DV, Speelman JD. Writers cramp treated with botulinum injections. Ned Tijdschr Geneeskd 1998;142(31):1768 71. Cordivari C, Misra VP, Catania S, Lees AJ. Treatment of dystonic clenched fist with botulinum toxin. Mov Disord 2001;16(5):907 13. Annese V, Bassotti G, Coccia G, Donofrio V, Gatto G, Repici A, et al. Comparison of two different formulations of botulinum toxin A for the treatment of oesophageal achalasia. The Gismad Achalasia Study Group. Aliment Pharmacol Ther 1999;13(10):1347 50. Greaves RR, Mulcahy HE, Patchett SE, Gorard DA, Fairclough PD, Alstead EM, et al. Early experience with intrasphincteric botulinum toxin in the treatment of achalasia. Aliment Pharmacol Ther 1999;13(9): 1221 5. Hep A, Dolina J, Plottova Z, Valek V, Novotny I, Kala Z. Is complex therapy of achalasia using botulinum toxin combined with balloon dilatation an effective approach? Bratisl Lek Listy 2000;101(8):433 7. Hep A, Dolina J, Dite P, Plottova Z, Valek V, Kala Z, et al. Restoration of propulsive peristalsis of the esophagus in achalasia. Hepatogastroenterology 2000;47(35): 1203 4. Zielinska M, Selmaj K. A case of laryngeal adductor dystonia treated with transcutaneous injections of botulinum toxin. Neurol Neurochir Pol 1998;32(5): 1273 80. Galardi G, Guerriero R, Amadio S, Leocani L, Teggi R,
[35]
[47]
[36]
[48] [49]
[37]
[50]
[38]
[51]
[52]
[39]
[53]
[40]
[54]
[41]
[55]
[56]
[42]
[57]
[43]
[44]
[58]
[59]
[45]
[60]
[46]
[61]
A.C. Markey / Dermatol Clin 22 (2004) 213219 Melloni G, et al. Sporadic failure of botulinum toxin treatment in usually responsive patients with adductor spasmodic dysphonia. Neurol Sci 2001;22(4):303 6. Schneider I, Thumfart WF, Pototschnig C, Eckel HE. Treatment of dysfunction of the cricopharyngeal muscle with botulinum A toxin: introduction of a new, noninvasive method. Ann Otol Rhinol Laryngol 1994;103(1): 31 5. Pototschnig CA, Schneider I, Eckel HE, Thumfart WF. Repeatedly successful closure of the larynx for the treatment of chronic aspiration with the use of botulinum toxin A. Ann Otol Rhinol Laryngol 1996;105(7): 521 4. Petit H, Wiart L, Gaujard E, Le Breton F, Ferriere JM, Lagueny A, et al. Botulinum A toxin treatment for detrusor-sphincter dyssynergia in spinal cord disease. Spinal Cord 1998;36(2):91 4. Schurch B, Schmid DM, Knapp PA. An update on the treatment of detrusor-sphincter dyssynergia with botulinum toxin type A. Eur J Neurol 1999;6:S83 9. Schulte-Mattler WJ, Wieser T, Zierz S. Treatment of tension-type headache with botulinum toxin: a pilot study. Eur J Med Res 1999;4(5):183 6. Rollnik JD, Dengler R. Botulinum toxin (Dysport) in tension-type headaches. Acta Neurochir Suppl 2002;79: 123 6. Bushara KO, Park DM, Jones JC, Schutta HS. Botulinum toxin a possible new treatment for axillary hyperhidrosis. Clin Exp Dermatol 1996;21(4):276 8. Schnider P, Binder M, Auff E, Kittler H, Berger T, Wolff K. Double-blind trial of botulinum A toxin for the treatment of focal hyperhidrosis of the palms. Br J Dermatol 1997;136(4):548 52. Heckmann M, Breit S, Ceballos-Baumann A, Schaller M, Plewig G. Axillary hyperhidrosis: successful treatment with botulinum toxin A. Hautarzt 1998;49(2): 101 3. Heckmann M, Breit S, Ceballos-Baumann A, Schaller G, Plewig G. Side-controlled intradermal injection of botulinum toxin A in recalcitrant axillary hyperhidrosis. J Am Acad Dermatol 1999;41(6):987 90. Heckmann M. Botulinum toxin A for axillary hyperhidrosis (excessive sweating). N Engl J Med 2001;344: 488 