Is there a gold standard for treating periorbital hyperpigmentation? – A narrative review of the latest evidence

INTRODUCTION

Periorbital hyperpigmentation (POH) is a very common complaint in esthetic medicine appointments. It is described as a light to dark brown pigmentation or violaceous discoloration involving the upper and/or lower eyelids and causes significant concern among patients, as it is often associated with tiredness and signs of aging.¹

Data on POH are limited due to its perception as a physiological phenomenon and its transient nature.² However, studies have shown that it is more prevalent among individuals aged 16–25 and predominantly affects women. It has an estimated prevalence of around 30%.³

Its etiology is typically multifactorial, with causes including loss of volume or skin laxity, excessive pigmentation, periorbital edema, and hypervascularity.⁴ A recent study proposed a classification system for POH, dividing it into four types: Pigmentary, vascular, combination (pigmentary and vascular), and tear through, with the vascular type being the most common.⁵

Identifying the main cause of hyperpigmentation is crucial for determining the most appropriate treatment. This can be achieved through a combination of clinical examination and, depending on the author, evaluation with Wood’s lamp and ultrasonography.⁴

Despite numerous treatments described for POH, it is still considered a resistant and challenging condition to treat. This study aims to conduct a systematic review of all available treatments for this condition.

MATERIAL AND METHODS

The search for eligible articles was conducted on MEDLINE (PubMed) using the combination of the terms (dark circles OR POH OR periocular hyperpigmentation OR periorbital darkening OR infraorbital darkening OR infraorbital dark circles). Only clinical trial studies written in English were included in the study. No time restriction was applied.

The study selection was performed by two authors and the articles were screened by title and subsequently by abstract. Exclusion criteria were (1) studies not classified as clinical trials, (2) studies conducted on non-human models, (3) investigations primarily centered on cosmetic interventions, and (4) research focusing on hollowing or tear through type of POH.

RESULTS

Our initial search identified 654 publications, which were reduced to a total of 55 studies, after selecting only clinical trials. Of those and after assessing the title, and when in doubt, the abstract, only 18 studies fulfilled the criteria with an aggregate of 619 participants.^6-23

The articles are highly diverse, providing a comprehensive evaluation of most of the available treatments for POH [Table 1].

Among the 18 studies, five focus on using platelet-rich plasma (PRP) for the treatment of POH. One study examines PRP as a monotherapy, while others compare it with carboxytherapy, fat transfer, and chemical peelings.^7,9,11,12,16

Regarding laser therapy, various types of treatments were assessed.¹⁹ These included monotherapy with neodymium-doped yttrium aluminum garnet (Nd:YAG) laser, dual-wavelength picosecond Nd:YAG versus fractionated picosecond 755 nm alexandrite laser, and comparisons between Nd:YAG laser and carboxytherapy.^14,19,20 The carbon dioxide (CO₂) laser was compared with carboxytherapy in one study and with microneedling in another.^22,23 In addition, one study evaluated the use of Q-switched ruby laser (QSRL), and another examined the efficacy of Erbium-doped yttrium-aluminum-garnet (Er:YAG) laser with and without PRP injections.^13,21

Carboxytherapy was evaluated not only in comparison with lasers, PRP, and in one study with peeling and mesotherapy but also as a monotherapy in three studies.^6,10,17,18

In addition, one study assessed the efficacy of various types of chemical peelings for treating POH, while another investigated the role of microneedling.^8,15

To evaluate the efficacy of existing treatments for POH, several studies were designed using only a single treatment modality.

