Periorbital Hyperpigmentation—Dark Circles under the Eyes; Treatment Suggestions and Combining Procedures

: Periorbital hyperpigmentation (POH) is a frequent concern among both young and adult patients. The etiology is multifactorial with a genetic background. Prevalence is higher in darker skin types. It has been estimated as high as 30% in a recent Indian study. Females are often more disappointed by POH than males. Treatment has to consider underlying pathologies and patients’ needs. We present our treatment algorithm for POH. In this study, 74 patients with POH, 64 females (86.5%) and 10 males (13.3%), were treated. Of these, 39 patients (53%) had a family history of POH. The age range of patients was 18 − 57 years (average: 36.1 years). In case of tear trough deformity, soft tissue augmentation was used by injection of hyaluronic acid gel, calcium hydroxylapatite, or autologous fat. Blepharoplasty with partial fat pad resection or repositioning via arcus marginalis release was used to correct severe orbital fat herniation and excess of the lower lid skin. Melanin hyperpigmentation of the skin was improved by sessions of Q-switched 1064 and 532 nm neodymium-doped yttrium aluminum garnet (Nd:YAG) laser. Small vessels (capillaries and veins) were targeted by a 1064 nm long-pulsed Nd-YAG laser. Sessions of intense pulsed light (IPL) or CO 2 fractional laser were employed to improve skin texture and ﬁne lines. Topical hyaluronic acid-based formulations may be used as adjuvant self-treatment by patients. For pigmented and mixed-type POH, ultraviolet light protection is recommended as a maintenance treatment. By the use of various technologies, treatment can be individually tailored.


Introduction
Periorbital hyperpigmentation (POH) or dark circles under the eyes is a very frequent concern among both young and adult patients of any skin type. POH interferes with perceived age. We define POH as the occurrence of bilateral hyperchromatic macules and patches usually affecting the lower eyelids. This hyperpigmentation can also be present on the upper eyelids, malar region, eyebrows, and neighboring regions.
The etiology of POH is multifactorial. Volume loss and tear trough, skin laxity and translucent skin, prominent vasculature or blood stasis, excessive pigmentation, allergy, asthma, atopic dermatitis, and orbital adipose tissue prolapse are contributing factors in POH [1]. The combination of Dennie-Morgan fold and POH is highly suspicious for atopic dermatitis [2]. Atopic dermatitis is probably the most common dermatosis associated with POH [3]. Several medical drugs may cause POH, such as prostaglandins or imatinib [4,5]. A cross-sectional study among Malaysian Chinese identified single nucleotid polymorphism in p53 and vascular endothelial growth factor A (VEGFA) genes. They found an association of TA (tyrosine -adenosine) genotype in rs1437756379 of p53 to mixed vascular-pigmented POH and AC (adenosine-cytosine) genotype in rs1377053612 of VEGFA to atopic (pollinosis) phenotype [6]. Family history is often positive [7].
A common concept in society is that POH is a symptom of lack of sleep or fatigue, but this aspect is discussed as controversial [8,9]. Contact-free hyperspectral imaging identified melanin as the dominant chromophore while hemoglobin oxygen saturation was secondary. Participation of local microcirculation in the visual assessment of POH was also noted [7]. Kikuchi et al. (2013) used a contact spectrophotometer to study POH. Their data demonstrated that melanin content increased, while hemoglobin oxygen saturation ratio decreased locally in the POH-affected skin [10]. POH can be classified according to causes and appearance [11] (Table 1). Huang et al. (2014) developed another classification that includes pigmented (brown), vascular (blue to purple), structural, and mixed-type. Mixed-type (78%) and vascular-type (14%) were the commonest subtypes in Taiwan [12]. In a Korean study of 100 patients with POH, vascular-type (35%) and mixed-type (54%) dominated [13]. A Malaysian study identified the vascular type as the major one (51%), while the pigmentary type was the least common with 6% [14]. A study from India reported constitutional (51.5%) and post-inflammatory (22.5%) POH types as the commonest [8]. Ethnical and geographical factors might contribute to the variable presentation of POH subtypes. Grading of the severity of POH is given in Table 2.  [11].

Constitutional
• Patients show a curved band of brownish to black skin pigmentation on lower eyelids approximating the shape of the orbital rim with frequent involvement of upper eyelids.

Post-inflammatory
Here, irregular patches of brownish or gray pigmentation can be found on the upper, lower, or both eyelids with lichenification, and eczematous lesions in the surrounding areas.

Vascular
• Patients present with erythema predominantly involving the inner aspect of lower eyelids, with prominent capillaries or telangiectasia, often with a thin translucent skin. There may be a bluish discoloration of the lower eyelid and visible bluish veins.
Shadow effect This type is mainly due to structural anatomical factors (e.g., overhanging tarsal muscle, eye bags, or a deep tear trough).

Others
• Such as internal disorders (e.g., anemia, hormonal disturbances, nutritional deficiencies), skin disease (e.g., acanthosis nigricans, cutis laxa, nevus Ota, nevus Hori, erythema dyschromicum perstans, fixed drug eruption), and drugs (latanoprost and bimatoprost eye drops). Epidemiological data on POH are scarce. In an Indian study, the prevalence was 30.8%. A total of 200 patients with POH were analyzed; 81% were females. The dominant age was 16 to 25 years. Of these patients, 63% had a positive family history, and 50% an iron deficiency anemia [8]. In a Brazilian study from Porto Alegre, 91% of POH patients were female. Females were unhappier with POH than males [9].

