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Pediatric Phototherapy
Symposium on Pediatric Dermatology
Pediatric Phototherapy Thomas F. Anderson, M.D.*
Phototherapy, utilizing the sun as a therapeutic light source, was first introduced by the ancient Greeks more than 3000 years ago. 19 Around the second century B. c., Herodotus stressed the usefulness of "heliotherapy" for the restoration of health. Christianity banned the practice of sun worship (and therapy) as paganism until the eighteenth century, when the salutary effects of "actinotherapy" for rickets were rediscovered. 5 With the impetus to devise artificial light sources for phototherapy, Niels Finsen initiated the use of the carbon arc lamp for lupus vulgaris (cutaneous tuberculosis) and was awarded a Nobel prize in 1903 for his work. Pediatric phototherapy had its heyday prior to the introduction of synthetic vitamin D for the treatment of rickets. Today, there still may be theoretic indications for phototherapy as a way of treating vitamin D-resistant rickets. 20 When the normal biotransformation of vitamin D cannot take place in the kidney or liver of the patient, photoactive precursors could be applied to the skin and transformed to the active metabolites following intermittent ultraviolet light phototherapy with subsequent slow percutaneous absorption. This would avoid the direct administration of these agents, which could easily result in hypercalcemia. 10 The work of Finsen prompted the use of ultraviolet radiation for all forms of tuberculosis and other cutaneous and respiratory infections as well. Indeed, a small amount of daily exposure to the sun has been credited with reducing the incidence of common infections in school children. 27 Today, the Madison Avenue epitome of health and well-being is a tanned body. This concept, unfortunately, supports the excesses of the "sun" industry, which promotes "vacations in the sun," tanning parlors, and tanning cosmetics. Although most dermatologists preach avoidance of sun to the majority of their patients, there are individuals, and even children, who may still benefit from phototherapy. With the development of the mercury vapor ultraviolet light source, physicians were first able to treat patients more conveniently than with the carbon arc lamp or natural sun. 19 These lamps emitted radiation produced by the ionization of mercury vapor under high pressure and heat, through *Associate Professor, Department of Dermatology, University of Michigan Hospitals and Veterans Administration Medical Center, Ann Arbor, Michigan
Pediatric Clinics of North America-Val. 30, No. 4, August 1983
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an ultraviolet transparent quartz filter (regular glass absorbs this radiation). The pioneer in the use of these "hot quartz" lamps in the treatment of skin disease was the famous Mayo Clinic dermatologist William Goeckerman (Fig. 1).16 His method, described in 1925, of combining the use of crude coal tar preparations and ultraviolet light in the treatment of psoriasis continues to be used today. 48 Modified by Ingram with the use of anthralin paste and later modified with the use of topical steroids, the Goeckerman regimen is useful for recalcitrant psoriasis, atopic dermatitis, and a wide variety of pruritic conditions. Other discoveries have paved the way for modern pediatric phototherapy. The low pressure mercury vapor lamps or "cold quartz" germicidal lamps have been advocated since the 1930s in the treatment of acne and pyodermas. 5 In 1956, a pediatric nurse, Sister J. Ward, noted the fading of jaundiced skin exposed to sunlight. Since then, visible light phototherapy of premature newborn hyperbilirubinemia has substantially lessened the need for exchange transfusions. 43 The 1970s brought the development of oral psoralen photochemotherapy and lasers to the practice of medicine. Considering the cumulative nature of electromagnetic radiation effects on living organisms, the question now for the '80s is the determination of the risk: benefit ratio for these potent therapies and their predecessors, particularly in children. Presented here is a review of the modern indications for phototherapy
Figure l. This typical portable "hot quartz" lamp, which produces midrange erythemal ultraviolet radiation (UVB), is commonly used for pediatric phototherapy.
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in children utilizing (1) high energy "germicidal" cold quartz ultraviolet (UVC) exposure, (2) mid-range ultraviolet (UVB) sunlamp treatment, (3) psoralen photochemotherapy utilizing long-wave ultraviolet light (PUVA), and (4) visible light phototherapy. A discussion of the indications, techniques, theoretical basis of the effects, benefits, and risks of each of these four forms of phototherapy will be highlighted. Table 1 illustrates the relationship of these therapies to all electromagnetic radiation therapy. Phototherapy generally pertains to electromagnetic radiation therapy within the range of 200 to 700 nm in wavelength. Germicidal (UVC) Phototherapy for Acne Since Fin sen's cure of lupus vulgaris with ultraviolet light at the turn of the century, a multitude of pyodermatous conditions have been treated with ultraviolet light phototherapy. With the development of the inexpensive cold quartz lamp, dermatologists attempted to treat acne. An early proponent of this therapy was Wright, who published his experience in 1935. 58 Citing the bactericidal effects of the 254 nm radiation, which constitutes more than 90 per cent of the output of the cold quartz lamp, Wright suggested a regimen that he had found to be effective. Utilizing as small a dose of UVC as 15 seconds at three inches, the cold quartz lamp was able to produce marked erythema within a few hours, followed in two or three days by desquamation. This regimen delivered once weekly resulted in improvement in 6 to 12 treatments. Of 94 patients with acne who were treated, more than 90 per cent improved (86), with nearly 50 per cent totally free of acne lesions. 43 Wright noted not only a decrease in inflammatory pustules and papules with this therapy but even an improvement in the appearance of old scars. The only untoward side effect of this treatment was the burning sensation following therapy and the resultant desquamation. Because shorter wave lengths are less efficient in stimulating melanocytes, patients receiving UVC develop very little pigmentation. The small degree of pigment produced may be, in part, due to the small amount of contaminating UVB produced by the cold quartz lamp. Recurrent herpes simplex labialis can be triggered in patients whose lips are not sufficiently protected. Moreover, care must be taken to protect patients' eyes, as direct exposure even for a few seconds can result in a very painful ocular keratitis. Citing the well-known improvement of many acne sufferers in the summertime, 43 Mills and Kligman studied patients exposed twice weekly for eight weeks to UVB, UVA, or both in the treatment of acne. 30 They used a bank of fluorescent bulbs emitting these long wavelength ultraviolet light components of natural sunlight. Exposure to this light source, or even direct sunlight, does not result in a significant exposure to UVC, as the latter is not produced to any great extent by the fluorescent phosphors of the bulbs and it is absorbed naturally by the atmosphere. They found that although UVB could produce marked erythema and desquamation, on the average, only a fair response with a modest decrease in inflammatory pustules and papules and no appreciable change in comedones was achieved.
Table 1.
Electromagnetic Radiation Therapy* WAVE LENGTH NM
<200
200--280
280-320
320--400
400-700
>700
Radiation
x-rays
uvc
UVB
UVA
visible
infra-red
Artificial source
variety
cold quartz "germicidal" fluorescent
hot quartz fluorescent sun lamp
long wave "black light" lamps
blue or white fluorescent lamps
variety
energy dependent
stratum corneum high epidermis
dermal-epidermal junction
dermis
subcutaneous fat
muscle & joints
++
+++
++++
+
radiodermatitis
desquamation
erythema
pigmentation
?
pigmentation
Representative indications
cancer
acne
psoriasis, eczema
PUVA, vitiligo
hyperbilirubinemia
arthritis
Long-term risks
cancer
unknown
aging, skin cancer, cataracts
aging, freckling, skin cancer, cataracts
unknown
unknown
Depth of skin penetration Relative biologic potency for erythema production Most prominent cutaneous effects
++
*Over the phototherapeutic range of 200 to 700 nm, the depth of penetration of radiation effect varies inversely with the energy, explaining why midrange ultraviolet light (UVB) is the most biologically potent. UVA and visible light penetrate deeper but are not sufficiently energetic to promote photochemical reactions without the assistance of a photosensitizer such as psoralen or bilirubin.
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This was decidedly less than what would be expected with conventional therapy with benzoyl peroxide or tretinoin. The results with UVA were worse, although patients noted a cosmetic improvement with the resulting tan. The combination of UVB and UVA produced the best results; however, again, only inflammatory lesions improved. The addition of topical psoralens to this regimen provided no advantage, and if a known comedogenic agent such as crude coal tar was added to the ultraviolet light phototherapy, the acne clearly worsened. Two other studies clearly show PUVA to be of no benefit other than cosmetic tanning in acne. 36· 41 Based on this work, Plewig and Kligman do not recommend ultraviolet light as adjunctive therapy for their acne patients. 49 However, it may be that germicidal UVC phototherapy could offer certain benefits to selected patients. Although there have been no controlled studies using germicidal radiation, dermatologists who have used UVC phototherapy down through the years will attest to the efficacy of this treatment. Moreover, preliminary results of a controlled trial of twice weekly UVC in acne suggest that this therapy is superior to the control (unpublished data). Germicidal UVC has potentially more damaging energy than UVB or UVA and is an excellent mutagen in vitro. However, it is scattered and absorbed to a great extent by the stratum corneum and only a small amount reaches the viable epidermis. 43 Presumably, any cells that might be damaged or killed by this radiation are subsequently desquamated. Hence, it is possible that the major action of this modality is a superficial bactericidal effect. Topical or systemic antibiotics used in the treatment of acne are generally bacteriostatic and associated with the development of resistant bacteria. 55 The superficial germicidal effect of this therapy could explain why UVC exposures theoretically might be beneficial. The desquamating effect of this therapy no doubt explains part of the efficacy, in that all known agents (chemical or physical) that produce this change seem to improve acne to some degree. A small amount of deeper penetrating, longer wavelength ultraviolet light (UVB) is produced by cold quartz lamps and may participate in this erythema and desquamating reaction. The theoretical risk of actinically induced aging or carcinogenesis is well-documented for these longer wavelengths. 43 Although only a small percentage (10 per cent) of the output of the cold quartz lamp penetrates to deeper layers, the biologic potency of these wavelengths recommends that caution be exercised. Thus, short courses of ultraviolet light (UVC) could be considered as an adjunctive therapy when traditional management fails. In these circumstances, the small risk of actinic damage can be weighed against the potential benefit of decreased acne scarring. Erythemal Phototherapy (UVB) for Psoriasis and Eczema Since the vast majority of patients with acne respond to conventional therapy without the need for adjunctive UVC, the most frequently recommended form of electromagnetic radiation prescribed by dermatologists is UVB phototherapy. Whether from the old hot quartz portable units (see Fig. 1) or the new fluorescent bulb total body cabinets, this potent midc range ultraviolet light is beneficial in a wide variety of conditions, including the following:
706 Psoriasis (vulgaris and guttata), 1. 13, 1s. 48 Eczema (chronic varieties), 1• Lichen planus Palmar/plantar dermatoses Mycosis fungoides
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Mucha-Habermann (pityriasis lichenoides et varioliformis acuta) Pityriasis rosea5 Uremic pruritus 14 Prurigo (of all types) 12 Polymorphous light eruption33
The most common indication for UVB phototherapy is psoriasis, followed closely by eczema. When these conditions are not easily controlled with topical therapy, including emollients, tars, keratolytics, or corticosteroids, or topical therapy cannot be used because of allergy or adverse reactions, ultraviolet light can be substituted or added to the therapeutic regimen.I 9 Severe, extensive cases of psoriasis (Fig. 2) may require hospitalization for a modified Goeckerman program. 48 This generally consists of daily applications of moisturizing emollients and tar preparations, with exposure to UVB radiation once or twice daily. The dose of UVB phototherapy is calculated to produce a minimal degree of erythema. The initial dose is based on minimal erythema dose phototesting or on the photosensitive skin type of the patient (Table 2). 19 The dose of ultraviolet light is gradually raised according to the patient's tolerance in an attempt to maintain a minimal degree of erythema. This is continued until there is a 95 to 100 per
Figure 2. Extensive infantile psoriasis may at times be best treated with the Goeckerman regimen of UVB and tar preparations in a hospital setting.