Eyraud et al., Roshdy et al., and Seirafianpour et al. evaluated the effect of carboxytherapy on improving dark circles.^10,17,18 Eyraud et al. performed subcutaneous injection of CO₂ once a week for 3 weeks.¹⁰ Using an infraorbital dark circle scale in pre and 6-month post-treatment photographs and three blinded evaluators, Eyraud et al. showed that carboxytherapy reduces skin discoloration and improves periorbital wrinkles without major side effects.¹⁰ Seirafianpour et al. also performed subcutaneous injections of CO₂ only once a session every week for 4 weeks.¹⁸ By assessing changes in periorbital pigmentation before, 1, and 5 weeks after the final session using Visioface and evaluating the patient satisfaction, the author showed a decrease in pigmentation post-intervention of around 20%, with patient satisfaction being higher, with 40% of the patients reporting good-to-excellent responses. Roshdy et al. aimed to study if different flow rates changed the therapeutic outcome of carboxytherapy by treating one group of patients with a flow rate of 30 ml/min and the other group with a flow rate of 60 mL/min, both weekly for 6 weeks.¹⁷ Using melanin and erythema index, dark circle and hollowness grade, investigator global assessment, and patient satisfaction scale, Roshdy et al. showed that both flow rates were effective in the treatment of infraorbital dark circles. However, no difference was noted between both flow rates, with the higher rates causing more adverse effects.¹⁷

Continuing with the monotherapy studies, Mehryan et al. studied the effectiveness of PRP in the treatment of dark circles.¹² Using subjective (investigator and participant evaluation) and objective (with instrumental devices such as skin surface analyzer, Mexameter, and corneometer) evaluations, the author concluded that PRP can improve infraorbital homogeneity but has no role in melanin content, stratum corneum hydration, periorbital wrinkles volume, or visibility index. However, 90% of the patients considered the results good or excellent.

Nilforoushzadeh et al.¹⁵ also used subjective (investigator and participant evaluation) and objective (colorimeter, Mexameter, cutometer, skin ultrasound, and Visioface) evaluations to assess the efficacy of three sessions, 2 months apart of microneedle fractional radiofrequency in the treatment of periorbital dark circles. The results showed improvement not only in the periorbital skin lightness and elasticity while decreasing the percent change in skin color but it also decreased melanin content, improved skin density and thickness, and decreased wrinkles in the periorbital area. The outcomes were confirmed by the physician and patient’s assessment, with 60% of patients describing an excellent reply.

Xu et al.²¹ published the first report on treating infraorbital dark circles using a low-fluence 1,064 nm Q-switched laser (spot size of 3.5 mm, fluence of 4.2 J/cm², and repetition of rate of 5 Hz). Patients underwent eight sessions separated by 3–4 day intervals.

The outcomes were evaluated using noninvasive instruments such as a spectrophotometer, reflectance confocal microscopy (RCM), and a blind evaluation by three investigators based on before and after photographs as well as patient satisfaction. The study showed a decrease in melanin and erythema index decrease in melanin deposition in the upper dermis and both the investigator and the patient evaluation agreed.

The same author also evaluated the efficacy of the treatment with QSRL, since this type of laser is more selective for melanin compared to the Q-switched Nd:YAG laser (1,064 nm). The patients were treated with eight sessions separated by 7 days, with a wavelength of 694 nm, pulse duration of 40 ns, spot size of 7.1 × 7.1 mm, fluence of 3.0–3.5 J/cm², number of fractional dots 14 × 14, the diameter of each dot was 300 μm, and the distance between adjacent dots was 200 μm. The outcomes were evaluated using mexameter, RCM, global assessment by three blind investigators, and patient satisfaction. The global improvement showed 93.33% of excellent or good improvement with the vast majority of the patients rating their results as excellent or good. The objective evaluations also confirmed the efficacy of the QSRL by showing a decrease in erythema and melanin index and a clearance of melanin deposition. Vanaman Wilson et al.¹⁹ evaluated the efficacy of one session of the dual wavelength picosecond Nd:YAG laser (first pass with 1,064 nm at 1.3 J/cm² and 5 Hz, followed by a second pass of 532 nm at 0.16J/cm² at 5Hz) and three sessions of the picosecond 755 nm alexandrite laser (through a fractionated lens with a 6 mm spot size and 0.71 J/cm² fluence at 1–5 Hz in a single pass) and the blinded-investigator assessment showed significant improvement with the latter and no improvement with the first laser.

The remaining studies focused on comparing various treatments in an attempt to identify the most effective option for POH.

