ORIGINAL ARTICLES
Treatment of Glabellar Frown Lines with C . Botulinum-A Exotoxin JEAN D.A. CARRUTHERS, MD, FRCS(C), FRCS(Eng) J. ALASTAIR CARRUTHERS, MA, BM, BCh, FRCP(C), FRCP(Lond)
Eighteen patients with glabellar frown lines were treated with C. botulinum-A exotoxin. Sixteen of the 17 patients followed showed improvement for periods rangingfrom 3 months to 11 months. Side-effects were minimal and transient. Because C . botulinum-A exotoxin therapy of glabellar frown lines treats the underlying cause of these lines, it is more effective than soft tissue augmentation although this improvement is temporary. Treatment with C. botulinum-A exotoxin is a simple, safe procedure. J Dermatol Surg Oncol 1992;18:17- 21.
labellar frown lines are common cosmetic deformities. The facial expressions involving ex' aggeration of these lines indicate socially less acceptable emotions especially anger, fear, sadness, and anxiety. Individuals with exaggerated glabellar frown lines often complain that others assume that they are angry when they are not. As a result, treatment for these lines is commonly requested. These lines are caused by action of the underlying facial musculature. This is thought to be because of contraction of corrugator superciliaris, but other muscle groups may be significant such as those directly beneath the furrows recently described by Pierard and Lapiere.' However, surgical treatment of these muscles involves a major surgical procedure with significant side-effects and complications. In consequence, treatment is largely aimed at soft tissue augmentation by injecting collagen, silicone, or autologous fat beneath the line. We wish to present an alternative treatment for glabellar frown lines that, like soft tissue augmentation, is a simple injection From the Department ofOpthalmology(lDAQ and Division ofDennatology (IAQ, University of British Columbia, Vancouver, British Columbia, Canada. Address reprint requests to: Dr. Jean Carruthers, 210-2730 Commercial Drive, Vancouver, British Columbia, Canada V5N 5P4.
0 1992 by Elsevier Science Publishing Co., Inc. 0148-0812/92/$3.50
but, like surgery, is aimed at the underlying muscular cause rather than the cutaneous effect. This treatment involves the injection of Clostridium botulinum-A exotoxin into the appropriate muscles. C. botulinum-A exotoxin produces reversible paralysis of striated muscles. This property has been used in the management of a number of conditions, especially benign essential blepharospasm, strabismus, and hemifacial spasm. During treatment of patients with blepharospasm, it was noted that glabellar frown lines would be improved by C. botulinum toxin injection. Therefore, treatment of glabellar frown lines was attempted in this study.
Materials and Methods Eighteen white patients were enrolled into this study. Seventeen were female and one was male. Their ages ranged from 34 to 51, with an average age of 41.4 years. Each patient underwent a full opthalmologic examination and was fully informed about the biology, mode of action, and potential complications of purified C . botuh u m - A exotoxin. Informed consent was obtained and recorded for each patient in the study. Until September 1990, the purified C . botulinum-A exotoxin was obtained from Dr. Alan Scott (Smith Kettlewell Institute of Visual Sciences, San Francisco, CA, USA) as part of a multicenter trial of C . botulinum toxin therapy of strabismus, benign essential blepharospasm, hemifacial spasm, and spastic lower eyelid entropion. After September 1990 it has been obtained from Allergan Pharmaceuticals (Markham, ON, Canada L3R 9R9). The toxin is kept freeze dried and frozen at - 4°C until ready for use. Each vial contains 100 units of toxin. It is diluted just prior to use with 1 mL of normal saline without preservative. Each 0.1 mL of the solution therefore contains 10 units. The compound in solution is very unstable and must be used within several hours of prepara-
17
J Dermatol Surg Oncol 1992;18:17- 21
18 CARRUTHERS AND CARRUTHERS
A
Figure 1 . A schematic representation of the important anatomic relationships of the corrugator superciliaris muscle and the technique of injection.