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Table 2.
Skin Types 19*
I.
Fair, always burns, never tans (Celts, albinos)
II.
Fair; usually burns, tans with difficulty (Northern Europeans, partial Celtic)
Ill.
Lightly pigmented; occasionally burns, always tans (Middle European, Scandinavians)
IV.
Lightly pigmented; never burns, only tans (Mexican-American, Southern European)
V.
Moderately pigmented (Indian, Asian, American blacks)
VI.
Heavily pigmented (Australian aborigines, African blacks)
*The initial dose of UVB phototherapy is usually a fraction of the minimal erythema dose (MED) found by actual phototesting or obtained by testing a series of patients who have been separated by skin type. For skin type III, an average MED might be 40 mj/cm 2 .
cent improvement within 10 to 30 days. This program generally results in remissions lasting an average of longer than one year. 48 Those with milder cases can be handled as outpatients, with as few phototherapy treatments as three per week. A variety of phototreatment protocols have been suggested, some utilizing a less messy coal tar preparation that is more suitable for home use. 1• 13• 19 Although the outpatient approach may extend the duration of therapy up to 12 weeks before the condition clears, it is ideally suited to keeping children in school. Acute poststreptococcal guttate psoriasis, the most common variety seen in children, is particularly responsive to outpatient UVB phototherapy, and often clears in two to four weeks. All patients require concomitant moisturizing emollient topical therapy. In more difficult cases, topical steroids, tar, or anthralin preparations may be added. However, care must be taken to avoid the accidental application of these products in or around the eyes or to intertriginous areas in order to avoid severe cutaneous or ocular side effects. As this may be impossible in small children, it is fortunate that younger patients tend to be more responsive than adults to phototherapy and emollients alone. Table 3 compares the results of inpatient pediatric phototherapy of psoriasis with those of adult phototherapy at the University of Michigan over a two-year period. Twenty-eight days of exposure is the average duration of treatment required for adult psoriatic phototherapy at Michigan; from this table it is obvious that children are relatively more responsive, often clearing in half the time. The mechanism of effectiveness in UVB phototherapy is not entirely understood. It has been shown that ultraviolet light can inhibit epidermal Table 3.
A Comparison of Adult and Pediatric Goeckerman Treatment at the University of Michigan from 1980 to 1982
Children under 2 Children 3 to 18 Adults (> 18)
NO. PATIENTS
AVERAGE NUMBER OF TREATMENTS TO
ADMITTED
CLEARING (RANGE)
4 40 766
10 (4-20) 15 (6--38) 28 (10-52)
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DNA synthesis, and it has been postulated that this is the major mechanism of antiproliferative action in psoriasis and other inflammatory proliferative conditions.I9 However, other immunologic effects of ultraviolet light, 37, 45 as well as effects on inflammatory mediators, may play an important role. Gilchrest et al. have shown that chronologie aging alters the response of ultraviolet light-induced inflammation in human skin. 15 In some unknown way, this increased responsiveness of young skin may be related to the increased efficacy of UVB phototherapy in children. After psoriasis, atopic eczema is probably the next most common indication for UVB phototherapy. Ultraviolet light is not nearly as effective in eczema as it is in psoriasis and is occasionally associated with an exacerbation of the dermatitis. However, in selected patients, UVB phototherapy (with or without tar products) can be a useful adjunct in reducing an atopic child's dependency on topical or (worse yet) systemic corticosteroids. Other conditions that may be responsive to ultraviolet light phototherapy include lichen planus, pityriasis rosea, and Mucha-Habermann disease (pityriasis lichenoides et varioliformis acuta, or PLEVA) (Fig. 3). The indication for UVB with perhaps the greatest benefit:risk ratio is the rare child who develops the cutaneous T-cell lymphoma mycosis fungoides. These children tend to have a long, chronic course, and UVB phototherapy is probably the least carcinogenic of the effective therapies for this condition. Pruritus is a common acute side effect of UVB phototherapy, perhaps
Figure 3. Ultraviolet light phototherapy may be used to treat the symptomatic childhood lymphocytic vasculitis called Mucha-Haberman or pityriasis lichenoides et varioliformis acuta (PLEVA).
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due to vasodilation or the drying effect of treatment. However, most chronically pruritic skin conditions (such as atopic eczema) are markedly improved after the completion of only the minimum number of treatments. The mechanism for this is unknown but may involve local and systemic effects. 12 In the treatment of uremic pruritus, for example, phototherapy of one-half of the body results in a reduction of itching over the entire body surface. 14 This suggests that a circulating itch factor is inactivated by phototherapy or a circulating photoproduct capable of suppressing pruritus is produced. Whatever the mechanism, a wide variety of pruritic conditions that are resistant to conventional therapy respond to ultraviolet light. Patients must wear eye protection during phototherapy in order to prevent acute exposure keratitis and the long-term risk of cataractogenesis. Children must be monitored especially closely, in that they often have an uncontrollable desire to "peek" at the light source. Young children are usually held down in place and monitored by a well-shielded nurse or technician, who then treats them utilizing a portable hot quartz lamp as the UVB light source (see Fig. 1). Older children can usually be trusted in the fluorescent UVB treatment cabinets. Although the acute side effects of "sunburn," dry skin, and pruritus do occur, these are generally easily resolved with decreases in ultraviolet light dosimetry or the application of topical moisturizers and antipruritic agents. The major theoretic concern with UVB phototherapy is the longterm risk of actinically induced aging, freckling, or skin cancer. The theoretic risk of ultraviolet mutagenic alteration of melanocytes or leukocytes is even more frightening. Many studies have demonstrated the ability of short and mid-range ultraviolet light to produce thymine dimers in DNA in vitro. Moreover, ultraviolet light can induce and promote cancer in certain animal models in vivo. 19 Considering the average life expectancy of a child, the cumulative result of ultraviolet light exposure theoretically seems to be a great risk for the pediatric population. Although actinically induced dyspigmentation and wrinkling are probably unavoidable consequences of UVB phototherapy, over 50 years of experience suggests that the risk of carcinogenesis may not be as great as one might expect. Two 25 year retrospective follow-up studies by physicians at the Mayo Clinic show that the Goeckerman treatment of psoriasis50 or atopic dermatitis, 27 despite the use of two known carcinogens in tar and UVB, is not associated with an increased risk of cutaneous or systemic cancer when compared with national statistics. Although further prospective studies are needed in order to insure the safety of UVB phototherapy, selected patients who do not respond to other forms of therapy may well benefit from this treatment regimen. In disabling psoriasis, atopic eczema that is unresponsive to topical steroids, or in mycosis fungoides this may even be the treatment of choice. Psoralen Photochemotherapy (PUVA) for Vitiligo and Other Disorders
Psoralens are a family of chemicals derived from a number of plant sources used from as early as 1400 B.C. in India in the treatment of depigmented skin conditions. Egyptian use of psoralen extracts of the Nile river
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plant Ammi majus in the treatment of leukoderma is recorded from around the twelfth century A.D. The twentieth century dermatologists El Mofty and Lerner studied the therapeutic efficacy of purified psoralens and sunlight treatment of vitiligo. By the 1950s, it was clear that topically or systemically administered psoralens combined with ultraviolet light was a modestly effective therapy for vitiligo.19, 43 After the finding that long wave ultraviolet light activated psoralens, bound to DNA, and inhibited cell proliferation in vitro, Walter et al. in 1973 showed that topical psoralen preparation plus UV A improved psoriasis. 56 The following year Parrish et al. reported that oral psoralen plus high intensity artificial UVA was a very effective antipsoriatic regimen. They coined the acronym "PUVA" and the term "photochemotherapy" to underscore the necessity for using both UVA and psoralen for efficacy.2. 43 How UVA-activated psoralens stimulate melanocytes is unknown. Because UVA-activated psoralens could covalently bind or crosslink DNA and were capable of producing mutation in vitro, concern over the long-term safety of this therapy was expressed. 10· 51 The long history of apparent safety with low dose psoralens and sunlight for vitiligo was weighed against the theoretical risks of this more intense regimen for psoriasis. Large cooperative trials were set up to study the short-term efficacy and safety of PUVA. Only adult patients with disabling forms of psoriasis participated in the study. In 1978, the American Academy of Pediatrics issued a statement that "under no circumstances should children be treated with PUVA, except under established IND [investigational new drug] protocols. "51 At the time, psoralen was packaged with an insert that suggested that its use in children (12 and under) was "contraindicated." Based on five years of human studies showing the effectiveness of this therapy in psoriasis with a minimum of adverse reactions, on May 7, 1982, the United States Food and Drug Administration (FDA) approved the use of oral psoralen photochemotherapy in the treatment of psoriasis (in addition to vitiligo). However, the current package insert, although not contraindicating pediatric PUVA, warns that "safety in children has not been established and potential hazards of long-term therapy include the possibilities of carcinogenicity and cataractogenicity as well as the probability of actinic degeneration." Vitiligo, the first indication for PUVA, continues to be a controversial subject. Affecting 1 per cent of the world's population, it can vary from a minor cosmetic complaint to an emotionally disturbing disfigurement. Many patients can be treated with sunscreens, cosmetic agents, and counseling. However, some would prefer to attempt repigmentation by stimulating melanocytes with PUVA, despite the risk of actinic damage. The results of psoralen photochemotherapy are far from perfect. In a recent study comparing oral trimethylpsoralen (TMP) or 8-methoxy-psoralen (8-MOP) with sunlight or high intensity artificial UVA, Parrish et al. found only limited success after one year of therapy. 40 Of 94 patients studied, only about 20 per cent showed greater than 75 per cent improvement, with none showing complete repigmentation after over a year of two to three treatments per week. About 30 per cent showed no response at all. In general, the face showed the best response, with the hands and feet
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showing the poorest. There appeared to be no statistical differences in repigmentation between drugs or light sources used in this vitiligo study. 26 Proponents of PUVA therapy for vitiligo point out that there are no effective alternative agents for repigmentation and that better results may be gained with a longer treatment period (with maximum repigmentation often occurring only after 300 treatments). Moreover, the results in children appear to be better than those in adults (Fig. 4). 21 · 53 In a long-term follow-up study of patients treated for vitiligo, Kenney showed that the majority of patients retained at least 90 per cent of the new pigment up to 14 years after therapy. 21 Table 4 illustrates how children responded better than adults in new pigment produced and permanency. Localized patches of vitiligo may be treated with topical psoralens and UVA, whereas extensive involvement requires systemic therapy. Topical therapy may decrease the extent of skin at risk for long-term toxicity and certainly reduces the risk of eye damage.l 7 Some suggest this treatment alternative as the therapy of choice for children. However, it must be pointed out that topical therapy is associated with a substantially increased risk of unpredictable acute blistering phototoxic reactions. The possibility that children might expose themselves to larger doses of natural outdoor UVA than recommended makes this an even greater risk. The protocol for oral psoralen photochemotherapy for vitiligo consists of 0.3 mg per kg of Oxsoralen (8-MOP) or 0.6 mg per kg of Trisoralen (TMP), or a combination of both, 46 given two to three hours prior to a measured dose of artificial UVA or sunlight. The initial dose is calculated to be safe for nonpigmented skin (skin type I). The dose is gradually increased once or twice weekly to a maintenance dose producing pigmentation or minimal erythema. Patients must be warned that the effects of one
Figure 4. Psoralen photochemotherapy has traditionally been used to repigment vitiligo. Seen here is the follicular coalescence of new-formed pigment occurring after only a few treatments in a child.