Two studies compared two of the most used therapies for the treatment of dark circles – carboxytherapy and PRP.^7,16 Asilian et al., using a split-face model, randomly assigned treatment with carboxytherapy once a week for 6 weeks and intradermal injections of PRP every 2 weeks for three sessions.⁷ The outcome was evaluated by automatic assessment of skin vascularity and pigmentation in digital camera analysis, dermatologist blind evaluation, and patient self-assessment. Both the automatic assessment and the dermatologist assessment showed no statistically significant improvement after any technique or between the two. However, the patient’s self-assessment showed improvement with both techniques, but again, not between the two. In terms of side effects, PRP has more remarkable ones, such as ecchymosis and pain. Nofal et al. also compared the two therapies, with the left periorbital area being treated with intradermal PRP injection every 2 weeks for seven sessions and the right side with carboxytherapy every week, also for seven sessions.¹⁶ The periorbital darkness improvement was evaluated pre- and post-treatment and the patient self-evaluated. In this study, there was a statistically significant improvement in both sides, without difference between them. Complaints of pain and ecchymosis on the PRP-treated side caused some patients to refuse to complete all sessions.

Ahmed et al. focused on comparing carboxytherapy, chemical peeling (with a combination of trichloroacetic acid [TCA] 3.75% and lactic acid [LA] 15%), and Vitamin C mesotherapy by splitting the 45 patients into three groups.⁶ The patients were treated once a week for 5 weeks. The outcomes were evaluated by comparing the degree of dark circles before and after treatment with digital photographs and patient satisfaction. In all the groups was an improvement in periorbital pigmentation without a statistically significant difference between them. However, among all of the therapies, mesotherapy showed the most impressive improvement in pigmentation and a higher level of patient satisfaction [Table 2].

Ellabban et al. compared the efficacy of four sessions, 2 weeks apart, of chemical peelings and PRP.⁹ The patients were randomly divided into two groups, one treated with a peeling agent consisting of TCA 3.75% and LA 15% and the other with autologous PRP injections. The dark circles’ improvement was assessed by digital photographs taken every session and evaluated by two dermatologists and by the patients. In both treatments, there was a statistically significant improvement in periocular dark circles, with a high statistically significant difference in favor of chemical peeling, which was confirmed by patient satisfaction.

Dayal et al. proposed to compare different types of peelings and Vitamin C.⁸ For that, the author randomly distributed the patients into three groups, the first one being treated with 20% glycolic acid peel, the second group with 15% lactic peel, and the third group only applying 20% topical Vitamin C daily. The two dermatologist assessments of the percentage of pigmentary clearance showed that the clinical improvement was maximum and fastest with the glycolic peel group, followed by the lactic peel group. However, all three groups had some level of skin lightening.

Kadry et al. aimed to evaluate whether combined fat transfer and nanofat were more effective than PRP in treating infraorbital dark circles.¹¹ For that, 30 patients were randomized into two groups: One was treated with PRP injections every 4 weeks for 3 sessions, and the other was injected with fat and emulsified fat in one session. Both the clinical assessment and the patient satisfaction showed superiority in terms of improvement and satisfaction with autologous emulsified fat.

The next group of studies aims to compare different types of lasers with each other or with different types of POH treatments.

Zaheri et al. compared the effects of four bi-weekly sessions of carboxytherapy on one side of the face with fractional CO₂ laser therapy on the other.²² Both physician and patient assessments indicated that CO₂ laser therapy resulted in greater improvement and higher patient satisfaction, with side effects similar to those of carboxytherapy.

Carboxytherapy was also compared with fractional Q-switched Nd:YAG laser in a study conducted by Nilforoushzade h et al.,¹⁴ in which the patients were divided into two groups, with one group treated by six sessions of carboxytherapy and the other group treated with four sessions of 1,064 nm fractional Q-switched Nd:YAG laser (fluency of 1.3 J/cm², pulse rate of 5 Hz, spot size of 7 × 7 mm, energy 500 spot size, and a pulse duration of 5 ns).¹⁴ The results were evaluated by objective assessment using a colorimeter, cutometer, Mexameter, and skin ultrasound imaging system and physician and patient satisfaction, and although both treatments showed to be effective in the treatment of POH, carboxytherapy proved to be significantly more effective by increasing skin lightness and decrease in melanin content.