93. Schnider P, Binder M, Kittler H, Birner P, Starkel D, Wolff K, et al. A randomized, double-blind, placebocontrolled trial of botulinum A toxin for severe axillary hyperhidrosis. Br J Dermatol 1999;140(4):677 80. Schnider P, Moraru E, Kittler H, Binder M, Kranz G, Voller B, et al. Treatment of focal hyperhidrosis with botulinum toxin type A: long-term follow-up in 61 patients. Br J Dermatol 2001;145(2):289 93. Whatling P, Collin J. Botulinum toxin injection is an effective treatment for axillary hyperhidrosis. Br J Surg 2001;88:814 5. Filosto M, Bertolasi L, Fincati E, Priori A, Tomelleri G, Chieregato G, et al. Axillary injection of botulinum
219
[62]
[77]
[78]
[63]
[79]
[64]
[80]
[65]
[81]
[66]
[82]
[67]
[83]
[68]
[69]
[84]
[70]
[85]
[86]
[71]
[87]
[72]
[88]
[73]
[89]
[74]
[90] [91]
[75]
[92]
[76]
A toxin in a patient with muscle cramps associated with severe axillary hyperhidrosis. Acta Neurol Belg 2001; 101(2):121 3. Boger A, Herath H, Rompel R, Ferbert A. Botulinum toxin for treatment of craniofacial hyperhidrosis. J Neurol 2000;247(11):857 61. Braune C, Erbguth F, Birklein F. Dose thresholds and duration of the local anhidrotic effect of botulinum toxin injections: measured by sudometry. Br J Dermatol 2001;144(1):111 7. Moraru E, Voller B, Auff E, Schnider P. Dose thresholds and local anhidrotic effect of botulinum A toxin injections (Dysport). Br J Dermatol 2001;145(2):368. von Lindern JJ, Niederhagen B, Appel T, Berge S, Reich RH. New prospects in the treatment of traumatic and postoperative parotid fistulas with type A botulinum toxin. Plast Reconstr Surg 2002;109:2443 5. Keegan DJ, Geerling G, Lee JP, Blake G, Collin JR, Plant GT. Botulinum toxin treatment for hyperlacrimation secondary to aberrant regenerated seventh nerve palsy or salivary gland transplantation. Br J Ophthalmol 2002;86(1):43 6. Olver JM. Botulinum toxin A treatment of overactive corrugator supercilii in thyroid eye disease. Br J Ophthalmol 1998;82(5):528 33. Heckmann M, Heyer G, Brunner B, Plewig G. Botulinum toxin type A injection in the treatment of lichen simplex: an open pilot study. J Am Acad Dermatol 2002;46(4):617 9. Chalkiadaki A, Rohr UP, Hefter H. Early pain reduction in the treatment of spasticity after a single injection of botulinum A toxin. Dtsch Med Wochenschr 2001; 126(48):1361 4. Carruthers A, Carruthers J. The treatment of glabellar furrows with botulinum A exotoxin. J Dermatol Surg Oncol 1990;16:83. Carruthers A, Carruthers J. Treatment of glabellar frown lines with C. botulinum-A exotoxin. J Dermatol Surg Oncol 1992;18:17 21. Ascher B, Klap P, Marion MH, et al. La toxine botulique dans le treatment de rides fronto-glabellaires et de la region orbitaire. Ann Chir Plast Esthet 1995;40:67 76. Le Louarn C. Toxine botulique et rides faciales: une nouvelle procedure dinjection. Ann Chir Plast Esthet 1998;43:526 33. Le Louarn C. Botulinum toxin A and facial lines: the variable concentration. Aesth Plast Surg 2001;25: 73 84. Erian A, Ionescu NE. Combination treatment of glabellar rhytids. Int J Cosmetic Surg 1999;7:14 7. Feller G, Bayerl C, Jung EG, Rzany B. Treatment of dynamic facial wrinkles with Botulinum toxin type A (Dysport). Aktuelle Dermatologie 2000;26:65 9. Heckmann M, Schon-Hupka G. Quantification of the efficacy of botulinum toxin type A by digital image analysis. J Am Acad Dermatol 2001;45:508 14.
Dermatol Clin 22 (2004) 221 226
Comparison of botulinum toxins A and B in the treatment of facial rhytides