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Table 4.
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Results of Photochemotherapy for Vitiligo 21
Average age (range) Average duration of treatment (months)
ADULTS
CHILDREN
(N=ll)
(N= 10)
46 (28--66)
5 (3--13)
23
17
Percent repigmentation
50%
92%
Percent stable after average 10 yr. follow-up without treatment
72%
99.6%
treatment (erythema, and so forth) may be delayed up to two or three days after exposure and that treatments closer than one to two days apart increase the risk for acute phototoxic sunburn. Natural exposure to the sun is usually preferred over artificial light sources owing to cost. In areas where winter weather prevents treatment, some patients prefer continued exposures with artificial sources to prevent the partial loss of pigment that is often seen with the cessation of therapy. When sunlight is the source, there is significant natural UVA even on cloudy days up until dusk. Patients should be encouraged to get as many treatments as possible (even in the spring or fall, as weather permits). Although some children will respond over the course of one summer, many require up to three summers for maximum repigmentation. However, if a child shows no response over the course of one summer at the appropriate dosage, further treatment should not be recommended. In general, the weaker photosensitizer Trisoralen is preferred over Oxsoralen, in that the margin of safety is such that treatment often may be increased to daily exposure without fear of excessive phototoxicity. The length of exposure to the sun is usually governed by the erythematous response due to natural UVB. This may be lessened by avoiding exposure between the hours of lO and 2 o'clock or by using a UVB sunscreen such as para-aminobenzoic acid, which does not block out solar UVA to any great extent. Guidelines for PUVA treatment of psoriasis have been published by the American Academy of Dermatology10 and may be followed for vitiligo if the drug or dosimetry is cut by about half to minimize erythema (assuming type I skin). Local therapy for vitiligo with topical psoralens is best accomplished with a 1:10 dilution of the commercially available 1 per cent Oxsoralen solution. 3• 17 This is applied to a vitiligenous spot ringed with an opaque sunscreen (for example, zinc oxide) to prevent surrounding hyperpigmentation. After a 30 to 60 minute delay, artificial or natural ultraviolet exposure should be given at a dose approximately one-half of that calculated for oral psoralen photochemotherapy. Again, this is gradually increased to tolerance and given once or twice weekly. After measured exposure, the area should be protected with clothing or a broad-spectrum sunscreen until the next treatment. The protocols for psoriasis therapy generally require approximately twice the oral dose for vitiligo (0.6 mg per kg of 8-MOP) given two to three times weekly with UVA dosimetry raised to the erythema threshold.2· 44 Patients usually respond with a clearing of more than 95 per cent
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in 20 to 30 treatments but may require weekly to monthly PUVA to maintain a reasonable remission. Some patients may experience long-term remissions without maintenance therapy that is similar to that achieved with the Goeckerman regimen. All patients must be warned of the acute side effects of oral psoralen photochemotherapy, which may include (in order of frequency) pruritus, dry skin, erythema (sunburn-like reactions), and, uncommonly, nausea, headache, and dizziness. With topical PUVA the major side effect is unpredictable acute, painful blistering phototoxicity. The risk of long-term side effects is a major problem with PUVA. 2 All patients will probably develop varying degrees of actinic damage, such as wrinkling, thinning, and freckling. Excessive use of PUVA may produce severe atypical stellate dyspigmentation, potentially more disfiguring than vitiligo. 29 Rare side effects of PUVA include hypertrichosis, cutaneous neuropathy, and toxic hepatitis. The most worrisome theoretic side effects of PUVA are possible carcinogenicity or cataractogenicity. 2 Although the prevalence of skin cancer has not been reported to be greater than normal in PUVA-treated vitiligo patients, 34 follow-up of higher dose psoriasis patients shows cause for concern. An increase in epithelial skin cancers (basal and especially squamous cell carcinomas) has been found in the patients who participated in the 16-center cooperative PUVA trial when compared with national statistics. 54 Patients with skin type I or with a previous history of skin cancer or carcinogen exposure are at greatest risk. Thus far, the biologic aggressiveness of these tumors compares favorably with nonPUVA related skin cancer in that the former lack metastase and are easily managed surgically. It can be argued that the patients with psoriasis who are presumably treated with known carcinogens (such as tar and UVB) and who are then followed very closely for skin cancer should not be compared with national statistics gained from presumably incomplete reporting on "normal" patients. However, if one only looks at the PUVA patients who develop skin cancer, a definite dose response can be found, suggesting a genuine relationship to PUVA therapy. The time of the development of these tumors suggests a "pseudo promotor" effect of PUVA, bringing out previously induced skin cancer earlier than it would normally manifest by some unknown (perhaps immunologic) mechanism. 24 • 45 The expected latency period following a theoretic PUVA mutation or cancer induction in humans will delay the determination of this risk for another 10 to 20 years. The apparent safety record in vitiligo and with UVB phototherapy supports an optimistic outlook for PUVA. However, because of these risks, care must be taken in patient selection to exhaust all other possibilities prior to use of PUVA. With proper eye protection, cataracts should be a totally preventable risk. In animal studies, lens opacities formed in mice given dosages of PUVA that inflicted acute phototoxic scarring of the cornea. At lower dosages capable of producing extensive cutaneous phototoxicity in rabbits, cataracts were not induced. This fact, along with the lack of ocular abnormalities found in vitiligo patients over the years before eye protection was advised, suggests that a child who occasionally "forgets" to wear his eye protection after PUVA treatment may not be at great risk for eye damage. Nevertheless, the American Academy of Dermatology has published
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guidelines for PUVA therapy that recommend the use of UVA-opaque wraparound protective eyewear for all the daylight hours following ingestion of psoralens.l9 Other conditions responsive to PUVA in addition to vitiligo and psoriasis have been reported in the medical literature. In the following list of such conditions, those marked with an asterisk are not typically treated with UVB phototherapy: Vitiligo* Psoriasis Mycoses fungoides Eczema Lichen planus Palmar and plantar dermatoses Prurigo nodularis PLEVA
Polymorphous light eruption Solar urticaria* Actinic reticuloid* Alopecia areata Keratoses lichenoides chronica Hyperpigmented sarcoidosis* Urticaria pigmentosa* Netherton syndrome*
Tolerance to photosensitivity, as in polymorphous light eruption, can be induced with either UVB or PUVA. 18• 33 Other papulosquamous conditions such as chronic atopic eczema, 32 lichen planus, 39 Mucha-Habermann disease, 6 recalcitrant dermatoses of the palms and soles, 31 and even the T -cell lymphoma mycosis fungoides 44 can respond to PUVA when not responsive to UVB or other therapy. Unusual circumstances may also suggest the use of PUVA in other childhood disorders not typically responsive to UVB, such as severe disseminated urticaria pigmentosa (Fig. 5), 7 keratosis
Figure 5. One rare indication for PUVA might be extensive urticaria pigmentosa, as seen here.
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lichenoides chronica, 52 Netherton syndrome, 35 and hypopigmented sarcoidosis. 47 The use of PUVA in alopecia areata is investigational. However, initial reports are encouraging. 8• 26· 57 Although the prognosis of hair regrowth of childhood areata is poor and PUVA is reported to work better in adults, there is one variant of childhood alopecia in which PUVA may be the treatment of choice. Ophiasic alopecia areata (Fig. 6) in children carries a very poor prognosis, yet seems to respond well to PUVA. 26 The proposed theoretic mechanism of action of PUVA is the induction of specific suppressor T-cells and other local immunologic alterations with psoralen photochemotherapy capable of reducing the autoimmune hair loss. Immunologic effects may explain some of the side effects of this therapy and also may suggest future experimental indications. The use of PUVA in children remains controversial. However, for selected patients with vitiligo and those patients with disabling psoriasis that is not responsive to UVB or other rare conditions, the benefits of PUVA may outweigh the risks. Further long-term follow-up of past patients and those presently being treated with PUVA will help us to make a more informed decision in the future. Visible Light Phototherapy of Neonatal Hyperbilirubinemia Perhaps the most widely used and best known form of phototherapy for the pediatrician is visible light exposure for neonatal jaundice of prematurity. Discovered in 1956 by pediatric nurse Sister J. Ward, 43 and subsequently established as effective by Lucey in 1968, 19 it has now become the treatment of choice for neonatal hyperbilirubinemia. Despite the resounding success in decreasing the necessity for exchange transfusion to prevent kernicterus, this therapy has become so widespread in the United States (with an estimated 10 per cent of all neonates being exposed), that
Figure 6. for PUVA.
Childhood ophiasis (bandlike alopecia areata) is an investigational indication
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concern has now been expressed about the abuse of this procedure in situations in which it is not warranted. 19 Initially, it was believed that bilirubin, which absorbs light in the blue range (400--500 nm), was removed as singlet oxygen oxidation photoproducts, which were found in vitro. 28 However, it has now been shown that visible light phototherapy increases the excretion of unconjugated bilirubin in the bile by converting it to water-soluble isomers. 25 Whether other biologic chemicals participate in this photoisomerization is unknown; however, it is interesting that administration of riboflavin (a known absorber of visible light) increases the efficiency of serum bilirubin removal.2 2 Known side effects of visible light phototherapy are minimal. Transient diarrhea and rashes (? miliaria rubra) are commonly seen. 38 A rare complication of phototherapy is the "bronze baby syndrome," featuring a prolonged grey-green discoloration of the skin, urine, and stool in children who suffer a component of obstructive jaundice. 23 Of concern but of unknown significance is the finding that neonatal phototherapy transiently decreases the concentration of human luteinizing hormone, suggesting an alteration of neuroendocrine (pituitary-gonadal) function. 11 As the longterm effects of phototherapy and associated photoproducts have not been completely studied, it makes sense to limit this therapy to only those neonates for whom it is absolutely necessary. The relative indications for visible light phototherapy (440--470 nm) are as follows: Hyperbilirubinemia of prematurity (serum bilirubin> 10 mg/100/ml) High risk infant (birth weight<1500 gm, respiratory distress, and so forth) (bilirubin>5 mg/100 ml) Mild hemolytic anemia (bilirubin>5 mg/100 ml) Congenital defect in bilirubin metabolism (Crigler-Najjar syndrome)
Guidelines for neonatal phototherapy include:l9, 38 1. Each clinical situation must be individualized to determine the proper risk:benefit analysis. 2. Infant body temperature (every 4 hours) and weight (every 12 hours) should be monitored to prevent hyperthermia and dehydration. 3. A plexiglass shield should be placed between the infant and the standard phototherapy lamp to prevent contaminating ultraviolet light exposure or accidental injury from lamp breakage. 4. Eyes and gonads should be protected with light-opaque material during radiation and removed during nonillumination periods of feeding and parental visits. 5. Serum bilirubin measurements should be obtained every 6 to 8 hours during phototherapy and 24 hours after in an attempt to determine the necessity of continued treatment. 6. Daily records of spectral irradiance (in milli Watts per cm2 of 450 nm light) and total phototherapy dosage should be kept for each child and phototherapy unit.
