Medicine

CLINICAL CASE REPORT

Nonallergic Eyelid Edema After Botulinum Toxin Type

A Injection
Case Report and Review of Literature
Yin-Shuo Chang, MD, Chang-Cheng Chang, MD, Jen-Hsiang Shen, MD, Yu-Tsung Chen, MD,
and Karen Kar-Wun Chan, MD

(Medicine 94(38):e1610)
Abstract: Periocular botulinum toxin type A (BoNTA) injections are
generally safe. Ptosis is the most common adverse effect, whereas eyelid
Abbreviation: BoNTA = botulinum toxin type A.
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-
INTRODUCTION
up, she presented with painless, nonpruritic, bilateral periorbital edema,
and erythema. Preliminary diagnosis was a local allergic reaction, and 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, result-
topical corticosteroid was administered, but upon lack of improvement,
edema secondary to venous and lymphatic congestion was hypothes- ing in blockage of neuromuscular transmission and paralyzing
ized, and she was advised to apply hot pads over her eyes, blink the target muscle. Therefore, injection of BoNTA can reduce
frequently, and massage the area. Her eyelid edema resolved 2 weeks muscle activities, decrease muscle tension, and smooth facial
later. At 4-month follow-up, the patient requested and received another wrinkles.1,2 BoNTA therapy is associated with a low rate of
course of BoNTA at half the dose. Frequent blinking was instructed, and adverse effects. In the largest multidepartment retrospective
the patient reported a satisfactory outcome with no adverse effects. study conducted to date, Kim et al3 reported that the incidence
In our literature review, incidence of BoNTA-induced eyelid edema of adverse events after BoNTA injection was only 3.73%.
was 1.4% and showed Asian tendency. Although rare, BoNTA-induced Most adverse events related to BoNTA injection are minor
periorbital edema is self-limiting, and normally resolves in 2 to 4 weeks and transient, and composed of eye disfiguration and vision
without medical treatment. Patients at risk for edema, including Asian blockage. Symptoms normally present approximately 2 weeks
ethnicity, dermatochalasis, and poor periocular muscle tone, are advised after injection and persist for about 15 days (range, 7–85
to receive injections at half the dosage. Examination of the function and days).4,5 To date, however, there is no consensus on the
tone of the orbicularis oculi and levator palpebrae superioris muscles incidence of and treatment for all types of adverse effects after
before treatment is recommended, and application of hot pads over the injection of BoNTA.
eyes, frequent blinking in the morning, and self-massage of the affected Although ptosis is a frequent side effect of BoNTA injec-
area to increase venous return have demonstrated to improve outcome. tion,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
Editor: Ismael Maatouk. BoNTA injection. Total duration of follow-up was 16 weeks.
Received: June 29, 2015; revised: August 9, 2015; accepted: August 26,
2015.
From the Department of Dermatology (Y-SC), Taipei Medical University CASE REPORT
Hospital, Taipei City, Taiwan; Aesthetic Medicine Center (Y-SC, C-CC, J- A 59-year-old woman with a history of well-controlled
HS), Department of Plastic Surgery, Chang Gung Memorial Hospital, Puzi
City, Chiayi County, Taiwan; Department of Cosmetic Science (C-CC), asthma received BoNTA therapy to smooth wrinkles on her
Chang Gung University of Science and Technology, Kwei-Shan, Taoyuan, forehead, glabella, and corners of her eyes (crow’s feet).
Taiwan; Department of Ophthalmology (J-HS), Chang-Gung Memorial Physical examination revealed thick, triangular-shaped eyelids
Hospital, Taoyuan County, Taiwan; Department of Dermatology (Y-TC), with infolding of the upper eyelid (Figure 1A).
Shung Ho Hospital, New Taipei City, Taiwan; and Hospital Authority (KK-
WC), Hong Kong SAR. Therapy compriss BoNTA (BOTOX1, Allergan, Inc,
Correspondence: Chang-Cheng Chang, Aesthetic Medicine Center, Depart- Irvine, CA, 100 U in 4 mL normal saline) injections to the
ment of Plastic Surgery, Chang Gung Memorial Hospital, No. 6 Chia- forehead (12.5 U), glabella (12.5 U), and eye corners (crow’s
Pu Rd., West Sec., Puzi City, Chiayi County 613, Taiwan feet) (12.5/12.5 U). A 5-point injection was performed to
(e-mail: [email protected]).
Informed Consent Patient has provided informed consent for the publication glabella and eye corners.
of the case report. The study was also approved by the institutional At 3-day follow-up, the patient presented with painless,
review board of the Chang Gung Memorial Hospital (CGMH 103- nonpruritic, bilateral periorbital swelling and erythema.
1942B). Physical examination revealed no evidence of skin rash, tender-
The authors have no funding and conflicts of interest to disclose.
Copyright # 2015 Wolters Kluwer Health, Inc. All rights reserved. ness, or conjunctival congestion. The preliminary diagnosis was
This is an open access article distributed under the Creative Commons a local allergic reaction to BoNTA. A topical corticosteroid
Attribution- NonCommercial License, where it is permissible to download, (Rinderon1 oph ointment, Shionogi, Taiwan) was adminis-
share and reproduce the work in any medium, provided it is properly cited. tered to the swollen periorbital region 2 times per day for 3 days.
The work cannot be used commercially.
ISSN: 0025-7974 However, the medication did not result in symptom relief
DOI: 10.1097/MD.0000000000001610 (Figure 1B).