tion. Special precautions for handling and autoclaving of used syringes and vials are prescribed. Patients are treated in the seated position. The glabella is cleaned with an alcohol swab. For injections into the brow furrow, the patient is asked to frown and maintain this expression throughout the procedure. The 30-gauge needle on the tuberculin syringe is inserted at the superior portion of the furrow and the needle passed down the vertical length of the furrow in a deep subdermal plane. The plunger is depressed as the needle is withdrawn so that toxin is evenly distributed along the length of the furrow. For injections into the corrugator muscle, the patient also is asked to frown. The contracted corrugator muscle is palpated above the inner canthus. The injection is made into the belly of the corrugator while the patient frowns (Figure 1). The initial dosage was 10 to 12.5 U/furrow and the final dose was 10 to 20 U/furrow or per corrugator. Bilateral furrows were treated at the same treatment session.
Results Figures 2 and 3 demonstrate the effect of successful injection of C. botulinum toxin into the corrugator muscles. Figure 2A shows the patient at rest with a glabellar frown line. When asked to frown (Figure 2B) the line becomes a
B Figure 2. A 34 year old female with a glabellar frown line prior to injection: A) at rest and B) when asked to frown.
deep furrow. In addition, the eyebrow moves inferomedially, there is bunching-up of the soft tissue overlying the contracting corrugator muscle, and there is increased "hooding" of the lateral part of the palpebral aperture as a result of contraction of part of orbicularis oculi. Figure 3A shows the same patient 1 week after injection of 15 units of C. botulinum toxin into each corrugator muscle. The line is improved at rest (Figure 3A) but the change is most obvious when the patient is asked to frown (Figure 3B). Increased hooding laterally shows that the patient is indeed attempting to frown, but there are none of the medial features of the frown indicating paralysis of the corrugator muscles. Table 1 shows the numbers of injection sessions that each patient underwent. Nine of the 10 patients who had multiple injections needed a second injection within 3 months of the first. All patients had their first injection into the furrow itself. Six patients had one or more subsequent injection sessions into the corrugator muscle. After the first 3-month period of follow-up had passed, the frequency of injections was every 4 months
CARRUTHERS AND CARRUTHERS GLABELLAR FROWN LINES
Dermatol Surg Oncol 1992;18:17- 21
19
Table 2. Time Between Injection Sessions in Patients who Have Undergone Six or More Sessions Number of Injections (Patien ts)
A
B Figure 3. The same individual as in Figure 2, 1 week after injection of 15 U of C . botulinum-A exotoxin into each corrugator muscle: 4) at rest and B) when asked to frown.
for most patients. In one patient, after the sixth injection, there was an interval of 11months prior to the next injection. Three additional patients had intervals ranging between 7 and 10 months after their seventh or more injection (Table 2).
Interval Between Sessions (mo)
The overall response to injection was analyzed by objective and subjectivecriteria. Objective analysis included cutaneous appearance (smooth -no furrow visible, minimal line, residual but improved line, or no response). Of those who responded, six had brows that became completely smooth, two had residual minimal lines; and eight still had a discernible brow crease but it was less deep. One patient did not respond at all to injection. One patient was lost to follow-up. On a subjective patient rating scale of 0 to 7 where 7 was the highest correlation with patient expectation (Table3), 13of 18patients felt the response was 5 out of 7 or better. Two patients thought they did not get a good enough response with the toxin and two further patients felt that they had a response that was just over half as good as they felt it would be (4 out of 7). Complications after injection were infrequent (Table 4). One patient each had a transient brow ptosis and lid ptosis with complete recovery in both cases after 10 to 14 days. Two patients had minimal headache or "tightness" immediately following the injection that was gone by the following day. One patient had numbness at the injection site that resolved after a few days and did not recur after subsequent injections.
Table 3. Subjective Patient Response to C . botulinum Toxin Injection for Brow Furrows' Table 1. Numbers of Patients Having Single or Multiple Injection Sessions Number of lnjections
Number of Patients
1 2
8 1
3
5
3 1 0
6
1
7 8 9
1
4
1
2
Patients Scale
(N= 18)
0 1 2 3 4
5 6
7 Lost to follow-up
*Based on a scale, 0 to 7, where 7 was an exact correlation between subjective expectations and perceived beneficial results.
