BAGGY, PUFFY EYELIDS are viewed by most people as a sign of exhaustion and aging. Many individuals will go to great lengths to improve the appearance of their periorbital skin using cosmetics, fillers, botulinum toxin, chemical peels, dermabrasion, lasers, and surgical procedures. In 2002, nearly 230,000 people in the United States had a blepharoplasty, the fourth most popular surgical cosmetic procedure, as a method to attain a more desirable appearance.  However, patients desire similarly effective yet less invasive solutions with faster recovery times.

Baggy eyelids result from periorbital fat herniation, excessive eyelid skin (blepharochalasis), and/or hypertrophied orbicularis muscle. Baggy infraorbital folds caused by herniation of infraorbital fat pads are anatomically defined as true herniation of one or more of the three lower lid fat pads between the capsulopalpebral ligament superiorly and the orbital septum inferiorly. These must be clinically differentiated from other causes of periorbital edema, including eczema, conjunctivitis, urticaria, angioedema, arthropod bites, trauma, sinusitis and uncommonly, rosacea, dermatomyositis, thyroid disease, amyloidosis, hypoproteinemia, hypervolemia, and lymphoma, among others.

Rittes was the first to demonstrate cosmetic improvement of bulging infraorbital skin using injectable phosphatidylcholine, a phospholipid derived from lecithin. A recent report by Hexsel et al. describes the use of phosphatidylcholine injections for cosmetic applications in 213 patients, 8 of whom had HIV lipodystrophy. In an effort to evaluate further the efficacy and safety of phosphatidylcholine injections and to provide a nonsurgical alternative for our patients, we conducted an open-label study for the treatment of localized infraorbital fat pads.

Methods

This study was approved by the appropriate institutional review boards and conformed to the ethical guidelines of the 1975 Declaration of Helsinki. Written informed consent was obtained from each patient.

In order to participate in the study, patients had to be greater than 25 years of age and be in good health with no other skin diseases. Exclusion criteria included a history of sensitivity to phosphatidylcholine, previous blepharoplasty, involvement in other clinical investigations concurrently or within the previous 4 weeks, a known bleeding disorder or concomitant use of anticoagulants, pregnancy, use of systemic retinoids during the past 6 months or during the study (except 12,000 IU or less of vitamin A daily), and an inability to avoid aspirin- or ibuprofen-containing products 2 weeks before injection sessions (acetaminophen derivatives were allowed). Patients were told not to use any medicated products around the eyes (e.g., corticosteroids), "antiwrinkle" products, or any over-the-counter aspirin- or ibuprofen-containing products.

Preprocedure examination included evaluation of location and size measurement of the infraorbital fat pads, inquiry and examination for any concomitant ocular or periocular pathology, systemic disease, and digital photography.

Injectable phosphatidylcholine at a concentration of 50 mg/mL was compounded under sterile conditions using United States Pharmacopeia-grade phosphatidylcholine (Table 1). The phosphatidylcholine used in our study was acquired from the manufacturer of an oral phosphatidylcholine nutritional supplement (American Lecithin Company, Oxford, CT). This substance is derived from soybean lecithins, half of which is composed of phospholipids. Phosphatidylethanolamine, phosphatidylinositol, and phosphatidic acid fractions naturally present in lecithin were removed, yielding 96% phosphatidylcholine. Moisture, neutral oils, and lysophosphatidylcholine, a natural degradation product, compose the balance. The other ingredients, similar to those found in the pharmaceutically prepared formulations, include sodium deoxycholate (a bile salt used to transform phosphatidylcholine into micelles small enough to pass through the sterile filtration manufacturing process), benzyl alcohol (a preservative and solubility factor), and sterile water (Zigmont RE, personal communication, March 2003).

After 5 minutes of applying an ice compress to the infraorbital skin, the injection procedure consisted of sitting the patient upright, pulling the skin of the lower lid downward with the forefinger, and gently pressing on the superior globe for enhanced fat pad visualization. A 0.5-inch, 30-gauge needle was used to inject 0.4 mL of phosphatidylcholine approximately 0.5 cm deep into the unanesthetized infraorbital fat pads. Based on the individual's distribution of fat along the infraorbital bulge, the medication was divided among the central, medial, and lateral fat pads. Both lower eyelids were injected at each session. An ice compress was then reapplied to the infraorbital skin for 10 minutes. Patients were instructed to remain upright for at least 4 hours after the procedure, not to engage in any vigorous physical activity for the rest of the day, and to sleep with their heads elevated to the height of at least two pillows the night of the treatment.

Patients were evaluated and injected at the beginning of the study and at 14-day intervals. The injecting physician remained the same throughout the study. No more than five injection sessions were performed. Treatment was discontinued at any time on request by the patient or if the injecting physician did not believe the patient would benefit from additional treatment. Both physician and patient were asked to score the degree of infraorbital fat herniation before any treatment (visit 1) as the baseline for comparison at follow-up. Patients were asked to report the presence and duration of any side effects developing after the previous injection (swelling, erythema, etc.). In addition, digital photographs were taken before injections. To reduce intraevaluator and interevaluator bias, both patient and physician were unaware of his or her previous evaluations and of the other's evaluations. Patient grading was given to the nurse before treatment, and physician grading was recorded separately.

