Dysport: A European Botulinum Type A Neurotoxin
Gary D. Monheit, M.D.
Associate Professor
Department of Dermatology
University of Alabama at Birmingham
Birmingham, Alabama

Botulinum type A neurotoxin has been available in the United States and Europe to treat a variety of neuromuscular disorders of spasm, spasticity and muscular rigidity. While Botox has been manufactured and studied in the US since 1985, Dysport has been studied in Europe since 1988. Manufactured by Ipsen Pharmaceutical in the U.K., the toxin is produced from separate incubator vats of clostridium Botulinum than the North American product. The final clostridium Botulinum toxin type A hemogglulinin complex from European vats – Dysport – thus has distinct attributes and characteristics different from that of its North American cousin, Botox. (Table I) The molecular weight of the toxin is the same (150K DA) as well as bulk active substrait of the hemogglulinun complex. The pharmacologic composition, though, differs in that Dysport is accompanied 125-µ gm human serum albumin with 2.5 mg lactose while Botox has 500-µ gm human serum albumin in 0.9 mg sodium chloride. Dysport is currently registered in 60 countries worldwide including all European union countries and currently under investigation in the United States.

In 1990, the toxin was first approved for blepharospasm and hemifacial spasm and in 1992 for spasmodic tortocolis. Leg and arm spasticity approved second in 2000 and 2001 with approval also for cerebral palsy. Approval for cosmetic indications was first granted for glabellar frown lines in 2002 (Argentina, Brazil, Columbia and Uruguay). Further clinical cosmetic studies for glabella, forehead and periorbital rhytids have been performed in Europe and the United States during the last four years. Efficacy and dose ranging studies will be summarized.

Dysport is a Botulinum A hemagglutinin neurotoxin and its action is similar to that of Botox. The toxin is a single chain protein with a light and heavy chain. The heavy chain targets the linking molecule to the cholinergic nerve ending while the light chain cleaves SNAP-25 inhibiting exocytosis of acetylcholine.(Fig 1)

BTX-A toxin is measured in units of physiologic action, as either Botox versus Dysport units. Though the units are not interchangeable, various published reports support a conversion ratio from 1:5 to 1:3. Units of potency and thus dilution should be evaluated independent of the Botox product.

The standard dilution of 500 Dysport units is performed with 2.5 ml saline solution. Dose ranging studies for cosmetic usage have varied this dilution ratio to both a higher and lower concentration. Ascher performed a multicenter, randomized double-blind placebo controlled study of efficacy and safety of each dilutional doses of Botulinum toxin A (Dysport) for the treatment of glabellar lines. The 119 patients were from 18-70 years of age with moderate to severe glabellar frown lines and no prior anesthetic treatment. The dosages used were: placebo, 25, 50 and 75 units in a double-blind control. They were injected in five controlled glabellar sites targeting the obicularis pars frontalis, the corrugators and the procerus muscle, each with appropriate divided units. (Fig 2) Outcome measurements were assessed from blinded standardized photographs, investigator assessments and patient evaluation. These were compared to a rating scale 0-4 of glabellar lines as follows: 0=no lines; 1=mild lines; 2=moderate lines; 3=severe lines.(Fig 3) A responder was defined as 0:1 on the rating scale. The results indicated that all groups except placebo showed a response at one month and at three months. At six months, approximately two-thirds of the BTX-A treated patients were still responders. (Fig 4) Though the primary statistical analysis was performed at rest, the assessment at maximal frown was similar up to three months confirming the activity of BTX on the glabellar musculature.

The safety protocol was favorable with a 7.0% rate of adverse events, all mild and reversible. Headache was the most common with all resolving within two to ten days. There were no reported cases of blepharoptosis or diptopia. The conclusions indicated the BTX-A (Dysport) was an effective cosmetic treatment for glabellar lines as evaluated by independent photographic analysis and investigator assessment. The result suggested that 50 units was the optimal dosage for the glabella and with 10 units injected into each of five glabellar sites. Most interesting was the long-term result indicating that 1/3 of the patients treated were still responders at six months.1 (Fig 5) Other studies by Asher have indicated similar results of efficacy and safety for BTX-A (Dysport) in other locations including the forehead and crow’s feet.