J Dermatol Surg Oncol
20 CARRUTHERS AND CARRUTHERS
1992;18: 17- 21
Table 4. Complications of C . botulinum Toxin Injection Treatment of Glabellar Frown Lines ~
~
Complications
N
Ptosis Brow Lid Transient headache Transient numbness
1 1 2 1
people have received multiple injection^.^ There is no evidence of antibody production by patients who have received repeated doses of C. botulinum toxin or of any systemic complications during the 64 years of continued
the rap^.^
Eight patients received both C. botulinum toxin and collagen injections. Six patients received collagen injection prior to C. botulinum chemodenervation. One patient was allergic to collagen and the other five also preferred the C. botulinum toxin effect. Two patients had collagen injections after C. botulinum toxin. One of these preferred the combination and one preferred collagen because she was concerned about the systemic toxicity of C. botu1inu m -A exotoxin. Not all patients continued with C. botulinum toxin therapy. Reasons for discontinuation of therapy are given in Table 5. The principal reason patients gave for continuing with C. botulinum toxin injection therapy was that they liked not being able to frown with the attendant positive self image. The simplicity of treatment from the patients’ viewpoint was another significant reason.
Discussion The A exotoxin of C. botulinum is a powerful neuroparalytic agent. It acts by inhibiting calcium metabolism in the presynaptic neuron at the cholinergic neuromuscular junction. This prevents neuromuscular transmission after a latent period of 3 to 5 days and the effect lasts a variable length of time but on average 3 months.2In experimental models, C. botulinum toxin injection causes denervation and a t r ~ p h yFibrosis .~ and atrophy have also been observed in the orbicularis oculi in humans treated with C. botulinum toxin3 Over 9900 cases of essential blepharospasm have been treated worldwide and most of these
Table 5. Reasons for Discontinuing C . botulinum Toxin Therapy Reason
N
Moved away No response cost Complications (brow ptosis) Frightened of botulism Short response Continuing Total
3 1 1 1 1 1 10 18
In our study of the treatment of glabellar frown lines with C. botulinum-A exotoxin, we believe that the experience with benign essential blepharospasm has largely been repeated, This treatment has been effective for the majority of our patients and it is possible that, with further experimentation, it would produce improvement in all patients with glabellar frown lines as is the case in benign essential blepharospasm. The paralysis of the corrugator muscle lasts for 3 to 4 months once the initial adjustments of dose and injection site have been accomplished, It is interesting that our patients who have undergone this mode of therapy for longer find that the effects of the injection persist for 7 to 11 months. In treating a large series of patients with benign essential blepharospasm over 8 years, one of us (JDAC)has observed that these patients require retreatment at approximately 6monthly intervals after the first 3 years. This may be owing to a ”retraining” effect on the treated individuals because, as we have shown, they cannot frown during the period of chemodenervation. Alternatively, as with essential blepharospasm treatment, repeated injection into a small area may be damaging the muscle or its innervation. Side-effects have been minimal. One patient developed transient central brow ptosis after injection under the furrow presumably into the underlying vertically oriented muscle (frontalis) and was naturally reluctant to try injection into the corrugator area. A second patient had minimal unilateral lid ptosis after her second injection that lasted only 10 days. Some toxin must have migrated through her orbital septum to affect levator palpebrae superioris. The improvement in her glabellar frown lines persisted for the usual 4 months on that occasion and she recently had her ninth injection with no further problems with ptosis. The use of C. botulinum-A exotoxin for benign essential blepharospasm is analogous to its use for glabellar frown lines. The difference between them is that in treating benign essential blepharospasm, a larger dose of toxin is injected via multiple injections into the brow and also into orbicularis oculi. An 11% incidence of ptosis has been reportedZin series of benign essential blepharospasm injections, which is similar to the 2 of 18 patients in our series. This is usually transient and is because of inappropriate positioning of the toxin. Of greater concern is the report of ectropion, entropion, and keratoconjunctivitis because of exposure in benign essential blepharospasm patient^.^ This is because of injection into orbicularis