Diagnosis
Diagnosis is primarily clinical. Wood's lamp examination is useful to differentiate between epidermal or dermal pigmentation. If there is no accentuation of pigment, then POH is due to dermal melanin pigmentation or vascularity. If there is an accentuation of pigment, then it is due to superficial melanin pigmentation [12]. Skin biopsy with histology is rarely necessary for differential diagnosis [15]. Patch and prick tests are recommended for suspected allergies.
Laser treatments have been used for the treatment of POH as well, including longpulsed and picosecond laser types for pigmentations, tattoo removal, and vascular lesions [22][23][24][25][26]. In addition, topical treatment may be combined with lasers to achieve a better outcome [1,27]. Tear trough-associated POH can be corrected by dermal fillers [28].
Inclusion criteria were age >18 years, no untreated comorbidities, no infections in the area to be treated, and informed patient consent. Exclusion criteria were age < 18 years, pregnancy or lactation, local or systemic infections, missing informed consent, unwillingness for follow-up, and drug-induced POH in case the drug has to be continued for medical reasons.
The first step in treatment is based on a careful medical history and clinical examination to identify the components of POH and includes: The treatment has to focus on the underlying pathology and components of POH. We considered comorbidities that could interfere with treatment selection, such as atopic dermatitis. In this case, dermatological treatment of the inflammatory dermatosis should precede treatment of POH.Tear trough deformity: For tear trough deformity, soft tissue augmentation is used. Injection of hyaluronic acid gel, calcium hydroxylapatite, or autologous fat has been reported [29,30]. In patients with more pronounced deformities, severe orbital fat herniation and excess of the lower eyelid blepharoplasty with partial fat pad resection or repositioning via arcus marginalis release is performed [31][32][33][34][35].
In our experience, fat injection is the most efficient option to correct this concave deformity of the orbital fat. The density and consistency of the fat provide a natural appearance.
Hyperpigmentation of the skin due to the presence of melanin: We performed several sessions of Q-switched 1064 nm and 532 nm neodymium-doped yttrium aluminum garnet (Nd:YAG) laser. The wavelength selection depends on the color of hyperpigmented areas (brown, red, or blue). The following laser parameters were used: pulse width of 2 msec, pulse repetition rate between 0.5 and 3 Hz, and fluency ranged from 4 to 16 J/cm 2 . The spot size diameter was 4 mm. By this laser technique, high energy is released in a very short period of time with leads to melanin fragmentation, allowing phagocytosis. Brightening of skin is the consequence.
Small vessels (capillaries and veins): In the case of vascular POH, we preferred treatment with long-pulsed Nd-YAG laser 1064 nm. On average, two or three sessions were performed every 3 or 4 weeks. The fluence ranged from 100 to 150 J/cm 2 with a 2.5 or 4.0 mm spot size. The pulse width varied from 3 msec to 15 msec [36].
Skin texture: To improve skin texture and address fine lines, sessions of intense pulsed light (IPL) or CO 2 fractional laser were employed. In this case, the laser was preferred for deeper lines. Both IPL and CO 2 laser are capable of improving skin quality and induce neo-collagenesis [37,38]. Topical hyaluronic acid-based formulations can be recommended as adjuvant self-treatment by patients [39,40].
Protection from ultraviolet (UV) light is essential for post-laser therapy. For pigmented and mixed-type POH, UV protection is also recommended as a maintenance treatment [41].

Results
Patient characteristics can be seen in Table 3. The treatment was well tolerated. Adverse events were mild and temporary. The main frequent events were ecchymosis and edema. Neither burn nor vascular problems or scarring were observed. There was neither significant pain nor discomfort after treatment. The major outcome of treatment was an improvement of POH. Most patients also achieved better skin texture and appearance (Figures 1-5). The patients' evaluation was excellent in 26 patients (35.1%), good in 36 patients (48.6%), fair in 9 patients (12.1%), and poor in 3 patients (4.0%). Of all patients treated, 83.7% reported a good or excellent outcome ( Table 4). All patients with vascular or post-inflammatory POH achieved a good or better result, while constitutional POH was the dominant subtype in patients with poor and fair outcomes. Follow-up 6 to 32 months Table 4. Improvement of periorbital hyperpigmentation aspect according to patient's assessment.

Discussion
POH is a multifactorial condition with esthetic importance and quality of life issues. POH results in a tired and exhausted appearance. It may be associated with an underlying pathology such as contact allergy or pollinosis, medical drug use, and sun exposure. Genetic predisposition is reported in about a third of patients [41].
Treatment is dependent upon causative factors, lifestyle, comorbidities, skin phototype, and resources. A systematic review considered laser therapy appropriate for pigmented and vascular POH, while dermal fillers and autologous fat transfer were most effective in case of volume loss. Excessive skin laxity is addressed by blepharoplasty. In contrast, topical treatment with creams and peels has only a moderate effect on pigmented POH [26].
We reported on our experience with POH using lasers, surgery, and fillers as primary tools. These procedures have a short downtime and are minimally invasive. Satisfying esthetic results can be achieved, as illustrated by our clinical cases. We recommend UV protection in combination with skincare as maintenance therapy in pigmented and mixedtype POH [42].

Conclusions
POH is a multifactorial condition. An accurate diagnosis is fundamental to achieve a good, safe, and effective treatment result. Different laser sources, fillers, fat injection, or surgery can be used as a monotherapy or in combination to improve this condition. This allows tailoring the treatment according to underlying pathologies and patients' needs [1].