Neil S. Sadick, MDa,*, Seth L. Matarasso, MDb
a
Department of Dermatology, Weill Medical College, Cornell University, 772 Park Avenue, New York, NY 10021, USA b Department of Dermatology, University of California School of Medicine, 490 Post Street, Suit 700, San Francisco, CA 94102, USA
Facial lines and wrinkles are caused by many variables, including intrinsic aging, photodamage, gravity, trauma, subcutaneous atrophy, and the activity of underlying facial muscles. Hyperfunctional facial lines are the result of the skin pleating when the underlying muscles contract chronically. These lines can be problematic to the patient because they can be the earliest signs of aging and can be misinterpreted as manifestations of negative emotion (ie, anger, anxiety, and sadness); fatigue; or stress. Historically, treatment has been aimed at improving the cutaneous defect with soft tissue augmentation, resurfacing, or facial surgery. These treatments, however, do not address the underlying musculature that causes the lines and can have prolonged morbidity and high risk potential. Botulinum toxin injections have become the most popular aesthetic procedure for both men and women in the United States [1]. The first reported use of botulinum toxin for facial rhytides was in 1992 [2]. It was fortuitously observed that there was a loss of facial wrinkles in patients whose periocular muscles were injected with botulinum toxin type A for benign essential blepharospasm. These findings were subsequently corroborated by others [3 5]. The mechanism
of action of botulinum toxin resides in its ability to immobilize striated muscles by inhibiting release of acetylcholine at the neuromuscular junction. In 2002, following substantial evidence from clinical studies and unparalleled patient acceptance, the Food and Drug Administration approved Botox for the temporary treatment of moderate-to-severe glabellar wrinkles in patients 65 years of age or younger. The type B serotype of botulinum toxin (Myobloc) has a similar mechanism of action and was approved by the Food and Drug Administration in 2000 for the treatment of cervical dystonia [6,7]. Although not currently approved for cosmetic use, Myobloc has also been used for off-label purposes with good results.
Pharmacology Botulinum toxins are produced by the anaerobic spore-forming bacterium Clostridium botulinum, and are among the most potent biologic substances found in nature [8 10]. Seven immunologically distinct serotypes of botulinum toxin are known to exist, designated A, B, C, D, E, F, and G. The different serotypes do not cross-react, and ultimately they have the same effect at the neuromuscular junction, but subtle differences in their molecular weight, biosynthesis, and site of action may contribute to differences in clinical efficacy. Botulinum toxins are large protein complexes that consist of a neurotoxin and other nontoxic proteins that exert their effect at the neuromuscular junction by inhibiting release of acetylcholine. The Botox com-
At the time this manuscript was developed, Dr. Sadick and Dr. Matarasso were not consultants for either Elan Pharmaceuticals or Allergan, Inc. No financial support was received for any studies involving botulinum toxins A or B. * Corresponding author. E-mail address: nssderm@sadickdermatology.com (N.S. Sadick).
222
N.S. Sadick, S.L. Matarasso / Dermatol Clin 22 (2004) 221226
plex has a total molecular weight of approximately 900 kd, whereas Myobloc is smaller at approximately 700 kd. These toxin complexes are most stable in slightly acidic conditions (pH 5.7) and dissociate in alkaline conditions. Within the large complex the active neurotoxins are synthesized as 150-kd dichain molecules consisting of a heavy chain (around 100 kd) and a light chain (around 50 kd) linked by a disulfide bond [11,12]. The neurotoxicity is a three-step process that includes neurotoxin binding to specific membrane receptors on presynaptic cholinergic neurons, toxinreceptor complex internalization by endocytosis into nerve terminals, and vesicle lysis with inhibition of acetylcholine release from inside the cell [13]. The heavy chain is responsible for irreversible binding of the toxin to specific acceptors on the neuronal cell membrane. Each serotype binds to a unique acceptor, which accounts for a lack of cross-neutralization among the serotypes. Following intramuscular injection, botulinum toxins cause a flaccid muscle paralysis with an onset of approximately 3 to 7 days. Muscle reanimation recovers through terminal sprouting of motor axons and formation of new motor end plates [14]. The sprouts grow rapidly, joining to new end plates formed at the same time along the damaged neuromuscular junction. After a period of remodeling the new motor end plates become activated, completely restoring muscle function. Recovery generally occurs in 3 to 6 months with reappearance of rhytides, although bulk sprouting and remodeling may continue for up to 3 years [15]. Reinjection of the muscle is necessary to maintain clinical effects and produce disuse muscle atrophy.