J Dermatol Surg Oncol
CARRUTHERS AND CARRUTHERS GLABELLAR FROWN LINES
1992;18:17-21
oculi, which is not part of the treatment of glabellar frown lines; therefore, these complications would not be expected to occur. The lack of side-effects with C. bofulinum-A exotoxin must be contrasted with soft tissue augmentation treatment in this area. Collagen, autologous fat, and silicone, if injected into the retinal circulation, will produce embolic necrosis of the retina and blindness. This has been reported with injectable collagen6and autologous By comparison, C. botulinum-A exotoxin is completely dissolved in sterile saline without preservative and the injection volume is small. In consequence it is extremely unlikely to produce embolic damage to the retina, optic nerve, or other surrounding structures. Allergy is a well-known complication of injectable collagen the rap^.^ Recent concern about adjuvant disease may limit the use of silicone.*0By contrast, immune reactions to C. botulinum-A exotoxin does not seem to occur.6 The relationship of C. botulinum-A exotoxin treatment to collagen treatment is interesting because this is currently the most widely used treatment of glabellar frown lines in North America. One of our patients was collagen allergic. Five had had previous treatment with collagen and preferred C. botulinum-A exotoxin. One patient with very deep glabellar frown lines found the combination of collagen and C. botulinum-A exotoxin to be more effective than either alone and one patient preferred collagen treatment because she believed it to be safer. We believe that we have shown that C. botulinum-A exotoxin is a safe and effective treatment for glabellar frown lines. We do not believe at present that it is the treatment of choice. Other treatments have been used for longer and in larger numbers of individuals. In addition, the relatively short duration of action of C. botulinum-A exotoxin is a nuisance to some patients who do not like having to return at this interval. Nonetheless, we have demonstrated that for some patients, especially those who are collagen-allergic or who are disinclined to un-
21
dergo surgery, C. botulinum-A exotoxin offers an alternative form of therapy for this common cosmetic problem.
References 1. Pierard GE, Lapiere CM. The microanatomical basis of facial frown lines. Arch Dermatol 1989;125:1090-92. 2. Carmthers JDA, Stubbs HA. Botulinum toxin for benign essential blepharospasm, hemifacial spasm and age-related lower eyelid entropion. Can J Neurol Sci 1987;14:42-5. 3. Therapeutics and Technology Assessment Committee of the American Academy of Neurology. The clinical usefulness of botulinum toxin-A in treating neurologic disorders. Report of the Therapeutics and Technology Assessment Committee of the American Academy of Neurology. Neurol 1990;40:1332-3. 4. Smith Kettlewell Institute of Visual Sciences. Botulinum toxin (OculinumR)study: IND-723. Patients treated as of 31 December 1989. San Francisco, CA. Smith Kettlewell Institute of Visual Sciences, 1990. 5. Tsui JK, Wong NLM, Wong E, Calne DB. Production of circulating antibodies to botulinum A toxin in patients receiving repeated injections for dystonia. (Abstract) Ann Neurol 1988;23:181. 6. Cucin RL, Barek D. Complications of injectable collagen implant. Plast Reconstr Surg 1983;71:731. 7. Driezen NG, Framm L. Sudden unilateral visual loss after autologous fat injection into the glabellar area. Am J Opthalmol 1989;107:85- 6. 8. Teimourian B. Blindness following fat injection. Plast Reconstr Surg 1988;92:361. 9. Stegman SJ,Chu S, Armstrong R. Adverse reactions to bovine collagen implant: clinical and histologic features. J Dermatol Surg Oncol 1988;13(Suppl 1):p 39. 10. Sergott TJ, Limoli JP, Baldwin CM, et al. Human adjuvant disease, possible autoimmune disease after silicone implantation: a review of the literature, case studies and speculation for the future. Plast Reconstr Surg 1986;78:104-14.
