Dermatol Ther (Heidelb) https://doi.org/10.1007/s13555-018-0259-9

CASE REPORT

Topical Sulfide for the Treatment of

Philip R. Cohen . Caesar A. Anderson

Received: August 13, 2018 Ó The Author(s) 2018

ABSTRACT individuals with hyperkeratosis involving their palms and/or soles are described; the hyperker- Hyperkeratosis presents as thickened . It can atosis was successful treated with topical sele- be congenital or acquired. Typically, it affects nium sulfide in either a 2.5% lotion/ the palms and soles; the distribution of epider- or a 2.75% foam. The response to topical sele- mal involvement is either diffuse, focal, or nium sulfide was not only rapid but also com- punctate. Microscopically, the pathologic sig- plete and sustained; none of the patients nature of hyperkeratosis is marked orthoker- experienced any adverse events secondary to atosis of the stratum corneum. Topical the therapy. In conclusion, we recommend that treatments provide the mainstay of therapy for topical selenium sulfide be added to the thera- hyperkeratosis. These include (such peutic armamentarium for congenital or as urea, , and lactic acid) and reti- acquired hyperkeratosis—particularly for those noids; physical debridement, topical corticos- patients with involvement of their palms and teroids, and phototherapy (using topical soles. psoralen and A phototherapy) are other local therapeutic modalities. Selenium is a non-metallic essential element; its water-insol- Keywords: Foot; Hand; Hyperkeratosis; uble , selenium sulfide, is an active ingredi- ; Palm; Plantar; Selenium; Soles; ent that is used (in either a foam, lotion, or Sulfide; Topical shampoo) to treat not only seborrheic der- matitis but also tinea versicolor. Three INTRODUCTION Enhanced Digital Features To view enhanced digital features for this article go to https://doi.org/10.6084/ Hyperkeratosis presents as thickening of the m9.figshare.7022126. skin. Selenium sulfide is an agent that is topi- cally used for the management of seborrheic P. R. Cohen (&) dermatitis and tinea versicolor. Three individ- San Diego Family Dermatology, National City, CA, uals with hyperkeratosis of their plantar feet, USA e-mail: [email protected] whose thickened skin was successfully treated with topical selenium sulfide, are described. C. A. Anderson Informed consent was obtained from the par- University of California San Diego Hyperbaric ticipants for inclusion in the study. Medicine and Wound Healing Center, Encinitas, CA, USA Dermatol Ther (Heidelb)