Formulations Botox is available in a vacuum-dried vial with 100 units of neurotoxin at a pH of 7 and requires reconstitution with saline before use. Myobloc is produced as a ready-to-use liquid formulation with a pH of 5.6 to stabilize the complex. It is available in vials of 2500, 5000, and 10,000 units, each with a concentration of 5000 units/mL. Each vial is actually overfilled, containing more type B toxin than is specified on the label. The toxins are expressed in terms of units, which refer to biologic activity or potency and not a specific weight or volume of protein. Specifically, one unit is defined as the amount of toxin that is lethal in 50% of female Swiss-Webster mice after intraperitoneal injection (mouse LD50 bioassay). Because of variations in the sensitivity of different species to each toxin serotype and the potency assay used, however, individualized dose-ranging studies in humans are necessary for each toxin serotype, and a conversion ratio can be imprecise [16]. Botox must be stored at or below 5C before the toxin is reconstituted with 0.9% saline. It is recommended that the reconstituted toxin be used as soon as possible, because loss of potency has been reported to occur over time [15]. Botox reportedly tends to be labile, and mechanical disruption and prolonged storage can inactivate the product. Recently, however, it was found that Botox retains its efficacy for at least 6 weeks following reconstitution if stored at 4C [26]. Myobloc is kept refrigerated at 2C to 8C and is stable in this environment for up to 3 years [13]. Clearly, storage and stability are important parameters to consider in toxin selection.
Immunoresistance Comparison studies As a protein, botulinum toxin is capable of eliciting an immune response [16]. Patients can develop neutralizing antibodies that prevent clinical effects. Resistance has been reported in 3% to 5% of patients with cervical dystonia who were treated with large doses of botulinum toxin type A (up to 1200 units) [17,18]. In patients treated for aesthetic purposes that require significantly lower doses, the risk of developing resistance is low and has not been well-documented. Because the botulinum toxin serotypes do not crossneutralize, patients who become resistant to one serotype may benefit from treatment with another serotype. The most significant risk factors associated with development of antibodies include injection of high doses of toxin and increased frequency of administration [17,18]. Despite its relatively recent Food and Drug Administration approval for cervical dystonia, Myobloc has been evaluated in several small clinical trials for aesthetic purposes. In these settings, most studies have been conducted to establish dosing guidelines. To date, however, definitive doses for effectively treating hyperfunctional facial lines have not been well-established. Ramirez et al [19] evaluated Myobloc in 24 subjects with facial rhytides. A total of 82% had been treated previously with Botox, although not within 6 months before the study. Patients received 200 to 400 units of Myobloc per injection site (total dose 400 to 800 units). The three sites injected included the frontalis, corrugator supercilium, and the orbicularis
223