Treatment of Glabellar Frown Lines with C . Botulinum-A Exotoxin JEAN D.A. CARRUTHERS, MD, FRCS(C), FRCS(Eng) J. ALASTAIR CARRUTHERS, MA, BM, BCh, FRCP(C), FRCP(Lond)
Eighteen patients with glabellar frown lines were treated with C. botulinum-A exotoxin. Sixteen of the 17 patients followed showed improvement for periods rangingfrom 3 months to 11 months. Side-effects were minimal and transient. Because C . botulinum-A exotoxin therapy of glabellar frown lines treats the underlying cause of these lines, it is more effective than soft tissue augmentation although this improvement is temporary. Treatment with C. botulinum-A exotoxin is a simple, safe procedure. J Dermatol Surg Oncol 1992;18:17- 21.
labellar frown lines are common cosmetic deformities. The facial expressions involving ex' aggeration of these lines indicate socially less acceptable emotions especially anger, fear, sadness, and anxiety. Individuals with exaggerated glabellar frown lines often complain that others assume that they are angry when they are not. As a result, treatment for these lines is commonly requested. These lines are caused by action of the underlying facial musculature. This is thought to be because of contraction of corrugator superciliaris, but other muscle groups may be significant such as those directly beneath the furrows recently described by Pierard and Lapiere.' However, surgical treatment of these muscles involves a major surgical procedure with significant side-effects and complications. In consequence, treatment is largely aimed at soft tissue augmentation by injecting collagen, silicone, or autologous fat beneath the line. We wish to present an alternative treatment for glabellar frown lines that, like soft tissue augmentation, is a simple injection From the Department ofOpthalmology(lDAQ and Division ofDennatology (IAQ, University of British Columbia, Vancouver, British Columbia, Canada. Address reprint requests to: Dr. Jean Carruthers, 210-2730 Commercial Drive, Vancouver, British Columbia, Canada V5N 5P4.
0 1992 by Elsevier Science Publishing Co., Inc. 0148-0812/92/$3.50
but, like surgery, is aimed at the underlying muscular cause rather than the cutaneous effect. This treatment involves the injection of Clostridium botulinum-A exotoxin into the appropriate muscles. C. botulinum-A exotoxin produces reversible paralysis of striated muscles. This property has been used in the management of a number of conditions, especially benign essential blepharospasm, strabismus, and hemifacial spasm. During treatment of patients with blepharospasm, it was noted that glabellar frown lines would be improved by C. botulinum toxin injection. Therefore, treatment of glabellar frown lines was attempted in this study.
Materials and Methods Eighteen white patients were enrolled into this study. Seventeen were female and one was male. Their ages ranged from 34 to 51, with an average age of 41.4 years. Each patient underwent a full opthalmologic examination and was fully informed about the biology, mode of action, and potential complications of purified C . botuh u m - A exotoxin. Informed consent was obtained and recorded for each patient in the study. Until September 1990, the purified C . botulinum-A exotoxin was obtained from Dr. Alan Scott (Smith Kettlewell Institute of Visual Sciences, San Francisco, CA, USA) as part of a multicenter trial of C . botulinum toxin therapy of strabismus, benign essential blepharospasm, hemifacial spasm, and spastic lower eyelid entropion. After September 1990 it has been obtained from Allergan Pharmaceuticals (Markham, ON, Canada L3R 9R9). The toxin is kept freeze dried and frozen at - 4°C until ready for use. Each vial contains 100 units of toxin. It is diluted just prior to use with 1 mL of normal saline without preservative. Each 0.1 mL of the solution therefore contains 10 units. The compound in solution is very unstable and must be used within several hours of prepara-
17
J Dermatol Surg Oncol 1992;18:17- 21
18 CARRUTHERS AND CARRUTHERS
A
Figure 1 . A schematic representation of the important anatomic relationships of the corrugator superciliaris muscle and the technique of injection.
