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C M E A RT I C L E

Seborrheic dermatitis
Blackwell Publishing Ltd.

AK Gupta,* R Bluhm Division of Dermatology, Department of Medicine, Sunnybrook and Womens College Health Science Center (Sunnybrook site) and the University of Toronto, Toronto, Canada, and Mediprobe Laboratories Inc., London, Ontario, Canada. *Corresponding author, Suite 6, 490 Wonderland Road South, London, Ontario, Canada N6K 1L6, Tel. (519) 657 4222; Fax (519) 657 4233; E-mail: agupta@execulink.com

ABSTRAC T
Seborrheic dermatitis is a common inammation of the skin, occurring most often on the face, scalp and chest. It is closely related to infantile seborrheic dermatitis, or diaper rash. Seborrheic dermatitis is particularly common in patients with Parkinsons disease or with HIV/AIDS. The recent resurgence of interest in Malassezia yeasts has revived the old hypothesis that seborrheic dermatitis is caused by an altered relationship between these skin commensals and the host. Moreover, the success of antifungal medications in treating seborrheic dermatitis provides new evidence for this view. Learning objective Upon completing this paper, the reader should be aware of the clinical presentation of seborrheic dermatitis and which populations are at particular risk of developing this disorder. In addition, s/he will be aware of the role of Malassezia yeasts in seborrheic dermatitis and the way in which knowledge of the importance of these yeasts has altered the treatment of this disorder.
Key words: dermatitis, fungus, Malassezia, review, seborrheic
Received: 4 January 2002, accepted 1 August 2002

Introduction
The name seborrheic dermatitis implies an oily inammation of the skin. Yet the disease is much more complex than the name would suggest. Studies have shown that the skin of patients with seborrheic dermatitis is not necessarily more oily than that of an unaffected individual.1 (Nor, for that matter, does the name imply that this should be the case.2) Research on the causes and treatment of seborrheic dermatitis often focuses on the appearance and course of the disease in special populations. Specically, investigators often tend to investigate infantile seborrheic dermatitis (ISD), seborrheic dermatitis in AIDS patients and seborrheic dermatitis in patients with Parkinsons disease. Differences in the course of the seborrheic dermatitis and/or its histopathology suggest that the underlying disease process is not the same. In these patients, at least, seborrheic dermatitis may be a sign of disease, rather than the disease itself. This paper will describe the aetiology of seborrheic dermatitis in special patient populations (infants, AIDS patients and patients with neurological disorders) and will examine seborrheic dermatitis in immunocompetent adults with special attention to its relationship with Malassezia yeasts.
2004 European Academy of Dermatology and Venereology

Seborrheic dermatitis in immunocompetent adults

Seborrheic dermatitis is characterized by the appearance of red, aking, greasy areas of skin, most commonly on the scalp, nasolabial folds, ears, eyebrows and chest. However, variations in this clinical picture are common. Patients may vary markedly with regard to erythema, degree of aking and greasy appearance of lesions, and it is not unusual to see involvement of other sites, especially exural areas. Moreover, the use of varying terms such as sebopsoriasis, seborrheic eczema, seborrheic dermatitis, dandruff and pityriasis capitis may sometimes make it difcult to interpret the literature on this disorder. The relationship between seborrheic dermatitis of the scalp and dandruff is unclear, with some authors suggesting that dandruff is a more generic term that refers to scalp aking regardless of aetiology.35 Others emphasize the role of Malassezia yeasts and the similarity between seborrheic dermatitis of the face and chest.6,7 In this paper, we will use the term seborrheic dermatitis and will take the name dandruff to refer to seborrheic dermatitis of the scalp, as the clinical studies we discuss tend to use the terms interchangeably and because the treatments evaluated in these studies tend to be effective in improving both scalp lesions and lesions of the face and body.
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Seborrheic dermatitis affects between 1% and 3% of adults who do not have AIDS or Parkinsons disease and is more common in males than females. It often has a seasonal aspect, being more common and, in chronic cases, often more severe in the winter months. There have been reports that exposure to sunlight can improve seborrheic dermatitis;8 however, cases have also been reported to develop subsequent to psoralen plus ultraviolet A (PUVA) therapy.9 Seborrheic dermatitis is especially common in adolescents and young adults, with the incidence increasing again in patients past the age of 50 years.10,11 It is also commonly observed in black patients.1214 The severity of seborrheic dermatitis is varied. Some patients experience only a mild aking dandruff, easily treated with over-the-counter medications. Others demonstrate a severe oily, dense scaling on the scalp, face and trunk. The distribution of lesions is generally symmetrical. While good hygiene is important in controlling persistent seborrheic dermatitis, the disease is not caused by a lack of cleanliness.

possible immunological,1719 nutritional,2023 environmental24,25 and lifestyle factors2628 that might increase the predisposition to seborrheic dermatitis. Often, it is difcult to separate out the roles of disease, lifestyle and nutrition in the development of seborrheic dermatitis: those suffering from alcoholism26 (but see reference 29) or depression30 often eat poorly and/or have inadequate hygiene practices which may contribute to their dermatological problems.