oculi muscles. Improvement in facial rhytides was assessed using two different scales: the Wrinkle Improvement Scale (0 indicated no improvement and 3 indicated significant improvement) and the Rated Numeric Kinetic Line Scale. The Rated Numeric Kinetic Line Scale assessment was found to characterize wrinkle severity more objectively because this scale encompasses a description of wrinkles both at rest and maximum frown. A score of 1 reflects no wrinkles at rest, which become fine lines with facial animation; a score of 4 denotes deep lines at rest, which become deep furrows with facial animation. Subjects were evaluated in repose and animation before and after injection at weeks 1, 2, 4, 8, and 12. Photographs were also obtained. All subjects had a relatively rapid onset of near complete paresis within 72 hours, and in many cases, within 24 hours. Scores on the Wrinkle Improvement Scale and Rated Numeric Kinetic Line Scale were moderately to significantly improved by two to three points following Myobloc treatment. The duration of effect was suboptimal, however, with a mean of 8 weeks. There were no adverse events, including dysphagia, dyspepsia, or dry mouth. This preliminary study showed that Myobloc is effective in treating facial lines of the glabella, forehead, and crows feet areas, but the authors concluded that doses higher than 400 to 800 units are necessary for a longer duration of action [19]. Pain on injection, usually described as a slight stinging sensation, has been reported to occur with Myobloc injections. In the study by Ramirez et al [19], the patients were also evaluated for pain associated with injection using the McGill Pain Scale. The McGill Pain Scale is a scale ranging from 0 (signifying no pain) to 5 (signifying excruciating pain). At the time of treatment, subjects were asked to rate the pain of Myobloc injections and to compare it to the pain of Botox injections. On average, Myobloc was found to be slightly more painful than the memory of Botox injections (2.3 versus 1.6, respectively). No patient indicated, however, that the discomfort would prevent him or her from undergoing a repeat injection with Myobloc [19]. The slightly higher pain rating with Myobloc reflects its acidic formulation. A much smaller open-label study investigated preliminary doses of Myobloc and also compared the effects of the drug with those of Botox in the treatment of glabellar lines [20]. Subjects received 1000 units (N = 4) or 2000 units (N = 4) of Myobloc, or 20 units of Botox (N = 5), divided equally over five sites (one injection at the procerus muscle and two injections at each of the inferomedial and superolateral aspects of the corrugator muscles). Subjects were photographed before and after injection, and glabellar line severity
was rated as absent, mild, moderate, or severe, both in a relaxed state and at maximum frowning. Results showed that both toxins were effective in treating glabellar frown lines. At the doses used, however, Myobloc had a more rapid onset of action by 1 to 2 days, but Botox had a longer duration of effect. The duration of effect of 20 units of Botox was at least 16 weeks, whereas it was 8 to 10 weeks with 1000 units of Myobloc and 10 to 12 weeks with 2000 units of Myobloc. This study suggests that the duration of Myobloc may be dose-dependent. Because limited adverse events were reported, the authors concluded that higher doses of Myobloc should be studied. Sadick [21,22] conducted two open-label studies using higher doses of Myobloc for treatment of glabellar wrinkles. Both studies were similar in design. The first study evaluated 1800 units of Myobloc (N = 30). The second study used higher doses of Myobloc: 2400 units (N = 16) and 3000 units (N = 18). Doses were divided equally among six injection sites: two into the procerus, two into each corrugator supercilia, and two into the orbicularis oculi muscle bilaterally. Most subjects in all treatment groups had not been previously treated with Botox. In the first study (using 1800 units of Myobloc), efficacy was assessed using photography and a clinical scoring system that was completed by both subjects and physicians: 0 noted marked frowning ability, 1 denoted partial frowning ability, and 2 denoted complete inability to frown because of paralysis. The second study used photography, the same clinical scoring system, and the Rated Numeric Kinetic Line Scale to assess efficacy. Subjects returned to the office daily postinjection until the effects of Myobloc were observed, then weekly thereafter. Both studies found Myobloc to be effective in treating glabellar frown lines based on photography (Fig. 1), patient satisfaction, and improvement in assessment scores. Overall, Myobloc was found to have a very rapid onset of action and a dose-related duration of response. The mean duration of effect was 8 weeks with 1800 units, 9.6 weeks with 2400 units, and 10.4 weeks with 3000 units. Lid ptosis was reported in one patient who received 2400 units and in one patient who received 3000 units. Headache and mild pain on injection were also reported. Overall, Myobloc was considered safe, and there was no increase in adverse effects with the higher doses. Matarasso [23] completed a study of 10 women comparing Myobloc and Botox in the lateral ocular canthal region [23]. All patients had been without botulinum toxin treatment in all areas for at least 6 months before undertaking the study. Based on the neurologic literature with cervical dystonia patients and the reported lowest conversion ratio of 1 unit of