As with all forms of phototherapy, care in patient selection, patient protection, and an understanding of the short-term risk: benefit ratio should allow the continued use of this valuable treatment regimen. However, as with other forms of electromagnetic radiation therapy, long-term follow-up studies must be done to further elucidate the risks of this therapy.
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The Future of Pediatric Phototherapy Photomedicine is still in its infancy. Further developments in photopharmacology, light source technology, and an understanding of the cutaneous pathology will enable medicine to invent new forms of phototherapy and improve older methods. New and safer photosensitizers (which do not interact with DNA) are being developed. 2 One example is a hematoporphyrin derivative that is selectively picked up by tumor cells and produces necrosis when exposed to red light. Experimental protocols using this phototherapy for solid human tumors are now underway. 43 New drugs may be developed that become activated with certain light wavelengths. This approach could someday improve the specificity of cutaneous therapy. Lasers are presently being used to destroy cutaneous hemangiomas, and new indications are being evaluated constantly. 9 As new phototherapy techniques are developed and we learn more about the long-term risks and benefits of the present phototherapy methods, photomedicine will increase its role in the physician's armamentarium.
REFERENCES l. Aeling, J. L., et a!.: Outpatient modified Goeckerman regimen. J. Assoc. Mil. Derm., 3:10-12. 2. Anderson, T. F., and Voorhees, J. J.: Psoralen photochemotherapy of cutaneous disorders. Ann. Rev. Pharmacol. Toxicol., 20:235-237, 1980. 3. Arora, S. K., and Willis, I.: Factors influencing methoxsalen phototoxicity in vitiligenous skin. Arch. Dermatol., 112:327-332, 1976. 4. Back, 0., et a!.: Absence of cataract ten years after treatment with 8-methoxypsoralen. Acta Dermatovener., 60:79-80, 1980. 5. Beckett, R. H.: Modern Actinotherapy. London, Whitefriars Press, 1955. 6. Boelen, R. E., et a!.: Long-term follow-up of photochemotherapy in pityriasis lichenoides. Acta Dermatovener., 62:442-444, 1982. 7. Christophers, E., eta!.: PUVA-treatment of urticaria pigmentosa. Brit. J. Derm., 98:701702, 1978. 8. Claudy, A. L., et a!.: Photochemotherapy for alopecia areata. Acta Dermatovener., 60:171-172, 1980. 9. Cotterill, J. A.: Laser treatments of port wine stains. Brit. Med. J., 284:766-767, 1982. 10. Current status of oral PUVA therapy for psoriasis (editorial). J. Am. Acad. Dermatol., 1:106, 1979. 11. Dacou-Voutetakis, C., et a!.: Effect of prolonged illumination (phototherapy) on concentration of luteinizing hormone in human infants. Science, 199:1229-1231, 1978. 12. Fjellner, B., and Hagervort, 0.: Influence of ultraviolet light on itch and flare reactions in human skin induced by histamine and the histamine liberator compound 40/80. Acta Dermatol. (Stockh.), 62:137-140, 1982. 13. Frost, P., et a!.: Tar gel-phototherapy for psoriasis. Arch. Dermatol., 115:840-846, 1979. 14. Gilchrest, B. A.: Ultraviolet phototherapy of uremic pruritus. Int. J. Derm., 18:741-748, 1979. 15. Gilchrest, B. A., et a!.: Chronologie aging alters the response to ultraviolet--induced inflammation in human skin. J. Invest. Derm., 79:11-15, 1982. 16. Goeckerman, W. H.: The treatment of psoriasis. Northwest Med., 24:229, 1925. 17. Grimes, P. E., et a!.: Determination of optimal topical photochemotherapy for vitiligo. J. Am. Acad. Dermatol., 7:771-778, 1982. 18. Gschnait, F., et a!.: Induction of UV light tolerance by PUVA in patients with polymorphous light eruption. Brit. J. Derm., 99:293-295, 1978. 19. Harber, L. C., and Bickers, D. R.: Photosensitivity Diseases. Philadelphia, W. B. Saunders Co., 1981.
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20. Holick, M. F., eta!.: The photoproduction of 1,25 dihydroxyvitamin 0 3 in skin. N. Engl. J. Med., 303:349, 1980. 21. Kenney, J. A.: Vitiligo treated by psoralens. Arch. Dermatol., 103:475-480, 1971. 22. Khosla, D., eta!.: A comparative trial of phototherapy, with and without riboflavin, in the management of neonatal hyperbilirubinemia. Ind. J. Med. Res., 74:852-856, 1981. 23. Kopelman, A. E., et a!.: The "bronze baby" syndrome: A complication of phototherapy. J. Pediat., 81:466-472, 1972. 24. Kripke, M. L.: Immunosuppressive effects of ultraviolet (280-320 nm) radiation and psoralen plus ultraviolet (320-400 nm) radiation in mice. J. Nat. Cancer Inst., 69:171-173, 1982. 25. Lamola, A., et a!.: Photoisomerized bilirubin in blood from infants receiving phototherapy. Proc. Nat. Acad. Sci., 78:1882-1886, 1981. 26. Lassus, A., et a!.: PUVA treatment for alopecia areata. Dermatologica, 161:298-304, 1980. 27. Maughan, W. Z., et a!.: Incidence of skin cancers in patients with atopic dermatitis treated with coal tar. J. Am. Acad. Dermatol., 3:612-615, 1980. 28. McDonagh, A. F., Palma, L. A., and Lightner, D. A.: Blue light and bilirubin excretion. Science, 208:145, 1980. 29. Miller, R. A.: Psoralens and UV-A-induced stellate hyperpigmented freckling. Arch. Dermatol., 118:619--620, 1982. 30. Mills, 0. H., and Kligman, A. M.: Ultraviolet phototherapy and photochemotherapy of acne vulgaris. Arch. Dermatol., 114:221-223, 1978. 31. Morison, W. L., et a!.: Oral methoxsalen photochemotherapy of recalcitrant dermatoses of the palms and soles. Brit. J. Derm., 99:297-302, 1978. 32. Morison, W. L., et a!.: Oral psoralen photochemotherapy of atopic eczema. Brit. J. Derm., 98:25-30, 1978. 33. Morison, W. L., et a!.: UV-B phototherapy in the prophylaxis of polymorphous light eruption. Brit. J. Derm., 106:231-233, 1982. 34. Mosher, D. B., et a!.: Development of cutaneous lesion in vitiligo during long-term PUVA therapy. J. Invest. Derm., 74:259, 1980. 35. Nagata, T.: Netherton's syndrome which responded to photochemotherapy. Dermatologica, 161:51-56, 1980. 36. Nielsen, E. B., and Thormann, J.: Acne-like eruptions induced by PUVA-treatment. Acta Dermatovener., 58:374, 1979. 37. Noonan, F. P., eta!.: Suppression of contact hypersensitivity by UV radiation and its relationship to UV-induced suppression of tumor immunity. Photochem. Photobiol., 34:683-689, 1981. 38. Ogawa, J., eta!.: Five years' experience with phototherapy. In Phototherapy for Neonatal Hyperbilirubinemia-Long-Term Implications. Washington, D.C., DHEW Publication No. (NIH) 76-1075, 1974, pp. 49--66. 39. Ortonne, J. P., eta!.: Oral photochemotherapy in the treatment of lichen planus (LP). Brit. J. Derm., 99:77, 1978. 40. Parrish, J. A., eta!.: Photochemotherapy of vitiligo. Arch. Dermatol., 112:1531-1534, 1976. 41. Parrish, J. A., et a!.: Oral methoxsalen photochemotherapy for acne vulgaris. Arch. Dermatol., 114:1241, 1978. 42. Parrish, J. A., et a!.: Dermatological and ocular examinations in rabbits chronically photosensitized with methoxsalen. J. Invest. Derm., 73:256--258, 1979. 43. Parrish, J. A., eta!.: Photomedicine. In Fitzpatrick, T. B., eta!. (eds.): Dermatology in General Practice, 2nd ed. New York, McGraw-Hill, 1979, pp. 942-994. 44. Parrish, J. A., eta!.: Oral methoxsalen photochemotherapy of psoriasis and mycosis fungoides. Int. J. Derm., 19:379--386, 1980. 45. Parrish, J. A., Morison, W. L., and Kripke, M.: Photoimmunology. Plenum Press, New York, 1982. 46. Pathak, M. A., et a!.: Relative effectiveness of three psoralens and sunlight in repigmentation of 365 vitiligo patients. J. Invest. Derm., 74:252, 1980. 47. Patterson, J. W., eta!.: Treatment ofhypopigmented sarcoidosis with 8-methoxypsoralen and long-wave ultraviolet light. Int. J. Derm., 21:476-480, 1982. 48. Perry, H. D., eta!.: The Goeckerman treatment of psoriasis. Arch. Dermatol., 98:178182, 1968.