In a study by Zamanian et al., CO₂ laser therapy was compared with microneedling for treating dark circles.²³ One group received fractional CO₂ laser treatment (power: 15; stack: 1; pulse duration: 1000; and spacing: 1000), while the other was treated with microneedling combined with topical TCA 10% application. Objective assessments, based on the difference in darkness intensity in digital photographs, along with evaluations by physicians and patients, indicated higher efficacy and satisfaction for the CO₂ laser treatment.

Finally, Nilforoushzadeh et al.¹³ evaluated whether combination therapy was superior to monotherapy by treating the right periorbital side with a combination of long pulse Er:YAG laser with energy of 500–700 mJ and autologous PRP, and the left side with only the Er:YAG laser.¹³ Both treatments were administered in three sessions at 4-week intervals. The evaluation utilized objective instruments (colorimeter, cutometer, Visioface, and Mexameter), along with assessments by independent blinded investigators and patient satisfaction ratings. While both treatments proved effective, the combination therapy showed superior results across all evaluated parameters, including skin lightness, percent change in color, and reduction of wrinkles, as well as higher patient and physician satisfaction.

DISCUSSION

As we can see from the results above, there are a lot of different treatments available for POH, mostly due to its complexity and various etiologies. In this systematic review, we focused on the POH, excluding the tear-through type.

With this article, we aimed to evaluate the most common treatments for POH, focusing on clinical trials that provided evidence-based insights. The treatments assessed included PRP, laser therapy, carboxytherapy, chemical peels, microneedle fractional radiofrequency, and autologous fat, and one of the most prominent findings is that while most treatments are effective in reducing POH, none of them completely eradicated it.

PRP was evaluated in five studies and while in monotherapy it improved infraorbital homogeneity and the patient satisfaction was extremely high, when in comparison with other treatments (such as chemical peelings or emulsified fat), it appeared to be less effective.^7,9,11,12,16 When studied in combination with laser Er:YAG, it boosted the efficacy of the laser, contributing to superior results in skin lightness, percent change in color, and reduction of wrinkles as well as higher patient satisfaction.¹³ Based on the reviewed studies, PRP is generally considered an effective treatment for POH, though it is likely not the most potent option when used alone. It appears to enhance efficacy when combined with other treatments.

Various types of lasers have been evaluated in studies, including Q-switched Nd:YAG laser, CO₂ laser, QSRL, and Er:YAG laser. In terms of monotherapy, both Q-switched Nd:YAG laser and QSRL demonstrated favorable outcomes in objective measurements and patient satisfaction.^20,21 However, when compared to carboxytherapy, the Nd:YAG laser, while effective for POH, showed reduced efficacy and increased side effects.¹⁴ A study evaluating fractionated picosecond lasers revealed that the 755 nm alexandrite laser improved hyperpigmentation, unlike the dual-wavelength picosecond Nd:YAG laser.¹⁹ Conversely, CO₂ laser lacked direct studies on its efficacy in monotherapy but exhibited superior results and higher patient satisfaction compared to carboxytherapy and microneedling.^22,23 It’s worth noting that only a single treatment was administered with the dual-wavelength picosecond Nd:YAG laser, whereas a series of treatments were performed with the 755 nm alexandrite laser. The ER: YAG laser also demonstrated effectiveness in treating dark circles and periorbital wrinkles, with enhancement of these results when combined with PRP.¹³