tion. Special precautions for handling and autoclaving of used syringes and vials are prescribed. Patients are treated in the seated position. The glabella is cleaned with an alcohol swab. For injections into the brow furrow, the patient is asked to frown and maintain this expression throughout the procedure. The 30-gauge needle on the tuberculin syringe is inserted at the superior portion of the furrow and the needle passed down the vertical length of the furrow in a deep subdermal plane. The plunger is depressed as the needle is withdrawn so that toxin is evenly distributed along the length of the furrow. For injections into the corrugator muscle, the patient also is asked to frown. The contracted corrugator muscle is palpated above the inner canthus. The injection is made into the belly of the corrugator while the patient frowns (Figure 1). The initial dosage was 10 to 12.5 U/furrow and the final dose was 10 to 20 U/furrow or per corrugator. Bilateral furrows were treated at the same treatment session.
Results Figures 2 and 3 demonstrate the effect of successful injection of C. botulinum toxin into the corrugator muscles. Figure 2A shows the patient at rest with a glabellar frown line. When asked to frown (Figure 2B) the line becomes a
B Figure 2. A 34 year old female with a glabellar frown line prior to injection: A) at rest and B) when asked to frown.
deep furrow. In addition, the eyebrow moves inferomedially, there is bunching-up of the soft tissue overlying the contracting corrugator muscle, and there is increased "hooding" of the lateral part of the palpebral aperture as a result of contraction of part of orbicularis oculi. Figure 3A shows the same patient 1 week after injection of 15 units of C. botulinum toxin into each corrugator muscle. The line is improved at rest (Figure 3A) but the change is most obvious when the patient is asked to frown (Figure 3B). Increased hooding laterally shows that the patient is indeed attempting to frown, but there are none of the medial features of the frown indicating paralysis of the corrugator muscles. Table 1 shows the numbers of injection sessions that each patient underwent. Nine of the 10 patients who had multiple injections needed a second injection within 3 months of the first. All patients had their first injection into the furrow itself. Six patients had one or more subsequent injection sessions into the corrugator muscle. After the first 3-month period of follow-up had passed, the frequency of injections was every 4 months
CARRUTHERS AND CARRUTHERS GLABELLAR FROWN LINES
Dermatol Surg Oncol 1992;18:17- 21
19
Table 2. Time Between Injection Sessions in Patients who Have Undergone Six or More Sessions Number of Injections (Patien ts)
A
B Figure 3. The same individual as in Figure 2, 1 week after injection of 15 U of C . botulinum-A exotoxin into each corrugator muscle: 4) at rest and B) when asked to frown.
for most patients. In one patient, after the sixth injection, there was an interval of 11months prior to the next injection. Three additional patients had intervals ranging between 7 and 10 months after their seventh or more injection (Table 2).
Interval Between Sessions (mo)
The overall response to injection was analyzed by objective and subjectivecriteria. Objective analysis included cutaneous appearance (smooth -no furrow visible, minimal line, residual but improved line, or no response). Of those who responded, six had brows that became completely smooth, two had residual minimal lines; and eight still had a discernible brow crease but it was less deep. One patient did not respond at all to injection. One patient was lost to follow-up. On a subjective patient rating scale of 0 to 7 where 7 was the highest correlation with patient expectation (Table3), 13of 18patients felt the response was 5 out of 7 or better. Two patients thought they did not get a good enough response with the toxin and two further patients felt that they had a response that was just over half as good as they felt it would be (4 out of 7). Complications after injection were infrequent (Table 4). One patient each had a transient brow ptosis and lid ptosis with complete recovery in both cases after 10 to 14 days. Two patients had minimal headache or "tightness" immediately following the injection that was gone by the following day. One patient had numbness at the injection site that resolved after a few days and did not recur after subsequent injections.
Table 3. Subjective Patient Response to C . botulinum Toxin Injection for Brow Furrows' Table 1. Numbers of Patients Having Single or Multiple Injection Sessions Number of lnjections
Number of Patients
1 2
8 1
3
5
3 1 0
6
1
7 8 9
1
4
1
2
Patients Scale
(N= 18)
0 1 2 3 4
5 6
7 Lost to follow-up
*Based on a scale, 0 to 7, where 7 was an exact correlation between subjective expectations and perceived beneficial results.