CASE REPORTS She achieved an excellent result with the selenium sulfide therapy; there was complete Case 1 resolution of her plantar hyperkeratosis within 2 weeks (Fig. 1). Subsequently, she was instruc- ted to taper the selenium sulfide therapy—every A 38-year-old African American woman pre- other day for 3 weeks and then as needed if the sented for treatment of plantar hyperkeratosis. hyperkeratosis reappeared. She continued to use Her past medical history was significant for Aquaphor ointment daily. spina bifida. However, she was otherwise Her feet remained clear of the hyperkeratotic healthy. skin. Therefore, she decided to discontinue the Four years earlier, she was seen for evalua- Aquaphor ointment and began topical treat- tion and management of a left trochanteric ment with ammonium lactate cream 12%. The pressure . At that time, her cutaneous plantar hyperkeratosis recurred; she stopped the examination revealed scaling and ulcers on her ammonium lactate cream 12% and treated her feet. She also had an ulcer overlying the left feet with the selenium sulfide foam 2.75%. trochanter. In addition, she had bilateral lower Promptly, the plantar hyperkeratosis resolved. extremity . Her leg edema was successfully managed with lower extremity dynamic compression Case 2 therapy. The pressure ulcer on her left tro- chanter completely healed. The ulcers on her A 32-year-old Caucasian man presented for feet underwent serial debridement; during these evaluation and treatment of congenital hyper- treatments, she also required a brief course of with fissures on his palms and soles. oral . In addition, weekly topical His sister also had a similar congenital palmo- management of the foot ulcers included plantar hyperkeratosis; correlation of the clini- antimicrobial dressings along with white pet- cal history and lesion morphology established a roleum . Also, cream was diagnosis of Unna–Thost disease. In addition, applied twice daily to her toes. Subsequently, the patient’s past medical history was signifi- the ulcers on her feet healed; however, the cant for poorly controlled diabetes mellitus and hyperkeratosis on her feet persisted. severe coronary artery disease with several prior Four years after her initial presentation, she myocardial infarctions and placement of coro- returned for treatment of her plantar hyperker- nary stents. atosis. She also had on her palms that Cutaneous examination of the plantar sur- developed secondary to the use of her manual face of his feet showed hyperkeratosis with wheelchair. Cutaneous examination of the multiple fissures (Fig. 2). Prior unsuccessful plantar surface of her bilateral feet showed topical therapies had included salicylic acid thickening of the skin (Fig. 1). ointment, urea cream, ammonium lactate Initially, her feet were treated with salicylic cream, and high-potency corticosteroid creams acid ointment 3% applied topically twice daily. and ointments. Therefore, a decision was made There was no improvement. The salicylic acid to implement selenium sulfide shampoo 2.5%. topical therapy was discontinued and she began He applied the shampoo daily and rubbed it daily treatment with selenium sulfide foam into his feet until it was in a lather form. Then 2.75%. he allowed the shampoo to remain present for She was instructed to apply the selenium 10 min prior to rinsing it off. He also applied sulfide foam onto her feet and continue to rub Aquaphor ointment daily. the area so that the selenium sulfide was in a He had excellent results. There was complete lather form. The foam remained present on her resolution of the plantar hyperkeratosis within feet for 10 min prior to being rinsed off. She also 2 weeks after initiating therapy (Fig. 2). continued to apply Aquaphor ointment daily, Prompted by the effectiveness of the topical as she had previously done. selenium sulfide treatment after 1 week of Dermatol Ther (Heidelb)

Fig. 1 The right plantar foot of a 38-year-old African foam 2.75% (bottom). The foam was applied to the area American woman. There is prominent hyperkeratosis on for 10 min prior to being rinsed off; after rinsing, the medial aspect of the plantar foot (top). Complete Aquaphor ointment was also applied daily resolution of the plantar hyperkeratosis is observed 2 weeks after the initiation of daily treatment with selenium sulfide application to his feet, he began to apply it for Three and one-half years earlier, he was ini- 30 min daily not only to his feet, but also to his tially seen for his lower extremity hyperkeratotic hands. He tolerated this regimen and associated numerous verrucous keratoses and noted significant improvement. Therefore, on his distal legs and feet. His management the following week, he kept the shampoo lather required bilateral lower extremity compression on his hands for up to 2 h. therapy—including manual lymphatic drainage Follow-up examination revealed that his therapy—coupled with extensive palmar hyperkeratosis had also almost com- debridement of the hyperkeratotic scaly skin of pletely resolved. The patient enthusiastically both legs. These interventions proved useful in discussed that none of his prior treatments had managing the lymphedema along with achiev- worked this well. He was instructed to use the ing a marked improvement in the extent of selenium sulfide 2.5% shampoo on an as-nee- papillomatous skin lesions of legs and feet. ded basis and to continue to apply Aquaphor The application of white petroleum prior to ointment daily. each compression wrap to his legs was contin- ued weekly. However, follow-up examination Case 3 showed that the hyperkeratosis of his legs and feet persisted. Yet, most of the hyperkeratosis An 80-year-old African American man pre- responded to weekly labor-intensive superficial sented for evaluation and treatment of exten- curette debridement of the skin, which resulted sive hyperkeratosis of his lower legs and feet. in the shedding of a substantial amount of His past medical history was significant for scales. chronic bilateral lymphedema of his distal Subsequently, two and one-quarter years lower extremities. He also had ongoing issues ago, he was again evaluated for the manage- with compliance to medical therapy. ment of his lower-extremity hyperkeratosis. Dermatol Ther (Heidelb)