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Chang et al Medicine  Volume 94, Number 38, September 2015

FIGURE 1. (A) Patient before botulinum neurotoxin type A injections. The patient presents with eye puffiness, eyelid hooding, and
dermatochalasis (arrow), which are risk factors for secondary lymphostasis and eyelid edema. (B) One week after botulinum neurotoxin
type A injections. Bilateral periorbital swelling and mild erythema are noted 3 days after injection. The patient was advised to apply hot
pads over her eyes, blink frequently, and self-massage the affected area in order to increase venous return. No antibiotics or antihistamines
were used. (C) Two weeks after the patient first presented with bilateral periorbital swelling and erythema. The swelling and erythema
have resolved.

Based on the clinical course, we hypothesized that eyelid (caused by the spread of toxin to the zygomaticus major).6 Little
edema was most likely due to impaired venous and lymphatic is known about the development of periocular eyelid edema
return caused by reduced muscle tone rather than allergic after botulinum toxin injection. In a retrospective study of 5310
reaction or infection. We advised the patient to apply hot pads botulinum toxin injection treatments among 1819 patients, only
over her eyes, blink frequently, and massage the affected area in 2 (0.04%) patients developed eyelid edema.3 In a meta-analysis
order to increase venous return. No antibiotics or antihistamines of BoNTA injection for the treatment of glabellar lines or
were prescribed. The patient’s eyelid edema eventually crow’s feet in 1678 patients, Brin et al4 found that the median
resolved 2 weeks later (Figure 1C). time of eyelid edema onset was 5 days (range, 2–106 days) and
At 4-month follow-up, the patient requested an additional that the median duration of symptoms was 15 days (range, 7–85
course of BoNTA therapy. This time, we adjusted the dose to days). They also found that the incidence of treatment-related
half of the original. We instructed the patient to blink fre- eyelid edema (1.4%, 21/1492) was significantly higher among
quently, especially in the early morning after long-term venous patients who received 20 U botulinum toxin A injection than
stasis during sleep, and to massage the periorbital area to among those who received placebo. Furthermore, the research-
increase venous return. No adverse effects were noted after ers noted that Asian populations are at greater risk for BoNTA-
the second treatment and the patient reported a satisfactory induced eyelid edema than Caucasian populations (3.1%, 8/260
outcome (Figure 2A,B). vs 0.7%, 4/614).4
Eyelid edema is often due to allergy, infection, or trauma,
DISCUSSION but can be caused by poor venous or lymphatic return to the
The most common complications among patients who eyelid or decreased muscle tone. Definitive diagnosis can be
receive BoNTA to eye corner for treatment of crow’s feet made by understanding the mechanism and tracing the clinical
are bruising, dry eye, corneal exposure, diplopia, ectropion, course if there is no response to antiallergic treatment. Pro-
lid retraction, other lid malpositions, and an asymmetrical smile cedural and possibly even local adverse effects are likely to be

FIGURE 2. (A) Four months later, the patient underwent a second procedure where BoNTA of half the previous dosage was injected in the
perioccular region. (B) One week after the injection. No adverse effects were noted this time.

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Medicine  Volume 94, Number 38, September 2015 Nonallergic Eyelid Edema After BoNTA Injection

FIGURE 3. (A) Asian eyelid: the orange arrow indicates the stretch direction of eyelid retraction. There are fewer fibrous attachments
between the levator aponeurosis, the orbicularis, and skin of the eyelid, which leads to less contracture and a decrease in venous drainage
function. More perioribital fat is noted. These features cause the characteristic puffiness and increase the possibility of venous stasis. (B)
Caucasian eyelid: less perioribital fat is noted. The end fibers of the aponeurosis implanted into the orbicularis and skin bring additional
traction force in the inner and upper directions (red arrows). The stretch between aponeurosis and the insertions further improves venous
drainage function and decreases the possibility of venous stasis.

