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DOI: 10.1111/j.1468-3083.2010.03625.x

REVIEW ARTICLE

Aesthetic effects of topical photodynamic therapy E Kohl,† LAR Torezan,‡ M Landthaler,† R-M Szeimies,†,§,* †

Department of Dermatology, Regensburg University Hospital, Regensburg, Germany Department of Dermatology, Universidade de Sa˜o Paulo, Sa˜o Paulo, Brazil § Department of Dermatology, Klinikum Vest, Recklinghausen, Germany *Correspondence: R-M Szeimies. E-mail: [email protected] ‡

Abstract Topical photodynamic therapy has shown to be effective for the treatment of several aspects of skin ageing. Multiple studies have demonstrated improvement of fine wrinkles, mottled hyperpigmentation, tactile roughness and sallowness. These results are supported by immunohistochemical analysis that revealed both upregulation of collagen production and increased epidermal proliferation. Neocollagenesis as an indirect dermal effect of photodynamic therapy is stimulated through cytokine induction. This article reviews the available literature for photodynamic rejuvenation while discussing cosmetic effects, light sources, adverse effects and the mechanism of action. Received: 7 December 2009; Accepted: 21 January 2010

Keywords aesthetic, photodynamic therapy, photorejuvenation, skin ageing, skin rejuvenation

Conflict of interest The authors certify that, to their knowledge, the work that is reported on in said manuscript has not received financial support from any pharmaceutical company or other commercial source except as described below. Neither the authors nor any first-degree relative have any special financial interest in the subject matter discussed in said manuscript. Dr Kohl and Prof. Landthaler declare no conflict of interest. Prof. Szeimies has received grants for participation in clinical trials from Abbott, Biofrontera AG, Galderma, 3M, meda Pharma, PhotoCure ASA, photonamic, Schering-Plough and Wyeth; has received honoraria for participation in advisory boards from Galderma, Intendis, and Peplin; has received honoraria as a speaker for Almirall-Hermal, Galderma, Intendis and photonamic. Dr Torezan has received grants for participation in clinical trials from Galderma; has received honoraria as a speaker for Galderma.

Introduction As a complex biological process, cutaneous ageing is affecting all constituents of the skin, resulting in a multitude of aesthetic and functional variances. Both, genetic and environmental factors, contribute as so-called intrinsic and extrinsic ageing. Ultraviolet (UV) irradiation is responsible for approximately 80% of premature skin ageing.1 Reactive oxygen species (ROS) generated after ultraviolet irradiation give rise to increased transcription of matrix metalloproteinases (MMPs) through complex signalling pathways, decreased expression of the procollagen I and procollagen III genes and in conclusion to reduced dermal matrix generation. UV radiation also involves an accumulation of degraded collagen in the dermis, which antagonises neocollagenesis. Sun-protected, chronologically aged skin differs clinically and histologically from sun-exposed areas such as face, neck and the back of hands. Features of aged, photoprotected skin include fold

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accentuation and laxity, yet skin appears soft and without pigmentary irregularities.2 One of the hallmarks of sun-related changes in the skin is elastosis in association with degeneration and decrease of collagen, clinically apparent as yellow discoloration and coarse wrinkles. Histologically accumulated abnormal elastic fibres in the papillary dermis can be detected. As a result of UV-induced hyperplasia of melanocytes or increased melanogenesis, pigmentary alterations like ephelides, lentigines and a diffuse irreversible hyperpigmentation are apparent. Moreover, alterations in cutaneous microvasculature like regression of small blood vessels and neoangiogenesis, resulting in teleangiectasias are seen on chronically light-exposed skin. Finally, sebaceous gland hyperplasia along with a downregulation of sebum production are found.3,4 As a result of a growing demand for aesthetic improvement of aged skin, not least on the basis of an increasing proportion of

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older people, dermatologists search for new modalities to reverse signs of age and UV-associated changes. Photodynamic therapy