J Dermatol Surg Oncol
20 CARRUTHERS AND CARRUTHERS
1992;18: 17- 21
Table 4. Complications of C . botulinum Toxin Injection Treatment of Glabellar Frown Lines ~
~
Complications
N
Ptosis Brow Lid Transient headache Transient numbness
1 1 2 1
people have received multiple injection^.^ There is no evidence of antibody production by patients who have received repeated doses of C. botulinum toxin or of any systemic complications during the 64 years of continued
the rap^.^
Eight patients received both C. botulinum toxin and collagen injections. Six patients received collagen injection prior to C. botulinum chemodenervation. One patient was allergic to collagen and the other five also preferred the C. botulinum toxin effect. Two patients had collagen injections after C. botulinum toxin. One of these preferred the combination and one preferred collagen because she was concerned about the systemic toxicity of C. botu1inu m -A exotoxin. Not all patients continued with C. botulinum toxin therapy. Reasons for discontinuation of therapy are given in Table 5. The principal reason patients gave for continuing with C. botulinum toxin injection therapy was that they liked not being able to frown with the attendant positive self image. The simplicity of treatment from the patients’ viewpoint was another significant reason.
Discussion The A exotoxin of C. botulinum is a powerful neuroparalytic agent. It acts by inhibiting calcium metabolism in the presynaptic neuron at the cholinergic neuromuscular junction. This prevents neuromuscular transmission after a latent period of 3 to 5 days and the effect lasts a variable length of time but on average 3 months.2In experimental models, C. botulinum toxin injection causes denervation and a t r ~ p h yFibrosis .~ and atrophy have also been observed in the orbicularis oculi in humans treated with C. botulinum toxin3 Over 9900 cases of essential blepharospasm have been treated worldwide and most of these
Table 5. Reasons for Discontinuing C . botulinum Toxin Therapy Reason
N
Moved away No response cost Complications (brow ptosis) Frightened of botulism Short response Continuing Total
3 1 1 1 1 1 10 18
In our study of the treatment of glabellar frown lines with C. botulinum-A exotoxin, we believe that the experience with benign essential blepharospasm has largely been repeated, This treatment has been effective for the majority of our patients and it is possible that, with further experimentation, it would produce improvement in all patients with glabellar frown lines as is the case in benign essential blepharospasm. The paralysis of the corrugator muscle lasts for 3 to 4 months once the initial adjustments of dose and injection site have been accomplished, It is interesting that our patients who have undergone this mode of therapy for longer find that the effects of the injection persist for 7 to 11 months. In treating a large series of patients with benign essential blepharospasm over 8 years, one of us (JDAC)has observed that these patients require retreatment at approximately 6monthly intervals after the first 3 years. This may be owing to a ”retraining” effect on the treated individuals because, as we have shown, they cannot frown during the period of chemodenervation. Alternatively, as with essential blepharospasm treatment, repeated injection into a small area may be damaging the muscle or its innervation. Side-effects have been minimal. One patient developed transient central brow ptosis after injection under the furrow presumably into the underlying vertically oriented muscle (frontalis) and was naturally reluctant to try injection into the corrugator area. A second patient had minimal unilateral lid ptosis after her second injection that lasted only 10 days. Some toxin must have migrated through her orbital septum to affect levator palpebrae superioris. The improvement in her glabellar frown lines persisted for the usual 4 months on that occasion and she recently had her ninth injection with no further problems with ptosis. The use of C. botulinum-A exotoxin for benign essential blepharospasm is analogous to its use for glabellar frown lines. The difference between them is that in treating benign essential blepharospasm, a larger dose of toxin is injected via multiple injections into the brow and also into orbicularis oculi. An 11% incidence of ptosis has been reportedZin series of benign essential blepharospasm injections, which is similar to the 2 of 18 patients in our series. This is usually transient and is because of inappropriate positioning of the toxin. Of greater concern is the report of ectropion, entropion, and keratoconjunctivitis because of exposure in benign essential blepharospasm patient^.^ This is because of injection into orbicularis