224
Fig. 1. Standardized photographs of a patient with glabellar wrinkles (A) at baseline and (B) 12 weeks after Myobloc injections (total dose 3000 units: 600 units into the procerus, 2400 units into the corrugator supercilii and orbicularis oculi muscles).
Botox to 50 units of Myobloc, a double-blind trial was undertaken primarily to evaluate duration of rhytid reduction [23,24]. Three aliquots of 5 units (total 15 units) of Botox were injected into one set of crows feet, and three aliquots of 250 units of Myobloc (750 units) were similarly injected into the contralateral canthal rhytides. The injections were blinded to both the physician and patient. Evaluation was undertaken at 7, 30, 60, and 90 days, and results were based on photographic images at rest and maximal muscle contraction (Fig. 2), and by patient and physician assessment. On unblinding of the solutions, the side treated with Myobloc was found to have a quicker onset of action (mean 2.3 days) and a shorter duration of action (mean 6.4 weeks). Conversely, the crows feet that were treated with Botox had a mean onset of action of 3.7 days and an average duration of 12.7 weeks. Other than a slightly higher degree of discomfort on injection at a Myobloc-treated site, there were no reported adverse events.
To date, the highest doses of Myobloc to be used for aesthetic purposes are 3125 units for glabellar lines and 3750 units for the frontalis region, as reported in an open-label study by Spencer et al [25]. Twenty-six patients received 1875, 2500, or 3125 units of Myobloc into the glabellar defect. Eighteen patients received 2250, 3000, or 3750 units of Myobloc into the frontalis muscle. Results were comparable with other Myobloc studies for wrinkles: a rapid onset and a doserelated duration. At these doses, there were no reports of lid or brow ptosis. Similar to all other reports, Myobloc seemed to yield a very uniform paralysis, which may reflect the distinct diffusion characteristics of the type B toxin [12]. The studies of Myobloc for the treatment of both cervical dystonia and facial wrinkles clearly show that it is safe, effective, has a very rapid onset of action, and has a dose-related duration of effect. It is anticipated that higher doses of Myobloc will produce an even longer duration of response in the treatment of facial
Fig. 2. Preinjection (A) and postinjection (B) of 750 units of Myobloc into the lateral fibers of the orbicularis oculi muscle.
N.S. Sadick, S.L. Matarasso / Dermatol Clin 22 (2004) 221226 Table 1 Provisional dosing guidelines for botulinum toxin injections for facial rhytides Botox Site Glabellar complex Forehead Muscle Procerus, corrugator supercilia Frontalis Adverse reaction Lid ptosis, brow ptosis, headache Brow ptosis, lid ptosis, quizzical brow (lateral brow elevation) Ecchymosis, diplopia Units 20 35 No. of injections 56 Myobloc Units 2000 3000
225
No. of injections 3
20 40
1000 2500
36
Crows feet (periorbital)
Orbicularis oculi
10 15 per side
3 per side
750 1500 per side
3 per side
wrinkles. Effective doses of Botox and Myobloc in the treatment of different types of facial wrinkles are speculated on in Table 1; however, these doses are based only on preliminary studies.
[3]
[4]
Summary
[5]
Facial rhytides of the upper one third of the face are common aesthetic concerns, and are caused principally by overactivity of the underlying facial musculature. Botulinum toxin, which acts by causing flaccid paralysis of facial mimetic muscles, has become a treatment of choice for the management of these hyperfunctional facial lines. Two antigenically distinct serotypes have been developed and are currently available for commercial use in the United States. There are major differences between the two toxins in terms of pharmacology and formulation that account for clinical differences, and precise interconversion is not well-established. Nevertheless, in these preliminary studies, Myobloc seems to have a faster onset of action and potentially a more even and smoother paralysis. The shorter duration of action of Myobloc seems to be dose-related. It is clear that both agents safely and effectively reduce dynamic facial rhytides. Based on individual efficacy, safety, diffusion pattern, onset, and duration, ultimately, with further trials and clinical experience, it is conceivable that each toxin will have its own set of indications.