Non-ablative skin resurfacing is becoming more popular allowing for treatment of various aspects of skin ageing without severe side-effects. In search of new possibilities for skin rejuvenation, topical photodynamic therapy (PDT) with various light sources is increasingly applied.5 PDT using aminolevulinic acid (ALA) in combination with blue light was approved by the FDA for the treatment of actinic keratoses (AK) in 1999. It became clear that PDT provides potential capacity for skin rejuvenation aside from treatment of non-melanoma skin cancer (NMSC). PDT requires a photosensitizer that is localized in the target tissue and irradiation with visible light. For topical PDT, ALA, either in a cream base or in a solution (Levulan Kerastick; DUSA Pharmaceuticals, Inc., Wilmington, MA, USA) and its methylester derivative (methylaminolevulinate; MAL) [Metvix (Metvixia in France and USA), Galderma, France] are applied. Modified enzyme activities in tumour cells and increased uptake in altered keratinocytes maintain the accumulation of the endogenous photosensitizer protoporphyrin IX. The activation by light of the appropriate wavelength leads to generation of singlet oxygen or ROS, resulting in selective destruction of the photosensitized cells. PDT is recommended as treatment of first choice for AK, Bowen’s disease, superficial basal cell carcinoma and thin nodular basal cell carcinoma.6 Photodynamic therapy with intense pulsed light sources (IPL)

The larger part of studies for photodynamic photorejuvenation, the term created for PDT for reversal the signs of photodamage, has been conducted with IPL devices. Three prospective, randomized split-face trials using 20% ALA as photosensitizer have been performed so far for photodynamic rejuvenation (Table 1).7–9 One randomized, IPL split-face trial was conducted by Dover et al.8 Twenty subjects receiving five treatments in 3 week intervals were included in this single-blinded study. ALA-solution (Levulan Kerastick; DUSA Pharmaceuticals, Inc.) was applied on the facial half 30–60 min prior to the first three IPL-treatments, the last two treatments consisted of IPL only. The ALA-IPL group showed better results for global score for photoaging (80% vs. 45%; P = 0.008), improvement of fine lines (60% vs. 25%; P = 0.008) and mottled pigmentation (85% vs. 20%; P < 0.001). The final cosmetic evaluation by the investigator and subject satisfaction scores were significantly superior to the IPL-only sides. Pretreatment with ALA did not enhance effectiveness on sallowness and tactile roughness. The incidence of adverse effects was higher at the ALA-IPL sides, subjects experienced more intense erythema (50% vs. 15%; P = 0.04), scaling and dryness (50% vs. 15%; P = 0.04), oedema (50% vs. 10%; P = 0.01) as well as crusting and vesiculation (20% vs. 5%; P = 0.11).

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Another trial was performed to compare short-contact ALA-PDT vs. IPL alone for enhancement of diffuse photodamage.9 Patients (n = 16) received three treatments in 1 month intervals. With respect to all treatment parameters (crow’s feet, teleangiectasias, mottled hyperpigmentation and tactile skin roughness) improvement was considerably better on the PDTside. A retrospective study of 17 patients evaluated the efficacy of ALA-PDT using IPL in the treatment of AK and signs of photoaging.10 Besides the healing up of 68% of AK, a 48% improvement in pigmentary irregularities and a 25% improvement in coarseness of skin texture were monitored, but no change in fine wrinkle appearance. Marmur et al.11 conducted a split-face study to investigate changes in collagen formation after ALA-PDT by electron microscopic ultrastructural analysis. Seven subjects with mild facial photodamage received two full face IPL treatments in a 1 month interval. A 560 nm cut-off filter was used to deliver light with 27– 30 J ⁄ cm2 using a double pulse of 2.4 and 4 ms and a 10 ms delay between pulses. Punch biopsies, which were performed prior to the treatment and 3 months after the last treatment, revealed an increase in type I collagen in the dermis, which was especially evident in the ALA-IPL group. A subjective advancement of skin quality was found in all seven patients, while observed side-effects were minimal. Photodynamic therapy with pulsed dye lasers (PDL)