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49. Plewig, G., and Kligman, A.: Acne: Morphogenesis and Treatment. New York, Springer Verlag, 1975. 50. Pittelkow, M. R., et al.: Skin cancer in patients with psoriasis treated with coal tar. Arch. Dermatol., 117:465-468, 1981. 51. PUVA: A caution (editorial). Pediatrics, 62:253, 1978. 52. Ryatt, K. S., et al.: Keratosis lichenoides chronica. Brit. J. Derm., 106:223-225, 1982. 53. Sehgal, V. N., et al.: Oral trimethylpsoralen in vitiligo in children. Brit. J. Derm., 85:454-456, 1971. 54. Stern, R. S., et al.: Risk of cutaneous carcinoma in patients treated with oral methoxsalen photochemotherapy for psoriasis. N. Engl. J. Med., 300:809--813, 1979. 55. Topical dilemmas in acne treatment (editorial). Lancet, 1:1138-1139, 1982. 56. Walter, J. F., et al.: Psoralen plus black light inhibits epidermal DNA synthesis. Arch. Dermatol., 107:861-865, 1973. 57. Weissman, 1., et al.: PUVA-treatment for alopecia areata. Arch. Derm. Res., 262:333, 1978. 58. Wright, C. S.: Therapy with the cold quartz lamp in dermatology. Arch. Dermatol., 31:374, 1935. Department of Dermatology Outpatient Building Box 031 University of Michigan Medical Center C-2065 Ann Arbor, Michigan 48109
Pediatric Phototherapy Thomas F. Anderson, M.D.*
Phototherapy, utilizing the sun as a therapeutic light source, was first introduced by the ancient Greeks more than 3000 years ago. 19 Around the second century B. c., Herodotus stressed the usefulness of "heliotherapy" for the restoration of health. Christianity banned the practice of sun worship (and therapy) as paganism until the eighteenth century, when the salutary effects of "actinotherapy" for rickets were rediscovered. 5 With the impetus to devise artificial light sources for phototherapy, Niels Finsen initiated the use of the carbon arc lamp for lupus vulgaris (cutaneous tuberculosis) and was awarded a Nobel prize in 1903 for his work. Pediatric phototherapy had its heyday prior to the introduction of synthetic vitamin D for the treatment of rickets. Today, there still may be theoretic indications for phototherapy as a way of treating vitamin D-resistant rickets. 20 When the normal biotransformation of vitamin D cannot take place in the kidney or liver of the patient, photoactive precursors could be applied to the skin and transformed to the active metabolites following intermittent ultraviolet light phototherapy with subsequent slow percutaneous absorption. This would avoid the direct administration of these agents, which could easily result in hypercalcemia. 10 The work of Finsen prompted the use of ultraviolet radiation for all forms of tuberculosis and other cutaneous and respiratory infections as well. Indeed, a small amount of daily exposure to the sun has been credited with reducing the incidence of common infections in school children. 27 Today, the Madison Avenue epitome of health and well-being is a tanned body. This concept, unfortunately, supports the excesses of the "sun" industry, which promotes "vacations in the sun," tanning parlors, and tanning cosmetics. Although most dermatologists preach avoidance of sun to the majority of their patients, there are individuals, and even children, who may still benefit from phototherapy. With the development of the mercury vapor ultraviolet light source, physicians were first able to treat patients more conveniently than with the carbon arc lamp or natural sun. 19 These lamps emitted radiation produced by the ionization of mercury vapor under high pressure and heat, through *Associate Professor, Department of Dermatology, University of Michigan Hospitals and Veterans Administration Medical Center, Ann Arbor, Michigan
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an ultraviolet transparent quartz filter (regular glass absorbs this radiation). The pioneer in the use of these "hot quartz" lamps in the treatment of skin disease was the famous Mayo Clinic dermatologist William Goeckerman (Fig. 1).16 His method, described in 1925, of combining the use of crude coal tar preparations and ultraviolet light in the treatment of psoriasis continues to be used today. 48 Modified by Ingram with the use of anthralin paste and later modified with the use of topical steroids, the Goeckerman regimen is useful for recalcitrant psoriasis, atopic dermatitis, and a wide variety of pruritic conditions. Other discoveries have paved the way for modern pediatric phototherapy. The low pressure mercury vapor lamps or "cold quartz" germicidal lamps have been advocated since the 1930s in the treatment of acne and pyodermas. 5 In 1956, a pediatric nurse, Sister J. Ward, noted the fading of jaundiced skin exposed to sunlight. Since then, visible light phototherapy of premature newborn hyperbilirubinemia has substantially lessened the need for exchange transfusions. 43 The 1970s brought the development of oral psoralen photochemotherapy and lasers to the practice of medicine. Considering the cumulative nature of electromagnetic radiation effects on living organisms, the question now for the '80s is the determination of the risk: benefit ratio for these potent therapies and their predecessors, particularly in children. Presented here is a review of the modern indications for phototherapy
Figure l. This typical portable "hot quartz" lamp, which produces midrange erythemal ultraviolet radiation (UVB), is commonly used for pediatric phototherapy.
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in children utilizing (1) high energy "germicidal" cold quartz ultraviolet (UVC) exposure, (2) mid-range ultraviolet (UVB) sunlamp treatment, (3) psoralen photochemotherapy utilizing long-wave ultraviolet light (PUVA), and (4) visible light phototherapy. A discussion of the indications, techniques, theoretical basis of the effects, benefits, and risks of each of these four forms of phototherapy will be highlighted. Table 1 illustrates the relationship of these therapies to all electromagnetic radiation therapy. Phototherapy generally pertains to electromagnetic radiation therapy within the range of 200 to 700 nm in wavelength. Germicidal (UVC) Phototherapy for Acne Since Fin sen's cure of lupus vulgaris with ultraviolet light at the turn of the century, a multitude of pyodermatous conditions have been treated with ultraviolet light phototherapy. With the development of the inexpensive cold quartz lamp, dermatologists attempted to treat acne. An early proponent of this therapy was Wright, who published his experience in 1935. 58 Citing the bactericidal effects of the 254 nm radiation, which constitutes more than 90 per cent of the output of the cold quartz lamp, Wright suggested a regimen that he had found to be effective. Utilizing as small a dose of UVC as 15 seconds at three inches, the cold quartz lamp was able to produce marked erythema within a few hours, followed in two or three days by desquamation. This regimen delivered once weekly resulted in improvement in 6 to 12 treatments. Of 94 patients with acne who were treated, more than 90 per cent improved (86), with nearly 50 per cent totally free of acne lesions. 43 Wright noted not only a decrease in inflammatory pustules and papules with this therapy but even an improvement in the appearance of old scars. The only untoward side effect of this treatment was the burning sensation following therapy and the resultant desquamation. Because shorter wave lengths are less efficient in stimulating melanocytes, patients receiving UVC develop very little pigmentation. The small degree of pigment produced may be, in part, due to the small amount of contaminating UVB produced by the cold quartz lamp. Recurrent herpes simplex labialis can be triggered in patients whose lips are not sufficiently protected. Moreover, care must be taken to protect patients' eyes, as direct exposure even for a few seconds can result in a very painful ocular keratitis. Citing the well-known improvement of many acne sufferers in the summertime, 43 Mills and Kligman studied patients exposed twice weekly for eight weeks to UVB, UVA, or both in the treatment of acne. 30 They used a bank of fluorescent bulbs emitting these long wavelength ultraviolet light components of natural sunlight. Exposure to this light source, or even direct sunlight, does not result in a significant exposure to UVC, as the latter is not produced to any great extent by the fluorescent phosphors of the bulbs and it is absorbed naturally by the atmosphere. They found that although UVB could produce marked erythema and desquamation, on the average, only a fair response with a modest decrease in inflammatory pustules and papules and no appreciable change in comedones was achieved.
Table 1.
Electromagnetic Radiation Therapy* WAVE LENGTH NM
<200
200--280
280-320
320--400
400-700
>700
Radiation
x-rays
uvc
UVB
UVA
visible
infra-red
Artificial source
variety
cold quartz "germicidal" fluorescent
hot quartz fluorescent sun lamp
long wave "black light" lamps
blue or white fluorescent lamps
variety
energy dependent
stratum corneum high epidermis
dermal-epidermal junction
dermis
subcutaneous fat
muscle & joints
++
+++
++++
+
radiodermatitis
desquamation
erythema
pigmentation
?
pigmentation
Representative indications
cancer
acne
psoriasis, eczema
PUVA, vitiligo
hyperbilirubinemia
arthritis
Long-term risks
cancer
unknown
aging, skin cancer, cataracts
aging, freckling, skin cancer, cataracts
unknown
unknown
Depth of skin penetration Relative biologic potency for erythema production Most prominent cutaneous effects
++
*Over the phototherapeutic range of 200 to 700 nm, the depth of penetration of radiation effect varies inversely with the energy, explaining why midrange ultraviolet light (UVB) is the most biologically potent. UVA and visible light penetrate deeper but are not sufficiently energetic to promote photochemical reactions without the assistance of a photosensitizer such as psoralen or bilirubin.
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This was decidedly less than what would be expected with conventional therapy with benzoyl peroxide or tretinoin. The results with UVA were worse, although patients noted a cosmetic improvement with the resulting tan. The combination of UVB and UVA produced the best results; however, again, only inflammatory lesions improved. The addition of topical psoralens to this regimen provided no advantage, and if a known comedogenic agent such as crude coal tar was added to the ultraviolet light phototherapy, the acne clearly worsened. Two other studies clearly show PUVA to be of no benefit other than cosmetic tanning in acne. 36· 41 Based on this work, Plewig and Kligman do not recommend ultraviolet light as adjunctive therapy for their acne patients. 49 However, it may be that germicidal UVC phototherapy could offer certain benefits to selected patients. Although there have been no controlled studies using germicidal radiation, dermatologists who have used UVC phototherapy down through the years will attest to the efficacy of this treatment. Moreover, preliminary results of a controlled trial of twice weekly UVC in acne suggest that this therapy is superior to the control (unpublished data). Germicidal UVC has potentially more damaging energy than UVB or UVA and is an excellent mutagen in vitro. However, it is scattered and absorbed to a great extent by the stratum corneum and only a small amount reaches the viable epidermis. 43 Presumably, any cells that might be damaged or killed by this radiation are subsequently desquamated. Hence, it is possible that the major action of this modality is a superficial bactericidal effect. Topical or systemic antibiotics used in the treatment of acne are generally bacteriostatic and associated with the development of resistant bacteria. 55 The superficial germicidal effect of this therapy could explain why UVC exposures theoretically might be beneficial. The desquamating effect of this therapy no doubt explains part of the efficacy, in that all known agents (chemical or physical) that produce this change seem to improve acne to some degree. A small amount of deeper penetrating, longer wavelength ultraviolet light (UVB) is produced by cold quartz lamps and may participate in this erythema and desquamating reaction. The theoretical risk of actinically induced aging or carcinogenesis is well-documented for these longer wavelengths. 43 Although only a small percentage (10 per cent) of the output of the cold quartz lamp penetrates to deeper layers, the biologic potency of these wavelengths recommends that caution be exercised. Thus, short courses of ultraviolet light (UVC) could be considered as an adjunctive therapy when traditional management fails. In these circumstances, the small risk of actinic damage can be weighed against the potential benefit of decreased acne scarring. Erythemal Phototherapy (UVB) for Psoriasis and Eczema Since the vast majority of patients with acne respond to conventional therapy without the need for adjunctive UVC, the most frequently recommended form of electromagnetic radiation prescribed by dermatologists is UVB phototherapy. Whether from the old hot quartz portable units (see Fig. 1) or the new fluorescent bulb total body cabinets, this potent midc range ultraviolet light is beneficial in a wide variety of conditions, including the following:
706 Psoriasis (vulgaris and guttata), 1. 13, 1s. 48 Eczema (chronic varieties), 1• Lichen planus Palmar/plantar dermatoses Mycosis fungoides
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Mucha-Habermann (pityriasis lichenoides et varioliformis acuta) Pityriasis rosea5 Uremic pruritus 14 Prurigo (of all types) 12 Polymorphous light eruption33
The most common indication for UVB phototherapy is psoriasis, followed closely by eczema. When these conditions are not easily controlled with topical therapy, including emollients, tars, keratolytics, or corticosteroids, or topical therapy cannot be used because of allergy or adverse reactions, ultraviolet light can be substituted or added to the therapeutic regimen.I 9 Severe, extensive cases of psoriasis (Fig. 2) may require hospitalization for a modified Goeckerman program. 48 This generally consists of daily applications of moisturizing emollients and tar preparations, with exposure to UVB radiation once or twice daily. The dose of UVB phototherapy is calculated to produce a minimal degree of erythema. The initial dose is based on minimal erythema dose phototesting or on the photosensitive skin type of the patient (Table 2). 19 The dose of ultraviolet light is gradually raised according to the patient's tolerance in an attempt to maintain a minimal degree of erythema. This is continued until there is a 95 to 100 per
Figure 2. Extensive infantile psoriasis may at times be best treated with the Goeckerman regimen of UVB and tar preparations in a hospital setting.