J Dermatol Surg Oncol
CARRUTHERS AND CARRUTHERS GLABELLAR FROWN LINES
1992;18:17-21
oculi, which is not part of the treatment of glabellar frown lines; therefore, these complications would not be expected to occur. The lack of side-effects with C. bofulinum-A exotoxin must be contrasted with soft tissue augmentation treatment in this area. Collagen, autologous fat, and silicone, if injected into the retinal circulation, will produce embolic necrosis of the retina and blindness. This has been reported with injectable collagen6and autologous By comparison, C. botulinum-A exotoxin is completely dissolved in sterile saline without preservative and the injection volume is small. In consequence it is extremely unlikely to produce embolic damage to the retina, optic nerve, or other surrounding structures. Allergy is a well-known complication of injectable collagen the rap^.^ Recent concern about adjuvant disease may limit the use of silicone.*0By contrast, immune reactions to C. botulinum-A exotoxin does not seem to occur.6 The relationship of C. botulinum-A exotoxin treatment to collagen treatment is interesting because this is currently the most widely used treatment of glabellar frown lines in North America. One of our patients was collagen allergic. Five had had previous treatment with collagen and preferred C. botulinum-A exotoxin. One patient with very deep glabellar frown lines found the combination of collagen and C. botulinum-A exotoxin to be more effective than either alone and one patient preferred collagen treatment because she believed it to be safer. We believe that we have shown that C. botulinum-A exotoxin is a safe and effective treatment for glabellar frown lines. We do not believe at present that it is the treatment of choice. Other treatments have been used for longer and in larger numbers of individuals. In addition, the relatively short duration of action of C. botulinum-A exotoxin is a nuisance to some patients who do not like having to return at this interval. Nonetheless, we have demonstrated that for some patients, especially those who are collagen-allergic or who are disinclined to un-
21
dergo surgery, C. botulinum-A exotoxin offers an alternative form of therapy for this common cosmetic problem.
References 1. Pierard GE, Lapiere CM. The microanatomical basis of facial frown lines. Arch Dermatol 1989;125:1090-92. 2. Carmthers JDA, Stubbs HA. Botulinum toxin for benign essential blepharospasm, hemifacial spasm and age-related lower eyelid entropion. Can J Neurol Sci 1987;14:42-5. 3. Therapeutics and Technology Assessment Committee of the American Academy of Neurology. The clinical usefulness of botulinum toxin-A in treating neurologic disorders. Report of the Therapeutics and Technology Assessment Committee of the American Academy of Neurology. Neurol 1990;40:1332-3. 4. Smith Kettlewell Institute of Visual Sciences. Botulinum toxin (OculinumR)study: IND-723. Patients treated as of 31 December 1989. San Francisco, CA. Smith Kettlewell Institute of Visual Sciences, 1990. 5. Tsui JK, Wong NLM, Wong E, Calne DB. Production of circulating antibodies to botulinum A toxin in patients receiving repeated injections for dystonia. (Abstract) Ann Neurol 1988;23:181. 6. Cucin RL, Barek D. Complications of injectable collagen implant. Plast Reconstr Surg 1983;71:731. 7. Driezen NG, Framm L. Sudden unilateral visual loss after autologous fat injection into the glabellar area. Am J Opthalmol 1989;107:85- 6. 8. Teimourian B. Blindness following fat injection. Plast Reconstr Surg 1988;92:361. 9. Stegman SJ,Chu S, Armstrong R. Adverse reactions to bovine collagen implant: clinical and histologic features. J Dermatol Surg Oncol 1988;13(Suppl 1):p 39. 10. Sergott TJ, Limoli JP, Baldwin CM, et al. Human adjuvant disease, possible autoimmune disease after silicone implantation: a review of the literature, case studies and speculation for the future. Plast Reconstr Surg 1986;78:104-14.