As it had been demonstrated that PDT with PDL enables treatment of NMSC equally efficient to non-coherent light sources, yet at significantly lower pain levels, PDL are frequently used light sources for PDT.12 Key et al.13 designed a split-face study to evaluate PDL-PDT for treatment of diffuse facial photodamage. One hour following ALA application, both sides of the face were treated with a PDL. All patients reported improved skin texture, disappearance of solar lentigines and clearance of skin roughness on the ALA-PDL sides, whereas no improvement of vascular irregularities was noticed. Opposite sides lacked improvement regarding these aspects. All 14 patients participating in the study asked for PDT of the facial halves that had not been treated with ALA. Treatment, as assessed by patients, was not painful. Orringer et al.14 examined molecular effects of ALA-PDT using a PDL for photoaged forearm skin. Ki67, an immunohistochemical marker of kerotinocyte proliferation was upregulated, and epidermal thickness was increased after treatment. PDLPDT was shown to induce collagen production, as there were elevated levels of procollagen I and III mRNA and procollagen I protein in the dermis. However, immunostaining for p53, a marker of photodamage, did not show a decrease following PDL-PDT. In comparison with pulsed dye laser treatment without photosensitizer, dermal remodelling was more pronounced with PDL-PDT.

ª 2010 The Authors Journal of the European Academy of Dermatology and Venereology ª 2010 European Academy of Dermatology and Venereology

JEADV 2010, 24, 1261–1269 ALA 30–60 min

Red light (37 J ⁄ cm2)

IPL (550 ⁄ 570 nm, 34 J ⁄ cm2)

IPL (560 nm, 28–32 J ⁄ cm2)

Zane et al. 2007

Gold et al. 2006

Avram et al. 2004 ALA 1 h

MAL 3 h

Red light (37 J ⁄ cm2) and fractional resurfacing vs. fractional resurfacing

RuizRodriguez et al. 2007

+

+

+

MAL 1 ⁄ 3 h

Red light (37 J ⁄ cm2)

RuizRodriguez et al. 2008

MAL 3 h

Splitface study

Photosensitizer and incubation time

Light source

Authors

17

13

20

4

10

No. patients

Face

Face

Face

Perioral

Face

Treatment area

1

3 (1-month intervals)

2 (1-month intervals)

2 (3 week intervals)

3

No. treatments

3 months

3 months

2 months

12 weeks

2 months

Follow-up period

AK and photodamage

AK and photodamage

AK and photodamage

Mild to moderate wrinkles

AK and photodamage

Indication

Table 1 Outcome of controlled studies using topical photodynamic therapy for the treatment of photoaging

Improvement in: – teleangiectasias (55%) – pigmentary irregularities (48%) – coarseness (25%) no change in fine wrinkle appearance

More improvement on the PDT side for: – crow’s feet – skin roughness – mottled hyperpigmentation – teleangiectasias

Significant improvement of: – mottled hyperpigmentation – fine lines – roughness and sallowness. No improvement of: – teleangiectasias, facial erythema – sebaceous gland hypertrophy

Increased improvement of fine wrinkles in the combined treatment side

Moderate improvement of: – skin tightness – fine wrinkles – tactile roughness in the side incubated with MAL for 3 h. No improvement of: – teleangiectasias – mottled pigmentation

Results

Erythema, oedema and desquamation

Erythema and oedema on both sides of the face in fewer than 10% of treatments, no downtime

Erythema and oedema, crusting and erosions limited to areas with AK

Erythema and oedema, scaling (more intense in the combined treatment side)

Erythema and oedema, scaling (more intense in the combined treatment side)

Side-effects

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FPDL (585 nm, 5–6 J ⁄ cm2, pulse width 40 ms, 3–4 passes)

IPL (560 nm, 27–30 J ⁄ cm2, double pulse of 2.4 and 4 ms)

Blue light (10 J ⁄ cm2)

IPL (515 nm, 23–28 J ⁄ cm2, double pulse of 2.4 and 4 ms)