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Table 2.
Skin Types 19*
I.
Fair, always burns, never tans (Celts, albinos)
II.
Fair; usually burns, tans with difficulty (Northern Europeans, partial Celtic)
Ill.
Lightly pigmented; occasionally burns, always tans (Middle European, Scandinavians)
IV.
Lightly pigmented; never burns, only tans (Mexican-American, Southern European)
V.
Moderately pigmented (Indian, Asian, American blacks)
VI.
Heavily pigmented (Australian aborigines, African blacks)
*The initial dose of UVB phototherapy is usually a fraction of the minimal erythema dose (MED) found by actual phototesting or obtained by testing a series of patients who have been separated by skin type. For skin type III, an average MED might be 40 mj/cm 2 .
cent improvement within 10 to 30 days. This program generally results in remissions lasting an average of longer than one year. 48 Those with milder cases can be handled as outpatients, with as few phototherapy treatments as three per week. A variety of phototreatment protocols have been suggested, some utilizing a less messy coal tar preparation that is more suitable for home use. 1• 13• 19 Although the outpatient approach may extend the duration of therapy up to 12 weeks before the condition clears, it is ideally suited to keeping children in school. Acute poststreptococcal guttate psoriasis, the most common variety seen in children, is particularly responsive to outpatient UVB phototherapy, and often clears in two to four weeks. All patients require concomitant moisturizing emollient topical therapy. In more difficult cases, topical steroids, tar, or anthralin preparations may be added. However, care must be taken to avoid the accidental application of these products in or around the eyes or to intertriginous areas in order to avoid severe cutaneous or ocular side effects. As this may be impossible in small children, it is fortunate that younger patients tend to be more responsive than adults to phototherapy and emollients alone. Table 3 compares the results of inpatient pediatric phototherapy of psoriasis with those of adult phototherapy at the University of Michigan over a two-year period. Twenty-eight days of exposure is the average duration of treatment required for adult psoriatic phototherapy at Michigan; from this table it is obvious that children are relatively more responsive, often clearing in half the time. The mechanism of effectiveness in UVB phototherapy is not entirely understood. It has been shown that ultraviolet light can inhibit epidermal Table 3.
A Comparison of Adult and Pediatric Goeckerman Treatment at the University of Michigan from 1980 to 1982
Children under 2 Children 3 to 18 Adults (> 18)
NO. PATIENTS
AVERAGE NUMBER OF TREATMENTS TO
ADMITTED
CLEARING (RANGE)
4 40 766
10 (4-20) 15 (6--38) 28 (10-52)
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DNA synthesis, and it has been postulated that this is the major mechanism of antiproliferative action in psoriasis and other inflammatory proliferative conditions.I9 However, other immunologic effects of ultraviolet light, 37, 45 as well as effects on inflammatory mediators, may play an important role. Gilchrest et al. have shown that chronologie aging alters the response of ultraviolet light-induced inflammation in human skin. 15 In some unknown way, this increased responsiveness of young skin may be related to the increased efficacy of UVB phototherapy in children. After psoriasis, atopic eczema is probably the next most common indication for UVB phototherapy. Ultraviolet light is not nearly as effective in eczema as it is in psoriasis and is occasionally associated with an exacerbation of the dermatitis. However, in selected patients, UVB phototherapy (with or without tar products) can be a useful adjunct in reducing an atopic child's dependency on topical or (worse yet) systemic corticosteroids. Other conditions that may be responsive to ultraviolet light phototherapy include lichen planus, pityriasis rosea, and Mucha-Habermann disease (pityriasis lichenoides et varioliformis acuta, or PLEVA) (Fig. 3). The indication for UVB with perhaps the greatest benefit:risk ratio is the rare child who develops the cutaneous T-cell lymphoma mycosis fungoides. These children tend to have a long, chronic course, and UVB phototherapy is probably the least carcinogenic of the effective therapies for this condition. Pruritus is a common acute side effect of UVB phototherapy, perhaps
Figure 3. Ultraviolet light phototherapy may be used to treat the symptomatic childhood lymphocytic vasculitis called Mucha-Haberman or pityriasis lichenoides et varioliformis acuta (PLEVA).
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due to vasodilation or the drying effect of treatment. However, most chronically pruritic skin conditions (such as atopic eczema) are markedly improved after the completion of only the minimum number of treatments. The mechanism for this is unknown but may involve local and systemic effects. 12 In the treatment of uremic pruritus, for example, phototherapy of one-half of the body results in a reduction of itching over the entire body surface. 14 This suggests that a circulating itch factor is inactivated by phototherapy or a circulating photoproduct capable of suppressing pruritus is produced. Whatever the mechanism, a wide variety of pruritic conditions that are resistant to conventional therapy respond to ultraviolet light. Patients must wear eye protection during phototherapy in order to prevent acute exposure keratitis and the long-term risk of cataractogenesis. Children must be monitored especially closely, in that they often have an uncontrollable desire to "peek" at the light source. Young children are usually held down in place and monitored by a well-shielded nurse or technician, who then treats them utilizing a portable hot quartz lamp as the UVB light source (see Fig. 1). Older children can usually be trusted in the fluorescent UVB treatment cabinets. Although the acute side effects of "sunburn," dry skin, and pruritus do occur, these are generally easily resolved with decreases in ultraviolet light dosimetry or the application of topical moisturizers and antipruritic agents. The major theoretic concern with UVB phototherapy is the longterm risk of actinically induced aging, freckling, or skin cancer. The theoretic risk of ultraviolet mutagenic alteration of melanocytes or leukocytes is even more frightening. Many studies have demonstrated the ability of short and mid-range ultraviolet light to produce thymine dimers in DNA in vitro. Moreover, ultraviolet light can induce and promote cancer in certain animal models in vivo. 19 Considering the average life expectancy of a child, the cumulative result of ultraviolet light exposure theoretically seems to be a great risk for the pediatric population. Although actinically induced dyspigmentation and wrinkling are probably unavoidable consequences of UVB phototherapy, over 50 years of experience suggests that the risk of carcinogenesis may not be as great as one might expect. Two 25 year retrospective follow-up studies by physicians at the Mayo Clinic show that the Goeckerman treatment of psoriasis50 or atopic dermatitis, 27 despite the use of two known carcinogens in tar and UVB, is not associated with an increased risk of cutaneous or systemic cancer when compared with national statistics. Although further prospective studies are needed in order to insure the safety of UVB phototherapy, selected patients who do not respond to other forms of therapy may well benefit from this treatment regimen. In disabling psoriasis, atopic eczema that is unresponsive to topical steroids, or in mycosis fungoides this may even be the treatment of choice. Psoralen Photochemotherapy (PUVA) for Vitiligo and Other Disorders
Psoralens are a family of chemicals derived from a number of plant sources used from as early as 1400 B.C. in India in the treatment of depigmented skin conditions. Egyptian use of psoralen extracts of the Nile river
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plant Ammi majus in the treatment of leukoderma is recorded from around the twelfth century A.D. The twentieth century dermatologists El Mofty and Lerner studied the therapeutic efficacy of purified psoralens and sunlight treatment of vitiligo. By the 1950s, it was clear that topically or systemically administered psoralens combined with ultraviolet light was a modestly effective therapy for vitiligo.19, 43 After the finding that long wave ultraviolet light activated psoralens, bound to DNA, and inhibited cell proliferation in vitro, Walter et al. in 1973 showed that topical psoralen preparation plus UV A improved psoriasis. 56 The following year Parrish et al. reported that oral psoralen plus high intensity artificial UVA was a very effective antipsoriatic regimen. They coined the acronym "PUVA" and the term "photochemotherapy" to underscore the necessity for using both UVA and psoralen for efficacy.2. 43 How UVA-activated psoralens stimulate melanocytes is unknown. Because UVA-activated psoralens could covalently bind or crosslink DNA and were capable of producing mutation in vitro, concern over the long-term safety of this therapy was expressed. 10· 51 The long history of apparent safety with low dose psoralens and sunlight for vitiligo was weighed against the theoretical risks of this more intense regimen for psoriasis. Large cooperative trials were set up to study the short-term efficacy and safety of PUVA. Only adult patients with disabling forms of psoriasis participated in the study. In 1978, the American Academy of Pediatrics issued a statement that "under no circumstances should children be treated with PUVA, except under established IND [investigational new drug] protocols. "51 At the time, psoralen was packaged with an insert that suggested that its use in children (12 and under) was "contraindicated." Based on five years of human studies showing the effectiveness of this therapy in psoriasis with a minimum of adverse reactions, on May 7, 1982, the United States Food and Drug Administration (FDA) approved the use of oral psoralen photochemotherapy in the treatment of psoriasis (in addition to vitiligo). However, the current package insert, although not contraindicating pediatric PUVA, warns that "safety in children has not been established and potential hazards of long-term therapy include the possibilities of carcinogenicity and cataractogenicity as well as the probability of actinic degeneration." Vitiligo, the first indication for PUVA, continues to be a controversial subject. Affecting 1 per cent of the world's population, it can vary from a minor cosmetic complaint to an emotionally disturbing disfigurement. Many patients can be treated with sunscreens, cosmetic agents, and counseling. However, some would prefer to attempt repigmentation by stimulating melanocytes with PUVA, despite the risk of actinic damage. The results of psoralen photochemotherapy are far from perfect. In a recent study comparing oral trimethylpsoralen (TMP) or 8-methoxy-psoralen (8-MOP) with sunlight or high intensity artificial UVA, Parrish et al. found only limited success after one year of therapy. 40 Of 94 patients studied, only about 20 per cent showed greater than 75 per cent improvement, with none showing complete repigmentation after over a year of two to three treatments per week. About 30 per cent showed no response at all. In general, the face showed the best response, with the hands and feet
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showing the poorest. There appeared to be no statistical differences in repigmentation between drugs or light sources used in this vitiligo study. 26 Proponents of PUVA therapy for vitiligo point out that there are no effective alternative agents for repigmentation and that better results may be gained with a longer treatment period (with maximum repigmentation often occurring only after 300 treatments). Moreover, the results in children appear to be better than those in adults (Fig. 4). 21 · 53 In a long-term follow-up study of patients treated for vitiligo, Kenney showed that the majority of patients retained at least 90 per cent of the new pigment up to 14 years after therapy. 21 Table 4 illustrates how children responded better than adults in new pigment produced and permanency. Localized patches of vitiligo may be treated with topical psoralens and UVA, whereas extensive involvement requires systemic therapy. Topical therapy may decrease the extent of skin at risk for long-term toxicity and certainly reduces the risk of eye damage.l 7 Some suggest this treatment alternative as the therapy of choice for children. However, it must be pointed out that topical therapy is associated with a substantially increased risk of unpredictable acute blistering phototoxic reactions. The possibility that children might expose themselves to larger doses of natural outdoor UVA than recommended makes this an even greater risk. The protocol for oral psoralen photochemotherapy for vitiligo consists of 0.3 mg per kg of Oxsoralen (8-MOP) or 0.6 mg per kg of Trisoralen (TMP), or a combination of both, 46 given two to three hours prior to a measured dose of artificial UVA or sunlight. The initial dose is calculated to be safe for nonpigmented skin (skin type I). The dose is gradually increased once or twice weekly to a maintenance dose producing pigmentation or minimal erythema. Patients must be warned that the effects of one
Figure 4. Psoralen photochemotherapy has traditionally been used to repigment vitiligo. Seen here is the follicular coalescence of new-formed pigment occurring after only a few treatments in a child.