related, to some extent, to injector experience, and are thus findings in this study, we propose that the mechanism governing
expected to decline with the number of treatment cycles. We the development of eyelid edema after BoNTA injection might
found that repeated treatments are associated with a lower be the combined effect of venous or lymphatic stasis related to
incidence of eyelid ptosis, eyelid sensory disorder, and eyelid the individual eyelid structure and decreased muscle tone
edema. Similar findings were reported by Brin et al.4 caused by local diffusion of neurotoxin, which lessens the
Multiple muscles are involved in the blinking reflex. In the interstitial fluid return against gravity. The mechanism of eyelid
upper eyelid, the levator palpebrae superioris, which divides edema is different from ptosis, which is caused by unintended
into an aponeurosis and a deeper portion that contains the relaxation of the levator muscle.4
Müller’s (superior tarsal) muscle, is responsible for eyelid Eyelid edema due to impaired mechanical venous return is
retraction. The orbicularis oculi is the main muscle that controls more common in Asians than Caucasians.4 In Asians, there are
closing of the eyes. Pretarsal and posttarsal plexuses contain the fewer fibrous attachments between the levator aponeurosis,
venous drainage of the eyelid, which included ophthalmic vein orbicularis, and skin of the eyelid. This results in a lack of
and the veins that drain the forehead and temple. Preauricular supratarsal crease and less eyelid retraction for venous drainage
and parotid nodes drain the lymphatics from the lateral segment while blinking.8,9 The fusion of the levator aponeurosis and
of the lids. Submandibular lymph nodes drain the medial side of orbital septum is closer to the eyelid margin, causing the
the lids.7 characteristic puffiness in Asian eyelids.9,10 This puffiness
In our case, eyelid edema onset was 3 days after 12.5 U compresses the vein and obstructs venous return, which is
botulinum toxin injections each to the glabella and bilateral eye already impeded by gravity (Figure 3A,B).
corners. The total duration of treatment was 2 weeks. Kim et al3 Another characteristic of Asian eyes is eyelid hooding
suggested that the local spread of toxin into adjacent muscle and (dermatochalasis). Patients with dermatochalasis tend to have
tissue might be responsible for the development of eyelid less elastic fibers and greater breakdown of collagen networks,
edema. Brin et al4 suggested that the relaxation of the under- which lead to secondary lymphostasis and eyelid edema.11
lying muscle tone after periocular injection with BoNTA and its Incidence of dermatochalasis increases with age,12 and was
secondary effects on interstitial fluid mechanics were the main also noted in our patient, who was 59 years old. The excess of
reasons for the development of eyelid edema. Based on the skinfolds also hinders venous return (Figure 1A). Based on the

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Chang et al Medicine  Volume 94, Number 38, September 2015

TABLE 1. The Mechanism, Clinical Course, Risk Factors, Treatment, and Prevention Strategies for Eyelid Edema After BoNTA
Injection Based on Findings in the Literature Review and Our Opinion

Study Mechanism Clinical Course Risk Factors Treatment Strategy Prevention

Brin et al 2009 Relaxation of the Onset: 5 Asian ethnicity N/A N/A

Total underlying muscle tone (2–106) d
and secondary effects on Duration: 15
interstitial fluid (7–85) d
mechanics
Kim et al 2013 Local spread of toxin into N/A Female Not needed N/A
South Korea adjacent muscle and Higher dose any treatment
tissue
Chang et al 2015 1. Mechanical venous or Onset: 3 d 1. Asian ethnicity 1. Applying hot pads 1. Performing
Taiwan lymphatic stasis related to Duration: 2 wk 2. Dermatochalasis 2. Frequent blinking winking test first
the individual eyelid 3. Poor periocular 3. Self-massage of 2. Dose and injection
structure muscle tone the affected area points adjustment
2. Decreased muscle tone 4. Higher dose 4. No medication required
caused by local diffusion
and of neurotoxin

mechanical factors governing eyelid edema after periocular 3. Kim BW, Park GH, Yun WJ, et al. Adverse events associated with
BoNTA injection, we suggest that patients undergo examination botulinum toxin injection: a multidepartment, retrospective study of
of the function and tone of the orbicularis oculi and levator 5310 treatments administered to 1819 patients. J Dermatolog Treat.
palpebrae superioris muscles before treatment as preventive 2014;25:331–336.
strategies. Doses of BoNTA and injection points should be 4. Brin MF, Boodhoo TI, Pogoda JM, et al. Safety and tolerability of
adjusted in patients at risk for developing periorbital edema onabotulinumtoxinA in the treatment of facial lines: a meta-
(Table 1). analysis of individual patient data from global clinical registration
studies in 1678 participants. J Am Acad Dermatol. 2009;61:
961–970.
CONCLUSION
5. Rzany B, Ascher B, Monheit G. Treatment of glabellar lines with
Although rare, periorbital edema due to BoNTA injection botulinum toxin type A (Speywood Unit): a clinical overview. J Eur
is self-limiting and does not require medical treatment. As Acad Dermatol Venereol. 2010;24 (suppl 1):1–14.
reflected from the case, edema can be managed by application
6. Klein AW. Complications with the use of botulinum toxin. Dermatol
of hot pads over the eyes, frequent blinking in the morning, and
Clin. 2004;22:197–205.
self-massage of the affected area in order to increase venous
return. Preventive strategies include examination of the func- 7. Paul RE, John PW. Anatomy & Embryology of the Eye. Vaughan &
tion and tone of the orbicularis oculi and levator palpebrae Asbury’s General Ophthalmology. 17th ed. McGraw Hill Profes-
superioris muscles before treatment. Patients at risk for edema sional; 2007. pp. 16–19.
such as Asian ethnicity, dermatochalasis, and poor periocular 8. Kikkawa DO, Kim JW. Asian blepharoplasty. Int Ophthalmol Clin.
muscle tone should receive half the usual dosage of BoNTA. 1997;37:193–204.
9. Nguyen MQ, Hsu PW, Dinh TA. Asian blepharoplasty. Semin Plast
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