Alster et al. 2005

Touma et al. 2004

Dover et al. 2005

Light source

Key et al. 2005

Authors

Table 1 Continued

ALA 30–60 min

ALA 1⁄2⁄3 h

ALA 1 h

ALA 1 h

Photosensitizer and incubation time

+

+

+

Splitface study

20

17

10

14

No. patients

Face

Face

Face

Upper half of the face

Treatment area

2 IPL-only treatments following 3 PDT-treatments

1

1

1

No. treatments

1 month

1 month

6 months

1 month

Follow-up period

Photodamage

AK and photodamage

Photodamage

Photodamage

Indication

Improvement in: – global score for photoaging (80% vs. 45%, mottled pigmentation (95% vs. 60%) – fine lines (60% vs. 25%)

Significant improvement of overall Griffiths score, sallowness, wrinkling, skin quality; improvement of mottled pigmentation of borderline significance; no improvement of coarse wrinkling

More improvement on the PDT-sides for global score for photoaging

Increased softness, improved texture on the ALA-treated side No similar changes on the PDL-only side No improvement in vascular irregularities

Results

Erythema, scaling, dryness, crusting (more often on the PDT-sides)

Erythema and edema

Erythema, oedema and desquamation (more intense on the combined treatment side)

Erythema on both sides (more intense on the combined treatment side)

Side-effects

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Photodynamic therapy with incoherent blue light

Discussion

Touma et al.15 evaluated short-contact ALA-PDT using blue light (417 ± 5 nm, fluence: 10 J ⁄ cm2) for treatment of photodamage including AK. Inclusion criteria consisted of mild to moderate facial photodamage and not less than four AK. PDT was performed following an incubation time of 1–3 h. Besides a high remission rate of AK of about 90%, statistically significant improvement of several parameters of photodamage including skin quality, fine wrinkling and sallowness was achieved. There was no significant enhancement of coarse wrinkling and mottled pigmentation. Overall patient satisfaction was high, since 76% of treated subjects reported good improvement.

Skin rejuvenation using ablative lasers results in effective improvement of all aspects of photoaging, although down-time and possible postprocedure side-effects such as redness, hyperpigmentation and hypopigmentation display big drawbacks. This is the reason why non-ablative skin rejuvenation is becoming more popular although limited in efficacy. PDT is a new promising tool for treating photodamage, as attainable cosmetic effects are considerably better than with non-ablative skin rejuvenation.8 In addition, side-effects are less severe and incidence of serious side-effects is lower than with ablative skin rejuvenation. Therefore, photodynamic skin rejuvenation takes up a middle position between ablative and non-ablative skin rejuvenation (Table 2). Several studies evaluated efficacy of PDT in regard to dyschromia. Improvement in mottled hyperpigmentation was significantly better with IPL-PDT than in the IPL-only side,8,9 a significant improvement was accomplished as well with red and blue lightPDT.15,16 In addition, Key et al.13 attained removal of brown spots with PDL-PDT, while PDL-treatment alone was not successful. In terms of enhanced roughness, several studies emphasize the effectiveness of PDT.9,10,13,15 However, one IPL split-face study failed to show additional improvement after pretreatment with ALA, as a result of the excellent results which had already been achieved through IPL-only treatment.8 For fine lines, studies have also documented that patients benefit from PDT.16,17 Both Gold et al.9 and Dover et al.8 demonstrated better improvement of fine rhytides for treatment sides receiving PDT with IPL activation than for the other sides receiving IPL treatment only. These results were not confirmed by another split-face study comparing IPL-PDT with IPL alone.7 This lack of improvement may be related to the single treatment performed in this trial, whereas therefore mentioned trials consisted of a series of at least three full-face treatments. With regard to sallowness, two clinical trials using red and blue lights reported on significant advancement of topical PDT.15,16 However, in the only split-face study evaluating sallowness, pretreatment with ALA did not seem to enhance the results of the IPL treatment.8 Two IPL ⁄ IPL-PDT split-face studies accounted for more improvement in the PDT sides as to global score for photoaging.7,8 One month after the last treatment, 80% of the subjects experienced a significant enhancement in the ALA followed by IPL-treated side concerning global score for photoaging, although just 40% of the subjects treated with IPL showed significant