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Table 4.
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Results of Photochemotherapy for Vitiligo 21
Average age (range) Average duration of treatment (months)
ADULTS
CHILDREN
(N=ll)
(N= 10)
46 (28--66)
5 (3--13)
23
17
Percent repigmentation
50%
92%
Percent stable after average 10 yr. follow-up without treatment
72%
99.6%
treatment (erythema, and so forth) may be delayed up to two or three days after exposure and that treatments closer than one to two days apart increase the risk for acute phototoxic sunburn. Natural exposure to the sun is usually preferred over artificial light sources owing to cost. In areas where winter weather prevents treatment, some patients prefer continued exposures with artificial sources to prevent the partial loss of pigment that is often seen with the cessation of therapy. When sunlight is the source, there is significant natural UVA even on cloudy days up until dusk. Patients should be encouraged to get as many treatments as possible (even in the spring or fall, as weather permits). Although some children will respond over the course of one summer, many require up to three summers for maximum repigmentation. However, if a child shows no response over the course of one summer at the appropriate dosage, further treatment should not be recommended. In general, the weaker photosensitizer Trisoralen is preferred over Oxsoralen, in that the margin of safety is such that treatment often may be increased to daily exposure without fear of excessive phototoxicity. The length of exposure to the sun is usually governed by the erythematous response due to natural UVB. This may be lessened by avoiding exposure between the hours of lO and 2 o'clock or by using a UVB sunscreen such as para-aminobenzoic acid, which does not block out solar UVA to any great extent. Guidelines for PUVA treatment of psoriasis have been published by the American Academy of Dermatology10 and may be followed for vitiligo if the drug or dosimetry is cut by about half to minimize erythema (assuming type I skin). Local therapy for vitiligo with topical psoralens is best accomplished with a 1:10 dilution of the commercially available 1 per cent Oxsoralen solution. 3• 17 This is applied to a vitiligenous spot ringed with an opaque sunscreen (for example, zinc oxide) to prevent surrounding hyperpigmentation. After a 30 to 60 minute delay, artificial or natural ultraviolet exposure should be given at a dose approximately one-half of that calculated for oral psoralen photochemotherapy. Again, this is gradually increased to tolerance and given once or twice weekly. After measured exposure, the area should be protected with clothing or a broad-spectrum sunscreen until the next treatment. The protocols for psoriasis therapy generally require approximately twice the oral dose for vitiligo (0.6 mg per kg of 8-MOP) given two to three times weekly with UVA dosimetry raised to the erythema threshold.2· 44 Patients usually respond with a clearing of more than 95 per cent
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in 20 to 30 treatments but may require weekly to monthly PUVA to maintain a reasonable remission. Some patients may experience long-term remissions without maintenance therapy that is similar to that achieved with the Goeckerman regimen. All patients must be warned of the acute side effects of oral psoralen photochemotherapy, which may include (in order of frequency) pruritus, dry skin, erythema (sunburn-like reactions), and, uncommonly, nausea, headache, and dizziness. With topical PUVA the major side effect is unpredictable acute, painful blistering phototoxicity. The risk of long-term side effects is a major problem with PUVA. 2 All patients will probably develop varying degrees of actinic damage, such as wrinkling, thinning, and freckling. Excessive use of PUVA may produce severe atypical stellate dyspigmentation, potentially more disfiguring than vitiligo. 29 Rare side effects of PUVA include hypertrichosis, cutaneous neuropathy, and toxic hepatitis. The most worrisome theoretic side effects of PUVA are possible carcinogenicity or cataractogenicity. 2 Although the prevalence of skin cancer has not been reported to be greater than normal in PUVA-treated vitiligo patients, 34 follow-up of higher dose psoriasis patients shows cause for concern. An increase in epithelial skin cancers (basal and especially squamous cell carcinomas) has been found in the patients who participated in the 16-center cooperative PUVA trial when compared with national statistics. 54 Patients with skin type I or with a previous history of skin cancer or carcinogen exposure are at greatest risk. Thus far, the biologic aggressiveness of these tumors compares favorably with nonPUVA related skin cancer in that the former lack metastase and are easily managed surgically. It can be argued that the patients with psoriasis who are presumably treated with known carcinogens (such as tar and UVB) and who are then followed very closely for skin cancer should not be compared with national statistics gained from presumably incomplete reporting on "normal" patients. However, if one only looks at the PUVA patients who develop skin cancer, a definite dose response can be found, suggesting a genuine relationship to PUVA therapy. The time of the development of these tumors suggests a "pseudo promotor" effect of PUVA, bringing out previously induced skin cancer earlier than it would normally manifest by some unknown (perhaps immunologic) mechanism. 24 • 45 The expected latency period following a theoretic PUVA mutation or cancer induction in humans will delay the determination of this risk for another 10 to 20 years. The apparent safety record in vitiligo and with UVB phototherapy supports an optimistic outlook for PUVA. However, because of these risks, care must be taken in patient selection to exhaust all other possibilities prior to use of PUVA. With proper eye protection, cataracts should be a totally preventable risk. In animal studies, lens opacities formed in mice given dosages of PUVA that inflicted acute phototoxic scarring of the cornea. At lower dosages capable of producing extensive cutaneous phototoxicity in rabbits, cataracts were not induced. This fact, along with the lack of ocular abnormalities found in vitiligo patients over the years before eye protection was advised, suggests that a child who occasionally "forgets" to wear his eye protection after PUVA treatment may not be at great risk for eye damage. Nevertheless, the American Academy of Dermatology has published
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guidelines for PUVA therapy that recommend the use of UVA-opaque wraparound protective eyewear for all the daylight hours following ingestion of psoralens.l9 Other conditions responsive to PUVA in addition to vitiligo and psoriasis have been reported in the medical literature. In the following list of such conditions, those marked with an asterisk are not typically treated with UVB phototherapy: Vitiligo* Psoriasis Mycoses fungoides Eczema Lichen planus Palmar and plantar dermatoses Prurigo nodularis PLEVA
Polymorphous light eruption Solar urticaria* Actinic reticuloid* Alopecia areata Keratoses lichenoides chronica Hyperpigmented sarcoidosis* Urticaria pigmentosa* Netherton syndrome*
Tolerance to photosensitivity, as in polymorphous light eruption, can be induced with either UVB or PUVA. 18• 33 Other papulosquamous conditions such as chronic atopic eczema, 32 lichen planus, 39 Mucha-Habermann disease, 6 recalcitrant dermatoses of the palms and soles, 31 and even the T -cell lymphoma mycosis fungoides 44 can respond to PUVA when not responsive to UVB or other therapy. Unusual circumstances may also suggest the use of PUVA in other childhood disorders not typically responsive to UVB, such as severe disseminated urticaria pigmentosa (Fig. 5), 7 keratosis
Figure 5. One rare indication for PUVA might be extensive urticaria pigmentosa, as seen here.
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lichenoides chronica, 52 Netherton syndrome, 35 and hypopigmented sarcoidosis. 47 The use of PUVA in alopecia areata is investigational. However, initial reports are encouraging. 8• 26· 57 Although the prognosis of hair regrowth of childhood areata is poor and PUVA is reported to work better in adults, there is one variant of childhood alopecia in which PUVA may be the treatment of choice. Ophiasic alopecia areata (Fig. 6) in children carries a very poor prognosis, yet seems to respond well to PUVA. 26 The proposed theoretic mechanism of action of PUVA is the induction of specific suppressor T-cells and other local immunologic alterations with psoralen photochemotherapy capable of reducing the autoimmune hair loss. Immunologic effects may explain some of the side effects of this therapy and also may suggest future experimental indications. The use of PUVA in children remains controversial. However, for selected patients with vitiligo and those patients with disabling psoriasis that is not responsive to UVB or other rare conditions, the benefits of PUVA may outweigh the risks. Further long-term follow-up of past patients and those presently being treated with PUVA will help us to make a more informed decision in the future. Visible Light Phototherapy of Neonatal Hyperbilirubinemia Perhaps the most widely used and best known form of phototherapy for the pediatrician is visible light exposure for neonatal jaundice of prematurity. Discovered in 1956 by pediatric nurse Sister J. Ward, 43 and subsequently established as effective by Lucey in 1968, 19 it has now become the treatment of choice for neonatal hyperbilirubinemia. Despite the resounding success in decreasing the necessity for exchange transfusion to prevent kernicterus, this therapy has become so widespread in the United States (with an estimated 10 per cent of all neonates being exposed), that
Figure 6. for PUVA.
Childhood ophiasis (bandlike alopecia areata) is an investigational indication
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concern has now been expressed about the abuse of this procedure in situations in which it is not warranted. 19 Initially, it was believed that bilirubin, which absorbs light in the blue range (400--500 nm), was removed as singlet oxygen oxidation photoproducts, which were found in vitro. 28 However, it has now been shown that visible light phototherapy increases the excretion of unconjugated bilirubin in the bile by converting it to water-soluble isomers. 25 Whether other biologic chemicals participate in this photoisomerization is unknown; however, it is interesting that administration of riboflavin (a known absorber of visible light) increases the efficiency of serum bilirubin removal.2 2 Known side effects of visible light phototherapy are minimal. Transient diarrhea and rashes (? miliaria rubra) are commonly seen. 38 A rare complication of phototherapy is the "bronze baby syndrome," featuring a prolonged grey-green discoloration of the skin, urine, and stool in children who suffer a component of obstructive jaundice. 23 Of concern but of unknown significance is the finding that neonatal phototherapy transiently decreases the concentration of human luteinizing hormone, suggesting an alteration of neuroendocrine (pituitary-gonadal) function. 11 As the longterm effects of phototherapy and associated photoproducts have not been completely studied, it makes sense to limit this therapy to only those neonates for whom it is absolutely necessary. The relative indications for visible light phototherapy (440--470 nm) are as follows: Hyperbilirubinemia of prematurity (serum bilirubin> 10 mg/100/ml) High risk infant (birth weight<1500 gm, respiratory distress, and so forth) (bilirubin>5 mg/100 ml) Mild hemolytic anemia (bilirubin>5 mg/100 ml) Congenital defect in bilirubin metabolism (Crigler-Najjar syndrome)
Guidelines for neonatal phototherapy include:l9, 38 1. Each clinical situation must be individualized to determine the proper risk:benefit analysis. 2. Infant body temperature (every 4 hours) and weight (every 12 hours) should be monitored to prevent hyperthermia and dehydration. 3. A plexiglass shield should be placed between the infant and the standard phototherapy lamp to prevent contaminating ultraviolet light exposure or accidental injury from lamp breakage. 4. Eyes and gonads should be protected with light-opaque material during radiation and removed during nonillumination periods of feeding and parental visits. 5. Serum bilirubin measurements should be obtained every 6 to 8 hours during phototherapy and 24 hours after in an attempt to determine the necessity of continued treatment. 6. Daily records of spectral irradiance (in milli Watts per cm2 of 450 nm light) and total phototherapy dosage should be kept for each child and phototherapy unit.
