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Nonallergic Eyelid Edema After Botulinum Toxin Type A Injection

Abstract Periocular botulinum toxin type A (BoNTA) injections are generally safe. Ptosis is the most common adverse effect, whereas eyelid edema is rarely reported. There is no consensus on the latter's incidence, clinical course, or treatment strategy. Here we managed a 59-year-old woman who received BoNTA injections to her forehead, glabella, and eye corner. At 3-day follow-up, she presented with painless, nonpruritic, bilateral periorbital edema, and erythema. Preliminary diagnosis was a local allergic reaction, and topical corticosteroid was administered, but upon lack of improvement, edema secondary to venous and lymphatic congestion was hypothesized, and she was advised to apply hot pads over her eyes, blink frequently, and massage the area. Her eyelid edema resolved 2 weeks later. At 4-month follow-up, the patient requested and received another course of BoNTA at half the dose. Frequent blinking was instructed, and the patient reported a satisfactory outcome with no adverse effects. In our literature review, incidence of BoNTA-induced eyelid edema was 1.4% and showed Asian tendency. Although rare, BoNTA-induced periorbital edema is self-limiting, and normally resolves in 2 to 4 weeks without medical treatment. Patients at risk for edema, including Asian ethnicity, dermatochalasis, and poor periocular muscle tone, are advised to receive injections at half the dosage. Examination of the function and tone of the orbicularis oculi and levator palpebrae superioris muscles before treatment is recommended, and application of hot pads over the eyes, frequent blinking in the morning, and self-massage of the affected area to increase venous return have demonstrated to improve outcome.


INTRODUCTION
B otulinum neurotoxin type A (BoNTA) is widely used in aesthetic medicine as treatment for glabellar lines. BoNTA blocks the release of the neurotransmitter acetylcholine, resulting in blockage of neuromuscular transmission and paralyzing the target muscle. Therefore, injection of BoNTA can reduce muscle activities, decrease muscle tension, and smooth facial wrinkles. 1,2 BoNTA therapy is associated with a low rate of adverse effects. In the largest multidepartment retrospective study conducted to date, Kim et al 3 reported that the incidence of adverse events after BoNTA injection was only 3.73%.
Most adverse events related to BoNTA injection are minor and transient, and composed of eye disfiguration and vision blockage. Symptoms normally present approximately 2 weeks after injection and persist for about 15 days (range, 7-85 days). 4,5 To date, however, there is no consensus on the incidence of and treatment for all types of adverse effects after injection of BoNTA.
Although ptosis is a frequent side effect of BoNTA injection, 3 eyelid edema is a less common adverse effect of BoNTA treatment, and few studies have investigated its etiology, clinical course, and treatment outcomes. Herein we present a case with bilateral periorbital swelling and erythema after BoNTA injection. Total duration of follow-up was 16 weeks.

CASE REPORT
A 59-year-old woman with a history of well-controlled asthma received BoNTA therapy to smooth wrinkles on her forehead, glabella, and corners of her eyes (crow's feet). Physical examination revealed thick, triangular-shaped eyelids with infolding of the upper eyelid ( Figure 1A).
At 3-day follow-up, the patient presented with painless, nonpruritic, bilateral periorbital swelling and erythema. Physical examination revealed no evidence of skin rash, tenderness, or conjunctival congestion. The preliminary diagnosis was a local allergic reaction to BoNTA. A topical corticosteroid (Rinderon1 oph ointment, Shionogi, Taiwan) was administered to the swollen periorbital region 2 times per day for 3 days. However, the medication did not result in symptom relief ( Figure 1B).
Based on the clinical course, we hypothesized that eyelid edema was most likely due to impaired venous and lymphatic return caused by reduced muscle tone rather than allergic reaction or infection. We advised the patient to apply hot pads over her eyes, blink frequently, and massage the affected area in order to increase venous return. No antibiotics or antihistamines were prescribed. The patient's eyelid edema eventually resolved 2 weeks later ( Figure 1C).
At 4-month follow-up, the patient requested an additional course of BoNTA therapy. This time, we adjusted the dose to half of the original. We instructed the patient to blink frequently, especially in the early morning after long-term venous stasis during sleep, and to massage the periorbital area to increase venous return. No adverse effects were noted after the second treatment and the patient reported a satisfactory outcome (Figure 2A,B).