Fig. 2 The left plantar foot of a 32-year-old Caucasian selenium sulfide shampoo 2.5% (bottom). The shampoo man who had Unna–Thost syndrome and congenital remained on the foot for 10 min after it had been rubbed hyperkeratosis of his palms and soles. There is confluent into the foot and was in a lather form; it was then rinsed hyperkeratosis of the mid and distal plantar foot (top). off and Aquaphor ointment was applied There is complete resolution of the plantar hyperkeratosis within 2 weeks after initiating daily topical therapy with

Ammonium lactate cream 12% was recom- He achieved excellent results. There was mended; however, the patient was unable to complete resolution of his bilateral lower tolerate the cream because of extensive burning. extremity hyperkeratosis (Fig. 3). The daily When the dosage was reduced to 5%, he had the application of selenium sulfide shampoo 2.5% same problem and had to discontinue the has become part of his maintenance routine; in treatment with ammonium lactate. After addition, he has not required any debridement 2 weeks, he also complained of burning with of hyperkeratosis. However, he continues to the 5% version. struggle with lymphedema management, and He resumed daily Aquaphor ointment the verrucous skin changes correlate inversely application to his legs. In addition, he contin- with his edema control: more lesions are pre- ued his maintenance compression therapy. sent when his lymphedema control is worse. However, during the subsequent 2 years, the hyperkeratotic lesions recurred on his legs and prompted further debridement. DISCUSSION Cutaneous examination showed extensive hyperkeratosis on his legs and feet (Fig. 3). Daily Hyperkeratosis, also often referred to as kerato- application of selenium sulfide shampoo 2.5% derma, can be an acquired condition or an was started. He applied the shampoo to both inherited disorder. It frequently affects the legs and feet daily in a lather form. The sham- palms and soles. It typically presents as thick- poo was allowed to remain present for ening of the skin; fissures and ulceration may 10–20 min each day prior to rinsing it off. develop [1, 2]. Afterwards, he continued to apply Aquaphor The classification of hyperkeratosis may be ointment daily to his lower extremities. determined by its manifestations of epidermal Dermatol Ther (Heidelb)