Other comorbid conditions

In addition, seborrheic dermatitis is more common in patients with Parkinsons disease31,32 or mood disorders30 and those with HIV/AIDS33,34 than in the general population. While these disorders have been the focus of the most research, studies have shown that seborrheic dermatitis is also associated with chronic alcoholic pancreatitis,29 hepatitis C virus35 and various cancers.36 It is also common in patients with genetic disorders, such as Downs syndrome,37 HaileyHailey disease38 and cardiofacio cutaneous syndrome.39

Aetiology
The cause of seborrheic dermatitis is unknown; however, many factors have been cited as possible contributors to the development of this disorder. These include exogenous factors (seborrheic dermatitis is more common in the winter) and various endogenous host factors.

Malassezia species
Early investigators proposed a causative role for Malassezia yeasts (then known as Pityrosporum yeasts) in seborrheic dermatitis.40,41 Because Malassezia species are normal human skin commensals, later researchers rejected the possibility that this yeast species plays a pathogenic role in seborrheic dermatitis. Unlike pityriasis versicolor, in which the Malassezia yeasts can be seen under light microscope in the pathogenic mycelial form, seborrheic dermatitis is not associated with these microscopic changes. Moreover, it is uncertain whether or not seborrheic dermatitis patients have higher Malassezia counts than normal controls,42,43 although a correlation between yeast density and severity of seborrheic dermatitis has been reported.44 For some time, seborrheic dermatitis was viewed, instead, as primarily a disorder of hyperproliferation: the aking of the skin was thought to be due to increased epidermal turnover. Moreover, the responsiveness of this condition to keratolytic and antiinammatory medications (such as salicylic acid and corticosteroids, respectively) was taken as evidence for this hypothesis.45 With the development of new antifungal agents there has been a renewed interest in the relationship between Malassezia yeasts and seborrheic dermatitis. Patients with seborrheic dermatitis, ISD and AIDS-related seborrheic dermatitis have been treated with ketoconazole, resulting in both amelioration of lesions and a decrease in the number of the yeasts on the skin.46,47 The Malassezia yeasts that are commonly found on the scalp have been reported to make up a higher proportion of scalp microora in patients with dandruff or seborrheic dermatitis,43 though other investigators42,47 have found no difference in the amount of Malassezia yeasts on lesional versus nonlesional skin of seborrheic dermatitis patients.

Lipids and hormones

Despite the lack of a clear correlation between sebum levels and the development of seborrheic dermatitis, there still appears to be some connection between seborrheic dermatitis and sebum levels. Except for infantile seborrheic dermatitis, the disease is rare before puberty, and is most common in adolescence and young adulthood, when sebaceous glands are at their most active. Moreover, the distribution of lesions on the body reects the distribution of sebaceous glands. The face, scalp, chest and back are the most commonly affected areas. In addition, the skin surface lipid composition in men with seborrheic dermatitis has been shown to differ from that of unaffected controls.15 One study16 has shown that the areas of the face that tend to be implicated in seborrheic dermatitis are consistently warmer than those areas that are not commonly involved. However, this may be related to the fact that skin temperature varies with the lipid composition of the skin surface.16 There may also be a hormonal inuence: not only does the disease begin to develop at puberty, but seborrheic dermatitis is more common in men than in women, suggesting an inuence of androgens on the pilosebaceous unit.

Other factors
Given that endogenous host factors appear to determine susceptibility to seborrheic dermatitis, researchers have investigated

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With the reclassication of the genus Malassezia into seven species in 199648 studies have been performed to determine whether the amount and/or species of Malassezia found on the skin of seborrheic dermatitis patients is different from that in normal controls. M. pachydermatis has rarely been recovered from human skin; it is more likely to be grown from skin specimens obtained from animals. Gupta et al.49 found that the predominant species in seborrheic dermatitis patients was M. globosa, as opposed to M. sympodialis in normal skin. Nakabayashi et al.50 found both M. globosa and M. restricta on diseased skin, but primarily M. globosa in controls. Sandstrm et al.51 found M. sympodialis in both patients with seborrheic dermatitis and controls. These results are far from conclusive, and it should be borne in mind that the relative prevalence of the six lipophilic species appears to vary with geographical region.

lipids and hormones, comorbid conditions and the immune response, may govern an individuals response to the yeasts on the skin.