Photodynamic therapy with incoherent red light

A clinical trial enclosing 20 patients was conducted by Zane et al.16 The aim of this study was to assess efficacy of MAL-PDT using red light from an LED (light-emitting-diode) (37 J ⁄ cm2) for treatment of AK and severe photodamage. A statistically significant improvement was achieved with regard to mottled hyperpigmentation, fine lines, roughness and sallowness. Clearance rate of AK was 88.3% after the second treatment. No modification was attained regarding deep wrinkles, teleangiectasias, facial erythema and sebaceous gland hyperplasia. Besides clinical evaluation, Zane et al.16 also performed a high frequency echographic evaluation to quantify epidermal and dermal changes through PDT. A significant increase of skin thickness was revealed. The subepidermal low-echogenic band, which is found in the upper dermis and normally increases in photoaged skin as a result of the accumulation of elastotic material, showed a significant reduction. The authors attributed these findings to new formation of collagen. Ruiz-Rodriguez investigated the effectiveness of PDT using red light in the treatment of facial photodamage and AK.17 Ten patients were treated three times within a split-face protocol with MAL and red light. Incubation time was 1 h and 3 h respectively. A blinded assessment was performed prior to the treatment and 2 months after the last treatment and revealed moderate improvement in tactile roughness, fine lines and skin tightness in most patients on the side, incubated with MAL for 3 h. No improvement in pigmentary irregularities and teleangiectasias were observed. Photodynamic therapy with fractional light exposure

Methylaminolevulinate-photodynamic therapy in connection with fractional photothermolysis was evaluated by Ruiz-Rodriguez et al.18 Four women received two treatments with a 1.5 lm laser system in a 3 week interval. Following the fractional treatment, one half of the perioral area was incubated with MAL for 3 h and illumination with red LED-light in a dose of 37 J ⁄ cm2 was carried out. Cosmetic results in respect of superficial rhytides and subject satisfaction scores were better in the combined treatment sides.

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Table 2 Positive effects of topical photodynamic therapy Improvement of fine wrinkles

8, 9, 15, 16, 17, 18

Improvement of tactile roughness

9, 10, 13

Improvement of skin tightness

17

Improvement of mottled hyperpigmentation

8, 9, 15, 16

Improvement of sallowness

15, 16

Improvement of teleangiectasias

9, 10

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improvement. Effects of PDT on teleangiectasias have been reported in two studies using IPL,9,10 although this effect was not detected in other trials using red light and PDL.13,16,17 Results of clinical trials assessing clearance of AK within the scope of photodynamic rejuvenation were comparable with those of other PDTstudies for treatment of AK. Both clinical results from the above mentioned studies and experimental aspects recently uncovered may help to understand the possible mechanism of action responsible for the clinical result. As a consequence of an upregulated ALA uptake and modified enzyme activities, PpIX accumulates in premalignant keratinocytes. Thus, selective destruction of those keratinocytes through PDT results in rapid healing.19 The epidermal renewal caused by exfoliative effects and epidermal proliferation improves the skin texture and leads to less roughness, increased epidermal thickness and less pigmentary changes (Fig. 1). Moreover, neocollagenesis as an indirect dermal effect of PDT is stimulated through cytokine induction.11,14,20 Karrer et al.20 demonstrated the indirect induction of MMP-1 and MMP-3 production in fibroblasts after PDT through keratinocyte-derived cytokines. As a result of sublethal damage of keratinocytes, photo-oxidative stress leads to epidermal release of several cytokines including TNF-a, IL-1 and IL-6. Those