As with all forms of phototherapy, care in patient selection, patient protection, and an understanding of the short-term risk: benefit ratio should allow the continued use of this valuable treatment regimen. However, as with other forms of electromagnetic radiation therapy, long-term follow-up studies must be done to further elucidate the risks of this therapy.
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The Future of Pediatric Phototherapy Photomedicine is still in its infancy. Further developments in photopharmacology, light source technology, and an understanding of the cutaneous pathology will enable medicine to invent new forms of phototherapy and improve older methods. New and safer photosensitizers (which do not interact with DNA) are being developed. 2 One example is a hematoporphyrin derivative that is selectively picked up by tumor cells and produces necrosis when exposed to red light. Experimental protocols using this phototherapy for solid human tumors are now underway. 43 New drugs may be developed that become activated with certain light wavelengths. This approach could someday improve the specificity of cutaneous therapy. Lasers are presently being used to destroy cutaneous hemangiomas, and new indications are being evaluated constantly. 9 As new phototherapy techniques are developed and we learn more about the long-term risks and benefits of the present phototherapy methods, photomedicine will increase its role in the physician's armamentarium.
REFERENCES l. Aeling, J. L., et a!.: Outpatient modified Goeckerman regimen. J. Assoc. Mil. Derm., 3:10-12. 2. Anderson, T. F., and Voorhees, J. J.: Psoralen photochemotherapy of cutaneous disorders. Ann. Rev. Pharmacol. Toxicol., 20:235-237, 1980. 3. Arora, S. K., and Willis, I.: Factors influencing methoxsalen phototoxicity in vitiligenous skin. Arch. Dermatol., 112:327-332, 1976. 4. Back, 0., et a!.: Absence of cataract ten years after treatment with 8-methoxypsoralen. Acta Dermatovener., 60:79-80, 1980. 5. Beckett, R. H.: Modern Actinotherapy. London, Whitefriars Press, 1955. 6. Boelen, R. E., et a!.: Long-term follow-up of photochemotherapy in pityriasis lichenoides. Acta Dermatovener., 62:442-444, 1982. 7. Christophers, E., eta!.: PUVA-treatment of urticaria pigmentosa. Brit. J. Derm., 98:701702, 1978. 8. Claudy, A. L., et a!.: Photochemotherapy for alopecia areata. Acta Dermatovener., 60:171-172, 1980. 9. Cotterill, J. A.: Laser treatments of port wine stains. Brit. Med. J., 284:766-767, 1982. 10. Current status of oral PUVA therapy for psoriasis (editorial). J. Am. Acad. Dermatol., 1:106, 1979. 11. Dacou-Voutetakis, C., et a!.: Effect of prolonged illumination (phototherapy) on concentration of luteinizing hormone in human infants. Science, 199:1229-1231, 1978. 12. Fjellner, B., and Hagervort, 0.: Influence of ultraviolet light on itch and flare reactions in human skin induced by histamine and the histamine liberator compound 40/80. Acta Dermatol. (Stockh.), 62:137-140, 1982. 13. Frost, P., et a!.: Tar gel-phototherapy for psoriasis. Arch. Dermatol., 115:840-846, 1979. 14. Gilchrest, B. A.: Ultraviolet phototherapy of uremic pruritus. Int. J. Derm., 18:741-748, 1979. 15. Gilchrest, B. A., et a!.: Chronologie aging alters the response to ultraviolet--induced inflammation in human skin. J. Invest. Derm., 79:11-15, 1982. 16. Goeckerman, W. H.: The treatment of psoriasis. Northwest Med., 24:229, 1925. 17. Grimes, P. E., et a!.: Determination of optimal topical photochemotherapy for vitiligo. J. Am. Acad. Dermatol., 7:771-778, 1982. 18. Gschnait, F., et a!.: Induction of UV light tolerance by PUVA in patients with polymorphous light eruption. Brit. J. Derm., 99:293-295, 1978. 19. Harber, L. C., and Bickers, D. R.: Photosensitivity Diseases. Philadelphia, W. B. Saunders Co., 1981.
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20. Holick, M. F., eta!.: The photoproduction of 1,25 dihydroxyvitamin 0 3 in skin. N. Engl. J. Med., 303:349, 1980. 21. Kenney, J. A.: Vitiligo treated by psoralens. Arch. Dermatol., 103:475-480, 1971. 22. Khosla, D., eta!.: A comparative trial of phototherapy, with and without riboflavin, in the management of neonatal hyperbilirubinemia. Ind. J. Med. Res., 74:852-856, 1981. 23. Kopelman, A. E., et a!.: The "bronze baby" syndrome: A complication of phototherapy. J. Pediat., 81:466-472, 1972. 24. Kripke, M. L.: Immunosuppressive effects of ultraviolet (280-320 nm) radiation and psoralen plus ultraviolet (320-400 nm) radiation in mice. J. Nat. Cancer Inst., 69:171-173, 1982. 25. Lamola, A., et a!.: Photoisomerized bilirubin in blood from infants receiving phototherapy. Proc. Nat. Acad. Sci., 78:1882-1886, 1981. 26. Lassus, A., et a!.: PUVA treatment for alopecia areata. Dermatologica, 161:298-304, 1980. 27. Maughan, W. Z., et a!.: Incidence of skin cancers in patients with atopic dermatitis treated with coal tar. J. Am. Acad. Dermatol., 3:612-615, 1980. 28. McDonagh, A. F., Palma, L. A., and Lightner, D. A.: Blue light and bilirubin excretion. Science, 208:145, 1980. 29. Miller, R. A.: Psoralens and UV-A-induced stellate hyperpigmented freckling. Arch. Dermatol., 118:619--620, 1982. 30. Mills, 0. H., and Kligman, A. M.: Ultraviolet phototherapy and photochemotherapy of acne vulgaris. Arch. Dermatol., 114:221-223, 1978. 31. Morison, W. L., et a!.: Oral methoxsalen photochemotherapy of recalcitrant dermatoses of the palms and soles. Brit. J. Derm., 99:297-302, 1978. 32. Morison, W. L., et a!.: Oral psoralen photochemotherapy of atopic eczema. Brit. J. Derm., 98:25-30, 1978. 33. Morison, W. L., et a!.: UV-B phototherapy in the prophylaxis of polymorphous light eruption. Brit. J. Derm., 106:231-233, 1982. 34. Mosher, D. B., et a!.: Development of cutaneous lesion in vitiligo during long-term PUVA therapy. J. Invest. Derm., 74:259, 1980. 35. Nagata, T.: Netherton's syndrome which responded to photochemotherapy. Dermatologica, 161:51-56, 1980. 36. Nielsen, E. B., and Thormann, J.: Acne-like eruptions induced by PUVA-treatment. Acta Dermatovener., 58:374, 1979. 37. Noonan, F. P., eta!.: Suppression of contact hypersensitivity by UV radiation and its relationship to UV-induced suppression of tumor immunity. Photochem. Photobiol., 34:683-689, 1981. 38. Ogawa, J., eta!.: Five years' experience with phototherapy. In Phototherapy for Neonatal Hyperbilirubinemia-Long-Term Implications. Washington, D.C., DHEW Publication No. (NIH) 76-1075, 1974, pp. 49--66. 39. Ortonne, J. P., eta!.: Oral photochemotherapy in the treatment of lichen planus (LP). Brit. J. Derm., 99:77, 1978. 40. Parrish, J. A., eta!.: Photochemotherapy of vitiligo. Arch. Dermatol., 112:1531-1534, 1976. 41. Parrish, J. A., et a!.: Oral methoxsalen photochemotherapy for acne vulgaris. Arch. Dermatol., 114:1241, 1978. 42. Parrish, J. A., et a!.: Dermatological and ocular examinations in rabbits chronically photosensitized with methoxsalen. J. Invest. Derm., 73:256--258, 1979. 43. Parrish, J. A., eta!.: Photomedicine. In Fitzpatrick, T. B., eta!. (eds.): Dermatology in General Practice, 2nd ed. New York, McGraw-Hill, 1979, pp. 942-994. 44. Parrish, J. A., eta!.: Oral methoxsalen photochemotherapy of psoriasis and mycosis fungoides. Int. J. Derm., 19:379--386, 1980. 45. Parrish, J. A., Morison, W. L., and Kripke, M.: Photoimmunology. Plenum Press, New York, 1982. 46. Pathak, M. A., et a!.: Relative effectiveness of three psoralens and sunlight in repigmentation of 365 vitiligo patients. J. Invest. Derm., 74:252, 1980. 47. Patterson, J. W., eta!.: Treatment ofhypopigmented sarcoidosis with 8-methoxypsoralen and long-wave ultraviolet light. Int. J. Derm., 21:476-480, 1982. 48. Perry, H. D., eta!.: The Goeckerman treatment of psoriasis. Arch. Dermatol., 98:178182, 1968.
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49. Plewig, G., and Kligman, A.: Acne: Morphogenesis and Treatment. New York, Springer Verlag, 1975. 50. Pittelkow, M. R., et al.: Skin cancer in patients with psoriasis treated with coal tar. Arch. Dermatol., 117:465-468, 1981. 51. PUVA: A caution (editorial). Pediatrics, 62:253, 1978. 52. Ryatt, K. S., et al.: Keratosis lichenoides chronica. Brit. J. Derm., 106:223-225, 1982. 53. Sehgal, V. N., et al.: Oral trimethylpsoralen in vitiligo in children. Brit. J. Derm., 85:454-456, 1971. 54. Stern, R. S., et al.: Risk of cutaneous carcinoma in patients treated with oral methoxsalen photochemotherapy for psoriasis. N. Engl. J. Med., 300:809--813, 1979. 55. Topical dilemmas in acne treatment (editorial). Lancet, 1:1138-1139, 1982. 56. Walter, J. F., et al.: Psoralen plus black light inhibits epidermal DNA synthesis. Arch. Dermatol., 107:861-865, 1973. 57. Weissman, 1., et al.: PUVA-treatment for alopecia areata. Arch. Derm. Res., 262:333, 1978. 58. Wright, C. S.: Therapy with the cold quartz lamp in dermatology. Arch. Dermatol., 31:374, 1935. Department of Dermatology Outpatient Building Box 031 University of Michigan Medical Center C-2065 Ann Arbor, Michigan 48109