Seborrheic dermatitis and other dermatological disorders

In addition to its appearance in patients with certain underlying diseases, seborrheic dermatitis may be coincident with other dermatological disorders, e.g. rosacea.58 Seborrheic dermatitis and acne rosacea may be associated with ocular irritation or blepharitis.5961 Seborrheic dermatitis is also commonly observed with acne vulgaris,62 supporting the stereotype that those with seborrheic dermatitis have greasy skin. Diseases associated with Malassezia spp. are also commonly found in patients with seborrheic dermatitis; these include pityriasis versicolor63 and pityrosporum folliculitis.64

Immune response
It is thought that the pathogenesis of seborrheic dermatitis has an immune component, and the increased prevalence in HIVpositive patients supports this hypothesis. Studies have shown that patients with seborrheic dermatitis exhibit an increased irritant reaction to sodium lauryl sulphate compared to controls52 and that lesions can be induced with nicotine of horsetails53 or by exposure to tobacco smoke.54 In addition to these cutaneous reactions, there may also be humoral and cellular immune responses in seborrheic dermatitis. Bergbrant et al.17 report that in patients with seborrheic dermatitis the T cell function may be depressed, the prevalence of natural killer cells increased, and/or the total levels of IgA and IgG antibodies in serum higher. The increased production of IgG antibodies has also been conrmed by other authors;55 however, in another study, Bergbrant and Faergemann42 found that this difference in IgG levels is not related to Malassezia: patients with seborrheic dermatitis did not have elevated IgG antibody titres against the yeasts. They hypothesized that seborrheic dermatitis is actually due to an abnormal reaction to the yeasts by the skin. Similarly, Parry and Sharpe56 found no difference in either the total number of antibodies produced by patients with seborrheic dermatitis and controls or the Malassezia proteins recognized by sera from either group. Instead, these authors suggest that the response to Malassezia may actually be due to toxin production or to lipase activity.56 Faergemann et al.57 investigated the role of an inammatory response in seborrheic dermatitis and found that there is an increase in NK1+ and CD16+ cells, activation of complement and an increase in the production of inammatory interleukins in lesional compared to normal skin in seborrheic dermatitis patients and controls. The relationship between seborrheic dermatitis and Malassezia yeasts is not yet completely understood. Endogenous host factors have always been implicated in the pathogenesis of seborrheic dermatitis, and other factors, e.g. the role of

Histology
The lesions of seborrheic dermatitis may resemble those of psoriasis. Their distribution, however, is generally different, with psoriasis manifesting generally on the elbows and knees while seborrheic dermatitis is most commonly present on the sebaceous areas of the skin: the scalp, face, chest and back. In addition, seborrheic dermatitis and psoriasis are histologically distinct, with biopsies from psoriatic lesions lacking the characteristic spongiform appearance of seborrheic dermatitis that is observed on histopathologic examination.65 However, longer-standing lesions of seborrheic dermatitis become less spongiotic and more like psoriasis65 with follicular plugs of orthokeratotic and parakeratotic cells and uneven rete ridges. The primary histological lesion of seborrheic dermatitis was rst identied by Civatte.66 This involves a cyclical squirting of granulocytes from the dermal papilla, preceded by oedema. Increased epidermal proliferation and focal parakeratosis are also noticeable.67

ISD
The two primary lesions of ISD are commonly called cradle cap and diaper rash, though not all cases of diaper rash are the result of ISD. Typically, ISD occurs within the rst 6 months of life68 and disappears spontaneously by 8 months of age. While ISD most commonly appears at the age of approximately 3 months, cases have been reported in younger infants.69 Often, in addition to the characteristic cradle cap of the scalp, the eyebrows, paranasal areas and the exural sites are affected. On the body, lesions may be found in exural areas. The distribution of lesions is helpful in distinguishing ISD from atopic dermatitis, as the latter generally involves the antecubital and popliteal fossae.70 A family history of atopy may also assist in the differential diagnosis of these two entities. The two disorders