[6]
[7]
[8] [9] [10]
[11] [12]
[13]
References
[1] ASAPS. 2000 Statistics on cosmetic surgery. New York: American Society of Aesthetic and Plastic Surgery; 2001. [2] Carruthers DA, Carruthers JA. Treatment of glabellar
[14]
[15]
frown lines with Clostridium botulinum A exotoxin. J Derm Surg Oncol 1992;18:17 21. Blitzer A, Brin MF, Keen MF, Aviv JE. Botulinum toxin for the treatment of hyperfunctional lines of the face. Arch Otolaryngol Head Neck Surg 1993;119:1018 22. Guyuron B, Huddleston SW. Aesthetic indications for botulinum toxin injection. Plast Reconstr Surg 1994;93: 913 8. Keen M, Blitzer A, Aviv J, Binder W, Prystowsky J, Smith H, et al. Botulinum toxin A for hyperkinetic facial lines: results of a double-blind placebo-controlled study. Plast Reconstr Surg 1999;94:94 9. Brashear A, Lew MF, Dykstra DD, Comella CL, Factor SA, Rodnitzky RL, et al. Safety and efficacy of Neurobloc (botulinum toxin type B) in type A-responsive cervical dystonia. Neurology 1999;53:1439 46. Brin MF, Lew MF, Adler CH, Comella CL, Factor SA, Jankovic J, et al. Safety and efficacy of Neurobloc (botulinum toxin type B) in type A-resistant cervical dystonia. Neurology 1999;53:1431 8. Kessler KR, Benecke R. Botulinum toxin: from poison to remedy. Neurotoxicology 1997;18:761 70. Lamanna C. The most poisonous poison. Science 1969; 130:763 72. Arnon SS, Schechter R, Inglesby TV, Henderson DA, Bartlett JG, Ascher MS, et al. Botulinum toxin as a biological weapon. JAMA 2001;285:1059 71. Sakaguchi G. Clostridium botulinum toxins. Pharmacol Ther 1982;19:165 94. Callaway JE, Arezzo JC, Grethlein AJ. Botulinum toxin type B: an overview of its biochemistry and preclinical pharmacology. Semin Cutan Med Surg 2001;20: 127 36. Simpson LL. Molecular pharmacology of botulinum toxin and tetanus toxins. Annu Rev Pharmacol Toxicol 1986;26:427 53. Olney RK, Aminoff MJ, Gelb DJ, Lowenstein DH. Neuromuscular effects distant from the site of botulinum neurotoxin injection. Neurology 1988;38:1780 3. Fagien S, Brandt FS. Primary and adjunctive use of botulinum toxin type A (Botox) in facial aesthetic surgery. Clin Plast Surg 2001;28:127 48.
226
N.S. Sadick, S.L. Matarasso / Dermatol Clin 22 (2004) 221226 toxin type B (Myobloc) at doses of 2400 and 3000 units for the treatment of glabellar wrinkles. Dermatol Surg 2003;29:501 7. Matarasso SL. Comparison of botulinum toxin types A and B: a bilateral double-blind randomized evaluation in the treatment of canthal rhytides. Dermatol Surg 2003;29:7 13. Matarasso SL, Matarasso A. Treatment guidelines for botulinum toxin type A for the periocular region and a report of partial lip ptosis following injections into the lateral canthal rhytides. Plast Reconstr Surg 2001;108: 208 14. Spencer JM, Gordon M, Goldberg DJ. Botulinum B treatment of the glabellar and frontalis regions: a doseresponse analysis. J Cosmet Laser Ther 2002;4:19 23. Hexsel DM, De Almeida AT, Rutowitsch M, De Castro IA, Silveira VL, Gabatto DO, et al. Multicenter, double-blind study of the efficacy of injections with botulinum toxin Type A reconstituted up to six consecutive weeks before application. Dermatol Surg 2003; 29:523 9.
[16] Greene P, Fahn S, Diamond B. Development of resistance to botulinum toxin type A in patients with torticollis. Mov Disord 1994;9:213 7. [17] Jankovic J, Schwartz KS. Response and immunoresistance to botulinum toxin injections. Neurology 1995;45: 1743 6. [18] Zuber M, Sebald M, Bathien N, de Recondo J, Rondot P. Botulinum antibodies in dystonic patients treated with type A botulinum toxin: frequency and significance. Neurology 1993;43:1715 8. [19] Ramirez AL, Reeck J, Maas CS. Botulinum toxin type B (Myobloc) in the management of hyperkinetic facial lines. Otolaryngol Head Neck Surg 2002;126:459 67. [20] Lowe NJ, Yamauchi PS, Lask GP, Patnaik R, Moore D. Botulinum toxins types A and B for brow furrows: preliminary experiences with type B toxin dosing. J Cosmet Laser Ther 2002;4:15 8. [21] Sadick NS. Botulinum toxin type B (Myobloc) for glabellar wrinkles: a prospective open-label response study. Dermatol Surg 2003;28:817 21. [22] Sadick NS. Prospective open-label study of botulinum
[23]
[24]
[25]
[26]