Patient self-assessment of infraorbital fat herniation was graded as mild (0-3), moderate (4-7), or severe (8-10). Physician grading of fat herniation was recorded as mild (0-3, fat herniation seen none to less than 1 mm above surrounding skin), moderate (4-7, fat herniation 1 to 2 mm above surrounding skin surface), and severe (8-10, fat herniation more than 2 mm elevation above surrounding skin surface).

A follow-up questionnaire was administered by telephone at least 6 months after the last treatment. Patient satisfaction was graded along a scale as 1 (unsatisfied), 5 (ambivalent), to 10 (very satisfied). The persistence of benefits (if any) was graded along a scale as 1 (my eyes look the same now as they looked before treatment), 5 (the results faded somewhat), to 10 (the benefits achieved have remained the same). Patients were also asked whether they would recommend the procedure to a friend and whether they would have paid for it. Additional comments about side effects and suggestions were solicited at that time as well. Three patients were digitally photographed 9 months after their last injections.

Results

Discussion

We report an open-label study evaluating the efficacy and safety of injectable phosphatidylcholine for the treatment of infraorbital fat pads. Most, but not all, of our patients obtained cosmetic improvement in infraorbital fat herniation, which impressed them more than the evaluating physician. The absence of a standardized grading scale precludes comparing one patient's score to that of another; nevertheless, a general trend in improvement of infraorbital herniation in most patients supports the observations of the physician.

There are several differences in outcome and methods between our study and the previous report by Rittes  regarding number of treatment sessions and patient response. Most patients (23 of 30) in the prior study received only one or two injections after it was thought that additional injections would not benefit the patient.  In contrast, benefits were observed in most of our patients after each treatment. Several patients may have had continued benefit with additional injections, but treatment was discontinued at five injections given the lack of established treatment protocol and unknown potential side effects. We found that with the exception of patient 4, patients who benefited the most after treatments had the longest persistence of results over time (up to 10 months at follow-up).

Three patients (8, 9, and 10) had no clinical improvement from the phosphatidylcholine treatment. However, we were unable to stratify patients to response based on age, gender, or immediate reaction to injection (burning, edema, erythema) because of limited sample size. Despite visualization of the fat pads on examination, it may be that patients who failed to respond had excessive hypertrophied muscle, rather than exclusively fat herniation. Based on her experience with over 600 patients, Rittes (personal communications, March 2003) believes that phosphatidylcholine has no apparent clinical effect on muscle tissue.

Adverse effects reported by this and the previous study were transient burning, erythema at the injection site, and mild infraorbital swelling resolving in most patients within 3 days.  However, the previous study did not report swelling beyond 3 days in any of the 30 subjects.  In our study, one patient experienced considerable swelling lasting 7 days that resolved after treatment with systemic corticosteroids. It is unknown whether the edema would have subsided without treatment but possible given the experience of the other patients. None of our patients withdrew from the study because of adverse effects.

Injectable phosphatidylcholine is available as Lipostabil (Aventis Pharmaceuticals) and Essentiale (Rhone-Poulenc Rorer). It is used worldwide for several medical conditions, including hyperlipidemia, peripheral vascular disease, cardiac ischemia, and liver disease. Since the published study by Rittes, treatment of localized fat collections using a phosphatidylcholine formula (especially on the thighs, abdomen, chin, and arms) has been escalating. Although limited in objective evaluation, a recent case series of over 200 patients treated with injectable phosphatidylcholine noted an unspecified reduction in subcutaneous fat in a "vast majority of patients. This report noted transient local reactions similar to those reported herein and did not describe any laboratory abnormalities or systemic complications. At the time of this study, there is considerable controversy over the use of Lipostabil and Essentiale, both non-FDA-approved drugs, in the United States. The media has publicized their use (advertised by some dermatologists as Lipo-Dissolve and Lipolight) as an alternative to liposuction. However, despite increasing reports of its effectiveness in these areas, there are no double-blinded, placebo-controlled clinical trials demonstrating the efficacy and potential long-term side effects of injectable phosphatidylcholine. To our knowledge, there are no Food and Drug Administration trials investigating injectable phosphatidylcholine.

In vitro and in vivo studies on intravenous or oral polyenylphosphatidylcholine (another name for phosphatidylcholine, as linoleic acid [a fatty acid] is bound to a majority of the molecules) have demonstrated antioxidant and antifibrotic effects mediated by anticollagenase activity.  Preliminary experiments on the phosphatidylcholine formulation used in our study have demonstrated lysis of keratinocyte cell membranes in vitro (unpublished data). Further investigation into themechanism of action of phosphatidylcholine in fat tissue and its clinical effect on other anatomic sites arepresently underway. Larger studies will determine optimal dosage, frequency, injection technique, and potentially additional adverse effects.

Overall, a majority of our patients were satisfied with the results of the phosphatidylcholine injections to the extent that they would have paid for the procedure and would recommend it to others. Relative to blepharoplasty, phosphatidylcholine injections may carry a decreased risk of scarring, asymmetry, trauma, ectropion, and prolonged recovery time. Despite its limitations, this study may assist physicians in evaluating the efficacy and utility of this novel substance. Although our findings suggest that phosphatidylcholine has promise for cosmetic applications, we urge physicians to use caution until it is evaluated in a larger population of patients.

Acknowledgment

The authors would like to thank Randy Zigmont and Gene Ragazzo for their technical assistance and advice in preparation of this manuscript. We are especially grateful to Michael Kolodney, MD, PhD, for his editorial assistance.

References