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also differ in relapse rate, with atopic infants more prone to recurrent dermatitis70 and less likely to experience spontaneous clearing of lesions. Despite this evidence, the differentiation between the two kinds of eruption may be difcult in some cases; in fact, some authors have suggested that ISD may simply be a variant of infantile atopic eczema.71 Atopic infants do tend to have more pronounced positive responses to allergens than infants with seborrheic dermatitis, however.72 In adults, Malassezia yeasts may play a role in the aetiology of atopic dermatitis73 and seborrheic dermatitis. However, the evidence for the involvement of these yeasts in ISD is conicting. One study74 has demonstrated that these yeasts are, in fact, involved in the development of ISD, while another75 has shown that ISD can be successfully treated with borage oil, which has no effect on the levels of Malassezia yeasts on the skin. In one study76 it was demonstrated that Pityrosporum ovale (an older name of Malassezia) was more frequently obtained from the skin of infants with ISD than from the skin of those with other infantile dermatoses or with healthy skin. Moreover, these infants experience both clinical and mycological clearing when treated with 2% topical ketoconazole. There is also controversy over the relationship between psoriasiform napkin dermatitis and ISD. Some authors regard this as a distinct disease, more closely related to psoriasis than to seborrheic dermatitis.77,78 At the same time, there is evidence that the development of psoriasiform napkin dermatitis is often preceded by seborrheic dermatitis in infants.79 The role of Candida albicans in ISD is also unclear. Studies have shown that C. albicans is often recovered from infants with diaper rash, though not necessarily from the diaper area.79 Other authors suggest that ISD itself is caused by C. albicans,19,80 while still others believe that, where present, C. albicans is a secondary invader of already inamed skin.79 A generalized severe eruption resembling seborrheic dermatitis may, in rare cases, turn out to be Leiners disease.81 While this is uncommon, the condition is potentially serious, as it may lead to death from superimposed bacterial infection if it remains untreated. The diffuse small papular form of histiocytosis X may also be mistaken for seborrheic dermatitis.82 In addition, one case has been reported of isolated leukaemia cutis originally misdiagnosed as seborrheic dermatitis.83 The cause of ISD is unknown. Studies have linked it with the inuence of maternal hormones on sebum production,84 though breast-fed infants do not maintain the high level of sebum production found in neonates.84 It has also been suggested that ISD is caused by deciencies in essential fatty acids85 or in biotin,86,87 although, again, there is evidence against both of these hypotheses.88 Other authors have emphasized a possible immune reaction in ISD.19,89,90 ISD can be treated with a number of different preparations. The possible link between biotin deciency and seborrheic dermatitis in infants has prompted investigators to give biotin injections to nursing mothers91 although oral administration of

biotin directly to the infants has been shown to be ineffective.92 Borage oil has also been shown to be effective,93 possibly due to its effects on fatty acids in the skin. When treating infants with topical preparations, it is important to be aware that they often have a higher level of percutaneous absorption of these medications than adults. This is especially true in infants with a severe cutaneous eruption, as the greatest absorption occurs through broken skin.94 Magenta paint BPC, for example, has been shown to be readily absorbed.95 Similarly, although glucocorticoids have been shown to be effective,96 these drugs may have severe systemic side-effects such as adrenocortical suppression,97 Cushings syndrome98 and growth retardation, which make them less desirable treatments of ISD. Even the much milder hydrocortisone can affect adrenocortical function.99 Absorption is also much more likely in children under the age of 18 months94 and so this problem is particularly relevant in the treatment of ISD. Topical ketoconazole has been used to treat ISD. In an open study100 78.9% of patients were almost cleared of the eruption after 10 days of once daily treatment with a 2% cream. No plasma absorption of the drug was detected.

Seborrheic dermatitis in HIV-positive and AIDS patients

The prevalence of seborrheic dermatitis in the general population is generally estimated at approximately 3%. Among HIV-positive and AIDS patients, the gure rises to somewhere between 34%101 and 83%.33 This trend is seen in women102 and children103 with HIV as well as in HIV-positive men. In Mali, where seborrheic dermatitis is quite rare, the development of this dermatosis in a patient has been used as a predictor for HIV infection.104,105 Some authors also report that seborrheic dermatitis in HIVpositive and AIDS patients is more severe than usual33,34,106 and that lesions of the extremities are more common.107 These clinical observations have led to the suggestion that seborrheic-like dermatitis of acquired immunodeciency syndrome should actually be regarded as a distinctive entity107 caused by immunologic defects. This hypothesis is further supported by the suggestion that the lesions are increasingly prevalent and more severe as the HIV/AIDS becomes more advanced.108,109 Again, however, there is disagreement. Some authors suggest that seborrheic dermatitis is more common in patients with AIDS, but do not believe that it is more severe.110 Others deny that the severity of seborrheic dermatitis is worse in patients at the more advanced stages of HIV infection.111 In addition to the clinical evidence that seborrheic dermatitis in AIDS is a distinct entity, there are also histological and molecular differences between lesions in the two populations. Unlike the common histological picture of seborrheic dermatitis, biopsies of lesions taken from AIDS patients demonstrate widespread parakeratosis, keratinocytic necrosis, leukoexocytosis

