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Botulinum A exotoxin for glabellar folds: a double-blind, placebo-controlled study with an electromyographic injection technique.

Local injections of botulinum A exotoxin (BTX) have been used successfully to treat strabismus, blepharospasm, and other hyperkinetic movement disorders [1].

BTX binds to specific receptors at the presynaptic cholinergic endplate membrane and is actively transported into nerve cells. BTX is split into heavy and light chains; the light chain blocks acetylcholine release. Changes at the endplate and the resulting muscle atrophy are reversible, at least after a single injection. Neuromuscular transmission is being normalized within 3 to 4 months [21.

Previous studies have suggested the use of BTX as therapy for the reduction of hyperactive facial lines after its successful use for blepharospasm [3,4], Our purpose was to evaluate, in a double-blind, placebo-controlled study, the efficacy of BTX in reducing glabellar frown lines.

Patients and methods

Thirty patients with established hyperactive glabellar frown lines were treated. They were provided with an informed consent form approved by an institutional review board. Patients were evaluated by one investigator; a severity scoring system was based on the subjects' ability to frown as follows: 0 = no muscle contractibility, 1 = minimal muscle contractibility, 2 = moderate muscle contractibility, and 3 = marked muscle contractibility. In addition, the subjects were evaluated for the severity of frown lines at rest according to the following scoring system: 0 = none, 1 = mild, 2 = moderate, and 3 = severe.

Patients were photographed by means of standardized facial photography both at rest and at maximum frowning. The upper and lower limits of the frown lines were marked at maximal frowning. The length and depth of the frown lines were measured with a millimeter measure at maximum attempted muscle contraction.

Patients were then randomly selected to receive either 10 units of BTX in 0.1 ml of nonpreserved normal saline or normal saline solution as a control. BTX (supplied by Allergan Pharmaceuticals, Irvine, Calif.) was diluted in normal saline solution to a concentration of 100 U/ml of solution. Saline (0.1 ml) or BTX solution (10 U) was injected into each corrugator muscle. The BTX was injected with a 1 cc tuberculin syringe connected to a metal-hubbed, 1-inch, 30-gauge needle that was connected via electrodes to an electromyography instrument. Injection was in an upward and lateral direction from the middle intereyebrow area.

Patients were observed 2 weeks after injection, and the frown lines were remeasured. They were also evaluated every 4 weeks after injection. The 15 patients who initially received placebo crossed over to receive BTX. Of these patients, 10 received BTX delivered in an upward and lateral direction, and five received it in a downward and medial direction. In addition, patients were assessed for efficacy and also for side effects.

Results

All 15 patients initially treated with BTX achieved a highly statistically significant reduction or improvement in their glabellar frown lines, most particularly in attempts at full muscle contractibility. Patients randomized to placebo had a mean preinjection severity score of 3.86 [+ or -] 1.13 and a postinjection severity score of 3 78 [+ or -] 1.42. Those who received the BTX had a preinjection score of 4.00 [+ or -] 1.32 and a postinjection score of 1.80 [+ or -] 1.59. These differences were statistically significant (P<0.01). Patients observed no difference in injection pain (which was minimal) between placebo and BTX. The changes in measurement comparing postinjection to preinjection data are summarized as follows. In the placebo group, total line length pretreatment was 62.71 [+ or -] 15.88; 4 weeks posttreatment, it was 63.79[+ or -] 15-95 (P = 0.17). The pretreatment depth in the placebo group was 8.15 [+ or -] 3.02; at 4 weeks it was 8.65 [+ or -] 3.02 ((P = 0.11). In the BTX treatment group, pretreatment length was 54.20 [+ or -] 10.14; posttreatment length was 30.80 [+ or -] 23.66 (P<0.01). The pretreatment depth for the BTX group was 7.53 [+ or -] 2.05. At 4 weeks posttreatment, depth was 2.03 [+ or -] 2.27 (P<0.01).

[FIGURE 1 OMITTED]

[FIGURE 2 OMITTED]

Measurements were also taken at 12 weeks after treatment. In the placebo group, pretreatment length was 62.71 [+ or -] 15.88; 12 weeks after treatment it was 64.92 [+ or -] 16.64 (P=0.09). Pretreatment depth in the placebo group was 8.15 [+ or -] 3-23; 12 weeks posttreatment it was 8.15 [+ or -] 3.23 (P=T). In the BTX treatment group, pretreatment length was 54.20 [+ or -] 10.l4; at 12 weeks after treatment, length was 37.93 [+ or -] 11.94 (P<0.05). Pretreatment depth in the BTX group was 7.53 [+ or -] 2.05; at 12 weeks after treatment, it was 3-40 [+ or -] 1.69 (P<0.01).

[FIGURE 3 OMITTED]

[FIGURE 4 OMITTED]

All 15 patients initially treated with placebo elected to receive BTX. Again, all showed a highly statistically significant reduction in glabellar frown lines by the fourth week after injection (P<0.01).

One of 10 patients who received BTX injected upwards and laterally had mild unilateral ptosis that lasted 10 days. Two of five patients receiving BTX injected downward and medially had mild transient ptosis that lasted 10 to 14 days. The duration of the BTX effect after the first injection was a mean of 17.8 weeks. This was assessed as the time for the lines to return to 30% of their preinjection status [see Figures 1-4].

Discussion

This study confirms that BTX is effective and safe as therapy improving glabellar frown lines. The use of the electromyography instrument connected to the delivery needle appears to be an effective means of assuring that BTX is delivered accurately into the body of the corrugator muscles.

It is possible that by delivering BTX directly intramuscularly rather than into the subcuticular tissue, efficacy may be increased and the incidence and severity of side effects may be reduced. Further studies are required to determine whether the incidence of ptosis is related to the direction of injection.

Studies of the duration of the effects of repeat injections of BTX arc being conducted. However, after repetitive BTX treatments in 42 patients with blepharospasm, there was no decline in benefit [5].

Reprinted with kind permission of the publishers from Journal of Investigative Dermatology, 1996, 35, 569-572.

References

[1.] Melling J, Hambleton P. Shone CC. Clostridium botulinum toxins: nature and preparation for clinical use. Eye, 1988, 2, 16-23.

[2.] Jarikovic J, Brin M. Therapeutic uses of botulinum toxin. N Engl J Med, 1991. 324 1186-1194.

[3.] Carruthers J, Carruthers A. Treatment of glabellar frown lines with C. botulinum-A exotoxin. J Dermatol Surg Oncol, 1992. 18. 17-21.

[4.] Carruthers J, Stubbs HA. Botulinum toxin for benign essential blepharospasm. Can J Neurol Sci, 1987. 14, 42-45.

[5.] Botulinum A exotoxin. Therapeutics and Technology Assessment Committee of the American Academy of Neurology. Neurology, 1990. 40, 1332-1333.
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Title Annotation:Leading Article
Author:Lowe, Nicholas J.; Maxwell, Anne; Harper, Heather
Publication:Clinical Dermatology
Article Type:Reprint
Date:Jun 1, 2009
Words:1128
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