DISCUSSION
The most common complications among patients who receive BoNTA to eye corner for treatment of crow's feet are bruising, dry eye, corneal exposure, diplopia, ectropion, lid retraction, other lid malpositions, and an asymmetrical smile (caused by the spread of toxin to the zygomaticus major). 6 Little is known about the development of periocular eyelid edema after botulinum toxin injection. In a retrospective study of 5310 botulinum toxin injection treatments among 1819 patients, only 2 (0.04%) patients developed eyelid edema. 3 In a meta-analysis of BoNTA injection for the treatment of glabellar lines or crow's feet in 1678 patients, Brin et al 4 found that the median time of eyelid edema onset was 5 days (range, 2-106 days) and that the median duration of symptoms was 15 days (range, 7-85 days). They also found that the incidence of treatment-related eyelid edema (1.4%, 21/1492) was significantly higher among patients who received 20 U botulinum toxin A injection than among those who received placebo. Furthermore, the researchers noted that Asian populations are at greater risk for BoNTAinduced eyelid edema than Caucasian populations (3.1%, 8/260 vs 0.7%, 4/614). 4 Eyelid edema is often due to allergy, infection, or trauma, but can be caused by poor venous or lymphatic return to the eyelid or decreased muscle tone. Definitive diagnosis can be made by understanding the mechanism and tracing the clinical course if there is no response to antiallergic treatment. Procedural and possibly even local adverse effects are likely to be  related, to some extent, to injector experience, and are thus expected to decline with the number of treatment cycles. We found that repeated treatments are associated with a lower incidence of eyelid ptosis, eyelid sensory disorder, and eyelid edema. Similar findings were reported by Brin et al. 4 Multiple muscles are involved in the blinking reflex. In the upper eyelid, the levator palpebrae superioris, which divides into an aponeurosis and a deeper portion that contains the Müller's (superior tarsal) muscle, is responsible for eyelid retraction. The orbicularis oculi is the main muscle that controls closing of the eyes. Pretarsal and posttarsal plexuses contain the venous drainage of the eyelid, which included ophthalmic vein and the veins that drain the forehead and temple. Preauricular and parotid nodes drain the lymphatics from the lateral segment of the lids. Submandibular lymph nodes drain the medial side of the lids. 7 In our case, eyelid edema onset was 3 days after 12.5 U botulinum toxin injections each to the glabella and bilateral eye corners. The total duration of treatment was 2 weeks. Kim et al 3 suggested that the local spread of toxin into adjacent muscle and tissue might be responsible for the development of eyelid edema. Brin et al 4 suggested that the relaxation of the underlying muscle tone after periocular injection with BoNTA and its secondary effects on interstitial fluid mechanics were the main reasons for the development of eyelid edema. Based on the findings in this study, we propose that the mechanism governing the development of eyelid edema after BoNTA injection might be the combined effect of venous or lymphatic stasis related to the individual eyelid structure and decreased muscle tone caused by local diffusion of neurotoxin, which lessens the interstitial fluid return against gravity. The mechanism of eyelid edema is different from ptosis, which is caused by unintended relaxation of the levator muscle. 4 Eyelid edema due to impaired mechanical venous return is more common in Asians than Caucasians. 4 In Asians, there are fewer fibrous attachments between the levator aponeurosis, orbicularis, and skin of the eyelid. This results in a lack of supratarsal crease and less eyelid retraction for venous drainage while blinking. 8,9 The fusion of the levator aponeurosis and orbital septum is closer to the eyelid margin, causing the characteristic puffiness in Asian eyelids. 9,10 This puffiness compresses the vein and obstructs venous return, which is already impeded by gravity ( Figure 3A,B).
Another characteristic of Asian eyes is eyelid hooding (dermatochalasis). Patients with dermatochalasis tend to have less elastic fibers and greater breakdown of collagen networks, which lead to secondary lymphostasis and eyelid edema. 11 Incidence of dermatochalasis increases with age, 12 and was also noted in our patient, who was 59 years old. The excess of skinfolds also hinders venous return ( Figure 1A). Based on the mechanical factors governing eyelid edema after periocular BoNTA injection, we suggest that patients undergo examination of the function and tone of the orbicularis oculi and levator palpebrae superioris muscles before treatment as preventive strategies. Doses of BoNTA and injection points should be adjusted in patients at risk for developing periorbital edema (Table 1).

CONCLUSION
Although rare, periorbital edema due to BoNTA injection is self-limiting and does not require medical treatment. As reflected from the case, edema can be managed by application of hot pads over the eyes, frequent blinking in the morning, and self-massage of the affected area in order to increase venous return. Preventive strategies include examination of the function and tone of the orbicularis oculi and levator palpebrae superioris muscles before treatment. Patients at risk for edema such as Asian ethnicity, dermatochalasis, and poor periocular muscle tone should receive half the usual dosage of BoNTA.