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and a supercial perivascular inltrate of plasma cells.106 Longstanding lesions also show hyperkeratosis.19 The expression of heat shock proteins (HSP65 and HSP72) in lesional skin of AIDS patients is also characteristic, and distinct from that seen in HIV-negative patients with seborrheic dermatitis or psoriasis.112 It is suggested that these changes are due to altered interactions between T cells and keratinocytes in AIDS patients.112 With regard to the role of Malassezia spp. in AIDS-related seborrheic dermatitis, some authors report that an overgrowth of the fungus is found in only a minority of cases106 while others suggest that the immune deciencies resulting from HIV infection result in abnormally high levels of Malassezia on the skin.113 Some authors, however, report that HIV patients with seborrheic dermatitis demonstrate a decrease in the amount of yeast that can be cultured from their lesions.114 While seborrheic dermatitis in HIV-positive and AIDS patients may not respond to sulphur-containing soaps and creams,33 ketoconazole has been benecial in some, though not all, cases.115117 Antifungal agents, in conjunction with low potency topical corticosteroids, have been used to control ares of seborrheic dermatitis lesions.118

Seborrheic dermatitis and neurological disease

It has long been recognized that patients with Parkinsons disease often develop seborrhea and seborrheic dermatitis.119,120 The lesions of seborrheic dermatitis appear to develop primarily in patients with longstanding and severe elevations in sebum levels, though the severity of seborrhea does not appear to correlate with the severity of Parkinsons.121 It has been suggested122 that the increased levels of sebum found in Parkinsons patients have a permissive effect on the growth of Malassezia, though further investigation is required to substantiate these results. Because patients with unilateral Parkinsonism may have bilateral seborrhea, the mechanism underlying changes in skin sebum levels is probably endocrine rather than neurotrophic123 (see also references 121, 124). This hypothesis is supported by a study that found an elevated circulating -melanocyte stimulating hormone (-MSH) in patients with Parkinsons disease;125 this increase was especially pronounced in patients who had bilateral involvement. Neither increased sebum levels nor increased blood -MSH were recorded in all patients. The severity of the disease, however, does not appear to correlate with a patients sebum excretion rate (SER).121 It is also possible that the relative facial immobility of Parkinsons disease patients allows a greater than average accumulation of sebum on the skin.122 The same author suggests that the skin of Parkinsons patients also changes, becoming coarse and thickened and having enlarged follicular openings. In addition, the levels of sebum production in Parkinsons patients have been shown to decrease when patients are treated

with L-Dopa,31,123 though mechanisms by which L-Dopa reduces sebum secretion appear to depend on the initial SER; it only has an effect in patients whose SER is higher than that found in the normal population.126 Moreover, L-Dopa does not have an effect on the increased sebum production found in patients with acne vulgaris.126 It has been suggested that the seborrhea of Parkinsons disease is due to disinhibition of MSH because of a decrease in the synthesis of MSH-inhibiting factor.126 L-Dopa restores the production of MSH-inhibiting factor. Sebum levels may be increased in patients with tardive dyskinesia,127,128 especially those whose symptoms involve limb axial movements rather than orofacial involvement.127 Patients whose Parkinsons symptoms are neuroleptic induced also tend to develop seborrheic dermatitis.32 Seborrheic dermatitis may be more common in patients with mood disorders30 though this could be due to the tendency of depressed patients to remain indoors; seborrheic dermatitis is more common in people who have little exposure to sunlight28 (see also reference 8). Similarly, alcoholics often have seborrheic dermatitis; as with depression, hygiene and lifestyle factors are thought to be important in these cases.26,27 There have also been suggestions that patients being treated with lithium experience an improvement in the symptoms of their seborrheic dermatitis129,130 but this claim remains controversial.131,132

Treatment (Table 1)
Topical treatments for seborrheic dermatitis
Earlier treatments for seborrheic dermatitis tended to focus on anti-inammatory agents; now it is increasingly common to treat seborrheic dermatitis with antimycotics.46,47 Some antifungal agents may also reduce the frequency of relapse of seborrheic dermatitis.133

Table 1 Treatments for seborrheic dermatitis Nonspecific agents Specific antifungal agents

Topical Selenium sulphide/sulphur Tar Lithium succinate Benzoyl peroxide Propylene glycol Corticosteroids

Topical Zinc pyrithione Bifonazole Miconazole Ketoconazole Fluconazole Metronidazole Ciclopirox Terbinafine Oral Ketoconazole Itraconazole Terbinafine