It is known that injection of CO₂ into tissue induces hypercapnia, increasing blood flow and thereby stimulating the production of growth factors that promote the formation of new blood vessels, collagen and elastin.¹⁰ Carboxytherapy, investigated in three articles as monotherapy, consistently demonstrated efficacy in improving periorbital pigmentation, high patient satisfaction, ease of use, and high tolerability.^10,17,18 However, concerns persist regarding the mode of administration and the required number of sessions. Research suggests that three sessions are generally sufficient to achieve results while maintaining patient compliance, with higher flow rates not necessarily correlating with improved outcomes. Lower flow rates are preferred due to comparable efficacy with fewer side effects in treating dark circles. Comparative studies with PRP peels and mesotherapy found carboxytherapy to yield similar results in improving POH.^6,7,16 Nevertheless, when compared to lasers such as CO₂ and Q-switched 1,064 nm Nd:YAG, carboxytherapy showed inferior efficacy.^14,22 Despite this, the majority of the eight studies, including carboxytherapy, reported improvements in periorbital pigmentation and patient satisfaction, underscoring its continued relevance as a treatment option.

Peelings have been proposed as a treatment in the POH due to their capacity to eliminate melanin from the stratum corneum and epidermis.²⁴ In the study of Dayal et al., the authors concluded that alpha hydroxy acids (20% glycolic peeling and 15% LA peeling) are effective, with the glycolic peeling being more effective and having the fastest results, despite being the one with the most side effects.⁸ Ellabban et al. also confirmed the efficacy of the chemical peelings (in this study, TCA 3.75% + LA 15% was used) and showed its superiority in efficacy, tolerance, and patient satisfaction when in comparison with PRP.⁹ Finally, Ahmed et al. compared the chemical peelings (TCA 3.75% + LA 15%) with carboxytherapy and Vitamin C mesotherapy, again corroborating the hypothesis that chemical peelings are an effective weapon in treating POH.⁶

Vitamin C mesotherapy merits mention as a valuable agent for treating dark circles. In the study by Ahmed et al. discussed above, while it did not demonstrate statistical superiority over other treatments, it resulted in the most significant improvement in pigmentation and the highest level of patient satisfaction.⁶ The only drawback reported was a burning sensation experienced during the procedure.

In a study by Nilforoushzadeh et al., microneedle fractional radiofrequency emerged as a viable option for treating hyperpigmentation.¹⁵ It not only diminishes melanin and improves skin lightness, elasticity, density, and thickness in the periorbital area, but it also improves wrinkles.

CONCLUSION

POH remains a significant concern in esthetic medicine, often associated with tiredness and signs of aging. Despite its prevalence, limited data and the multifactorial etiology of this condition present substantial challenges in selecting effective treatments. A narrative review of clinical trials highlighted in this study assessed various treatment modalities for POH. Many treatments demonstrated partial but notable improvements, even if they did not fully eliminate the pigmentation.

The clinical trials reviewed involved a diverse range of interventions, each one with advantages and limitations, emphasizing the need for tailored approaches based on individual patient characteristics and preferences. For instance, PRP enhances skin homogeneity and is generally associated with good patient satisfaction. However, it carries a risk of notable side effects in certain cases, which may impact individual experiences. Carboxytherapy effectively reduces periorbital pigmentation, significant improvement in skin lightness and decreased melanin content while offering high patient satisfaction, ease of use, and excellent tolerability. Laser therapies, such as QSRL and fractional CO₂ laser, showed significant reductions in pigmentation and improved skin texture, though not all patients achieved the desired outcomes with every modality. Microneedling combined with topical treatments proved effective in enhancing skin elasticity and reducing pigmentation.

Furthermore, comparisons between different treatment strategies highlighted the potential benefits of combination therapies. For instance, combining long-pulse Er:YAG laser with PRP yielded superior results over monotherapy alone, offering enhanced skin lightness, reduced pigmentation, and higher patient satisfaction. These findings suggest that a one-size-fits-all approach may not be optimal for treating POH, as individual patient response varies widely based on factors such as skin type, the degree of pigmentation, and the presence of underlying conditions.

Given the limited data and the diverse treatment outcomes observed across the reviewed studies, further research and comparative studies are warranted to elucidate optimal treatment strategies for this challenging condition. Future studies should focus on long-term outcomes, patient-centered assessments, and the development of new, innovative approaches to managing POH effectively.