Fig. 3 The right distal leg of an 80-year-old African was completely resolved after 2 weeks of applying selenium American man with a history of chronic lymphedema of sulfide shampoo 2.5% daily for 10–30 min; after rinsing his lower extremities. There was extensive hyperkeratosis off the shampoo, Aquaphor was applied (right) on the distal right pretibial leg (left). The hyperkeratosis involvement: diffuse or focal or punctate. Cat- hyperkeratosis can also have additional changes egories of acquired palmoplantar hyperkeratosis in the epidermis, such as epidermolysis of the include chemically induced, dermatoses-re- granular layer [1, 2]. lated, drug-related, idiopathic, -re- The initial treatment of acquired hyperker- lated, keratoderma climactericum, malignancy- atosis (particularly of the palms and soles) is to associated, malnutrition-associated, and sys- identify and treat the underlying cause of the temic-disease-related. Hereditary palmoplantar associated condition. For those individuals with keratoderma may be limited to persistent idiopathic acquired hyperkeratosis and patients thickening of the palms and soles or may be with hereditary hyperkeratosis, there are several associated with syndromes characterized by potential conservative treatment options that additional extracutaneous manifestations, such have each been associated with variable success as cardiomyopathy, deafness, inborn errors of for any given individual; they include topical metabolism, internal organ involvement, keratolytics (such as urea, salicylic acid, and mucosal lesions, or sexual development disor- lactic acid), repeated physical debridement, ders [1, 2]. topical , topical psoralen and ultravio- Hyperkeratosis is histologically defined by let A phototherapy, and topical corticosteroids. marked orthokeratosis: an increased thickness Systemic therapy (such as acitretin) has of the stratum corneum. Other epidermal also been utilized for patients with severe pathologic changes that may be present include hyperkeratosis that does not respond to con- parakeratosis (demonstrated by retained nuclei servative measures. We report our observations in the stratum corneum), acanthosis (in which of successful hyperkeratosis management using there is thickening of the entire epidermis) and topical selenium sulfide [1–4]. of the granular layer and stratum Selenium is a member of group IVa of the spinosum; a perivascular lymphocytic infiltrate periodic table; other elements in this group may also be seen in the dermis. Congenital include oxygen, , polonium, and Dermatol Ther (Heidelb) tellurium. It is a nonmetallic element that has Selenium sulfide is used as a therapeutic four natural oxidative states. However, the agent in dermatological conditions. It is the water-soluble selenite and selenate salts are active ingredient in anti- shampoo toxic [5]. [14–16]. In addition, it is also used to treat tinea Selenium has a role in preventing oxidative versicolor [14, 17, 18]. degradation of lipids in polysaturated mem- Selenium sulfide can be an effective agent for branes. Selenium is an essential component of the treatment of hyperkeratosis—not only for the antioxidant peroxidase. the soles of the feet and palms of the hands, but Indeed, selenium deficiency has been linked to also for thick skin on the distal legs. Either the endemic diseases in the Chinese population: 2.5% lotion/shampoo or the 2.75% foam Keshan disease and Kashin–Beck disease [6, 7]. preparation of selenium sulfide can be used. The Keshan disease results in cardiac enlarge- treatment protocol is simple and can readily be ment, congestive , cardiogenic performed by the patient or a caregiver. The shock, and death. It occurs secondary to mul- selenium sulfide is applied topically and then tifocal necrosis of the myocardium. Keshan continuously rubbed into the affected area of disease primarily occurs in children and young skin for at least 10 min; longer treatment dura- women [6]. tions—ranging from 20 min to 2 h—can also be The main feature of Kashin–Beck disease is used. Thereafter, the treated area is cleaned with shortened stature. Multiple focal areas of water and dried. Improvement can be observed necrosis in the tubular bone growth plates cause within 2 weeks. it. The endemic chronic osteoarthropathy All of our patients had plantar hyperkerato- results from atrophy, degeneration and necrosis sis. One man had congenital hyperkeratosis of of cartilage. Kashin–Beck disease has been the palms and soles consistent with observed not only in China, but also in Russia Unna–Thost disease [19, 20]. The other patients and Korea [7]. both had lower extremity edema and acquired However, excess selenium can be associated hyperkeratosis; the woman had spina bifida and with acute and chronic toxicity. Acute ingestion hyperkeratosis of her plantar feet whereas the of selenious acid (which is usually fatal) results man’s hyperkeratosis was idiopathic and he had in garlic breath and red pigmentation of hyperkeratosis of his hands, feet, and distal legs. the hair, nails, and teeth [8]. Garlicky breath Prior to using topical selenium sulfide for and changes (transverse ridges), in addition their hyperkeratosis, all of our patients had tried to a metallic taste in the mouth, have been several other topical therapies, all of which observed following inhalation of hydrogen failed. Indeed, after initiating treatment with selenide [9, 10]. Residents of geographic areas selenium sulfide, all of the patients had rapid, with high levels of selenium may develop complete, and sustained improvement of their chronic selenium poisoning; changes charac- hyperkeratosis. In addition, none of them teristically involve the skin (erythema and red experienced any adverse events from the discoloration, pruritic scalp rash, vesicles, and therapy. secondary ), hair (which becomes Investigators have suggested that the mech- brittle and breaks easily), and nails (which anism of action of selenium sulfide in the become brittle and develop yellowish-white or management of seborrheic dermatitis and tinea red longitudinal lines or transverse streaks) [11]. versicolor is secondary to its anti-Pityrosporum