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Non-specic agents Seborrheic dermatitis may be treated with keratolytic agents, some of which are available over the counter. Selenium sulphide/sulphur preparations Sulphur has a keratolytic action due to its interaction with keratinocytes and subsequent formation of hydrogen sulphide.134 Perhaps the most common sulphur-based treatment for seborrheic dermatitis is selenium sulphide shampoo,135,136 which is available over the counter. Tar Both whole coal tar137 and crude coal tar extract138 have been shown to be effective against seborrheic dermatitis. In one study these were as effective as selenium sulphide.136 Lithium succinate Lithium succinate ointment, available in some countries as a combination of 8% lithium succinate and 0.05% zinc sulphate, may be effective in the treatment of seborrheic dermatitis, both in immunocompetent individuals139,140 and in those with AIDS.141 While some authors142 have suggested that lithium succinate is effective in vitro against Malassezia spp., others143 report that it is not a specic antifungal agent but rather has an anti-inammatory effect. Other non-specic topical treatments Successful treatment of seborrheic dermatitis has also been reported using benzoyl peroxide,144 propylene glycol145 and bufexamac cream.146 Photochemotherapy147 has been reported to be effective, though other authors document the development of seborrheic dermatitis in patients undergoing PUVA therapy.9 Corticosteroids Topical corticosteroids remain a popular treatment for seborrheic dermatitis. Their efcacy is thought to be due to their antiinammatory action. Frequently, these agents are prescribed in combination with antibiotics.148 At one time, intermediate and high potency uorinated topical corticosteroids, such as betamethasone benzoate, betamethasone valerate and betamethasone dipropionate, were used in the treatment of seborrheic dermatitis.149151 The emphasis 30 years ago was on developing the most potent treatments possible.152,153 Over time it became apparent that the long-term effects of these drugs on the adrenal cortex and on the skin made them less attractive therapeutic choices;154157 therefore, low potency (e.g. hydrocortisone) preparations are prescribed today.158 Even the lower potency steroids may sometimes be associated with atrophy, telangiectasias or perioral dermatitis.159 Their efcacy, however, ensures that they remain a popular treatment choice. Antifungal medications Zinc pyrithione Zinc pyrithione has both a non-specic keratolytic and an antifungal activity. While in vitro tests suggest that it is more effective than selenium sulphide against

Pityrosporum ovale,160 clinical trials show that the shampoo formulations of the two medications may be equally effective in the treatment of seborrheic dermatitis of the scalp.136 Zinc pyrithione may be effective as a 2% shampoo, 1% shampoo161 and in a cream formulation.162 A shampoo containing a combination of zinc pyrithione and crude coal tar extract has also been shown to treat the itching and scaling of seborrheic dermatitis.163 Azoles Bifonazole may be effective in the treatment of seborrheic dermatitis of the scalp164,165 and face.166 A combination ointment containing 1% bifonazole and 40% urea has also been shown to be benecial for scalp involvement.167 Miconazole may be effective, both as monotherapy and in combination with hydrocortisone in a solution.168 Whereas bifonazole and miconazole therapy can reduce the number of Malassezia yeasts found on the scalp, monotherapy with hydrocortisone may not have the same effect.168 Ketoconazole cream 2% may be effective in treating nonscalp seborrheic dermatitis.169172 A 2% ketoconazole shampoo formulation is more effective than vehicle in the treatment of dandruff and seborrheic dermatitis of the scalp133,173 and is signicantly more effective than a 1% shampoo in reducing both aking and Malassezia counts.174 Ketoconazole 2% shampoo, however, does not cause a signicant reduction of scalp sebum levels,175 further supporting the claim that seborrheic dermatitis may not be closely related to increased seborrhea. An oil in water emulsion containing ketoconazole 2% has also been shown to be more effective than vehicle in the treatment of seborrheic dermatitis of both face and scalp176 and a 2% cream may also be effective for seborrheic dermatitis of the scalp.170 Finally, ketoconazole 2% shampoo has been shown to have a signicant prophylactic effect when used once weekly.133 One comparative study has shown ketoconazole 2% shampoo to be as effective as selenium sulphide 2.5% in the treatment of seborrheic dermatitis of the scalp, but ketoconazole appeared to be better tolerated.177 Unlike topical steroids, ketoconazole does not carry a risk of patients developing atrophy or telangiectasias with prolonged use. In addition, ketoconazole foaming gel has been found to be signicantly more effective than betamethasone dipropionate 0.05% in the global reduction of the symptoms of seborrheic dermatitis. 47 Treatment with ketoconazole also resulted in a signicant decrease in the number of Malassezia yeasts on the scalp; almost no change occurred in the betamethasone group.47 Ketoconazole cream 2% has been shown to be as effective as hydrocortisone 1% cream when used once daily to treat seborrheic dermatitis of the face, scalp and body;178 Stratigos et al. report that after 4 weeks of use the incidence of side-effects in both groups was comparably low. New topical treatments for seborrheic dermatitis With the success of ketoconazole in the treatment of seborrheic dermatitis, there has been a renewal of interest in the role of