cytokines penetrate the basal layer and trigger MMP production in dermal fibroblasts by a paracrine loop. In contrast to UV-mediated induction of ROS, which also takes place in the dermis and is responsible for skin ageing processes e.g. by a direct effect on fibroblasts and extracellular matrix,21 PDT acts only in the epidermis as no relevant sensitization of dermal tissue is achieved after topical application of ALA or MAL. The accumulation of partially degraded and fragmented collagen, such as it is present in photoaged skin, inhibits neocollagenesis.22 Proteolytic clearance of fragmented collagen by MMPs plays therefore a decisive role in restoring collagen biosynthesis,23,24 whereas induction of MMPs by non-ablative laser energy and PDT is quantitatively more modest than with CO2-laser.14,22,25,26 Marmur et al.11 demonstrated that PDT using IPL induces a greater increase in type I collagen than IPL treatment alone, indicating that PDT is superior to other non-ablative laser treatments. In line with these results, Orringer et al.14 demonstrated that PDLPDT enhances collagen production. Molecular changes associated with neocollagenesis were not as pronounced as those following carbon dioxide laser resurfacing, yet quantitatively greater than after non-ablative laser therapy using a PDL alone. Besides an increase in dermal collagen, a decrease in the amount of solar

Figure 1 Photodynamic therapy for ageing skin – mechanism of action. Typical features of ageing skin are positively affected by photodynamic therapy: Besides a direct effect on the epidermis based on the photosensitization of altered keratinocytes and their subsequent destruction followed by a normal restoration, there is an indirect effect based on the secretion of cytokines such like IL-6 or TNFa. After penetrating the basement membrane, they induce MMP-1 and MMP-3 in dermal fibroblasts thus leading to degradation of elastotic material and neocollagenesis in the upper dermal parts which results in reduction of fine wrinkling. This effect also masks subepidermal enlarged vessels thus resulting in less erythema.

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ª 2010 The Authors Journal of the European Academy of Dermatology and Venereology ª 2010 European Academy of Dermatology and Venereology

Aesthetic effects of photodynamic therapy

elastotic material after PDT was observed (Fig. 1). A clinical picture for skin rejuvenation by PDT is shown in Fig. 2. The fact that PDT is successfully applied for treatment of localized scleroderma, which stands apparently in contrast to skin rejuvenation, may be ascribed to entirely different molecular and cellular environment. Numerous light sources including red light, blue light, PDL and IPL have been used for photodynamic rejuvenation. As a result of the maximum absorption peak of PpIX at 410 nm, blue light has been shown to be approximately 50 times more potent for activating PpIX than red light, which uses one of the smaller absorption peaks at 630 nm. However, at shorter wavelengths significant tissue and melanin absorption provide less light penetration, resulting in a penetration depth of 1–2 mm27 contrary to a penetration depth of up to 4 mm of red light. Both red and blue lights are mainly used for PDT of AK and BCC, although red light sources are being preferred when deeper lesions are treated. Many studies evaluating topical PDT for the treatment of AK document the excellent cosmetic outcome besides high remission rates using red light.28–30 Patients with AK are therefore especially suited for photorejuvenation with red-light PDT, as a safe and effective treatment of AK may be performed within the scope of the rejuvenation procedure. Pulsed light sources are commonly used for photodynamic rejuvenation. Both PDL and IPL also exploit other Q-bands of minor

(a)

(b)

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absorption peaks. Karrer et al.12 performed an in vitro and in vivo study comparing PDL and an incoherent light source (580 nm– 740 nm). Using the PDL at a wavelength of 585 nm (18 J ⁄ cm2; pulse duration 1.5 ms), no difference between both light sources regarding complete remission rate of AK was detected. Both light sources resulted in excellent cosmetic results, yet with purpura as side-effect with PDL. Besides the photochemical reactions, PDL selectively targets haemoglobin, making it a suitable light source for simultaneous treatment of teleangiectasias. Several studies have indicated that IPL devices are suitable for treatment of AK.31,32 Babilas et al.33 were able to show that MALPDT for AK using an IPL light source was significantly less painful than an LED system. Besides rapid treatment, patients benefit from PDT using IPL with respect to synergistic effects. Bitter et al. demonstrated that a series of full-face IPL-treatments without a photosensitizer resulted in an improvement of all aspects of photoaging, including fine lines, irregular pigmentation, skin texture, pore size and teleangiectasias. This possibly accounts for the exceptional good results following IPL-PDT for patients presenting with irregular pigmentation and teleangiectasias. The most prominent side-effect of PDT is pain during illumination. Pain was mostly documented as simply mild to moderate, whereas PDT using pulsed light was usually better tolerated as red or blue light PDT. A forced cool-air device is helpful for pain