Selenium sulfide (SeS2 or Se=S) is a selenium effect [15–17, 21]. However, the antiseborrheic salt. At room temperature, it is a yellow-orange properties of selenium sulfide are also the result tablet or powder. In contrast to the water-sol- of it significantly reducing the mitotic rate and uble selenium salts, selenium sulfide is not only cell turnover of the epidermis basal layer due to insoluble in water but also nontoxic when a cytostatic effect it has not only on the epi- taken orally. Indeed, it has been found to be safe dermal cells but also the follicular , in animal studies and not carcinogenic when thereby diminishing the formation rate of the applied topically [12–14]. stratum corneum [22, 23]. These latter effects of Dermatol Ther (Heidelb) selenium sulfide may, in part, contribute to its tinea versicolor. The successful use of topical effectiveness in the treatment of hyperkeratosis. selenium sulfide (as a 2.5% lotion/shampoo or a In addition, selenium sulfide has been asso- 2.75% foam) to treat either congenital or ciated with an increased sebum excretion rate acquired hyperkeratosis—particularly of the [23, 24]. This clinical observation corresponds palms and/or soles—is described for three to an increase in the size of the existing seba- patients. All of these individuals had a rapid, ceous glands [23]. However, since the palms and complete, and sustained response to treatment, soles have no sebaceous glands, hyperplasia of without any adverse events. In conclusion, we the sebaceous gland and subsequent increased recommend that topical selenium sulfide be sebum secretion probably did not play a role in added to the therapeutic armamentarium for the resolution of our patients’ hyperkeratosis. hyperkeratosis, especially of the palms and Topical selenium sulfide has also been soles. demonstrated to effectively treat , an immunologically driven hyperproliferative dis- order of the epidermis. The researchers treated ACKNOWLEDGEMENTS more than 100 patients with psoriasis; similar to our methodology, they applied selenium sulfide We thank the participants of the study. shampoo (25 mg/ml) to the affected sites and allowed the shampoo to remain on the skin Funding. No funding was received for the surface for 15 min before washing it off. There publication of this article. The authors are fully was prompt and sustained improvement of the responsible for all content and editorial deci- psoriatic plaques—even in those individuals sions, and received no financial support or who had been refractory to topical tar or high- other form of compensation related to the potency corticosteroids or both [25]. It is rea- development of this manuscript. sonable to speculate a similar mechanism of action of selenium sulfide in our patients who Authorship. All named authors meet the were treated for hyperkeratosis and those indi- International Committee of Medical Journal viduals who were treated for psoriasis. Editors (ICMJE) criteria for authorship of this manuscript, take responsibility for the integrity CONCLUSIONS of the work as a whole, and have given final approval for the version to be published. Hyperkeratosis can be congenital or acquired. Disclosures. Philip R. Cohen and Caesar A. Clinically it presents as thickened skin, often Anderson have nothing to disclose with regards affecting the palms and soles. Pathologic chan- to the publication of this article. ges in affected skin uniformly show marked orthokeratosis of the stratum corneum. Cur- Compliance with Ethics Guidelines. In- rently, topical treatment options include kera- formed consent was obtained from the partici- tolytics and retinoids; other local therapeutic pants for inclusion in the study. modalities that have been initiated are physical debridement, topical corticosteroids, and pho- Open Access. This article is distributed totherapy (using topical psoralen and ultravio- under the terms of the Creative Commons let A phototherapy). Selenium is a nonmetallic Attribution-NonCommercial 4.0 International essential element; deficiency can result in sys- License (http://creativecommons.org/licenses/ temic diseases. However, acute and chronic by-nc/4.0/), which permits any non- toxicity have been associated with excess commercial use, distribution, and reproduction ingestion. The water-insoluble selenium salt in any medium, provided you give appropriate selenium sulfide is a safe active ingredient in credit to the original author(s) and the source, foam, lotion, and shampoo; it has been used to provide a link to the Creative Commons license, treat not only seborrheic dermatitis but also and indicate if changes were made. Dermatol Ther (Heidelb)

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