2004, Vol.22, Issues 2, The Clinical Use of Botulinum Toxin

Загружено:

Сведения о документе

Авторское право

Доступные форматы

Поделиться этим документом

Поделиться или встроить документ

Параметры публикации

Этот документ был вам полезен?

Это неприемлемый материал?

Авторское право:

Доступные форматы

2004, Vol.22, Issues 2, The Clinical Use of Botulinum Toxin

Загружено:

Авторское право:

Доступные форматы

Dermatol Clin 22 (2004) ix

The clinical use of botulinum toxin

Arnold W. Klein, MD Guest Editor

Dermatol Clin 22 (2004) 131 133

Development of botulinum toxin therapy

E-mail address: abs@ski.org

A.B. Scott / Dermatol Clin 22 (2004) 131133

A.B. Scott / Dermatol Clin 22 (2004) 131133

Dermatol Clin 22 (2004) 135 136

Dilution, storage, and electromyographic guidance in the use of botulinum toxins

E-mail address: dralan@pacbell.net

A.M. Mantell / Dermatol Clin 22 (2004) 135136

8 Centigrade for a maximum of 4 hours to ensure that it remains sterile [11].

Dermatol Clin 22 (2004) 137 144

Botulinum toxin type A for the treatment of glabellar rhytides

A. Carruthers, J. Carruthers / Dermatol Clin 22 (2004) 137144

Fig. 2. Glabellar frown lines.

A. Carruthers, J. Carruthers / Dermatol Clin 22 (2004) 137144

A. Carruthers, J. Carruthers / Dermatol Clin 22 (2004) 137144

Fig. 4. Injection sites for the treatment of glabellar rhytides.

A. Carruthers, J. Carruthers / Dermatol Clin 22 (2004) 137144

A. Carruthers, J. Carruthers / Dermatol Clin 22 (2004) 137144

A. Carruthers, J. Carruthers / Dermatol Clin 22 (2004) 137144

Dermatol Clin 22 (2004) 145 149

Botox for the eyes and eyebrows

E-mail address: melissa.hollis@doctorklein.md

A.W. Klein / Dermatol Clin 22 (2004) 145149

Fig. 1. Understanding facial anatomy is critical to the successful use of Botox.

A.W. Klein / Dermatol Clin 22 (2004) 145149

Fig. 3. Brow dynamics.

A.W. Klein / Dermatol Clin 22 (2004) 145149

A.W. Klein / Dermatol Clin 22 (2004) 145149

Dermatol Clin 22 (2004) 151 158

Botulinum toxin A in the mid and lower face and neck

* Corresponding author. E-mail address: drjean@carruthers.net (J. Carruthers).

J. Carruthers, A. Carruthers / Dermatol Clin 22 (2004) 151158

J. Carruthers, A. Carruthers / Dermatol Clin 22 (2004) 151158

J. Carruthers, A. Carruthers / Dermatol Clin 22 (2004) 151158

Fig. 1. Treatment of depressor anguli oris with botulinum type A.

J. Carruthers, A. Carruthers / Dermatol Clin 22 (2004) 151158

J. Carruthers, A. Carruthers / Dermatol Clin 22 (2004) 151158

J. Carruthers, A. Carruthers / Dermatol Clin 22 (2004) 151158

Dermatol Clin 22 (2004) 159 166

F.S. Brandt, A. Boker / Dermatol Clin 22 (2004) 159166

F.S. Brandt, A. Boker / Dermatol Clin 22 (2004) 159166

F.S. Brandt, A. Boker / Dermatol Clin 22 (2004) 159166

Fig.5. Treating physicians perspective of platysmal band injection.

F.S. Brandt, A. Boker / Dermatol Clin 22 (2004) 159166

F.S. Brandt, A. Boker / Dermatol Clin 22 (2004) 159166

Dermatol Clin 22 (2004) 167 175

* Corresponding author. E-mail address: Andrew.m.Blumenfeld@kp.org (A.M. Blumenfeld).

A.M. Blumenfeld et al / Dermatol Clin 22 (2004) 167175

+++ +++ ++ +++ + ++ ++ +++ ++ + +

+++ +++ ++ +++ + +++ +++ ++ ++ + +

A.M. Blumenfeld et al / Dermatol Clin 22 (2004) 167175

Fig. 2. Injection site: temporalis and masseter muscles.

Fig. 1. Injection sites: glabellar and frontal regions.

Fig. 3. Injection site: occipital, suboccipital, and trapezius muscles.

A.M. Blumenfeld et al / Dermatol Clin 22 (2004) 167175

Mauskop and Basedo (2000)

Retrospective chart review (N=27)

Miller and Denny (2002)

Average dose 63.2 units

Smuts and Barnard (2000)