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Malassezia yeasts in this disorder. A number of recent studies have investigated the efcacy of known antifungal agents in the treatment of seborrheic dermatitis and it is likely that a new range of treatment options will be developed for this indication. Fluconazole Fluconazole is another azole medication that is commonly used to treat dermatoses caused by Malassezia spp. In an open trial179 patients with seborrheic dermatitis of the face used uconazole 2% shampoo twice weekly for 4 weeks. There was complete recovery or improvement in all patients, with cultures being negative for Malassezia spp. at the end of the treatment period. Metronidazole Metronidazole may be a promising treatment for seborrheic dermatitis.180,181 One recent double-blind, randomized study has investigated the possibility that metronidazole can be effective in the treatment of seborrheic dermatitis.180 It was found that metronidazole 1% gel, applied twice daily for 8 weeks, was more effective than placebo in the treatment of seborrheic dermatitis of the scalp, face and chest. Ciclopirox Ciclopirox olamine has a broad-spectrum antifungal action, including efcacy against Malassezia spp.182 In addition, this hydroxypyridone has an anti-inammatory effect.183 Doubleblind, randomized controlled trials indicate that ciclopirox olamine shampoo 1% may be an effective treatment for seborrheic dermatitis of the scalp184 with the cream 1% formulation improving the erythema and scaling of facial lesions.185 A ciclopirox gel, containing ciclopirox as the free acid rather than the olamine salt, has also been shown to be signicantly more effective than vehicle in treating moderately inammatory seborrheic dermatitis of the scalp.186 This difference was evident as early as 2 weeks after the beginning of therapy, with twice daily application of the gel to lesions. Terbinane Terbinane is a fungicidal allylamine and works by disrupting membrane formation in fungi by inhibiting squalene epoxidation during sterol synthesis.187 A terbinane 1% solution, used once daily for 4 weeks, may improve the lesions of seborrheic dermatitis of the scalp and reduce the number of Malassezia organisms colonizing the treated areas.188 Other antifungal therapies In vitro, cinnamic acid may reduce the growth of Malassezia species; therefore, mild formulations may prove to have therapeutic use.189 Recently, a report has been published in which 90% honey diluted in warm water was used to treat seborrheic dermatitis and dandruff.190 Honey appears to have some antifungal activity.

an oral medication may be preferred by both physician and patient. There are relatively fewer data concerning oral treatments in the literature, however, compared to topical use. Oral ketoconazole, 200 mg daily for 4 weeks, when used in conjunction with a bland shampoo, is an effective treatment of seborrheic dermatitis of the scalp and body.46 However, given the increased possibility of side-effects from oral ketoconazole used for a duration longer than 4 weeks, it may not be a feasible therapy for many patients. Preliminary results indicate that itraconazole 200 mg /day for 7 days is effective in the treatment of seborrheic dermatitis.191,192 This drug seems to be the treatment of choice when the seborrheic dermatitis is widely diffuse, when resistance to topical preparations is observed, when chronic application of topical steroids should be avoided, or when seborrheic dermatitis induces psychological problems that could modify the lifestyle of the patient. This triazole does not have the same potential to cause hepatotoxicity as ketoconazole, and may therefore be a safer alternative for patients who require an oral treatment. Oral terbinane is an effective treatment in some fungal infections, including onychomycosis.193 A recent study suggests that oral terbinane, 250 mg /day for 4 weeks, may improve the clinical signs of seborrheic dermatitis.194 However, oral terbinane is not an effective therapy for pityriasis versicolor, another skin disorder caused by Malassezia spp.193 There is some evidence that the efcacy of itraconazole and terbinane as oral treatments for seborrheic dermatitis may be explained by the excretion of these agents in the sebum.195,196 Sebum levels of itraconazole after 4 days of treatment (200 mg/ day) are much higher than those of the older antifungal agents, ketoconazole and griseofulvin.195 Itraconazole is also detectable in sebum for up to 2 weeks after completion of therapy.195

Conclusion
Over the past 5 years or so, there has been a renewed interest in the treatment of seborrheic dermatitis as evidenced by the increase in the number of controlled trials and the variety of new treatment options being evaluated. The evidence also indicates that Malassezia yeasts play an important role in seborrheic dermatitis both in immunocompetent adults and in those with HIV or AIDS. With regard to ISD, the case is less clear; however, antifungal medications appear to have some efcacy in this condition.

Appendix A: CME questions

1. Causal factors of seborrheic dermatitis may include (a) immunosuppression, (b) climate, (c) Malassezia yeasts, (d) all of the above. 2. Which of the following conditions is often associated with seborrheic dermatitis? (a) Blepharitis. (b) Rosacea. (c) Acne vulgaris. (d) All of the above.