(c)

Figure 2 Clinical picture for the use of photodynamic therapy (PDT) in skin rejuvenation. (a) A 59-year-old female patient before photodynamic therapy and (b) 1 day after treatment. After incubation with ALA for 150 min (Levulan Kerastick, DUSA Pharmaceuticals, Inc.) a full face IPL treatment (30 J ⁄ cm2, two passes) and illumination with blue light was performed. (c) The same patient was followed-up and the final result (after 3 months) following PDT for skin rejuvenation purposes is shown. A significantly smoother skin surface structure and markedly reduced wrinkles can be seen on the follow-up picture.

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Table 3 Side-effects of topical photodynamic therapy Erythema and oedema

9, 10, 15, 16, 17, 18

Scaling

7, 8, 10, 17, 18

Crusting

8, 16

relief during treatment, as application of topical anaesthesia did not significantly reduce pain.34 In addition, a continuing, calmative and motivating negotiation with the patient during the illumination is of particular importance (Table 3). The second most common side-effects are erythema and oedema, which emerged more frequently and more intense in the PDT-sides than in the IPL or PDL-only sides. The difference in the incidence of erythema and oedema, which ranged from < 10% to 100%,9,15 is resulting from chosen parameters, as a short incubation time results in less erythema. Unlike ablative rejuvenation, a prophylaxis for herpes simplex infections is not necessary for photodynamic rejuvenation. Bacterial infections are unusual as well, and attributable to contamination of the treatment area, as PDT has antimicrobial effects.35 Finally, in our experience, incubation time is of pivotal importance for cosmetic outcome. Insufficient application time implicates moderately satisfying results as a result of low synthesis of protoporphyrin IX. Therefore, incubation time for MAL should take 3 h, considerably longer than in most of the studies mentioned above. As far as pain is concerned, IPL light sources are particularly eligible for aesthetic indications as a result of the short light exposure. In case PDT is not only used for pure cosmetic effects but also for AK and other superficial NMSC, treatment parameters (photosensitizer, application time, light source and fluence) should always be adjusted to achieve a secure destruction of those tumours, as otherwise recurrent or insufficiently treated lesions will result. We are convinced of PDT as a novel technique for skin rejuvenation, because of effective improvement of photoaged skin, contemporaneous treatment of NMSC, the possibility of repeated treatment sessions and, in contrast to ablative skin rejuvenation, both limited and calculable side-effects. Therefore, photodynamic skin rejuvenation takes up a middle position between ablative and non-ablative skin rejuvenation both in reference to effectiveness and possible side-effects.

References 1 Kadunce DP, Burr R, Gress R, Kanner R, Lyon JL, Zone JJ. Cigarette smoking: risk factor for premature facial wrinkling. Ann Intern Med 1991; 114: 840–844. 2 Lavker RM. Cutaneous aging: chronologic versus photoaging. In Gilchrest BA, ed. Photodamage. Blackwell Science, Cambridge, 1995. p. 123–135. 3 Plewig G, Kligman AM. Proliferative activity of the sebaceous glands of the aged. J Invest Dermatol 1978; 70: 314–317. 4 Luderschmidt C, Plewig G. Circumscribed sebaceous gland hyperplasia: autoradiographic and histoplanimetric studies. J Invest Dermatol 1978; 70: 207–209. 5 Goldberg DJ. Photodynamic therapy in skin rejuvenation. Clin Dermatol 2008; 26: 608–613.

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ª 2010 The Authors Journal of the European Academy of Dermatology and Venereology ª 2010 European Academy of Dermatology and Venereology