Inamed – Ipsen designed a multicentered North American study to evaluate three doses of BTX-A (Dysport) to determine the optimal dose in reducing the severity of hyperfunctional glabellar lines for efficacy and safety. A total of 373 patients were tested with the following dosages in a double-blind placebo-controlled dose-ranging study: 20, 50 and 75 units – Dysport. A validated scale was developed both at rest and maximal frown. Each scale was comprised of four photographs, grade 0 to 3: 0=no wrinkles; 1=mild wrinkles; 2=moderate wrinkles; 3=severe wrinkles. Live assessment was used in this study as it was considered to have advantages over photographic evaluations. The assessor was able to note the level of effort being made by the patient in the act of frowning and truly note the dynamic nature of frowning. Thus – at maximal frown – the dynamic act of frowning is an indicator of pharmacologic activity of the toxin that cannot be truly evaluated by a static photograph. The live assessment of maximal frown proved more objective than photographs in which factors of lighting and position can blur the accuracy of assessment. An additional assessment at rest was also made on a 0 to 4 scale. The resting phase was felt to represent how the patient appeared in daily life and thus corresponded to treatment efficacy and patient satisfaction. A responder was defined as a patient with a rating of 0-none or 1-mild on day 30. Evaluations though were continued until day 120, or 4 months. (Fig 6, Fig 7)

A further language descriptor of glabellar wrinkles was formulated as much confusion has arisen in the literature concerning wrinkles, lines and grooves. The definitions at maximal frown were as follows:

1) Relaxed Skin Tension Line – no wrinkle

2) Wrinkle Line – a line visualized on the skin no greater than .2 mm. in diameter and no greater than 2 cm. in length – either dynamic or photoaging with no appreciable visible depth.

3) Wrinkle Crease – a wider line visible on skin with diameter .5-1 mm and 1 to 3 cm in length with no noticeable depth as perceived by shoulders on either side of the skin-divided crease.

4) Wrinkle Furrow – 1-2 mm. bulging on either side with deformity of surrounding shortening and dynamic movement

The results indicated that all doses of Dysport resulted in a statistically better response in the appearance of glabellar frown lines compared with placebo. Twenty units – the smallest dose – was effective at 30 days and remained apparent at 90 days but not at 120 days. Fifty units Dysport was found to be as effective as 75 units, Dysport for efficacy and duration. Close to half the patients continued to show an effect at 120 days. In this study, greater benefit was found among women than in men.

All doses were well tolerated with only minor side effects including headache, needle pricks and bruising but blepharoptosis was observed in only three patients. Of those reported cases, only one demonstrated to the investigator a true clinical ptosis. Ptosis had been reported in other product studies but not in other studies involving Dysport.

Antibody production has always been of concern with clinical usage of Botulinum toxin, but studied only with cervical dystonia. None of the patients in this study showed any evidence of neutralizing antibodies either at baseline or on follow up evaluations. From these observations, the 50-unit dosage was recommended as the optimal dose for safety and efficacy.

Dysport is best injected for cosmetic indications with Diablo or tuberculin syringes, 1.0 ml or 0.5 ml and using a 30-gauge needle. The standard dilution of 500 units per vial is best performed with 2.5 ml. of saline, bactereostatic. This produces a clinical usage concentration of 10 units Dysport per 0.05/ml, an easily measured quantity in the 1 ml tuberculin syringe. Thus, for the glabellar injection, aliquots of 10 units per 5 sites are easily administered. (Fig 8, Fig 9)

The forehead is best treated through five injection sites located at mid forehead at a distance of at least 2.5 cm above the brow. A dosage of 40 to 60 Dysport units is effective for forehead wrinkle relaxation. The lateral forehead injection site should be above the highest point of the outer one-third of the brow. This will prevent an undesirable lateral brow elevation, the “Mephisto look.”

Laugh lines or crow’s feet are treated with 30 units of Dysport injected lateral to each orbital rim. The injection sites are 1.0 cm lateral to the orbital rim in the three positions, representing the muscle bulges, superior, mid and inferior. Care must be taken not to inject the upper or lower lid obicularis muscles as ptosis or ectropion can result.

Lower eyelid wrinkles formed from an overactive or hypertrophic obicularis muscle can be treated judiciously with 3-4 units Dysport injected in the lower lid at the mid papillary line just below the tarsal plate. This will flatten the bulging muscle and create an image of “open eye.” Overaggressive treatment may, though, create an unwanted ectropion.

Areas of the lower face have been treated with similar results as those found with Botox. These include vertical rhagades of the upper lip, marionette lines at the corners of the mouth and chin wrinkles. Dosages should be conservative relying primarily on dermal fillers and only using chemodenervation as a secondary procedure. (Table II)

The activity of BTX-A for cosmetic usage has been firmly established in North America with Botox. Similarly, the use of BTX-A Dysport is also proving to be an effective agent for cosmetic usage for glabellar, forehead and crow’s feet under objective controlled studies. Most recent studies will show us differences in the two products as to time of onset, longevity, clinical application and technical usage. The objective evaluations in these studies should add much valuable data to our true understanding of Botulinum toxin.