Oral treatments for seborrheic dermatitis

In cases where the lesions of seborrheic dermatitis are particularly widespread, or are refractory to topical treatment,

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20 Gupta and Bluhm

3. Seborrheic dermatitis is most often seen in which of the following groups of patients? (a) Adolescents. (b) Blacks. (c) HIV positive/AIDS patients. (d) All of the above. 4. Lesions of seborrheic dermatitis are commonly found on (a) the face, (b) the legs, (c) the knees and elbows, (d) the hands. 5. The Malassezia species least commonly associated with seborrheic dermatitis is (a) M. globosa, (b) M. obtusa, (c) M. sympodialis, (d) M. restricta. 6. The Malassezia species least likely to be recovered from skin is (a) M. sympodialis, (b) M. globosa, (c) M. restricta, (d) M. pachydermatis. 7. Under the new nomenclature for Malassezia the number of lipophilic species is (a) four, (b) six, (c) seven, (d) eight. 8. The new nomenclature for Malassezia species does not include the following: (a) M. furfur, (b) M. orbicularis, (c) M. globosa, (d) all of the above. 9. Infantile seborrheic dermatitis (ISD) generally disappears by (a) 6 months, (b) 8 months, (c) 1 year, (d) 2 weeks after it appears. 10. Seborrheic dermatitis in HIV-positive and AIDS patients (a) is strongly correlated with an increase in Malassezia yeasts; (b) is much more severe than in non-AIDS patients; (c) is the same, clinically and histologically, as seborrheic dermatitis in non-AIDS patients; (d) is more common than in non-AIDS patients. 11. Patients with Parkinsons disease (a) do not respond to conventional treatments for seborrheic dermatitis; (b) usually develop seborrheic dermatitis following elevations in skin sebum levels; (c) always show improvement in their seborrheic dermatitis when treated with L-Dopa; (d) only develop seborrheic dermatitis when their Parkinsons symptoms are neuroleptic induced. 12. Treatments for seborrheic dermatitis include (a) keratolytic agents, (b) corticosteroids, (c) antifungal medications, (d) all of the above. 13. When corticosteroids are used to treat seborrheic dermatitis they should be (a) of as high a potency as possible; (b) of as low a potency as possible; (c) used prophylactically after the initial lesions have improved; (d) always uorinated. 14. Oral antifungal therapies for seborrheic dermatitis include (a) terbinane, (b) itraconazole, (c) uconazole, (d) all of the above. 15. Which of the following may not be used topically for the treatment of seborrheic dermatitis? (a) Ketoconazole. (b) Itraconazole. (c) Fluconazole. (d) Terbinane.

2.

3.

4.

5.

6.

7. 8. 9. 10.

11.

12. 13.

14.

15.

yeasts found on the skin, and is more common in immunosuppressed patients and during the winter months. (d) Both rosacea and seborrheic dermatitis may be found in patients with blepharitis. Rosacea and seborrheic dermatitis may also frequently coexist in the same patient. Also, seborrheic dermatitis is seen in individuals with acne vulgaris. (c) All three of these groups have higher incidence rates of seborrheic dermatitis over the general population, but the disorder is by far the most common in HIV-positive and AIDS patients. (a) Seborrheic dermatitis is most commonly found on areas of the body that are rich in sebaceous glands, such as the face, scalp and trunk. Lesions of the elbows and knees are more common in patients with psoriasis. (b) The other three Malassezia species have been implicated in seborrheic dermatitis by different researchers, though the particular species found most often in patients with seborrheic dermatitis appears to vary with geographical location. (d) M. pachydermatis does not require an exogenous lipid source for growth. It colonizes animals and is only rarely found on human skin. (b). (b). (b). (d) For all of the other statements, the evidence available is controversial. According to the published evidence, seborrheic dermatitis may or may not be associated with an overgrowth of Malassezia yeasts, and may or may not be more severe in HIV-positive and AIDS patients than in the general population. (b) Most, but not all, Parkinsons patients who develop seborrheic dermatitis also have elevated levels of sebum on the skin. It is this group of patients whose lesions tend to resolve upon treatment with L-Dopa. (d). (b) The side-effects associated with long-term treatment with potent topical corticosteroids make the choice of a low potency drug the safest for the patient. (d) Recently there has been evidence that oral, as well as topical, terbinane may also be effective for seborrheic dermatitis. (b) Itraconazole is used only orally. There is no commercially available topical formulation.

References
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Answers
1. (d) The precise cause of seborrheic dermatitis is not known, but it is associated with changes in the Malassezia

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